Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis

CONTEXT: Many studies have investigated the association between male infertility and trinucleotide repeat polymorphisms in the androgen receptor (AR) gene, but no comprehensive meta-analysis of all published studies has been conducted. OBJECTIVE: Our goals were to summarize published data on associations between AR CAG and GGC repeat lengths and male infertility and investigate sources of variation between study results. DATA SOURCES: We searched for reports published before October 2006 using Medline, PubMed, and Web of Science. STUDY SELECTION: All selected studies included the following: a case group with infertility as measured by semen parameters, a control group of known or presumed fertile men, and measurement of CAG and/or GGC repeat lengths among cases and controls. Thirty-nine reports were selected based on these criteria, and 33 were ultimately included in the meta-analysis. DATA EXTRACTION: One investigator extracted data on sample size, mean and sd of trinucleotide repeat length, and study characteristics. DATA SYNTHESIS: Estimates of the standardized mean difference (95% confidence interval) were 0.19 (0.09-0.29) for the 33 studies and 0.31 (0.14-0.47) for a subset of 13 studies that used more stringent case and control selection criteria. Thus, in both groups, cases had statistically significantly longer CAG repeat length than controls. Publication date appeared to be a significant source of variation between studies. CONCLUSIONS: This meta-analysis provides support for an association between increased androgen receptor CAG length and idiopathic male infertility, suggesting that even subtle disruptions in the androgen axis may compromise male fertility.     

Neuroprotective and neuroregenerative potential of pharmacologically-induced hypothermia with D-alanine D-leucine enkephalin in brain injury

Neurovascular disorders, such as traumatic brain injury and stroke, persist as leading causes of death and disability – thus, the search for novel therapeutic approaches for these disorders continues. Many hurdles have hindered the translation of effective therapies for traumatic brain injury and stroke primarily because of the inherent complexity of neuropathologies and an inability of current treatment approaches to adapt to the unique cell death pathways that accompany the disorder symptoms. Indeed, developing potent treatments for brain injury that incorporate dynamic and multiple disorder-engaging therapeutic targets are likely to produce more effective outcomes than traditional drugs. The therapeutic use of hypothermia presents a promising option which may fit these criteria. While regulated temperature reduction has displayed great promise in preclinical studies of brain injury, clinical trials have been far less consistent and associated with adverse effects, especially when hypothermia is pursued via systemic cooling. Accordingly, devising better methods of inducing hypothermia may facilitate the entry of this treatment modality into the clinic. The use of the delta opioid peptide D-alanine D-leucine enkephalin(DADLE) to pharmacologically induce temperature reduction may offer a potent alternative, as DADLE displays both the ability to cause temperature reduction and to confer a broad profile of other neuroprotective and neuroregenerative processes. This review explores the prospect of DADLE-mediated hypothermia to treat neurovascular brain injuries, emphasizing the translational steps necessary for its clinical translation.     

Pregnancy and primary pulmonary hypertension : successful outcome with epoprostenol therapy

Primary pulmonary hypertension (PPH) associated with pregnancy carries a high maternal mortality rate. Short-term epoprostenol infusion has been demonstrated to improve the hemodynamic profile in patients with PPH. We report a successful maternal-fetal outcome with epoprostenol therapy during pregnancy, cesarean section, and postpartum in a patient with PPH. Epoprostenol therapy did not produce any physical or developmental abnormalities in the fetus. A favorable maternal-fetal outcome may occur with a multidisciplinary approach.     

Skeletal and cardiac muscle involvement in severe, late leptospirosis

Information is lacking on the prevalence and severity of cardiac and striated muscle injury in late leptospirosis, and it is unclear whether patients with one type of myositis are at increased risk of developing another. Therefore, 38 patients with severe, late Weil's disease were evaluated for heart and skeletal muscle involvement: 37% had myositis and 39% had abnormal electrocardiograms (ECGs). First-degree atrioventricular heart block and changes suggestive of acute pericarditis were the most common ECG findings. Two patients had transient pericardial friction rubs, but neither pericardial effusion, shock, nor congestive heart failure occurred. Cardiac involvement was not associated with skeletal muscle injury (P = .35), although both manifestations were correlated with severity of disease. Thus, ECG changes and myositis were prominent features of late Weil's disease but cardiac morbidity was not.     

A serologic survey of rice-field leptospirosis in Central Luzon, Philippines

Although human cases of leptospirosis have been reported from the Philippines, there is a lack of data on its prevalence. We therefore surveyed three rice-farming villages for the presence of leptospiral antibody. Out of 155 sera tested, 63 (43.6%) tested positive using the standard microagglutination test. Antibodies were more frequent in men than women (48 vs. 31%, respectively, p less than 0.01), and less common in the elderly. Exposure to leptospires occurs frequently in rice farmers, and leptospirosis is likely to be an underdiagnosed cause of both mild and severe febrile illness in the Philippines.     

Trimetrexate-leucovorin dosage evaluation study for treatment of Pneumocystis carinii pneumonia

To determine the maximal tolerable dosage of trimetrexate for treatment of pneumocystis pneumonia, 25 patients were treated each day with 45 mg/m2 of trimetrexate and 80 mg/m2 of leucovorin; 10 received 60 mg/m2 and 80 mg/m2; 12 received 60 mg/m2 and 160 mg/m2; and 6 received 90 mg/m2 and 160 mg/m2, respectively. Leucovorin was increased twofold and trimetrexate reduced by 50% or suspended briefly for various levels of neutropenia and thrombocytopenia until blood counts increased. Dosage-modifying hematologic toxicity occurred in 12 (46%), 8 (80%), 9 (75%), and 4 (67%) patients with the respective groups. Cytopenias were in each case reversible and other toxicities were well tolerated. All survivors but one were able to receive a full 21 doses of trimetrexate. Twenty-four (92%), 10 (100%), 7 (58%), and 4 (80%) of patients in the respective groups survived. Thus, the 45 mg/m2/day dosage of trimetrexate with 80 mg/m2/day of leucovorin resulted in the least dosage-modifying toxicity and excellent efficacy. This combination should be selected for studies to compare trimetrexate with other therapies for pneumocystis pneumonia.     

Limulus lysate positivity and Herxheimer-like reactions in leptospirosis: a placebo-controlled study

Jarisch-Herxheimer reactions are characteristic of some spirochetal diseases and have been reported in leptospirosis, but their pathogenesis and relationship to endotoxin remain unclear. Serial limulus amebocyte lysate assays (LAL) for endotoxin were performed on 40 patients with proven leptospirosis who were monitored for reactions after receiving either intravenous penicillin (24) or saline placebo (16). No Herxheimer-like reactions were observed, although 78% of patients had at least one positive LAL. Serum creatinine, serum bilirubin, and white blood cell counts were significantly higher (P less than .01) in simultaneously drawn LAL-positive specimens than in negative ones. Delayed hepatic clearance of endotoxin due to liver dysfunction may explain the high LAL positivity rate, since assay results correlated with severity of disease but not with the presence or absence of spirochetes. Fear of a Herxheimer-like reaction should not dissuade clinicians from administering antibiotics to patients with leptospirosis.     

Bactericidal Activity of Alveolar Macrophages is Suppressed by V-ATPase Inhibition

Bafilomycin A₁, a selective inhibitor of V-type H⁺-translocating ATPase (V-ATPase), may be a useful adjunct in cancer chemotherapy (Altan et al. [1998] J Exp Med 187:1583–1598). Therapeutic uses of the enzyme inhibitor need to consider the agent's potential effects on normal (nontumor) cells. This study determined the effects of bafilomycin A₁ on resident alveolar macrophages (mφ). Treatment of alveolar mφ with bafilomycin A₁ (10 μM, 1 h) caused a significant decrement in cytosolic pH. This was accompanied by marked alteration of mφ bactericidal capabilities. The enzyme inhibitor caused a marginal reduction in the phagocytosis of opsonized Staphylococcus aureus and significantly suppressed intracellular killing of the phagocytosed bacteria. In keeping with the effects on intracellular killing, bafilomycin A₁ significantly reduced the production of reactive oxygen species (ROS). On the other hand, cell spreading was enhanced significantly by bafilomycin A₁. Comparable changes in ROS generation and mφ spreading were produced by altering cytosolic pH through changes in extracellular pH (pH_o) in the absence of bafilomycin A₁. These findings suggest that the agent's effects on ROS production and mφ spreading were related to the accompanying changes in cytosolic pH. The enzyme inhibitor also altered mφ morphology, leading to the shortening of microvilli and focal loss of surface ruffles. These morphologic effects differed from those produced by altering cytosolic pH by changes in pH_o. The results demonstrate that V-ATPase activity is an important determinant of mφ functioning and structure. Therapeutic use of V-ATPase inhibitors might be expected to compromise the bactericidal activity of alveolar mφ. Accepted for publication: 20 January 2000