Mechanism of bilateral communication in the suprachiasmatic nucleus

The central circadian pacemaker of the suprachiasmatic nuclei (SCN) is a bilaterally symmetrical structure. Little is known about the physiological mechanisms underlying communication between the left and right SCN and yet the degree of synchronization between SCN neurons can have a critical impact on the properties of the circadian system. In this study, we used electrophysiological tools and calcium (Ca²⁺) imaging to examine the mechanisms underlying bilateral signaling in mouse SCN. Electrical stimulation of one SCN produced responses in the contralateral SCN with a short delay (approximately 5 ms) and Ca²⁺‐dependence that are consistent with action potential‐mediated chemical synaptic transmission. Patch‐clamp recordings of stimulated cells revealed excitatory postsynaptic inward‐currents (EPSCs), which were sufficient in magnitude to elicit action potentials. Electrical stimulation evoked tetrodotoxin‐dependent Ca²⁺ transients in about 30% of all contralateral SCN neurons recorded. The responding neurons were widely distributed within the SCN with a highest density in the posterior SCN. EPSCs and Ca²⁺ responses were significantly reduced after application of a glutamate receptor antagonist. Application of antagonists for receptors of other candidate transmitters inhibited the Ca²⁺ responses in some of the cells but overall the impact of these antagonists was variable. In a functional assay, electrical stimulation of the SCN produced phase shifts in the circadian rhythm in the frequency of multiunit activity rhythm in the contralateral SCN. These phase shifts were blocked by a glutamate receptor antagonist. Taken together, these results implicate glutamate as a transmitter required for communication between the left and right SCN.     

Functional analysis of Gscl in the pathogenesis of the DiGeorge and velocardiofacial syndromes

Gscl encodes a Goosecoid-related homeodomain protein that is expressed during mouse embryogenesis. In situ hybridization and immunohistochemistry studies show that Gscl is expressed in the pons region of the developing central nervous system and primordial germ cells. Gscl expression is also detected in a subset of adult tissues, including brain, eye, thymus, thyroid region, stomach, bladder and testis. Gscl is located within a region of the mouse genome that is syntenic with the region commonly deleted in DiGeorge and velocardiofacial syndrome (DGS/VCFS) patients. DGS/VCFS patients have craniofacial abnormalities, cardiac outflow defects and hypoplasia of the parathyroid gland and thymus due to haploinsufficiency of a gene or genes located within the deleted region. Thus, the genomic location of Gscl and its expression in a subset of the tissues affected in DGS/VCFS patients suggest that Gscl may contribute to the pathogenesis of DGS/VCFS. To determine the role of Gscl during mouse embryogenesis and in DGS/VCFS, we have deleted Gscl by gene targeting in mouse embryonic stem cells. Both Gscl heterozygous and Gscl null mice were normal and fertile, suggesting that Gscl is not a major factor in DGS/VCFS. Interestingly, expression of the adjacent Es2 gene in the pons region of Gscl null fetuses was absent, suggesting that mutations within the DGS/VCFS region can influence expression of adjacent genes. In addition, embryos that lacked both Gscl and the related Gsc gene appeared normal. These studies represent the first functional analysis of a DGS/VCFS candidate gene in vivo. These Gscl null mice will be an important genetic resource for crosses with other mouse models of the DGS/VCFS.      

Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons

The mammalian suprachiasmatic nucleus (SCN) is a master circadian pacemaker. It is not known which SCN neurons are autonomous pacemakers or how they synchronize their daily firing rhythms to coordinate circadian behavior. Vasoactive intestinal polypeptide (VIP) and the VIP receptor VPAC(2) (encoded by the gene Vipr2) may mediate rhythms in individual SCN neurons, synchrony between neurons, or both. We found that Vip(-/-) and Vipr2(-/-) mice showed two daily bouts of activity in a skeleton photoperiod and multiple circadian periods in constant darkness. Loss of VIP or VPAC(2) also abolished circadian firing rhythms in approximately half of all SCN neurons and disrupted synchrony between rhythmic neurons. Critically, daily application of a VPAC(2) agonist restored rhythmicity and synchrony to VIP(-/-) SCN neurons, but not to Vipr2(-/-) neurons. We conclude that VIP coordinates daily rhythms in the SCN and behavior by synchronizing a small population of pacemaking neurons and maintaining rhythmicity in a larger subset of neurons.     

Penile vibratory stimulation yields increased spermatozoa and accessory gland production compared with rectal electroejaculation in a neurologically intact primate (Saimiri boliviensis)

Assisted reproductive techniques require an efficient semen collection procedure in cases of ejaculatory dysfunction. Anejaculation may be of psychogenic or neurogenic origin but can be overcome with stimulatory techniques. Penile vibratory stimulation (PVS) therapy for anejaculation has recently emerged as an alternative to rectal probe electroejaculation (RPE) and more invasive testicular procedures. Comparison of the stimulatory procedures in neurologically intact subjects is not ethically possible due to the discomfort involved with electroejaculation, and comparison in spinal cord injured men may be compromised due to the intricate effects of chronic denervation on semen quality. We have previously shown the efficacy of PVS in a non- human primate, the squirrel monkey. A cross-over study design comparing semen collected by PVS and RPE was employed during the breeding season in which 15 donor males were divided into two groups. One group received PVS and the other RPE, then, three days later, treatments were reversed. Twelve of 15 animals responded to PVS (80%), all with spermatozoa in the ejaculate. Mean volume (436 +/- 90 microl), motility (80.6 +/- 4.3%), and total spermatozoa (32.8 +/- 10.2 x 10(6)) were significantly higher than in the semen after RPE. RPE resulted in ejaculation in all 15 animals with a semen volume of 205 +/- 25 microl, but fewer samples contained spermatozoa (9/15) resulting in a low total count (0.5 +/- 0.3 x 10(6)). The motility was reduced in those samples with spermatozoa (n = 9; 44.1 +/- 11.4%). Additionally, accessory gland activity was measured via the seminal vesicle and prostrate markers, fructose and citric acid, respectively. The PVS specimens had significantly more fructose (2.9 +/- 0.7 mg/ejaculate) and citric acid (0.46 +/- 0.14 mg/ejaculate) compared to RPE collected specimens (1.2 +/- 0.3 mg/ejaculate and 0.24 +/- 0.04 mg/ejaculate, respectively). In conclusion, PVS produces a much greater sperm yield and increased accessory gland secretion compared to RPE in our neurologically intact squirrel monkey model.      

Dental endosseous implant assessments in a type 2 diabetic population: a prospective study

Diabetes mellitus, a prevalent disorder worldwide, is associated with systemic adverse sequelae, such as wound healing alterations, which may affect osseointegration of dental implants. This prospective multicenter study assessed the success of 2-stage endosseous root-form implants (3 different implant systems) placed in the mandibular symphysis of 89 male type 2 diabetic subjects. The implants were uncovered approximately 4 months after placement, restored with an implant-supported, Hader bar clip-retained overdenture, and maintained at scheduled follow-up data collection examinations for 60 months after loading. Sixteen (9.0%) of the 178 implants failed. Life table methods calculated implant survival at approximately 88%, from prosthesis placement through the 60-month follow-up, and at approximately 90% from implant placement through the observation period. No implants failed between surgical placement and uncovering, 5 failed at uncovering, 7 failed after uncovering before prosthesis placement, and 4 failed after prosthesis placement. Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) values were determined before implant placement (baseline) and approximately 4 months later at surgical uncovering (follow-up). The 5-year implant outcomes (successes versus failures) were analyzed against the following predictor variables: (1) baseline and follow-up FPG values, (2) baseline and follow-up HbA1c values, (3) subject age, (4) duration of diabetes (years), (5) baseline diabetic therapy, (6) smoking history, and (7) implant length. Regression analysis found only duration of diabetes (P < .025) and implant length (P < .001) to be statistically significant predictors of implant failure. There was no statistically significant difference in failure rates between the 3 different implant systems used. This study supports the use of dental implants in type 2 diabetic patients.     

Effects of an irritable bowel syndrome educational class on health-promoting behaviors and symptoms

Objective: The degree to which patient education in the areas of diet, exercise, and stress management can improve symptoms of irritable bowel syndrome (IBS) through healthier lifestyle behaviors is unknown. The aim of this study was to determine the effects of outpatient education on the short and long term outcomes, and the association between health-promoting behaviors and symptoms.
Methods: Pender's Health Promotion Model provided the theoretical framework. The study had a prospective longitudinal design. A consecutive sample of 52 adult outpatients with IBS attended a structured class that taught health-promoting modifications of lifestyle. Participants completed the Health-Promoting Lifestyle Profile (HPLP) and selected items from a Bowel Disease Questionnaire (BDQ) before the class and 1 month and 6 months later. Spearman rank correlations were used to assess the association between HPLP and symptom scores. Wilcoxon rank sum tests compared changes in scores versus their baseline values.
Results: Response rates at 1 and 6 months were 75% and 83%, respectively. Results revealed significant 1- and 6 month-improvements in pain and Manning symptoms (   p < 0.01  ) and in some HPLP scores (exercise at 1 month,   p < 0.05  ; stress management at 6 months,   p < 0.01  ). Significant associations were found between some, but not all, HPLP and symptom scores over time.
Conclusion: A structured IBS educational class for patients with IBS improved symptoms and some health-promoting behaviors. However, relationships among specific behaviors and specific symptoms did not consistently correspond with this improvement.     

Abdominal contouring procedures increase activity of the coagulation cascade

One of the most serious complications in plastic surgery is a thromboembolic event. However, little physiologic evidence exists to support the observed hypercoagulable state seen in contouring procedures. Twenty-one consecutive patients were enrolled prospectively to assess thrombin generation, which measures activity of the coagulation cascade, at baseline, intraoperative, and 24 hours after surgery. Compared with preoperative values, total thrombin generation increased by a mean of 997 nM intraoperatively (1.3-fold, P<0.004) and 1406 nM postoperatively (1.4-fold, P<0.001) in 9 patients undergoing abdominoplasty without deep venous thrombosis (DVT) chemoprophylaxis. The mean thrombin generation did not significantly change during or after surgery in 12 patients who received heparin for DVT prophylaxis (P=0.3). Thrombin generation was significantly less in patients receiving chemoprophylaxis compared with those who received no prophylaxis (P<0.01). This suggests abdominal contouring procedures induce a significant increase in the activity of the coagulation cascade that can be prevented by DVT chemoprophylaxis.     

Complications of peristomal recurrence of Crohn's disease: a case report and a review of literature

Patients with Crohn's disease and colonic inflammation that proves refractory to medical therapy often require a proctocolectomy and end ileostomy. Disease recurrence can occur despite creation of an end ileostomy and may lead to peristomal complications such as fistula formation, abscesses, stoma retraction, or strictures. We present the case of a 51-year-old man with medically refractory ileocolonic Crohn's disease who underwent a proctocolectomy with end ileostomy. The disease course was complicated by recurrence of ileal Crohn's disease despite biological therapy. The patient presented with peristomal complications including an enterocutaneous fistula, stoma retraction, and an ileal stricture necessitating surgical revision of the ileostomy. Review of literature confirms an approximately 30% risk of recurrence of Crohn's disease after an end ileostomy. A penetrating phenotype and preexisting ileal disease are risk factors for disease recurrence. A thorough evaluation of the stoma/peristomal area and evaluation of the small bowel by ileoscopy and small bowel imaging are required to assess the extent of disease and extraluminal complications such as stomal retraction and fistulas that require further surgical intervention. While postoperative medical treatment with immunosuppression or biological therapy is often employed, these therapies are unproven to prevent postoperative recurrence in the setting of a stoma.