Continuous exposure to dibromoacetic acid delays pubertal development and compromises sperm quality in the rat.

Previously our work on the haloacid by-products of drinking water disinfection focused on adult exposures. Herein we evaluate the consequence of continuous exposure to dibromoacetic acid (DBA) via drinking water through reproductive development into adulthood. An initial study in which offspring were exposed from gestation day (GD) 15 through adulthood revealed significant delays in preputial separation and vaginal opening, dose-related decreases in the fertility of cauda epididymal sperm, and dose-related diminutions in the sperm membrane protein SP22. Subsequent studies consisted of groups in which exposure ceased on postnatal day 21 (PND 21) versus adulthood. For each exposure, animals were evaluated after puberty (PND 56) as well as at adulthood (PND 120). Exposure to 4, 40, or 400 ppm DBA from GD 15 through PND 21 failed to result in any significant reproductive alterations. By contrast, continuous exposure until adulthood resulted in dose-related alterations consistent with those observed in the dose-finding study. Preputial separation and vaginal opening were delayed 4 and 3 days in males and females exposed to 400 ppm (76.3 mg/kg) DBA. This was associated with increased responsiveness of both the testis and ovary to hCG ex vivo; hCG-stimulated testosterone production by testicular parenchyma on PND 56 was increased at 4 ppm (0.6 mg/kg) DBA and higher. Finally, the quality of proximal cauda epididymal sperm was compromised by continuous exposure to DBA. The sperm membrane proteome was altered in a dose-related manner with SP22, and one of its charged variants, diminished at 40 ppm (3.6 mg/kg) DBA and higher. As more sensitive endpoints are evaluated, lower effect levels can be attributed to haloacid exposure. We are now extending our evaluations to epidemiology studies designed to evaluate sperm quality in men exposed to varying levels of disinfection by-products.     

Prediction of shoulder dystocia using multivariate analysis

We evaluated the use of multivariate analysis in the prediction of shoulder dystocia (SD). One hundred consecutive cases with SD were matched with 100 controls without dystocia. All patients had term, vaginal delivery. Multivariate analysis was used to identify independent variables significantly related to shoulder dystocia. The regression coefficients for the identified factors were used to calculate a composite score from which receiver operating characteristics (ROC) curves were derived. Birthweight (BW), 1-hour Glucola (GLU), operative vaginal delivery (OVD), and height of fundus (HOF) were related independently to SD. The sensitivity and specificity reached 84 and 80%, respectively, with BW + GLU + OVD. Significant associations persisted when HOF and carbohydrate intolerance were substituted for BW and GLU, respectively. SD is independently associated with BW, GLU, and OVD, and may be predicted with clinically acceptable accuracy using multiple variables. This model may be useful in the design of prospective studies for managing suspected macrosomia.     

Factors associated with poor outcomes in patients with lupus nephritis

The objective of this study was to identify the factors associated with important clinical outcomes in a case-control study of 213 patients with lupus nephritis. Included were 47% Hispanics, 44% African Americans and 9% Caucasians with a mean age of 28 years. Fifty-four (25%) patients reached the primary composite outcome of doubling serum creatinine, end-stage renal disease or death during a mean follow-up of 37 months. Thirty-four percent African Americans, 20% Hispanics and 10% Caucasians reached the primary composite outcome (P < 0.05). Patients reaching the composite outcome had predominantly proliferative lupus nephritis (WHO classes: 30% III, 32% IV, 18% V and 5% II, P < 0.025) with higher activity index score (7 +/- 6 versus 5 +/- 5, P < 0.05), chronicity index (CI) score (4 +/- 3 versus 2 +/- 2 unit, P < 0.025), higher baseline mean arterial pressure (MAP) (111 +/- 21 versus 102 +/- 14 mmHg, P < 0.025) and serum creatinine (1.9 +/- 1.3 versus 1.3 +/- 1.0 mg/dL, P < 0.025), but lower baseline hematocrit (29 +/- 6 versus 31 + 5%, P < 0.025) and complement C3 (54 +/- 26 versus 65 + 33 mg/dL, P < 0.025) compared to controls. More patients reaching the composite outcome had nephrotic range proteinuria compared to controls (74% versus 56%, P < 0.025). By multivariate analysis, CI (hazard ratio [95% CI] 1.18 [1.07-1.30] per point), MAP (HR 1.02 [1.00-1.03] per mmHg), and baseline serum creatinine (HR 1.26 [1.04-1.54] per mg/dL) were independently associated with the composite outcome. We concluded that hypertension and elevated serum creatinine at the time of the kidney biopsy as well as a high CI are associated with an increased the risk for chronic renal failure or death in patients with lupus nephritis.     

A strategy to improve treatment‐related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays

Background

Treatment‐related mortality and abandonment of therapy are major barriers to successful treatment of childhood acute lymphoblastic leukemia (ALL) in the developing world.

Procedure

A collaboration was undertaken between Instituto Nacional de Cancerologia (Bogota, Colombia), which serves a poor patient population in an upper‐middle income country, and Dana‐Farber/Boston Children's Cancer and Blood Disorders Center (Boston, USA). Several interventions aimed at reducing toxic deaths and abandonment were implemented, including a reduced‐intensity treatment regimen and a psychosocial effort targeting abandonment. We performed a cohort study to assess impact.

Results

The Study Population comprised 99 children with ALL diagnosed between 2007 and 2010, and the Historic Cohort comprised 181 children treated prior to the study interventions (1995–2004). Significant improvements were achieved in the rate of deaths in complete remission (13% to 3%; P = 0.005), abandonment (32% to 9%; P < 0.001), and event‐free survival with abandonment considered an event (47% to 65% at 2 years; P = 0.016). However, relapse rate did not improve. Medically unnecessary treatment delays were common, and landmark analysis revealed that initiating the PIII phase of therapy ≥4 weeks delayed predicted markedly inferior disease‐free survival (P = 0.016). Conversely, patients who received therapy without excessive delays had outcomes approaching those achieved in high‐income countries.

Conclusions

Implementation of a twinning program was followed by reductions in abandonment and toxic deaths, but relapse rate did not improve. Inappropriate treatment delays were common and strongly predicted treatment failure. These findings highlight the importance of adherence to treatment schedule for effective therapy of ALL. Pediatr Blood Cancer 2015;62:1395–1402. © 2015 Wiley Periodicals, Inc.     

Increased synthesis and production of prostaglandin E2 by monocytes from drug addicts with AIDS

We analysed the production of prostaglandin E2 (PGE2) by monocytes in 11 drug addicts with AIDS and opportunistic infections and in 13 controls. In three patients and six controls we isolated the PGE2 fraction from culture supernatants of purified monocytes (greater than 95%) incubated in medium containing (3H) arachidonic acid, using silicic acid columns. In two of three patients PGE2-fraction values (21.9 and 21.6 pmol/g protein) were significantly higher than controls (10 +/- 4). In eight AIDS patients and seven controls, PGE2 levels were determined by high-performance liquid chromatography and radioimmunoassay (HPLC and RIA). In three out of eight patients PGE2 levels were markedly higher (736, 419 and 208 pg/ml) than the mean + 2 s.d. values from controls (73 +/- 51). We tested the effect of PGE2 on the production of interleukin-2 by normal phytohemagglutinin-stimulated peripheral blood lymphocytes (PBL). There was a significant suppression of interleukin-2 production by PGE2 released from AIDS monocytes. PGE2 may be one of the factors involved in the severe immune dysfunction associated with AIDS.     

Primary cardiomyopathy in identical twins

Seventeen year old identical twin brothers with no family history of cardiopathy began experiencing palpitations almost simultaneously. In both, examination revealed marked cardiomegaly and hypokinesia of the ventricular walls, and clinical and radiologic signs of progressive cardiac failure developed a few days later. Both boys died suddenly, 49 days and 5 months, respectively, after the initial examination. Electrocardiographic and vectorcardiographic studies revealed a severe intraventricular conduction disturbance that coincided with histologic changes in the myocardial tissue, including profuse interstitial fibrosis, hypertrophy and degeneration of the myocardial fibers, aberrant arrangement of the muscular fibers and considerable alteration of the structure of cardiac tissue. In the absence of hereditary and chromosomal factors, and excluding possible viral intervention during fetal life, it is believed that a teratogenic factor can produce the structural alterations of the tissue and derangement of the fibers observed in these hearts.The irregular contractions of the heart at the level of the net-like meshwork, disarrangement of myocardial fibers, and adaptative mechanisms of the heart inherent in the destruction of the contractile tissue contributed to the functional cardiac disorders that resulted in congestive heart failure and sudden death in these twins.     

Exploring the effects of ACE inhibitor tissue penetration on vascular inflammation following acute myocardial infarction

BACKGROUND: Questions remain as to the existence of a class effect amongst angiotensin converting enzyme (ACE) inhibitors, and some literature suggests that pharmacological effects and outcomes may be determined by an ACE inhibitor's propensity to penetrate and inhibit the ACE enzyme at the vascular tissue level. Because vascular inflammation contributes to adverse outcomes following acute myocardial infarction (AMI), and angiotensin II influences inflammation at the vascular level, we hypothesized that high-tissue penetrating ACE inhibitors would provide more favorable effects on C-reactive protein (CRP) after AMI compared to low-tissue penetrating ACE inhibitors. METHODS AND RESULTS: In a randomized open-label trial, patients received the high-tissue penetrating quinapril (n = 15) or low-tissue penetrating enalapril (n = 15) following AMI. C-reactive protein was measured at baseline and periodically over 14 days following drug initiation. All baseline characteristics and blood pressure response to treatment between groups were equivalent. Prior to initiating study medication, CRP concentrations (mg/g) were similar between enalapril and quinapril (0.327 +/- 0.571 versus 0.273 +/- 0.380, respectively, p = 0.77). The percent magnitude of change in CRP concentrations favored quinapril at all time points, starting 12 h after treatment initiation. When characterizing CRP production during treatments, the time courses were significantly different and demonstrated lower CRP concentrations with quinapril (p = 0.0107). CONCLUSIONS: Overall, this investigation into the importance of ACE inhibitor tissue penetration on a common marker of vascular inflammation, suggests a potential vascular anti-inflammatory benefit with a more highly tissue penetrating ACE inhibitor following AMI. Further investigation into the true pharmacological similarities and differences amongst this class of drugs is warranted.