Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA).

BACKGROUND: To assess the efficacy and tolerability of saxagliptin and C-peptide secretion in patients with diagnosed type 2 diabetes classified as glutamic acid decarboxylase antibody (GADA)-positive or GADA-negative. METHODS: Post hoc analysis of data pooled from five randomized, placebo-controlled, 24-week phase 3 studies (n = 2709) was conducted. We evaluated mean change from baseline at week 24 in HbA1c , fasting plasma glucose, postprandial plasma glucose, fasting and postprandial C-peptide, and HOMA2-%ß and the proportion of patients achieving HbA1c < 7% (53 mmol/mol) at week 24. RESULTS: Saxagliptin produced greater adjusted mean reductions from baseline in HbA1c versus placebo for GADA-negative [difference vs placebo (95% CI), -0.62% (-0.71% to -0.54%); -6.8 mmol/mol (-7.8, -5.9)] and GADA-positive patients [-0.64% (-1.01% to -0.27%); -7.0 mmol/mol (-11.0, -3.0)]. Consistently, saxagliptin produced a greater reduction from baseline in fasting plasma glucose and postprandial plasma glucose versus placebo in GADA-positive versus GADA-negative patients, and more patients achieved HbA1c < 7% (53 mmol/mol) with saxagliptin versus placebo in both GADA-negative and GADA-positive patients. Saxagliptin increased ß-cell function as assessed by HOMA2-%ß and postprandial C-peptide area under the curve from baseline in patients in both GADA-positive and GADA-negative patients. Adverse events and hypoglycaemic events were similar across treatment groups and GADA categories. CONCLUSION: Saxagliptin was effective in lowering blood glucose levels and generally well tolerated in GADA-positive patients. Interestingly, saxagliptin appears to improve ß-cell function in these patients, although a longer treatment duration may be needed to confirm this finding.

Frequency of cancer events with saxagliptin in the SAVOR-TIMI 53 trial.

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial randomized trial of 16,492 patients (placebo, n = 8212; saxagliptin, n = 8280) treated and followed for a median of 2.1 years afforded an opportunity to explore whether there was any association with cancer reported as a serious adverse event. At least one cancer event was reported by 688 patients (4.1%): 362 (4.3%) and 326 (3.8%) in the placebo and saxagliptin arms, respectively (p = 0.13). There were 59 (0.6%) deaths adjudicated as malignancy deaths with placebo and 53 (0.6%) with saxagliptin. Stratification by gender, age, race and ethnicity, diabetes duration, baseline glycated haemoglobin and pharmacotherapy did not show any clinically meaningful differences between the two study arms. The overall number of cancer events and malignancy-associated mortality rates were generally balanced between the placebo and saxagliptin groups, suggesting a null relationship with saxagliptin use over the median follow-up of 2.1 years. Multivariable modelling showed that male gender, dyslipidaemia and current smoking were independent predictors of cancer. These randomized data with adequate numbers of cancer cases are reassuring but limited, by the short follow-up in a trial not designed to test this hypothesis.

A post hoc analysis of saxagliptin efficacy and safety in patients with type 2 diabetes stratified by UKPDS 10-year cardiovascular risk score.

BACKGROUND AND AIMS: To assess the efficacy and safety of saxagliptin 2.5 and 5 mg/d in patients with type 2 diabetes mellitus (T2DM) and high risk of coronary heart disease (CHD) or stroke as estimated by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. METHODS AND RESULTS: Post hoc analysis of data pooled from 5 previously reported phase 3, randomized, placebo-controlled, 24-week studies was conducted. Patients were stratified into subgroups by UKPDS 10-year CHD and/or stroke risk ≥20% and CHD and stroke risk <20%. End points were adjusted mean change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), 120-min postprandial glucose (PPG), and body weight and the proportion of patients achieving HbA1c <7% and ≤8% at week 24. Pooled safety data were analyzed for adverse events (AEs) and hypoglycemia. Both doses of saxagliptin reduced HbA1c, FPG, and PPG to a greater extent than placebo regardless of UKPDS risk score. The proportions of patients achieving HbA1c <7% and ≤8% were greater with saxagliptin than placebo and consistent across risk score groups. AE profile and hypoglycemia incidence were similar for saxagliptin and placebo across UKPDS risk score groups. CONCLUSION: Saxagliptin was well tolerated and improved glycemic control in patients with T2DM regardless of their CHD and stroke UKPDS risk score. Clinical trial registration numbers: Clinicaltrials.gov NCT00121641, NCT00316082, NCT00121667, NCT00313313, and NCT00295633.

Impact of treatment with saxagliptin on glycaemic stability and ß-cell function in the SAVOR-TIMI 53 study.

AIMS: To study the effects of saxagliptin, a dipeptidyl peptidase-4 inhibitor, on glycaemic stability and ß-cell function in the SAVOR-TIMI 53 trial. METHODS: We randomized 16,492 patients with type 2 diabetes (T2D) to saxagliptin or placebo, added to current antidiabetic medications, and followed them for a median of 2.1 years. Glycaemic instability was defined by: (i) a glycated haemoglobin (HbA1c) increase of ≥ 0.5% post-randomization; (ii) the initiation of new antidiabetic medications for ≥ 3 months; or (iii) an increase in dose of oral antidiabetic medication or ≥ 25% increase in insulin dose for ≥ 3 months. ß-cell function was assessed according to fasting homeostatic model 2 assessment of ß-cell function (HOMA-2ß) values at baseline and at year 2 in patients not treated with insulin. RESULTS: Compared with placebo, participants treated with saxagliptin had a reduction in the development of glycaemic instability (hazard ratio 0.71; 95% confidence interval 0.68-0.74; p < 0.0001). In participants treated with saxagliptin compared with placebo, the occurrence of an HbA1c increase of ≥ 0.5% was reduced by 35.2%; initiation of insulin was decreased by 31.7% and the increases in doses of an oral antidiabetic drug or insulin were reduced by 19.5 and 23.5%, respectively (all p < 0.0001). At 2 years, HOMA-2ß values decreased by 4.9% in participants treated with placebo, compared with an increase of 1.1% in those treated with saxagliptin (p < 0.0001). CONCLUSIONS: Saxagliptin improved glycaemia and prevented the reduction in HOMA-2ß values. Saxagliptin may reduce the usual decline in ß-cell function in T2D, thereby slowing diabetes progression.

Ab initio and semi-empirical Molecular Dynamics simulations of chemical reactions in isolated molecules and in clusters.

Recent progress in "on-the-fly" trajectory simulations of molecular reactions, using different electronic structure methods is discussed, with analysis of the insights that such calculations can provide and of the strengths and limitations of the algorithms available. New developments in the use of both ab initio and semi-empirical electronic structure algorithms are described. The emphasis is on: (i) calculations of electronic properties along the reactive trajectories and the unique insights this can contribute to the processes; (ii) electronic structure methods recently introduced to this topic to improve accuracy, extend applicability or enhance computational efficiency. The methods are presented with examples, including new results, of reactions of both isolated molecules and of molecules in media, mostly clusters. Possible future directions for this fast growing field are suggested.

Baseline characteristics of the patient population in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus (SAVOR)-TIMI 53 trial.

BACKGROUND AND AIMS: SAVOR-TIMI 53 was designed to study the effects of the DPP-4 inhibitor saxagliptin on cardiovascular outcomes in high risk type 2 diabetes patients with diverse levels of diabetes control and background anti-diabetic drugs. The goal of this article is to describe the baseline characteristics of this hypothesis driven study. MATERIALS AND METHODS: A total of 16 496 diabetic patients from North America (31.9%), Western Europe (26.0%), Eastern Europe (17.3%), Latin America (16.4%) and Asia (8.3%), with either established cardiovascular disease (78.3%) or with ≥two additional cardiovascular risk factors (21.7%) were randomised to saxagliptin or placebo. Biomarkers of inflammation and insulin resistance were taken at baseline and 2 years later in order to correlate saxagliptin effect on cardiovascular outcome to its effect on inflammation and insulin resistance. RESULTS: Mean [+/-standard deviation (SD)] age was 65.0 (+/-8.6) years, 66.9% were male, body mass index was 31.2 kg/m² (+/-5.6), mean diabetes duration was 11.9 years (+/-8.9) and the mean HbA1c 8.0% (+/-1.4%). HbA1c < 7% was most prevalent among North Americans (30.8%) and least among Asians (15.1%), whereas HbA1c > 9% was 30.7% in Latin America 27.0% in Asia and 15.1% in North America. Diabetic retinopathy was reported in 12.3% of patients, nephropathy in 17.7% and amputation in 2.5%. Diabetic treatments categories were as follows: no medication (5.4%), 1 oral anti-diabetic drug (OAD) (25.0%), ≥2 OAD (27.7%) and/or insulin (40.9%). The prevalence of micro-albuminuria was twice as high among insulin users compared with users of ≥2 OAD. Baseline statin use (78.3% overall) varied by region. CONCLUSION: The SAVOR-TIMI 53 patient population, with differing background diabetes control and anti-diabetic treatment, provides global representation of diabetic patients with established cardiovascular disease or at high risk for cardiovascular disease and is well-positioned to determine the effect of saxagliptin on cardiovascular events.

Adding saxagliptin to extended-release metformin vs. uptitrating metformin dosage.

AIM: To investigate whether patients taking metformin for type 2 diabetes mellitus (T2DM) have improved glycaemic control without compromising tolerability by adding an agent with a complementary mechanism of action vs. uptitrating metformin. METHODS: Adults with T2DM and glycated haemoglobin (HbA1c) between 7.0 and 10.5% receiving metformin extended release (XR) 1500 mg/day for ≥8 weeks were randomized to receive saxagliptin 5 mg added to metformin XR 1500 mg (n = 138) or metformin XR uptitrated to 2000 mg/day (n = 144). Endpoints were change from baseline to week 18 in HbA1c (primary), 120-min postprandial glucose (PPG), fasting plasma glucose (FPG) and the proportion of patients achieving HbA1c <7%. RESULTS: At week 18, the adjusted mean reduction from baseline HbA1c was -0.88% for saxagliptin + metformin XR and -0.35% for uptitrated metformin XR (difference, -0.52%; p < 0.0001). For 120-min PPG and FPG, differences in adjusted mean change from baseline between saxagliptin + metformin XR and uptitrated metformin XR were -1.3 mmol/l (-23.32 mg/dl) (p = 0.0013) and -0.73 mmol/l (-13.18 mg/dl) (p = 0.0030), respectively. More patients achieved HbA1c <7.0% with saxagliptin + metformin XR than with uptitrated metformin XR (37.2 vs. 26.1%; p = 0.0459). The proportions of patients experiencing any adverse events (AEs) were generally similar between groups; neither group showed any notable difference in hypoglycaemia or gastrointestinal AEs. CONCLUSION: Adding saxagliptin to metformin XR provided superior glycaemic control compared with uptitrating metformin XR without the emergence of additional safety concerns.

Pancreatic perfusion of healthy individuals and type 1 diabetic patients as assessed by magnetic resonance perfusion imaging.

AIMS/HYPOTHESIS: Loss of pancreatic beta cell mass and function leads to the development of diabetes mellitus. Currently there is no technical way to non-invasively image islet function and mass. Murine models suggest that islets are highly vascularised organs that make a significant contribution to the total pancreatic blood flow. The current study was undertaken to test with arterial spin labelling (ASL) magnetic resonance imaging if islet mass and/or stimulation of human pancreatic islets by hyperglycaemia can differentially increase whole-pancreas perfusion, thereby distinguishing non-diabetic from type 1 diabetic patients. METHODS: We assessed pancreatic blood flow using ASL at baseline, during a hyperglycaemia clamp study (glucose at 11 mmol/l) and during recovery to euglycaemia. RESULTS: Seventeen healthy volunteers and seven type 1 diabetic patients were studied. In healthy volunteers we observed no change in pancreatic blood flow during the three phases of the study. A trend for an increase in blood flow was observed in the two control tissues, the liver and kidney. Similarly, there was no significant difference in blood flow during the three stages (baseline, hyperglycaemia and recovery) in diabetic patients and there was no significant difference observed between diabetic patients and normal volunteers. CONCLUSIONS/INTERPRETATION: Our data suggest that in humans neither increased demand nor islet mass has a substantial influence on pancreatic perfusion. It is possible, however, that the current state-of-the art imaging technology employed in this study might not be sensitive enough to distinguish between a true effect and noise. TRIAL REGISTRATION: ClinicalTrials.gov NCT00280085.

Pancreatic beta cell function persists in many patients with chronic type 1 diabetes, but is not dramatically improved by prolonged immunosuppression and euglycaemia from a beta cell allograft.

AIMS/HYPOTHESIS: We measured serum C-peptide (at least 0.167 nmol/l) in 54 of 141 (38%) patients with chronic type 1 diabetes and sought factors that might differentiate those with detectable C-peptide from those without it. Finding no differences, and in view of the persistent anti-beta cell autoimmunity in such patients, we speculated that the immunosuppression (to weaken autoimmune attack) and euglycaemia accompanying transplant-based treatments of type 1 diabetes might promote recovery of native pancreatic beta cell function. METHODS: We performed arginine stimulation tests in three islet transplant and four whole-pancreas transplant recipients, and measured stimulated C-peptide in select venous sampling sites. On the basis of each sampling site's C-peptide concentration and kinetics, we differentiated insulin secreted from the individual's native pancreatic beta cells and that secreted from allografted beta cells. RESULTS: Selective venous sampling demonstrated that despite long-standing type 1 diabetes, all seven beta cell allograft recipients displayed evidence that their native pancreas secreted C-peptide. Yet even if chronic immunosuppression coupled with near normal glycaemia did improve native pancreatic C-peptide production, the magnitude of the effect was quite small. CONCLUSIONS/INTERPRETATION: Some native pancreatic beta cell function persists even years after disease onset in most type 1 diabetic patients. However, if prolonged euglycaemia plus anti-rejection immunosuppressive therapy improves native pancreatic insulin production, the effect in our participants was small. We may have underestimated pancreatic regenerative capacity by studying only a limited number of participants or by creating conditions (e.g. high circulating insulin concentrations or immunosuppressive agents toxic to beta cells) that impair beta cell function.

Repaglinide-induced factitious hypoglycemia.

We report the first case of repaglinide-induced factitious hypoglycemia in a young male. This case posed a challenging diagnostic dilemma because commercial assays for repaglinide are not available. Furthermore, the patient had a series of positive diagnostic tests such as high proinsulin and localizing intra-arterial calcium stimulation suggestive of insulinoma. This case, again, demonstrates the importance of pure clinical judgment in the face of often-conflicting laboratory data in making a correct diagnosis and the requirement of definitive data for an appropriate therapeutic resolution.

Forty-eight-hour fast: the diagnostic test for insulinoma.

Insulinoma causes fasting hypoglycemia due to inappropriate insulin secretion. Its diagnosis is based on demonstrating Whipple's triad during a supervised 72-h fast. For 75 yr, the 72-h fast has been the cornerstone for the diagnosis; however, it has never been critically assessed using newer assays for insulin, C peptide, and proinsulin. Thus, the aim of the current study is to assess the need for a full 72-h fast for the diagnosis of insulinoma. Patients with suspected hypoglycemia with documented glucose concentrations below 45 mg/dL were admitted to the NIH. Data obtained during the supervised fast of patients with pathologically proven insulinoma over a 30-yr period (1970-2000) were reviewed. We identified 127 patients with insulinoma. The average age of patients was 42.7 +/- 15.9 yr, with a predominance of females (62%). 107 patients had a benign tumor, 20 had malignant insulinoma, and 15 patients had multiple endocrine neoplasia type 1. The fast was terminated due to hypoglycemia in 44 patients (42.5%) by 12 h, 85 patients (66.9%) by 24 h, and 120 (94.5%) by 48 h. Seven patients fasted beyond 48 h despite subtle neuroglycopenic symptoms and glucose and insulin concentrations diagnostic of insulinoma. Immunoreactive proinsulin was elevated at the beginning of the fast in 90% of 42 patients. Proinsulin in noninsulinoma, in contrast to insulinoma, patients is usually suppressible; therefore, samples taken in the suppressed state have the greatest diagnostic value. We conclude that with the current available insulin and proinsulin assays, the diagnosis of insulinoma can be made within 48 h. Thus, the 48-h fast should replace the 72-h fast in textbooks and hospital protocols as the new diagnostic standard.

The syndrome of inappropriate antidiuretic hormone secretion in the elderly.

OBJECTIVE: To determine clinical characteristics of elderly patients presenting with the syndrome of inappropriate antidiuretic hormone secretion (SIADH), their outcome, and the extent of evaluation that is warranted. DESIGN: A retrospective study. SETTING: An 800-bed primary and tertiary care center in Jerusalem, Israel. PATIENTS: Fifty elderly patients, hospitalized with serum sodium levels below 130 mmol/L consistent with a diagnosis of SIADH. MEASUREMENTS: Data collection of the medical history, functional status, physical examination, laboratory evaluation, length of hospital stay, treatment, and outcome. RESULTS: The neurological clinical presentation on admission ranged widely: 48% were fully alert, 42% were stuporotic, and 10% had seizures. Sensorial impairment was significantly associated only with sodium values of less than 110 mmol/L. The majority of patients underwent a comprehensive work-up including chest x-ray, computerized tomography (CT) scans, and thyroid and adrenal function tests. The cause of SIADH in most of the patients remained obscure (60% of cases were idiopathic). The 2 main causes identified were pneumonia in 9 cases (18%) and medication in 6 cases (12%). Most of the patients survived the event; only two patients died, both because of sepsis and not due to hyponatremia. The average hospital stay was 12.8 +/- 9 days. CONCLUSIONS: Elderly patients with SIADH usually have an idiopathic form of this condition and a benign course. Extensive routine diagnostic procedures are not warranted. Simple measures like medical history taking with special emphasis on medications, physical examination, and chest x-rays can lead to a treatable diagnosis in most patients who do not have the idiopathic form of SIADH.

Hemoptysis: etiology, evaluation, and outcome in a tertiary referral hospital.

OBJECTIVES: Hemoptysis, an important and alarming symptom, often indicates serious disease. This study was designed to assess the different causes of hemoptysis, the relative importance of the different diagnostic modalities employed, and the outcome in an Israeli population cohort. DESIGN: A retrospective analysis of 208 patients with hemoptysis at the Hadassah University Hospital, Jerusalem, Israel between January 1980 and August 1995. RESULTS: Bronchiectasis (20%), lung cancer (19%), bronchitis (18%), and pneumonia (16%) accounted for most causes of hemoptysis. In contrast to older studies, active tuberculosis was a rare finding (1.4%). Bronchiectasis and bleeding diathesis were major causes of moderate to severe hemoptysis while bronchitis and lung cancer were commonly associated with milder degrees of bleeding. CT scan was the most sensitive diagnostic test when employed alone, with a positive yield of 67%. However, it failed to locate at least three cases of lung cancer. When combining a CT study together with a bronchoscopy, the positive yield increased to 93%. The mortality rate for patients with mild to moderate hemoptysis was low (2.5% and 6%, respectively), while patients with massive hemoptysis had high mortality rates (38%). Patients with lung cancer or bleeding diathesis had higher mortality rates compared with the rest of the cohort. CONCLUSIONS: Hemoptysis is a common symptom with a good prognosis in most cases. However, patients exhibiting massive bleeding or those with lung malignancy and patients with bleeding diathesis had a poorer prognosis. Patients older than 50 years with a positive smoking history need an extensive evaluation and follow-up to exclude lung carcinoma. The combined use of bronchoscopy and chest CT has the best yield in evaluating hemoptysis.

Factors predicting mortality of patients with lung abscess.

BACKGROUND: The rates of morbidity and mortality associated with lung abscess are still significant despite the introduction of antibiotic treatments. The aim of this work was to identify the factors that predict a poor outcome for patients with lung abscess. METHODS: We retrospectively reviewed the records and the roentgenographic files of adult patients with lung abscess who were hospitalized from 1980 to 1996 at the Hadassah University Hospital, in Jerusalem, Israel. RESULTS: The study population comprised 75 patients, and the mean age was 52 years old (range, 12 to 89 years). The mean (+/- SD) hospitalization duration was 25.7+/-21.5 days (range, 5 to 94 days). Fifteen patients (20%) succumbed to the infection. The patients who died had more predisposing factors (+/-SD), such as pneumonia, neoplasm, and altered consciousness, than those who survived, respectively: 2.73+/-1.4 vs 1.9+/-1.3 (p < 0.03). The patients with anemia on admission (hemoglobin levels of < 10 g/dL) had a higher mortality rate than those with higher hemoglobin levels, respectively: 58.3 vs 12.9% (p = 0.0008). A higher mortality rate was also associated with infection by Pseudomonas aeruginosa (83%), Staphylococcus aureus (50%), and Klebsiella pneumoniae (44%). The patients who died had larger abscess volumes (+/-SD) than those who survived (233+/-99 vs 157+/-33 mL), although it did not reach statistical significance. The diameter of the abscess correlated with the hospitalization time (r = 0.5; p < 0.001). CONCLUSION: High rates of morbidity and mortality are associated with lung abscess despite appropriate antibiotic therapy and better supportive care. In patients with several predisposing factors, such as a large abscess size and a right-lower-lobe location, the prognosis was worse. The patients infected with S aureus, K pneumoniae, and particularly P aeruginosa had an ominous prognosis. As the prognosis for lung abscess has not improved sufficiently since the introduction of antibiotics, other modalities should be considered for patients with poor prognostic signs.

Recovery from blast lung injury: one-year follow-up.

BACKGROUND: Blast injury to the lung is one of the devastating threats facing victims of an explosion. Although the pathogenesis of blast injury has been studied, little is known about the long-term effects on lung function in survivors. OBJECTIVE: To examine the pulmonary function of survivors 1 year after sustaining a blast injury. DESIGN: Prospective study. SETTING: Pulmonary function test laboratory at Hadassah Medical Center, Jerusalem. PARTICIPANTS: Eleven surviving victims of a blast injury sustained during a bus terrorist explosion. MEASUREMENTS: Twelve months after the injury, physical examinations, lung function tests, and progressive cardiopulmonary exercise examinations were conducted, and chest radiographs were obtained. RESULTS: The average age was 28 +/- 9.8 years. Most of the victims had multiple injuries in addition to the lung injury. Ten patients received mechanical ventilation, and 6 patients required chest drainage. All patients were treated in the ICU, with an average stay of 11.8 +/- 9 days. The patients were discharged to their homes or to a rehabilitation center 32.4 +/- 27. 3 days after the explosion. One year later, none had any pulmonary-related complaints. Physical examination of the lungs was normal. Most of the patients demonstrated normal lung function tests and complete resolution of the chest radiograph findings. CONCLUSION: Most patients who survive lung blast injury will regain good lung function within a year.

6;9 translocation in myelodysplastic syndrome.

The 6;9 chromosomal translocation [t(6;9)] is usually associated with acute nonlymphocytic leukemia, and carries a poor prognosis. We present a case of refractory anemia with excess of blasts (RAEB) accompanied by t(6;9). Review of the literature revealed an additional ten patients in which myelodysplastic syndrome (MDS) was associated with the chromosomal translocation 6;9. The patients tend to be younger then the average MDS patient and, unlike leukemia, in which this translocation is associated with a poor prognosis, these patients tend to have the same overall RAEB and refractory anemia with excess of blasts in transformation (RAEBt) prognosis. It is therefore possible that this chromosomal aberration should not be considered as an unfavorable prognostic factor in MDS.

Diurnal thyrotropin secretion in short-term profound primary hypothyroidism: does it ever persist?

Circulating serum thyrotropin (TSH) levels in euthyroid humans show a definite circadian variation, which is maintained in both mild hyperthyroidism and mild hypothyroidism. Yet conflicting data exist with regard to whether this variation persists in at least some patients with severe primary hypothyroidism. We, therefore, studied the diurnal variation in serum TSH in 10 patients (age range 20 to 84 years) with a history of thyroid failure due to prior total thyroidectomy and radioiodine (RAI) ablative treatment performed for thyroid cancer after short-term discontinuation of thyroid hormone (TH) therapy. Serum TSH was measured hourly for a 24-hour period. All data were normalized by converting the TSH values to a percentage (%), designating the 11:00 hour value as 100% (baseline). The average serum TSH levels were markedly elevated in all patients. There was no statistically significant difference between the TSH % values at any time during the 24-hour period when compared with baseline. Further, cosine regression analysis showed absence of rhythmicity in TSH % values over time; notably, no patient showed a variation in TSH % values > or = 15% of baseline. In conclusion, diurnal rhythmicity in serum TSH levels was abolished in a uniform cohort of patients with short-term severe primary hypothyroidism. We speculate that the complete lack of peripheral negative feedback input to the hypothalamus or pituitary or both may override the central rhythm-sustaining influences on TSH secretion.

Asymptomatic temporary atrioventricular dissociation complicating meningococcal meningitis.

We present a case of a young man with meningococcal meningitis and various asymptomatic temporary ECG abnormalities, including sinus bradycardia, atrioventricular dissociation and non specific ST-T changes.