IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.

CONTEXT: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. OBJECTIVE: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. METHODS: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. RESULTS: Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. CONCLUSION: IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.

Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts.

BACKGROUND: CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. METHODS: Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. RESULTS: At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. CONCLUSIONS: ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.

Towards Excellence in Asthma Management: final report of an eight-year program aimed at reducing care gaps in asthma management in Quebec.

BACKGROUND AND OBJECTIVES: Asthma care in Canada and around the world persistently falls short of optimal treatment. To optimize care, a systematic approach to identifying such shortfalls or 'care gaps', in which all stakeholders of the health care system (including patients) are involved, was proposed. METHODS: Several projects of a multipartner, multidisciplinary disease management program, developed to optimize asthma care in Quebec, was conducted in a period of eight years. First, two population maps were produced to identify regional variations in asthma-related morbidity and to prioritize interventions for improving treatment. Second, current care was evaluated in a physician-patient cohort, confirming the many care gaps in asthma management. Third, two series of peer-reviewed outcome studies, targeting high-risk populations and specific asthma care gaps, were conducted. Finally, a process to integrate the best interventions into the health care system and an agenda for further research on optimal asthma management were proposed. RESULTS: Key observations from these studies included the identification of specific patterns of noncompliance in using inhaled corticosteroids, the failure of increased access to spirometry in asthma education centres to increase the number of education referrals, the transient improvement in educational abilities of nurses involved with an asthma hotline telephone service, and the beneficial effects of practice tools aimed at facilitating the assessment of asthma control and treatment needs by general practitioners. CONCLUSIONS: Disease management programs such as Towards Excellence in Asthma Management can provide valuable information on optimal strategies for improving treatment of asthma and other chronic diseases by identifying care gaps, improving guidelines implementation and optimizing care.

Neurophysiological correlates of error correction in sensorimotor-synchronization.

In a sensorimotor synchronization task requiring subjects to tap in synchrony with an auditory stimulus, occasional perturbations (i.e., interval changes) in an otherwise isochronous sequence of auditory metronome stimuli are known to be compensated remarkably swift and with surprising precision, even when they are too small to be consciously perceived. To investigate the neural substrate and the informational basis of error correction in sensorimotor synchronization, we recorded movement-related, auditory-evoked, and error-related EEG potentials. Experiment 1 confirmed rapid adjustment to stimulus phase shifts, with faster correction of large (50 ms) compared to small (15 ms) shifts. In addition to being corrected faster, there was overcorrection of the 50 ms shifts, attributed to engagement of period correction mechanisms. For +50 ms shifts, a neural correlate of period correction was identified in the form of medial frontal cortex activation, preceded by an error-related brain potential (ERN). Auditory-evoked potential (AEP) amplitudes were sensitive to stimulus phase shifts of both large and small magnitude. Further experiments with a smaller magnitude 10 ms phase shift (Experiment 2) and passive auditory stimulation (Experiment 3) provided evidence that the modulation of AEP amplitudes is not due to metronome interval changes, but may represent auditory-somatosensory activation. Together, behavioral and neurophysiological data support the hypothesis that phase correction is a largely automatic process, not dependent on conscious perception of changes in timing. By contrast, perceivable phase shifts may invoke timekeeper adjustments accompanied by medial frontal cortex activity.

Clinical and methodological factors related to reliability of the best-estimate diagnostic procedure.

OBJECTIVE: The reliability and accuracy of the best-estimate diagnostic procedure were examined, and factors associated with reliability were determined. METHOD: The subjects were 134 members of large multigenerational pedigrees densely affected by bipolar disorders or schizophrenia. Three best-estimate diagnoses were derived: first, by a research psychiatrist and research assistant unblind to the relatives' diagnoses; second, by two blind independent psychiatrists; third, by a panel of four blind psychiatrists. The subjects were characterized on several clinical and methodological variables, which were used to compare the agreements of two types of best-estimate diagnoses with the disagreements. RESULTS: There was satisfactory agreement between the unblind and blind consensus best-estimate diagnoses and between the two blind independent psychiatrists. Latent class analyses revealed that limited sensitivity was the main source of imperfect reliability. Confusability analyses revealed that the most problematic diagnostic distinctions involved schizoaffective disorder, which was confused with schizophrenia, bipolar I disorder, and schizophreniform disorder. Blindness significantly affected diagnostic outcome in latent class analyses. Moreover, for diagnostic disagreements, unblind diagnoses had greater continuity with the most predominant diagnosis in the pedigree than did blind diagnoses. Diagnostic disagreements were associated with the presence of mixed affective and psychotic symptoms, less diagnostic certainty, and shorter duration of illness. CONCLUSIONS: These results suggest that it is possible to identify cases that are more likely to lead to diagnostic disagreements in family and epidemiological studies and that blind diagnoses may help to prevent false positive diagnoses, which may be particularly detrimental to genetic linkage analyses.

6p24-22 region and major psychoses in the Eastern Quebec population. Le Groupe IREP.

Recent reports of a linkage trend in 6p24-22 for schizophrenia (SZ), in different samples, were tempered by the concurrent evidence of negative reports in other samples. In the studies showing positive results, different definitions of affection and a wide spectrum of diagnoses were used. Our objectives were not only to test for linkage at 6p24-22 in the Eastern Quebec population, but also to test whether this putative vulnerability locus was either selectively linked to schizophrenia (SZ), or to bipolar disorder (BP), or to both major psychoses. Parametric and nonparametric linkage analyses with 12 microsatellite markers in 6p24-p22 were performed on a sample of 18 large multigenerational pedigrees (N = 354) either affected by SZ, or by BP, or equally affected by both major psychoses (i.e., mixed pedigrees). Three affection definitions were usually tested in our program: one on schizophrenia (SZ), one on bipolar disorder (BP), and one that comprised SZ and BP under the hypothesis of a susceptibility locus common to both in major psychoses (common locus, CL). The results of parametric analyses did not support a major gene hypothesis. However, in one large mixed pedigree (#151), we observed with the common locus phenotype (CL) lod scores of 2.49 and 2.15, respectively, at the D6S296 and D6S277 loci under a dominant model. Our data suggest the presence of a potential vulnerability locus at 6p24-22 that could be related to both schizophrenia and bipolar affective disorder. These results may be seen as congruent with former studies that used schizoaffective as well as schizophrenia diagnoses as entry criteria for the affected families, and used an affection definition that comprised affective psychoses as well as schizophrenia.

[Diabetic nephropathy]. / La néphropathie diabétique.

Diabetic nephropathy morbidity and mortality rates are high for both Type I and Type II diabetes. The various stages of diabetic nephropathy have been well documented for Type I diabetes, but not for Type II. We examine the natural history of this problem and recommended treatments, with emphasis on the characteristics of each type.

A nontraditional approach to medical laboratory technology education.

The nontraditional program in medical laboratory technology for adult students was initiated at Corning Community College in 1975. The overall design of the model permits adults who have gained knowledge and skills as a result of their work experience to have opportunities for the assessment of these learnings and for flexible, modular instruction to increase their level of competency in medical technology. The central goal of this model is to increase the educational alternatives available to the adult population, specifically, the working adult in the medical laboratory. This approach enables individuals who are currently employed to attain an Associate in Applied Science (AAS) degree and eligibility for certification as a medical (clinical) laboratory technician.