Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency.

Clinical and immunologic features of a recently recognized X-linked combined immunodeficiency disease (XCID) suggested that XCID and X-linked severe combined immunodeficiency (XSCID) might arise from different genetic defects. The recent discovery of mutations in the common gamma chain (gamma c) gene, a constituent of several cytokine receptors, in XSCID provided an opportunity to test directly whether a previously unrecognized mutation in this same gene was responsible for XCID. The status of X chromosome inactivation in blood leukocytes from obligate carriers of XCID was determined from the polymorphic, short tandem repeats (CAG), in the androgen receptor gene, which also contains a methylation-sensitive HpaII site. As in XSCID, X-chromosome inactivation in obligate carriers of XCID was nonrandom in T and B lymphocytes. In addition, X chromosome inactivation in PMNs was variable. Findings from this analysis prompted sequencing of the gamma c gene in this pedigree. A missense mutation in the region coding for the cytoplasmic portion of the gamma c gene was found in three affected males but not in a normal brother. Therefore, this point mutation in the gamma c gene leads to a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID.     

Sobriety outcome after alcoholism treatment with biofeedback participation: a pilot inpatient study

The effect of the amount of biofeedback training received upon abstinence from alcohol was studied at 3, 6, and 12 months postdischarge for 233 male veterans in an inpatient alcoholic rehabilitation unit (ARU). The frequency of sobriety for those patients with at least 6 training sessions was significantly better than for those with less or no training at all three time periods. The effect was most prominent for those receiving the highest level of biofeedback training (8+ sessions), and at the earlier time frame (3 months). The discussion focused upon the implications for overall rehabilitation programming for the alcoholic and on factors involved in the efficacy of biofeedback therapy.     

Minding Your “ps and qs” When Using Forced-Choice Recognition Tests

Denney (1996), and Frederick, Carter, and Powel (1995) described a forced-choice recognition test (FCRT) to evaluate suspicious complaints of remote memory loss. Although the two-alternative forced-choice trials in symptom validity testing have equal prior probabilities of correct answers (p) and incorrect answers (q), ps and qs might vary from 0.5 on individual trials of FCRTs. FCRTs nonetheless remain conservative procedures for evaluating suspicious memory loss, as long as the overall p approximates 0.5. In computer simulations, distributions in which p q 0.5 resulted in more conservative decision making than distributions in which p = q = 0.5. The authors demonstrate the ease in constructing FCRTs with overall p = 0.5 and discuss the proper application of FCRT findings in a clinical evaluation.     

Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist

Aims

Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy.

Methods

An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure−response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose−response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated.

Results

The results suggested that a 20 mg dose of MK-3207 (EC₅₀ of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose−response would be reached around 40–100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial.

Conclusions

The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose−response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.     

The population prevalence of adverse concentrations and associations with adiposity of liver tests among Australian adolescents

Aim: Paediatric overweight has a high incidence and has serious consequences for health, including non‐alcoholic fatty liver disease (NAFLD). However, very little is known about NAFLD among young people, particularly from a population perspective. This paper reports the prevalence of elevated concentrations of four liver enzymes and their associations with adiposity in a representative population sample of Australian adolescents. Methods: Overnight fasting blood samples were collected from a representative population sample of 500 Grade 10 students (15‐years‐old) attending schools in Sydney, Australia, between February and May, 2004. Weight, height and waist girth were measured. The prevalence of adverse concentrations of the enzymes alanine aminotransferase (ALT), gamma‐glutamyltransferase (GGT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were described for all boys and girls and by body mass index (BMI) categories. The nature of the associations between the enzyme concentrations and indices of adiposity were characterised, and regression equations for estimating enzyme concentrations from BMI were prepared. Results: The prevalence of adverse concentrations of ALT (most likely as a result of NAFLD) and GGT were approximately 10%, while the prevalence of adverse concentrations of AST and ALP were approximately 7% and 5% respectively. The prevalence of adverse concentrations of ALT, GGT and AST increased across BMI categories, while the prevalence of adverse concentrations of ALP declined across BMI categories. Conclusions: The high prevalence of NAFLD in a population sample of healthy Australian adolescents represents a significant burden of disease.     

The eye blink electro-oculogram.

An electro-oculogram (EOG) was derived from potentials recorded from electrodes placed above and below the eye during voluntary vertical eye movements. Concurrent measurement of the amplitude of eye blink potentials recorded from the same electrodes produced curves which were highly correlated with the EOG measured from stereotyped eye movements. Recordings from a patient with a missing globe, owing to trauma, revealed eye movement and blink responses only from the intact side. A patient with no light perception showed blink responses which were less variable than responses measured during attempts voluntarily to move the eyes vertically in 60 degrees excursions. An EOG calculated by measurement of eye blink potentials may be possible in clinical situations where traditional electro-oculography techniques are not feasible.