Alterations in the testis and epididymis associated with loss of function of the cystatin-related epididymal spermatogenic (CRES) protein

Cystatin-related epididymal spermatogenic protein (CRES) or cystatin 8 (Cst8 gene) is a member of the cystatin superfamily of cysteine protease inhibitors. It differs from typical cystatins because it lacks consensus sites for cysteine protease inhibition and exhibits reproductive-specific expression. In the present study, we examined CRES expression within the testes, efferent ducts, and epididymides of normal mice by light microscope immunolocalization. Alterations to these tissues in male mice lacking the Cst8 gene (Cst8(-/-2)) were also characterized by histomorphometry and electron microscopy. In the normal testis, CRES was localized exclusively in mid and late elongating spermatids. In the efferent ducts, CRES was localized to the apical region of the epithelial cells suggestive of localization in the endosomes. In the initial segment of the epididymis, principal cells showed supranuclear and luminal reactions. In the cauda region, CRES was present exclusively as aggregates in the lumen and was detected in clear cells. Compared with wild-type mice (Cst8(+/+)), older (10-12 months) Cst8(-/-) mice had modest but statistically significant reductions in tubular, epithelial, and/or luminal profile areas in the testis and epididymis. By electron microscopy, some Cst8(-/-) tubules in the testis were normal in appearance, but others showed a vacuolated seminiferous epithelium, degenerating germ cells, and alterations to ectoplasmic specializations. In the epididymal lumen, abnormally shaped sperm heads and tails were noted along with immature germ cells. In addition, principal cells contained numerous large irregularly shaped lysosomes suggestive of disrupted lysosomal functions. In both the testis and epididymis, however, these abnormalities were not apparent in younger mice (4 months), only in the older (10-12 months) Cst8(-/-) mice. These findings suggest that the altered testicular and epididymal histology reflects a cumulative effect of the loss of CRES and support a role for CRES in maintaining the normal integrity and function of the testis and epididymis.     

Post-transplant Lymphoproliferative Syndrome in the Pediatric Liver Transplant Population

Post-transplant lymphoproliferative disease remains a complication with a high morbidity and mortality. The present study examined 291 pediatric liver transplants performed in 263 children from October 1984 to December 1999. Post-transplant lymphoproliferative disease has an overall incidence of 12%. Tacrolimus and cyclosporine had a similar incidence of post-transplant lymphoproliferative disease. Fifty-six per cent of patients who developed post-transplant lymphoproliferative disease were Epstein-Barr virus negative at the time of transplantation. Mean time of conversion to Epstein-Barr virus positivity was 1.1 years after liver transplantation. Ten per cent of those who developed post-transplant lymphoproliferative disease never had Epstein-Barr virus detected. Mean time from Epstein-Barr virus positivity to detection of post-transplant lymphoproliferative disease was 2.68 years, and 3.13 years from liver transplantation (OLTx) to post-transplant lymphoproliferative disease. There was a 35% incidence of mortality. Deaths occurred a mean of 0.76 years after diagnosis of post-transplant lymphoproliferative disease. Most cases of post-transplant lymphoproliferative disease had extranodal location. There was one recurrence in 10% of patients, and two in 3%. All recurrent cases were seen in recipients who became Epstein-Barr virus positive after transplantation. There has been a decrease in the incidence of post-transplant lymphoproliferative disease from 15% to 9% to 4%. Post-transplant lymphoproliferative disease should be diagnosed promptly and treated aggressively. The best treatment, however, seems to be prevention, starting in the immediate postoperative period. Survivors should be monitored for both recurrence of post-transplant lymphoproliferative disease and acute cellular rejection.     

Safety and efficacy of a novel polyethylene glycol hydrogel sealant for watertight dural repair

OBJECT: The authors prospectively evaluated the safety and efficacy of a novel polyethylene glycol (PEG) hydrogel sealant in patients undergoing elective cranial surgery with documented cerebrospinal fluid (CSF) leakage after sutured dural repair. METHODS: The PEG hydrogel sealant was used at 11 different study sites in 111 patients with documented intraoperative CSF leakage after neurosurgical dural repair for a variety of conditions. Intraoperative CSF leakage was either spontaneous or induced by a Valsalva maneuver. Patients were monitored for 3 months postoperatively with physical examinations, clinical laboratory analyses, and diagnostic imaging. The PEG hydrogel sealant was 100% effective in stopping CSF leakage in all patients. There were no sealant-related adverse events and all clinical outcomes were consistent with expectations for seriously ill patients undergoing prolonged neurosurgical procedures. CONCLUSIONS: The PEG hydrogel sealant provides a safe and effective watertight closure when used as an adjunct to sutured dural repair during cranial surgery.     

Task-Induced Brain Activity Patterns in Type 2 Diabetes: A Potential Biomarker for Cognitive Decline

Patients with type 2 diabetes demonstrate reduced functional connectivity within the resting state default mode network (DMN), which may signal heightened risk for cognitive decline. In other populations at risk for cognitive decline, additional magnetic resonance imaging abnormalities are evident during task performance, including impaired deactivation of the DMN and reduced activation of task-relevant regions. We investigated whether middle-aged type 2 diabetic patients show these brain activity patterns during encoding and recognition tasks. Compared with control participants, we observed both reduced 1) activation of the dorsolateral prefrontal cortex during encoding and 2) deactivation of the DMN during recognition in type 2 diabetic patients, despite normal cognition. During recognition, activation in several task-relevant regions, including the dorsolateral prefrontal cortex and DMN regions, was positively correlated with HbA_1c and insulin resistance, suggesting that these important markers of glucose metabolism impact the brain’s response to a cognitive challenge. Plasma glucose ≥11 mmol/L was associated with impaired deactivation of the DMN, suggesting that acute hyperglycemia contributes to brain abnormalities. Since elderly type 2 diabetic patients often demonstrate cognitive impairments, it is possible that these task-induced brain activity patterns observed in middle age may signal impending cognitive decline.     

A practical approach to cerebral near‐infrared spectroscopy (NIRS) directed hemodynamic management in noncardiac pediatric anesthesia

Safeguarding cerebral function is of major importance during pediatric anesthesia. Premature, ex‐premature, and full‐term neonates can be vulnerable to physiological changes that occur during anesthesia and surgery. Data from studies performed during pediatric cardiac surgery and in neonatal/pediatric intensive care units have shown the benefits of near‐infrared spectroscopy (NIRS) monitoring of regional cerebral oxygenation (c‐rSO₂). However, NIRS monitoring is seldom used during noncardiac pediatric anesthesia. Despite compelling evidence that blood pressure does not reflect end‐organ perfusion, it is still regarded as the most important determinant of cerebral perfusion and the most relevant hemodynamic management target parameter by most (pediatric) anesthetists. The principle of NIRS monitoring is not self‐explanatory and sometimes seems even counterintuitive, which may explain why many anesthesiologists are reserved regarding its use. The first part of this paper is dedicated to a clinical introduction to NIRS monitoring. Despite scientific efforts, it has not yet been possible to define individual lower limit c‐rSO₂ values and it is unlikely this will succeed in the near future. Nonetheless, published treatment algorithms usually specify c‐rSO₂ values which may be associated with cerebral hypoxia. Our treatment guideline for maintaining sufficient cerebral oxygenation differs fundamentally from all previously published approaches. We define a baseline c‐rSO₂ value, registered in the awake child prior to anesthesia induction, as the lowest acceptable limit during anesthesia and surgery. The cerebral rSO₂ is the single target parameter, while blood pressure, heart rate, P_aCO₂, and SaO₂ are major parameters that determine the c‐rSO2. Cerebral NIRS monitoring, interpreted together with its continuously available contributing parameters, may help avoid potentially harmful episodes of cerebral desaturation in anesthetized pediatric patients.     

Benign cecal ulcers

Benign ulceration of the cecum is an uncommon lesion. Most cases are diagnosed intraoperatively and most authors have advocated right hemicolectomy due to the difficulty in differentiating benign from malignant lesions. Recently colonoscopic diagnosis and conservative treatment have been reported. We describe six cases of cecal ulcer ranging from asymptomatic lesions diagnosed at colonoscopy and healing with conservative management to perforated ulcers with intra-abdominal abscesses requiring right hemicolectomy. A selective approach to patient management is advocated, including stapler wedge cecectomy with frozen section diagnosis to avoid extensive bowel resection and retain the ileocecal valve.     

The association of concurrent vitamin D and sex hormone deficiency with bone loss and fracture risk in older men: The osteoporotic fractures in men (MrOS) study

Low 25‐hydroxyvitamin D (VitD), low sex hormones (SH), and high sex hormone binding globulin (SHBG) levels are common in older men. We tested the hypothesis that combinations of low VitD, low SH, and high SHBG would have a synergistic effect on bone mineral density (BMD), bone loss, and fracture risk in older men. Participants were a random subsample of 1468 men (mean age 74 years) from the Osteoporotic Fractures in Men Study (MrOS) plus 278 MrOS men with incident nonspine fractures studied in a case‐cohort design. “Abnormal” was defined as lowest quartile for VitD (<20 ng/mL), bioavailable testosterone (BioT, <163 ng/dL), and bioavailable estradiol (BioE, <11 pg/mL); and highest quartile for SHBG (>59 nM). Overall, 10% had isolated VitD deficiency; 40% had only low SH or high SHBG; 15% had both SH/SHBG and VitD abnormality; and 35% had no abnormality. Compared to men with all normal levels, those with both SH/SHBG and VitD abnormality tended to be older, more obese, and to report less physical activity. Isolated VitD deficiency, and low BioT with or without low VitD, was not significantly related to skeletal measures. The combination of VitD deficiency with low BioE and/or high SHBG was associated with significantly lower baseline BMD and higher annualized rates of hip bone loss than SH abnormalities alone or no abnormality. Compared to men with all normal levels, the multivariate‐adjusted hazard ratio (95% confidence interval [CI]) for incident nonspine fracture during 4.6‐year median follow‐up was 1.2 (0.8–1.8) for low VitD alone; 1.3 (0.9–1.9) for low BioE and/or high SHBG alone; and 1.6 (1.1–2.5) for low BioE/high SHBG plus low VitD. In summary, adverse skeletal effects of low sex steroid levels were more pronounced in older men with low VitD levels. The presence of low VitD in the presence of low BioE/high SHBG may contribute substantially to poor skeletal health. © 2012 American Society for Bone and Mineral Research.     

Tumour necrosis factor receptor type II 196M/R genotype correlates with circulating soluble receptor levels in normal subjects and with graft-versus-host disease after sibling allogeneic bone marrow transplantation

BACKGROUND: A single nucleotide polymorphism in the tumor necrosis factor type II receptor (TNFRII) gene, codon 196, results in the substitution of arginine (R allele) for methionine (M allele). The 196R allele is reportedly associated with an increased susceptibility to autoimmune disease, and donor 196R allele carriage correlates with increased severity of acute graft-versus-host disease (GVHD) after matched unrelated bone marrow transplantation (BMT). METHODS: We investigated the impact of donor and recipient TNFRII genotype on GVHD incidence and severity among 104 adult recipients of myeloablative sibling BMTs. RESULTS: 196R allele frequency was 0.28 among recipients, donors, and controls. There was an increased incidence of acute GVHD among 196R-positive recipients (odds ratio [OR] 3.6, P=0.05). This association was confirmed in multivariate analysis (relative risk 4, P=0.04), correcting for previously established clinical and genetic risk factors. Donor 196R homozygosity was associated with an increased incidence of extensive chronic GVHD (OR 18.5, P=0.02). This association was also confirmed in multivariate analysis (OR 11, P=0.02). To investigate the functional impact of the TNFRII 196 M/R polymorphism, 79 volunteer blood donors were genotyped at this locus, by polymerase chain reaction and single-strand conformational polymorphism analysis, and plasma soluble TNFRII (sTNFRII) levels were measured by ELISA. Mean plasma sTNFRII levels (pg/mL: +/-SEM) were 1224 (+/-26) and 1063 (+/-65) for 196M-postive (196 M homozygous or heterozygous) individuals and 196R homozygotes, respectively (P=0.02). CONCLUSIONS: Because sTNFRIIs can act as TNF antagonists, the association between recipient and donor TNFRII 196R allele status and acute or extensive chronic GVHD incidence, respectively, may reflect reduced circulating sTNFRII.     

Canadian Association of General Surgeons Evidence Based Reviews in Surgery. 6. "GERD" as a risk factor for esophageal cancer. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.

Question: Is gastroesophageal reflux a risk factor for the development of esophageal adenocarcinoma? Design: A case control study. Setting: A population-based study in Sweden between 1994 and 1997. Participants: Cases included all patients with gastric or esophageal adenocarcinoma and half of all patients with esophageal squamous cell cancer, under the age of 80 years and living in Sweden between Dec. 1, 1994, and Dec. 31, 1997. Controls were selected randomly from among persons matched for age (within 10 yr) and sex in the entire Swedish population, through the use of a population register, which is computerized and updated continuously. Assessment of risk factors: Symptomatic reflux was assessed according to the severity of the symptoms (heartburn only, regurgitation only, heartburn and regurgitation combined, nightly symptoms), frequency and duration. Adjustment was made for age, sex, body mass index, smoking history, alcohol ingestion, socioeconomic status, intake of fruit and vegetables, overall energy intake, posture and the degree of physical activity both at work and during leisure. Main outcome measures: Gastric and esophageal adenocarcinoma and esophageal squamous cell cancer. Main results: Among participants with recurrent symptoms of reflux, as compared with those without such symptoms, the odds ratios were 7.7 (95% CI, 5.3–11.4) for development of esophageal adenocarcinoma and 2.0 (95% CI, 1.4–2.9) for adenocarcinoma of the cardia. The more frequent, more severe and longer duration the symptoms of reflux were, the greater was the risk. Among persons with long-standing, severe symptoms of reflux, the odds ratios were 43.5 (95% CI, 18.3–103.5) for development of esophageal adenocarcinoma and 4.4 (95% CI, 1.7–11.0) for adenocarcinoma of the cardia. The risk of esophageal squamous cell carcinoma was not increased with reflux (odds ratio, 1.1; 95% CI, 0.7–1.9). Conclusion: The study identified a strong and probably causal relation between symptomatic reflux as a strong risk factor for esophageal adenocarcinoma and a relatively weak risk factor for adenocarcinoma of the gastric cardia.