Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta). 1. Urogenital morphology and placental androgen production during fetal life

The pre-T cell receptor (TCR) associates with CD3-transducing subunits and triggers the selective expansion and maturation of T cell precursors expressing a TCR-beta chain. Recent experiments in pre-Talpha chain-deficient mice have suggested that the pre-TCR may not be required for signaling allelic exclusion at the TCR-beta locus. Using CD3-epsilon- and CD3-zeta/eta-deficient mice harboring a productively rearranged TCR-beta transgene, we showed that the CD3-gammadeltaepsilon and CD3-zeta/eta modules, and by inference the pre-TCR/CD3 complex, are each essential for the establishment of allelic exclusion at the endogenous TCR-beta locus. Furthermore, using mutant mice lacking both the CD3-epsilon and CD3-zeta/eta genes, we established that the CD3 gene products are dispensable for the onset of V to (D)J recombination (V, variable; D, diversity; J, joining) at the TCR-beta, TCR-gamma, and TCR-delta loci. Thus, the CD3 components are differentially involved in the sequential events that make the TCR-beta locus first accessible to, and later insulated from, the action of the V(D)J recombinase.     

Fixed-dose combination therapy: panacea or poison?

A 42-year-old-women with sigmoid colon adenocarcinoma was found to have isolated prolonged activated partial thromboplastin time (aPTT 102.5 s, normal range 24-36 s) preoperatively. Her medical history included an episode of prolonged postdelivery uterine bleeding 16 years previously. A mixed aPTT test showed immediate correction of the prolonged aPTT, indicating a coagulation factor deficiency in the intrinsic pathway. Factor assays showed factor XI was below 1% of average normal value whereas factor VIII, IX and XII activities were normal. Family screening revealed one sister among the three siblings also had isolated prolonged aPTT. The patient was transfused with four units (5mL/kg) of fresh frozen plasma the day before surgery, then with two units during surgery. The operation was uneventful with no bleeding problems. The patient recovered smoothly and is currently undergoing adjuvant chemotherapy. This is the first formal report of a patient with factor XI deficiency undergoing major surgery in Taiwan. Careful monitoring of aPTT, with fresh frozen plasma transfusion, when needed, may safely overcome bleeding problems during surgery.     

Intestinal obstruction caused by caecal volvulus

The case of a 6-month-pregnant woman who had an uneventful postoperative recovery and normal vaginal delivery following a right hemi-colectomy for volvulus of the caecum with gangrene is reported.     

Antisocial behavioral syndromes among residential drug abuse treatment clients

We compared residential addictions treatment clients meeting full criteria for antisocial personality disorder (ASPD+) with those reporting syndromal levels of antisocial behavior only in adulthood (AABS+) on demographics, antisocial symptomatology, drug history, axis I comorbidity and characteristics of index treatment episode. We examined these issues in the sample as a whole, as well as separately in male and female respondents. Among both men and women, ASPD+ initiated their antisocial behavior earlier, met more ASPD criteria and endorsed more violent symptoms, than AABS+. Male ASPD+ also met criteria for more lifetime axis I diagnoses and reported more years of drug involvement than male AABS+. Trends were observed toward poorer retention in treatment among ASPD+ than among AABS+ participants of both genders randomized to a planned duration of 180 days, but retention did not differ between ASPD+ and AABS+ randomized to a planned duration of 90 days. Our findings, which replicate and extend previously published results, carry potential implications for treatment programming and for the nosology of ASPD.     

The effect of voluntary eye movements on associations and mood

OBJECTIVE: Our aim was to compare the outcome of esophageal resection for carcinoma in elderly patients (aged over 70 and over 80 years) with that of younger patients managed within a single specialist thoracic surgery unit. PATIENTS AND METHODS: Between January 1987 and November 1997, 523 patients underwent esophagectomy for carcinoma in the Nottingham City Hospital Thoracic Surgery Unit. The patients were divided into 3 groups by age: group I, under 70 years (n = 337); group II, 70 to 79 years (n = 150), and group III, 80 to 86 years (n = 36). These groups were compared with regard to preoperative medical status, operability and resectability, complications, operative mortality, and longterm survival. RESULTS: Patients in groups II (6.0%) and III (2.8%) had fewer preexisting respiratory problems than patients in group I (12.5%), and the patients in group III had fewer preexisting cardiovascular problems (16.7%) than patients in groups I (25.2%) and II (32.7 %). Although patients in group III were generally less likely to have operable lesions (64.3%), no significant differences in resectability rate were detected among the 3 groups (80.8%, 77.7%, and 80%). Elderly patients (groups II and III) had a higher incidence of overall (34% and 36.1%), respiratory (24.7% and 19.4%), and cardiovascular (7.3% and 11.1%) complications than those aged under 70 years (24.6%, 16.3%, and 2.1%, respectively). However, operative mortality (4.7%, 6.7%, and 5.6%) and 5-year survivals inclusive of operative mortality (25.1%, 21.2%, and 19.8%) were similar among the 3 groups. CONCLUSIONS: Accumulated experience in all aspects of perioperative management may account for a low hospital mortality in elderly patients despite a greater operative risk. The survival benefit is similar to that in the younger age groups, enforcing the view that esophagectomy within specialist thoracic units can be safely offered (in appropriately selected patients) with acceptable long-term survival in all age groups.     

Time-dependent changes of inflammatory mediators in the lungs of humans exposed to 0.4 ppm ozone for 2 hr: a comparison of mediators found in bronchoalveolar lavage fluid 1 and 18 hr after exposure

Acute exposure of humans to ozone results in reversible respiratory function decrements and cellular and biochemical changes leading to the production of substances which can mediate inflammation and acute lung injury. While pulmonary function decrements occur almost immediately after ozone exposure, it is not known how quickly the cellular and biochemical changes indicative of inflammation occur in humans. Increased bronchoalveolar lavage (BAL) fluid levels of neutrophils (PMNs) and prostaglandins (PGE2) have been reported in humans as early as 3 hr and as late as 18 hr after exposure. The purpose of this study was to determine whether a broad range of inflammatory mediators are elevated in BAl fluid within 1 hr of exposure. We exposed eight healthy volunteers twice: once to 0.4 ppm ozone and once to filtered air. Each exposure lasted for 2 hr during which the subjects underwent intermittent heavy exercise (66 liters/min). BAL was performed 1 hr after the exposure. Ozone induced rapid increases in PMNs, total protein, LDH, alpha-1 antitrypsin, fibronectin, PGE2, thromboxane B2, C3a, tissue factor, and clotting factor VII. In addition, there was a decrease in the recovery of total cells and alveolar macrophages, and decreased ability of alveolar macrophages to phagocytize Candida albicans. A comparison of these changes with changes observed in an earlier study in which subjects underwent BAL 18 hr after an identical exposure regimen indicates that IL-6 and PGE2 levels were higher 1 hr after exposure than 18 hr after exposure, fibronectin and tissue-plasminogen activator levels were higher 18 hr after exposure, and that PMNs, protein, and C3a were present at essentially the same levels at both times. These results indicate that (i) several inflammatory mediators are already elevated 1 hr after exposure; (ii) some mediators achieve their maximal levels in BAL fluid at different times following exposure. These data suggest that the inflammatory response is complex, depending on a cascade of timed events, and that depending on the mediator of interest one must choose an appropriate sampling time.     

Functional characterization of adenosine receptors in the nucleus tractus solitarius mediating hypotensive responses in the rat

1. The aim of this study was to characterize adenosine receptors located in the nucleus tractus solitarius (NTS) that mediate decreases in blood pressure in the anaesthetized rat. To determine the adenosine receptor subtype involved, a range of selective agonists and antagonists were studied and their relative potencies evaluated. 2. The rank order of agonist potency in inducing decreases in diastolic blood pressure was N6-cyclopentyladenosine (CPA) > N6-cyclohexyladenosine (CHA) > N-ethyl-carboxamidoadenosine (NECA) > or = 2-phenylaminoadenosine (CV1808) > 2-p-(carboxyethyl)phenethylamino-5' N-ethylcarboxamidoadenosine (CGS 21680) > N6-(2-(4-aminophenyl)ethyl)-adenosine (APNEA). 3. The hypotensive action of CPA following microinjection into the NTS was antagonized by i.v. infusions (50 micrograms kg-1 min-1) of adenosine receptor antagonists, 8-cyclopentyl-1,3 dipropylxanthine (DPCPX), 8-phenyltheophylline (8-PT), 8-(p-sulphophenyl)theophylline (8-SPT), and 1,3-dipropyl-8-N-(2-diethylamino)ethyl)-N methyl-4-(2,3,6,7-tetrahydro-2,6-dioxo) benzenesulphonamidexanthine (PD 115199). The antagonist potency order was DPCPX > PD115199 > or = 8-PT. Intravenous infusion of 8-SPT had no effect on blood pressure responses to microinjection of CPA into the NTS. 4. The results suggest that adenosine A1 receptors in the NTS mediate hypotensive responses in the anaesthetized rat preparation.     

The intragraft CD8+ T cell response in renal allograft rejection in the mouse

To identify the role of donor class I alloantigens in regulating the CD8+ T cell response to a kidney allograft, we analyzed and compared the CD8+ infiltrate in kidney transplants from MHC class I-deficient (class I-) mouse donors and class I+ controls. One week after transplantation, there was a prominent CD8+ infiltrate in control allografts, whereas CD8+ T cells were virtually absent in grafts from class I- donors. In class I+ allografts, infiltrating CD8+ cells utilized a wide range of T cell receptor (TCR) Vbeta families and their Vbeta usage was similar to that of the systemic CD8+ population. However, there was a modest but significant overrepresentation of cells bearing Vbeta8 in the graft compared with the spleen due to an expansion of CD8+ Vbeta8.3+ cells. This could be detected as early as 1 week and became more pronounced by 3 weeks after transplantation. In 3-week allografts, only 52% of CD8+ cells expressed alphabetaTCR. Among T cells isolated from class I+ grafts, the CD8+ Vbeta8+ cells demonstrated allospecific responses that were numerically larger than responses of the CD8+ Vbeta8- population. In contrast to the early (1 week) time point, significant numbers of CD8+ cells could be isolated from class I- grafts by 3 weeks after transplantation and their Vbeta repertoire resembled that seen in controls. While increasing numbers of CD8+ Vbeta8+ were present in the class I- grafts at 3 weeks, this increase was not statistically significant. Thus, expression of class I alloantigens on a kidney graft plays an important role in regulating the rate of accumulation of CD8+ T cells in rejecting kidney grafts. However, the TCR Vbeta repertoire of the CD8+ T cell infiltrate is largely determined by factors that are independent of normal class I expression on the graft.     

Voluntary wheel running decreases adipose tissue mass and expression of leptin mRNA in Osborne-Mendel rats

The purpose of this study was to assess the effects of voluntary wheel running on the expression of leptin mRNA in rats that are either sensitive (OM) or resistant (S5B/Pl) to diet-induced obesity. Male OM and S5B/Pl rats had ad libitum access to standard rodent diet and water. At 3-5 weeks of age, animals of both strains were randomly assigned to either an exercise or sedentary control group. The exercise groups had 24-h access to a running wheel, and they trained for 7 weeks. During weeks 1-4, animals in both OM and S5B/Pl exercise groups progressively increased their running. During weeks 5-7, S5B/Pl exercisers tended to run more than did OM (approximately 60 vs. 45 km/week), but by the end of the study both groups had an equally greater heart weight (mg/g body weight) and planteris citrate synthase activity than their sedentary controls. Oral glucose tolerance tests performed during the last week of training revealed that compared with their appropriate controls, insulin sensitivity was enhanced (P < 0.05) in OM but not in the S5B/Pl wheel-running groups. Inguinal, epididymal, and retroperitoneal fat pads weighed less in the running than in the nonrunning groups of both strains (P < 0.01). Additionally, exercised animals had an increased percentage of smaller cells (40-60 microm; P < 0.05) and a decreased percentage of larger cells (120-160 microm; P < 0.05) in the epididymal fat depot. Epididymal leptin mRNA measured by Northern blot analysis was reduced in the exercise-trained rats of both strains (P < 0.05). Furthermore, serum leptin was reduced in exercise-trained compared with the control animals of both strains. In comparison to S5B/Pl, control OM animals exhibited both a higher expression and higher circulating levels of leptin (P < 0.05). While serum leptin levels were decreased and food intake was increased in the exercise-trained animals of both strains (P < 0.05), the exact relationship between exercise, leptin, and food intake in this rat model of dietary obesity remains to be determined. Nonetheless, these results suggest that the expression and secretion of leptin can be influenced by exercise training and that these changes (i.e., reduced expression and secretion of protein) can occur independently of changes in whole-body insulin sensitivity and susceptibility to diet-induced obesity.