Diagnostic challenges for a novel SH2D1A mutation associated with X‐linked lymphoproliferative disease

Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X‐linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21‐year‐old patient with fatal Epstein‐Barr virus infection–associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.     

Uptake of iodine-123 MIBG by pheochromocytomas, paragangliomas, and neuroblastomas: a histopathological comparison

The percentage uptake of [123I]metaiodobenzylguanidine (MIBG) by tumors of the paraganglion system is compared with the number of neurosecretory granules (assessed by both light and electron microscopy) in the subsequently resected tumors in six patients. Iodine-123 MIBG was injected intravenously; the tumor uptake of [123I]MIBG varied between 0.001% and 0.14% of the injected dose per gram of tumor tissue at 22 hr. The number of neurosecretory granules in tissue sections was scored on a scale of I-III. A direct proportional correlation was found between the percentage uptake of [123I]MIBG by the tumor and the number of neurosecretory granules in the tissue sections but not with plasma or urinary catecholamines. This technique for imaging reflects the storage status of the tumor better than plasma and urinary catecholamine measurements.     

The effect of uterine fibroids on embryo implantation

Uterine fibroids are common but their role in infertility and effect on embryo implantation is unclear. There is evidence that submucosal fibroids are associated with poor reproductive outcome and that treatment with myomectomy is associated with an improvement in pregnancy rates. Various theories have been proposed to explain this relationship. Fibroids cause a mechanical distortion of the endometrial cavity-their presence may alter gamete and embryo transport (due to blockage of the tubal ostia or by altering uterine contractility and peristalsis) and subsequent embryo implantation (due to compression of the endometrium). They may lead to disruption of the junctional zone within the myometrial layer, affecting general uterine function in the initial stages of embryo invasion and later placentation. Altered vasculature due to the abnormal expression of angiogenic factors by uterine fibroids (such as basic fibroblast growth factor and platelet-derived growth factor) could play a role in a reduced implantation rate in patients with fibroids. Similarly, changes in the endometrium mediated by inflammation and factors involved in the process of fibrosis (such as transforming growth factor) could also have a detrimental effect. In addition, fibroids may affect gene expression pattern in the endometrium (such as HOXA10), disrupting the window of implantation. The supporting evidence for these theories is discussed in this review.     

Fractures of the lateral process of the talus

This study is a retrospective review of nine patients who sustained isolated fractures of the lateral process of the talus. The majority were caused by inversion or a combination of inversion and dorsiflexion of the foot. Following a review of the literature and anatomical dissections the authors recommend a classification based on anterior-posterior tomography of the talus, into intra- and extra-articular fractures.     

Psychological treatment of phobic anxiety associated with adjuvant chemotherapy

A 50-year-old patient with breast cancer was about to withdraw from her adjuvant chemotherapy regimen because of a long-standing phobia about being injected, which had been compounded by anxieties that were associated with the severe side-effects of adjuvant chemotherapy. She experienced a conditioned nausea response to hospital and medical situations. A psychological programme that incorporated relaxation training, systematic desensitization by way of the patient's visual imagination and videotape modelling, allowed her to complete the course of chemotherapy and to feel less anxious in hospital and medical settings.     

The pharmacology of recombinant GABAA receptors containing bovine alpha 1, beta 1, gamma 2L sub-units stably transfected into mouse fibroblast L-cells.

1. Responses to gamma-aminobutyric acid (GABA) were evoked in mouse fibroblast L-cells stably transfected with bovine, alpha 1, beta 1, gamma 2L sub-units of the GABAA receptor. Expression was stimulated via a steroid-inducible promoter system. 2. In near symmetrical intracellular and extracellular chloride concentrations, GABA evoked inward currents at negative holding potentials that reversed at +5 mV and displayed slight outward rectification. Concentration-response curves were fitted well by the logistic equation. GABA had a pEC50 = 5.1 +/- 0.1 and the curves had a slope of 1.9 +/- 0.1. 3. Responses to GABA were antagonized by bicuculline, picrotoxin and penicillin. The action of bicuculline was competitive (pA2 = 6.4) whilst the block by picrotoxin was uncompetitive and strongly agonist-dependent. 4. Benzodiazepine receptor agonists potentiated responses to 3 microM GABA. The rank order of potency was FG 8205 > flunitrazepam > zolpidem > C1218872. FG 8205 and C1218872 produced markedly lower maximal potentiations with efficacies 0.4 and 0.6 x that of flunitrazepam, respectively. The potencies of zolpidem and C1218872 observed are in agreement with the BZ1 type pharmacology of this sub-unit combination. The potentiation of GABA by flunitrazepam was antagonized by flumazenil with a Ki of 3.8 nM. 5. GABA responses were potentiated in the presence of pentobarbitone and alphaxalone. The response was also noticeably broadened by these compounds due to a decrease in the response decay rate. Concentrations of pentobarbitone of 100 microM and above evoked an inward current in the absence of GABA. Alphaxalone up to 10 microM did not evoke a direct response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hip fractures: a future epidemic?

Recent studies from the United Kingdom and Sweden have demonstrated a dramatic rise in the number of people with hip fractures. It is our hypothesis that New Zealand is experiencing a similar rise in the number of hip fractures. The number of elderly people (over age 65 years) admitted to public hospitals in New Zealand over a 38-year period was reviewed. In people over age 75 years, we observed a disproportionate increase in the number of fractures compared with the increase in population. The highest risk group was women over age 85 years. Because of the differing age-specific fracture rates, the proportion of females over age 85 increased from 17% in 1950 to 40% by 1987. Through weighted regression analysis of fracture rate and population predictions, the projected number of fractures in the year 2001 and 2011 was predicted. By 2011 the number of people sustaining hip fractures will more than double. The proportion of the very elderly (85+) will increase from 40 to 65%.