Acceptance of Preventive Surgeries by Israeli Women Who had Undergone BRCA Testing

Using a specially constructed questionnaire, the effect of BRCA test results for the Jewish founder mutations and genetic counseling on womenȁ9s attitudes towards and acceptance of preventive surgeries was evaluated. The subjects consisted of 99 women 43% of whom were found to be carriers as opposed to 57%––non-carriers. After learning of their genetic status, 94% of the carriers and 28% of the non-carriers declared having positively considered the option of preventive oophorectomy. However, only about 25% of the carriers and 4.5% of the non-carriers had positively considered the option of preventive mastectomy. In practice, 78% of the carriers and 18% of the non-carriers who proved to be eligible for these procedures underwent preventive oophorectomy compared with 19% of carriers and 1.8% of non-carriers who underwent preventive mastectomy. Almost all carriers, as well as a majority of the non-carriers, who finally opted for the preventive surgeries did so after learning the result of their genetic test. The different attitudes toward the two surgeries were found to be based on varied beliefs regarding the two procedures. Preventive oophorectomy was perceived as being more acceptable to women than preventive mastectomy both from an attitudinal as well as practical aspect. These differences may be the result of cultural factors, of womenȁ9s trust in the ability of screening tests to prevent morbidity and/or mortality, of the effect of the surgeries on body image and of different counseling protocols. An erratum to this article can be found at     

Nomogram for bretylium dosing in renal impairment

Bretylium (Bretylol), an antiarrhythmic agent, is currently being used in the prophylaxis and treatment of patients with life-threatening ventricular fibrillation and tachycardia not responsive to conventional therapy. Because bretylium has a delayed onset of action that commonly causes hypotension and may increase ventricular irritability, its use in patients (especially patients with renal impairment) must be exercised with caution. Our results show that the maximum plasma concentration (Cmax) observed at the end of bretylium infusion, when normalized to the dose, increases significantly as renal function diminishes. Significant reductions in renal and total body clearance of bretylium have been observed in patients with renal insufficiency. In order to minimize the risk of potential toxicity following multiple dosing in such patients, dosage adjustments are necessary. Based on correlations developed between the total body clearance of bretylium and renal function, we present a nomogram herein that can be effectively used for adjusting the dosage of bretylium in patients with renal impairment.     

Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure

The pharmacokinetics of nicotine and its major metabolites was evaluated in male rats after multiple-cigarette smoke exposure. A smoke-exposure apparatus was used to deliver cigarette smoke to the exposure chamber. The rats were exposed to smoke from a single cigarette every 8 hr for 14 days and to the smoke of a cigarette spiked with radiolabeled nicotine on the 15th day. Blood and urine samples were collected at timed intervals during the 10-min smoke-exposure period of the last cigarette and up to 48 hr thereafter. Nicotine, cotinine, and other polar metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. The data were analyzed by computer fitting, and the derived pharmacokinetic parameters were compared to those observed after a single iv injection of nicotine and after a single-cigarette smoke exposure. The results indicated that the amount of nicotine absorbed from multiple-cigarette smoke was approximately 10-fold greater than that absorbed from a single cigarette. Also, unlike the single-cigarette smoke exposure experiment, nicotine plasma levels did not decay monotonically but increased after the 5th hr, and high plasma concentrations persisted for 30 hr. The rate and extent of the formation of cotinine, the major metabolite of nicotine, were decreased as compared with their values following a single-cigarette smoke exposure. It was concluded that nicotine or a constituent of tobacco smoke inhibits the formation of cotinine and may affect the biotransformation of other metabolites. Urinary excretion tended to support the conclusions that the pharmacokinetic parameters of nicotine and its metabolites were altered upon multiple as compared to single dose exposure.     

Genetics and education: the ethics of shaping human identity

This paper suggests an analogy between education and genetic interventions as means of shaping the identity of children and future adults. It proposes to look at issues discussed in the philosophy of education as a possible source of insight for ethical guidelines regarding future genetic interventions. The paper focuses on situations of conflict between parents and state regarding the authority to determine the child s best interests. It describes the current formulation of the conflict in the literature as lacking the crucial element of the child s right to a cultural identity. It argues that this element is a necessary component in an ethical analysis of the child s best interests in a multicultural, liberal society which respects diversity. The paper therefore proposes a better model for the moral evaluation of identity-shaping decisions and offers some implications of this model for genetics.     

A transgenic insertional inner ear mutation on mouse chromosome 1

OBJECTIVES/HYPOTHESIS: To clone and characterize the integration site of an insertional inner ear mutation, produced in one of fourteen transgenic mouse lines. The insertion of the transgene led to a mutation in a gene(s) necessary for normal development of the vestibular labyrinth. STUDY DESIGN: Molecular genetic analysis of a transgene integration site. METHODS: Molecular cloning, Southern and northern blotting, DNA sequencing and genetic database searching were the methods employed. RESULTS: The integration of the transgene resulted in a dominantly inherited waltzing phenotype and in degeneration of the pars superior. During development, inner ear fluid homeostasis was disrupted. The integration consisted of the insertion of a single copy of the transgene. Flanking DNA was cloned, and mapping indicated that the genomic DNA on either side of the transgene was not contiguous in the wild-type mouse. Localization of unique markers from the two flanks indicated that both were in the proximal region of mouse chromosome 1. However, in the wild-type mouse the markers were separated by 6.3 cM, indicating a sizable rearrangement. Analysis of the mutant DNA indicated that the entire region between the markers was neither deleted nor simply inverted. CONCLUSIONS: These results are consistent with a complex rearrangement, including at least four breakpoints and spanning at least 6.3 cM, resulting from the integration of the transgene. This genomic rearrangement disrupted the function of one or more genes critical to the maintenance of fluid homeostasis during development and the normal morphogenesis of the pars superior.     

Low-dose methotrexate treatment for oligoarticular juvenile idiopathic arthritis nonresponsive to intra-articular corticosteroids

The objective of this study was to evaluate the efficacy of low-dose (0.2 mg/kg) methotrexate (MTX) in the treatment of children with oligoarticular juvenile idiopathic arthritis (JIA) who do not respond to nonsteroidal anti-inflammatory drugs (NSAIDs) and repeated intra-articular corticosteroid (IA) injections. Nineteen consecutive patients (age: 2–14 years, 18 females) with oligoarticular JIA were studied prospectively. Sixteen had a persistent course and three had an extended course of the disease. Patients were defined as nonresponders to IA injections if the duration of improvement following two consecutive injections was less than 4 weeks. These patients were offered low-dose oral MTX, administered once a week for at least 6 months. Of the 19 patients in this series, 2 responded to NSAIDs alone. Forty-eight IA injections were given to 17 patients; 11 (64%) of them did not respond to this treatment. Nine of the nonresponders were treated with low-dose MTX for a median duration of 15±3.8 months. Except for one patient with an extended disease course, all responded very well to treatment and went into remission after a median of 6.4±2.9 months, and none required additional IA injections after initiation of MTX treatment. Low-dose oral MTX appears to be very effective in the management of children with oligoarticular JIA, who are unresponsive to IA injections.     

Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema,hypsarrhythmia and optic atrophy may be allelic syndromes

In 2003, a new syndrome was described in the Sephardi Jewish population, named progressive cerebello-cerebral atrophy (PCCA) based on the typical neuroradiological findings. Following the identification of the causal genes in 2010 and 2014, two types were defined: PCCA type 1 due to SEPSECS mutations and PCCA type 2 due to VPS53 mutations.Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) was described in 1991 in Finland. The clinical and radiological phenotype resembles PCCA. The genetic background has been elusive for many years. Recently, mutations in multiple genes including SEPSECS have been described in patients with a PEHO-like syndrome.In 2007 two siblings of Moroccan-Jewish origin were diagnosed as having PEHO due to a severe developmental encephalopathy, limb and facial edema, intractable epilepsy, optic atrophy in one sibling and dysmorphic features. Six years ago an extensive workup, including whole exome sequencing, did not reveal the cause. Recently, a clinical reevaluation of the siblings suggested the possibility that they suffer from PCCA. A reanalysis of the exome data from 2014 revealed that the siblings indeed carried the two VPS53 mutations (exon 19 c.2084A>G p.(Gln695Arg) and c.1556 + 5G>A) and the parents were found to be carriers.The discovery that mutations in both VPS53 and SEPSECS can present with a PEHO-like phenotype, place PCCA and PEHO on the same clinical spectrum and suggest they may be allelic syndromes.     

Successful treatment with plasma exchange in life-threatening hyperhemolytic syndrome unrelated to sickle cell disease

Introduction

Hyperhemolytic syndrome (HHS) is a severe form of delayed transfusion reaction primarily described in sickle cell anemia patients which is characterized by a hemoglobin decrease to pre-transfusion levels or lower, often with reticulocytopenia and no evidence of auto- or allo-antibodies.

Case Presentation

We present two cases of severe HHS in patients without sickle cell anemia refractory to treatment with steroids, immunoglobulins, and rituximab. In one case, temporary relief was achieved with eculizumab. In both cases, plasma exchange resulted in a profound and immediate response allowing for splenectomy and resolution of hemolysis.

Discussion/Conclusion

We discuss the pathophysiology of HHS, its presentation and treatment and expand on the possible role of plasma exchange in this setting.     

European Society of Cardiology quality indicators for the care and outcomes of adults with pulmonary arterial hypertension. Developed in collaboration with the Heart Failure Association of the European Society of Cardiology

Aims

To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH).

Methods and results

We followed the European Society of Cardiology (ESC) methodology for the development of QIs. This included (i) the identification of key domains of care for the management of PAH, (ii) the proposal of candidate QIs following systematic review of the literature, and (iii) the selection of a set of QIs using a modified Delphi method. The process was undertaken in parallel with the writing of the 2022 ESC/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved the Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH: structural framework, diagnosis and risk stratification, initial treatment, follow-up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected.

Conclusion

This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes.