Regulation of the immune system by SOCS family adaptor proteins

Signal transduction via cytokine receptors is regulated by several mechanisms that control initiation, magnitude and duration of the signaling pathways. Cytokine-induced SOCS family adaptors function as feedback inhibitors of cytokine receptor signaling by inhibiting the JAK-STAT signal transduction pathway. Specific gene-targeted mice have unveiled critical, non-overlapping functions for SOCS1 and SOCS3 in lymphocyte development and homeostasis, and in the regulation of macrophage and dendritic cell functions. In this review, we will discuss the structure of SOCS proteins, mechanisms by which they control the JAK-STAT pathway and their role in immune regulation.     

Follicular dendritic cell tumor of mesentery--a case report

Follicular dendritic cell sarcoma also known as dendritic reticulum cell tumor is uncommon. It can arise in lymph nodes and extra nodal sites namely tonsils and intra abdominal locations. The tumor morphologically mimicks soft tissue sarcomas and hence requires immunohistochemical study for correct diagnosis. It pursues an indolent protracted course with recurrence and still be compatible with long survival. We report a case of follicular dendritic cell tumor of mesentery.     

Structure-activity relationships of N-acyl pyrroloquinolone PDE-5 inhibitors

The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.     

Immune responses against Salmonella enterica serovar enteritidis infection in virally immunosuppressed chickens

To understand the role of immune mechanisms in protecting chickens from Salmonella infections, we examined the immune responses of Salmonella enterica serovar Enteritidis-infected chickens and the effect of chicken anemia virus (CAV), a T-cell-targeted virus, on S. enterica serovar Enteritidis-induced immune responses. One-day-old chicks were orally inoculated with S. enterica serovar Enteritidis with or without intramuscular injection of CAV. The bacterial infection, pathology, and immune responses of chickens were evaluated at 14, 28, and 56 days postinoculation. The infection increased the levels of S. enterica serovar Enteritidis-specific mucosal immunoglobulin A (IgA), the number of gut-associated T cells, and the titer of serum IgG specific for S. enterica serovar Enteritidis surface antigens. CAV infection depressed these immune responses, especially the mucosal immune responses, but did not increase the number of S. enterica serovar Enteritidis-infected cells in the intestine. The severity of pathological lesions appeared to be reciprocal to the level of immune responses, but the S. enterica serovar Enteritidis infection persisted. These results suggest that oral infection of S. enterica serovar Enteritidis in chickens induces both mucosal and systemic immune responses, which have a limited effect on the S. enterica serovar Enteritidis infection under conditions designed to mimic the field situation.     

Intravascular lymphomatosis presenting as systemic inflammatory response syndrome

Intravascular lymphomatosis is an unusual form of non-Hodgkin lymphoma characterized by intravascular proliferation of atypical lymphoid cells in multiple organs. It can cause systemic inflammatory response syndrome due to primary release of cytokines by the tumor cells or secondary release of cytokines after vascular occlusion by the tumor cells. It is a potentially fatal condition, because multiorgan failure can ensue due to thrombotic vascular occlusion. This is a very rare condition and most cases are diagnosed post mortem. We present a case of systemic inflammatory response syndrome and subsequent death from multiorgan failure in a patient with intravascular lymphoma.     

Protein-free diets do not protect high-incidence diabetes-prone BioBreeding rats from diabetes

Dietary factors have been reported to affect the development of spontaneous diabetes in various colonies of inbred and outbred diabetes-prone (DP) BioBreeding (BB) rats. Several studies have attributed a protective effect to a diet omitting crude protein mixtures in favor of purified casein, hydrolyzed casein, or free amino acids. We have used inbred BB rats, all of which become diabetic in specific pathogen-free (SPF) conditions when fed ordinary rat chow, to test the capacity of 2 different protein-free diets to modulate BB rat diabetes in 2 distinct pathogen-free environments. BB rats known to all develop diabetes by 100 days of age were fed from birth with 1 of 3 diets. By 120 days of age, 100% of the animals on a standard diabetogenic chow diet, 83% of animals on an amino acid-based protein-free diet, and 100% of animals on a hydrolyzed casein-based diet had developed diabetes (P >.05). A slight delay in the age of onset was observed among rats fed the amino acid-based diet, but this delay coincided with a reduction in weight gain among these animals compared with the rats on a standard diet. Histology showed insulitis in all rats at either diabetes onset or 120 days of age. We conclude that our unique strain of specific pathogen-free BB rats are not protected from diabetes when fed an amino acid-based diet and suggest that their insensitivity to dietary manipulation may be due to an as yet unknown factor present in the diabetes-resistant (DR), but not the DP BB rat genetic background.     

Failure of arteriovenous fistula maturation: an unintended consequence of exceeding dialysis outcome quality Initiative guidelines for hemodialysis access

PURPOSE: The Dialysis Outcome Quality Initiative (DOQI) guidelines recommend that arteriovenous fistulas (AVF) be constructed in at least 50% of hemodialysis access procedures. Preoperative duplex ultrasound (US) scanning and venography may increase options for AVF with identification of veins that are not clinically evident. However, maturation of autogenous fistulas created on the basis of findings at duplex US scanning and venography has not been carefully examined. METHODS: From January 1999 to July 2002, 256 new hemodialysis access procedures were performed in 202 patients in an academic tertiary care center. If physical examination failed to disclose adequate vessels for hemodialysis access, patients underwent duplex US scanning mapping. Venography was performed when no usable vein or only a basilic vein was identified at duplex US scanning. Functional maturation rate and mean maturation time (time from fistula creation to initiation of hemodialysis) were determined. This experience was compared with that in a group of 128 patients in whom 148 hemodialysis access fistulas were created before we implemented liberal use of preoperative duplex US scanning and venography (January 1997-December 1998). RESULTS: From January 1999 to July 2002, preoperative duplex US scanning was performed in 68% of patients, and venography in 32% of patients. Autogenous fistula creation rate increased from 61% to 73% in all patients with hemodialysis access fistulas (P =.15) and from 66% to 83% in patients undergoing a first access procedure (P <.05). The use of basilic vein transposition also increased, from 3% in the earlier period to 13% in the later period (P <.05). Mean maturation time for arteriovenous fistulas was 70 days. Functional maturation rate decreased from 73% to 57% (P <.05) after implementation of preoperative imaging and more aggressive vein use. CONCLUSION: Implementation of preoperative duplex US scanning and venography as a component of a more aggressive protocol to create native fistulas was pivotal in exceeding DOQI guidelines for hemodialysis access. However, this approach resulted in the unintended sequela of decreased fistula maturation rate. Our experience suggests that improved selection criteria based on findings at preoperative imaging are needed to further refine and optimize arteriovenous access surgery.     

Women's health and the internet: understanding emerging trends and implications

Internet has become a major information source, yet little is known about why women use the internet for obtaining health information. In this paper, we propose and test three exploratory models to explain internet use for obtaining health information: health and wellness model, health needs model, and search costs model. The health and wellness model is based on the notion that internet has become such an integral part of daily life that health-conscious women use the internet in a pro-active manner for health promotion. The health needs model posits that women with greater health needs or concerns are more likely to use the internet. Finally, the search costs model explores the idea that women may view the internet as a resource for reducing high information search costs. These models were tested using data collected through telephone surveys of women in three southern New Jersey counties in the USA. Consistent with expectations, our findings show that internet use to search for health information is greater among women with higher levels of income and education. There is support for all three models, with surprisingly strong support for the health and wellness model. We conclude that women increasingly rely on the internet to supplement health information received from traditional sources and discuss the implications of our findings for policymakers and health professions.     

The safety of the use of ethyl oleate in food is supported by metabolism data in rats and clinical safety data in humans

The absorption, distribution, and excretion of radiolabeled ethyl oleate (EO) was studied in Sprague-Dawley rats after a single, peroral dose of 1.7 or 3.4 g/kg body weight and was compared with a radiolabeled triacylglycerol (TG) containing only oleic acid as the fatty acid (triolein). Both test materials were well absorbed with approximately 70-90% of the EO dose absorbed and approximately 90-100% of the TG dose absorbed. At sacrifice (72 h post-dose), tissue distribution of EO-derived radioactivity and TG-derived radioactivity was similar. The tissue with the highest concentration of radioactivity in both groups was mesenteric fat. The other organs and tissues had very low concentrations of test material-derived radioactivity. Both test materials were rapidly and extensively excreted as CO(2) with no remarkable differences between their excretion profiles. Approximately 40-70% of the administered dose for both groups was excreted as CO(2) within the first 12 h (consistent with beta-oxidation of fatty acids). Fecal elimination of EO appeared to be dose-dependent. At the dose of 1.7 g/kg, 7-8% of the administered dose was eliminated in the feces. At the dose of 3.4 g/kg, approximately 20% of the administered dose was excreted in the feces. Excretion of TG-derived radiolabel in the feces was approximately 2-4% for both doses. Overall, the results demonstrate that the absorption, distribution, and excretion of radiolabeled EO is similar to that of TG providing evidence that the oleic acid moiety of EO is utilized in the body as a normal dietary TG-derived fatty acid. To confirm the expected safety of EO in humans, a total of 235 subjects participated in a 12-week trial where two levels of ethyl oleate in a milk-based beverage were investigated: 8 g/day in a single serving (approximately 0.1 g/kg) and 16 g/day taken in two divided servings (approximately 0.2 g/kg). Adverse events (AEs) were recorded throughout the 12-week trial. In addition, a brief physical exam (including vital signs and body weight), ECGs, fasting serum chemistry profile, serum lipid profile, and urinalysis were performed at baseline and after study completion. Results showed the incidence of reported AEs was similar between the EO groups and the control groups. Analysis of comprehensive laboratory data revealed no EO exposure-related, clinically significant adverse changes in laboratory parameters. These studies demonstrated that EO has a highly favorable safety profile and is well tolerated in the diet.