Interplay between heredity and environment in the recent explosion of type 1 childhood diabetes mellitus

The fast increase in the incidence of childhood type 1 diabetes mellitus (T1DM) that cannot be explained by changes in the genetic susceptibility, led us to look for environmental causes. To test the hypothesis that the initiation of the autoimmune process of childhood T1DM in genetically susceptible subjects begins in the perinatal period by a viral infection, we studied the seasonal variations in the month of birth of several cohorts of patients compared to the general population. Population groups with high or low T1DM incidence were analyzed separately by t-test and the Cosinor methods. In areas with populations with a high incidence (Israeli Jews, Sicily, Sardinia, Slovenia, Germany) we found that the children (in Sicily also young adults) who subsequently developed T1DM, have a higher incidence of births in the summer months than in other seasons of the year, a mirror image of the seasonality of the clinical onset of disease. This pattern differed significantly from the seasonality of the total live births in the same populations. In populations with a low T1DM incidence, (China, Japan and Cuba) no seasonality of month of birth was found. Similar findings have been reported, from five counties in the U.K. and the Netherlands. It is hypothesized that mothers who become pregnant during the period of yearly viral epidemics transmit to the fetus, either a virus or antiviral antibodies, which determine whether an autoimmune process against the pancreatic beta is initiated or whether the fetus is protected against that process.     

Sildenafil citrate for the sexual dysfunction in antidepressant-treated male patients with posttraumatic stress disorder. A preliminary pilot open-label study

BACKGROUND: Previous studies have suggested that posttraumatic stress disorder (PTSD) may be associated with pervasive sexual dysfunction. Sildenafil citrate was established as a highly effective and well-tolerated oral agent for the treatment of sexual dysfunction of various etiologies. There are no studies that have examined the efficacy of oral sildenafil in PTSD patients with sexual dysfunction. OBJECTIVE: The current study evaluated the impact of sildenafil added to an ongoing antidepressive treatment in male PTSD patients. METHODS: Ten consecutive male PTSD patients who complained of sexual dysfunction were enrolled in an open-label 4-week fixed-dose study of sildenafil citrate 50 mg/day p.r.n. Patients were evaluated at baseline and after treatment with the Clinician-Administered PTSD Scale (CAPS); sexual function assessments were performed using the International Index of Erectile Function. RESULTS: All patients completed the study and statistically significant improvement was observed in all evaluated domains of sexual functioning: erectile function (53.5%), orgasmic function (40.3%), sexual desire (53%), intercourse satisfaction (82%) and overall satisfaction (57.4%). Oral sildenafil treatment appeared to be well tolerated and no single patient stopped the treatment. Improvements in various CAPS subscales were also obtained; however, there was no significant correlation between improvement in sexual functioning and the changes in CAPS subscale scores. CONCLUSION: Sildenafil seems to be an efficacious, safe and well-tolerated treatment of sexual dysfunction in antidepressant-treated male PTSD patients.     

Steroid Hormone Action in Musculoskeletal Cells Involves Membrane Receptor and Nuclear Receptor Mechanisms

Steroid hormones regulate target cells through traditional nuclear mechanisms as well as by membrane mechanisms. 1 &#102 ,25(OH) 2 D 3 and 24R,25(OH) 2 D 3 bind membrane receptors (mVDR) and mediate their effects on the physiological responses of musculoskeletal cells via protein kinase C (PKC). In cultures of costochondral growth plate chondrocytes, 1 &#102 ,25(OH) 2 D 3 binds the 1,25-mVDR in growth zone cells, activating phospholipase C (PLC), leading to diacylglycerol (DAG) production and PKC translocation to the plasma membrane. It also activates PLA 2 , increasing arachidonic acid release and prostaglandin synthesis. 24R,25(OH) 2 D 3 binds its membrane receptor in resting zone chondrocytes, activating phospholipase D (PLD), and increasing DAG and PKC activity, but translocation does not occur. PLA 2 activity is decreased, reducing arachidonic acid and prostaglandin production. 17 &#103 -Estradiol (E 2 ) activates PKC in both cartilage cells, but DAG is not involved. 1 &#102 ,25(OH) 2 D 3 and 24R,25(OH) 2 D 3 also increase PKC in osteoblasts in a cell-specific manner. Antibodies to the 1,25-mVDR block PKC activation. Membrane-mediated events influence gene expression via signaling cascades, including the ERK1/2 MAP kinases. The ability of steroid hormones to initiate events nongenomically is important for regulation of matrix vesicle (MV) function in the extracellular matrix. MVs have mVDRs, but ligand binding inhibits PKC-zeta (PKC &#145 ) via a mechanism that differs from PKC &#102 activation in the plasma membranes. Treatment of MVs from growth zone chondrocyte cultures with 1 &#102 ,25(OH) 2 D 3 releases stromelysin-1 (MMP-3) and increases TGF- &#103 activation. MMP-3 is also involved in proteoglycan degradation, facilitating calcification. 24R,25(OH) 2 D 3 inhibits PKC &#145 in MV from resting zone cell cultures and inhibits MMP-3 release. Chondrocytes and osteoblasts produce 1,25(OH) 2 D 3 , 24,25(OH) 2 D 3 , and E 2 ; thus, locally produced steroids may function as autocrine regulators of matrix events, including matrix vesicle enzyme activity and matrix protein remodelling during longitudinal growth, calcification, and growth factor activation.     

Laser Sintered Porous Ti–6Al–4V Implants Stimulate Vertical Bone Growth

The objective of this study was to examine the ability of 3D implants with trabecular-bone-inspired porosity and micro-/nano-rough surfaces to enhance vertical bone ingrowth. Porous Ti–6Al–4V constructs were fabricated via laser-sintering and processed to obtain micro-/nano-rough surfaces. Male and female human osteoblasts were seeded on constructs to analyze cell morphology and response. Implants were then placed on rat calvaria for 10 weeks to assess vertical bone ingrowth, mechanical stability and osseointegration. All osteoblasts showed higher levels of osteocalcin, osteoprotegerin, vascular endothelial growth factor and bone morphogenetic protein 2 on porous constructs compared to solid laser-sintered controls. Porous implants placed in vivo resulted in an average of 3.1 ± 0.6 mm³ vertical bone growth and osseointegration within implant pores and had significantly higher pull-out strength values than solid implants. New bone formation and pull-out strength was not improved with the addition of demineralized bone matrix putty. Scanning electron images and histological results corroborated vertical bone growth. This study indicates that Ti–6Al–4V implants fabricated by additive manufacturing to have porosity based on trabecular bone and post-build processing to have micro-/nano-surface roughness can support vertical bone growth in vivo, and suggests that these implants may be used clinically to increase osseointegration in challenging patient cases.     

Sarcoidosis Presenting as “Corset-like” Myelopathy: A Description of Six Cases and Literature Review

Sarcoidosis of the spinal cord is rare, even more so as the initial presentation of the disease. We describe six cases of spinal cord sarcoidosis and delineate a distinguishing feature which may allow for a timely diagnosis. All patients were admitted with complaints of a “corset-like” pressure in the lower chest and later developed cranial nerve palsies (two patients), parasthesias/paraparesis (two patients), fever of unknown origin (one patient), and bilateral proptosis (one patient). Serological tests, immunological screening, cerebrospinal fluid (CSF) analysis, bacteriological and viral testing were performed in all patients. Spinal and cerebral MRI, high-resolution computed tomography (HRCT) of the chest and gallium scan suggested the diagnosis of neurosarcoidosis of the spine while a biopsy of mediastinal lymph nodes, extra-ocular muscles, or spinal cord confirmed it. CSF showed inflammatory signs in 66% of patients and serum ACE levels were increased in a similar fraction. MRI revealed a gadolinium-enhanced thickening of the cord at the thoracic level in three patients whereas three other patients had normal spinal MRI despite similar symptoms. The presence of mediastinal lymphadenopathy on HRCT of the chest suggested the diagnosis in a third of patients. Patients were treated with steroid, immunosuppressive therapy and/or biologic therapies, with complete resolution in one case, improvement in four, and a somewhat deteriorating course, with development of spinal cord atrophy in the final case. As spinal cord involvement of sarcoidosis is extremely rare, making the diagnosis in the absence of systemic disease is challenging. The cases herein described suggest that sensory disturbance in a “corset-like” distribution may be indicative of neurosarcoidosis, especially when accompanied by extra-axial involvement such as cranial nerve palsies. This should prompt an evaluation for systemic involvement, keeping in mind that serum ACE and chest radiographs may be normal in the presence of primarily CNS-limited disease.     

Maternal and neonatal outcome following cerebrovascular accidents during pregnancy

Objective. To assess the clinical characteristics of maternal and neonatal outcome among women with cerebrovascular accidents (CVA) during pregnancy.

Methods. Our computerized database was used to identify patients with CVA during pregnancy and puerperium from January 1988 to March 2004. Their medical records were identified and reviewed.

Results. There were 16 cases of CVA among 173 803 deliveries, giving a risk of almost one case per 10 000 pregnant women. Out of 16 patients, 14 (88%) had a stroke and the remaining two cases were diagnosed with venous thrombosis. Of those 14 cases, nine (64%) had ischemic strokes and five (36%) had hemorrhagic strokes. Ten of the CVAs occurred antepartum, two intrapartum and four postpartum. Hypertensive disorders were diagnosed in 75% (12/16) of the patients. Out of these 12 patients with hypertension, 9 (75%) suffered from preeclampsia. One woman had a history of chronic hypertension. Smoking was associated with 63% (10/16) of the cases. There were two maternal deaths, both in women who had hemorrhagic strokes, and both in the first half of the study (1994 and 1996). Nine out of 16 women (56%), were delivered within 48 hours of the CVA including 7 (78%) antepartum, and two (22%) intrapartum. Cesarean deliveries were performed in 11/16 women (69%) including 8/10 with CVAs occurring antepartum, 1/2 intrapartum and 2/4 postpartum. One case of neonatal mortality was identified in a patient who was delivered at 24 gestational weeks.

Conclusions. (1) Hypertensive disorders and smoking were the most important factors associated with CVA during pregnancy. (2) Maternal mortality was high among patients with CVA during pregnancy. (3) Neonatal outcome was considered generally good in cases of CVA.     

Laparoscopic sleeve gastrectomy as a revisional option after gastric band failure

Background  

Laparoscopic adjustable gastric banding (LAGB) is an effective bariatric procedure with low morbidity and mortality. Unfortunately, it is fraught with high failure rates in long-term follow-up. Laparoscopic sleeve gastrectomy (LSG) is an emerging procedure, quickly gaining momentum in the arsenal of bariatric practice as a first step toward gastric bypass/biliopancreatic diversion or as a stand-alone operation. Recently, it has been described as a revisional option for previous bariatric surgery failures. We report our early experience with LSG as a revisional procedure for failed LAGB.