Immune checkpoint inhibitor-induced Type 1 diabetes: a systematic review and meta-analysis.

AIM: To conduct a systematic review and meta-analysis to understand the timing and factors associated with anti-programmed cell death protein-1 (PD-1)/anti-programmed cell death protein-1 ligand (PD-L1) inhibitor-induced Type 1 diabetes. METHODS: We searched MEDLINE, EMBASE, SCOPUS and Cochrane databases (August 2000-2018) for studies of any design on immune checkpoint inhibitors. A total of 71 cases were reviewed from 56 publications. Comparisons were made using Fisher's exact and Student's t-tests. RESULTS: The mean ± sd age at Type 1 diabetes presentation was 61.7±12.2 years, 55% of cases were in men, and melanoma (53.5%) was the most frequent cancer. The median time to Type 1 diabetes onset was 49 (5-448) days with ketoacidosis in 76% of cases. The average ± sd HbA1c concentration was 62 ± 0.3 mmol/mol (7.84±1.0%) at presentation. All cases had insulin deficiency and required permanent exogenous insulin treatment. Half of the cases had Type 1 diabetes-associated antibodies at presentation, and those with antibodies had a more rapid onset (P=0.005) and higher incidence of diabetic ketoacidosis (P=0.02) compared to people without antibodies. CONCLUSIONS: Many people developed Type 1 diabetes within 3 months of initial PD-1/PD-L1 inhibitor exposure. People presenting with Type 1 diabetes-associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state-of-the-art therapies need to be aware of this potential severe adverse event.

Continuous electroencephalography (cEEG) changes precede clinical changes in a case of progressive cerebral edema.

BACKGROUND: Continuous electroencephalogram (cEEG) is tightly linked to cerebral metabolism and is sensitive to cerebral ischemia and hypoxia. The severity of cerebral ischemia can be seen on cEEG as changes in morphology, amplitude, or frequency, and cEEG may detect neuronal dysfunction at a reversible stage. METHODS: Case report and imaging. RESULTS: We present a case of focal cerebral edema with changes seen on cEEG 24 h before clinical signs of increased intracranial pressure. cEEG showed developing asymmetry in the left hemisphere followed by burst suppression. The right hemisphere showed similar progression to burst suppression. Complete suppression of both hemispheres was noted 6 h before clinical signs of herniation. Computed tomography (CT) head confirmed a large left parietal intracerebral hematoma with mass effect. CONCLUSIONS: cEEG has applications in monitoring cerebral dysfunction in addition to detecting seizure activity in the intensive care unit. It may serve a vital role in multi-modality monitoring for early recognition of neurological complications from brain injuries that may not be noticed clinically, which is paramount to early intervention.

Protective effect of plant sterols against chemically induced colon tumors in rats.

Diets rich in vegetables are associated with a low incidence of colon cancer. Since plant sterols are plentiful in vegetarian diets, we studied the effect of beta-sitosterol on colon tumor formation in rats treated with the carcinogen N-methyl-N-nitrosourea. We demonstrated that beta-sitosterol nullified in part the effect of this direct-acting carcinogen on the colon. We suggest that plant sterols may have a protective dietary action action to retard colon tumor formation. The beneficial effects of vegetarian diets may be enhanced because of the presence of these compounds.

[(18)F]-Fluoro-Deoxy-Glucose Positron Emission Tomography Scan Should Be Obtained Early in Cases of Autoimmune Encephalitis.

Introduction. Autoimmune encephalitis (AE) is a clinically challenging diagnosis with nonspecific neurological symptoms. Prompt diagnosis is important and often relies on neuroimaging. We present a case series of AE highlighting the importance of an early [(18)F]-fluoro-deoxy-glucose positron emission tomography (FDG-PET) scan. Methods. Retrospective review of seven consecutive cases of autoimmune encephalitis. Results. All patients had both magnetic resonance imaging (MRI) and FDG-PET scans. Initial clinical presentations included altered mental status and/or new onset seizures. Six cases had serum voltage-gated potassium channel (VGKC) antibody and one had serum N-methyl-D-aspartate (NMDA) antibody. MRI of brain showed mesial temporal lobe hyperintensity in five cases of VGKC. The other two patients with VGKC or NMDA AE had restiform body hyperintensity on MRI brain or a normal MRI, respectively. Mesial temporal lobe hypermetabolism was noted in three cases on FDG-PET, despite initial unremarkable MRI. Malignancy workup was negative in all patients. Conclusion. A high index of suspicion for AE should be maintained in patients presenting with cognitive symptoms, seizures, and limbic changes on neuroimaging. In cases with normal initial brain MRI, FDG-PET can be positive. Additionally, extralimbic hyperintensity on MRI may also be observed.

Ursodeoxycholic acid. Effects on sterol metabolism in rats.

Sterol balance studies using isotopic and chromatographic techniques were performed in rats fed diets supplemented with ursodeoxycholic acid. Compared to controls, ursodeoxycholic acid dramatically altered sterol metabolism. Ursodeoxycholic acid was absorbed and circulated in the enterohepatic circulation. The biliary bile acid composition was significantly altered with ursodeoxycholic acid the predominant biliary bile acid (67%). Cholesterol absorption was depressed by 34%; bile acid synthesis was depressed by 30%; however, cholesterol balance was significantly increased. It is apparent that the effects of ursodeoxycholic acid on sterol metabolism are different in several respects from chenodeoxycholic acid.

Synthesis and catalytic activity of poly-L-histidyl-L-aspartyl-L-seryl-glycine.

Poly(His-Asp-Ser-Gly) was synthesized from the fully protected tetrapeptide active ester hydrochloride, which was prepared by stepwise coupling, using pentachlorophenyl ester and mixed anhydride methods. Complete deprotection of the protected tetrapeptide polymer was achieved by using 90% trifluoroacetic acid. The free polymer was dialyzed for 24 hr using a membrane (which retains molecules with molecular weights greater than 5000). The catalytic activity was determined by studying the hydrolysis of p-nitrophenyl acetate in 0.2 M phosphate buffer (pH 7.4) at 37 degrees. The catalytic coefficient of the dialyzed polymer was found to be 138 liters/mole/min.

Effect of colestipol on sterol metabolism in the rat.

Sterol metabolism studies using isotopic and chromatographic techniques were performed on rats fed diets supplemented with colestipol (Upjohn). Compared to controls, colestipol altered sterol metabolism dramatically. Bile acid output increased from 7.0 mg/day to 12.2 mg/day (0.42% colestipol) and 39.6 mg/day (1.67% colestipol). Daily fecal neutral sterol output and daily endogenous neutral sterol output increased 36% and 55%, respectively, on the 1.67% colestipol diet. Cholesterol absorption was reduced by colestipol feeding. Cholesterol balance increased dramatically with 1.67% colestipol administration (43.5 mg/day vs -1.0 mg/day in controls). Colestipol exerts its effect by binding bile acids and by bile acid depletion interfering with cholesterol absorption.

A gray-level thinning method for delineation and representation of arteries.

The quantification of three dimensional (3D) properties of coronary arteries is of significant importance. The performance of the 3D analysis is critically based on low-level representation of the arterial tree for different projections. A skeletal representation of arteries can provide appropriate data structure for registration of multiple angiographic projections and it can be further utilized for 3D reconstruction of the arterial tree. This paper presents an automated method for extracting the skeletal points of an arterial tree directly from the gray-level information without determining the edges a priori. It offers the advantage of improved reliability compared to methods based on detecting dual edges of the arteries. Novel application of filtering techniques provide accurate estimates of the statistics of the background. A recursive search scheme is used to aggregate the skeletal representation at multiple resolutions. Results on a set of Digitally Subtracted Angiograms (DSA) have been presented.

Three dimensional reconstruction of coronary arteries from two views.

Geometric representation and measurements of localized lumen stenosis of coronary arteries are important considerations in the diagnosis of cardiovascular diseases. This discrete narrowing of the arteries typically impairs blood flow in regions of the heart, and can be present along the entire length of the artery. Three-dimensional (3-D) reconstruction of coronary arterial tree allows clinician to visualize vascular geometry. Three-dimensional representation of tree topology facilitates calculation of hemodynamic measurements to study myocardial infarction and stenosis. The 3-D arterial tree, computed from two views, can provide more information about the tree geometry than individual views. In this paper, a 3-step algorithm for 3-D reconstruction of arterial tree using two standard views is presented. The first step is a multi-resolution segmentation of the coronary vessels followed by medial-axis detection along the entire arterial tree for both views. In the second step, arterial trees from the two views are registered using medial-axis representation at the coarsest resolution level to obtain an initial 3-D reconstruction. This initial reconstruction at the coarsest level is then modified using 3-D geometrical a priori information. In the third step, the modified reconstruction is projected on the next higher-resolution segmented medial-axis representation and an updated reconstruction is obtained at the higher resolution. The process is iterated until the final 3-D reconstruction is obtained at the finest resolution level. Linear programming based constrained optimization method is used for registering two views at the coarse resolution. This is followed by a Tree-Search method for registering detailed branches at higher resolutions. The automated 3-D reconstruction method was evaluated on computer-simulated as well as human angiogram data. Results show that the automated 3-D reconstruction method provided good registration of computer-simulated data. On human angiogram data, the computed 3-D reconstruction matched well with manual registration.

Variability in diagnosing Creutzfeldt-Jakob disease using standard and proposed diagnostic criteria.

INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive dementia with a median survival of 2-14 months. The diagnosis can only be made accurately by biopsy/autopsy. However, this is not always feasible or desirable. Thus, diagnostic criteria have been proposed by UCSF, European MRI-CJD Consortium, and WHO. We will compare these criteria. PATIENTS AND METHODS: Retrospective study of 31 patients (average age of 69.2 years) between 2003 to 2010 by ICD9 codes 046.1, 046.11, and 046.19. RESULTS: All patients presented with rapidly progressive dementia (mean duration of 4.25 months). Pyramidal and extrapyramidal findings, myoclonus, cerebellar changes, akinetic mutism, and visual disturbances were observed in 6.5-48.4%. Five had periodic pattern on EEG. CSF biomarker 14-3-3 was positive in 11. Tau was positive in 6. Neuron specific enolase was positive in 9. By consensus (kappa = 0.62), MRI was "typical" of CJD in 23 with cortical ribboning (n = 16), basal ganglia hyperintensity (n = 15), or combination (n = 8). By WHO criteria, which does not include neuroimaging, CJD was diagnosed in 10, but 14 if any CSF biomarker was used (p = NS). The UCSF criteria, which does not include CSF biomarkers, diagnosed 18 cases, and the European MRI-CJD Consortium, which includes neuroimaging and CSF biomarkers but with less neurological signs, diagnosed 23 cases (p < 0.05 and p < 0.001, respectively). CJD-mimics included urosepsis, neurosarcoidosis, idiopathic left temporal lobe epilepsy, alcohol intoxication, central nervous system vasculitis, viral encephalitis, and non-Hodgkin's lymphoma. CONCLUSION: This study illustrates the variability in diagnosing CJD and emphasizes the diagnostic utility of neuroimaging. It also highlights false-positives that occur with neuroimaging.

School screening for scoliosis in India. The evaluation of a scoliometer.

All school children in Patiala City (25,376) were examined to find out the incidence of scoliosis. There were 12,934 boys and 12,442 girls. Their ages ranged from 5 to 18 years. Adam's forward-bending test and a newly designed "Scoliometer" was used to detect and measure the rib hump in all cases. There was an overall incidence of scoliosis of 0.13%. This was higher in boys (0.15%) than in girls (0.10%). The majority of the curves were mild (81.25%). Paralytic scoliosis was the major group (43.7%) and most the result of poliomyelitis. The incidence was higher in the low socioeconomic group (0.4%), compared to the middle (0.12%) and high (0.01%) income groups.

Phase I study of cancer therapy with recombinant interleukin-2 administered by intravenous bolus injection.

Sixty-six patients with disseminated malignancy were treated with recombinant interleukin-2 (IL-2) on a three times a week (M, W, F) IV-bolus injection schedule. Doses ranged from 0.001 to 14.0 x 10(6) units/M2 body surface area. Consecutive groups of 3-5 patients were placed on each dose level and were maintained on that level except for dosage de-escalation for toxicity. Toxicity to all major organ systems were noted with major toxicity including fever and chills, anorexia, fatigue and malaise, arthralgias and arthritis as well as hepatic and renal toxicity. All toxicity reversed within one week of drug cessation. Renal toxicity manifested by azotemia, arthritis and fatigue were the common dose limiting toxicities and the maximally tolerated dose was 12 x 10(6) units/M2. Pharmacokinetic studies indicated a short half-life (T1/2 alpha = 7-23 minutes). At doses over 0.5 x 10(6) units/M2 increases in absolute lymphocytes and eosinophil counts were noted. All T lymphocyte subsets increased. Maximal increases were seen at 4-8 x 10(6) units/M2 with a lesser increase at 10-14 x 10(6) units/M2 dosage level. Circulating NK cells also increased while circulating LAK cells were detected during therapy. Partial responses were noted in 3 patients with melanoma. These lasted 4, 6 and 16 months and involved pulmonary, pulmonary plus mesenteric and retro-orbital plus hepatic metastases respectively in these patients.