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Sex seems to be a contributing factor in the pathogenesis of bronchial asthma. This study aimed to find sex-related differences in metabolome measured by hydrogen-1 nuclear magnetic resonance (1H NMR) spectroscopy in healthy and ovalbumin (OVA)-sensitized guinea pigs. Adult male and female animals were divided into controls and OVA-sensitized groups. OVA-sensitization was performed by OVA systemic and inhalational administration within 14 days; on day 15, animals were killed by anesthetic overdose followed by exsanguination. Blood was taken and differential white blood cell count was measured. Left lung was saline-lavaged and differential cell count in the bronchoalveolar lavage fluid (BALF) was measured. After blood centrifugation, plasma was processed for 1H NMR analysis. Metabolomic data was evaluated by principal component analysis (PCA). Eosinophil counts elevated in the BALF confirming eosinophil-mediated inflammation in OVA-sensitized animals of both sexes. Sex differences for lactate, glucose, and citrate were found in controls, where these parameters were lower in males than in females. In OVA-sensitized males higher glucose and lower pyruvate were found compared to controls. OVA-sensitized females showed lower lactate, glucose, alanine, 3-hydroxybutyrate, creatine, pyruvate, and succinate concentrations compared to controls. In OVA-sensitized animals, lactate concentration was lower in males. Data from females (healthy and OVA-sensitized) were generally more heterogeneous. Significant sex differences in plasma concentrations of metabolites were found in both healthy and OVA-sensitized animals suggesting that sex may influence the metabolism and may thereby contribute to different clinical picture of asthma in males and females. [ABSTRACT FROM AUTHOR]

Nicolelis wrote in his 2003 review on brain-machine interfaces (BMIs) that the design of a successful BMI relies on general physiological principles describing how neuronal signals are encoded. Our study explored whether neural information exchanged between brains of different species is possible, similar to the information exchange between computers. We show for the first time that single words processed by the guinea pig auditory system are intelligible to humans who receive the processed information via a cochlear implant. We recorded the neural response patterns to single-spoken words with multi-channel electrodes from the guinea inferior colliculus. The recordings served as a blueprint for trains of biphasic, charge-balanced electrical pulses, which a cochlear implant delivered to the cochlear implant user's ear. Study participants completed a four-word forced-choice test and identified the correct word in 34.8% of trials. The participants' recognition, defined by the ability to choose the same word twice, whether right or wrong, was 53.6%. For all sessions, the participants received no training and no feedback. The results show that lexical information can be transmitted from an animal to a human auditory system. In the discussion, we will contemplate how learning from the animals might help developing novel coding strategies. [ABSTRACT FROM AUTHOR]

The metabolism of DNA methylation is reported to be sensitive to oxidant molecules or oxidative stress. Hypothesis: early-life oxidative stress characterized by the redox potential of glutathione influences the DNA methylation level. The in vivo study aimed at the impact of modulating redox potential of glutathione on DNA methylation. Newborn guinea pigs received different nutritive modalities for 4 days: oral nutrition, parenteral nutrition including lipid emulsion Intralipid (PN-IL) or SMOFLipid (PN-SF), protected or not from ambient light. Livers were collected for biochemical determinations. Redox potential (p < 0.001) and DNA methylation (p < 0.01) were higher in PN-infused animals and even higher in PN-SF. Their positive correlation was significant (r2 = 0.51; p < 0.001). Methylation activity was higher in PN groups (p < 0.01). Protein levels of DNA methyltransferase (DNMT)-1 were lower in PN groups (p < 0.01) while those of both DNMT3a isoforms were increased (p < 0.01) and significantly correlated with redox potential (r2 > 0.42; p < 0.001). The ratio of SAM (substrate) to SAH (inhibitor) was positively correlated with the redox potential (r2 = 0.36; p < 0.001). In conclusion, early in life, the redox potential value strongly influences the DNA methylation metabolism, resulting in an increase of DNA methylation as a function of increased oxidative stress. These results support the notion that early-life oxidative stress can reprogram the metabolism epigenetically. This study emphasizes once again the importance of improving the quality of parenteral nutrition solutions administered early in life, especially to newborn infants. Abbreviation of Title: Parenteral nutrition and DNA methylation [ABSTRACT FROM AUTHOR]

A tourist was infected with a new strain of leptospires namely, Leptospira icterohemorrhagiae serovar Lai strain Langkawi, when he was on vacation in Langkawi, Malaysia. The leptospiral strain was successfully isolated from the patient in the Netherland. In this study, the bacteria were retrieved from Holland and inoculated into fifteen guinea pigs in Universiti Putra Malaysia (UPM) to determine its pathogenicity. The main clinical symptoms in the guinea pigs were decreased appetite and jaundice. Blood profile showed high neutrophil, lymphocyte, PCV, RBC, haemoglobin, leukocyte and thrombocyte counts. Besides that, enhancement of electrolytes such as sodium (Na), chloride (Cl), and potassium (K) was also noted. Biochemical examination showed an increase alkaline phosphatase (ALP), aspartate transaminase (AST) and bilirubin levels. Albumin, alanine transaminase (ALT), blood urea, total protein and creatinine were low values. Histopathological examination under haematoxylin and eosin staining showed evidence of haemorrhages, congestion and oedema in all organs, with inflammatory cell infiltration characterized by neutrophils, lymphocytes and macrophages. Hydropic degeneration and cell necrosis were also common in the findings. Leptospires were detected from Day 2 p.i by silver staining and transmission electron microscopy (TEM). Rise in antibody titre was seen as early as Day 5 p.i and leptospiral DNA was detected by PCR in the kidneys and liver on Day 3 and Day 5, respectively. The findings were indicative of leptospirosis. This study demonstrated that guinea pigs are a suitable animal model to illustrate the clinical symptoms and pathological changes seen following infection with Leptospira icterohaemorrhagiae serovar Lai strain Langkawi. In general, the symptoms and changes seen in leptospirosis are similar to viral infections and the information and data from this present study would help differentiate infection due to leptospires from that of viral infection. Leptospiral infection has often been misdiagnosed to be viral infection such as influenza and dengue which have similar signs and symptoms as leptospirosis. [ABSTRACT FROM AUTHOR]

Abstract Capsaicin has anti-inflammatory and antioxidant effects, as well as some benefits on the cardiovascular system. The exact effects of capsaicin on atherosclerosis are poorly understood. To investigate the effects of capsaicin on hyperlipidemia and atherosclerosis in guinea pigs fed on a high-fat diet, as well as its potential mechanisms. Guinea pigs (n = 48) were randomly divided into six groups (n = 8/group): normal diet (control); high fat diet (model); model + low-dose capsaicin (2.5 mg/kg); model + moderate-dose capsaicin (5 mg/kg); model + high-dose capsaicin (10 mg/kg), and model + simvastatin (1.5 mg/kg) (positive control). After 14 weeks, serum lipids, apolipoprotein B100, malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), and endothelin-1 were measured. Aortic atherosclerotic lesions were histologically examined. eNOS and iNOS were assessed by immunohistochemistry. The model group developed severe dyslipidemia and associated histologic changes and endothelial dysfunction. All doses of capsaicin decreased total cholesterol, triglycerides, low-density lipoprotein cholesterol, and apolipoprotein B-100, and increased high-density lipoprotein cholesterol (all P < 0.05). Capsaicin alleviated the plaque area (−17.9–70.5%), plaque area to intima ratio (−18.0–73.6%), and intima thickness (−20.5–83.6%) (all P < 0.05). Capsaicin decreased MDA (−45.5–76.1%), ET-1 (−19.6–51.6%), and average gray value (AGV) of eNOS (−10.9–48.8%), and increased SOD activity (+31.7–76.1%), NO (+11.2–36.8%), and AGV of iNOS (+6.8-+93.0%) (all P < 0.05). Similar changes were observed with simvastatin. Capsaicin is beneficial to hyperlipidemia and atherosclerosis in guinea pigs fed on a high-fat diet. Reduced oxidative stress and endothelial dysfunction were involved in these benefits. This could represent a novel approach to prevent cardiovascular diseases. Highlights • Capsaicin decreased cholesterol, TG, LDL-C, and apoB-100, and increased HDL-C. • Capsaicin alleviated plaque area, plaque area to intima ratio, and intima thickness. • Capsaicin decreased MDA, ET-1, and eNOS. • Capsaicin increased SOD activity, NO, and iNOS. • Similar changes were observed with simvastatin. [ABSTRACT FROM AUTHOR]

Abstract Introduction Haemophilus parasuis , one of the major swine pathogens, has at least fifteen different types, all of which have significant economic effects on the global swine industry. The aim of this study was to establish an experimental intraperitoneal infection model for H. parasuis in neutropenic guinea pigs. Methods Intraperitoneal administration of cyclophosphamide and Haemophilus parasuis was conducted in guinea pigs. Clinical signs, gross pathology, and histopathology were observed in neutropenic guinea pigs infected with H. parasuis. Results Intraperitoneal administration of 100 mg/kg cyclophosphamide led to immunosuppression with white blood cells, lymphocytes, and neutrophils all <1000 mm3, while no histological tissue damage was observed. Intraperitoneal administration of 109 colony-forming units (CFU) of H. parasuis led to typical respiratory symptoms, 90% morbidity, and 20% mortality in a 72 h-period. Bacteriological screening revealed that multiple organs, including the heart, liver, spleen, lungs, kidneys, and blood, were infected with H. parasuis. The threshold loads of bacteria in blood and the lungs were (7.04 ± 0.53)log 10 CFU/mL and (6.24 ± 0.62)log 10 CFU/g, respectively, at 3 d after infection. Gross pathology examination showed celiac effusion, intestinal mucosal hemorrhage, and liver, spleen, or lung swelling, necrosis, and hemorrhage. Congestion, mild interstitial pneumonia, inflammatory exudation, and endothelial cell proliferation were observed in the histological examination. Discussion All the results suggest that we have established an experimental intraperitoneal infection model for H. parasuis in neutropenic guinea pigs. It is especially useful as a tool for pharmacokinetics, pharmacodynamics, or a pharmacokinetics/pharmacodynamics (PK/PD) model of antimicrobial agents against respiratory disease. [ABSTRACT FROM AUTHOR]

Cigarette smoking causes microvascular dysfunction and skin aging. Relaxin, primarily but not exclusively involved in reproduction, has connective tissue among its targets. Within a project on the interference of relaxin with the effects of smoke on guinea pigs, we examined the skin response to those stimuli. Adult guinea pigs were exposed to cigarette smoke daily for 8 weeks, and some of them were treated also with relaxin, 1 or 10 μg/die. Controls were treated with relaxin vehicle alone. The skin was analyzed by light and electron microscopy and histochemistry for mast cells and the collagen specific chaperonin Hsp47. The epidermis appeared unaffected by any treatment. In the superficial dermis, smoke led to a decrease in mast cell number and intensity of astra blue staining, suggestive of granule discharge. Relaxin caused further significant reduction in mast cell number. In the superficial and deep dermis, the staining intensity of Hsp47 positive cells, assumed as active fibroblasts, increased upon smoke. The staining intensity decreased gradually in the superficial dermis upon relaxin, reaching significance after treatment with 10 μg/die relaxin, while in the deep dermis it decreased significantly upon treatment with 1 μg/die relaxin and underwent further, significant increase with 10 μg/die relaxin. The results suggest that relaxin can enhance skin mast cell secretory response, possibly antagonizing nicotine induced vasoconstriction and, depending on dose and localization of responding cells, can counteract the profibrotic stimulus of smoke on dermal fibroblasts. [ABSTRACT FROM AUTHOR]

Abstract The efficacy and pharmacokinetics of the aqueous co-formulation contents of the Trobigard™ (atropine sulfate, obidoxime chloride) auto-injector were evaluated in a sarin exposed guinea pig model. Two subcutaneous (sc) sarin challenge doses were evaluated in guinea pigs instrumented with brain and heart electrodes for electroencephalogram (EEG) and electrocardiogram (ECG). Sarin challenge doses were chosen to reflect exposure subclasses with sublethal (moderate to severe clinical signs) and lethal consequences. The level of protection of intramuscular human equivalent doses of the co-formulation was defined by (1) the mitigation of signs and symptoms at a sublethal level and (2) the increase of survival time at the supralethal sarin dose levels. Pharmacokinetics of both atropine sulfate and obidoxime were proportional at 1 and 3 human equivalent doses, and only a small increase in heart rate was observed briefly as a side effect. At both sarin challenge doses, 54 μg/kg and 84 μg/kg, the co-formulation treatment was effective against sarin-induced effects. Survival rates were improved at both sarin challenge levels, whereas clinical signs and changes in EEG activity could not in all cases be effectively mitigated, in particular at the supralethal sarin challenge dose level. Reactivation of sarin inhibited cholinesterase was observed in blood, and higher brain cholinesterase activity levels were associated with a better clinical condition of the co-formulation treated animals. Although the results cannot be directly extrapolated to the human situation, pharmacokinetics and the effects over time related to plasma levels of therapeutics in a freely moving guinea pig could aid translational models and possibly improve prediction of efficacy in humans. Highlights • Atropine/obidoxime pharmacokinetics were dose proportional and not affected by Sarin challenge. • Survival rates were improved by atropine/obidoxime at two sarin challenge levels. • Reactivation of sarin inhibited cholinesterase was observed in blood. • Effective mitigation of CNS effects was only apparent at the lower sarin challenge. • The primary benefit is a gain in time to allow for supportive treatment. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Dipyrithione demonstrated potent antifungal efficacy in vitro. • Dipyrithione caused morphological changes in T. rubrum. • Dipyrithione showed great anti-dermatophyte activity effects in vivo. Abstract The treatment of dermatophytosis has improved considerably over the past several decades following the introduction of the oral antifungals such as azoles and amphotericin B. However, these drugs have had limited success because the treated fungi often develop drug resistance, resulting in recurrence when applied in various topical formulations. Thus, there are constant needs for new topical agents that are effective against dermatophytosis. Dipyrithione is an attractive candidate to become an antifungal agent due to its broad spectrum of antimicrobial activities. In this study, we determined that dipyrithione could potently inhibit the growth of Trichophyton rubrum , which is the most common cause of dermatophytosis. The MIC 50 value of dipyrithione against T. rubrum was measured as 6.03 μM, as compared with miconazole (MIC 50 : 1.38 μM). Additionally, the compound caused morphological changes in the fungi, which was examined using the morphological interference assay. The in vivo experiment further revealed that dipyrithione had a healing effect on the skin of guinea pigs infected with T. rubrum. Our studies have demonstrated that dipyrithione had a potent antifungal activity in vitro and in vivo , suggesting that it could be formulated as a potential antifungal lead compound in search for novel therapeutic agents against dermatophytosis. [ABSTRACT FROM AUTHOR]

Highlights • Sphingosine-1-phosphate (S1P) is an inflammatory mediator increased in the tissue in a variety of inflammatory conditions. • Literature data indicate that the vagal afferent neurons express several S1P receptors including S1PR 1-5. • We evaluated the effect of inhaled S1P on the cough reflex as an indicator of airway inflammation. • Data have shown that neither inhaled S1P alone nor in combination with TRPA1 or TRPV1 agonists did not enhance coughing. • S1P was ineffective to induce/sensitize cough in naïve guinea pigs, but its role can be important in pathological conditions. Abstract Sphingosine-1-phosphate (S1P) is an inflammatory mediator increased in the tissue in the number of inflammatory conditions. Preliminary data indicate that the vagal afferent neurons express several S1P receptors including S1PR 2-3. We therefore evaluated the hypothesis that S1P induces cough and/or enhances the cough evoked by other tussive stimuli (TRPA1 and TRPV1 activators) in naïve guinea pigs. Inhalation of S1P in the concentrations of 0.1 mM and 1 mM did not evoke cough. Preinhalation and continuing inhalation of S1P (1 mM) during citric acid (0.2 M) challenge did not enhance citric acid-induced cough. Preinhalation of S1P and continuing inhalation during AITC (3 mM) challenge also did not enhance AITC-induced cough. We conclude that S1P was not efficient to evoke cough in awake naïve guinea pigs. S1P was also not effective to sensitize the cough evoked by stimulation of TRPV1 and TRPA1 receptors. Nonetheless it cannot be excluded that S1P influences cough in the context of inflamed airways when the cough-mediating nerves undergo sensory neuroplasticity. [ABSTRACT FROM AUTHOR]

Background: Postoperative ileus (POI) is abdominal surgery‐induced impaired gastrointestinal (GI) motility. We aimed to investigate the effects of DA‐9701, a prokinetic agent formulated from Pharbitis Semen and Corydalis tuber, likely mediated via corticotrophin‐releasing factor (CRF) pathways, in a POI model. Methods: A laparotomy with cecal manipulation was performed to induce POI in guinea pigs. GI transit was measured based on charcoal migration after intragastric administration of DA‐9701 1, 3, and 10 mg kg−1. CRF1 receptor antagonist, CP‐154 526 (subcutaneous) or agonist, human/rat (h/r) CRF (intraperitoneal) was injected. Then, plasma adrenocorticotropic hormone (ACTH) levels were measured, and the average intensity of the CRF expression was analyzed in the proximal colon and hypothalamus, and c‐Fos in the hypothalamus. Key Results: DA‐9701 significantly increased delayed GI transit in POI in a dose‐dependent manner and decreased plasma ACTH levels at 10 mg kg−1. CP‐154 526 significantly decreased plasma ACTH levels but was not as effective on GI transit as DA‐9701 was. h/r CRF did not significantly affect GI transit and plasma ACTH levels. No significant difference was observed in GI transit and plasma ACTH levels in both groups administered DA‐9701 with h/r CRF and h/r CRF alone. CRF expression in the proximal colon decreased after DA‐9701 administration, but not significantly, compared with levels in POI alone. However, CRF expression in the hypothalamus was significantly lower in the DA‐9701‐pretreated POI than in the untreated POI. Conclusions and Inferences: The DA‐9701‐induced improvement in GI transit and inhibition of plasma ACTH levels was mediated by the central CRF pathway. [ABSTRACT FROM AUTHOR]

Background: Many antimalarial agents and calcium channel blockers have been demonstrated to alter male reproductive activity. Increasing prevalence of hypertension, therefore, increases concern of male infertility, and concurrent administration of antihypertensive and antimalarial agents in malaria-prone areas. Objective: The study evaluates the reproductive effect of co-administration of artesunate (Ats)-amodiaquine (Amod) and nifedipine (Nif) in male guinea pigs. Materials and Methods: In this experimental study, 24 adult male pigs were divided into four groups (n=6/each) as one control (given distilled water) and 3 intervention groups (given standard daily dose equivalents of Ats-Amod, Nif or combination of both drugs) for 14 days. Serum levels of testosterone, folliclestimulating hormone and luteinizing hormone were measured using enzyme-linked immunosorbent assay. Testicular weight was measured and the relative weight (organ-to-body weight ratio) was obtained. Sperm count, motility, and morphology were equally analyzed. Results: Nif treatment produced no significant effect on the hormone levels (p=0.058) and sperm parameters (p=0.0568) that were measured, whereas Ats-Amod and Ats-Amod+Nif decreased testosterone level (p=0.0482), sperm count and motility (p<0.0001), but failed to cause an alteration in follicle-stimulating hormone, luteinizing hormone and sperm morphology. Percentage of motility reduction by Ats-Amod+Nif was greater (p=0.025) compared to Ats-Amod effect. Relative testicular weight was decreased (p=0.046) by Ats-Amod and Ats-Amod+Nif, but unaffected by Nif. Conclusion: The result suggests that short-term administration of standard daily dose equivalent of Nif does not alter hormone levels and sperm indices, while Ats- Amod alone or in combination with Nif decreases testosterone, sperm count, and motility. The combination also results in synergistic inhibition of sperm motility. [ABSTRACT FROM AUTHOR]

New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as yrazinoic acid/ester ry owder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends. [ABSTRACT FROM AUTHOR]

Impaired wound healing may cause economic and social problems and seriously reduce the quality of life. The uses of herbal medicines as new alternative treatments are under investigation. This study investigated the effect of Glycyrrhiza glabra L. extract on the full-thickness wound healing in Guinea Pig model. Eight male Guinea Pigs (700-800 g) were used to be creared a square full-thickness wound with 1.5 x1.5 dimensions on the lumbodorsal area. The wounds were randomly divided into four groups: I; control, II; 1% phenytoin, III; 5% G. glabra and IV; 10 % G.glabra. On day 3, 5, 7, 9 and 12, wound size was measured for assessment of the percent of wound healing. In order to determine the wound healing activity, excisional biopsies were evaluated histopathologically on the 12th days of treatments. Acute inflammation, granulation tissue fibroblast maturation, collagen deposition, epidermal layer formation, neovascularization, keratin layer formation were evaluated according to the Abramov score method. Hydroalcoholic extract of G.glabra exhibited total phenolic and flavonoid contents of 114.1 ± 5.45 and 82.85 ± 6.38 mg, respectively. G.glabra creams (5% and 10% w/w)were significantly increased the epidermal formation, collagen deposition and neovascularization, and was decreased acute inflammation in comparison to the control group. Wound healing rate were increased in the G. glabra groups. G.glabra creams 10 % was more effective than 5% w/w. Our findings proved that 5% and 10% w/w G. glabra creams were effective in acute dermal wound healing. More studies with different doses of G. glabra extract are recommended. [ABSTRACT FROM AUTHOR]

Irreversible hearing loss induced by aminoglycoside in human through local or systemic administration route negatively impacts quality of life. The aim of this work was to develop and validate an analytical method suitable for the detection and quantification of neomycin in cochlear perilymph of guinea pig after local application. The SupelMIP SPE column was used for the pre-treatment of matrix. Chromatographic separation was conducted by a reversed phase ODS column (100 × 2.1 mm, 3 μm) at 40 °C in gradient mode with 0.2‰ (v/v) HFBA in water and 0.2‰ (v/v) HFBA in acetonitrile as mobile phase, at a flow rate of 0.30 mL/min, with retention time of 3.50 and 3.62 min for internal standard tobramycin and analyte neomycin, respectively. The MS was performed with positive ionization mode, with data acquisition in Multi Reaction Monitor (MRM) mode. This method was proved to be specific, accurate (97.1–115% of nominal values) and precise (CV% < 15%). Calibration curves for matrix matched standard of neomycin ranged from 1.25 to 200 μg/mL, with LOD and LLOQ of 0.625 and 1.25 μg/mL in blank matrix. The matrix effect was corrected to (−0.1) - 1.33 by adding internal standard. The relative SPE recovery values were ≥98.9% in low, medium and high QC samples. Neomycin in matrix proved to be stable under room temperature - and −20 °C, or under three freeze-thawing cycles, or under processing as well. Finally, the proposed method was successfully applied to a toxicokinetics study of neomycin in perilymph after round window membrane (RWM) administration, which was in accordance with threshold shift of auditory brainstem response (ABR) test related to hearing loss. [ABSTRACT FROM AUTHOR]

Post-exposure nerve agent treatment usually includes administration of an oxime, which acts to restore function of the enzyme acetylcholinesterase (AChE). For immediate treatment of military personnel, this is usually administered with an autoinjector device, or devices containing the oxime such as pralidoxime, atropine and diazepam. In addition to the autoinjector, it is likely that personnel exposed to nerve agents, particularly by the percutaneous route, will require further treatment at medical facilities. As such, there is a need to understand the relationship between dose rate, plasma concentration, reactivation of AChE activity and efficacy, to provide supporting evidence for oxime infusions in nerve agent poisoning. Here, it has been demonstrated that intravenous infusion of HI-6, in combination with atropine, is efficacious against a percutaneous VX challenge in the conscious male Dunkin-Hartley guinea-pig. Inclusion of HI-6, in addition to atropine in the treatment, improved survival when compared to atropine alone. Additionally, erythrocyte AChE activity following poisoning was found to be dose dependent, with an increased dose rate of HI-6 (0.48 mg/kg/min) resulting in increased AChE activity. As far as we are aware, this is the first study to correlate the pharmacokinetic profile of HI-6 with both its pharmacodynamic action of reactivating nerve agent inhibited AChE and with its efficacy against a persistent nerve agent exposure challenge in the same conscious animal. [ABSTRACT FROM AUTHOR]

The prolonged systemic exposure that follows skin contamination with low volatility nerve agents, such as VX, requires treatment to be given over a long time due to the relatively short half-lives of the therapeutic compounds used. Bioscavengers, such as butyrylcholinesterase (BChE), have been shown to provide effective post-exposure protection against percutaneous nerve agent when given immediately on signs of poisoning and to reduce reliance on additional treatments. In order to assess the benefits of administration of bioscavenger at later times, its effectiveness was assessed when administration was delayed for 2 h after the appearance of signs of poisoning in guinea-pigs challenged with VX (4 × LD 50 ). VX-challenged animals received atropine, HI-6 and avizafone on signs of poisoning and 2 h later the same combination with or without bioscavenger. Five out of 6 animals which received BChE 2 h after the appearance of signs of poisoning survived to the end of the study at 48 h, compared with 6 out of 6 which received BChE immediately on signs. All the animals (n = 6 + 6) that received only MedCM, without the addition of BChE, died within 10 h of poisoning. The toxicokinetics of a sub-lethal challenge of percutaneous VX were determined in untreated animals. Blood VX concentration peaked at approximately 4 h after percutaneous dosing with 0.4 × LD 50 ; VX was still detectable at 36 h and had declined to levels below the lower limit of quantification (10 pg/mL) by 48 h in 7 of 8 animals, with the remaining animal having a concentration of 12 pg/mL. These studies confirm the persistent systemic exposure to nerve agent following percutaneous poisoning and demonstrate that bioscavenger can be an effective component of treatment even if its administration is delayed. [ABSTRACT FROM AUTHOR]

We report a type of dissolving microneedles (DMNs) which was made of composite matrix materials of hydroxypropyl methyl cellulose (HPMC) and poly(methylvinylether‑ co ‑maleic anhydride) (PMVE/MA copolymer, Gantrez S-97), and was successfully loaded with lidocaine hydrochloride. The weight of lidocaine hydrochloride loaded in the microneedles tip was 70% of the weight of the whole tip. The content was 3.43 ± 0.12 mg in weight, which was determined by high performance liquid chromatography (HPLC). The results for mechanical test showed that these microneedles were able to penetrate into the skin of the experimental animals, that was proved using organic staining, texture analyzer and histological examination. The fracture force of the microneedles was 5.442 ± 0.412 N, which was much higher than the one required for the skin penetration. The DMNs with lidocaine hydrochloride could be dissolved inside of the rat skin in 5 min. The onset time would be faster (in <5 min) when it was applied to the guinea pig model, in comparing with a commercially available anesthesia cream that had an onset time for 100 min. However, the efficacy of the DMNs for the local anesthesia only lasted for 16 min. It was shorter than that of the commercially available anesthesia cream with which the efficacy could last for about 130 min. After the DMNs was packaged under the vacuum and dark condition, it was stable for 3 months under the condition of a temperature of 40 ± 2 °C and a humidity of 75 ± 5%. The result of the experiment for the safety evaluation showed that the microneedles were non-irritating and non-allergenic to the skin. In conclusion, the DMNs with lidocaine hydrochloride could be safely administered to the skin with a quick onset time for the local anesthesia. [ABSTRACT FROM AUTHOR]

Genome reassortment in Lassa virus (LASV) has been reported in nature, but phenotypic consequences of this phenomenon are not well described. Here we characterize, both in vitro and in vivo, reassortment between 2 LASV strains: the prototypic 1976 Josiah strain and a more recently isolated 2015 Liberian strain. In vitro analysis showed that although cis- and trans-acting elements of viral RNA synthesis were compatible between strains, reassortants demonstrated different levels of viral replication. These differences were also apparent in vivo, as reassortants varied in pathogenicity in the guinea pig model of LASV infection. The reassortant variant containing the Josiah S segment retained the virulence of the parental Josiah strain, but the reassortant variant containing the S segment of the Liberian isolate was highly attenuated compared to both parental strains. Contrary to observations in reassortants between LASV and other arenavirus species, which suggest that L segment-encoded factors are responsible for virulence, these studies highlight a role for S segment-encoded virulence factors in disease, and also suggest that inefficient interactions between proteins of heterologous strains may limit the prevalence of reassortant LASV variants in nature. [ABSTRACT FROM AUTHOR]

Myopia is generally regarded as a failure of normal emmetropization process, however, its underlying molecular mechanisms are unclear. To investigate the retinal protein profile changes during emmetropization, we studied differential protein expressions of ocular growth in young guinea pigs at 3 and 21 days old respectively, when significant axial elongation was detected (P < 0.001, n = 10). Independent pooled retinal samples of both eyes were subjected to SWATH mass spectrometry (MS) followed by bioinformatics analysis using cloud-based platforms. A comprehensive retina SWATH ion-library consisting of 3138 (22,871) unique proteins (peptides) at 1% FDR was constructed. 40 proteins were found to be significantly up-regulated and 8 proteins down-regulated during emmetropization (≥log2 of 0.43 with ≥2 peptides matched per protein; P < 0.05). Using pathway analysis, the most significant pathway identifiable was ‘phototransduction’ (P = 1.412e−4). Expression patterns of 7 proteins identified in this pathway were further validated and confirmed (P < 0.05) with high-resolution Multiple Reaction Monitoring (MRM-HR) MS. Combining discovery and targeted proteomics approaches, this study for the first time comprehensively profiled protein changes in the guinea pig retina during normal emmetropization-associated eye growth. The findings of this study are also relevant to the myopia development, which is the result of failed emmetropization. Significance Myopia is considered as a failure of emmetropization. However, the underlying biochemical mechanism of emmetropization, a visually guided process in which eye grows towards the optimal optical state of clear vision during early development, is not well understood. Retina is known as the key tissue to regulate this active eye growth. we studied eye growth of young guinea pigs and harvested their retinal tissues. A comprehensive SWATH ion library with identification of a total 3138 unique proteins were established, in which 48 proteins exhibited significant differential expressions between 3 and 21 days old. After MRM-HR confirmation, ‘phototransduction’ were found as the most active pathway during emmetropic eye growth. This study is the first in discovering key retinal protein players and pathways which are presumably orchestrated by biological mechanism(s) underlying emmetropization. [ABSTRACT FROM AUTHOR]

The pancreatic duct epithelium secretes the HCO3−-rich pancreatic juice. The HCO3− transport across the luminal membrane has been proposed to be mediated by SLC26A Cl−-HCO3− exchangers. To examine the electrophysiological properties of Cl−-HCO3− exchangers, we directly measured HCO3− conductance in the luminal membrane of the interlobular pancreatic duct cells from guinea pigs using an inside-out patch-clamp technique. Intracellular HCO3− increased the HCO3− conductance with a half-maximal effective concentration value of approximately 30 mM. The selectivity sequence based on permeability ratios was SCN− (1.4) > Cl− (1.2) = gluconate (1.1) = I− (1.1) = HCO3− (1.0) > methanesulfonate (0.6). The sequence of the relative conductance was HCO3− (1.0) > SCN− (0.7) = I− (0.7) > Cl− (0.5) = gluconate (0.4) > methanesulfonate (0.2). The current dependent on intracellular HCO3− was reduced by replacement of extracellular Cl− with gluconate or by H2DIDS, an inhibitor of Cl−-HCO3− exchangers. RT-PCR analysis revealed that the interlobular and main ducts expressed all SLC26A family members except Slc26a5 and Slc26a8. SLC26A1, SLC26A4, SLC26A6, and SLC26A10 were found to be localized to the luminal membrane of the guinea pig pancreatic duct by immunohistochemistry. These results demonstrate that these SLC26A Cl−-HCO3− exchangers may mediate the electrogenic HCO3− transport through the luminal membrane and may be involved in pancreatic secretion in guinea pig ducts. [ABSTRACT FROM AUTHOR]

This study aimed at investigating the potential ghrelin relaxing effect on guinea pig isolated tracheal smooth muscle (TSM). Using an in vitro experimental approach, the physiological role of the airway epithelium on smooth muscle relaxation has been investigated by analyzing the dose-response curves for carbachol- or histamine-induced contractions on epithelium intact versus denuded tracheal tissue. The relaxant effect of ghrelin (5-200 μmol/L) then investigated on carbachol-contracted, non-sensitized, and ovalbumin (OVA)-sensitized guinea pig TSM with an intact or denuded epithelium. The isolated TSMs from identical guinea pigs were incubated in Krebs solution aerated with 95% O2 and 5% CO2 through an automated tissue organ bath system (n = 6 for each group). The ghrelin relaxation mechanism was assessed by adding L-NAME, indomethacin, and YIL-781 for GHS-R1 into the tissue chamber. The spasmogens carbachol and histamine have shown a significantly higher contracting effect on epithelium-denuded than in epithelium-intact TSM confirmed by the significantly higher mean pEC50 of both agonists on the epithelium-denuded trachea (p < 0.05). Ghrelin has shown a concentration-dependent relaxing effect on carbachol-contracted TSM (r = 0.96, p = 0.00). The effect was more evident in the intact non-sensitized than in epithelium-denuded or OVA-sensitized groups (p < 0.05). Preincubation with nitric oxide (NO) and prostaglandin E2 (PGE2) inhibitors has significantly reduced the ghrelin-induced relaxation on epithelium-intact TSM suggesting an epithelium-dependant mechanism. However, GHS-R1a antagonist has also succeeded to reduce ghrelin relaxant effect, which needs further clarification. Ghrelin proved to have a potential TSM relaxant effect possibly through epithelium-dependant mechanisms involving NO and PGE2. [ABSTRACT FROM AUTHOR]

This study aimed at investigating the potential ghrelin relaxing effect on guinea pig isolated tracheal smooth muscle (TSM). Using an in vitro experimental approach, the physiological role of the airway epithelium on smooth muscle relaxation has been investigated by analyzing the dose-response curves for carbachol- or histamine-induced contractions on epithelium intact versus denuded tracheal tissue. The relaxant effect of ghrelin (5-200 μmol/L) then investigated on carbachol-contracted, non-sensitized, and ovalbumin (OVA)-sensitized guinea pig TSM with an intact or denuded epithelium. The isolated TSMs from identical guinea pigs were incubated in Krebs solution aerated with 95% O2 and 5% CO2 through an automated tissue organ bath system (n = 6 for each group). The ghrelin relaxation mechanism was assessed by adding L-NAME, indomethacin, and YIL-781 for GHS-R1 into the tissue chamber. The spasmogens carbachol and histamine have shown a significantly higher contracting effect on epithelium-denuded than in epithelium-intact TSM confirmed by the significantly higher mean pEC50 of both agonists on the epithelium-denuded trachea (p < 0.05). Ghrelin has shown a concentration-dependent relaxing effect on carbachol-contracted TSM (r = 0.96, p = 0.00). The effect was more evident in the intact non-sensitized than in epithelium-denuded or OVA-sensitized groups (p < 0.05). Preincubation with nitric oxide (NO) and prostaglandin E2 (PGE2) inhibitors has significantly reduced the ghrelin-induced relaxation on epithelium-intact TSM suggesting an epithelium-dependant mechanism. However, GHS-R1a antagonist has also succeeded to reduce ghrelin relaxant effect, which needs further clarification. Ghrelin proved to have a potential TSM relaxant effect possibly through epithelium-dependant mechanisms involving NO and PGE2. [ABSTRACT FROM AUTHOR]

Defective acoustic transmission in the cochlea is closely related with various auditory and vestibular symptoms. Among them, semicircular canal dehiscence (SCD) with a defective semicircular bone is typical. Currently, the pathogenesis of SCD is usually explained by the third window hypothesis; however, this hypothesis fails to explain the variability in the symptoms and signs experienced by superior SCD (SSCD) patients. We evaluated the mechanism of hearing loss in a guinea pig model of bony dehiscence with various sizes and locations along the superior semicircular canal. Auditory brainstem responses (ABRs) and laser Doppler velocimetry were used to measure hearing loss and vibration changes before and after fenestration, as well as after restorative patching. ABR thresholds at low frequencies (e.g., 1000 Hz) increased after fenestration and decreased back to the normal range after we repaired the defect. Energy leakage from the surgically introduced third window was detected in the range of 300–1500 Hz, accompanied by increased vibration at the umbo, stapes head, and the dehiscence site, while decreased vibration was observed at the round window membrane in the same frequency range. After the patching procedure, the deviant vibrations were recovered. The degree of postfenestration energy leakage was proportional to the size of fenestration and the proximity of the fenestration site to the oval window. These results suggest that the bony fenestration of the superior semicircular canal mimics the hearing loss pattern of patients with SSCD. The decrease in perilymph wave impedance likely accounts for the auditory changes. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate the differential protein expression in guinea pig retinas in response to lens‑induced myopia (LIM) before fully compensated eye growth. Four days old guinea pigs (n=5) were subjected to ‑4D LIM for 8 days. Refractive errors were measured before and at the end of the lens wear period. Ocular dimensions were also recorded using high‑frequency A‑scan ultrasonography. After the LIM treatment, retinas of both eyes were harvested and soluble proteins were extracted. Paired retinal protein expressions in each animal were profiled and compared using a sensitive fluorescence difference two‑dimensional gel electrophoresis. The quantitative retinal proteomes of myopic and control eye were analysed using computerised DeCyder software. Those proteins that were consistently changed with at least 1.2‑fold difference (P<0.05) in the same direction in all five animals were extracted, trypsin digested and identified by tandem mass spectrometry. Significant myopia was induced in guinea pigs after 8 days of lens wear. The vitreous chamber depth in lens‑treated eyes was found to be significantly elongated. Typically, more than 1,000 protein spots could be detected from each retina. Thirty‑two of them showed differential expression between myopic and untreated retina. Among these proteins, 21 spots were upregulated and 11 were downregulated. Eight protein spots could be successfully identified which included β‑actin, enolase 1, cytosolic malate dehydrogenase, Ras‑related protein Rab‑11B, protein‑L‑isoaspartate (D‑aspartate) O‑methyltransferase, PKM2 protein, X‑linked eukaryotic translation initiation factor 1A and ACP1 protein. The present study serves as the first report to uncover the retinal 2D proteome expressions in mammalian guinea pig myopia model using a top‑down fluorescent dyes labelling gel approach. The results showed a downregulation in glycolytic enzymes that may suggest a significant alteration of glycolysis during myopia development. Other protein candidates also suggested multiple pathways which could provide new insights for further study of the myopic eye growth. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of melatonin on oxidative stress, the expression of transient receptor potential melastatin-2 (TRPM2) in guinea pig brains, and the influence of melatonin on oxidative stress in lungs and airway inflammation induced by particulate matter 2.5 (PM2.5). A particle suspension (0.1 g/ml) was nasally administered to the guinea pigs to prepare a PM2.5 exposure model. Cough frequency and cough incubation period were determined through RM6240B biological signal collection and disposal system. Oxidative stress markers, including malondialdehyde (MDA), total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px), in the medulla oblongata were examined through spectrophotometer. Reactive oxygen species (ROS) were detected in the hypoglossal nucleus, cuneate nucleus, Botzinger complex, dorsal vagal complex, and airway through dihydroethidium fluorescence. Hematoxylin-eosin (HE) staining and substance P expression via immunohistochemistry revealed the inflammatory levels in the airway. TRPM2 was observed in the medulla oblongata through immunofluorescence and Western blot. The ultrastructure of the blood-brain barrier and neuronal mitochondria was determined by using a transmission electron microscope. Our study suggests that melatonin treatment decreased PM2.5-induced oxidative stress level in the brains and lungs and relieved airway inflammation and chronic cough. TRPM2 might participate in oxidative stress in the cough center by regulating cough. [ABSTRACT FROM AUTHOR]

The slowly activating delayed rectifier K + current ( I Ks ) is one of the main repolarizing currents in the human heart. Evidence has shown that angiotensin II (Ang II) regulates I Ks through the protein kinase C (PKC) pathway, but the related results are controversial. This study was designed to identify PKC isoenzymes involved in the regulation of I Ks by Ang II and the underlying molecular mechanism. The whole-cell patch-clamp technique was used to record I Ks in isolated guinea pig ventricular cardiomyocytes and in human embryonic kidney (HEK) 293 cells co-transfected with human KCNQ1/KCNE1 genes and Ang II type 1 receptor genes. Ang II inhibited I Ks in a concentration-dependent manner in native cardiomyocytes. A broad PKC inhibitor Gö6983 (not inhibiting PKCε) and a selective cPKC inhibitor Gö6976 did not affect the inhibitory action of Ang II. In contrast, the inhibition was significantly attenuated by PKCε-selective peptide inhibitor εV1–2. However, direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) increased the cloned human I Ks in HEK293 cells. Similarly, the cPKC peptide activator significantly enhanced the current. In contrast, the PKCε peptide activator inhibited the current. Further evidence showed that PKCε knockdown by siRNA antagonized the Ang II-induced inhibition on KCNQ1/KCNE1 current, whereas knockdown of cPKCs (PKCα and PKCβ) attenuated the potentiation of the current by PMA. Moreover, deletion of four putative phosphorylation sites in the C-terminus of KCNQ1 abolished the action of PMA. Mutation of two putative phosphorylation sites in the N-terminus of KCNQ1 and one site in KCNE1 (S102) blocked the inhibition of Ang II. Our results demonstrate that PKCε isoenzyme mediates the inhibitory action of Ang II on I Ks and by phosphorylating distinct sites in KCNQ1/KCNE1, cPKC and PKCε isoenzymes produce the contrary regulatory effects on the channel. These findings have provided new insight into the molecular mechanism underlying the modulation of the KCNQ1/KCNE1 channel. [ABSTRACT FROM AUTHOR]

Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use, highlighting doubt over the effectiveness of the therapy. Progesterone can be rapidly metabolized into a number of steroids, but to date, there has been a lack of investigation into the fetal steroid profiles following administration and whether this impacts fetal neurodevelopment. The objective of this study was to determine the effect of progesterone treatment on allopregnanolone and cortisol levels in the fetus and on a marker of myelination in the fetal brain. We used a guinea pig model where pregnant dams were administered vehicle (β-cyclodextrin) or progesterone orally throughout pregnancy (GA29-61). Maternal and fetal fluids and tissues were collected at both preterm (GA61) and term (GA68) ages. Maternal and fetal progesterone and cortisol were analyzed by enzyme immunoassay and allopregnanolone by radioimmunoassay. Measurement of myelination of fetal brains (hippocampus, cingulum, and subcortical white matter) at preterm and term ages was performed by immunohistochemistry staining for myelin basic protein. We found that dams receiving progesterone had significantly elevated progesterone and cortisol concentrations, but there was no effect on allopregnanolone. Interestingly, the increased cortisol concentrations were not reflected in the fetuses, and there was no effect of progesterone treatment on myelination. Therefore, we conclude that in our guinea pig model, maternal administration of progesterone has no effect on cortisol levels or markers of mature oligodendrocytes in the fetus and suggest this is potentially due to the protective cortisol barrier in the placenta. [ABSTRACT FROM AUTHOR]

A feature of cough variant asthma is a heightened cough response to bronchoconstriction. The mediators of this response are unknown. This study was designed to elucidate the role of lipid mediators in bronchoconstriction-triggered cough response in an experimental animal model. We examined the influence of bronchoconstriction on cell components and mediators including prostaglandin E 2 (PGE 2 ) in bronchoalveolar lavage fluid (BALF). We studied the cough response to bronchoconstriction (CRB) by measuring the correlation between the increase in enhanced pause (Penh), an index of bronchoconstriction, and cough counts induced by methacholine (Mch) inhalation in conscious guinea pigs. We then examined the effects of intraperitoneal pretreatment with 16, 16-dimethyl-prostaglandin E 2 (dm-PGE 2 ) on CRB and cough counts. The total number of cells and cell components in the BALF were not influenced by bronchoconstriction. While levels of PGE 2 , prostaglandin I 2 , and cysteinyl leukotrienes were significantly increased, levels of prostaglandin D 2 , thromboxane B 2 , and substance P in the BALF were not. Dm-PGE 2 significantly decreased the Mch-induced increase in Penh. Following bronchoconstriction by additional Mch inhalation, dm-PGE 2 produced an increase in CRB and cough counts in a dose-dependent manner. Additionally, the heightened CRB following dm-PGE 2 treatment was suppressed by pretreatment with PGE 2 receptor (E-prostanoid EP) -1 and EP-3 antagonists in a dose-dependent manner, but not by EP-2 and EP-4 antagonists. The EP-1 antagonist also decreased cough counts. These results suggest that PGE 2 acts as an exacerbating factor for bronchoconstriction-triggered cough. EP1 and EP3 may provide new therapeutic targets for cough variant asthma. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the effect of Trypanosoma cruzi infection on fertility, gestation outcome, and maternal-fetal transmission in guinea pigs (Cavia porcellus). Methods: Animals were infected with T. cruzi H4 strain (TcI lineage) before gestation (IBG) or during gestation (IDG). Tissue and sera samples of dams and fetuses were obtained near parturition. Results: All IBG and IDG dams were seropositive by two tests, and exhibited blood parasite load of 1.62±2.2 and 50.1±62 parasites/μl, respectively, by quantitative PCR. Histological evaluation showed muscle fiber degeneration and cellular necrosis in all infected dams. Parasite nests were not detected in infected dams by histology. However, qPCR analysis detected parasites-eq/g heart tissue of 153±104.7 and 169.3±129.4 in IBG and IDG dams, respectively. All fetuses of infected dams were positive for anti-parasite IgG antibodies and tissue parasites by qPCR, but presented a low level of tissue inflammatory infiltrate. Fetuses of IDG (vs. IBG) dams exhibited higher degree of muscle fiber degeneration and cellular necrosis in the heart and skeletal tissues. The placental tissue exhibited no inflammatory lesions and amastigote nests, yet parasites-eq/g of 381.2±34.3 and 79.2±84.9 were detected in IDG and IBG placentas, respectively. Fetal development was compromised, and evidenced by a decline in weight, crow-rump length, and abdominal width in both groups. Conclusions: T. cruzi TcI has a high capacity of congenital transmission even when it was inoculated at a very low dose before or during gestation. Tissue lesions, parasite load, and fetal under development provide evidence for high virulence of the parasite during pregnancy. Despite finding of high parasite burden by qPCR, placentas were protected from cellular damage. Our studies offer an experimental model to study the efficacy of vaccines and drugs against congenital transmission of T. cruzi. These results also call for T. cruzi screening in pregnant women and adequate follow up of the newborns in endemic areas. [ABSTRACT FROM AUTHOR]

Noninvasive bimodal auditory stimulation targets the dorsal cochlear nucleus and reduces tinnitus in guinea pigs and humans. The sound of silence: Tinnitus reduces quality of life for millions of tinnitus sufferers worldwide. Using a guinea pig model of tinnitus induced by noise trauma, Marks et al. delivered precisely timed bimodal auditory-somatosensory stimulation designed to induce long-term depression (LTD) in the cochlear nucleus of these animals. Twenty minutes per day of bimodal stimulation to induce LTD in the cochlear nucleus reduced physiological and behavioral evidence of tinnitus in the animals. The same bimodal protocol reduced tinnitus loudness in human subjects in a double-blinded, sham-controlled, crossover clinical study. Unimodal stimulation did not reduce tinnitus in the animals or the humans. Bimodal auditory-somatosensory stimulation that induces LTD may hold promise for suppressing chronic tinnitus in patients. The dorsal cochlear nucleus is the first site of multisensory convergence in mammalian auditory pathways. Principal output neurons, the fusiform cells, integrate auditory nerve inputs from the cochlea with somatosensory inputs from the head and neck. In previous work, we developed a guinea pig model of tinnitus induced by noise exposure and showed that the fusiform cells in these animals exhibited increased spontaneous activity and cross-unit synchrony, which are physiological correlates of tinnitus. We delivered repeated bimodal auditory-somatosensory stimulation to the dorsal cochlear nucleus of guinea pigs with tinnitus, choosing a stimulus interval known to induce long-term depression (LTD). Twenty minutes per day of LTD-inducing bimodal (but not unimodal) stimulation reduced physiological and behavioral evidence of tinnitus in the guinea pigs after 25 days. Next, we applied the same bimodal treatment to 20 human subjects with tinnitus using a double-blinded, sham-controlled, crossover study. Twenty-eight days of LTD-inducing bimodal stimulation reduced tinnitus loudness and intrusiveness. Unimodal auditory stimulation did not deliver either benefit. Bimodal auditory-somatosensory stimulation that induces LTD in the dorsal cochlear nucleus may hold promise for suppressing chronic tinnitus, which reduces quality of life for millions of tinnitus sufferers worldwide. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the extent of stromal cell-derived factor-1's (SDF-1) involvement in the pathogenesis of idiopathic versus post-traumatic OA by comparing differences in synovial membrane morphology, SDF-1 synovial fluid (SF) concentrations, and matrix metalloproteinase-13 (MMP-13) SF concentrations.Methods: Thirty-six 3-month-old Hartley guinea pigs were obtained and divided into 6 groups. Upon sacrifice, India Ink staining was used to evaluate gross morphology, Safranin O/Fast green staining was used to assess cartilage damage, H/E staining was employed to visualize the synovium, and SF samples were obtained for biochemical analyses. Sandwich ELISA was used to quantify the SF concentrations of SDF-1 and MMP-13.Results: 12 month-old, idiopathic OA guinea pigs and 5.5 month-old ACLT animals had comparable cartilage damage when evaluated by the Modified Mankin Score. SDF-1 and MMP-13 concentrations were not statistically different between the two groups. The synovial membrane of the 5.5 month ACLT group had severe synovitis compared to the idiopathic OA group.Conclusion: In this study, it was found that synovial inflammation, independent of cartilage morphology, SDF-1 concentration, and MMP-13 concentration, was markedly different between idiopathic and post-traumatic OA. These results highlight the differing morphological and biochemical profiles of post-traumatic versus idiopathic osteoarthritis and calls for a more thorough examination of the sole of the synovial membrane in the pathogenesis of post-traumatic osteoarthritis. [ABSTRACT FROM AUTHOR]

Background Parathyroid hormone-related protein ( PTHrP) that causes hypercalcemia of malignancy appears to function as an endogenous smooth muscle relaxant. For example, PTHrP released upon bladder wall distension relaxes detrusor smooth muscle to accommodate urine. Here, we explored mechanisms underlying PTHrP-induced suppression of the smooth muscle contractility in the gastric antrum that also undergoes a passive distension. Methods Effects of PTHrP on phasic contractions and electrical slow waves in the antral smooth muscle of the guinea pig stomach were studied using isometric tension and intracellular microelectrode recordings, respectively. Fluorescent immunohistochemistry was also carried out to identify the distribution of PTH/ PTHrP receptors. Key Results Parathyroid hormone-related protein (1-100 nM) reduced the amplitude of phasic contractions and the basal tension. Nω-nitro- l-arginine (L-NA, 100 μM), a nitric oxide ( NO) synthase inhibitor, or 1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ, 10 µM), a guanylate cyclase inhibitor, diminished the PTHrP (10 nM)-induced reduction in the amplitude of phasic contractions. SQ22536 (300 μM), an adenylate cyclase inhibitor, attenuated the PTHrP-induced reduction in basal tension. The combination of ODQ (10 μM) and SQ22536 (300 μM) inhibited the PTHrP-induced reductions in both phasic contractions and basal tension. PTHrP (100 nM) had no inhibitory effect on the electrical slow waves in the antral smooth muscle. PTH/ PTHrP receptors were expressed in cell bodies of PGP9.5-positive neurons in the myenteric plexus. Conclusions & Inferences Parathyroid hormone-related protein exerts its inhibitory actions on the antral smooth muscle via both nitric oxide-cyclic guanosine monophosphate (NO-cGMP) and cyclic adenosine monophosphate (AMP) pathways. Thus, PTHrP may act as an endogenous relaxant of the gastric antrum employing the two complementary signaling pathways to ensure the adaptive relaxation of stomach. [ABSTRACT FROM AUTHOR]

Theophylline has been used in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD) for over 70 years. In order to maximize the effectiveness and safety of theophylline therapy it is important to individualize the dosage of the drug. In our study we focused on determination of theophylline concentrations in guinea pig plasma. A rapid, specific, and reliable LC-MS/MS-based method was developed and validated according to European Medicine Agency (EMA) guidelines. A hydrophilic interaction liquid chromatography (HILIC) separation mode for reduction time of sample preparation was used. The analysed sample was quantified in a positive ionization mode. Multiple reaction monitoring (MRM) using transition m/z 181.06→124.06 and m/z 187.17→127.06 was performed to quantify theophylline with deuterated internal standard ([²H6]-theophylline), respectively. Modification of collision energies was performed in parallel with chromatographic separation to further eliminate interference from the matrix. The method was validated for a range of 0.5 to 30 µg/mL of plasma sample. The intra-day and inter-day precision and accuracy of the quality control samples at low, me dium, and high concentration levels exhibited relative standard deviations (RSD) of less than 10%. The method was successfully applied for the quantitation of theophylline in guinea pig plasma for better understanding its effects in a model of ovalbumin-induced allergic inflammation. [ABSTRACT FROM AUTHOR]

In this study, we evaluated the effect of oral administration of riboflavin combined with whole-body ultraviolet A (UVA) irradiation on the biochemical and biomechanical properties of sclera in a guinea pig model to control the progression of myopia. Experimental groups were administered 0.1% riboflavin solution with or without vitamin C by gavage from 3 days before myopic modeling and during the modeling process. Guinea pigs underwent 30 min of whole-body UVA irradiation after each gavage for 2 weeks. For control groups, guinea pigs were administered vitamin C and underwent either whole-body UVA irradiation without 0.1% riboflavin solution or whole-body fluorescent lamp irradiation with or without 0.1% riboflavin solution. Resultantly, myopia models were established with an increased axial length and myopic diopter. Compared with myopic eyes in the control groups, the net increase in axial length, diopter and strain assessment decreased significantly, and the net decrease in sclera thickness, ultimate load, and stress assessment decreased significantly in experimental groups. MMP-2 expression showed a lower net increase, while TIMP-2 expression showed a lower net decrease. In addition, hyperplasia of scleral fibroblasts was more active in myopic eyes of experimental groups. Overall, our results showed that oral administration of riboflavin with whole-body UVA irradiation could increase the strength and stiffness of sclera by altering the biochemical and biomechanical properties, and decreases in axial elongation and myopic diopter are greater in the guinea pig myopic model. [ABSTRACT FROM AUTHOR]

Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex. [ABSTRACT FROM AUTHOR]

The study was conducted on four healthy guinea pigs (Cavia porcellus) of either sex in which the nerve was identified and subjected to crush injury with the tip (3mm) of a curved hemostatic forceps. 30 days after the injury nerve samples were collected and subjected to Hematoxylin and Eosin staining with or without pretreatment with Marchi's solution. The routine Hematoxylin and Eosin (H&E) stained all neural elements in various intensities of pink and in purple and the degenerative changes were seen as vacuoles ranging from vacuolated foci-containing eosinophilic material and associated with a distorted cell nucleus to larger, multilocular, linear array of compartmentalized digestion chambers supposed to contain myelin debris. The myelin on the other hand appeared as empty zones in H&E staining. Combining Marchi's and H & E procedures revealed the presence black aggregates/deposits in the vacuoles and digestion chambers. This method confirmed the presence of degenerated myelin inside the vacuoles and digestion chambers and thus may allow better analysis of nerve damage and regeneration. [ABSTRACT FROM AUTHOR]

Noise-induced hearing loss (NIHL) severely impacts the quality of life of affected individuals. Oxidative stress resulting from noise exposure is a significant cause of NIHL. Although histone deacetylase (HDAC) inhibitors were shown to protect against NIHL, the underlying mechanism remains unclear, and it is not known how they act on noise-induced oxidative stress. In the current study, we investigated the expression levels of acetyl-histone H3 (Lys9) (H3-AcK9), histone deacetylase 1 (HDAC1), and 3-nitrotyrosine (3-NT), an oxidative stress marker, in a guinea pig model of NIHL using immunohistology and Western blotting. We then assessed the effects of systemic administration of the HDAC inhibitor, sodium butyrate (SB), on noise-induced permanent threshold shifts (PTS), hair cell (HC) loss, and changes in the above mentioned markers. The results showed that SB attenuated noise-induced PTS and outer hair cell loss. SB treatment promoted H3-AcK9 expression and repressed HDAC1 expression in the nuclei of HCs and Hensen's cells after noise exposure. Furthermore, SB attenuated the noise-induced increase of 3-NT expression in HCs and Hensen's cells. These findings suggest that SB protects against NIHL by reversing the noise-induced histone acetylation imbalance and inhibiting oxidative stress in cochlear HCs and Hensen's cells. SB treatment may represent a potential strategy to prevent and treat NIHL. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) and asthma belong to the category of type I allergic diseases, whose pathological features are airway remodeling of the lung and allergic inflammation. The aim of the present study was to evaluate inflammation and remodeling of lung tissue in a guinea pig model of AR in order to confirm consistent pathological changes of upper and lower airways in AR. Male guinea pigs were randomly divided into an experimental and a control group (n=10 in each). The AR model was established by sensitization through intraperitoneal injection of ovalbumin for three weeks and bilateral nasal local excitation for twelve weeks. All tissues of nasal mucosa and lung were subjected to hematoxylin and eosin as well as toluidine blue staining, and characteristics of remodeling of lung tissue, including thickness of bronchial wall, epithelial mucosa and smooth muscle were histologically determined. Collagen deposition in lung tissue was observed by Masson's trichrome stain. Severe paroxysmal nose scratching action, frequent sneezing, visible outflow of secretion from the anterior naris and frequent nose friction were observed in the AR model group within 30 min after local excitation. The total symptom scores were significantly increased in the AR model group compared with those in the control group. Obvious inflammatory cell infiltration was observed in the AR model group. Compared with those in the control group, the numbers of eosinophils and mast cells in nasal mucosa and lung tissue were significantly increased. Obvious airway remodeling of the lung was observed in the AR model group. Compared with those in the control group, bronchial wall thickness, epithelial layer thickness and smooth muscle thickness in the airways were significantly increased in the AR model group. Increased collagen deposition was found in the AR model group compared with that in the control group. The results of the present study revealed that inflammation and airway remodeling of lungs arose in guinea pigs with AR, suggesting that pathological changes of upper and lower airways are consistent in this AR model. [ABSTRACT FROM AUTHOR]

The anthrax vaccine candidate AV7909 is being developed as a next generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the Anthrax Vaccine Adsorbed (AVA, BioThrax®) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. The studies described here provide initial information on AV7909-induced toxin-neutralizing antibody (TNA) levels associated with the protection of animals from lethal Bacillus anthracis challenge. Guinea pigs or nonhuman primates (NHPs) were immunized on Days 0 and 28 with various dilutions of AV7909, AVA or a saline or Alhydrogel + CPG 7909 control. Animals were challenged via the inhalational route with a lethal dose of aerosolized B. anthracis (Ames strain) spores and observed for clinical signs of disease and mortality. The relationship between pre-challenge serum TNA levels and survival following challenge was determined in order to calculate a threshold TNA level associated with protection. Immunisation with AV7909 induced a rapid, highly protective TNA response in guinea pigs and NHPs. Surprisingly, the TNA threshold associated with a 70% probability of survival for AV7909 immunized animals was substantially lower than the threshold which has been established for the licensed AVA vaccine. The results of this study suggest that the TNA threshold of protection against anthrax could be modified by the addition of an immune stimulant such as CPG 7909 and that the TNA levels associated with protection may be vaccine-specific. [ABSTRACT FROM AUTHOR]

We investigated the therapeutic effects of an extract ofPsidium guajava(guava) leaf on experimentally induced osteoarthritis in guinea pig. The left knee of 30 male guinea pigs was anesthetized and the cranial cruciate ligament was severed. The animals were followed for 8 weeks until osteoarthritis was confirmed by radiography and histopathology. Animals were divided randomly into five groups; group 1, the ligament was severed and untreated; group 2, the ligament was severed and treated with piascledine, an extract of soybean and avocado; group 3, the ligament was severed and treated with 200 mg/kg hydroethanolic extract of guava; group 4, the ligament was severed and treated with 400 mg/kg hydroethanolic extract of guava; and group 5, control animals without surgery or extracts. Radiological and histopathological evaluations after 8 weeks showed reduced severity of osteoarthritis in the piascledine treatment group compared to group 1. The guava extract also reduce the severity of osteoarthritis compared to controls. Histopathological examination of treatment and control groups showed that treatment the guava extract improved lesions significantly. Hydroethanolic extracts of guava leaf appears to prevent osteoarthritis by inhibition of free radical formation in the knee joint. [ABSTRACT FROM AUTHOR]

The periosteal arterioles of the compact bone may play a critical role in bone growth. To explore the contractile properties of tibial arterioles, spontaneous and nerve-evoked constrictions were compared in preparations from 3-week-old and 1-year-old guinea-pigs. Changes in arteriole diameters were measured using video microscopy. Their innervation was investigated using fluorescence immunohistochemistry. Fifty per cent and 40% of tibial arterioles from 3-week-old and 1-year-old guinea-pigs, respectively, exhibited spontaneous phasic constrictions that were inhibited by 1 μM nifedipine, 10 μM cyclopiazonic acid or 100 μM 2-APB. Nerve-evoked phasic constrictions in both age groups were largely suppressed by phentolamine (1 μM), an α-adrenoceptor antagonist, or sympathetic neurotransmitter depletion using guanethidine (10 μM) but were enhanced by spanttide (1 μM), a substance P receptor antagonist, or L-nitro arginine (L-NA; 100 μM), an inhibitor of nitric oxide synthase (NOS). Nerve-evoked constrictions in 1-year-old animals were smaller than those in younger animals but greatly enhanced by L-NA. Immunohistochemistry revealed sympathetic and substance P-positive primary afferent nerves running along the arterioles as well as endothelial NOS expression in both age groups. Spontaneous arteriolar constrictions appear to rely on both Ca release from the sarcoplasmic reticulum and Ca influx through L-type Ca channels. Noradrenaline released from sympathetic nerves triggers arteriolar constriction, while substance P released from primary afferent nerves dilates the arterioles by releasing nitric oxide (NO), presumably from the endothelium. Thus, the enhanced endothelial NO release in adult guinea-pigs may be important to increase the blood supply to meet the increased metabolic demands during bone growth. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate possible ototoxicity associated with topical rifamycin application via electrophysiological tests and ultrastructural examinations. Methods: Electrophysiological assessment was performed with tympanometry, auditory brainstem response (ABR), and distortion product otoacoustic emission (DPOAE) measurements. This study was conducted on 40 ears of 20 guinea pigs that were detected to have normal hearing thresholds. The animals were randomly assigned to three groups: Group 1 (n=12) received 0.1 mL rifamycin, Group 2 (n=8) received 0.1 ml gentamycin, and Group 3 (n=20) received 0.1 mL physiological saline. The antibiotics and saline solutions were administered via intratympanic injections. After five injections every other day, electrophysiological tests were performed again on the 15th day. After electrophysiological measurements, the temporal bones of all guinea pigs were prepared for ultrastructural examinations and the cochlear surface morphology was examined by scanning electron microscopy (SEM). Results: The animals in group 3 did not show a statistically significant change in their DPOAE signal/noise ratio (SNR) or ABR thresholds (p>0.05). In groups 1 and 2, the reduction in the DPOAE SNR and the increase in the ABR threshold were statistically significant (p<0.05). Regarding SEM examination results, the animals in groups 1 and 2 showed statistically significant outer hair cell damage and cochlear degeneration due to the ototoxic effect of the drugs (p<0.05), whereas the animals in group 3 showed no significant damage (p>0.05). Conclusion: The results indicate that rifamycin application to the middle ears of guinea pigs has mild ototoxic effects on their inner ears. [ABSTRACT FROM AUTHOR]

A collection of Old and New World arenaviruses are etiologic agents of viral hemorrhagic fever, a syndrome that features hematologic abnormalities, vascular leak, hypovolemia, and multi-organ failure. Treatment is limited to ribavirin for Lassa fever and immune plasma for Argentine hemorrhagic fever. Improved therapeutic options that are safe, more effective and widely available are needed. Here, we show that modification of favipiravir treatment to include a high-dose loading period achieves complete protection in a guinea pig model of Argentine hemorrhagic fever when treatment was initiated two days following challenge with Junin virus (JUNV). This loading dose strategy also protected 50% of animals from lethal disease when treatment was delayed until 5 days post-infection and extended the survival time in those that succumbed. Consistent with the survival data, dramatic reductions in serum and tissue virus loads were observed in animals treated with favipiravir. This is the first report demonstrating complete protection against uniformly lethal JUNV infection in guinea pigs by administration of a small molecule antiviral drug. [ABSTRACT FROM AUTHOR]

Foot and mouth disease is a highly contagious disease affecting cloven footed animals. Vaccination using inactivated virus is followed to control the disease. As the immune response conferred by the inactivated vaccine is short lived, there is a need for an alternate vaccine with increased duration of immunity. Inclusion of adjuvant which enhances B and T cell responses is one of the strategies to increase the duration of immune responses of the vaccine. Interleukin 15 is one such a cytokine which improves the cell mediated immune response and also involved in the maintenance of memory T and B cells. In the present communication, we evaluated the role of bovine IL-15 as an adjuvant to inactivated FMD vaccine in guinea pig model. Animals injected with FMD inactivated vaccine and IL-15 plasmid showed improved levels of neutralizing antibodies which were maintained up to 6 months (as the level of neutralizing antibodies is more >1.5 which is considered to give protection). Increased Th1 and Th2 responses (by measuring the level of IL-4 and IFN- gamma responses) were seen in IL-15 adjuvanted guinea pigs compared to animals injected with inactivated vaccine alone. [ABSTRACT FROM AUTHOR]

Eye lenses are exposed to thermal, solar radiations, dryness that enhances cataractogenesis. Some animal lenses contain novel proteins in bulk quantities. ζ-crystallin occurred in three ecologically divergent species, but it's physiological role not known. The truncated variant of ζ-crystallin causes hereditary cataract. Guinea pig ζ-crystallin is temperature-sensitive and rapidly aggregates at 41 °C. Camels adopted to survive above 50 °C, which raises an interesting question about how it retains lens proteins in the soluble state? Here, we have optimized expression and purification of recombinant camel ζ-crystallin. We have studied thermodynamic and spectroscopic properties using orthogonal techniques. Dynamic multimode spectroscopy results showed that camel ζ-crystallin unfolds via single transition with T m value of 60.8 ± 0.1 °C and van’t Hoff enthalpy of 714.7 ± 7.1 kJ/mol. Thermal-shift assay calculates T m value of 62 °C at pH 7. Additionally, the conformational stability of ζ-crystallin increases with ionic-strength. The influence of pH on ζ-crystallin was evaluated where the protein was found to be stable in the pH range of 6–9, but its stability drastically decreases below pH 6. Our results also showed that quaternary structure of ζ-crystallin drastically changed as a result of lowering pH. This study provides significant understandings onto the conformational, thermodynamic and unfolding pathway of camel ζ-crystallin. [ABSTRACT FROM AUTHOR]

Exposure to Particulate Matter (PM) could function as an adjuvant depending on the city of origin in mice allergic asthma models. Therefore, our aim was to determine whether inhalation of fine particles (PM2.5) from Mexico City could act as an adjuvant inducing allergic sensitization and/or worsening the asthmatic response in guinea pig, as a suitable model of human asthma. Experimental groups were Non-Sensitized (NS group), sensitized with Ovalbumin (OVA) plus Aluminum hydroxide (Al(OH)3) as adjuvant (S + Adj group), and sensitized (OVA) without adjuvant (S group). All the animals were exposed to Filtered Air (FA) or concentrated PM2.5 (5 h/daily/3 days), employing an aerosol concentrator system, PM2.5 composition was characterized. Lung function was evaluated by barometric plethysmography (Penh index). Inflammatory cells present in bronchoalveolar lavage were counted as well as OVA-specific IgG1 and IgE were determined by ELISA assay. Our results showed in sensitized animals without Al(OH)3, that the PM2.5 exposure (609 ± 12.73 μg/m3) acted as an adjuvant, triggering OVA-specific IgG1 and IgE concentration. Penh index increased ∼9-fold after OVA challenge in adjuvant-sensitized animals as well as in S + PM2.5 group (∼6-fold), meanwhile NS + FA and S + FA lacked response. S + Adj + PM2.5 group showed an increase significantly of eosinophils and neutrophils in bronchoalveolar lavage. PM2.5 composition was made up of inorganic elements and Polycyclic Aromatic Hydrocarbons, as well as endotoxins and β-glucan, all these components could act as adjuvant. Our study demonstrated that acute inhalation of PM2.5 acted as an adjuvant, similar to the aluminum hydroxide effect, triggering allergic asthma in a guinea pig model. Furthermore, in sensitized animals with aluminum hydroxide an enhancing influence of PM2.5 exposure was observed as specific-hyperresponsiveness to OVA challenge (quickly response) and eosinophilic and neutrophilic airway inflammation. Fine particles from Mexico City is a complex mix, which play a significant role as adjuvant in allergic asthma. [ABSTRACT FROM AUTHOR]

Patients undergoing cochlear implantation could benefit from a simultaneous application of drugs into the ear, helping preserve residual low-frequency hearing and afferent nerve fiber populations. One way to apply drugs is to incorporate a cannula into the implant, through which drug solution is driven. For such an approach, perilymph concentrations achieved and the distribution in the ear over time have not previously been documented. We used FITC-labeled dextran as a marker, delivering it into perilymph of guinea pigs at 10 or 100 nL/min though a cannula incorporated into a cochlear implant with the outlet in the mid basal turn. After injections of varying duration (2 hours, 1 day or 7 days) perilymph was collected from the cochlear apex using a sequential sampling technique, allowing dextran levels and gradients along scala tympani to be quantified. Data were interpreted quantitatively using computer simulations of the experiments. For injections of 2 hours duration, dextran levels were critically influenced by the presence or absence of fluid leakage at the cochleostomy site. When the cochleostomy was fluid-tight, substantially higher perilymph levels were achieved at the injection site, with concentration declining along scala tympani towards the apex. Contrary to expectations, large dextran gradients along scala tympani persisted after 24 hours of sustained injection and were still present in some animals after 7 days injection. Functional changes associated with implantation and dextran delivery, and the histological state of the implant and cannula were also documented. The persistent longitudinal gradients of dextan along the ear were not readily explained by computer simulations of the experiments based on prior pharmacokinetic data. One explanation is that inner ear pharmacokinetics are altered in the period after cochlear implantation, possibly by a permeabilization of the blood-labyrinth barrier as part of the immune response to the implant. [ABSTRACT FROM AUTHOR]

Key points The mucosa may have neuron-like functions as urinary bladder mucosa releases bioactive substances that modulate sensory nerve activity as well as detrusor muscle contractility. However, such mucosal function in other visceral organs remains to be established., The role of mucosa in generating spontaneous contractions in seminal vesicles (SVs), a paired organ in the male reproductive tract, was investigated., The intact mucosa is essential for the generation of spontaneous phasic contractions of SV smooth muscle arising from electrical slow waves and corresponding increases in intracellular Ca2+. These spontaneous events primarily depend on Ca2+ handling by sarco-endoplasmic reticulum Ca2+ stores., A population of mucosal cells developed spontaneous rises in intracellular Ca2+ relying on sarco-endoplasmic reticulum Ca2+ handling., The spontaneously active cells in the SV mucosa appear to drive spontaneous activity in smooth muscle either by sending depolarizing signals and/or by releasing humoral substances., Abstract The role of the mucosa in generating the spontaneous activity of guinea-pig seminal vesicle (SV) was explored. Changes in contractility, membrane potential and intracellular Ca2+ dynamics of SV smooth muscle cells (SMCs) were recorded using isometric tension recording, intracellular microelectrode recording and epi-fluorescence Ca2+ imaging, respectively. Mucosa-intact but not mucosa-denuded SV preparations generated TTX- (1 μ m) resistant spontaneous phasic contractions that were abolished by nifedipine (3 μ m). Consistently, SMCs developed mucosa-dependent slow waves (SWs) that triggered action potentials and corresponding Ca2+ flashes. Nifedipine (10 μ m) abolished the action potentials and spontaneous contractions, while suppressing the SWs and Ca2+ flashes. Both the residual SWs and spontaneous Ca2+ transients were abolished by cyclopiazonic acid (CPA, 10 μ m), a sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor. DIDS (300 μ m) and niflumic acid (100 μ m), blockers for Ca2+-activated Cl− channels (CACCs), or low Cl− solution also slowed or prevented the generation of SWs. In SV mucosal preparations detached from the muscle layer, a population of mucosal cells generated spontaneous Ca2+ transients that were blocked by CPA but not nifedipine. These results suggested that spontaneous contractions and corresponding Ca2+ flashes in SV SMCs arise from action potential generation due to the opening of L-type voltage-dependent Ca2+ channels. Spontaneous Ca2+ transients appear to primarily result from Ca2+ release from sarco-endoplasmic reticulum Ca2+ stores to activate CACCs to develop SWs. The mucosal cells firing spontaneous Ca2+ transients may play a critical role in driving spontaneous activity of SV smooth muscle either by sending depolarizing signals or by releasing humoral substances. [ABSTRACT FROM AUTHOR]