Functional consequences of a decreased potassium affinity in a potassium channel pore. Ion interactions and C-type inactivation

We have shown previously that the inactivation of macrophages in nonobese diabetic (NOD) mice results in the prevention of diabetes; however, the mechanisms involved remain unknown. In this study, we found that T cells in a macrophage-depleted environment lost their ability to differentiate into beta cell-cytotoxic T cells, resulting in the prevention of autoimmune diabetes, but these T cells regained their beta cell-cytotoxic potential when returned to a macrophage-containing environment. To learn why T cells in a macrophage-depleted environment lose their ability to kill beta cells, we examined the islet antigen-specific immune response and T cell activation in macrophage-depleted NOD mice. There was a shift in the immune balance, a decrease in the T helper cell type 1 (Th1) immune response, and an increase in the Th2 immune response, due to the reduced expression of the macrophage-derived cytokine IL-12. As well, there was a deficit in T cell activation, evidenced by significant decreases in the expression of Fas ligand and perforin. The administration of IL-12 substantially reversed the prevention of diabetes in NOD mice conferred by macrophage depletion. We conclude that macrophages play an essential role in the development and activation of beta cell-cytotoxic T cells that cause beta cell destruction, resulting in autoimmune diabetes in NOD mice.     

In vitro glutathione supplementation enhances interleukin-2 production and mitogenic response of peripheral blood mononuclear cells from young and old subjects

Oral administration of porcine insulin has been shown to be effective in preventing the spontaneous occurrence of diabetes in the Non-Obese Diabetic (NOD) mouse model. In the present study, we demonstrate that feeding 6-week-old female mice with 20 units of human insulin every 2-3 days for 30 days induces an active mechanism of suppression through the generation of regulatory T cells. Adult irradiated NOD males i.v. injected with 5 x 10(6) T cells from the spleens of diabetic female donors and the same number of T cells from the spleens of insulin-fed animals had less successful diabetes transfer than controls (4/15 vs. 8/16, P < 0.001). Protection from clinical diabetes was associated with a reduction in severe insulitis (16.4 +/- 3.6% vs. 52.3 +/- 12.8%, P = 0.023). However, more than 85% of the islets were inflamed. Feeding animals for 15 days reduced the magnitude of this protection since the number of successful transfers after 1 month was comparable (12/17 vs. 14/17) despite a significant delay in diabetes onset (P < 0.001). No difference in the contribution of T cell subsets was noted by cytofluorometry in the spleens of treated animals. When T cell subsets from insulin-fed animals were co-injected with diabetogenic T cells, only purified CD4+ T cells were able to transfer protection since only 3/12 mice became diabetic after 36 days in comparison to 3/6 in the group co-injected with CD4+ T cells from PBS-fed animals, or 5/6 in the group injected with CD8+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incidence and clinical features of splenic abscesses, with special reference to tuberculous etiology in a general hospital

BACKGROUND: The aim of this revision is to know the incidence of splenic abscess (SA) in our hospital, its etiology, with special reference to tuberculosis, and clinical characteristics. PATIENTS AND METHODS: Abdominal CT-scan performed during the period 1987-1997, with the diagnosis of splenic abscess were reviewed. Etiologic diagnosis standed on blood or sputum cultures, PAAF and/or histologic study of lymph nodes. RESULTS: Seventeen cases of SA were obtained, 12 males and 5 females. Limits of age: 13 and 77 years. The causal microorganisms were: M. tuberculosis (7), Mycobacterium aviumintracellulare (1), S. aureus (2), S. anginosus (1), S. milleri (1), E. coli (1), C. albicans (1), T. biguelle (1) and polymicrobian flora (1). One case was of unknown etiology. Underlying illnesses were: AIDS (7), malignant neoplasms (3), diabetes (2), endocarditis (2), Sj?gren syndrome (1) and complications of abdominal surgery (2). Clinical presentation in nontuberculous splenic abscess was fever and upper-left abdominal pain. Predominant symptoms in tuberculous splenic abscess were fever and weight loss. Blood cultures were positive in 80% of non tuberculous splenic abscess. Specific treatment for tuberculosis improved all patients with tuberculous splenic abscess, without needing surgery or corticosteroids. CONCLUSIONS: From the total of splenic abscess, 41.1% were tuberculous, six with AIDS and one with Sj?gren syndrome. Diabetes and malignant neoplasms were the commonest underlying illnesses in the non-tuberculous. In these, clinical presentation consisted in fever and upper-left abdominal pain. In patients with tuberculous splenic abscess, the main complaint was weight loss. A prompt treatment is generally succesful.     

Thoracic polyradiculopathy--abdominal wall swelling and sensory symptoms in diabetes mellitus

We describe two patients with type 2 diabetes who presented with abdominal pain secondary to thoracic polyradiculopathy. In the first patient abdominal pain occurred in association with marked abdominal distension; extensive negative gastrointestinal investigations were performed before the correct diagnosis was made by electromyography showing thoracic paraspinal muscle denervation. In the second case, truncal sensory symptoms alone were evident at the time of diagnosis of diabetes mellitus. While muscle laxity was absent, extensive paraspinal muscle denervation was detected. Tolrestat, an aldose reductase inhibitor, was associated with good clinical response of symptoms due to peripheral neuropathy and thoracic polyradiculopathy. The pathogenesis of thoracic polyradiculopathy is uncertain but is likely to be the result of multiple infarcts along the course of thoracic spinal nerves accounting.     

The role of lymphocyte subsets in accelerated diabetes in nonobese diabetic-rat insulin promoter-B7-1 (NOD-RIP-B7-1) mice

B7-1 transgene expression on the pancreatic islets in nonobese diabetic (NOD) mice leads to accelerated diabetes, with >50% of animals developing diabetes before 12 wk of age. The expression of B7-1 directly on the pancreatic beta cells, which do not normally express costimulator molecules, converts the cells into effective antigen-presenting cells leading to an intensified autoimmune attack. The pancreatic islet infiltrate in diabetic mice consists of CD8 T cells, CD4 T cells, and B cells, similar to diabetic nontransgenic NOD mice. To elucidate the relative importance of each of the subsets of cells, the NOD-rat insulin promoter (RIP)-B7-1 animals were crossed with NOD.beta2microglobulin -/- mice which lack major histocompatibility complex class I molecules and are deficient in peripheral CD8 T cells, NOD.CD4 -/- mice which lack T cells expressing CD4, and NOD.muMT -/- mice which lack B220-positive B cells. These experiments showed that both CD4 and CD8 T cells were necessary for the accelerated onset of diabetes, but that B cells, which are needed for diabetes to occur in normal NOD mice, are not required. It is possible that B lymphocytes play an important role in the provision of costimulation in NOD mice which is unnecessary in the NOD-RIP-B7-1 transgenic mice.     

Streptozotocin-induced diabetes in mice lacking alphabeta T cells

Multiple low-dose streptozotocin (MD-STZ) is widely used for the experimental induction of diabetes, but, as non-obese diabetic (NOD)-scid/scid mice have been found to display enhanced susceptibility to MD-STZ, whether or not the model is genuinely autoimmune and T cell-mediated has been unclear. Mice bearing a targeted mutation of the T cell receptor (TCR) alpha-chain were therefore used to assess whether TCR alphabeta+ cells are involved in the diabetogenic effects of MD-STZ injections. Young NOD mice lacking TCR alphabeta cells, when given five daily injections of 40 mg/kg STZ, developed diabetes at low frequency (2/12), despite the widespread destruction of pancreatic islet cells. By comparison, most normal control mice became hyperglycaemic (12/23). We conclude that whilst much of the tissue destruction observed in this model is due to the direct toxic effect of STZ, a significant amount is also due to the action of TCR alphabeta cells tipping the balance between tolerable and clinically damaging action on islet cells.     

Normal appearance and size of the diaphragmatic crura in children: CT evaluation

PURPOSE: The objectives of the study were to document the normal CT appearance and size of the crura of the diaphragm in children. MATERIALS AND METHODS: The CT scans of 80 children (0-15 years) were reviewed. The children were divided into eight age groups. The maximal transverse diameters of the right and left crura were measured. They were normalized by comparison with the transverse and anterior-posterior diameters of the 12th thoracic vertebra (T12) and the transverse abdominal diameter at T12. The crura were also evaluated as to whether their contour was smooth or nodular. RESULTS: The diaphragmatic crura of smaller children appear large, relative to body size and the diameters of the T12 vertebral body, compared with those in older children. Crural width does not increase significantly with age. Additionally, the crura were found to have a greater tendency to be nodular in appearance in children under the age of 5 years than in older children. CONCLUSION: Diaphragmatic crura are more nodular and larger relative to body size in younger children.     

The acute abdomen in spinal cord injury individuals

A review of 1300 patients with spinal cord injury (SCI), over a period of 14 years, revealed 12 patients with an 'acute abdomen'. Seven events occurred during the initial admission, ranging from 10 days to 9 months from injury, and five during readmission of 'chronic' SCI patients. Four were in the acute stage 10-30 days from injury, all with peptic ulcer perforations. The remainder had either an intestinal obstruction, appendicitis or peritonitis. All of the neurological levels were above T6 except for one patient who had a low level paraplegia. The classical signs of an 'acute abdomen' may be missing in such patients thus delaying diagnosis by 1-4 days. The most important signs were autonomic dysreflexia, referred shoulder tip pain, abdominal pain, abdominal distension, increased spasticity and abdominal pain with nausea and vomiting. Less importance was given to the classical signs of abdominal tenderness, abdominal muscle rigidity, rebound, fever and of leukocytosis. Prompt diagnosis and treatment will minimise morbidity and mortality.     

Small doses of triiodothyronine can change some risk factors associated with abdominal obesity

OBJECTIVE: To elucidate whether the administration of small doses of triidothyronine (T3) can increase concentrations of sex hormone binding globulin (SHBG) in obese women with different types of obesity and to evaluate the potential metabolic benefits of such treatment. DESIGN: Daily administration of 20 micrograms of T3 during six weeks while maintaining habitual food intake and physical activity. SUBJECTS: Seventy premenopausal obese women (age: 41.2 +/- 1.5 y mean +/- s.e.m., body mass index (BMI): 34.4 +/- 0.7). MEASUREMENTS: Plasma concentrations of SHBG, lipids, insulin, thyroid hormones, sex hormones, blood glucose and insulin sensitivity (by euglycemic insulin clamp in 12 patients) at base line after six weeks of treatment. RESULTS: Six weeks treatment with small doses of T3 resulted in a significant increase in plasma SHBG. The increase of SHBG was higher in abdominal obesity and not associated with a significant change in body weight, plasma insulin concentration, insulin/glucose ratio of plasma insulin sensitivity (glucose disposal during insulin clamp). In patients with initially high SHBG the significant increase of insulin removal (as judged from the increase of c-peptide/insulin ratio) was observed. Treatment resulted in a reciprocal increase of T3, decrease of thyroxine (T4), and a more than double increase of T3/T4 ratio. CONCLUSIONS: Administration of small doses of T3 can increase the concentration of SHBG without changing insulin concentrations or sensitivity. As there was a significant decrease (by 36%) of T4 and parallel increase of T3 with a clear increase of T3/T4 ratio it seems possible that rather than lack of thyroid hormones a lower peripheral deiodination of T4 might be a factor contributing to the low SHBG concentration in abdominal obesity. Treatment with small doses of T3 may be considered to ameliorate some of the risk factors associated with abdominal obesity, particularly in some subgroups of obese women with a relative resistance to thyroid hormones possibly dependent on decreased peripheral deiodination of thyroxine.     

Reflex vascular responses to alterations in abdominal arterial pressure and flow in anaesthetized dogs

The existence of abdominal arterial baroreceptors has long been controversial. Previously difficulties have been encountered in localizing a stimulus to abdominal arteries without affecting reflexogenic areas elsewhere. In these experiments, using anaesthetized dogs, the abdomen was vascularly isolated at the level of the diaphragm, perfused through the aorta, and drained from the inferior vena cava to a reservoir. Changes in abdominal arterial pressure were effected by changing the perfusion pump speed. During this procedure the flow back to the animal from the venous outflow reservoir was held constant. Increases and decreases in abdominal arterial pressure resulted, respectively, in decreases and increases in perfusion pressure to a vascularly isolated hind-limb and in some dogs also a forelimb. Responses were significantly larger when carotid sinus pressure was high (120-180 mmHg) than when it was low (60 mmHg). Responses were still obtained after cutting vagus, phrenic and splanchnic nerves, but were abolished by spinal cord lesion at T12. These experiments provide evidence for the existence of abdominal arterial baroreceptors. The afferent pathway for the reflex vasodilatation appears to run in the spinal cord.     

Overexpression of natural killer T cells protects Valpha14- Jalpha281 transgenic nonobese diabetic mice against diabetes

Progression to destructive insulitis in nonobese diabetic (NOD) mice is linked to the failure of regulatory cells, possibly involving T helper type 2 (Th2) cells. Natural killer (NK) T cells might be involved in diabetes, given their deficiency in NOD mice and the prevention of diabetes by adoptive transfer of alpha/beta double-negative thymocytes. Here, we evaluated the role of NK T cells in diabetes by using transgenic NOD mice expressing the T cell antigen receptor (TCR) alpha chain Valpha14-Jalpha281 characteristic of NK T cells. Precise identification of NK1.1(+) T cells was based on out-cross with congenic NK1.1 NOD mice. All six transgenic lines showed, to various degrees, elevated numbers of NK1.1(+) T cells, enhanced production of interleukin (IL)-4, and increased levels of serum immunoglobulin E. Only the transgenic lines with the largest numbers of NK T cells and the most vigorous burst of IL-4 production were protected from diabetes. Transfer and cotransfer experiments with transgenic splenocytes demonstrated that Valpha14-Jalpha281 transgenic NOD mice, although protected from overt diabetes, developed a diabetogenic T cell repertoire, and that NK T cells actively inhibited the pathogenic action of T cells. These results indicate that the number of NK T cells strongly influences the development of diabetes.     

Role of macrophages and macrophage-derived cytokines in the pathogenesis of Kilham rat virus-induced autoimmune diabetes in diabetes-resistant BioBreeding rats

The diabetes-resistant BioBreeding (DR-BB) rat, derived from diabetes-prone forebears, does not normally develop spontaneous insulitis or diabetes, but when infected with Kilham rat virus (KRV) this animal develops autoimmune diabetes similar to the diabetes-prone BioBreeding (DP-BB) rat. In this study, we attempted to determine whether macrophages and macrophage-derived cytokines play a role in the development of KRV-induced diabetes in DR-BB rats. Seventy-eight percent of DR-BB rats treated with KRV and poly(I:C) develop diabetes, whereas depletion of macrophages with liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP) in KRV and poly(I:C)-treated DR-BB rats results in the near-complete prevention of insulitis and diabetes. Measurement of the macrophage-derived cytokines IL-12, TNF-alpha, and IL-1beta revealed a selective increase of their expression, after KRV infection, in the splenic lymphocytes and the pancreatic islets. Measurement of CD4+ T cell-derived cytokines revealed that IL-2 and IFN-gamma cytokine gene expression closely correlates with an elevation of IL-12, but IL-4 and IL-10 do not change. Depletion of macrophages before the isolation of splenic lymphocytes from DR-BB rats treated with KRV and poly(I:C) resulted in the loss of ability to transfer diabetes to young DP-BB rats. On the basis of these observations, we conclude that macrophages and macrophage-derived cytokines play a critical role in the cascade of events leading to the destruction of pancreatic beta cells, culminating in the development of insulin-dependent diabetes mellitus.     

Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group

OBJECTIVE: To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone. RESEARCH DESIGN AND METHODS: There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed. RESULTS: Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy CONCLUSIONS: Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.     

Pancreatoduodenectomy for chronic pancreatitis: anatomic selection criteria and subsequent long-term outcome analysis

OBJECTIVE: The authors sought to provide a framework through outcome analysis to evaluate operations directed toward the intractable abdominal pain of severe chronic pancreatitis centered in the pancreatic head. Pancreatoduodenectomy (PD) was used as an example. SUMMARY BACKGROUND DATA: Head resection for severe chronic pancreatitis is the treatment of choice for a ductal system in the head obliterated by severe disease when associated with intractable abdominal pain. To evaluate the effectiveness of promising head resection substitutes for PD, a framework is necessary to provide a reference standard (i.e., an outcome analysis) of PD. METHODS: Inclusion criteria were severe chronic pancreatitis centered in the pancreatic head, intractable abdominal pain, and a main pancreatic duct obstruction or stricture resulting in absent drainage into the duodenum from the uncinate process and adjacent pancreatic head areas or the entire gland. Since 1986, 57 consecutive cases with these criteria underwent PD (47 head only and 10 total pancreatectomy). Clinical and anatomic predictor variables were derived from the history, imaging studies, and pathologic examination. These variables then were tested for association with the following outcome events gathered during annual follow-up: pain relief, onset of diabetes, body weight maintenance, and peptic ulceration. RESULTS: Operative mortality was zero. In 57 patients with a mean follow-up of 42 months, the 5-year outcome event for survival was 93% and the onset of diabetes was 32%. All new cases of diabetes occurred more than 1 year after resection. In 43 cases > or =1 year postoperative with a mean follow-up of 55 months, all patients indicated significant pain relief and 76% were pain free. Pain relief was more common in patients with diabetes or in those patients with a pancreatic duct disruption. Death was more common in patients with diabetes. Weight maintenance was more common if preoperatively severe ductal changes were not present. Total pancreatectomy was associated with peptic ulceration. CONCLUSIONS: Using selection criteria, the outcome analysis standardized anatomic and clinical variables as to how they were associated with the outcome events (calibrated the effects of the operation with each variable). In these selected patients, PD is safe and significantly relieves pain. Sequelae are from diabetes, provided total pancreatectomy is avoided.     

Genetic control of diabetes progression

Autoimmune diabetes in both the human and the nonobese diabetic mouse has elaborate genetics; in the latter case, the disease is influenced by at least 15-20 loci. We anticipated that the genetics would be simpler in the BDC2.5 T cell receptor transgenic mouse model of diabetes, wherein many T cells express a particular diabetogenic specificity. Initiation of insulitis in this model was the same on the two genetic backgrounds analyzed, but the kinetics and penetrance of diabetes were strikingly different, permitting us to focus on genetic influences during a defined window of disease progression. The differences correlated with variations in five genomic intervals, certain ones of which have been previously implicated in susceptibility to autoimmune disease. This reductionist approach indeed simplified the analysis of diabetes susceptibility loci.     

Effect of environmental temperature on muscle protein turnover and heat production in tube-fed broiler chickens

The present experiments were undertaken to investigate the effects of environmental temperatures on growth, abdominal fat content, rate of muscle protein turnover, and heat production in tube-fed intact male broiler chickens. Plasma concentrations of thyroxine (T4), triiodothyronine (T3), and corticosterone (CTC) were also examined. Chicks (15 d old) were kept at different environmental temperatures (16, 19, 22, 25, 28, 31, and 34 degrees) and given the experimental diet (200 g crude protein/ kg, 13.57 MJ/kg metabolizable energy) by tube three times daily throughout the 12 d experimental period. In the hot conditions, except for 34 degrees, body-weight gain was significantly higher than in the cold conditions. Thus, food conversion ratios (food:gain ratios) were lower when the birds were exposed to the hot conditions other than 34 degrees. Likewise, abdominal fat content was significantly increased, and heat production was lower in the groups kept under the hot conditions other than 34 degrees. The rate of skeletal muscle protein turnover and plasma concentration of CTC were decreased when the birds were exposed to hot conditions other than 34 degrees, suggesting a role of CTC in the regulation of muscle protein turnover. Plasma concentrations of T4 and T3 were significantly decreased as environmental temperature increased. These results clearly show that plasma concentrations of thyroid hormones and CTC are associated with accelerated muscle protein turnover and heat production.     

Improved survival in patients with advanced colorectal carcinoma failing 5-fluorouracil who received irinotecan hydrochloride and have high intratumor C-fos expression

INTRODUCTION: We optimized the technique of contrast-enhanced Magnetic Resonance Angiography (MRA) with a .5 T superconductive magnet. MATERIAL AND METHODS: Forty patients with normal blood pressure and heart rate gave their informed consent to MRA studies with contrast agent administration. The carotid arteries were studied in 10 patients, the pulmonary arteries in 10, the thoracic aorta in 10 and the abdominal aorta and renal arteries in 10. All the examinations were performed with a .5 T superconductive magnet (Philips T5) acquiring 3D T1-weighted GE sequences with contrast agent administration. The parameters were: TR/TE/FA 13 ms/4 ms/60 degrees; 256 x 256 MA; 2 mm slice thickness; 1 NEX. The contrast agent was administered with an automatic injector (.2 mmol/kg at 1.5 flowrate) after a bolus test to evaluate circulation time. The images were studied by a radiologist rating artery visualization as "good" or "poor" on a multiple choice card. The signal-to-noise ratio was evaluated using regions of interest positioned on the examined vessels (signal) and muscles (noise). RESULTS: The mean start delay was 12.2 s for the abdominal aorta, 10.3 s and 8.7 s for the thoracic aorta and pulmonary arteries, and 10.3 for the carotid arteries. Fifty-eight of 70 vessels were well visualized and 12 were poorly visualized. The signal-to-noise ratio exceeded 1 in all districts. CONCLUSIONS: Our experience shows that enhanced MRA provides diagnostic images of body arteries even at .5 T.     

IL-10 impacts autoimmune diabetes via a CD8+ T cell pathway circumventing the requirement for CD4+ T and B lymphocytes

IL-10 is essential for an early phase of diabetes in nonobese diabetic (NOD) mice, but later becomes protective against its development. The mechanism by which IL-10 mediates the pathway to diabetes in these mice is unknown. Herein, we dissected the cellular and costimulation requirements for diabetes in transgenic (tg) NOD mice that expressed IL-10 in their pancreatic islets (IL-10-NOD mice). We found that IL-10 alone did not cause diabetes because the offspring (IL-10-NOD-scid mice) from back-crosses of IL-10-NOD mice with NOD-scid mice had no diabetes. Moreover, these IL-10-NOD-scid mice were free of lymphocytic infiltration. Treatment of IL-10-NOD mice with depleting anti-CD4 mAb or control mAb had no effect on diabetes. Surprisingly, depletion of CD8+ T cells by treatment with the corresponding mAb inhibited diabetes without attenuating insulitis, demonstrating a critical role for CD8+ T cells in the disease process. Interestingly, B cell-deficient IL-10-NOD mice readily developed diabetes with kinetics and incidence similar to those observed in wild-type mice, demonstrating that B lymphocytes as APCs were not required in the disease process. Administration of anti-CD40 ligand (CD40L) mAb did not prevent disease, indicating that CD40/CD40L costimulation is not required for diabetes in IL-10-NOD mice. Immunization of IL-10-NOD mice with CFA or heat-shock protein 65, known to block diabetes in NOD mice, had no effect on their diabetes. We demonstrate that IL-10 contributes early to the pathology of diabetes via a CD8+ T cell pathway, eliminating the requirement for B lymphocytes and CD40-CD40L costimulation. Our findings provide a mechanism for the participation of IL-10 in the early development of diabetes.     

Gadolinium-enhanced magnetic resonance angiography of abdominal blood vessels

Contrast enhanced (CE) magnetic resonance angiography (MRA) provides high resolution angiograms within 20-40 sec. The technique is based on the acquisition of heavily T1-weighted three-dimensional (3D) gradient-echo data sets (FISP) with ultrashort echo-(< 2ms) and repetition times (< 5 ms) during arterial phase of an intravenously injected bolus of a T1-shortening agent such as Gd-DTPA. For MR-angiography of abdominal vessels CE-MRA is better suited than "time-of flight" (TOF) and phase-contrast (PC) MRA because motional artifacts can be obviated with breath-held acquisitions. We have optimised the technique and evaluated its potential for angiography of the abdominal aorta and its branches as well as the portal vein and its tributaries. Whilst CE-MRA provides reliable diagnostic accuracy in the aorta and the proximal sections of its branches, small peripheral arteries cannot be assessed accurately. The portal vein and its tributaries can often be depicted better with CE-MRA than with conventional angiography but, like conventional angiography, CE-MRA is hampered by slow and reversed flow, conditions under which TOF or "true FISP" MRA may perform bst. We have also investigated FLASH-echo-planar imaging (EPI) hybrid techniques, a further technical development which due to shorter acquisition times of 12-15 sec. allows semi-dynamic imaging of the arterial and venous phase and provide better vessel contrast due to the use of fat-suppression.