GsMTx-4 normalizes the exercise pressor reflex evoked by intermittent muscle contraction in early stage type 1 diabetic rats.

Emerging evidence suggests the exercise pressor reflex is exaggerated in early stage type 1 diabetes mellitus (T1DM). Piezo channels may play a role in this exaggeration, as blocking these channels attenuates the exaggerated pressor response to tendon stretch in T1DM rats. However, tendon stretch constitutes a different mechanical and physiological stimuli than that occurring during muscle contraction. Therefore, the purpose of this study was to determine the contribution of Piezo channels in evoking the pressor reflex during an intermittent muscle contraction in T1DM. In unanesthetized decerebrate rats, we compared the pressor and cardioaccelerator responses to intermittent muscle contraction before and after locally injecting grammostola spatulata mechanotoxin 4 (GsMTx-4, 0.25 µM) into the hindlimb vasculature. Although GsMTx-4 has a high potency for Piezo channels, it has also been suggested to block transient receptor potential cation (TRPC) channels. We, therefore, performed additional experiments to control for this possibility by also injecting SKF 96365 (10 µM), a TRPC channel blocker. We found that local injection of GsMTx-4, but not SKF 96365, attenuated the exaggerated peak pressor (ΔMAP before: 33 ± 3 mmHg, after: 22 ± 3 mmHg, P = 0.007) and pressor index (ΔBPi before: 668 ± 91 mmHg·s, after: 418 ± 81 mmHg·s, P = 0.021) response in streptozotocin (STZ) rats (n = 8). GsMTx-4 attenuated the exaggerated early onset pressor and the pressor response over time, which eliminated peak differences as well as those over time between T1DM and healthy controls. These data suggest that Piezo channels are an effective target to normalize the exercise pressor reflex in T1DM.NEW & NOTEWORTHY This is the first study to demonstrate that blocking Piezo channels is effective in ameliorating the exaggerated exercise pressor reflex evoked by intermittent muscle contraction, commonly occurring during physical activity, in T1DM. Thus, these findings suggest Piezo channels may serve as an effective therapeutic target to reduce the acute and prolonged cardiovascular strain that may occur during dynamic exercise in T1DM.

Reduced sensitivity to ethanol and excessive drinking in a mouse model of neuropathic pain.

The co-occurrence of chronic pain and alcohol use disorders (AUDs) involves complex interactions between genetic and neurophysiological aspects, and the research has reported mixed findings when they both co-occur. There is also an indication of a gender-dependent effect; males are more likely to use alcohol to cope with chronic pain problems than females. Recently, a new conceptualization has emerged, proposing that the negative affective component of pain drives and maintains alcohol-related behaviors. We studied in a longitudinal fashion alterations in alcohol drinking patterns and pain thresholds in a mouse model of chronic neuropathic pain in a sex-dependent manner. Following partial denervation (spared nerve injury [SNI]), stimulus-evoked pain responses were measured before chronic alcohol consumption, during drinking, during a deprivation phase, and following an episode of excessive drinking. During the course of alcohol drinking, we observed pronounced sex differences in pain thresholds. Male mice showed a strong increase in pain thresholds, suggesting an analgesic effect induced by alcohol over time, an effect that was not observed in female mice. SNI mice did not differ from sham-operated controls in baseline alcohol consumption. However, following a deprivation phase and the reintroduction of ethanol, male SNI mice but not female mice showed more pronounced excessive drinking than controls. Finally, we observed decreased central ethanol sensitivity in male SNI mice but not in females. Together with our finding, that ethanol is able to decrease a pain-induced negative affective memory we come to following conclusion. We propose that a lower sensitivity to the intoxicating effects of alcohol together with the ability of alcohol to reduce the negative affective component of pain may explain the higher co-occurrence of AUD in male chronic pain patients.

Anomalous baroreflex functionality inherent in floxed and Cre-Lox mice: an overlooked physiological phenotype.

The last two decades have seen the emergence of Cre-Lox recombination as one of the most powerful and versatile technologies for cell-specific genetic engineering of mammalian cells. Understandably, the primary concerns in the practice of Cre-Lox recombination are whether the predicted genome has been correctly modified and the targeted phenotypes expressed. Rarely are the physiological conditions of the animals routinely examined because the general assumption is that they are normal. Based on corroborative results from radiotelemetric recording, power spectral analysis, and magnetic resonance imaging/diffusion tensor imaging in brain-derived neurotrophic factor-floxed mice, the present study revealed that this assumption requires amendment. We found that despite comparable blood pressure and heart rate with C57BL/6 or Cre mice under the conscious state, floxed and Cre-Lox mice exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex. We further found that the capacity and plasticity of baroreflex of these two strains of mice under isoflurane anesthesia were retarded, as reflected by reduced connectivity between the nucleus tractus solitarii and rostral ventrolateral medulla or nucleus ambiguus. The identification of anomalous baroreflex functionality inherent in floxed and Cre-Lox mice points to the importance of incorporating physiological phenotypes into studies that engage gene manipulations such as Cre-Lox recombination.NEW & NOTEWORTHY We established that anomalous baroreflex functionality is inherent in floxed and Cre-Lox mice. These two mouse strains exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex under the conscious state, retarded capacity and plasticity of baroreflex under isoflurane anesthesia, and reduced connectivity between key nuclei in the baroreflex neural circuits.

Botulinum toxin injection causes hyper-reflexia and increased muscle stiffness of the triceps surae muscle in the rat.

Botulinum toxin is used with the intention of diminishing spasticity and reducing the risk of development of contractures. Here, we investigated changes in muscle stiffness caused by reflex activity or elastic muscle properties following botulinum toxin injection in the triceps surae muscle in rats. Forty-four rats received injection of botulinum toxin in the left triceps surae muscle. Control measurements were performed on the noninjected contralateral side in all rats. Acute experiments were performed, 1, 2, 4, and 8 wk following injection. The triceps surae muscle was dissected free, and the Achilles tendon was cut and attached to a muscle puller. The resistance of the muscle to stretches of different amplitudes and velocities was systematically investigated. Reflex-mediated torque was normalized to the maximal muscle force evoked by supramaximal stimulation of the tibial nerve. Botulinum toxin injection caused severe atrophy of the triceps surae muscle at all time points. The force generated by stretch reflex activity was also strongly diminished but not to the same extent as the maximal muscle force at 2 and 4 wk, signifying a relative reflex hyperexcitability. Passive muscle stiffness was unaltered at 1 wk but increased at 2, 4, and 8 wk (P < 0.01). These data demonstrate that botulinum toxin causes a relative increase in reflex stiffness, which is likely caused by compensatory neuroplastic changes. The stiffness of elastic elements in the muscles also increased. The data are not consistent with the ideas that botulinum toxin is an efficient antispastic medication or that it may prevent development of contractures.

Comparison of physical development and rate of formation sensory-motor reflexes offspring of rats with different experimental model of preeclampsia.

Summary: A comparative study of the physical development and the rate of formation of sensory-motor reflexes offspring of rats with experimental preeclampsia (EP) was carried out. In the first experimental group EP was modeled intraperitoneal conduct of L-NAME at a dose of 25 mg/kg from 14 to 21 days of gestation, the second experimental group - the replacement of drinking water by 1.8% sodium chloride solution for the entire period of gestation. In the offspring of both groups, there was a delay of physical development, which was reflected in the later timing of the hair coat development, incisor eruption, pinna detachment as compared to the pups in the control group. It also noted the gap in the formation of sensory-motor reflexes and vestibular reactions. This was manifested in the delayed appearance of the olfactory response, auditory sensitivity, later performing tests «righting reflex¼, «negative geotaxis¼, «aerial righting reflex¼, «cliff avoidance¼, «horizontal wire test¼, «raising the head and forelegs¼, «supporting their bodies on hind legs¼ as compared to the indices of the pups of the female rats with an uncomplicated pregnancy. The most pronounced lag in postnatal development was observed in the offspring of rats with EP, which instead of drinking water was prepared 1.8% sodium chloride during the entire period of gestation. The purpose: To make a comparative study of the impact of ADMA-like preeclampsia (PE) and preeclampsia modeled by the replacement of drinking water consumed by female rats during gestation with 1.8% NaCl solution on the physical development and the rate of the maturation of sensory motor reflexes of their offspring. Methods: The study was performed on three groups of pregnant female rats aged 3-4 months whose original weight was 210-250 g and their pups. They were divided into three groups: 1: Control group including female rats with an uncomplicated pregnancy (n = 6) and their pups (n = 49); 2. Experimental group 1 - pregnant female rats with PE (n = 6) induced by intraabdominal introduction of L-NAME at a dose of 25 mg/kg from 14 to 21 day of gestation (ADMA-like preeclampsia) and their offspring (n = 35); 3. Experimental group 2 - pregnant female rats with PE (n = 6) modeled by the replacement of drinking throughout gestation with 1.8% NaCl solution and their pups. When studying the physical development of the pups we considered the terms of pinna detachment, hair coat development, incisor eruption and the time when they began to open their eyes. To estimate the rate of the maturation of sensory motor reflexes and motor coordination of the pups of the rats with PE we analyzed the time when they started to support their bodies on hind legs, lift their bodies off the floor, crawl, raise their head and forelegs, show the aerial righting reflex and the righting reflex, negative geotaxis, reactions to auditory and olfactory stimuli as well as the time they managed to stay on the horizontal wire. Results: The pups of the female rats with PE of both experimental groups were found to have later pinna detachment, incisor eruption and hair coat development as compared to the indices of the control group. In addition, the offspring of the experimental groups demonstrated a delay in the performance of the following tests: «righting reflex¼, «negative geotaxis¼, «aerial righting reflex¼, «cliff avoidance¼, «horizontal wire test¼, «raising the head and forelegs¼, «supporting their bodies on hind legs¼, «reaction to an olfactory stimulus¼ and «reaction to an auditory stimulus¼ as compared to the indices of the pups of the female rats with an uncomplicated pregnancy. Conclusion: PE induced by the introduction of ADMA to pregnant female rats and by the replacement of drinking water consumed by female rats during gestation with 1.8% NaCl solution causes a delay in physical development, maturation of sensory motor reflexes and vestibular reactions in their offspring.

Role played by interleukin-6 in evoking the exercise pressor reflex in decerebrate rats: effect of femoral artery ligation.

IL-6 signaling via the soluble IL-6 receptor (sIL-6r) has been shown to increase primary afferent responsiveness to noxious stimuli. This finding prompted us to test the hypothesis that IL-6 and sIL-6r would increase the exercise pressor reflex in decerebrate rats with freely perfused femoral arteries. We also tested the hypothesis that soluble glycoprotein (sgp)130, an inhibitor of IL-6/sIL-6r signaling, would decrease the exaggerated exercise pressor reflex that is found in decerebrate rats with ligated femoral arteries. In rats with freely perfused femoral arteries, coinjection of 50 ng of IL-6 and sIL-6r into the arterial supply of the hindlimb significantly increased the peak pressor response to static (control: 14 ± 3 mmHg and IL-6/sIL-6r: 17 ± 2 mmHg, P = 0.03) and intermittent isometric (control: 10 ± 2 mmHg and IL-6/sIL-6r: 15 ± 4 mmHg, P = 0.03) hindlimb muscle contraction. In rats with ligated femoral arteries, injection of 50 ng of sgp130 into the arterial supply of the hindlimb reduced the peak pressor response to static (control: 24 ± 2 mmHg and sgp130: 16 ± 3 mmHg, P = 0.01) and intermittent isometric (control: 16 ± 2 mmHg and sgp130: 13 ± 2 mmHg, P = 0.04) hindlimb muscle contraction, whereas there was no effect of sgp130 on the exercise pressor reflex in rats with freely perfused femoral arteries. We conclude that coinjection of exogenous IL-6 and sIL-6r increased the exercise pressor reflex in rats with freely perfused femoral arteries. More importantly, we also conclude that IL-6 and sIL-6r play an endogenous role in evoking the exercise pressor reflex in rats with ligated femoral arteries but not in rats with freely perfused femoral arteries.

Isoniazid induced motor-dominant neuropathy.

Isoniazid though a very effective treatment for tuberculosis can cause severe motor-dominant neuropathy which can be reversible with pyridoxine supplementation. A 45-year-old female diagnosed with psoas abscess, culture positive for mycobacterium tuberculosis, was started on anti- tuberculous treatment with four drugs, including isoniazid at a dose of 5 mg/kg/day. Three months later she developed severe motor weakness of lower limbs with loss of ankle and knee reflexes. She was treated with vitamin B6 injections and isoniazid treatment was continued. Her motor weakness gradually improved in a few months, but mild sensory impairment persisted even after two years. There is need for vigilance regarding neurological effects of isoniazid in seemingly low-risk individuals in whom development of symptoms should raise the suspicion about slow acetylator status. Timely therapeutic intervention with high-dose vitamin B6 can reduce the long-term morbidity associated with this easily reversible condition.

Development of attenuated baroreflexes in obese Zucker rats coincides with impaired activation of nucleus tractus solitarius.

Adult obese Zucker rats (OZR; >12 wk) develop elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) with impaired baroreflexes compared with adult lean Zucker rats (LZR) and juvenile OZR (6-7 wk). In adult OZR, baroreceptor afferent nerves respond normally to changes in MAP, whereas electrical stimulation of baroreceptor afferent fibers produces smaller reductions in SNA and MAP compared with LZR. We hypothesized that impaired baroreflexes in OZR are linked to reduced activation of brain stem sites that mediate baroreflexes. In conscious adult rats, a hydralazine (HDZ)-induced reduction in MAP evoked tachycardia that was initially blunted in OZR, but equivalent to LZR within 5 min. In agreement, HDZ-induced expression of c-Fos in the rostral ventrolateral medulla (RVLM) was comparable between groups. In contrast, phenylephrine (PE)-induced rise in MAP evoked markedly attenuated bradycardia with dramatically reduced c-Fos expression in the nucleus tractus solitarius (NTS) of adult OZR compared with LZR. However, in juvenile rats, PE-induced hypertension evoked comparable bradycardia in OZR and LZR with similar or augmented c-Fos expression in NTS of the OZR. In urethane-anesthetized rats, microinjections of glutamate into NTS evoked equivalent decreases in SNA, heart rate (HR), and MAP in juvenile OZR and LZR, but attenuated decreases in SNA and MAP in adult OZR. In contrast, microinjections of glutamate into the caudal ventrolateral medulla, a target of barosensitive NTS neurons, evoked comparable decreases in SNA, HR, and MAP in adult OZR and LZR. These data suggest that OZR develop impaired glutamatergic activation of the NTS, which likely contributes to attenuated baroreflexes in adult OZR.

Synthesis, anticonvulsant, sedative and anxiolytic activities of novel annulated pyrrolo[1,4]benzodiazepines.

Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation. Their anticonvulsant, sedative and anxiolytic activities were evaluated by drug-induced convulsion models, a pentobarbital-induced hypnotic model and an elevated plus maze in mice. PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests. There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

[Behavior and functional state of the dopaminergic brain system in pups of depressive WAG/Rij rats].

In the present work, it has been studied for the first time behavior and functional state of the dopaminergic brain system in pups of "depressive" WAG/Rij rats. Offspring of "depressive" WAG/Rij rats at age of 6-16 days compared with offspring of "normal" (non-depressed) outbred rats of the same age exhibited reduced rate of pshychomotor development, lower body weight, attenuation in integration of coordinated reflexes and vestibular function (greater latency of righting reflex, abnormal negative geotaxis), hyper-reactivity to tactile stimulation, reduced motivation to contact with mother (reduced infant-mother attachment). Differences in a nest seeking response induced by olfactory stimuli (olfactory discrimination test) and in locomotor activity (tests "gait reflex" and "small open field") have not been revealed. Acute injection of the antagonist of D2-like dopamine receptors clebopride 20 min before testing aggravated mother-oriented behavior in 15-days-old pups of both "depressive" and "non-depressive" rats. However this effect was greater in pups of "depressive" WAG/Rij rats compared with pups of "normal" rats that may indicate reduced functional activity of the dopaminergic brain system in offspring of "depressive" rats. It is proposed that reduced attachment behavior in pups of "depressive" WAG/Rij rats might be a consequence of maternal depression and associated with it reduced maternal care. Moreover, reduced attachment behavior in pups of "depressive" rats might be an early precursor (a marker) of depressive-like pathology which become apparent later in life (approximately at age of 3 months).

Bradykinin B2 receptor contributes to the exaggerated muscle mechanoreflex in rats with femoral artery occlusion.

Static muscle contraction activates the exercise pressor reflex, which in turn increases sympathetic nerve activity (SNA) and blood pressure (BP). Bradykinin (BK) is considered as a muscle metabolite responsible for modulation of the sympathetic and cardiovascular responses to muscle contraction. Prior studies have suggested that kinin B2 receptor mediates the effects of BK on the reflex SNA and BP responses during stimulation of skeletal muscle afferents. In patients with peripheral artery disease and a rat model with femoral artery ligation, amplified SNA and BP responses to static exercise were observed. This dysfunction of the exercise pressor reflex has previously been shown to be mediated, in part, by muscle mechanoreflex overactivity. Thus, in this report, we determined whether kinin B2 receptor contributes to the augmented mechanoreflex activity in rats with 24 h of femoral artery occlusion. First, Western blot analysis was used to examine protein expression of B2 receptors in dorsal root ganglion tissues of control limbs and ligated limbs. Our data show that B2 receptor displays significant overexpression in ligated limbs as compared with control limbs (optical density: 0.94 ± 0.02 in control and 1.87 ± 0.08 after ligation, P < 0.05 vs. control; n = 6 in each group). Second, mechanoreflex was evoked by muscle stretch and the reflex renal SNA (RSNA) and mean arterial pressure (MAP) responses to muscle stretch were examined after HOE-140, a B2 receptors blocker, was injected into the arterial blood supply of the hindlimb muscles. The results demonstrate that the stretch-evoked reflex responses were attenuated by administration of HOE-140 in control rats and ligated rats; however, the attenuating effects of HOE-140 were significantly greater in ligated rats, i.e., after 5 µg/kg of HOE-140 RSNA and MAP responses evoked by 0.5 kg of muscle tension were attenuated by 43% and 25% in control vs. 54% and 34% in ligation (P < 0.05 vs. control group; n = 11 in each group). In contrast, there was no significant difference in B1 receptor expression in both experimental groups, and arterial injection of R-715, a B1 receptors blocker, had no significant effects on RSNA and MAP responses evoked by muscle stretch. Accordingly, results obtained from this study support our hypothesis that heightened kinin B2 receptor expression in the sensory nerves contributes to the exaggerated muscle mechanoreflex in rats with femoral artery occlusion.

Exercise training normalizes the blunted central component of the baroreflex in rats with heart failure: role of the PVN.

Exercise training (ExT) normalizes the increased sympathetic outflow in chronic heart failure (HF). The underlying mechanisms are not clearly understood. We hypothesized that ExT normalized the blunted central component of the baroreflex control of renal sympathetic nerve activity (RSNA) in HF. Four groups of rats [sham operated (sham)-sedentary (Sed), sham-ExT, HF-Sed, and HF-ExT] were used. HF was induced by left coronary artery ligation, and ExT consisted of 3 wk of treadmill running. In anesthetized rats, the decrease in RSNA in response to aortic depressor nerve stimulation (5-40 Hz) in the HF-Sed group was significantly lower than that in the sham-Sed group (-37 ± 7% vs. -63 ± 8% at 40 Hz, P < 0.05). In the HF-ExT group, responses in RSNA, mean arterial pressure (MAP), and heart rate (HR) were not significantly different from those in the sham-Sed or sham-ExT groups. ExT normalized blunted RSNA, MAP, and HR responses to bicuculline microinjections into the paraventricular nucleus (PVN) in rats with HF. Activation of the PVN by blockade of GABA receptors with bicuculline in normal control rats blunted the centrally component of the baroreflex arc. GABAA-α1 and -ß1 receptor protein expression were significantly lower (by 48% and 30%) in the HF-Sed group, but ExT normalized this difference between the HF and sham groups. These data suggest that one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of central integrative mechanisms, perhaps via improving the inhibitory GABAergic mechanism within the PVN, on the baroreflex arc.

[Clinical treatment of spasticity--spastic movement disorders]. / Klinik der Spastik--spastische Bewegungsstörung.

Spasticity develops as a consequence of damage to the central nervous system (CNS). Clinically, spasticity is characterized by muscle hypertension and exaggerated reflexes and is associated with varying degrees of paresis. Together this results in the syndrome of spastic paresis. Patients suffer from impeded and retarded movement ability. Electrophysiological investigations of functional arm and leg movements (e.g. in walking) show a reduced activation of arm and leg muscles which can be explained by the loss of activating signals from motor brain centers and functional reflex systems. This effect predominates over the increased tendon-reflex activity. The reduced muscle activation caused by paresis is partially compensated by structural alterations of the muscle fibers (e.g. loss of sarcomeres). For this reason a functional improvement mostly cannot be achieved by antispastic medication which targets the deactivation of tendon-reflexes. However, they are useful in immobilized patients. In mobile patients functional improvement can be achieved by functional training which is accompanied by an adapted, i.e. reduced, spastic muscle tone.

Miller Fisher's syndrome.

Miller Fisher's syndrome is a rare variant of Guillain-Barré's syndrome characterized by the acute development of ataxia, ophthalmoparesis, and areflexia. Most patients have a measureable antibody in serum directed against the GQ1b ganglioside. This antibody is also present in the serum of patients with other forms of Guillain-Barré's syndrome who have prominent ataxia or ophthalmoplegia as part of their clinical presentation. Miller Fisher's syndrome generally is self-limited and has an excellent prognosis.

Changes in chemosensitivity and mechanosensitivity in aging and Parkinson's disease.

The risk of aspiration pneumonia in Parkinson's disease (PD) may be increased by sensory loss in the laryngopharynx and a reduced cough reflex. This study investigated changes in chemo- and mechanosensation with age and in PD and documented cough thresholds and cortical influences over cough. Single-breath citric acid inhalation cough challenge and flexible nasendoscopy were performed in 32 participants with idiopathic PD (mean age = 68.5 years, range = 45.8-82.5) and 16 healthy young adults (8 males, mean age = 25.1 years, range = 21.3-32.4), and 16 healthy elders (8 males, mean age = 72.8 years, range = 61.5-84.7) as controls. Individuals with PD had reduced sensation at the base of the tongue compared to age- and gender-matched counterparts (p < 0.005). All groups demonstrated lower natural cough thresholds than suppressed cough thresholds. No differences in natural cough thresholds were found across groups. Young adults demonstrated greater ability to suppress cough compared to healthy elders (p = 0.021). Tongue-base mechanosensory impairment in PD may account for vallecular residue and complaints of globus sensation. However, decreased cough response was not found to be a characteristic of PD. This study provided evidence for voluntary control of cough and the lack of decline of chemosensitivity with age or disease.

Toxic leukoencephalopathy due to transdermal fentanyl overdose.

Children with altered mental status who present to the emergency department have a broad differential diagnosis. We report a case of a 19-month-old girl who presented in coma and who was later found to have a fentanyl patch adhered to her back. She was found to have changes on brain magnetic resonance imaging consistent with a toxic spongiform leukoencephalopathy but had a good neurologic outcome. This case report illustrates the importance of a thorough physical examination in children in coma and a rarely reported magnetic resonance imaging finding that has been seen in opioid intoxication and is usually associated with severe morbidity and mortality.

Expression and function of CXCL12/CXCR4 in rat urinary bladder with cyclophosphamide-induced cystitis.

Chemokines, otherwise known as chemotactic cytokines, are proinflammatory mediators of the immune response and have been implicated in altered sensory processing, hyperalgesia, and central sensitization following tissue injury or inflammation. To address the role of CXCL12/CXCR4 signaling in normal micturition and inflammation-induced bladder hyperreflexia, bladder inflammation in adult female Wistar rats (175-250 g) was induced by injecting cyclophosphamide (CYP) intraperitoneally at acute (150 mg/kg; 4 h), intermediate (150 mg/kg; 48 h), and chronic (75 mg/kg; every 3rd day for 10 days) time points. CXCL12, and its receptor, CXCR4, were examined in the whole urinary bladder of control and CYP-treated rats using enzyme-linked immunosorbent assays (ELISAs), quantitative PCR (qRT-PCR), and immunostaining techniques. ELISAs, qRT-PCR, and immunostaining experiments revealed a significant (P < or = 0.01) increase in CXCL12 and CXCR4 expression in the whole urinary bladder, and particularly in the urothelium, with CYP treatment. The functional role of CXCL12/CXCR4 signaling in micturition was evaluated using conscious cystometry with continuous instillation of saline and CXCR4 receptor antagonist (AMD-3100; 5 microM) administration in control and CYP (48 h)-treated rats. Receptor blockade of CXCR4 using AMD-3100 increased bladder capacity in control (no CYP) rats and reduced CYP-induced bladder hyperexcitability as demonstrated by significant (P < or = 0.01) increases in intercontraction interval, bladder capacity, and void volume. These results suggest a role for CXCL12/CXCR4 signaling in both normal micturition and with bladder hyperreflexia following bladder inflammation.

Coma with absent brainstem reflexes resulting from zolpidem overdose.

Zolpidem is a nonbenzodiazepine hypnotic with a favorable adverse effect profile. There are single reports of respiratory decompensation associated with zolpidem overdose. We report a case ofa young woman with depression who developed deep coma with respiratory failure and a loss of brainstem reflexes as a result of zolpidem overdose. Supportive management led to a complete recovery of neurologic function. Acute zolpidem overdose should be considered in the differential diagnosis of coma with absent brainstem reflexes.

Relationship between abnormal pupillary reactivity and the outcome of a psychotropic drug overdose.

OBJECTIVE: The association between abnormal pupil reactivity (abnormal) and the outcome among patients with psychotropic drug overdose (OD) was retrospectively investigated. METHODS: The study included patients that had experienced an OD between January and December 2007. The subjects were divided into 2 groups, namely, abnormal and normal groups. RESULTS: There were 12 subjects in the abnormal and 74 subjects in the normal group. Glasgow Coma Scale in the abnormal was significantly smaller that that in the normal group. An average quantity of ingested tranquilizer per subject in the abnormal was significantly larger that those in the normal group. However, the duration of admission and survival rates between the two groups were not significantly different. CONCLUSION: The patients that experienced an OD, who demonstrated abnormal pupil reactivity, tended to have ingested larger amounts of drugs while also demonstrating severe unconsciousness. However, the patients with abnormal pupil reactivity had a favorable outcome.

Orbital trauma, bradycardia, and vomiting: trapdoor fracture and the oculocardiac reflex: a case report.

The presentation of vomiting and bradycardia after closed head trauma should invariably prompt concern for significant intracranial injury, yet other less common causes for the clinical picture do exist. This case reports one such scenario in which fracture to the patient's inferior orbital wall resulted in the rare though potentially life-threatening oculocardiac reflex, a vagally mediated phenomenon with possible respiratory, cardiovascular, and gastric motility effects.