Nicholas Jospe

Comprehensive Assessment of Professional Competence: The Rochester Experiment

Background: A required 2-week comprehensive assessment (CA) for 2nd-year medical students that integrates basic science, clinical skills, information management, and professionalism was implemented. Description: The CA links standardized patients (SPs) with computer-based exercises, a teamwork exercise, and peer assessments; and culminates in student-generated learning plans. Evaluation: Scores assigned by SPs showed acceptable interrater reliability. Factor analyses defined meaningful subscales of the peer assessment and communication rating scales. Ratings of communication skills were correlated with information gathering, patient counseling, and peer assessments; these, in turn, were strongly correlated with the written exercises. Students found the CA fair, with some variability in opinion of the peer and written exercises. Useful learning plans and positive curricular changes were undertaken in response to the CA results. Conclusion: A CA that integrates multiple domains of professional competence is feasible, useful to students, and fosters reflection and change. Preliminary data suggest that this format is reliable and valid.

Continuous subcutaneous insulin infusion in toddlers and children with type 1 diabetes mellitus is safe and effective

Abstract:  Objective:  The aim of this study was to investigate the safety and efficacy of continuous subcutaneous insulin infusion (CSII) for type 1 diabetes mellitus (T1DM) in toddlers and children.

Comparison of Transdermal and Oral Estrogen Therapy in Girls with Turner's Syndrome

Eight girls with Turners syndrome were given low dose oral ethinyl estradiol or transdermal 17 beta-estradiol in order to compare the effect of the route of administration on selected markers of hepatic metabolism, and various hormonal concentrations. Oral estrogen was given at a dose of 100 ng/kg/day and transdermal estrogen via adhesive skin patch at 0.0125 mg/kg/day. The subjects received one form of estradiol for one month, and after a one month washout period, received the other form. Both oral and transdermal estradiol caused a significant decrease in FSH while only transdermal resulted in a significant decrease in LH. Oral estradiol, though not transdermal estradiol, increased serum high density lipoprotein, thyroxine binding protein and growth hormone binding protein. Urinary growth hormone excretion increased after both forms of therapy, while insulin-like growth factor-I and insulin-like growth factor binding protein-3 remained unchanged. Thus, in girls with Turners syndrome, estrogen replacement by the transdermal route may have less deleterious effect on hepatic metabolism than oral estrogen.

Prevalence of polymorphic 21-hydroxylase gene (CA21HB) mutations in salt-losing congenital adrenal hyperplasia

Using genomic restriction analysis of 14 unrelated patients with salt-losing congenital adrenal hyperplasia, we identified three different CA21HB mutation patterns: no detectable restriction fragment abnormalities (16/28 haplotypes), deletion of the active CA21HB gene (9/28), and apparent conversion of the active CA21HB gene to the pseudogene CA21HA (3/28). CA21HB gene deletion was associated with HLA-Bw47 in 6 haplotypes and with absent C4B expression in 7. A variety of HLA and C4 types was associated with the other mutations. Apparent conversion of CA21HB to CA21HA was identified by the disparity between the intensity ratios for the major TaqI and BglII hybridization fragments.

Uncoupling of Proliferation and Cytokines From Suppression Within the CD4+CD25+Foxp3+ T–Cell Compartment in the 1st Year of Human Type 1 Diabetes

OBJECTIVE The mechanistic basis for the breakdown of T-cell tolerance in type 1 diabetes is unclear and could result from a gain of effector function and/or loss of regulatory function. In humans, the CD4+CD25+Foxp3+ T–cell compartment contains both effector and regulatory T cells, and it is not known how their relative proportions vary in disease states. RESEARCH DESIGN AND METHODS We performed a longitudinal study of CD4+CD25+ T–cell function in children with type 1 diabetes at onset and throughout the 1st year of disease. Function was assessed using single-cell assays of proliferation, cytokine production, and suppression. Type 1 diabetic individuals were compared with age-matched control subjects, and suppression was directly assessed by coculture with control T–cell targets. RESULTS We identify novel functional changes within the type 1 diabetes CD4+CD25+ compartment. Type 1 diabetic CD4+CD25+ cells exhibited a striking increase in proliferative capacity in coculture with CD4 T cells that was present at onset and stable 9–12 months from diagnosis. Elevated type 1 diabetes CD4+CD25+ cell proliferation correlated with increased inflammatory cytokines interleukin 17 and tumor necrosis factor-α but not γ-interferon. Type 1 diabetes CD4+CD25+ cytokine production occurred coincident with suppression of the same cytokines in the control targets. Indeed, enhanced proliferation/cytokines by CD4+CD25+ cells was uncoupled from their suppressive ability. Longitudinally, we observed a transient defect in type 1 diabetes CD4+CD25+ suppression that unexpectedly correlated with measures of improved metabolic function. CONCLUSIONS Type 1 diabetes onset, and its subsequent remission period, is associated with two independent functional changes within the CD4+CD25+ T–cell compartment: a stable increase in effector function and a transient decrease in regulatory T–cell suppression.

Immunology of diabetes society T-Cell workshop: HLA class I tetramer-directed epitope validation initiative T-Cell workshop report-HLA class I tetramer validation initiative

Identification of T‐cell reactivity to β‐cell antigen epitopes is an important goal for studying pathogenesis and for designing and monitoring of immunotherapeutic interventions in type 1 diabetes (T1D).

Immunology of Diabetes Society T‐Cell Workshop: HLA class II tetramer‐directed epitope validation initiative

Islet‐antigen‐specific CD4+ T cells are known to promote auto‐immune destruction in T1D. Measuring T‐cell number and function provides an important biomarker. In response to this need, we evaluated responses to proinsulin and GAD epitopes in a multicentre study.

Temporal and individual variations in the dose of glucocorticoid used for the treatment of salt‐losing congenital virilizing adrenal hyperplasia due to 21‐hydroxylase deficiency

The dose of glucocorticoid was evaluated in the treatment of 19 patients with salt‐losing congenital adrenal hyperplasia due to complete or nearly complete 21‐hydroxylase deficiency. In most cases, follow‐up was from infancy to puberty. The dose of steroid was expressed as oral cortisol (mg/m2 body surface area 124 hours); the equivalent doses of the various glucocorticoid preparations was as follows: 100 mg oral cortisol = 120 mg oral cortisone acetate = 25 mg oral prednisone = 50 mg intramuscular cortisol = 60 mg intramuscular cortisone acetate. The dose of glucocorticoid producing good laboratory and clinical control varied significantly with age. The dose fell from 26 mg/m2/24 hours in early infancy to 19 mg/m2/24 hours between 6 and 8 years of age, and then rose to 23–24 mglm2/hour in adolescence. In addition to these age‐related changes, there were large individual variations at each age. Indeed, the values from 4 of the 19 patients were not included in the calculation of the mean because they were more than 3 SD either above or below the mean. For the rest of the patients, the coefficient of variation ranged from 14.5% to 37.2%. It is concluded that glucocorticoid therapy must be adjusted carefully to the age and needs of each patient.

Avidity-dependent programming of autoreactive T cells in T1D.

Fate determination for autoreactive T cells relies on a series of avidity-dependent interactions during T cell selection, represented by two general types of signals, one based on antigen expression and density during T cell development, and one based on genes that interpret the avidity of TCR interaction to guide developmental outcome. We used proinsulin-specific HLA class II tetramers to purify and determine transcriptional signatures for autoreactive T cells under differential selection in type 1 diabetes (T1D), in which insulin (INS) genotypes consist of protective and susceptible alleles that regulate the level of proinsulin expression in the thymus. Upregulation of steroid nuclear receptor family 4A (NR4A) and early growth response family genes in proinsulin-specific T cells was observed in individuals with susceptible INS-VNTR genotypes, suggesting a mechanism for avidity-dependent fate determination of the T cell repertoire in T1D. The NR4A genes act as translators of TCR signal strength that guide central and peripheral T cell fate decisions through transcriptional modification. We propose that maintenance of an NR4A-guided program in low avidity autoreactive T cells in T1D reflects their prior developmental experience influenced by proinsulin expression, identifying a pathway permissive for autoimmunity.

Factitious transient neonatal hyperthyrotropinemia

We report an infant with abnormally elevated levels of TSH determined in the Maryland State Laboratory for Neonatal Thyroid Screening, but normal levels in three other laboratories. The TSH level in the infant normalized by six months of age. The mother, who had a history of sarcoidosis, also had factitious hyperthyrotropinemia in the Maryland State Laboratory. Gel chromatography and ammonium sulfate precipitation of maternal serum demonstrated that the factor responsible for the factitious hyperthyrotropinemia was an immunoglobulin G. Maternal TSH levels in the Maryland State Laboratory were normalized by treatment of serum with polyethylene glycol. However, protein electrophoresis, immunoglobulin levels and immunofixation electrophoresis were all normal. We conclude that a subclass of immunoglobulins G, probably resulting from sarcoidosis, interfered with the precipitation of the TSH-antibody complex in the TSH radioimmunoassay of the Maryland State Laboratory.