1. Introduction

Aminoglycosides (AGs) are a well-known and successful class of antibiotics. The initial isolation of streptomycin from Streptomyces griseus provided the long-sought treatment for tuberculosis and an effective antibiotic against gram-negative bacteria [1, 2]. In subsequent years, other AGs were isolated from Streptomyces spp., commonly integrating the ending “-mycin” in their nomenclature [3, 4]. With the isolation of gentamicin from Micromonospora purpurea [5], the ending “-micin” was implemented to specify the bacterial origin of the individual AG. In contrast to these organic derivatives of soil-dwelling bacteria, synthetic AGs such as amikacin could be developed in vitro [6]. Currently, nine AGs (streptomycin, neomycin, tobramycin, kanamycin, paromomycin, spectinomycin, gentamicin, netilmicin, and amikacin) are approved by the Food and Drug Administration (FDA) [7].

In addition to their potent antimicrobial efficacy, all AGs can cause toxic side effects to the kidneys and inner ear. While damage inflicted by AG on the kidney is usually reversible [8, 9], damage to the inner ear is permanent [10]. This nephro- and ototoxicity was initially discovered in the first clinical trials of streptomycin [11, 12]. Within the inner ear, streptomycin preferably damages the vestibular organ [12]. Modification of streptomycin to dihydrostreptomycin, however, resulted in a shift of ototoxic damage from the vestibular organ to the cochlea [13]. Generally, each AG is capable of irreversibly damaging both the auditory and vestibular organs, but “typically affects one more than the other” [14]. Gentamicin and tobramycin are predominantly vestibulotoxic, whereas neomycin, kanamycin, and amikacin are mainly cochleotoxic [15]. Ototoxic side effects occur within days or weeks after systemic application and are often bilateral in presentation [16]. Vestibulotoxicity occurs in up to 15% of patients after AG administration [17], whereas cochleotoxicity in 2% to 25% of patients [17, 18]. Different regimens of AG administration and different definitions of ototoxic damage may have contributed to the variation of incidence [19].

Symptoms of cochleotoxicity include hearing loss and/or tinnitus, while those of vestibulotoxicity consist of disequilibrium and dizziness. Unfortunately, these symptoms may not be detected until after the acute phase of severe infection and diagnosis is thus delayed. AG cochleotoxicity typically affects first the high frequency and then extends towards the lower frequency and ranges over time in a dose-dependent manner [20, 21]. Because the ultrahigh frequencies of hearing are not routinely tested (>8 kHz), the true incidence of AG-induced hearing loss is often underestimated. Indeed, when ultra-high frequency testing was performed, hearing loss was reported in 47% patients with a history of AG treatment [22].

Despite the nephro- and ototoxic side effects, AGs are still the most commonly prescribed antibiotics [23, 24]. In the industrialized world, use of AGs is usually limited to severe infections including those caused by multidrug resistant tuberculosis [25, 26]. Neonates frequently receive AGs for suspected or proven gram-negative infection, as sepsis is associated with high mortality [27]. In the developing world, however, AG use has been popular because of their low cost and potent antibacterial activities, outrivaling more expensive antibiotics with less severe side effects. There, AGs are even prescribed as first-line therapy for less severe conditions such as bronchitis or otitis media [28]. Additional safety precautions such as blood level monitoring or hearing tests are also limited [19]. As a result, the incidence of AG ototoxicity in developing countries may increase in comparison to the industrialized world.

2. Pharmacokinetics and Antimicrobial Mechanism of Aminoglycosides

The AG class of compounds consists of an aminocyclitol moiety with two or more amino sugar rings [29]. A characteristic quaternary ammonium group makes AGs polycationic (positive charge) and highly polar [30, 31]. As a result, enteral absorption is poor and AGs are generally administered parenterally or topically [32]. After parenteral administration, AG plasma levels peak between 30 and 90 minutes [7, 33]. Drug metabolism is minimal as approximately 99% of the administered AGs are eliminated unaltered by glomerular filtration in the proximal tubule [34, 35]. The plasma half-life of AGs ranges from 1.5 to 3.5 hours [7, 36], but is prolonged in neonates, infants, and conditions with decreased kidney function [7, 37].

The most common indication to administer AGs is for empirical treatment of patients with severe infections such as septicemia, nosocomial respiratory tract infection, complicated urinary tract infections, and complicated intra-abdominal infection [25], partly because AGs are shown effective against aerobic, gram-negative bacteria [38]. AGs demonstrate an increased selective antimicrobial activity in an alkaline environment [39]. It has been suggested that an alkaline pH compromises the bacterial membrane [40, 41], which might facilitate AG penetration into bacteria. Additionally, AGs have up to 6 amines with pKs varying more than two orders of magnitude, thus making the molecules much less charged at alkaline pH and so more able to interact with a lipid environment. Normally, the positively charged nature of the AG molecule precludes free passage through lipid barriers such as cell membranes, but promotes bacterial uptake and rapid binding to negatively charged lipopolysaccharides (LPS) in the outer membrane of gram-negative bacteria [42]. By competitive displacing bridging divalent cations such as Mg2+ or Ca2+, AGs can disrupt cross-links between adjacent LPS [43]. Such a disruption damages membrane integrity and leads to blebbing of the outer membrane, ultimately resulting in transient holes of the gram-negative cell wall [44, 45]. This formation of holes in the cell wall facilitates further AG uptake and appears to significantly contribute to the bactericidal effect of AGs [46]. With this first step, AGs enter the periplasmic space of gram-negative bacteria in a passive and non-energy-dependent manner [47]. In a second step (also referred to as energy-dependent phase I), AGs are transported further through the inner bacterial membrane in an oxygen-requiring process [47]. Therefore, uptake is facilitated in aerobic bacteria [47]. Once in the cytosol, AGs interact with the 30S subunit of bacterial ribosomes [48, 49] in a third and energy-dependent step (energy-dependent phase II) [47, 50]. At the 30S subunit, AGs bind to the decoding site located at the A site of the 16S rRNA [51, 52]. Binding of AGs at this site perturbs the recognition and selection of tRNA during translation and increases misreading [52, 53]. Furthermore, binding of AGs inhibits ribosomal translocation [5456]. Perturbation of both ribosomal translation and translocation ultimately inhibits protein synthesis. Interestingly, the affinity for different rRNA binding sites varies amongst different classes of AGs [5759]. This slightly different AG-ribosome interaction, therefore, appears to be beneficial against bacterial resistance [19].

3. Ototoxicity and Mechanism of Hair Cell Damage

3.1. Susceptibility and Genetic Predisposition for Aminoglycoside Ototoxicity

While AGs preferentially target the bacterial ribosome, the inner ear and kidney are known to receive collateral damage in many patients receiving treatment [11, 12]. However, a meta-analysis comparing once versus multiple-daily regimens of different AGs could not determine a statistical significant correlation between ototoxicity and treatment regimens [60]. One main susceptibility factor (17%–33% of patients with reported ototoxic damage [61]) is the genetic predisposition to AG ototoxicity [62]. The fact that this increased susceptibility was inherited maternally suggested mitochondrial involvement [62]. This is compelling in light of the endosymbiotic theory as mitochondrial ribosomes demonstrate more similarities to prokaryotic ribosomes than cytosolic ribosomes [63, 64]. Therefore, the small subunit of the mitochondrial ribosome is one of the primary targeting sites for AGs [48, 49].

Several mutations in mitochondrial DNA are linked to increased susceptibility to AG ototoxicity [61, 65, 66]. Exposure to AG leads to impairment of RNA translation within mitochondria through interaction with binding sites on mitochondrial 12S rRNA [65]. This interaction was mapped to an adenine-to-guanine mutation at nucleotide 1555 in the 12S rRNA gene [65]. Of additional note, bacterial resistance mutations are described at this locus [67, 68]. This mutation increases structural similarity of mitochondrial rRNA to bacterial rRNA [65], which promotes binding of AG to mutated mitochondrial 12S rRNA [69, 70]. As a result, damage can result from decreased protein synthesis [69]. Although no direct evidence exists to link ototoxicity to an inhibition of mitochondrial protein synthesis, inhibition of mitochondrial protein synthesis potentiates AG toxicity [71]. Also, electron microscopy reveals mitochondrial disruption following AG treatment [72].

This susceptibility mutation has been reported in 17%–33% of patient with reported AG ototoxicity [61]; in the general population of the European Union, it is estimated to be 1 : 500 [73, 74]. Other mutations leading to increased AG susceptibility have also been described, including C1494T [66]. The C1494T mutations have varying degrees of penetrance [75], are less common than the A1555G mutation [76], and are sporadic with multiple origins [77]. In sum, the prevalence of the most common mutations across varying ethnic backgrounds is 0.9%–1.8% [76, 78], of which 5%-6% are sporadic [63, 79, 80].

Although this genetic susceptibility is present in all organs, the mitochondrial mutations target the cochlea but not the vestibular organs or the kidneys [81]. This is intriguing as this selective cochleotoxicity also occurs with preferably vestibulotoxic AGs such as streptomycin [81]. One proposed explanation for this phenomenon is that AGs cause misreading in mitochondrial protein synthesis rather than direct inhibition of protein synthesis [82] such that tissues rich in mitochondria would be predominately affected [81]. Exposure to AGs would decrease mitochondrial ATP synthesis resulting in compromised ion pump activity [81, 82]. Reduced ion pump activity in strial intermediate cells could ultimately lead to a progressive decrease of the endocochlear potential [81]. This scenario conceivably explains the slow progression of hearing loss after exposure to AGs observed in patients with increased genetic susceptibility [81]. The strial impairment, furthermore, would explain the little effect on vestibular function in these patients [81]. Interestingly, the stria vascularis demonstrates extensive degeneration in syndromal mitochondrial diseases [83]. This further supports the hypothesis of the stria vascularis as the cochlear cells targeted by the mitochondrial mutations in patients with increased genetic susceptibility to AG ototoxicity. An alternative simple explanation is that susceptibility to the mitochondrial disease is a function of metabolic demand so that hair cells operating at higher frequencies will be more susceptible to a reduced mitochondrial function than lower frequency cells, that is, cochlea versus vestibular, basal versus apical, and type I versus type II. Similarly the highly metabolically active strial cells would also have increased sensitivity.

In genetically susceptible individuals, it is postulated that a single injection of AG can cause ototoxic damage [84], implying that genetic factors can reduce the threshold concentration at which AGs cause damage [61]. At higher concentrations or more frequent doses of AG, the incidence of ototoxic damage exceeds the prevalence of genetic predispositions [76, 81, 85]. Although in vitro, a clear relationship between damage and AG concentration is observed, the extent of ototoxic damage in vivo does not seem to correlate with AG concentration in targeted tissues [86]. This discrepancy requires further evaluation.

3.2. Route of Aminoglycosides into Hair Cells

After systemic administration, AGs are detected in the cochlea within minutes. Fluorescently labeled gentamicin was detected in the stria vascularis 10 minutes after injection in mouse [87]. In the stria vascularis, the fluorescently tagged gentamicin increased over time mainly in marginal cells, but also in intermediate and basal cells as well as fibrocytes, plateauing after 3 hours [87]. These observations suggest that gentamicin enters the inner ear fluids from the strial capillaries through the strial marginal cells [87]. In the organ of Corti, fluorescence from labeled gentamicin starts increasing 1 hour after systemic injection. Hair cells demonstrate fluorescent gentamicin intracellularly after 3 hours [87]. Earlier studies demonstrated similar pharmacokinetics in rat and guinea pig [88, 89]. In rat cochlear tissues, gentamicin concentrations were measured by a radioimmunoassay and peaked 3 hours after systemic application [89]. In guinea pig, gentamicin appeared in the stria vascularis 30 minutes after systemic injection. In outer hair cells (OHCs), gentamicin was detected after 30 minutes and peaked 6 hours after systemic injection [88]. Although these studies had different specific time points for measurements, they are roughly in agreement as to the time course of uptake into cochlear tissues [8789]. Based on the cochlear structures, where AGs are located, entry into various cochlear structures suggests a complex uptake mechanism (Figure 1).

Both endocytosis and transport through ion channels are proposed to mediate AGs uptake into sensory hair cells. While some publications describe endocytosis as the mechanism of entry into hair cells [90, 91] others advocate for the mechanoelectrical transducer (MET) channel located at the top of hair cell stereocilia [9294]. The endocytic mechanism of AG entry arose because researchers observed the appearance of vesicles in the subcuticular region of hair cells after systemic injection in guinea pigs [95]. Hashino and Shero observed kanamycin in intracellular vesicles 27 hours after systemic injection in chicken [90]. These findings were interpreted as evidence for endocytosis as mechanism of AG uptake as the vesicle membranes contained cationic ferritin, a membrane bound marker [90]. However, no differences in intravesicular AG, compared to a control group, were observed until 12 hours after injection [90].

Myosin7a was hypothesized to play a role in endocytosis-mediated AG uptake due to its concentrated expression at the apical part of hair cells in a region with high amounts of vesicles known as the pericuticular necklace [91, 96]. The lack of AG uptake in Myosin7a6j mutant mice was considered evidence supporting AG toxicity mediated by endocytosis [91]. Further investigation found that Myosin7a-deficient hair cells exhibit closed MET channels at rest, confounding initial interpretations [97].

Furthermore, the rate of endocytosis correlates with temperature and, therefore, is decreased in hypothermic conditions [98]. AG uptake demonstrates little temperature-dependent kinetics, indicating a minor relevance of endocytosis in the process [99]. Instead, there is strong evidence that AGs enter hair cells through the MET channel located at the top of the stereocilia. AGs act as open channel blockers of the MET-channel [100, 101]. Initially, AGs were not considered to be permeable because diameter estimates of the MET-channel pore were low (0.6 nm) [102]. However, work by Gale and coworkers suggested that larger molecules could pass through the MET channel [103]. This was quantified by Farris et al. with a new pore size estimate of 1.25 nm [104], which is large enough to pass AGs. Marcotti et al. demonstrated directly that AGs could pass through the channel [92]. Interestingly, this block was decreased significantly for AG approaching the channel from the internal as opposed to the external face [92]. As this difference between internal and external blocking of AG makes the MET channel function like a one-way valve, intracellular accumulation of AGs is promoted and might explain the increased susceptibility of hair cells compared to other cell types [94]. The significance of the MET channel as a major route of AG entry is furthermore supported by the exacerbation of ototoxic damage with noise exposure [105]. Acoustic stimuli increase the open probability of the MET channel and thereby, increase AG uptake [106]. Additionally, the distribution of ototoxic damage with increasing hair cell susceptibility from apex to base corresponds to the transduction currents in the cochlea, which are larger in basal than in apical OHCs and, in general, more decreased in inner hair cells (IHC) [107109]. Moreover, fluorescently labeled gentamicin has been observed first in the tips of hair cell stereocilia before the fluorescent signal increases in the hair cell body [87].

Several other ion channels might also contribute to AG uptake into hair cells. Channels of the transient receptor potential (TRP) class such as TRPC3, TRPV4, TRPA1, and TRPML3 are expressed in the cochlea [110112] and are permissive to AGs in kidney cells [113, 114]. It is unclear at this point under what conditions the TRP channels might be open and whether these channels are expressed in the plasma membrane or in other cytosolic compartments. The glycoprotein megalin is another potential mediator for AG uptake. Megalin is predominantly expressed in the proximal tubules of the kidney. Megalin is capable of binding AGs and is also expressed in the inner ear [115]. Therefore, it was considered a candidate protein for the uptake of AG into hair cells. However, megalin is a drug receptor engaging in endocytosis and is not expressed in the organ of Corti and sensory hair cells [115117]. Notwithstanding, megalin has been detected in marginal cells of the stria vascularis, suggesting a role in the transport of AGs into the inner ear fluids [116, 117].

3.3. Apoptotic Pathways of Ototoxic Hair Cell Death

Inside the hair cell, AGs cause damage, either directly or indirectly, by first inducing disarray of stereocilia and ultimately ending with apoptotic cell death [118121]. The presence of AGs within hair cells leads to increased formation of reactive oxygen species (ROS) or free radicals [122125]. A common mechanism for the formation of ROS is the Fenton reaction: Here, the presence of iron salts is required [126]. When gentamicin combines with iron salts, the gentamicin-iron complex enhances iron-catalyzed oxidations and, thereby, directly promotes the formation of ROS [122]. This requires electrons for which unsaturated fatty acids can act as electron donors. In return, those fatty acids, predominantly arachidonic acid, are oxidized to lipid peroxides [125, 127]. As arachidonic acid is an essential fatty acid present in cellular membranes, ROS can affect membrane fluidity and permeability [128, 129]. Via lipid peroxidation, ROS can also affect proteins and nucleic acids thereby disrupting the activity of enzymes, ion channels, and receptors [128131]. ROS naturally occur in the cell as a regular byproduct of cellular metabolism [130132]. Normally, the cell protects itself from lethal ROS accumulation with intrinsic antioxidants such as glutathione [132, 133]. This intrinsic protective system is capable of neutralizing ROS to some extent [134]. When formation of ROS, however, overwhelms the capacity of these intrinsic protective and repair systems, the cell then undergoes apoptotic cell death [135, 136].

The mechanism of involvement of mitochondrial mutations in ototoxic hair cell death is not completely understood. Exposure to AG leads to impairment of RNA translation and inhibition of protein synthesis within mitochondria [65, 69, 137]. It is further suggested that inhibition of mitochondrial protein synthesis leads to a decrease in ATP [137]. With the decrease of energy production, the mitochondrial integrity is compromised and predispose to a leakage of cytochrome c and subsequent activation of the apoptotic cascades. Furthermore, it is hypothesized that the mitochondrial RNA mutations when exposed to AG cause an increased formation of ROS, which then promote apoptotic cell death [137].

Independent extrinsic and intrinsic apoptotic pathways exist [138, 139]. The extrinsic pathway is mediated by death receptors including the tumor necrosis factor (TNF) family. When stimulated, death receptors activate cysteine-dependent, aspartate-specific proteases also known as caspases. The prototype of death receptors is the FAS (CD95/APO-1) receptor, which activates caspase-8 on stimulation. Caspase-8 in turn initiates a cascade involving the activation of caspase-3, caspase-6, and caspase-7, which ultimately execute cellular degeneration [140]. The intrinsic pathway, in contrast, is the major apoptotic pathway initiated by aminoglycoside ototoxicity (Figure 2) [120]. The intrinsic pathway is predominantly triggered by nonreceptor stimuli such as cytokine deprivation, DNA damage, and cytotoxic stress [141]. Characteristic for the intrinsic apoptotic pathway is the permeabilization of the outer mitochondrial membrane resulting in leakage of proapoptotic factors from the mitochondrial intermembrane space into the cytoplasm. Mitochondrial membrane integrity and components of the intrinsic pathway are regulated by proteins of the B-Cell Lymphoma-2 (Bcl-2) family [141].

Bcl-2 is the prototype of this equally named protein family. Studies in other systems report these molecules as key apoptosis mediators, acting upstream of caspase activation [142144]. The Bcl-2 proteins function as a checkpoint for cell death and survival signals in the mitochondria (Figure 2). The Bcl-2 protein family can be anti- or pro-apoptotic [136, 145, 146]; anti-apoptotic Bcl-2 proteins include Bcl-2 and Bcl-XL [143, 147], whereas pro-apoptotic Bcl-2 proteins which promote cell death include Bax, Bak, Bcl-Xs, Bid, Bad, and Bim [143, 147]. Bcl-2 proteins form hetero- and homodimers within the cell. When a cell is challenged, the balance between anti- and pro-apoptotic Bcl-2 proteins regulate whether or not apoptotic cell death is initiated [148]. Anti-apoptotic Bcl-2 proteins are able to bind to pro-apoptotic Bcl-2 proteins, thus neutralizing the pro-apoptotic signal [149]. When the balance moves in favor of apoptosis, the pro-apoptotic cytoplasmic Bcl-2 member Bax translocates to the mitochondria, causing pores in the mitochondrial membrane [143, 144]. This leads to loss of mitochondrial transmembrane potential, generation of ROS, and leakage of cytochrome c into the cytoplasm [143, 144, 150154], thus activating the upstream caspase pathway as mentioned above. Supporting a role of this pathway in the inner ear, hair cell loss, and caspase-9 activation were prevented in utricles from Bcl-2 overexpressing mice when treated with neomycin [155]. This suggests a role for Bcl-2 in the upstream caspase cascade in aminoglycoside-induced hair cell death.

Another group of mediators of apoptotic hair cell death is the stress-activated protein kinases, including the mitogen-activated protein (MAP) kinases (Figure 2) [120]. A particular group of MAP kinases are c-jun N-terminal kinases (JNK). These JNKs are located in the cytoplasm and regulated by c-Jun-interacting protein-1 (JIP-1) [156, 157]. In response to cellular insults, JIP-1 facilitates the phosphorylation and thus activation of JNK [158161]. Activated JNK in turn phosphorylates and thereby activates the transcription factors c-Jun, c-Fos, ELK-1, and activated transcription factor 2 (ATF-2) in the nucleus and Bcl-2 in mitochondria [120]. After AG treatment, increases in JNK, c-Jun, c-FOS, and Bcl-2 have been reported in hair cells [120, 152, 161, 162]. Activation of the JNK signaling pathway appears to precede the release of mitochondrial cytochrome c, which then activates caspases [152, 163].

Caspases execute cell death in apoptosis [141]. The caspase family consists of 14 members in mammals, with only a subset involved in apoptosis [142, 164]. Caspases can thus be segregated into upstream and downstream enzymes, which are normally inactive [136, 164]. Caspases exist in the cytoplasm normally inactivated by inhibitor of apoptosis proteins (IAP) [136, 141]. Activation of upstream caspases occurs by apoptosis-inducing signals such as p53, which has been shown to activate caspases after administration of cisplatin. Downstream caspases are activated by upstream caspases through cleavage of an inactivating prodomain to produce the mature enzyme [136].

Caspase-8 is an upstream member that is tightly linked to membrane-associated death domain-containing receptors. When ligands such as Fas ligand or tumor necrosis factor alpha bind to this receptor, caspase-8 is recruited intracellularly, leading to clustering and autoactivation of other caspase-8 molecules [165]. This subsequently causes activation of downstream caspases such as caspases-3, -6, and -7. Although caspase-8 is detected in HC after AG administration [166, 167], it does not play a key role in HC death, as inhibition of this pathway does not prevent HC death or prevent caspase-3 activation [166, 168, 169].

Caspase-9 is an upstream caspase activated by apoptotic signals from the mitochondria. This pathway is initiated by cytochrome c release from mitochondria, which then binds to apoptosis protease activating factor, dATP, in the cytoplasm and procaspase-9 [164, 170]. This binding causes cleavage and activation of caspase-9, which subsequently cleaves and activates downstream caspases, ultimately resulting in apoptotic cell death (Figure 2). Activated caspase-9 is detected in cochlear and utricular hair cells after AG treatment in vitro [151, 166, 167].

Caspase-3 is a primary downstream caspase that executes the apoptotic program by cleavage of proteins necessary for cell survival, including Bcl-2, inhibitors of deoxyribonucleases, and cytoskeletal proteins (Figure 2) [171174]. This enzyme activation has been detected in HC due to ROS after AG dosing [150, 151, 166, 167, 175].

Further mechanisms of apoptotic hair cell death following AG administration involve activation of NF-κβ as well as calcium-dependent proteases such as calpains. Inhibition of NF-κβ in rat cochlear explants after exposure to gentamicin altered the ratio of activated over inactivated pro-apoptotic factors such as c-Jun and p38 as well as of anti-apoptotic factors such as akt [176]. Exposure of mice cochlear cultures to neomycin resulted in apoptotic DNA fragmentation, which could be prevented by a calpain inhibitor [177].

Overall, apoptotic death of hair cells due to AG exposure is complex and our understanding of it has increased in recent years. A simplified model of the apoptotic cascade in aminoglycoside damaged hair cells is presented in Figure 2, but it is important to point out that many components of the overall cascade and the interactions among these components are still poorly understood. This complexity is in part reflected by crosstalks among pathways. Death receptor stimulation, for example, is also capable of activating the intrinsic pathway despite primary involvement in the extrinsic pathway [141].

4. Efforts in Hair Cell Protection

With increasing understanding of ototoxic cell death, a myriad of therapeutic efforts have been proposed to target various steps of the complex cascades to hair cell death. Those strategies include inhibition of apoptosis, neutralization of ROS, and administration of neurotrophic factors. A detailed overview of relevant studies including applied drugs, dosage, and outcome is presented in a table at the end of each subchapter.

4.1. Inhibition of Apoptotic Enzymes

Permeable caspase inhibitors such as z-Val-Ala-Asp(O-Me)-CH2F-fluoromethyl ketone (zVAD) were applied against different AGs in a variety of species. zVAD inhibits by irreversibly binding to the active site of a broad spectrum of caspases [167]. Caspase inhibitors conferred significant protection against hair cell damage from AG, preserving hair cell morphology as well as function in vitro and in vivo [167, 178182] (Table 1).

Agents targeting upstream stress kinases in the apoptotic cascades also prevented AG-induced hair cell death. D-JNKI-1 is a cell permeable peptide that binds to all three isoforms of JNK, thereby blocking JNK-mediated activation of the apoptotic transcription factor c-Jun [156]. Inhibition of the MAP-JNK pathway by application of D-JNKI-1 prior to treatment with neomycin resulted in significant protection from hair cell loss in vitro and hearing loss in vivo [161]. Other JNK inhibitors that successfully prevented AG ototoxicity are CEP-1347, CEP 11004, and 17β-Estradiol [152, 183186] (Table 1).

Targeting the Bcl-2 family as the upstream key mediator of apoptosis also prevented AG-induced hair cell loss. Overexpression of the anti-apoptotic Bcl-2 in transgenic mice significantly decreased hair cell loss and preserved hearing function following AG exposure in vitro and in vivo [155, 187]. Inoculation of mouse cochlea with an adenovirus vector expressing the anti-apoptotic Bcl-XL before treatment with kanamycin also protected from hair cell loss and preserved hearing function [188] (Table 1).

Another class of stress-activated proteins are the family of heat shock proteins (HSPs), which are upregulated in stressed cells in multiple organ systems. HSPs can not only prevent protein aggregation by promoting proper folding of nascent or denaturated polypeptides [189], but also inhibit apoptosis. Induction of HSP expression in cultured mouse utricle led to upregulation of HSP-70, HSP-90, and HSP-27 [190]. Overexpression of HSP-70 in transgenic mice significantly protected from hair cell loss from neomycin treatment in vitro, but also significantly protected from hearing loss and hair cell death in mice injected with kanamycin over the course of 14 days [191, 192].

Application of anti-apoptotic agents raises several concerns. The protective results of anti-apoptotic drugs are mainly based on acute studies. Therefore, the sustainability of therapeutic potential and safety remain to be evaluated in chronic exposure scenarios. There is evidence that the protective effects of caspase inhibitors to the inner ear are short term [167]. Considering that AGs are not metabolized [7, 34, 73] and remain in the hair cells for months [88, 194], potential sustainable regimens would conceivably require long-term treatment. Unfortunately, long-term treatment with anti-apoptotic drugs bears a potential carcinogenic risk, as apoptosis has a crucial primary function in preventing uncontrolled cell proliferation [195]. This carcinogenic risk, therefore, prohibits potential application in human otologic patients. Whether this risk is decreased over a long period by local application to the inner ear remains to be studied. The therapeutic application of anti-apoptotic agents to rescue hair cells after AG exposure has not been reported, but is of further translational interest.

4.2. Neutralization of Reactive Oxygen Species

Aminoglycosides form complexes with iron, thereby, catalyzing the formation of ROS [122]. Competitive blocking of the Fenton reaction involved by iron chelators, thus, is a reasonable approach to avoid oxidative damage from the beginning. Therefore, much efforts aiming at prevention of AG-induced hair cell death have focused on iron. Administration of the iron chelators deferoxamine and 2,3-dihydroxybenzoate before AG exposure significantly attenuated hearing threshold shifts and protected from hair cell loss in vivo [196198].

Acetylsalicylate (ASA) is another iron chelator with additional direct antioxidant properties. ASA prevents cleavage of PKC zeta, a key regulator of NFκβ activated by exposure to amikacin [199]. Systemic administration of ASA effectively protects guinea pigs from gentamicin-induced hearing loss [200]. As ASA is a long-approved and routinely prescribed drug, application in human patients is the logical next step. In randomized, double-blind placebo-controlled studies, ASA significantly protected human patients from ototoxic damage without compromising the antimicrobial efficacy of gentamicin [201203]. However, ASA itself is ototoxic and potentially causes tinnitus, vertigo, and hearing loss [204]. Although these symptoms are known to be reversible [204], AGs remain in hair cells for months [88, 194] and ototoxic damage can occur after many years [81]. Thus chronic treatment with ASA appears necessary and ototoxic effects of both, AGs and ASA, need to be evaluated over a long period. In this context, recent studies discovered a decrease of activity in auditory neurons in long-term treatment [205]. Of further concern is that AGs are frequently prescribed in children and neonates. ASA, however, is strictly contraindicated in children as it is associated with Reye’s syndrome, which is a serious and often fatal disease predominantly affecting the brain and liver [206208].

N-Acetylcysteine (NAC) is another drug commonly used in patients. Beside its mucolytic effect, NAC is also a known antioxidant. In short-term cultures of guinea pig cochlea, AG alone caused less than 30% of basal OHC survival but 90% of the apical OHC survived. This observation correlated with lower levels of the intrinsic antioxidant glutathione in basal OHC. However, survival of basal OHC was significantly improved by cotreatment with NAC as well as glutathione and salicylate [209]. In hemodialysis patients who received gentamicin treatment for bacteremia, application of NAC resulted in significantly less high frequency hearing threshold shifts compared to a control group receiving gentamicin alone. Treatment with NAC was continued for one week after cessation of the gentamicin therapy and the protective effects persisted after another six weeks [210]. Compared to ASA, NAC does not demonstrate intrinsic ototoxic side effects.

A myriad of other agents with known antioxidant capacity has been tested for protection and treatment of AG ototoxicity. These agents are primarily antioxidants such as D-Methionine (D-Met) [211213] and α-lipoic acid (α-LA) [214], vitamins such as α-tocopherol (vitamin E) [215217] and vitamin C [218] as well as the herbal extracts Gingko biloba [219] and Danshen [220]. The hormone melatonin, normally excreted by the pineal gland, also has antioxidant capacity and successfully protected from AG ototoxicity [175, 221223]. An alternative protective strategy against AG ototoxicity is the upregulation of intrinsic antioxidant mechanisms such as the superoxide dismutase (SOD) [209, 224, 225] (Table 2).

Overall, antioxidants attenuate ototoxic damage from AGs. However, the majority of antioxidants did not demonstrate complete protection from AG ototoxicity [211213, 215217, 227, 229] and effects of long-term treatment remain to be studied.

4.3. Alternative Otoprotective Strategies

There exists a number of alternative approaches to protect against AG ototoxicity. One intriguing approach is moderate exposure to ototoxic stimuli with the intent to increase intrinsic antioxidant mechanisms within the ear. Exposure to low doses of amikacin or gentamicin for 30 days and consecutive high-dose treatment for another 10 to 12 days resulted in significantly less morphologic and functional hair cell damage [230, 231] (Table 3). However, this bears the undesirable risk of increased bacterial resistance and, thereby, undermines the primary antimicrobial purpose of the AG application. Exposure to moderate noise also protects from gentamicin ototoxicity in gerbils [232] (Table 3). As this does not allow for immediate application of AG in therapeutic doses, applicability in human patients appears difficult.

Other studies successfully target NMDA receptors to protect auditory nerves [233, 234]. However, the NMDA receptor antagonists dizocilpine and ifenprodil exist as maleate and tartrate salts, which carry intrinsic metal chelating properties [235]. Their vehicle, dimethyl sulfoxide (DMSO), can also act as a radical scavenger [236]. Therefore, the results of Basile and coworkers [233, 234] were challenged by Sha and Schacht [237]. Nonetheless, NMDA antagonists do interact with receptors of afferent auditory nerve fibers [238]. Thus, targeting the auditory nerve appears reasonable as AGs interact with certain nerve synapses. AGs can aggravate myasthenia gravis and cause postoperative respiratory suppression suggesting a direct neuromuscular blockade [239242] (Table 3). Presynaptically, AGs interfere with the calcium internalization essential for acetylcholine release [243]. At the postsynaptic level, streptomycin directly blocks the acetylcholine receptor primarily, whereas neomycin affects the open probability of the ion channel of the acetylcholine receptor [244]. Also, in rat and mouse cochlear cultures, fluorescently tagged gentamicin accumulates in the afferent auditory nerve fibers in addition to the hair cells [245].

This direct interaction with the auditory nerve also might explain therapeutic effects by neurotrophic growth factors. Ciliary neurotrophic factor (CDNF), glial-cell-line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3) demonstrated partial protective effects against AG ototoxicity [213, 246250] (Table 3). The contribution of neurotrophic growth factors in preventing AG ototoxicity suggests an involvement of the auditory nerve. However, there is evidence that the effects of neurotrophic growth factors are short term. Local application of BDNF (62.5 μg/mL, 0.25 μL/h over 28 d) to guinea pigs exposed to kanamycin (400 mg/kg, single dose, s.c.) and furosemide (100 mg/kg, single dose, i.v.) demonstrated initial protection from ototoxicity. Cessation of the therapy, however, resulted in an accelerated neuronal degeneration and after another 14 d, the survival of BDNF-treated auditory neurons did not differ from the deafened, untreated control animals [251].

Ethacrynic acid (EA) is a diuretic which increases AG ototoxicity when administered simultaneously [252]. Delayed co-treatment with application of EA 12–18 hr after gentamicin injections in guinea pigs resulted in significantly protected hair cell function and morphology [253]. The authors suggest that EA disrupts the blood-labyrinth barrier, thus creating a gradient promoting efflux of AG from the inner ear fluids back into the bloodstream. However, the protective effects are time dependent and could not be found when EA was injected 20 hr after the AG [253]. Moreover, simultaneous AG and EA in patients resulted in ototoxic damage after a single treatment [254], thereby excluding EA as a treatment option.

Overall, prevention of apoptotic hair cell death following AG exposure has been targeted effectively on various levels. Direct inhibition of apoptotic cascades resulted in functional and morphological preservation of hair cells. Neutralization of free radicals by antioxidants prevented activation of apoptotic enzymes. Furthermore, application of NMDA-receptor antagonists, neurotrophic growth factors, and sound conditioning have prevented ototoxic hair cell damage from AG. However, these protective results are mainly based on acute studies and the sustainability of therapeutic potential and safety remains to be evaluated in chronic exposure scenarios or in clinical trials.

5. Potential Targets for Hair Cell Protection

In light of recent insight and increasing understanding of the mechanisms involved in AG ototoxicity, newer and more effective targets may be revealed in the near future. Those target sites involve the mitochondrial rRNA as well as AG entry into the inner ear fluids and hair cells. Considering the one-way valve function of the MET channel as a site of AG entry into hair cells [92, 94], the prolonged persistence of AG in hair cells poses another obstacle to overcome [194]. Therefore, avoiding entry of AG into hair cells is potentially promising. On the level of the MET channel, at least two possibilities of preventing AG entry exist. The first one involves a reversible block of the MET channel. The process of hearing requires depolarization of the inner hair cell through the MET channel [101, 260, 261]. Blocking of the MET channel would then prevent hair cell depolarization and, therefore pause hearing function. Thus, the MET channel block has to be temporary. MET channel blockers have been tested successfully in vitro [104]. Yet their in vivo effects are largely unknown. The second possibility of preventing AG entry through the MET channel involves steric modification of the chemical structure of AGs. From electrophysiological measurements, the narrowest part of the MET channel pore has been estimated to be 1.25 nm [104]. As dihydrostreptomycin is capable of blocking the MET channel [92], the difference in the dimensions of the MET channel and certain AGs appears to be small. Therefore, widening of the AG diameter by binding of inert molecules on sites irrelevant for antimicrobial activity appears a promising strategy to prohibit passage of AGs through the MET channel into the hair cells. As the passage through the bacterial membrane is self-promoting and depends on the relative positive charge of the AG [4247, 262264], the intended increase of size should not affect bacterial uptake of the AG as long as the polarity and the charge of the new AG molecule remains the same. However, interference with the antimicrobial activity due to sterical impairment of binding to the bacterial ribosome needs to be tested.

Another target lies in preventing AG from entering the inner ear fluids. AGs enter the inner ear fluids through the stria vascularis [87]. Blocking the passage of AG requires the identification of the transport mechanism in the blood-labyrinth barrier.

AGs are potent antibiotics with limited application due to their side effects. Until the problem of AG ototoxicity is solved, it is crucial to be judicious in prescribing AGs for defined clinical indications. Furthermore, it is important for clinicians to remember the genetic mutations as a cause for increased susceptibility to ototoxic damage. However, indiscriminate genetic screening is not cost-effective at present. Instead, a thorough history of the patient and their family regarding ototoxic symptoms from antibiotics helps assessing the individual risk. Independent from genetic mutations, patients should undergo a baseline hearing test including ultrahigh frequencies prior to AG administration to allow for early and unambiguous assessment of potential ototoxic damage.

M. E. Huth is supported by the Swiss National Science Foundation (Fellowships for prospective researchers; PBSKP3_130635/1). A. J. Ricci and A. G. Cheng are supported by the National Institutes of Health, NIDCD RO1 DC003896, R21 DC012183, K08 DC011043, and internal funding via Stanford SPARK program.


Why Are Bobcats Called Bobcats?

Disclaimer: The information presented below is for general informational & educational purposes only. Always consult with animal professionals in case of specific concerns.

There are many animals that go by more than one name.

Chipmunks, for example, can also be called ground squirrels.

Raccoons are sometimes called masked bandits.

And then there are bobcats.

So, why are bobcats called bobcats?

What’s the story behind their funny name?

Read on to find out.

Why are bobcats called bobcats?

The main reason why bobcats are called bobcats is because of their short, stubby tail.

“Bob” is simply another word for “short”.

So, when you put it all together, a bobcat is simply a short-tailed cat.

But why do they have such a short tail in the first place? It’s not entirely clear, but one theory is that it helps them balance when they’re climbing trees.

Their short tail also gives them their scientific name: Felis Rufus – which means “red cat” in Latin.

Bobcats aren’t the only animals that are named after their physical features.

There are also plenty of other animals with interesting names, like the elephant shrew (a small mammal with a long snout that resembles an elephant’s trunk) and the okapi (a mammal that looks like a cross between a zebra and a giraffe).

Do bobcats have any other names?

They sure do.

Bobcats are also sometimes generally called wildcats.

This is because they’re members of the Felidae family.

So, technically, bobcats are wildcats…

but not all wildcats are bobcats (if that makes sense.)

Bobcats are also known by their scientific name, Felis Rufus.

This scientific name comes from the Latin words ‘felix’ (meaning cat) and ‘rufus’ (meaning red).

And when it comes to scientific papers and research, bobcats are usually referred to by their Latin name, not their usual bobcat name.

Do people in different states/English-speaking countries call them bobcats as well?

Yes, the name “bobcat” is used in most English-speaking countries.

In fact, it’s one of the few animal names that is used almost universally.

There are a few other animals with similar names, but for the most part, bobcats are called bobcats wherever you go.

Who coined the name ‘bobcat’ in the first place?

The name ‘bobcat’ was first used in the early 1800s by American settlers.

At that time, bobcats were common throughout the eastern United States.

The native settlers saw these animals as a nuisance, and they would often shoot them on sight.

If the bobcat tail is so short, can it help the wildcat in any way?

Yes, it can.

In fact, there are many uses for the bobcat’s tail.

First, the short, stubby tail helps the bobcat balance when it’s climbing trees.

This is important since bobcats are known to be excellent climbers.

The tail also helps the bobcat keep its balance when it’s running, which is why you’ll often see a bobcat’s tail wagging back and forth when it’s chasing its prey.

Next, the bobcat’s tail can be used as a warning signal.

When a bobcat feels threatened, it will often raise its tail straight up in the air.

This is a warning sign to other animals that the bobcat is feeling threatened and they should stay away.

In addition, the short tail is very efficient in escaping from potential predators.

When a bobcat is being chased by another animal, it can quickly turn around and use its tail as a shield.

This will often confuse the predator and give the bobcat enough time to escape.

Lastly, the bobcat’s tail can be used as a communication tool.

Bobcats use their tails to communicate with other bobcats – for example, when they’re trying to find a mate.

When a male bobcat sees a female that he’s interested in, he will often wave his tail back and forth to let her know that he’s interested.

Are there any other characteristics that make up the name bobcats?

why are bobcats called bobcats

No, the name bobcat is simply derived from their short, stubby tail.

This is the main reason why they’re called bobcats in the first place.

Are male and female bobcats called differently?

No, the names of male and female bobcats are the same.

They are both called bobcats.

Bobcats are so named for their short, stubby tails.

These tails help the cats balance when they climb trees or run, and can also act as a warning sign to other animals, a communication tool, and an escape mechanism.

While the reasons for their name might be amusing, bobcats are nonetheless fascinating creatures with unique adaptations that allow them to thrive in their natural environment.


How Oatly Became the Trendiest Plant Milk on the Market

Considering that 70% of the global population don’t produce the enzyme lactase to properly break down lactose - the sugar found in dairy products - cow milk’s rise to become one of our staple food items has been a marvel. But this is about to change.

As consumers grow increasingly aware of cow’s milk nutritional shortcomings, demand for dairy milk has been declining. At the same time, in the United States, plant-based milk sales rose to more than $2 billion in 2017, up 61% from 5 years earlier.

One company in particular has been leading the plant-based milk race: Oatly. Founded 25 years ago, the Swedish company first tiptoed into the United States 2 years ago by persuading small coffee shops to use its product. Today, Oatly is expanding its product line in the US and is slowly popping up at coffee shops all around the world. By using the 4 facets of brand positioning, let’s examine how Oatly rose to prominence and maintained its success.

Truth: The Benefits of Oat Milk

The myriad health benefits of oat milk make it a clear winner among the many milk alternatives available on the market. It is low in overall calories, cholesterol and saturated fat while being rich in dietary fiber, which is almost nonexistent in cow milk. What makes Oatly a standout, however, is its rich and smooth texture resembling that of actual whole milk. The addition of canola oil, a plant-based fat that holds foam like dairy milk, gives Oatly a full and delicious texture that is normally absent in other plant-based alternatives. As a result, Oatly became an instant hit among baristas in the café scene and among health-conscious individuals who are also regular coffee drinkers.

Vision: A Sustainable Option

When Rickard Oste first founded Oatly, he saw an opportunity to use oats (it was a particularly abundant crop in Sweden) as a milk source to cater for those who were allergic or lactose-intolerant to dairy. As the company grew, Oatly’s vision remained the same but also to “provide a more sustainable option that’s gentler on the plant compared to traditional dairy milk.” In other words, they wanted Oatly to become a dairy milk substitute that is good to the planet and the drinker. It certainly seems that they are living up to that promise.

Most people assume plant-based milk production causes less ecological damage than dairy production. But while the statement is generally true, not all plant-based milks are created with the same process. Almonds, for example, require 6 times more water to grow than oats do. Soy? A whopping 21 times. So, oat milk not only tastes good, but also has a lot less carbon footprint compared to other milk substitutes.

Universe: The Artisanal Coffee Shop

Oat milk, while popular in parts of Europe, has been mostly a fringe product in the United States. So instead of introducing its product on grocery shelves when the brand entered the US market, Oatly opted for a different distribution strategy. The company persuaded small coffee chains and specialty coffee shops to use its products.

By doing this, Oatly successfully integrates itself into the “hipster” coffee culture - the artisan coffee shop with minimalistic interior, where baristas explain the flavor of different coffee beans and perform latte art in front of you.

Gone is the Starbucksification of coffee. In this new wave of coffee culture, the coffee drinking experience is centered around aesthetics, high-quality ingredients and transparency in the creation process (Starbucks is itself trying to catch on with its new Reserve Roastery stores). When consumers see baristas - the taste makers and influencers in the brewing and roasting community - use Oatly, the “hip” vibe associated with café culture is indirectly projected onto the brand. This creates the key emblematic moment – customers go to their favorite artisan coffee shop, grabs a coffee made with freshly grounded and aromatic coffee beans, infused with a cup of healthy yet delicious Oatly milk.

Personality: The Honest Friend

Besides of a great product, Oatly is also known for its creative, graphic-filled packaging and sleek carton design.

Oatly’s cheeky advertisements and taglines also often carry a tone that is self-deprecating and funny. Here are just few examples:

“It’s like milk, but made for humans.”

Combined, Oatly is like that witty friend who is not afraid to voice out his or her opinions on controversial issues. This friend might be a little assertive at times, but ultimately is still someone you appreciate because of his or her authenticity and honesty. If Oatly were a person, it is who you would want to hang out with.

Conclusion: Stealing the Scene

Today, with the increased accessibility of information and the plethora of products available on the market, consumers are more conscious of their purchases and more willing to try out new products than ever before. It is up to brands to rise to the occasion by not only delivering a great product, but also to consider the touchpoints that reach the customers and the messages that are going to be embedded in the marketing materials. For Oatly, it has successfully achieved that by fully committing to its noble cause and carefully crafting its brand image to be relevant yet emotionally resonant. As Oatly’s Creative Director John Schoolcraft puts it, “We don’t really think of ourselves as a corporation. We’re real people working together to try to help other people get a good product.”

  • Corporate Branding Team,

    Labbrand, Shanghai


2024 Lotus Eletre EV Base HP, Design, AWD Powertrain: What We Know so Far

This article was updated for clarity on 8/2/2022.

Lotus built its brand with iconic two-seater supercars, but now, it makes a radical departure. The automaker recently debuted the 2024 Lotus Eletre, a high-performance electric SUV. Find out what we know so far about the release date, price, and specs of the Eletre.

When will the 2024 Lotus Eletre be available?

Front angle view of yellow 2024 Lotus Eletre, highlighting its release date and price
2024 Lotus Eletre | Lotus

Lotus has shown images for the production version of this model, so we still expect the 2024 Lotus Eletre to hit roads in 2024. It will be available at Lotus dealerships in the United States, as well as in select international markets, including China.

Lotus, owned by Chinese multinational Geely, will build the Eletre in Wuhan, China. A significant amount of the sales of the Eletre will likely be from automotive buyers in China.

How much is the 2024 Lotus Eletre expected to cost?

Lotus did not yet release information about the price and trims/configurations of the 2024 Eletre. However, Car and Driver estimates that the 2024 Eletre will have a starting cost of around $120,000. For the more powerful versions of the Eletre, the price will be higher.

2024 Lotus Eletre specs: Performance, acceleration, driving range, and battery

Rear angle view of yellow 2024 Lotus Eletre, highlighting its release date and price
2024 Lotus Eletre | Lotus

So far, the only details that Lotus released about the powertrain of the 2024 Eletre are that it will have an all-wheel drive system, and the base model will have a performance output of 600 hp. This likely means that the Eletre has two electric motors, with one at the front and the other at the rear.

Other versions of the Eletre will likely have considerably more power. Also, Lotus claims that at least one version of the Eletre will have a 0-100 kph (0-62 mph) acceleration time of less than three seconds.

The Eletre features a battery pack with around a 100.0-kWh capacity. Lotus claims the electric SUV has an estimated driving range of 373 miles on the European WLTP cycle. The U.S.-specific EPA rating for the Eletre will be lower. MPGe fuel economy estimates for the Eletre are not yet available.

2024 Lotus Eletre: Exterior design and features

While the 2024 Lotus Eletre shows much promise on the performance front, its dramatic design might be the thing that stands out the most. With its sculpted shape, the Eletre looks like a futuristic concept car, but the images you see here are for the production version.

Notable exterior design features for the Eletre include a closing grille shutter, a three-position rear spoiler, and either 22” or 23” wheels. Also, the Eletre has futuristic exterior features, including “lidar sensors which rise out of the bodywork and will allow eventual high-level autonomous operation.” Also, the Eletre has a full-width light bar on the liftgate with the ability to change to green, blue, red, and orange.

Additionally, the electric SUV will offer a “camera-based side mirror system, which will be [available] in territories where this is permitted.” However, in the U.S., “conventional door mirrors will be standard.”

2024 Lotus Eletre: Interior design and features

Dashboard and front seats in 2024 Lotus Eletre, highlighting its release date and price
2024 Lotus Eletre | Lotus

The cabin is what makes the 2024 Lotus Eletre feel the most different from preceding Lotus models. While many Lotus supercars have a bare-bones interior with most of the focus on performance, the Eletre has a greater emphasis on comfort, luxury, and ambiance.

Notable interior features offered for the Eletre include milled bronze metal rocker switches, a full-length panoramic glass roof, a 15.1-inch OLED central touchscreen, a head-up display, and either a 15- or 23-speaker sound system. For seating configurations, the Eletre offers “either a four-seater with two individual buckets in the rear or as a five-seater with a three-place rear bench.”

RELATED: 2023 BMW XM: Hybrid Specs, Range, and Features


Flexible Fitness: Run strong and injury-free

Leah Jensen and Ashley Saulnier

This is the time of year when people's motivation to run peaks. Whether you have been running for years or are breaking out your first pair of running sneakers, it is important to make sure your body is properly prepared.

While the motivation to run may spring from many sources, the need for adequate preparation remains consistent. Running is an excellent form of cardiovascular exercise but it places a great deal of demand on the body. Without proper muscle strength to support this demand there is a large risk for injury. Studies have estimated that as many as 70 percent of runners experience an overuse injury in any given year. Examples can include shin splints, achilles tendonitis (heel pain), plantar fasciitis (foot pain) and stress fractures, among others. Consider that with each stride, a runner hits the ground with up to 400 times their normal body weight. Without proper muscular strength and balance your body becomes highly prone to injury.

For those runners entering races, increasing strength can help to boost performance and decrease risk of injury. There is a growing body of evidence to show that incorporating dynamic strength and balance exercises into your regular training program can increase speed, running efficiency and overall endurance.

Many runners are concerned that strength training will bulk them up too much, potentially harming their running performance. That does not need to be the case. There are a considerable number of studies demonstrating that strength training will not only improve overall body composition, but increase lean body mass. Strength training allows your body to use oxygen and become more efficient at producing the energy necessary for running. This will simultaneously promote faster recoveries from those long runs and allow you to get right back on your feet again.

When designing a strength-training program, the runner should start at the core. This is the foundation which works to control all of the additional muscle groups necessary for running. If the core is strong, the rest of the body tends to follow. Training the abdominal and low back muscles will provide a stable base from which to generate power.

The hips and buttocks are essential to improving speed and efficiency. Leg exercises are particularly important when it comes to decreasing risk of injury in runners. Knowing that the hips and knees are the most common sites for injury in runners, strengthening exercises can help to decrease your risk for injury. The more supported by surrounding muscles they are, the more stable the joints become and the risk of repetitive stress injuries is less.

Running can be extremely rewarding and fun but it also requires determination, balance and a strong body.

Physical therapist Leah Jensen graduated from Boston University and is a clinical supervisor at Spaulding Framingham. Physical therapist Ashley Saulnier graduated from Massachusetts General Hospital's Institute of Health Professions and is physical therapy intern at Spaulding Framingham. Both have a special interest in sports and orthopedic physical therapy.


Why is rheumatoid arthritis (RA) sometimes called an autoimmune disease?

Rheumatoid arthritis (RA) is a chronic and potentially debilitating inflammatory disease that causes pain, swelling, stiffness and loss of function in the joints.

According to the Arthritis Foundation, RA affects about 1.3 million Americans, mostly women; two to three times more women have RA than men, and the number of women with the disease appears to be increasing. The age of onset can vary, but it typically occurs between ages 30 and 60, with the risk increasing as a person ages. The good news is that new advancements in treatment have made it possible to slow or stop the progression of RA.

Unlike the more common osteoarthritis, which is mainly a disease of the cartilage in joints, RA occurs when the body’s immune system attacks and damages the joints and, sometimes, other organs. RA often occurs in a symmetrical pattern, meaning that if one knee or hand is involved, the other one is, too.

The condition is considered an autoimmune disease. Such diseases area unit characterised by Associate in Nursing immune-system attack on the body’s healthy tissues. In RA, white blood cells travel to the synovium (the membranes that line the inner surface of the joint capsule) and cause inflammation, namely synovitis. The ensuing warmth, redness, swelling and pain are typical symptoms of RA, which usually affects the wrists, fingers, knees, feet and ankles.

The continuous inflammation associated with RA gradually destroys cartilage- the specialized tissue that coats and cushions the bony ends in the joints. The loss of cartilage leads to narrowing and loss of joint space and, eventually, damage to the bone. The surrounding muscles, ligaments and tendons that support and stabilize the joint also become weak and unable to work normally.

Systemic symptoms often include fatigue, general sense of malaise, low-grade fever, morning joint stiffness and difficulty moving a joint or several joints. Pain and signs of inflammation such as redness and warmth in or around a joint are often severe.

RA varies from person to person, but most cases are chronic, meaning they never go away. Some people have mild or moderate disease, with flares (periods of worsening symptoms) and remissions. For others, the disease is active most of the time. The resulting joint damage can be disabling.

The disease can affect more than just the joints, bones and surrounding muscle. About one-quarter of these with RA develop creaky nodules. These area unit bumps beneath the skin that always kind on the point of the joints. Many people with rheumatoid arthritis develop anemia. Other effects, which occur less often, include neck pain and dry eyes and mouth. Very rarely, RA results in inflammation of the blood vessels, the lining of the lungs, or the sac enclosing the heart. If you have RA, you may also be at increased risk for infections and gastrointestinal ailments.

Although no one knows the causes of rheumatoid arthritis, it seems to develop as a result of an interaction of several factors, including genetics, environment andhormones.

Diagnosing and treating rheumatoid arthritis can sometimes be difficult. It may require a team effort between you and several types of health care professionals, including arheumatologist, a physician who specializes in arthritis and other diseases of the joints, bones and muscles. Physical therapists, psychologists and social workers can also play a role.

RA can be devastating, but current treatment strategies can help you cope and possibly reduce the impact of the disease. These strategies can include pain relievers and other medications, rest, appropriate exercise, education and support programs. Involvement of the medicine health care skilled is crucial within the care of RA.

The psychological element is important: Some studies indicate that if you are well informed about your condition and participate in your own treatment plan, you will probably have less pain and create fewer visits to your health care skilled than otherwise. You can find treatment support groups in many cities.

Rheumatoid arthritis (RA) can be difficult to diagnose in its initial stages, but an early diagnosis can be crucial to limiting its progress and severity. Some studies indicate that rheumatoid arthritis causes the most joint damage in the first two years.

There is no single test to determine if you have RA. The symptoms often are similar to those of other types of arthritis and joint conditions. The types of symptoms you experience—and the severity—may differ markedly from those of another person with RA. To make matters more confusing, symptoms can vary in the same person: Symptoms develop over time, and only a few may be present in the early stages of RA.

Often, RA is diagnosed by recognizing the type and pattern of joint involvement; it is a hallmark of RA, for example, if the same areas are affected symmetrically on both sides of the body.

The typical symptoms of RA include:

  • tender, warm and swollen joints
  • symmetrical pattern
  • joint inflammation often affecting the wrists, fingers, knees, feet and ankles
  • fatigue
  • occasional fever
  • a general sense of malaise
  • pain and stiffness lasting for more than 30 minutes in the morning or after a long rest
  • rheumatoid nodules (bumps under the skin—often formed close to the joints—that affect about a quarter of those with RA)

Less common symptoms can include neck pain and dry eyes and mouth. Very rarely, RA may cause inflammation of the blood vessels, the lining of the lungs or the sac enclosing the heart.

If you have any of these symptoms, you should visit a health care professional. He or she will take several factors into consideration before rendering a diagnosis:

  • Medical history. Your description of the symptoms—including their duration and intensity—can help with the diagnosis.
  • Physical examination. Your health care professional will do a physical exam and pay particular attention to your joints, skin, reflexes and muscle strength.
  • Laboratory tests. Some laboratory tests will facilitate establish the presence of RA. Your health care skilled can most likely order a take a look at to notice autoantibody (an protein eventually gift within the blood of most of the people with unhealthy arthritis). It’s inconclusive, however, since not all people with RA test positive for rheumatoid factor, especially in the early stages. Some individuals with different sorts of rheumatic illness and alittle range of healthy people even have a positive autoantibody take a look at, so you could test positive and never develop the disease. A test called anti-cyclic citrullinated peptide, or anti-CCP, is now available and is more specific than rheumatoid factor tests. Specificity is even higher when both of the tests are positive. Other common tests include one that indicates the presence of inflammation in the body (the erythrocyte sedimentation rate, or ESR, and the C-reactive protein, or CRP), a test for antinuclear antibodies (antibodies that appear in about 30 percent to 40 percent of people with RA), a white blood cell count and a blood test for anemia.
  • X-rays. These can help determine the extent of joint destruction. If you identify RA in its early stages, X-rays may not be helpful in diagnosis. However, they can be used to monitor the disease’s progress. Other imaging techniques, such as MRI and particularly joint ultrasound, have been shown to be very useful in assessment of the extent of inflammation and joint damage in RA.

The main goals of rheumatoid arthritis (RA) treatment are to relieve symptoms of inflammation and to significantly slow the progression of joint damage. Although there’s no cure, you and your health care professional can develop strategies for keeping the disease under good control. You may need to try several approaches and different types of medication before you can satisfactorily relieve pain, reduce inflammation, slow joint damage and improve your ability to function.

In addition to the guidance of your primary health care professional, you may need care from a physical therapist, a rheumatologist (a physician who specializes in diagnosing and treating disorders that affect the joints, muscles, tendons, ligaments and bones) or an orthopedist.

When symptoms occur, you can take steps to lessen their severity. Protecting your joints from undue stress can help. Your health care professional can help you obtain a properly fitting splint. You may want to talk to him or her about self-help devices that can reduce stress on the joints while you participate in everyday activities. Zipper pullers, long-handled shoehorns and products that help you get on and off chairs, toilet seats and beds can all ease the strain on your joints.

Most likely, your treatment plan will include medications to relieve pain and/or reduce inflammation. Although there is no cure, disease-modifying antirheumatic drugs (DMARDs) may slow or stop the course of the disease. In the past, health care professionals often hesitated to prescribe these strong drugs until the disease had become relatively advanced. However, this approach has changed, especially for those who suffer from severe, rapidly progressing RA. Most rheumatologists believe that early treatment with additional powerful medication and therefore the use of drug combos is that the best thanks to halt RA’s progression and to scale back or stop joint harm. It is therefore important to establish care of RA with a rheumatologist as early as possible.

The following are commonly used rheumatoid arthritis medications:

  • Analgesics. Analgesics are drugs that provide pain relief, and they can be used either orally or topically in people with RA. Analgesics include topical capsaicin (Capsagel), oral acetaminophen (Tylenol), tramadol (Ultram) and the more potent narcotics oxycodone (OxyContin) and hydrocodone (Vicodin). Narcotics are usually discouraged in the treatment of rheumatoid arthritis, however, because of the long-term nature of the condition and the danger of dependence.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs such as aspirin, ibuprofen, ketoprofen and naproxen help diminish pain, swelling and inflammation. However, each NSAID is a different chemical and can have different effects in the body.NSAIDs may cause side effects including ringing in your ears, bruising, heart problems, gastric ulcers, stomach irritation, and liver and kidney damage. The longer you use NSAIDs, the more likely you are to have side effects, and the more serious those effects can be. Many other drugs cannot be taken with NSAIDs—in particular, the blood thinner warfarin (Coumadin). NSAIDS should be used with caution in people over 65 and in those with any history of ulcers or gastrointestinal bleeding, congestive heart failure, renal insufficiency and hypertension. Even the nonprescription, over-the-counter forms of these medications have the same risks. It’s important to raise your health care skilled for safety info related to pain relievers together with your personal health history in mind.A newer NSAID (called a COX-2 specific inhibitor) inhibits an enzyme (COX-2), which triggers pain and inflammation, while sparing an enzyme called COX-1, which helps maintain the normal stomach lining. The COX-2 inhibitor celecoxib (Celebrex) is sometimes prescribed for RA, osteoarthritis and other pain-causing conditions, such as acute pain and menstrual cramps. Celebrex is presently the sole anti-inflammatory drug on the market. Celebrex might increase the chance of heart failure and stroke; discuss these risks together with your health care skilled. And if you’re presently taking Cox-2 inhibitor ANd suppose you’re having an hypersensitivity or produce other severe or uncommon symptoms whereas taking any nonsteroidal anti-inflammatory, decision your health care professional immediately. For more information on the risks associated with Celebrex.
  • Disease-modifying antirheumatic drugs (DMARDs). These are slower-acting drugs, which work by altering the natural course of the disease and therefore slow or even prevent joint and cartilage destruction. They can produce significant results. You may need to wait weeks—even months—before seeing any effect, and you may use some or all of these, depending on the specifics of your condition. In some cases, one DMARD is used by itself. In other cases, more than one DMARD may be prescribed at the same time. You may have to try different medicines or combinations to find one that works best with the fewest side effects.Common DMARDs include: methotrexate (Rheumatrex, Trexall), sulfasalazine (Azulfidine), hydroxychloroquine (Plaquenil), leflunomide (Arava), cyclosporine (Sandimmune, Neoral), and azathioprine(Imuran, Azasan). People taking methotrexate and most other DMARDs need periodic monitoring to make sure that toxicity to the liver or bone marrow does not occur. Although there is clearly a potential for toxicity of a powerful drug like methotrexate, it actually has a remarkable safety profile in RA and can be taken continuously for many years. Side effects of DMARDS vary greatly but may include nausea or vomiting, diarrhea, heartburn, high blood pressure, sun sensitivity, rash, temporary hair loss, damage to the retina, liver or kidney damage, lung infections and bone marrow suppression.Pay attention to how your body responds to these drugs. Not only do you need to make sure the medications are effective (since efficacy can occasionally diminish over time), you also need to be alert to any problems arising from the drugs.
  • Corticosteroids. Also known as glucocorticoids, corticosteroids such as prednisone and methylprednisolone (Medrol) reduce inflammation and pain and may slow joint damage from RA. Because they can cause dramatic improvements in a very short time, health care professionals often use them while waiting for DMARDs to kick in, and then may gradually discontinue use. They may be an option if your RA doesn’t respond to NSAIDs and DMARDs. These medications also have serious side effects, especially at high doses, including increased bruising, thinning of bones, increased appetite, weight gain, worsening of diabetes and cataracts.RA can increase bone loss, leading to osteoporosis. This bone loss is more likely in people who use corticosteroids for longer periods of time. To keep your bones as strong as possible, use the lowest possible dose of corticosteroids for the shortest amount of time, consume at least 1,000 to 1,200 milligrams of calcium and 400 to 1,000 IUs of vitamin D a day and talk to your doctor about medications called bisphosphonates, such as alendronate sodium (Fosamax) and ibandronate sodium (Boniva), that can help reduce bone loss.
  • Biologic response modifiers. These are protein drugs that must be administered by subcutaneous injection or intravenous infusion. These drugs help to reduce joint-damaging inflammation by interfering with the inflammation process. The most commonly used short-acting drugs in this category are adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade). The longer-acting drugs in this category are certolizumab pegol (Cimzia) and golimumab (Simponi). They all target and inactivate a protein called tumor necrosis factor, or TNF-alpha, which is involved in the cascade of immune responses that cause inflammation in people with RA. Other biologic response modifiers target different molecules involved in the inflammation process. For instance, the drug anakinra (Kineret) blocks a cytokine called interleukin-1 (IL-1). Abatacept (Orencia) blocks the activation of T cells, and rituximab (Rituxan) blocks B lymphocytes. Tocilizumab (Actemra) is a biologic response modifier that inhibits interleukin-6. The biologic response modifiers are used as a second line drugs in individuals who do not respond to one or several TNF-alpha blocking agents.There have been very rare reports of serious nervous system disorders such as multiple sclerosis, seizures or inflammation of the nerves of the eyes, and serious infections, including sepsis and tuberculosis, with the TNF-inhibitors. The risk of tuberculosis has been greatly decreased with pre-therapy screening of TB skin tests and/or chest X-rays and treating with anti-TB drugs if these tests are positive.Additionally, there is some evidence that people treated with TNF inhibitors might have a somewhat higher risk of lymphomas. Although you need to be aware of these risks, it is equally important to recognize that the benefits can be substantial
  • Non-biological DMARD. Recently, the U.S. Food and Drug Administration approved a new non-biological DMARD for RA treatment named tofacitinib (Xeljanz). This medication is the first in the new category of RA drugs that work by inhibiting intracellular enzymes called kinases. Tofacitinib is a JAK (Janus kinase) 1 and 3 inhibitor. Kinases are involved in generation of inflammation in RA. Tofacitinib has been approved as a second-line drug for RA patients who have inadequate response or are intolerant to a first- line DMARD methotrexate. Similarly to biologic response modifiers, Tofacitinib may increase risk for infection and cause liver abnormalities. In addition, in clinical trials, it has been associated with lipid and various blood cell count abnormalities in a small percentage of people. Your health professional will be able to tell if and when this new drug would be appropriate for treatment of your RA.

If you are taking a biologic response modifier and have an infection severe enough to require antibiotics, the biologic should not be given until the infection is gone.

If you are using DMARDs or biologics, you should not receive live-virus vaccinations. Discuss how to handle live-virus vaccinations with your health care provider.

Surgery could also be associate degree possibility if you’ve got severe joint harm. In the right circumstance, it can help reduce pain, improve the affected joint’s function and appearance and enhance your ability to perform daily activities. However, surgery is not right for everyone, and you and your health care professional need to discuss the best approach. Factors to consider include your overall health, the condition of the joint or tendon that will be operated on and cost of the surgery.

A common type of surgery prescribed for people with RA is joint replacement, which replaces your damaged joint with an artificial one. One thing to consider is that the artificial joints can wear out, necessitating additional surgery.

Tendon repair, most frequently performed on the hands, is a surgery that repairs overly loose or tight tendons around a joint.

In synovectomy, the inflamed synovial tissue is removed. Synovectomy is performed if the lining around your joint (synovium) is inflamed and causing pain, joint damage and loss of function that do not respond to conventional treatments.

RA may also require joint fusion (arthrodesis) or the surgical fusion of a joint to stabilize or realign it for pain relief in cases where joint replacement isn’t possible.

ClinicalTrials.gov, a service of the National Institute of Health, provides easy access to information on clinical trials for a wide range of diseases and conditions, including rheumatoid arthritis. The website is located.

What You Can Do to Combat RA Symptoms

While health care professionals must be involved in your care, there are a number of lifestyle changes you can make to help manage RA. Experts suggest that eating a healthy diet can enhance your overall health and thus help you better manage your RA. Although drinking has no known impact on the disease itself, you may need to avoid alcoholic beverages, depending on the RA medications you are taking, especially the often-prescribed methotrexate. Check with your health care professional. Stress reduction is also important, since your stress level may affect the amount of pain you feel.

Rest and exercise—seemingly opposite ends of the spectrum—are important to your health. When your RA is active, you will want more rest. But moderate exercise is critical to healthy muscles, joint mobility and flexibility. (Note: Discuss any exercise program with your health care professional before starting.)

While exercise may seem unappealing if you’re experiencing frequent pain, there are a number of techniques to help you get through a program:

  • Moist heat equipped by heat towels, hot packs, a bath or a shower can be used at home for 15 to 20 minutes three times a day to relieve symptoms. Applying heat before exercise can be a good way to start. A health care professional can apply deep heat using short waves, microwaves and ultrasound to relieve pain.
  • Cold equipped by a bag of ice or frozen vegetables wrapped during a towel helps stop pain and cut back swelling once used for ten to fifteen minutes. This treatment often is recommended for acutely inflamed joints. Do not use cold treatments if you have numbness or poor circulation.
  • Hydrotherapy (water therapy) can decrease pain and stiffness. Exercising during a massive pool could also be easier as a result of water takes some weight off painful joints. Many community centers, YMCAs and YWCAs have water exercise classes developed for people with arthritis. You may also find relief from the heat and movement of a whirlpool.
  • When performed by a trained professional, massage and manipulation (using the hands to restore normal movement to stiff joints) can help control pain and increase joint motion and muscle and tendon flexibility.

Although these forms of physiatrics will briefly relieve symptoms, none have documented anti-inflammatory effects or affect the rate of joint damage that can occur in RA.

Alternative Therapies for RA Pain Relief

  • Relaxation techniques: Deep breathing, guided imagery and visualization (where you focus on “seeing” pleasant pain-free scenes or activities in your mind) and stress reduction help provide some pain relief. Physical therapists can teach relaxation techniques. The inflammatory disease Foundation includes a aid course that has relaxation therapy; establish a lot of regarding the inflammatory disease Foundation aid Program at
  • Acupuncture: Acupuncture is an important component of traditional Chinese medicine that involves the insertion of thin needles at specific points, which are mostly along the body’s nerve pathways, to improve health. A handful of small studies have been conducted on the use of acupuncture in RA, and the findings do not clearly answer the question of whether or not it works. Individuals who want to use acupuncture should discuss their interest with their health care team. Only a licensed acupuncturist should be used.
  • Thunder god vine: Studies indicate that preparations made from the peeled root of this plant, used in traditional Chinese medicine to treat inflammatory and autoimmune disorders, may be helpful in the treatment of RA. Possible side effects include menstrual changes, hair loss and diarrhea.
  • Nutritional supplements: A few studies have shown that the nutritional supplement gamma-linolenic acid (GLA) and the fish oils eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may help reduce some of the symptoms of RA.Discuss your interest or questions about such products and reports with your health care professional.
  • Biofeedback: Biofeedback is a way to enhance an awareness of your body so that you become focused on how your body functions; usually this enhanced focus is turned toward something—such as muscle control—that usually happens at a subconscious level. During biofeedback, an electronic device provides information about a body function (such as heart rate) so you can learn to control that function. Biofeedback may help people with arthritis learn to relax their muscles. In this case, an electronic device amplifies the sound of a muscle contracting, so you know that the muscle is not relaxed. The therapy is typically learned with the help of a health care professional and then may be practiced at home once you have mastered the technique, either with a biofeedback machine or without one.
  • Some additional techniques under investigation include tai chi (a movement- based form of meditation) and cognitive behavioral therapy (a method of anticipating and preparing yourself for situations and bodily sensations that will cause pain).

With all of these treatments—lifestyle, medical and surgical—monitoring which treatments work and which don’t and watching for side effects is critical. Monitoring can involve regular consultations with your health care professional as well as blood, urine and other laboratory tests and X-rays.

Prevention and Risk Reduction

Genetic, environmental and hormonal factors probably all play a role in the development of rheumatoid arthritis (RA). However, there is no known way to prevent RA. Cigarette smoking is one environmental risk factor for RA that you can avoid.

Certain genes involved in immune system responses are associated with a predisposition for developing RA, although there is no single “rheumatoid arthritis gene.” People with RA are more likely to have human leukocyte antigen (HLA) genes than people without the disease, and other genes also play roles in the development of RA. Having any of these genes is no guarantee that you’ll develop RA (in fact, many individuals with this common gene do not develop the disease); likewise, the absence of these genes doesn’t rule out the possibility of developing the disease. It appears that a person’s genetic make-up is an important part of the story, but not the whole answer.

Recent research shows that tobacco smoking can increase risk for RA. One study was conducted in Sweden and specifically looked at a population of more than 30,000 women. The study found significant association between development of RA and both smoking intensity and duration of smoking in women. The same study showed that such risk decreases over time, but it may take up to 15 years after smoking cessation to significantly reduce the risk. More and more studies seem to indicate that dental health is another important factor associated with RA. These are important advances in understanding the role of environmental factors in RA, because these factors can be avoided by not smoking and by flossing and brushing your teeth.

Facts to Know

  1. According to the Arthritis Foundation, rheumatoid arthritis affects approximately 1.3 million Americans, and two to three times more women have RA than men.
  2. RA is considered an autoimmune disease. Such diseases are characterized by the immune system attacking the body’s healthy tissues. Although RA affects other parts of the body, joint inflammation is the hallmark of this disease.
  3. Although no one knows the precise causes of rheumatoid arthritis, it seems to develop as a result of an interaction of several factors, including genetics, environmental factors and hormones. A virus or bacterium could serve as the environmental trigger in people genetically susceptible to the disease.
  4. Many researchers think a viral or bacterial infection may help trigger the development of RA. However, this remains unproven.
  5. Tobacco smoking may increase risk for developing RA.
  6. Rheumatoid arthritis appears to cause considerable joint damage in the first two years. An early diagnosis can be crucial in preventing the worst effects of the disease, especially since there are more effective treatment options today.
  7. Common RA symptoms can include fatigue, occasional fever, morning stiffness, difficulty moving a joint or several joints, pain and inflammation in or around a joint and a general sense of malaise.
  8. There is no single test you can take to find out if you have RA, although tests are used as part of the diagnosis.
  9. Arthritis literally means joint inflammation, but the term often is used to refer to more than 100 rheumatic diseases that can affect children and adults. Osteoarthritis is the most common form.

Key Q&A

  1. Why is rheumatoid arthritis (RA) sometimes called an autoimmune disease?Autoimmune diseases are characterized by an immune system attack on healthy tissues. In RA, white blood cells travel to the synovium (the membranes that surround joints) and cause inflammation, or synovitis. The ensuing warmth, redness, swelling and pain are typical symptoms of rheumatoid arthritis, which usually affects the wrists, fingers, knees, feet and ankles.
  2. What causes rheumatoid arthritis?A combination of factors—genetic, environmental and hormonal—probably plays a role in the onset of the disease. Those with a genetic susceptibility may develop RA when it is triggered by an environmental agent, perhaps a virus or bacterium, although no pathogenic agent has yet been identified. Hormones also appear to play a role. Tobacco smoking may increase risk for RA.
  3. Is RA preventable?No one has found a way to prevent RA.
  4. What can be done to reduce the pain or slow the disease?The symptoms of RA are highly treatable in most cases, and new research shows that the long-term outcome can be affected by how quickly the disease is diagnosed and treatment initiated. Consulting with your health care professional, you will find that there is a wide range of options—medical, surgical and lifestyle—available for modifying the disease and treating pain, swelling and other symptoms.
  5. How can I find out if I have RA?The symptoms you describe to a health care professional are the foundation of an RA diagnosis. The most common symptoms are tender, warm, swollen joints; symmetrical pattern of pain; joint inflammation; fatigue; occasional fever; a general sense of malaise; pain and stiffness lasting for more than 30 minutes in the morning or after a long rest; and rheumatoid nodules (bumps under the skin). Because many of these symptoms are also indicative of other diseases (for example, lupus), your health care professional may recommend lab tests for those diseases or for confirmation of an RA diagnosis, as well as X-rays and/or joint ultrasound to detect any joint damage. A full medical history and physical exam are also part of a typical diagnostic workup for RA.
  6. Is it safe to exercise if I have RA?Yes, moderate exercise is good for RA. However, you should consult with a health care professional before beginning any new exercise regimen and make sure that inflammation is reasonably well controlled. Moist heat applied before an exercise session and a cold pack applied afterward can help alleviate pain. Exercising in a swimming pool is also a good option for preventing joint stress during a workout.
  7. Can diet make a difference in preventing or managing RA?There is no scientific evidence that any specific food or nutrient helps or harms most people with rheumatoid arthritis. However, an overall nutritious diet with enough—but not an excess of—calories, protein and calcium is important. Some studies have shown that the omega-3 fatty acids in certain fish or plant seed oils also may reduce rheumatoid arthritis inflammation. However, many people are not able to tolerate the large amounts of oil necessary for any benefit, and both fish oils and plant oils have side effects, including risk of bleeding and interactions with certain medications, including blood pressure medications and psychiatric drugs. More research is necessary to find the optimal dosage of fish and plant seed oils for the management of RA.Some people may need to be careful about drinking alcoholic beverages because of the medications they take for rheumatoid arthritis. Those taking methotrexate may need to avoid alcohol altogether. You should ask your health care professional or a registered dietitian for guidance on the issue of diet.
  8. If I have the “RA gene,” does that mean I will develop the disease?There is no single RA gene. People with specific human leukocyte antigen (HLA) genes are more likely to develop RA than people without them, and other genes also play a role in the onset of disease. Having any of these genes is no guarantee that you’ll develop RA, and their absence doesn’t rule out the possibility of developing the disease. It appears that a person’s genetic makeup is an important part of the story but not the whole answer.


Tech Transfers

Salim Nasser never thought he’d reinvent the wheel. But he’s done it, in a sense, for wheelchairs.

Nasser, a NASA engineer, inventor and quadriplegic, has created a wheel that could dramatically reduce how much energy a wheelchair user expends moving his or her chair forward. Now Rowheels, the company he cofounded in 2012, hopes to bring the wheel to market later this year. If successful, it should mean more efficient mobility and healthier bodies for users, Nasser says.

Standard manual wheelchairs require users to grasp and push a rim that extends from the chair’s back wheels. It’s a decent enough method for self-propulsion, but it taxes small, weak muscles in the shoulders and arms and can lead to repetitive stress injuries.

Nasser’s wheel helps target bigger muscles. How it works: Using a mechanical device called a planetary gear, Nasser redesigned the wheel hub so that users pull it backwards in a rowing motion to go forward. Planetary gears are used in automatic transmissions and power tools to reverse and reduce motion, but no wheelchair wheels on the market currently use this design, Nasser says.

Jackie Justus, a spinal cord nursing educator at Zablocki Veterans Administration Medical Center in Milwaukee, says a rowing motion for wheelchair users would be a “big step forward and save them a lot of wear and tear.” She has been working independently for the past two years with an engineering team to redesign the wheelchair.

Pulling, she says, uses larger stronger muscle groups, while pushing a wheelchair uses little muscles in the front of the body and also hunches over the upper body. The rowing motion makes wheelchair users sit up straight, she says, allowing the diaphragm to function properly and significantly improve breathing.

Nasser is a native of Colombia who now lives near the Kennedy Space Center in Florida. His day job is designing and analyzing equipment for mobile launchers used to assist space shuttles. He led a relatively normal life until age 20 when a drunk ran a stop sign and smashed into Nasser’s car. “Three vertebrae were broken and I was paralyzed from the chest down,” Nasser says. “Initially, I couldn’t move anything.”

After the accident, he moved to Miami to recover. “Within a year, I regained a bit of shoulder and arm strength, but it was a slow process,” he says.

NASA scientist and Rowheels inventor Salim Nasser

Four years later, he’d gained enough confidence to apply at Florida International University in Miami. He was accepted and excelled, earning his undergraduate and master’s degrees in mechanical engineering over the next 5.5 years. During several summers, he was an intern at the Johnson Space Center in Houston.

An inventor at heart, Nasser began working on a new kind of wheelchair wheel in college. “It was an idea for a senior design project nearly seven years ago,” Nasser says. “I came up with the idea and worked on it with a group to refine it and build the prototype. Then it just sat there.”

In 2010, Nasser dusted off his plan and entered a NASA Tech Briefs “Create the Future” competition.

“I redesigned it to be more ergonomic and lighter,” Nasser says. “And much to my surprise, I won. I’d always wanted to make something out of it, but I wasn’t doing anything with the idea.”

Following his win, he began getting calls from companies that wanted to manufacture his wheel. But nothing clicked.

Then, while checking his spam folder in October of 2011, he noticed a message from Rimas Buinevicius, an entrepreneur in Madison, Wisconsin.

Buinevicius, who led a software company called Sonic Foundry for nearly two decades, had spent eight weeks in a manual wheelchair after breaking a leg. During that time, he said his shoulders and arms hurt from pushing his manual wheelchair wheels forward.

“When I read about what Salim had invented, I wanted to contact him because I knew–from my own experience–that there was a need for a better wheelchair wheel design,” says Buinevicius, who runs “Madcelreator,” a company that helps early stage firms bring their ideas to market.

“I was initially looking at trying to buy a set of these wheels as a consumer,” Buinevicius says. Then he realized he could do a lot more with Nasser’s idea.

“I figured it could help a lot of people–some 1.8 million folks use manual wheelchairs in the U.S.–so there’s a big market out there for these wheels,” Buinevicius says. “Over time, damage to shoulders means a lot of pain and ending up in a motorized chair, which most people want to avoid.”

Rowheels wheel

The wheel is expected to go into production later this year.

Though wheelchairs have evolved over the decades–and racing wheelchairs can look like a bit like sleek motorcycles–wheel technology hasn’t changed much since it was designed more than 100 years ago, he said.

After talking with Buenevicius, Nasser says he “got quite excited and redesigned the wheel completely to further reduce the likelihood of people suffering from repetitive stress syndrome while using the wheel.

“I figured out that if a typical user pushes 2,000 to 3,000 times a day, on average, my redesign came out to 330,050 less strokes a year,” Nasser says.

Buinevicius–who is now the chief executive officer at Rowheels–flew to Florida. The pair hit it off and cofounded Rowheels in 2012. Next, as Nasser continued to improve the wheel design, they entered and won the Grand Prize in the Wisconsin Governor’s Business Plan Contest in June of 2012.

Recently, Rowheels showed off the beta design of the wheel at MedTrade, a big medical conference in Atlanta; and the International Seating Symposium in Nashville. Nasser is also working with Georgia Tech’s RERC/Wheeled Mobility lab and the Shepherd Center, a hospital in Atlanta that specializes in treatment, research and rehabilitation of people with spinal cord and brain injuries, to improve the wheels. Though the cost hasn’t been determined yet, Buinevicius estimated that a set of wheels will cost between $2,000 and $3,000.

“We vetted the product last month with over 100 researchers, therapists and end users in Nashville,” Buinevicius says. “There, the attendees were able to try the product firsthand and we received very favorable responses. We are still doing our own internal testing and using select groups of users. Independent tests will start soon.” If all goes well, Buinevicius says they hope Rowheels will be on the market by later this year, “using a combination of third party manufacturers, suppliers and our own people to manufacture and distribute the product.”