Predicting pregnancy and spermatogenesis by survival analysis during gonadotrophin treatment of gonadotrophin-deficient infertile men

BACKGROUND: Predictors of fertility or spermatogenesis during gonadotrophin therapy of gonadotrophin-deficient men remain poorly defined. METHODS AND RESULTS: In order to evaluate potential predictors, this study evaluated 29 consecutive gonadotrophin-deficient men all desiring paternity who received 43 courses of therapy in one centre between 1982 and 1998. The Kaplan-Meier survival analysis estimates of median (SE) time to a sperm concentration of >0, >5 and >20 x 10(6)/ml were 5.5 (1.1), 12.4 (2.3) and 29.1 (1.9) months respectively. Conception occurred in 22/43 cycles (with eight men achieving two pregnancies) with a median (SE) Kaplan-Meier estimate of 20.5 (4.7) months. The median sperm concentration at conception was 5.0 (SE 2.0; range 0.0-59.5) x 10(6)/ml. Multivariate correlated Cox proportional hazards models predicting these same sperm thresholds and conception were developed by forward stepwise variable selection with verification of the model by backward stepping. Larger testicular volume, prior gonadotrophin therapy, completion of puberty, older age, the absence of adverse fertility factors and the absence of multiple pituitary hormone deficiency predicted a favourable response. Multivariate modelling suggests that the two most important predictors of sperm output are testicular volume and pubertal status. The most important potentially modifiable predictor was prior gonadotrophin therapy. The efficacy of recombinant and urinary FSH were similar. Prior androgen therapy and partner's age did not appear to be significant. CONCLUSIONS: Since prolonged treatment may be required to induce spermatogenesis, attention to these predictors may allow appropriate early use of advanced reproductive technologies.     

Long-Term Follow-Up of the Changes in Circulating Cytokines, Soluble Cytokine Receptors, and White Blood Cell Subset Counts in Patients with Rheumatoid Arthritis (RA) After Monoclonal Anti-TNFα Antibody Therapy

To investigate the mechanism of the long-lasting efficacy of chimeric monoclonal anti-TNF antibody (cA2) therapy for rheumatoid arthritis (RA), eight patients with refractory RA were treated with a single infusion of cA2 and the changes in circulating cytokines (IL-1, IL-6, TNF, and IL-10), soluble cytokine receptors (TNF-RI, RII, and sIL-6R) and peripheral white blood cell (WBC) subset counts were followed up long-term (12 weeks) after cA2 therapy in them. Significant clinical responses (>20% improvement according to Paulus' criteria) were observed just after cA2 infusion and lasted more than 4 weeks in all patients, as reported elsewhere. Moreover, five of the eight patients showed prolonged clinical responses (>12 weeks). The elevated serum IL-6 and sTNF-RI (or RII) levels before treatment rapidly decreased after treatment. The serum IL-10 levels also significantly elevated before treatment. The elevations of serum IL-10 levels were augmented after treatment and stayed higher than the baseline in four patients with prolonged clinical responses. No significant TNF, IL-1 and -, or sIL-6R were detected in the sera of the patients before treatment and during the whole study period. On the other hand, peripheral lymphocytes as well as total WBC and neutrophils increased for 4 weeks after treatment. However, thereafter, only the lymphocyte count decreased gradually and stayed below the baseline long-term (12 weeks). FACS analysis revealed the predominance of T lymphocytes in the decrease in lymphocyte counts. These results suggest that the augmentation of IL-10 production and the decrease in T cells might partly contribute to the long-lasting efficacy of cA2 treatment in RA.     

多曲方丝弓生物力学特性的三维有限元研究

采用三维有限元法比较分析后倾弯多曲方丝弓、理想弓和 Ni Ti弓在无牵引力、长 类牵引力作用下的矫治效果 ,在此基础上研究多曲方丝弓的整体力学特性 ,揭示多曲方丝弓技术矫治特点 ,探讨其作用机理。结果表明 :(1)无牵引力时 ,以第一、二前磨牙之间为界 ,多曲方丝弓矫治分别使前后牙向前后倾斜 ,且对前牙有压低作用 ;理想弓 (ss方弓 )与 Ni Ti弓矫治力的方向相同但大小不同 ,Ni Ti弓的作用更趋柔和 ,对前牙有轻微伸长作用 ,对后牙有一定压低作用 ,且使磨牙后倾、其余牙前倾。 (2 )长 类牵引时 ,三种弓丝对后牙的后倾作用有所增大 ,但 Ni Ti弓增加比例最大 ;多曲弓使切牙前倾 ,其余牙均向后倾 ;理想弓和 Ni Ti弓则没改变牙的倾斜方向。 (3)无论是预应力单独作用或预应力与牵引力同时作用 ,在牙根上产生的最大压应力均呈现出理想弓矫治时最大、Ni Ti弓居中而多曲弓最小。由此从理论上证明 ,多曲方丝弓矫治技术有利于下颌 Spee氏曲线的整平和牙齿的个别调控 ;对牵引力的传递作用强 ;同时矫治力柔和持久。     

以头晕为主诉的无症状性脑梗死患者焦虑状态的临床分析

目的:探讨以头晕为主诉的无症状性脑梗死(ACI)患者的情绪状态及临床体验并观察抗焦虑/抑郁治疗的疗效.方法:对98例ACI患者采用汉密尔顿焦虑抑郁量表进行筛查,并根据ICD-10的诊断标准做出诊断后,给予抗焦虑/抑郁药物治疗和支持性心理治疗,以治疗前后的汉密尔顿焦虑量表(HAMA)的减分率和临床症状缓解程度来评定疗效.结果:处于焦虑状态的ACI患者,医检证实均有脑血管系统的轻微病损,头晕史0.5～7年,有心悸、气短、眩晕发作、失眠等自诉躯体症状,67.55%伴有高血压;经帕罗西汀和支持性心理治疗,100%显效,临床症状缓解.结论:以头晕为主诉的ACI患者,若经改善脑血流循环治疗无效者,则应实施抗焦虑/抑郁药物治疗和支持性心理治疗,可望获得良好疗效.     

Reconstitution of CD4+ T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness

Reconstitution of functional CD4(+) T cell responsiveness to in vitro stimuli is associated with continuous highly active antiretroviral therapy (HAART). Thirty-six antiretroviral naive patients received HAART over 16 weeks. Antigen-specific, mitogen and interleukin (IL)-2 induced lymphocyte proliferative responses and specific IL-2 and IL-4 production were assessed at each time-point, together with quantification of HIV-1 RNA load and lymphocyte populations. Reconstitution of recall responses was limited largely to persistent antigens such as Herpes simplex virus and Candida, rather than to HIV-1 or neo-antigens. Recall antigens, mitogens and IL-2-induced renewed responses were associated with in-vitro production of IL-2, but not IL-4. Differential responsiveness to low versus high concentration IL-2 stimulus increases in a stepwise manner, suggesting normalization of IL-2 receptor expression and improved functionality. These increases in in-vitro proliferative responses thus probably reflect short lived effector clones, driven by ongoing antigenic stimulus associated with persisting long-term organisms. In this context non-responsiveness to HIV-1 antigens suggests ongoing HIV-1 specific clonal T cell anergy.     

Progressive dilated cardiomyopathy in a patient with longstanding and complete prednisone-induced hematological remission of idiopathic hypereosinophilic syndrome

Summary A female patient is described in whom the diagnosis of idiopathic hypereosinophilic syndrome (HES) with heart disease and peripheral neuropathy was made at the age of 32 years. Although prednisone induced a prompt and longstanding complete hematological remission, progressive and eventually intractable heart failure developed, and the patient died 6 years later. Endomyocardial biopsy at diagnosis showed infiltration with intact and disintegrated eosinophils and Charcot-Leyden crystals. Echocardiographic follow-up (including Doppler-Echocardiography) revealed mitral regurgitation with thickening and impaired motility of the posterior mitral leaflet, as well as progressive dilated cardiomyopathy. At autopsy, a diffuse interstitial fibrosis with patchy prominence in an eccentric hypertrophic and highly dilated heart was found. There were no significant endocardial thickening and no mural thrombi. In contrast to the findings of the initial endomyocardial biopsy, autopsy revealed no eosinophilic infiltrate.In this case, eosinophil-induced heart disease manifested as dilated cardiomyopathy, without endocardial fibrosis as originally described by Löffler. We speculate, that eosinophils have been deposited predominantly in the myocard at an early stage of disease, and — activated locally — secreted their granule proteins producing an initial damage to capillary endothelial cells and myocytes. After prednisone-induced clearance of eosinophils from blood and tissues, progressive, self-perpetuating interstitial fibrosis of the myocard and loss of myocytes eventually resulted in end-stage dilated cardiomyopathy.Abkürzungsverzeichnis HES idiopathic hypereosinophilic syndrome - UBBC unsaturated vitamin B₁₂ binding capacity - ECP eosinophil cationic protein - MBC major basic protein - EDD end-diastolic diameter of the left ventricle - LA left atrium diameter - LVEDP left ventricular end-diastolic pressure - NIH National Institutes of Health     

Problem‐maintaining circles: Case illustrations of formulations that truly guide therapy

The cognitive behaviour therapy (CBT) emphasis on treatment relevance in assessment, and on evidence‐based intervention, has led to an increasing focus on problem maintenance factors (vs. precipitants) in both its models of psychopathology and in its individual case formulations. This article describes the reasons for this growing focus, and presents a generic CBT model based on the functional analysis of “problem‐maintaining circles” (PMCs) of causes. Some samples of the profuse literature implicating PMCs in many psychological disorders are presented, and the utility of PMC‐based functional analysis, case formulation, or modelling of psychopathology is advanced, not only as a guide to selection of therapeutic interventions, but as an alternative to standard psychiatric diagnosis. A sampling of a taxonomy of such PMCs is presented. And finally, the clinical application of PMC‐based functional analysis, case formulation, and treatment selection is illustrated in five case illustrations drawn from a recent clinical caseload.     

Genetic testing for inherited eye conditions in over 6,000 individuals through the eyeGENE network

Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross‐referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community.     

Changes in the withdrawal bleeding pattern and endometrial histology during 17β-estradiol —dydrogesterone therapy in postmenopausal women: a 2 year prospective study

Objective: To describe changes in the withdrawal bleeding pattern and endometrial histology during a sequential 17β-estradiol —dydrogesterone regimen in postmenopausal women. Design: Open-label, non-comparative, prospective study. Setting: Gynecological outpatient department of a university hospital. Patients: Twenty-seven healthy nonhysterectomized postmenopausal women. Interventions: Continuous micronized 17β-estradiol supplementation, 2 mg daily, and cyclic administration of dydrogesterone, 10 mg daily for the first half of each 28 day treatment cycle. Main Outcome Measures: Changes in the characteristics of the withdrawal bleeding pattern and the endometrial biopsy histology during 2 years of treatment. Results: The initial withdrawal bleeding was comparable to normal menstruation with respect to amount and duration. During the 2 years of treatment the bleeding showed a significant tendency to become shorter with less blood loss. This was mainly the result of the decrease (P < 0.001) in the number of days per cycle with bleeding grade II (normal menstruation). None of the women developed endometrial hyperplasia, and in almost all women the given hormone replacement therapy regimen induced secretory or atrophic changes of the endometrium. Conclusions: This sequential 17β-estradiol —dydrogesterone regimen can be regarded as safe with respect to the prevention of endometrial disease and appeared to foster patient compliance.     

Life in the Future Versus Life in the Present

Roemer and Orsillo have provided an integrative perspective for developing more effective therapies for generalized anxiety disorder, based on existing knowledge about the disorder, cognitive behavioral approaches to its treatment, and conceptualizations and treatment methods from the acceptance/mindfulness tradition. The present commentary expands upon the notion of the adaptive value of focused attention on present-moment experience and cognitive perspectives that can facilitate that process.