Acid-base and electrolyte effects of shortening steeplechase in a three-day-event

This study was designed to characterise the acid-base and electrolyte effects of shortening the distance required during steeplechase (Phase B) in the face of hot and humid weather conditions during a treadmill-simulated Speed and Endurance test. Eight conditioned Thoroughbred horses underwent 3 randomised permutations of a standardised exercise test on a high speed treadmill. Each test consisted of trotting at 3.7 m/s for 10 min (Phase A); galloping at 11 m/s (Phase B) for 4 (cool laboratory conditions), 3 (hot and humid), or 2 (hot and humid) min; trotting at 3.7 m/s for 30 min (Phase C); and walking at 1.8 m/s for 10 min (Phase X). The treadmill slope was 4% for trotting and galloping and 0% for walking. Cool versus hot and humid conditions were 20 degrees C and 50-60% relative humidity vs. 26-28 degrees C and 80-85% relative humidity, respectively. Pulmonary artery blood samples were obtained at rest prior to exercise (Rest); at the end of Phases A (A10) and B (B2-4); at 10 (C10), 20 (C20) and 30 (C30) min through Phase C; and at 5 min into Phase X (X5). Additional samples for lactate (LA) and glucose (GLC) analysis were obtained 5 min into Phase C (C5) and at the end of Phase X (X10). Samples were analysed for packed cell volume (PCV), haemoglobin (HB), total plasma protein (TP), sodium (Na), potassium (K), chloride (Cl), anion gap (AG), plasma glucose (GLC) and lactate (LA), pH, PCO2, bicarbonate (HCO3) and base excess (BE). Shortening steeplechase distance by 50% under hot and humid conditions (2 min B) resulted in a consistent return to control measurements (4 min B) only for plasma LA. Changes in PCV, HB, TP, K and Cl were related more to the longer galloping distance in the 4 min B trials than to hot vs. cold laboratory conditions. Alternatively, changes in LA, GLC, pH, PCO2 and AG were more related to hot and humid laboratory conditions than they were to galloping distance. These latter variables, when combined with physical measures such as core temperature, bodyweight loss, point of fatigue on Phase C and recovery heart rates may serve as the best monitors of positive responses in future studies of proposed modifications to Phase C, rather than those variables which were more distance than weather-related.     

Low prevalence of human papillomavirus in a geographic region with a high incidence of head and neck cancer

BACKGROUND: The main purpose of this study was to determine the prevalence of human papillomavirus (HPV) infection in patients with head and neck carcinomas from Brazil. MATERIALS AND METHODS: Forty-five patients with head and neck squamous cell carcinoma were included in the study, from 1995 to 1996. Forty-two were male and 3 female, with age ranging from 32 to 82 years (median 61). Five patients (11%) did not have previous history of use of tobacco and 38 (90.5%) were heavy smokers. Tumor sites were pyriform sinus, 10; tongue, 11 (oral, 6; base, 5); larynx, 7; floor of mouth, 3; tonsil, 6; retromolar area, 3; inferior gingiva 2; buccal mucosa, 2; and maxillary sinus in 1 patient. Twenty-five were stage IV, 17 stage III, and 3 stage II. RESULTS: The presence of HPV DNA was detected in 5 of 45 patients (11%), all of them with HPV 16. Two patients had HPV DNA in normal mucosa and tumor tissue, 1 patient had HPV DNA only in the normal mucosa and tumor tissue, 1 patient had HPV DNA only in the normal mucosa, and 2 patients were positive for HPV DNA in tumor tissue. Four patients were male and 1 was female; 2 patients were nonsmokers. Three patients had tonsil carcinoma, 1 patient had a tongue carcinoma, and 1 patient had a pyriform sinus cancer. CONCLUSIONS: The role of chemical carcinogens seems to be more important in the genesis of head and neck cancer than is HPV infection. The presence of HPV DNA in 5 of 45 patients stimulates further investigation to determine the role of HPV as a risk factor for head and neck carcinoma.     

Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.     

IFN-tau: a novel subtype I IFN1. Structural characteristics, non-ubiquitous expression, structure-function relationships, a pregnancy hormonal embryonic signal and cross-species therapeutic potentialities

IFN-tau (IFN-tau) constitutes a new class of type I IFN which is not virus-inducible, unlike IFN-alpha and IFN-beta, but is constitutively produced by the trophectoderm of the ruminant conceptus during a very short period in early pregnancy. It plays a pivotal role in the mechanisms of maternal recognition of pregnancy in ruminants and it displays high antiviral and antiproliferative activities across species with a prominent lack of cytotoxicity at high concentrations in vitro in cell culture and possibly in vivo. It exhibits high antiretroviral activity against HIV and exhibits immunosuppressive activity in a multiple sclerosis model and reduces embryo and fetal mortality by stimulation of IL-10 production. In this review all the biochemical and para-hormonal properties of this novel IFN-tau are described in detail: structural characteristics of proteins and genes, trophoblast expression, regulation of its expression, structure of its gene promoter, its absence in human species and in non-ruminant animals, the evolution of the IFN-tau genes, its structure-function relationships with its three-dimensional structure, structural localization of biological activities, its lack of cytotoxicity and its receptor. Surprisingly, for an IFN, IFN-tau is also a pregnancy-embryonic signal with paracrine antiluteolytic activity. In order to maintain luteal progesterone secretion, IFN-tau inhibits PGF-2alpha pulsatile secretion and oxytocin uterine receptivity in early pregnancy. It is believed to suppress pulsatile release of endometrial PGF-2alpha by preventing oxytocin and estrogen receptor expression. Additionally, it directly regulates prostaglandin metabolism and possibly the PGE:PGF-2alpha ratio.     

Comparison of skin reflectances between Bolivian lowlanders and highlanders of European ancestry

I compared one genetic marker, skin reflectances, between Bolivians of European ancestry residing at high altitude in La Paz (3600 m; 41 boys and 65 girls) and at low altitude in Santa Cruz (400 m; 140 boys and 117 girls). Reflectances were measured at three wavelengths (425 nm, 545 nm, and 685 nm) on two different sites: the medial surface of the inner upper arm and the forehead. Principal components analysis was used to reduce age-, sex-, and surname-standardized reflectances to three independent components. The first principal component, which assesses the genetic component of melanin concentration, did not differ between samples, indicating that there are no significant differences between lowland and highland Bolivians of European ancestry with respect to the genetic component of skin reflectances. The second principal component, which assesses the influence of tanning on skin reflectance, also did not differ significantly between highlanders and lowlanders. Finally, the third principal component, which assesses the impact of vascularity on skin reflectance, was significantly lower in residents of La Paz than in residents of Santa Cruz, suggesting a greater vascularity-induced darkening of skin color in highlanders than lowlanders, possibly reflecting the higher hemoglobin concentrations that are typical of highland populations.     

Reactivation of Chagas' disease in a human immunodeficiency virus-infected patient leading to severe heart disease with a late positive direct microscopic examination of the blood

We report a human immunodeficiency virus (HIV)-infected man with chronic Chagas' disease who developed a congestive heart failure that could not be clinically controlled. Endomyocardial biopsy revealed severe myocarditis and the xenodiagnosis result was positive, but Trypanosoma cruzi by direct microscopic examination of the blood was found only four months after the symptoms had started. Treatment with benznidazole was effective in reducing parasitemia, stabilizing the clinical status, and controlling tissue damage related to the parasite. Although the finding of T. cruzi trypomastigotes by direct microscopic examination of the blood has been considered the mark of Chagas' reactivation in immunocompromised patients with chronic disease, in this case it was a late finding.     

Synthesis of new bifunctional compounds which selectively alkylate guanines in DNA

The aim of this work was to develop new bifunctional alkylating agents which damage DNA in a selective manner. In order to extend our previously published work on conformationally restricted nitrogen mustards containing one piperidine ring, new bispiperidine derivatives were designed with varying lengths of carbon chain between the two rings and structure-activity relationships in these systems were studied. Thus samples of new bispiperidine salts 22-26 with chloromethyl groups at the 2-positions and a bridge between the two nitrogen atoms of 2-6 carbon atoms were synthesized. The analogous new bis(p-nitrophenylcarbamates) 17-21 were also prepared. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation with different distances between the two alkylating sites. The bispiperidines 22-24 were shown to alkylate guanines at the 7-position in the major groove of DNA more selectively than melphalan. The bispiperidine 22 with the shortest two carbon bridge was the most reactive but it was less cytotoxic than melphalan in a human colon carcinoma cell line (IC50 value approximately 30 microM) and in a human chronic myeloid leukaemia cell line (IC50 value approximately 12 microM). The most cytotoxic compound in the latter cell line was the carbamate 17, with an IC50 value of approximately 0.3 microM, and carbamates 17, 19 and 20 were most potent in a panel of human ovarian carcinoma cell lines. These compounds also showed circumvention of acquired cisplatin resistance in three paired cell lines. The carbamates 17-21, however, were less efficient at alkylating and cross-linking naked DNA than the bispiperidines 22-26.     

Preoperative irradiation therapy and radical hysterectomy: prognostic value of tumor regression after initial irradiation of squamous cell carcinoma of the cervix

OBJECTIVE: To investigate the role of tumor persistence in patients submitted to irradiation therapy and radical hysterectomy. DESIGN: A retrospective analysis of prognostic factors. LOCATION: Hospital A.C. Camargo, S?o Paulo, Brazil, a private non-profitmaking foundation and tertiary referral centre. PATIENTS: A total of 629 cases of invasive squamous cell carcinoma of the cervix were studied. Criteria for inclusion in the study were: confirmed histological diagnosis of squamous cell carcinoma and no previous treatment (except for preoperative radiotherapy carried out at the Hospital A.C. Camargo itself). At the end of the follow-up period, 410 patients (65%) had no evidence of disease and 219 (34.8%) had died because of the tumor. INTERVENTION: The patients were submitted to radical surgery and radiation therapy, separately or in combination between 1953 and 1982. MAIN OUTCOMES MEASURES: Multivariate analysis of the different variables was performed according to the Cox regression method. RESULTS: The variables of prognostic value were, in decreasing order of importance: the decade of patient admission (p = 0.0001), the modality of therapy employed (p = 0.0005), the presence of residual tumor in the surgical specimens (p = 0.0055) and the clinical stage of the disease (p = 0.0575). CONCLUSION: Radiation therapy controlled a considerable number of local tumors and pelvic lymph nodes but not all of them in every patient. There is a specific group of patients for whom radical surgery is necessary to achieve control of the disease.     

Embryonic cardiomyocyte hypoplasia and craniofacial defects in G alpha q/G alpha 11-mutant mice

Heterotrimeric G proteins of the Gq class have been implicated in signaling pathways regulating cardiac growth under physiological and pathological conditions. Knockout mice carrying inactivating mutations in both of the widely expressed G alpha q class genes, G alpha q and G alpha 11, demonstrate that at least two active alleles of these genes are required for extrauterine life. Mice carrying only one intact allele [G alpha q(-/+);G alpha 11(-/-) or G alpha q(-/-);G alpha 11(-/+)] died shortly after birth. These mutants showed a high incidence of cardiac malformation. In addition, G alpha q(-/-);G alpha 11(-/+) newborns suffered from craniofacial defects. Mice lacking both G alpha q and G alpha 11 [G alpha q(-/-);G alpha 11(-/-)] died at embryonic day 11 due to cardiomyocyte hypoplasia. These data demonstrate overlap in G alpha q and G alpha 11 gene functions and indicate that the Gq class of G proteins plays a crucial role in cardiac growth and development.     

The interaction of DNA-targeted platinum phenanthridinium complexes with DNA

Cisplatin analogues were synthesised that consisted of platinum(II) diamine complexes tethered via a polymethylene chain ( n = 3, 5, 8 and 10) to a phenanthridinium cation. Both chloro and iodo leaving groups were examined. DNA adduct formation was quantitatively analysed using a linear amplification system with the plasmid pGEM-3Zf(+). This system utilised Taq DNA polymerase to extend from an oligonucleotide primer to the damage site. This damage site inhibited the extension of the DNA polymerase. The products were electrophoresed on a DNA sequencing gel enabling adduct formation to be determined at base pair resolution. The damage intensity at each site was determined by densitometry. The platinum phenanthridinium complexes were shown to damage DNA at shorter incubation times than cisplatin. To produce similar levels of damage, an 18 h incubation was required for cisplatin compared to 30 min for the n = 3 platinum phenanthridinium complexes; this indicates that the intercalating chromophore causes a large increase in the rate of platination. A reaction mechanism involving direct displacement of the chloride by the N-7 of guanine may account for the rate increase. These results indicate that further development of these compounds could lead to more effective cancer chemotherapeutic agents.