Quantifying the risks and benefits of efavirenz use in HIV‐infected women of childbearing age in the USA

Objectives

The aim of the study was to quantify the benefits (life expectancy gains) and risks (efavirenz‐related teratogenicity) associated with using efavirenz in HIV‐infected women of childbearing age in the USA.

Methods

We used data from the Women's Interagency HIV Study in an HIV disease simulation model to estimate life expectancy in women who receive an efavirenz‐based initial antiretroviral regimen compared with those who delay efavirenz use and receive a boosted protease inhibitor‐based initial regimen. To estimate excess risk of teratogenic events with and without efavirenz exposure per 100 000 women, we incorporated literature‐based rates of pregnancy, live births, and teratogenic events into a decision analytic model. We assumed a teratogenicity risk of 2.90 events/100 live births in women exposed to efavirenz during pregnancy and 2.68/100 live births in unexposed women.

Results

Survival for HIV‐infected women who received an efavirenz‐based initial antiretroviral therapy (ART) regimen was 0.89 years greater than for women receiving non‐efavirenz‐based initial therapy (28.91 vs. 28.02 years). The rate of teratogenic events was 77.26/100 000 exposed women, compared with 72.46/100 000 unexposed women. Survival estimates were sensitive to variations in treatment efficacy and AIDS‐related mortality. Estimates of excess teratogenic events were most sensitive to pregnancy rates and number of teratogenic events/100 live births in efavirenz‐exposed women.

Conclusions

Use of non‐efavirenz‐based initial ART in HIV‐infected women of childbearing age may reduce life expectancy gains from antiretroviral treatment, but may also prevent teratogenic events. Decision‐making regarding efavirenz use presents a trade‐off between these two risks; this study can inform discussions between patients and health care providers.     

Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response

Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7 nM, range 15.6-1035.2 nM; normal (n = 28): median 1.3 nM, range 0.8-2.7 nM). The method developed for mass spectrometric quantification of plasma glucosylsphingosine is sensitive and robust. Plasma glucosylsphingosine levels correlate with established plasma markers of Gaucher cells, chitotriosidase (ρ = 0.66) and CCL18 (ρ = 0.40). Treatment of Gaucher disease patients by supplementing macrophages with mannose-receptor targeted recombinant glucocerebrosidase results in glucosylsphingosine reduction, similar to protein markers of Gaucher cells. Since macrophages prominently accumulate the lysoglycosphingolipid on glucocerebrosidase inactivation, Gaucher cells seem a major source of the elevated plasma glucosylsphingosine. Our findings show that plasma glucosylsphingosine can qualify as a biomarker for type 1 Gaucher disease, but that further investigations are warranted regarding its relationship with clinical manifestations of Gaucher disease.     

Saposin C is a frequent target of paraproteins in Gaucher disease-associated MGUS/multiple myeloma

Patients with Gaucher disease (GD) have an increased risk of monoclonal gammopathies for which antigenic targets might play a role in their pathogenesis. Here we report the identification of saposin C (sapC) as high-titre (1:1 000 000) target structure of 7/16 GD-associated paraproteins. Anti-sapC immunoglobulin (Ig) showed identity with the paraprotein Ig type and subclass in each patient that showed anti-sapC immunoreactivity. Absorption and depletion studies completely removed the paraprotein from the sera of GD patients. No immunoreactivity against sapC was detected in healthy donors and in other plasma cell dyscrasias, demonstrating that anti-sapC reactivity is highly restricted to GD. Several uncharacterized forms of post-translational modified sapC were detected but their role in the pathogenesis is not clear. We confirm the frequent presence of low-titre (1:250) anti-lysolipid reactivities in the sera of GD patients but we could show that this immunoreactivity is not mediated by the paraprotein and is not restricted to GD patients.     

Novel therapeutic targets for the treatment of Fabry disease

Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of alpha-galactosidase A. The traditional concept that is used to explain the complications of the disease involves progressive accumulation of globotriaosylceramide in endothelial and smooth muscle cells, resulting in vascular damage. Clinically, progressive renal insufficiency, cardiac involvement and brain pathology evolves. Two pharmaceutical companies have developed enzyme replacement therapy in Fabry disease. Although the first clinical trials showed great promise, it is clear that long-term effects are not as robust as was anticipated. Stabilisation of renal function and decreases in cardiac hypertrophy has been observed, but some patients may experience progressive complications. As there are recent indications that serum components contribute to the pathophysiology of Fabry disease, fundamental studies are needed to unravel the precise role and identity of these factors. Combination of these basic studies with clinical follow up may ultimately reveal when the 'point of no return' is reached. Advanced renal insufficiency seems to be a clinical indicator of lack of response, but other signs and symptoms are probably related to adverse outcome. It is anticipated that in the future controlled studies in early symptomatic or presymptomatic patients will be required. In addition, alternative strategies such as substrate reduction or chaperone therapy, either alone or in combination with enzyme replacement therapy, should be explored. Because Fabry disease is rare, collaborative efforts should be undertaken and openness of data should be strived for.     

Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT1A receptor antagonist and potential novel antidepressant

Background and purpose

As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT_1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT_1A receptor antagonist activities, was evaluated in preclinical models.

Experimental approach

Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.

Key results

WAY-211612 inhibited 5-HT reuptake (K_i = 1.5 nmol·L⁻¹; K_B = 17.7 nmol·L⁻¹) and exhibited full 5-HT_1A receptor antagonist activity (K_i = 1.2 nmol·L⁻¹; K_B = 6.3 nmol·L⁻¹; I_max 100% in adenyl cyclase assays; K_B = 19.8 nmol·L⁻¹; I_max 100% in GTPγS). WAY-211612 (3 and 30 mg·kg⁻¹, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT_1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg⁻¹, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg⁻¹, s.c.) and a 5-HT_1A antagonist (WAY-100635; 0.3 mg·kg⁻¹, s.c). WAY-211612 (3.3–30 mg·kg⁻¹, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg⁻¹, i.p. and 10–56 mg·kg⁻¹, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg⁻¹, i.p.) in the rat scheduled-induced polydipsia model.

Conclusions and implications

These findings suggest that WAY-211612 may represent a novel antidepressant.     

Prominent increase in plasma ganglioside GM3 is associated with clinical manifestations of type I Gaucher disease

BACKGROUND: Patients with Gaucher disease show signs of insulin resistance. The ganglioside GM3 has recently shown to be a negative regulator of insulin sensitivity. In fibroblasts of Gaucher patients, deficient in degradation of glucosylceramide, an increased anabolism of this lipid to gangliosides occurs. The goal of the current study was to establish whether GM3 is elevated in plasma of type I Gaucher disease patients, and is related to disease manifestations. METHODS: Plasma GM3, glucosylceramide, and ceramide were determined and compared to overall severity of disease, hepatomegaly, and plasma chitotriosidase activity. RESULTS: The ceramide concentration in plasma of untreated Gaucher patients was slightly but not significantly lower than in controls (median: 9.8 micromol/L, range: 5.7-14.7 micromol/L, (n=40) vs. median: 11.0 micromol/L, range: 5.1-18.0 micromol/L, (n=30)). Glucosylceramide was significantly (p<0.0001) elevated. GM3 was also significantly (p<0.0001) increased (median: 10.2 micromol/L, range: 4.3-19.1 micromol/L, (n=40) vs. median: 3.6 micromol/L, range: 2.7-5.4 micromol/L, (n=30)). Plasma GM3 concentrations correlated with those of plasma chitotriosidase activity (rho=0.45, p=0.0036), overall severity of disease (rho=0.39, p=0.012), and hepatomegaly (rho=0.49, p=0.0015). CONCLUSIONS: GM3 is strikingly elevated in plasma of most Gaucher patients. The increase is comparable to that of glucosylceramide, the primary storage lipid. The marked elevations in GM3 may play a role in the insulin resistance of Gaucher patients.     

精神卫生防治机构医务人员工作现状及满意度调查分析

目的了解精神卫生防治机构医务人员的工作现状、满意度水平以及对精神卫生防治工作的建议,分析影响满意度的主要因素,为针对性的制定相关政策和采取相应措施提供科学依据。方法1成立调研组：2抽取两所县级精神卫生机构的医务人员代表召开座谈会;3发放无记名调查问卷,使用SPSSI1．5统计软件进行数据处理。结果调查结果显示：医务人员对工作现状满意程度不高,特别是在工作压力、社会地位、工作待遇、工作环境等方面满意度较低,且满意度与学历、职称、岗位及工龄有关,其差异有统计学意义。结论应根据医务人员对工作的满意度情况,分别采取针对性的管理措施及激励机制,提高他们的工作积极性,从而提高医疗服务质量,促进精神卫生事业的健康发展。     

Impact of growing up with Fabry disease on achievement of psychosocial milestones and quality of life

Little is known on the impact of growing up with Fabry disease (FD) on psychosocial development. Children with FD may suffer from severe recurrent pains in hands and feet, gastro-intestinal symptoms and heat intolerance. These symptoms may influence quality of life and may interfere with a normal psychosocial development. It is important to evaluate psychosocial outcomes of patients with FD into adulthood to be able to optimize support of children with FD. The current cross-sectional questionnaire study investigated psychosocial development and quality of life of 28 young adults with FD, aged 18–35 years (9 males, 19 females), using the Course of Life questionnaire and the Short Form-36 questionnaire for quality of life. The results were compared with an age-matched normative population. We found significant differences in the achievement of milestones in social development of male Fabry patients. The milestones that were affected were ‘going out to bars’ and ‘participation in sports activities’. Other than that FD patients appear to be able to achieve a rather normal psychosocial development until adulthood. Quality of life was decreased in Fabry males in the domains of physical functioning and bodily pain and of general health perception in females.     

Response of women with Fabry disease to enzyme replacement therapy: comparison with men, using data from FOS--the Fabry Outcome Survey

Fabry disease (α-galactosidase A deficiency) is an X-linked disorder. Women who are heterozygous for disease-causing mutations often manifest signs and symptoms of Fabry disease, but most studies of the effects of enzyme replacement therapy (ERT) have included only men. To date, no direct comparison has been made of the relative effectiveness of long-term ERT between men and women. The aim of this analysis was to report the effectiveness of agalsidase alfa in a cohort of 78 women treated for 4 years and to compare outcomes with those of 172 men. All data were obtained from the Fabry Outcome Survey--an international database of patients with Fabry disease sponsored by Shire Human Genetic Therapies. Quantifiable clinical parameters were assessed at baseline and the 4-year time point. Measures of pain, health-related quality of life, cardiac structure and function, and renal function changed to a similar extent in women and men during treatment, with the exception of left ventricular mass, which only reduced significantly in women. Changes in the presence of each of 27 clinical features after 4 years of ERT were evaluated in two subpopulations: patients with and patients without clinical features at baseline. It was clear for most types of clinical features that a number of women with a feature at baseline were no longer reported to have it at the 4-year time point, and that clinical features were observed in only a small percentage of women in whom they had been absent at baseline. The percentage of patients who were symptomatic at the 4-year time point was calculated for each type of clinical feature. The results showed no significant differences between men and women for most clinical features evaluated. Overall, both sexes responded to agalsidase alfa in a similar way, suggesting there should be no difference in the criteria for assessment of treatment in women and men.