rKv1.2 overexpression in the central medial thalamic area decreases caffeine-induced arousal.

The voltage-gated potassium channel Kv1.2 belongs to the shaker-related family and has recently been implicated in the control of sleep profile on the basis of clinical and experimental evidence in rodents. To further investigate whether increasing Kv1.2 activity would promote sleep occurrence in rats, we developed an adeno-associated viral vector that induces overexpression of rat Kv1.2 protein. The viral vector was first evaluated in vitro for its ability to overexpress rat Kv1.2 protein and to produce functional currents in infected U2OS cells. Next, the adeno-associated Kv1.2 vector was injected stereotaxically into the central medial thalamic area of rats and overexpression of Kv1.2 was showed by in situ hybridization, ex vivo electrophysiology and immunohistochemistry. Finally, the functional effect of Kv1.2 overexpression on sleep facilitation was investigated using telemetry system under normal conditions and following administration of the arousing agent caffeine, during the light phase. While no differences in sleep profile were observed between the control and the treated animals under normal conditions, a decrease in the pro-arousal effect of caffeine was seen only in the animals injected with the adeno-associated virus-Kv1.2 vector. Overall, our data further support a role of the Kv1.2 channel in the control of sleep profile, particularly under conditions of sleep disturbance.

Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response.

Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here, we demonstrate that loss of HtrA2 results in transcriptional upregulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson's disease patients' brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.

The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects.

BACKGROUND AND PURPOSE: Atypical cannabinoids are thought to cause vasodilatation through an as-yet unidentified 'CBx' receptor. Recent reports suggest GPR55 is an atypical cannabinoid receptor, making it a candidate for the vasodilator 'CBx' receptor. The purpose of the present study was to test the hypothesis that human recombinant GPR55 is activated by atypical cannabinoids and mediates vasodilator responses to these agents. EXPERIMENTAL APPROACH: Human recombinant GPR55 was expressed in HEK293T cells and specific GTPgammaS activity was monitored as an index of receptor activation. In GPR55-deficient and wild-type littermate control mice, in vivo blood pressure measurement and isolated resistance artery myography were used to determine GPR55 dependence of atypical cannabinoid-induced haemodynamic and vasodilator responses. KEY RESULTS: Atypical cannabinoids O-1602 and abnormal cannabidiol both stimulated GPR55-dependent GTPgammaS activity (EC50 approximately 2 nM), whereas the CB1 and CB2-selective agonist WIN 55,212-2 showed no effect in GPR55-expressing HEK293T cell membranes. Baseline mean arterial pressure and heart rate were not different between WT and GPR55 KO mice. The blood pressure-lowering response to abnormal cannabidiol was not different between WT and KO mice (WT 20+/-2%, KO 26+/-5% change from baseline), nor was the vasodilator response to abnormal cannabidiol in isolated mesenteric arteries (IC50 approximately 3 micro M for WT and KO). The abnormal cannabidiol vasodilator response was antagonized equivalently by O-1918 in both strains. CONCLUSIONS: These results demonstrate that while GPR55 is activated by atypical cannabinoids, it does not appear to mediate the vasodilator effects of these agents.

Free-grafting of mandibular condyle fractures: clinical outcomes in 10 consecutive patients.

"Free-grafting" of the superior segment, either alone or in combination with a posterior ramus osteotomy, is occasionally required when managing displaced condylar neck fractures. This allows ideal reduction and fixation, but carries the risk of proximal segment resorption, possibly requiring secondary reconstruction. The purpose of this study was to evaluate the clinical and radiographic outcomes of this technique in all patients who underwent this procedure during a seven-year period at a tertiary care centre. Ten patients who had undergone 11 free graft procedures were included in the study. Three patients required secondary costochondral reconstruction due to advanced resorption of the free-grafted condylar segment, this occurring from 3 to 9 months following the initial trauma surgery. All but one of the remaining patients exhibited varying degrees of condylar resorption/flattening radiographically, occurring within the first year only. However, no occlusal changes occurred in this group either objectively or subjectively during this year or during the subsequent follow-up period. The mean inter-incisal opening was 47mm (range 40-56). With the exception of one patient that had a non-painful reciprocal click of the treated side, no patients demonstrated either objective or subjective signs of TMJ pathology. No patients reported dietary limitations, and all reported satisfaction with treatment to date. Based on objective and subjective evaluation, free grafting of the fractured condylar segment in this patient population had a 70% success rate. All failures occurred within 9 months and required secondary costochondral reconstruction.

Prevalence and significance of retinopathy in subjects with type 1 diabetes of less than 5 years' duration screened for the diabetes control and complications trial.

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated the powerlul impact of glycemic control on the progression of diabetic retinopathy. A large number of individuals (2,771) underwent stereoscopic color photography and fluorescein angiography as part of screening for participation in the DCCT. A subgroup of those individuals screened participated in the DCCT and underwent evaluation of their retinal vasculature semiannually for 4-9 years. These data were evaluated to determine how the 2000 American Diabetes Association position statement would apply to the DCCT experience. Specifically, the position statement indicates that the first dilated eye examination should be performed after 3-5 years' duration of diabetes because vision-threatening retinopathy virtually never develops in patients with type 1 diabetes during that interval RESEARCH DESIGN AND METHODS: We examined the experience of the DCCT in evaluating retinal photographs in 1,613 patients with type 1 diabetes of <5 years' duration and follow-up photographs every 6 months for 4-9 years in 855 members of that group. RESULTS: Of 1,613 subjects with type 1 diabetes of <5 years' duration screened for the DCCT, 716 (44.4%) had stereo-color photographic evidence of diabetic retinopathy, and 6 had preproliferative or worse pathology. Fluorescein angiography revealed retinopathy in 158 of 713 subjects with no evidence of retinopathy on color photographs. Thus, 874 (54.2%) of the original 1,613 subjects had retinopathy at baseline. DCCT follow-up identified 341 additional individuals in whom retinopathy was developing before 5 years; 1,083 of 1,613 (67.1%) individuals screened for the DCCT had retinopathy before 5 years' duration of diabetes. Those with retinopathy before 5 years had more rapid three-step progression of vascular pathology than those with no retinopathy. CONCLUSIONS: Dilated eye examinations and retinal photography should be included in the routine management of type 1 diabetes during the first 5 years to identify the individuals at greatest risk for vision-threatening problems.

Obstructive sleep apnea syndrome: diagnosis and management.

Increased awareness that changes in sleeping habits and daytime behaviour may be attributable to obstructive sleep apnea syndrome (OSAS) has led many patients to seek both information and definitive treatment. The purpose of this article is to provide information to dentists that will enable them to identify patients who may have OSAS and to assist these patients in making informed decisions regarding treatment options. In patients who have identifiable anatomic abnormalities of the maxilla and mandible resulting in a narrow pharyngeal airway, orthognathic surgery appears to be an excellent treatment option.

Cleft lip and palate: a review for dentists.

The goals of primary closure of cleft lip and palate include not only re-establishing normal insertions for all of the nasolabial muscles but also restoring the normal position of all the other soft tissues, including the mucocutaneous elements. Conventional surgical wisdom, which recommends waiting until growth is complete before undertaking surgical correction of the postoperative sequelae of primary cheiloplasty, carries with it many disadvantages. If, after primary surgery of the lip, orolabial dysfunctions remain, they will exert their nefarious influences during growth and will themselves lead to long term dentofacial imbalances. These imbalances can significantly influence facial harmony. Unless accurate, symmetric and functional reconstruction of the nasolabial muscles is achieved during the primary surgery, not only will the existing dentoskeletal imbalances be exaggerated, but other deformities will be caused during subsequent growth, among which the most important are nasal obstruction and mouth breathing, reduced translation of the maxilla, dysymmetry of the nose and inability of the patient to symmetrically project the upper lip

Diabetic cardiomyopathy and carnitine deficiency.

This study was designed to study the pathogenesis of cardiomyopathy in animals with longstanding (6 months) diabetes mellitus. Male Wistar rats were made diabetic by the injection of streptozotocin (35 mg/kg) intraperitoneal at 6 months of age. Myocardial contractility was evaluated at 1 year of age by an echocardiogram. Blood was collected at that time to measure blood glucose and hemoglobin A1c as an indicator of metabolic control. Serum carnitine was also measured on the same sample to evaluate the availability of this substance so essential for fatty acid metabolism in the myocardium. Myocardial anatomy was evaluated by both light and electron microscopy after the animals had diabetes for 6 months. It was found that the left ventricular volume was greater at the end of systole and diastole. There was the suggestion of left ventricular fractional shortening and calculated reduced ejection fraction indicating decreased contractility consistent with cardiomyopathy. The hearts had no evidence of coronary vascular occlusion, and the serum cholesterol was normal. Myocardial ultrastructure revealed abnormal-appearing mitochondria consistent with carnitine deficiency. Serum and myocardial carnitine levels in the animals with diabetes and reduced myocardial function were low. Carnitine levels and metabolism could be important in the pathogenesis of diabetic cardiomyopathy.

Preparing for medical emergencies in the dental office.

If you discover an unconscious patient in your office, attend to the ABCs while you evaluate the patient's medical history and piece together the events leading up to the emergency. These actions will help you arrive at a diagnosis. Then as the emergency cart and team arrive, you will be able to provide good, safe care to stabilize the patient and get him or her to a medical facility.

A computerized model for home glucose monitoring proficiency testing: efficacy of an innovative testing program.

PURPOSE: A newly instituted computerized system for proficiency testing of home glucose monitoring was evaluated comparing accuracy of patient determination of glucose with serum values measured in the laboratory. METHODS: Patients returning for routine blood glucose testing ordered by their care provider brought their glucose monitoring equipment to the laboratory. They performed a finger-stick glucose check in the laboratory while the laboratory phlebotomist drew blood for glucose determination; both results were computer analyzed. Patients with a 25% or less variation from the laboratory were considered proficient, while those with greater than 25% variation were defined as nonproficient. RESULTS: Over a 19-month period, 300 of the 3208 patients notified about the study completed proficiency testing at least once. Using the defined proficiency of 25% variation or less, 12% of the participants were nonproficient. Using a variation of 15% or less, 31% of patients were nonproficient. CONCLUSIONS: An annual methodology evaluation such as the one in this study should become a standard of care to identify patients for remedial classes to correct the source of error. The goal must be to meet or exceed the American Diabetes Association standard of 15% total error in home glucose monitoring.

1 + 1 = r4 and much much more.

Expression and mutational analysis has shown that the vertebrate Hox genes are instrumental in patterning of the developing embryo. However, the combined effects of functional redundancy, compensation, and synergy often obscure the precise roles of these genes. By combining gene targeting strategies with the analysis of regulatory sequences from the Hoxa1 and Hoff1 genes, it has been possible to bypass some of these complications and demonstrate their genetic and functional interactions during the development of the hindbrain and branchial arches.

The management of first seizures in adults in a district general hospital.

This study considered the management of first seizures in adults in Stirling Royal Infirmary over a six month period. Thirty-four patients presented of whom 19 were admitted to medical wards. Alcohol was implicated in 35% of cases. Blood tests were done in many but provided little useful information. CT Scan was performed in 53% and was abnormal in 15% (five patients). EEG was requested for 21% and failed to influence management in any. Six patients (18%) were started on anticonvulsant therapy. It was recorded in only three cases that advice on driving had been given. The literature concerning single seizures is complex, especially with regards to recurrence risk and treatment benefits. We await with interest the publication of the SIGN (Scottish Intercollegiate Guidelines Network) guidelines for seizure investigation and treatment in Scotland.

The use of silastic as an orbital implant for reconstruction of orbital wall defects: review of 311 cases treated over 20 years.

PURPOSE: A retrospective review of silicone rubber (Silastic; Dow Corning, Midland, MI) implants placed in orbits was undertaken. These implants were used to reconstruct defects in the orbital floor and/or walls secondary to trauma, or those created during malar or orbital osteotomies. The purpose of the study was to determine the incidence of removal of these implants from the surgical site. MATERIALS AND METHODS: The records of 311 patients treated over a 20-year period were reviewed. Of these, 302 had received silastic implants secondary to trauma. RESULTS: Forty-one patients (13%) had their implant removed at a second operation. The reasons for removal included infection, migration of the implant, worsening eye sign such as diplopia, and others. CONCLUSION: Because there was a clinically significant rate of removal of this material, consideration should be given to the use of other available materials.

Effect of inhibition of polyol pathway activity on aortic smooth muscle metabolism.

The relationship was examined between increased polyol pathway activity and the changes in water content, respiration, and glycolysis that occur when tubular segments of rabbit aortic smooth muscle cells are incubated with elevated glucose concentrations. The presence of 1.0 mmol/L ibuprofen resulted in a 65% reduction in fructose production by tissue incubated with 50 mmol/L glucose. This was associated with an increase in intracellular glucose and decreases in aortic smooth muscle sorbitol and fructose consistent with an inhibition of aldose reductase. Inhibition of increased polyol pathway activity usually observed in tissue incubated with 50 mmol/L glucose, is accompanied by a decrease in tissue water, an increase in oxygen uptake, and a decrease in lactate production. This suggests a causal relationship between increased polyol pathway activity and the changes in the aortic water content and metabolism induced by an elevated medium glucose concentration, although this would not be predicted by the osmotic hypothesis. The mechanism(s) responsible for the prevention of metabolic changes seen in an elevated glucose concentration by the aldose reductase inhibitor remain to be elucidated.

Glucose concentration in the dialysate and lipid abnormalities in chronic hemodialysis patients.

In order to assess the effect of varying glucose concentrations on plasma lipids, we first compared the hormonal response of nine non-diabetic patients during dialysis with a high (200 mg/dl) and a low (100 mg/dl) glucose bath. Insulin and growth hormone production increased (p less than 0.05) only with the high glucose bath, and no hemodynamic differences were noted during either dialyses. We then compared lipid profiles of 18 patients for 6 months, changing the glucose dialysate concentrations in each patient after three months. We found that all patients had hypertriglyceridemia, mild hypercholesterolemia, low HDL, normal LDL, and high VLDL cholesterol. We therefore conclude that episodic hyperinsulinemia and episodic excessive growth hormone secretion do not contribute significantly to the lipid abnormalities of the dialysis patients.

Rapid glucose-dependent increases in phosphatidic acid and phosphoinositides in rat pancreatic islets.

Glucose effects on islet phospholipids were examined during direct incubation or after 3 days of 32P prelabeling in primary culture. In both cases, glucose increased the 32P content of phosphatidic acid (PA), phosphatidylinositol (PI), and polyphosphoinositides (PPI). Glucose-induced increases in PA, PI, and PPI in the culture-prelabeling experiments were evident within 1 min, dose related, and reflective of increases in phospholipid mass, which was confirmed in direct incubations by measurement of PI phosphorus. Thus, in addition to increasing PI-PPI hydrolysis, glucose increases de novo phospholipid synthesis in pancreatic islets. The latter may result from enhanced glycolysis and substrate availability for PA-PI-PPI synthesis, since glyceraldehyde and pyruvic acid also increased PI levels. Our findings raise the possibility that increases in PA, PI, and PPI synthesis could serve as a mechanism to enhance the generation of intracellular mediators, which are purported to regulate insulin secretion.

Oral sulfonylureas for the treatment of type II diabetes: an update.

Oral hypoglycemic agents have been in clinical use since 1956 in the United States. Two new second-generation sulfonylureas, glipizide and glyburide, have been marketed recently. This article reviews the pharmacology of the oral sulfonylureas, compares the drugs from a safety and efficacy standpoint, and provides updated information regarding their use in the management of type II non-insulin-dependent diabetes mellitus.