Two-Generation Reproductive Toxicity Study of Dietary Tributyl Phosphate in CD Rats

Tributyl phosphate (TBP) was tested for reproductive toxicityin rats. Thirty weanlings/sex (F0) were exposed to TBP in thediet ad libitum at 0, 200, 700, or 3000 ppm for 10 weeks andthen randomly mated within groups for 3 weeks with continuedexposure. F0 parents and 10 F1 weanlings/sex/dose were necropsied,and adult reproductive organs, urinary bladders (both sexes),kidneys (males), and livers (females) were evaluated histologically.Thirty F1 weanlings/sex/dose continued exposure for 11 weeksand were bred as described above. F1 parents and P2 weanlings,10/sex/dose, were then necropsied as described above. Adulttoxicity was observed in both sexes and generations at 700 and3000 ppm; observations included reduced body weights, weightgain and feed consumption, urinary bladder epithelial hyperplasia(both sexes), renal pelvis epithelial hyperplasia only at 3000ppm (male kidneys), and centrilobular hypertrophy (female livers).At 200 ppm, transient reductions in body weight were observedin F0 and F1 females, with urinary bladder epithelial hyperplasiain F0 males and females and in F1 males. There was no evidenceof reproductive toxicity, of reproductive organ pathology, orof effects on gestation or lactation at any dose tested. Postnataltoxicity was evidenced by consistent reductions in F1 and F2pup body weights at 3000 ppm and by occasional weight reductionsin F2 litters at 700 ppm, and was associated with maternal toxicityobserved at these doses and times. Under the conditions of thisstudy, a NOAEL was not determined for adult toxicity; the NOAELfor reproductive toxicity was at least 3000 ppm and the NOAELfor postnatal toxicity was approximately 200 ppm.     

Permanent CD8+ T Cell Depletion Prevents Proteinuria in Active Heymann Nephritis

Active Heymann nephritis (HN) is a rat model of human idiopathic membranous nephropathy in which injury is thought to be mediated by membrane attack complex of complement (MAC) activated by antibody (Ab) to glomerular epithelial cells. Recent work has shown that HN develops in C6-deficient rats which cannot assemble MAC, and that infiltration of activated cytotoxic CD8⁺ T cells and macrophages into glomeruli coincides with proteinuria. This study examined the role of CD8⁺ T cells in mediating glomerular injury in HN by permanent CD8⁺ cytotoxic T cell depletion via adult thymectomy (ATx) and anti-CD8 mAb. Groups of rats were depleted of CD8⁺ T cells either before immunization for HN or 6 wk after immunization when Ab responses and glomerular IgG deposition were well established. These were compared with groups of HN, ATx/HN, and complete Freund''s adjuvant (CFA) controls. Neither group of CD8⁺ T cell–depleted rats developed proteinuria, although there was normal development and deposition of Ab. CD8⁺ T cell–depleted rats developed neither T cell or macrophage infiltrates nor their effector cytokines, which are present in glomeruli of rats with HN. Examination of lymph node (LN) draining sites of immunization showed these findings were not explained by altered immune events within these LNs. It was concluded that CD8⁺ cytotoxic T cells are essential to the mediation of glomerular injury in HN and may be relevant to the pathogenesis and treatment of membranous nephropathy.     

Current Patterns of Prehospital Trauma Care in Kampala,Uganda and the Feasibility of a Lay-First-Responder Training Program

Background  

Uganda currently has no organized prehospital emergency system. We sought to measure the current burden of injury seen by lay people in Kampala, Uganda and to determine the feasibility of a lay first-responder training program.     

Drug Induced Refractory Headache - Clinical Features and Management

Two hundred patients who were taking daily symptomatic or immediate relief medications, often in excessive quantities, yet suffering from daily or near daily severe headaches were studied. One hundred and sixteen (58%) of them were also taking concomitant prophylactic medications and they were ineffective. Low tyramine, low caffeine dietary instructions and biofeedback training were given to all patients. The effect of continuing symptomatic medications, discontinuing symptomatic medications, and adding or changing prophylactic medications were studied in the various treatment groups. It is concluded that; 1.) Daily use of symptomatic or immediate relief medications result in chronic daily headache. 2.) Discontinuing daily symptomatic medications itself result in improvement of headache. 3.) Concomitant use of symptomatic medications nullifies the effect of prophylactic medications. 4.) Discontinuing daily symptomatic medications enhances the beneficial effect of prophylactic medications.     

Diagnostic Parameters to Differentiate Benign From Malignant Ovarian Masses With Contrast‐Enhanced Transvaginal Sonography

Objective. The aim of this study was to evaluate diagnostic parameters to differentiate between benign versus malignant ovarian masses using contrast‐enhanced transvaginal sonography (TVS). Methods. Thirty‐three consecutive patients with 36 morphologically abnormal ovarian masses (solid or cystic with papillary excrescences, focally thickened walls, or irregular solid areas) smaller than 10 cm received a microbubble contrast agent intravenously while undergoing pulse inversion harmonic TVS. The following parameters were assessed: presence of contrast enhancement, time to peak enhancement, peak contrast enhancement, half wash‐out time, and area under the enhancement curve (AUC). Tumor histologic analysis was used to distinguish benign from malignant ovarian tumors. Results. Twenty‐six benign masses and 10 malignancies were studied. Of all examined criteria, an AUC of greater than 787 seconds^?1 was the most accurate diagnostic criterion for ovarian cancer, with 100.0% sensitivity and 96.2% specificity. Additionally, peak contrast enhancement of greater than 17.2 dB (90.0% sensitivity and 98.3% specificity) and half wash‐out time of greater than 41.0 seconds (100.0% sensitivity and 92.3% specificity) proved to be useful. Conclusions. Our data suggest that the AUC, peak enhancement, and half wash‐out time had the greatest diagnostic accuracy for contrast‐enhanced TVS in differentiation between benign and malignant ovarian masses.     

Risk analysis of severe myelotoxicity with temozolomide: The effects of clinical and genetic factors

A benefit of temozolomide (TMZ) is that myelotoxicity is uncommon. Recently, several small series have reported significant myelotoxicity resulting in treatment delays or death. The ability to predict risk of myelotoxicity may influence patient care. We retrospectively reviewed 680 malignant glioma patients and developed a clinical risk formula for myelotoxicity for each gender by logistic regression. The variables that remained were assigned a score of 1 and added together for a final risk score. Women experienced more myelotoxicity than did men (p = 0.015). For males, risk factors included body surface area (BSA) ≥ 2 m² (odds ratio [OR] = 2.712, p = 0.04), not on steroids (OR = 2.214, p = 0.06), and on bowel medication (OR = 3.955, p = 0.008). For females, final factors included no prior chemotherapy (OR = 3.727, p = 0.001), creatinine ≥ 1 mg/dl (OR = 6.08, p = 0.002), platelets < 270,000/mm³ (OR = 2.438, p = 0.03), BSA < 2 m² (OR = 4.178, p = 0.04), not on medication for gastroesophageal reflux disease (OR = 2.942, p = 0.01), and on analgesics (OR = 2.169, p = 0.05). Age was included because of observable trends. Risk of developing myelotoxicity ranged from 0% to 33% (male) and from 0% to 100% (females). Polymorphisms in NQO1 (NAD(P)H dehydrogenase, quinone 1), MGMT (O⁶-methylguanine-DNA methyltransferase), and GSTP1 (glutathione S-transferase pi 1) were related to risk of developing myelotoxicity in a subset of patients. Myelotoxicity with TMZ is a significant clinical issue for those at risk. Use of a clinical model to predict risk and evaluation of identified genetic polymorphisms related to myelotoxicity may allow for individualized dosing, optimizing patient management.