Citations

Abstract Context: Prenatal androgen excess can cause a phenocopy of polycystic ovary syndrome (PCOS) in mammals. Retrospective studies have suggested that girls at risk for PCOS have low birth weight, and prospective studies have suggested an increased prevalence of small-for-gestational-age offspring in women with PCOS. Objective: The objective of the study was to determine whether infants of women with PCOS have reduced birth weight or increased intrauterine androgen levels. Design: This was a prospective case-control study. Participants: Thirty-nine PCOS and 31 control women and their infants participated in the study. Main Outcome Measures: Birth weight and mixed cord blood testosterone, androstenedione (A), dehydroepiandrosterone, 17-hydroxyprogesterone, estradiol (E2), and dihydrotestosterone levels were measured. Results: Mean birth weight did not differ, but there was a significant increase in the prevalence of large-for-gestational-age infants in the PCOS group. Cord blood E2 and A levels were lower (P < 0.05), but testosterone to E2 ratios did not differ in female PCOS compared with control offspring. There was no difference in E2 and A levels in the male PCOS and control offspring. There was no difference in 17-hydroxyprogesterone or other androgen levels in either male or female PCOS offspring compared with their respective control group. Conclusion: Infants of women with PCOS were more likely to be large for gestational age. Female offspring of affected women have lower cord blood A levels; other cord blood androgen levels do not differ compared with female control offspring. Cord blood E2 levels are also significantly decreased in PCOS, without any difference in the testosterone to E2 ratio, suggesting decreased fetal or placental production of steroids.

Abstract Mortality in National Heart, Lung and Blood Institute–sponsored clinical trials of treatments for acute lung injury (ALI) has decreased dramatically during the past two decades. As a consequence, design of such trials based on a mortality outcome requires ever-increasing numbers of patients. Recognizing that advances in clinical trial design might be applicable to these trials and might allow trials with fewer patients, the National Heart, Lung and Blood Institute convened a workshop of extramural experts from several disciplines. The workshop assessed the current state of clinical research addressing ALI, identified research needs, and recommended: (1) continued performance of trials evaluating treatments of patients with ALI; (2) development of strategies to perform ALI prevention trials; (3) observational studies of patients without ALI undergoing prolonged mechanical ventilation; and (4) development of a standardized format for reporting methods, endpoints, and results of ALI trials.

Tumor lysis syndrome (TLS) presenting in absence of chemotherapy is a rare occurrence. One of the true oncological emergencies, it can lead to significant morbidity and mortality. TLS is a phenomena usually associated with tumor cell death after treatment. The etiology of the spontaneous TLS is not well understood, which complicates the diagnosis. TLS is well known to oncologists but physicians outside of this specialty have little or no experience with this condition. Early recognition and treatment are the keys to limiting the sequela of the condition. Spontaneous tumor lysis syndrome is rare but presents added risks to the patient because of the potential for delayed diagnosis and no benefit of pretreatment. Diagnosis may be further delayed because this may be the first symptom of underlying malignancy. Therefore, it is imperative that all clinicians are familiar with the syndrome to assure timely recognition.

Abstract Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurine medications such as azathioprine. In humans, activity varies widely among individuals, primarily because of genetic polymorphisms. Low TPMT activity increases the risk of myelosuppression from azathioprine and 6-mercaptopurine, whereas high TPMT activity is associated with poor drug efficacy. The purpose of this study was to determine whether dogs also show a wide range of TPMT activity. Heparinized blood samples were obtained from 177 dogs associated with a veterinary teaching hospital. Red blood cell (RBC) TPMT activity was measured by means of a modification of a radiochemical method as established for use in people. TPMT activity varied across a 9-fold range (7.9–71.8 U of RBC per milliliter; median, 21.7). Variation in TPMT activity was not associated with age, sex, or neutering status. Giant Schnauzers had much lower TPMT activity (7.9–20 U of RBC per milliliter; median, 13.1; P < .001) than did other breeds, and Alaskan Malamutes had much higher TPMT activity (22.7–71.8 U of RBC per milliliter; median, 36.0; P < .001) than did other breeds. Such variations in TPMT activity in the canine population and within groups of related dogs could affect thiopurine drug toxicity and efficacy in canine patients.

Abstract The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double-blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C-telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (−2.1% to −0.8%) at the distal radius after 12 months. Alendronate prevented the decline (−0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab. © 2010 American Society for Bone and Mineral Research

Abstarct Myasthenia gravis (MG) was diagnosed in four cats–one had an apparently congenital form and three had the acquired autoimmune form. All four cats were examined because of episodes of weakness including gait abnormalities, voice change, neck ventroflexion, and regurgitation. Palpebral reflexes were absent in all cats. Administration of edrophonium chloride resulted in transient resolution of clinical signs in all four cats. Three cats were tested for the presence of serum autoantibodies against acetylcholine receptor (AChR) by radioimmunoassay. Two cats with acquired MG had anti-AChR antibody titers of 10.5 and 96.8 nmol/1 (normal, ≤0.03 nmol/1). Antibodies were not detected in the cat with presumptive congenital MG. All four cats were treated with pyridostigmine bromide. Two cats with acquired MG were euthanatized because of clinical deterioration. The third cat with acquired MG has been asymptomatic since 2 months after diagnosis. The cat with presumed congenital MG is alive 3 years after diagnosis.

Although several studies have examined the cardiac functional determinants of exercise capacity, few have investigated the effects of structural remodeling. The current study evaluated the association between cardiac geometry and exercise capacity. Subjects with ejection fraction ≥50% and no valvular disease, myocardial ischemia, or arrhythmias were identified from a large prospective exercise echocardiography database. Left ventricular mass index and relative wall thickness were used to classify geometry into normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. All of the subjects underwent symptom-limited treadmill exercise according to standard Bruce protocol. Maximal exercise tolerance was measured in metabolic equivalents. Of 366 (60±14 years; 57% male) subjects, 166 (45%) had normal geometry, 106 (29%) had concentric remodeling, 40 (11%) had eccentric hypertrophy, and 54 (15%) had concentric hypertrophy. Geometry was related to exercise capacity: in descending order, the maximum achieved metabolic equivalents were 9.9±2.8 in normal, 8.9±2.6 in concentric remodeling, 8.6±3.1 in eccentric hypertrophy, and 8.0±2.7 in concentric hypertrophy (all P <0.02 versus normal). Left ventricular mass index and relative wall thickness were negatively correlated with exercise tolerance in metabolic equivalents ( r =−0.14; P =0.009 and r =−0.21; P <0.001, respectively). Augmentation of heart rate and ejection fraction with exercise were blunted in concentric hypertrophy compared with normal, even after adjusting for medications. In conclusion, the pattern of ventricular remodeling is related to exercise capacity among low-risk adults. Subjects with concentric hypertrophy display the greatest limitation, and this is related to reduced systolic and chronotropic reserve. Reverse remodeling strategies may prevent or treat functional decline in patients with structural heart disease.

Abstract The optimal design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics “fail” in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials, further emphasize the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II trial design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical design (e.g., two-stage designs versus multiple-group adaptive designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer designs, we acknowledge that objective response as an endpoint and single-arm designs remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on characteristic specific to the situation. Clin Cancer Res; 16(6); 1764–9