New-onset Insulin-dependent Diabetes Research Articles

ODP264 An Unusual Etiology of Hypothyroidism and New-Onset Insulin-Dependent Diabetes: A Rare Side Effect of Opdivo

Abstract Introduction Nivolumab, a monoclonal antibody targeting programmed cell death 1 receptor, is prescribed for many advanced cancers like malignant melanoma, non-small cell lung cancer, renal cell carcinoma (RCC), etc. with increased use of this medication, the incidence of immune-related side effects is also on the rise. A combined medication side effect of new-onset diabetes and hypothyroidism associated with Nivolumab use is rare. We present a case of Nivolumab-induced hypothyroidism with new-onset insulin-dependent diabetes. Case presentation A 59-year-male with a past medical history of right RCC status post nephrectomy, non-ischemic cardiomyopathy with an ejection fraction of 25-30% on goal-directed therapy/implantable cardioverter-defibrillator, hypertension, hyperlipidemia, and chronic kidney disease stage 3 who presented to the emergency department with complaints of chest pain at rest. The pain was 5/10 in severity and non-radiating. It was relieved by sublingual nitroglycerine en route to the hospital. It was associated with fatigue, nausea, polyuria, and polyphagia. He denied any history of pre-diabetes/diabetes or thyroid disease. Of note, about six months prior to this admission, he was placed on nivolumab for his RCC. Vitals were BP 121/83, RR 20, HR 85, T 97.8°F, and 97% oxygen saturation on room air. The cardiopulmonary exam was unremarkable. An electrocardiogram showed sinus rhythm with normal rate and no ST/T wave changes. Troponin level was 0. 01 ng/mL (normal:: <0. 04 ng/mL) Chest x-ray revealed no acute pathology. Labs showed glucose of 1090 mg/dL (normal:: 70-100 mg/dL) and thyroid-stimulating hormone (TSH) of >50,000 IU/L (normal:: 0.3-4.2 IU/L). Urinalysis was positive for ketones; 20 mg/dL (normal:: negative). Venous blood revealed a pH level of 7.344. An acute coronary syndrome was ruled out, and he was admitted for management of hyperosmolar hyperglycemic state (HHS) and hypothyroidism. Due to a low level of C-peptide: <0.5 ng/mL (normal:: 1.1-4.4 ng/mL) and high TSH, a new-onset insulin-dependent autoimmune diabetes and hypothyroidism induced as a side effect of nivolumab was suspected. Nivolumab was discontinued from his medication regimen. Endocrinology was consulted for the management of HHS and hypothyroidism. Insulin drip and levothyroxine were started, and he was transferred to the intensive care unit for close monitoring. Thereafter, his metabolic derangements improved with the resolution of hyperglycemia and electrolyte disturbances. On discharge, his symptoms improved and he was advised to stop taking nivolumab. Discussion Nivolumab has been reported in the literature to cause worsening of glycemic control and is also rarely reported as a cause of insulin-dependent diabetes due to autoimmune effects. Its effects on the thyroid are usually reported as transient thyrotoxic period which either resolves to euthyroid or rarely hypothyroidism which is what happened with our patient. Recognizing the side effects of Nivolumab and periodic monitoring can help earlier diagnosis and management with better outcomes. Presentation: No date and time listed

Delayed Management of Insulin-Dependent Diabetes Mellitus in Children

Diabetic ketoacidosis (DKA) is a common presentation for pediatric new-onset insulin-dependent diabetes mellitus (IDDM). Delayed diagnosis is the major risk factor for DKA at disease onset. Two pediatric endocrinologists independently reviewed the admission records to assess the appropriateness of preadmission management in various health care settings. Eighteen percent (n=45) of patients with new-onset IDDM had a delayed diagnosis. Twenty-eight were misdiagnosed (respiratory [n=9], nonspecific [n=7], genitourinary [n=4], gastrointestinal [n=8] issues) and 17 were mismanaged. One child died within 4 hr of hospitalization, presumably because of a hyperosmolar coma. Forty-six percent (n=21) of patients with delayed diagnosis presented with DKA, comprising 18% of all DKA cases. A significant number of patients with new-onset IDDM were either misdiagnosed or mismanaged. All providers must be appropriately trained in diagnosing new-onset IDDM and follow the standard of clinical care practices.

Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetes

ObjectiveInsulin-dependent diabetes can occur with immune checkpoint inhibitor (ICI) therapy. We aimed to characterize the frequency, natural history and potential predictors of ICI-induced diabetes.Research design and methodsWe reviewed 1444 patients...

Direct dorsal pancreatoscopy with narrow-band imaging for the diagnosis of intraductal papillary mucinous neoplasm and pancreas divisum (with video)

A 65-year-old woman presented with new-onset insulin-dependent diabetes. A CT scan revealed a dilated main pancreatic duct (MPD) without a mass. EUS demonstrated a 16-mm MPD with nonshadowing intraductal filling defects. A pediatric colonoscope with an outer diameter of 11.7 mm (PCF-Q180A; Olympus Medical Systems, Center Valley, Pa) was advanced to the afferent limb of a Billroth II reconstruction where a patulous major papilla was seen. Just proximal to the major papilla, a large mass of mucin occupied much of the lumen, and papillary fronds were seen emanating from the minor papilla (A).

Middle pancreatectomy with pancreaticogastrostomy: A technique, operative outcomes, and long‐term pancreatic function

Middle pancreatectomy is infrequently performed in selected patients. The rationale is to preserve pancreatic function. This study evaluates a technique, operative outcomes, and long-term exocrine and endocrine pancreatic function of the middle pancreatectomy procedure. Nineteen patients who underwent middle pancreatectomy between 1996 and 2008 were reviewed. Indications included eight intraductal papillary-mucinous neoplasms, five endocrine tumors, one serous and two mucinous cystadenomas, and three other benign lesions. Reconstruction of the distal pancreatic remnant was performed with pancreaticogastrostomy using the duct-to-mucosa method in 16 patients and with Roux-en-Y end-to-end pancreaticojejunostomy in 3 patients. Median operative time was 215 min. Perioperative mortality was nil. Morbidity was 53%, including 9 (47%) pancreatic fistulas. One patient with hemorrhage, complicated by a pancreatic fistula was successfully treated by endovascular embolization. No patients required postsurgical reoperation. Only one patient had clinical exocrine insufficiency requiring pancreatic enzyme supplementation. None developed postresection new-onset insulin-dependent diabetes. Middle pancreatectomy with pancreaticogastrostomy is feasible and reasonable technique. Although the incidence of pancreatic fistula formation may still be higher compared to conventional resection, long-term exocrine, and endocrine pancreatic function may be preserved. Thus, careful patient selection and experienced pancreatic surgeons in high-volume centers are of great importance.

Distal Pancreatectomy is Not Associated with Increased Perioperative Morbidity when Performed as Part of a Multivisceral Resection

PurposeTo evaluate the indications for and the outcomes from distal pancreatectomy. MethodsRetrospective chart review of 171 patients who underwent distal pancreatectomy at Brigham and Women’s Hospital between January 1996 and August 2005. ResultsNearly one-third of distal pancreatectomies were performed as part of an en bloc resection for a contiguous or metastatic tumor. Fifty-six percent of the patients underwent a standard distal pancreatectomy +/− splenectomy (group 1), whereas 44% of distal pancreatic resections included additional organs or contiguous intraperitoneal or retroperitoneal tumor (group 2). The overall post-operative complication rate was 37%; the most common complication was pancreatic duct leak (23%). When compared to patients undergoing standard distal pancreatectomy, those with a more extensive resection including multiple viscera and/or metastatic or contiguous tumor resection had no significant difference in overall complication rate (35% v. 39%, p = 0.75), leak rate (25% v. 20%, p = 0.47), new-onset insulin-dependent diabetes mellitus (3% v. 4%, p = 1.0), and mortality (2% v. 4%, p = 0.656). ConclusionThis series includes a large number of patients in whom distal pancreatectomy was performed as part of a multivisceral resection or with en bloc resection of contiguous tumor. Complications were no different in these patients when compared to patients undergoing straightforward distal pancreatectomy.

Differential binding of IgG and IgA antibodies to antigenic determinants of bovine serum albumin.

The aim of this study was to investigate the recognition pattern of bovine serum albumin (BSA), a major dietary protein by serum IgG and IgA antibodies. Anti-BSA IgG and IgA antibodies were measured by ELISA technique in 3 different cohorts: 578 unselected persons, 84 new-onset insulin-dependent diabetes mellitus (IDDM) patients and 103 atopic persons. In order to characterize the recognition pattern of the different BSA domains, recombinant BSA and recombinant fragments covering the 3 BSA domains were produced. BSA digestion was monitored in simulated gastric fluid experiments by means of domain specific monoclonal antibodies. IgG and IgA antibody titres to native BSA were highest in IDDM patients. The three major BSA domains were equally well recognized by IgG antibodies of the three cohorts. Interestingly all three study groups showed a dissociation of their IgG and IgA antibody response to the first BSA domain. The ratio of IgG to IgA antibodies recognizing this domain was 93%/42% in controls, 92%/37% in IDDM patients and 80%/47% in atopic persons. In simulated gastric fluid experiments, the first BSA domain was the first to become undetectable to specific monoclonal antibodies during digestion. In conclusion humoral IgG and IgA antibodies recognize the major BSA domains with different frequencies. The N-terminal domain of BSA, the first to be degraded during simulated gastric digestion is less well recognized by IgA antibodies. This suggests that early digestion is negatively correlated to the IgA antibody response and that the IgA response associated to the gut associated lymphoid tissue (GALT) and the systemic IgG antibody responses are independent.

Corticosteroid-Free Immunosuppression with Tacrolimus, Mycophenolate Mofetil, and Daclizumab Induction in Renal Transplantation

Corticosteroid-free maintenance immunosuppression after organ transplantation eliminates the well-known corticosteroid-related side effects and may help to improve long-term outcome. We investigated whether a corticosteroid-free tacrolimus (Tac)/mycophenolate mofetil (MMF) regimen, in combination with daclizumab (Dac) induction therapy, provides adequate immunosuppression after renal transplantation. This 6-month, open-label, multicenter, parallel-group study involved 538 renal patients randomized (1:1) to a Dac/Tac/MMF regimen (n = 260) or a Tac/MMF/corticosteroids regimen (n = 278) as a control group. Of the patients who completed the study, 88.8% in the Dac/Tac/MMF group were free from corticosteroid therapy at month 6. The incidence of biopsy-proven acute rejection was 16.5% in both treatment groups; the incidence of biopsy-proven corticosteroid-resistant acute rejection was 4.3% and 5.0% with Tac/MMF/corticosteroids and Dac/Tac/MMF, respectively (P = NS for both comparisons). Renal function was also similar in both groups: median serum creatinine at month 6 was 125.0 micromol/L (Tac/MMF/corticosteroids) and 131.0 microml/L (Dac/Tac/MMF), P = 0.277. The overall safety profile was similar with both regimens. However, compared with the Tac/MMF/steroid regimen, a significantly reduced incidence of new-onset insulin-dependent diabetes mellitus (5.4% vs. 0.4%, P = 0.003) was found with steroid-free immunosuppression. Moreover, mean total cholesterol concentrations increased from baseline in the Tac/MMF/corticosteroids group by 0.19 mmol/L, whereas in the Dac/Tac/MMF group, levels decreased by 0.19 mmol/L, P = 0.005. Corticosteroid-free immunosuppression with a Dac/Tac/MMF regimen is as effective at preventing acute rejection after renal transplantation as a standard triple regimen of Tac/MMF/corticosteroids. Furthermore, the safety benefits reported with Dac/Tac/MMF treatment may help improve the long-term outcome for renal-transplant patients.

A PILOT STUDY OF SWITCHING CSA TO LOW DOSE OF TACROLIMUS ON CHRONIC ALLOGRAFT NEPHROPATHY AFTER KIDNEY TRANSPLANTATION

P178 Aims: The two principal factors implicated in late kidney allograft failure are chronic allograft nephropathy(CAN) and death of the patient with a functioning graft (mainly from cardiovascular causes). CAN is the leading cause of graft failure. Both nonimmunological and immunological mechanisms contribute to this pathology. Tacrolimus is a new, high-potential immunosuppressive agent, possible strategies to stabilize or improve allograft function in patients with already established CAN are the addition of mycophenolate mofetil and conversion from cyclosporine to tacrolimus. Methods: A total of 58 cadaveric kidney transplants were performed at CHAO YANG HOSPITAL from 1998-2000,these patients were first grafts. All recipients received CsA-based triple immunosuppressive regimen. The mean age was 36±14 years, 0.5 to 7.5years after operation. The patients with abnormal grafted renal function after operation and chronic renal allograft nephropathy proved pathologically were collected. A cyclosporine based regimen was converted to a tacrolimus-based regimen. Recipients began to received tacrolimus-based triple immunosuppressive regimen (tacrolimus + MMF +prednisone) after 12 hours discontinuation of CsA. The initial dosage of tacrolimus ranged from 0.04 mg/kg/d to 0.07mg/kg/d,. Dosage adjustments were based on whole blood trough levels. The targeting whole blood trough levels was 8-10ng/ml within 6 months after operation, 5-7 ng/ml after 6 months operation. The dosage of MMF was 1500mg/day. Fellow up at least twelve months. Monitoring the slope of serum creatinine and GFR(ml/min/1.73m2) and 24-hours urine protein output and blood pressure and lipid before and after twelve months of switching CsA to Tacrolimus. Results: The result are shown in Fig 1, 2 and Table 1. The 58 patients of serum creatinine level decreased from 387.5 ±49.7mmol/l to 165.1±56.2mmol/L(p<0.01), 185.1±48.2mmol/L, 180.1±51.2mmol/L. The slope of serum creatinine were from-1.35±1.3 to 2.43±1.7(p<0.05), 2.33±1.5, 2.45±1.5,The result are shown in Fig 2. GFR (ml/min/1.73m2) were from 38.79±2.25 to 49.21±3.19 (p<0.05), 47.21±3.38, 43.37±2.54,24-hours urine protein output were from 4.3±0.8g to 1.9±0.5g(p<0.05), 1.7±0.8g,1.8±0.6g,Cholesterol were from 288±46 mg/dL to 159±55 mg/dL, 169±39 mg/dL,152±47mg/dL, Triglyceride were from 308±56 mg/dL to 217±48 mg/dL, 197±52 mg/dL, 201±43 mg/dL,MAP were from 126±39 mmHg to 90±25 mmHg, 95±38 mmHg, 87±40 mmHg before and after 12,24,36 months of switching CsA to Tacrolimus. The patients survival rates were 100%(58/58),96.5%(56/58), 94.8%(55/58) at 1 year,2 year,3 year respectively. Graft function recovered in 38 cases,improved in 11 recipients, stabilized in 6 patients. Therapy failed in 3 cases and begin hemodialysis. 3 recipients withdrawn from the study because of liver toxicity. The incidence of acute rejection in our study was 10.34%(6/58) after 1 years fellow up. Adverse events in our study were bilirubinemia3.45% (2/58), tremor17.24%(10/58). None of all the patients developed new-onset insulin-dependent Diabetes Mellitus. Conclusions: Many investigators have noted that CAN is the mainly factor of the late kidney allograft failure. Our reports cited that Tacrolimus+MMF is better than CsA in delaying kidney transplant function,(1) Combine Tacrolimus and MMF treatment results in a low incidence of biopsy-confirmed rejection.(2) Tacrolimus reduced TGF-β transforming.(3)Tacrolimus requred less antihypertension,antihyperlipid therapy.(4)To the extent that MMF gives clinicans confidence to reduce the CNI (calcineurin inhibitor) this minimized drug-related toxicities.(5)Mycophenolate mofetil is more bioavailable when used with tacrolimus, compared with cyclosporine, probably because cyclosporine reduces MMF’s bioavailability. The use of a lower dose of MMF in combination with Tacrolimus as maintenance therapy may decrease the incidence of adverse effects while maintaining efficacy. In summary, in this study we demonstrated that conversion from cyclosporine to tacrolimus based regimen was an effective and safe alternative for delaying the course of renal function induced by Chronic Allograft Nephropathy after kidney transplantation.

A low incidence of New-Onset Insulin-Dependent diabetes mellitus using tacrolimus in kidney recipients in Europe

Employing tacrolimus (Tac) for routine immunosuppression in renal transplantation (RT), produced an incidence of new-onset, insulin-treated, diabetes mellitus (newDM) as high as 20%. More recently, several large multicenter kidney studies using Tac as the primary immunosuppressant have been reported in Europe. Between 1997 and 2001, we performed 155 RTs using Tac (0.2 mg/k/per day, targeting whole blood trough levels <15 ng/mL) with a rapid steroid taper. The acute rejection rate was 13%, and 89% of grafts are still functioning. Only 5 Tac-treated patients not previously requiring insulin needed insulin therapy for ≥30 days (3.2%). Eight separate studies employing Tac in at least one arm (N = 2728) have been reported between 1997 and 2002. Tac was combined with azathioprine or MMF, and/or steroids. The incidence of new DM at study end ranged from 2.3% to 8.3%. The only trial with >6% incidence was the first one, using an initial dose of 0.3 mg/kg per day. The most recent studies utilized an initial dose of 0.2 mg/kg per day, targeting whole blood trough levels of <15 ng/mL and a steroid taper, with newDM at <6%. On the basis of these data, we confirm in that the use of Tac as a first-line immunosuppressant in renal transplant patients affords protection against acute rejection with a low level of newDM. The tendency to employ lower oral doses of Tac, lower blood target levels, and a reduced steroid dose appear to minimize glucose disturbances in RT.

Distal pancreatectomy: indications and outcomes in 235 patients.

Distal pancreatectomy is performed for a variety of benign and malignant conditions. In recent years, significant improvements in perioperative results have been observed at high-volume centers after pancreaticoduodenectomy. Little data, however, are available concerning the current indications and outcomes after distal pancreatectomy. This single-institution experience reviews the recent indications, complications, and outcomes after distal pancreatectomy. A retrospective analysis was performed of the hospital records of all patients undergoing distal pancreatectomy between January 1994 and December 1997, inclusive. The patient population (n = 235) had a mean age of 51 years, (range 1 month to 82 years); 43% were male and 84% white. The final diagnoses included chronic pancreatitis (24%), benign pancreatic cystadenoma (22%), pancreatic adenocarcinoma (18%), neuroendocrine tumor (14%), pancreatic pseudocyst (6%), cystadenocarcinoma (3%), and miscellaneous (13%). The level of resection was at or to the left of the superior mesenteric vein in 96% of patients. A splenectomy was performed in 84% and a cholecystectomy in 15% of patients. The median intraoperative blood loss was 450 ml, the median number of red blood cell units transfused was zero, and the median operative time was 4.3 hours. Two deaths occurred in the hospital or within 30 days of surgery for a perioperative mortality rate of 0.9%. The overall postoperative complication rate was 31%; the most common complications were new-onset insulin-dependent diabetes (8%), pancreatic fistula (5%), intraabdominal abscess (4%), small bowel obstruction (4%), and postoperative hemorrhage (4%). Fourteen patients (6%) required a second surgical procedure; the most common indication was postoperative bleeding. The median length of postoperative hospital stay was 10 days. Patients who underwent a distal pancreatectomy with splenectomy (n = 198) had a similar complication rate (30% vs. 29%), operative time (4.6 vs. 5.1 hours), and intraoperative blood loss (500 vs. 350 ml) and a shorter postoperative length of stay (13 vs. 21 days) than the patients who had splenic preservation (n = 37). This series represents the largest single-institution experience with distal pancreatectomy. These data demonstrate that elective distal pancreatectomy is associated with a mortality rate of <1%. These results demonstrate that, as with pancreaticoduodenectomy, distal pancreatectomy can be performed with minimal perioperative mortality and acceptable morbidity.

Primary adult liver transplantation under tacrolimus: more than 90 months actual follow-up survival and adverse events.

The introduction of tacrolimus has shown decreased rates of acute and steroid-resistant rejection after liver transplantation (LTx). The aim of the present study is to examine the long-term efficacy and safety of tacrolimus in primary liver transplant recipients. The first 121 consecutive adults (aged >16 years) who underwent primary LTx at a single center from August 1989 to February 1990 were followed up until August 1997. The mean follow-up was 93.2 +/- 1.2 months (range, 90.5 to 96.5 months). Patient survival, graft survival, rate of rejection, and adverse events were examined. The actual 7-year patient survival rate was 67.8%, and the graft survival rate was 63.6%. Infections, recurrence of disease, de novo malignancies, and cardiovascular events constituted the main causes of graft loss and death in the long term. Graft loss related to acute or chronic rejection was rare. The rate of acute rejection beyond 2 years was approximately 3% per year, and most rejections were steroid responsive. Approximately 70% of the patients received only tacrolimus after 1 year. Four patients developed end-stage renal disease, and 2 patients underwent kidney transplantation. Hyperkalemia and hypertension were observed in one third of the patients. New-onset insulin-dependent diabetes mellitus was observed in 9% and 13% of the patients at the 1-year and 7-year follow-up, respectively. Seven patients developed de novo malignancies, including two skin malignancies. Six patients developed posttransplantation lymphoproliferative disorder during the entire follow-up period. Actual patient and graft survival at 7 years was excellent, and few adverse events developed after the first year. Graft loss from acute or chronic rejection was rare under tacrolimus, and approximately 70% of the patients were steroid free on tacrolimus monotherapy after the first year after LTx.

Diagnostic Significance of Antibodies to Glutamic Acid Decarboxylase in Japanese Diabetic Patients with Secondary Oral Hypoglycemic Agents Failure

Some non-insulin-dependent diabetes mellitus (NIDDM) patients are positive for antibodies to glutamic acid decarboxylase (anti-GAD), and they tend to develop insulin deficiency. The aim of this study was to evaluate the prevalence of anti-GAD in NIDDM with secondary failure of sulfonylurea agents (NIDDM-SF) and to investigate the diagnostic significance of seropositivity for anti-GAD in NIDDM-SF patients by evaluating human leukocyte antigen (HLA)-DRB1 alleles concurrently. The prevalence of anti-GAD in NIDDM-SF, NIDDM, and new-onset (within 1 year after onset) insulin-dependent diabetes mellitus (IDDM) was 9.3% (39/420), 3.1% (12/392), and 65.0% (13/20), respectively. Pancreatic beta cell function deteriorated in NIDDM-SF patients positive for anti-GAD. HLA-DRB1 allele typing revealed that NIDDM-SF patients positive for anti-GAD were significantly associated with DRB1*0901 (RR = 2.81,P< 0.01), which is one of the susceptible alleles to IDDM. Shorter interval before development of secondary failure and insulin deficiency were significantly associated with the presence of DRB1*0901 (P< 0.05) in NIDDM-SF patients positive for anti-GAD. In conclusion, nearly 10% of NIDDM-SF patients are positive for anti-GAD, suggesting that an autoimmune mechanism might play an important role in the pathogenesis of NIDDM-SF patients. In addition, a combination of serological marker (anti-GAD) and genetic marker (HLA-DRB1) is useful for predicting clinical course of NIDDM patients with secondary failure of sulfonylurea agents.

Hydrocephalus Requiring Urgent External Ventricular Drainage in a Patient with Diabetic Ketoacidosis and Cerebral Edema: Case Report

Neurological deterioration, typically attributed to cerebral edema, is a rare but life-threatening complication in the treatment of diabetic ketoacidosis (DKA). We report the case of a child with DKA who became comatose but demonstrated acute obstructive hydrocephalus, instead of cerebral edema. An 11-year-old male patient presented with new-onset insulin-dependent diabetes mellitus and DKA. He was initially responsive but, after several hours of treatment, became unresponsive, with dilated pupils and decerebrate posturing. Cranial computed tomographic scanning demonstrated obstructive hydrocephalus resulting from focal cerebellar and brain stem edema. The patient was initially managed with medical treatment but ultimately required urgent ventricular drainage to arrest a progressive herniation syndrome. To our knowledge, this report describes only the second such case reported and the first requiring urgent ventriculostomy. These observations emphasize the importance of recognizing hydrocephalus as a potentially reversible cause of coma in DKA and of initiating prompt neurosurgical intervention, if warranted.

Use of FK506 in pancreas transplantation

Until recently, FK 506 was used only for rescue therapy after pancreas transplantation. We report our initial experience with FK 506 for 67 pancreas recipients (treated between 1 May 1993 and 30 April 1995). Of these recipients, 49 (73 %) received FK.506 for induction and maintenance therapy, 12 (18 %) for rescue or antirejection therapy, and 6 (9 %) for reasons other than rescue or antirejection therapy. In our induction and maintenance therapy group, 32 recipients (65 %) underwent a simultaneous pancreas-kidney transplant (SPK), 8 (16 %) a pancreas transplant alone (PTA), and 9 (19 %) a pancreas after previous kidney transplant (PAK). Quadruple immunosuppression was used for induction; the median FK 506 starting dose was 4 mg/day p. 0. and target levels were 10–20 ng/ ml. The most common side effects were nephrotoxicity (16 %) and neurotoxicity (14 %); transient episodes of hyperglycemia were also noted (12 %), in particular in the presence of concurrent rejection and infection episodes. A matched-pair analysis was done to compare graft outcome with FK506 versus cyclosporin A (CsA). For SPK recipients, pancreas graft survival at 6 months was 79 % with FK506 versus 65 % with CsA (P= 0.04), for PTA, 100 % versus 63 % (P > 0.35), and for PAK, 88 % versus 33 % (P > 0.01). Pancreas graft loss due to rejection at 6 months posttransplant was lower with FK 506 versus CsA. Two FK506 recipients died from B-cell lymphomas (Epstein-Barr virus positive) at 6 and 7 months post-transplant. In our rescue or anti-rejection group, 5 recipients underwent SPK, 3 PTA, and 4 PAK. The mean average FK506 dose was 10 mg/day p. o. and the mean average FK506 blood level was 11 ng/ml. The most common side effects were nephrotoxicity (33 %) and neurotoxicity (16 %). Two recipients developed hyperglycemic episodes, of whom 1 has remained on insulin with good exocrine pancreas graft function. Graft survival at 6 months after conversion was 75 % for SPK, 67 % for PTA, and 50 % for PAK. Only one graft was lost due to chronic rejection. Our single-center experience shows that FK 506 after pancreas transplantation is associated with: (1) a low rate of graft loss due to rejection when used for induction, in particular for solitary pancreas transplants, (2) a high rate of graft salvage when used for rescue, (3) a 1 % rate of new-onset insulin-dependent diabetes mellitus, and (4) a 3 % rate of posttransplant lymphoma. Further studies are necessary to analyze the long-term impact of FK 506 on pancreas transplant outcome.

Use of FK 506 in pancreas transplantation.

Until recently, FK 506 was used only for rescue therapy after pancreas transplantation. We report our initial experience with FK 506 for 67 pancreas recipients (treated between 1 May 1993 and 30 April 1995). Of these recipients, 49 (73%) received FK 506 for induction and maintenance therapy, 12 (18%) for rescue or antirejection therapy, and 6 (9%) for reasons other than rescue or antirejection therapy. In our induction and maintenance therapy group, 32 recipients (65%) underwent a simultaneous pancreas-kidney transplant (SPK), 8 (16%) a pancreas transplant alone (PTA), and 9 (19%) a pancreas after previous kidney transplant (PAK). Quadruple immunosuppression was used for induction; the median FK 506 starting dose was 4 mg/day p.o. and target levels were 10-20 ng/ml. The most common side effects were nephrotoxicity (16%) and neurotoxicity (14%); transient episodes of hyperglycemia were also noted (12%), in particular in the presence of concurrent rejection and infection episodes. A matched-pair analysis was done to compare graft outcome with FK 506 versus cyclosporin A (CsA). For SPK recipients, pancreas graft survival at 6 months was 79% with FK 506 versus 65% with CsA (P = 0.04), for PTA, 100% versus 63% (P > 0.35), and for PAK, 88% versus 33% (P > 0.01). Pancreas graft loss due to rejection at 6 months posttransplant was lower with FK 506 versus CsA. Two FK 506 recipients died from B-cell lymphomas (Epstein-Barr virus positive) at 6 and 7 months posttransplant. In our rescue or anti-rejection group, 5 recipients underwent SPK, 3 PTA, and 4 PAK. The mean average FK 506 dose was 10 mg/day p.o. and the mean average FK 506 blood level was 11 ng/ml. The most common side effects were nephrotoxicity (33%) and neurotoxicity (16%). Two recipients developed hyperglycemic episodes, of whom 1 has remained on insulin with good exocrine pancreas graft function. Graft survival at 6 months after conversion was 75% for SPK, 67% for PTA, and 50% for PAK. Only one graft was lost due to chronic rejection. Our single-center experience shows that FK 506 after pancreas transplantation is associated with: (1) a low rate of graft loss due to rejection when used for induction, in particular for solitary pancreas transplants, (2) a high rate of graft salvage when used for rescue, (3) a 1% rate of new-onset insulin-dependent diabetes mellitus, and (4) a 3% rate of posttransplant lymphoma. Further studies are necessary to analyze the long-term impact of FK 506 on pancreas transplant outcome.

Serologic Evidence of an Association between Enteroviruses and the Onset of Type 1 Diabetes Mellitus

Serum was collected from 128 patients < or = 18 years of age admitted to the Children's Hospital of Pittsburgh with new-onset insulin-dependent diabetes mellitus (IDDM) and from 120 control-patients who were frequency-matched to case-patients for age, sex, and date of bleed. Serum was tested for IgM against 14 enterovirus serotypes: coxsackieviruses B1-B6 and A9, echoviruses 4, 6, 9, 11, 30, and 34, and enterovirus 71. Case-children 13-18 years of age were more likely than control-patients to be IgM-positive for 9 of 14 serotypes (P < or = .05 for each). In contrast, case-children 10-12 years of age and 1-9 years of age were each more likely than age-matched control-children to be IgM positive for 1 serotype (P < or = .05 for each). In addition, the association between IgM positivity and IDDM occurred earlier in girls than in boys. These data support an association between IDDM and enterovirus IgM positivity in older children.

Criterion and predictive validity of the diagnosis of adjustment disorder: a prospective study of youths with new-onset insulin-dependent diabetes mellitus.

The authors examined the criterion and predictive validity of the diagnosis of adjustment disorder in a pediatric study group. Ninety-two school-age children with new-onset insulin-dependent diabetes mellitus were evaluated repeatedly and were diagnosed by using DSM-III. The criteria for adjustment disorder were further operationalized by requiring four clinically significant symptoms or signs; the time frame for its onset was extended to 6 months after the diagnosis of insulin-dependent diabetes. Predictive validity was assessed in terms of new psychiatric disorders other than adjustment disorder during the next 5 years. Of the 92 children, 33 developed adjustment disorder and five developed other psychiatric disorders in response to the diagnosis of insulin-dependent diabetes mellitus. Mean time from diabetes diagnosis to onset of adjustment disorder was 29 days, the average episode length was 3 months, and the recovery rate was 100%. Among youths with adjustment disorder in response to the medical diagnosis, the 5-year cumulative probability of a new psychiatric disorder was 0.48, compared to 0.16 among the other youths. The findings generally support the criterion validity of the diagnosis of adjustment disorder. However, episode duration and the predictive validity of the diagnosis appear to be functions of the study group being examined. In nonpsychiatrically referred pediatric patients, early problems in adaptation to the stress of changed health status, as evidenced by adjustment disorder, appear to signal vulnerability to later psychopathology.

Effect of insulin on the insulin-like growth factor system in children with new-onset insulin-dependent diabetes mellitus

Effect of insulin on the insulin-like growth factor system in children with new-onset insulin-dependent diabetes mellitus

A longitudinal study of life events and metabolic control among youths with insulin-dependent diabetes mellitus.

In a study of school-age children with new-onset insulin-dependent diabetes mellitus (IDDM), life stress, metabolic control (glycosylated hemoglobin), and psychiatric and psychosocial variables were assessed repeatedly for up to 6 years. Life stress was defined as the number of undesirable life events and extent of life change necessitated by all life events. In univariate longitudinal analyses, total life change units were related to metabolic control, with a trend for number of undesirable events to be associated with metabolic control. In multivariate analyses, metabolic control was related to life change units, whether the glycosylated hemoglobin was in the 1st year of IDDM, IDDM duration, and the diagnosis of pervasive noncompliance with medical regimen. The relationship of life stress to metabolic control among youths with diabetes in significant but clinically modest and may be partially mediated by serious noncompliance with the medical regimen.