Genetic damage detected in CD-1 mouse pups exposed perinatally to 3'-azido-3'-deoxythymidine or dideoxyinosine via maternal dosing, nursing, and direct gavage: II. Effects of the individual agents compared to combination treatment

We previously reported extraordinary increases in micronucleated erythrocytes in CD-1 mouse pups exposed to 3'-azido-3'-deoxythymidine (AZT) and dideoxyinosine (ddI; 50/250, 75/375, 150/750 mg/kg/day AZT/ddI) by gavage throughout gestation and lactation, followed by direct pup dosing beginning postnatal day (PND) 4 (Bishop et al. [2004]: Environ Mol Mutagen 43: 3-9). That study was conducted to explore the potential for genetic damage in newborns exposed perinatally to antiretrovirals in order to reduce maternal-infant transmission of HIV-1. Because dramatic increases in frequencies of micronucleated erythrocytes were seen in exposed pups, additional studies were conducted to clarify the relative contribution of each drug to the observed damage. Pregnant CD-1 mice were administered AZT (50, 75, 150 mg/kg/day) or ddI (250, 375, 750 mg/kg/day) by gavage twice daily in equal fractions beginning prior to mating and continuing throughout gestation and lactation. Direct pup dosing (same regimens) began on PND 4. Peripheral blood erythrocytes of male pups were screened for micronuclei on PNDs 1, 4, 8, and 21. Significant increases in micronucleated erythrocytes were observed in pups and dams exposed to AZT at all doses and sampling times. The highest micronucleus levels were observed in pups on PND 8 after the initiation of direct dosing. In contrast, effects seen in pups and dams treated with ddI were minimal. These results demonstrate that AZT, a component of many anti-HIV combination therapies, induces chromosomal damage in perinatally exposed neonatal mice. Comparison of micronucleated cell frequencies induced by AZT alone or in combination with ddI suggests that ddI potentiates AZT-induced chromosomal damage following direct exposure.     

Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or hypochondroplasia

We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.     

Intestinal Spirochetosis and Acquired Immunodeficiency Syndrome: Ultrastructural Studies of Two Cases

Two cases of intestinal spirochetosis (IS) with acquired immunodeficiency syndrome are reported. In case 1, a 48-year-old homosexual black man presented with a 1-month history of alternating watery diarrhea and constipation, which dissipated following the removal of two colonic hyperplastic polyps containing IS. In case 2, a 26-year-old homosexual black man presented with a 3-month history of persistent bloody diarrhea and was found to have chronic shigellosis and IS. Pathologic findings of IS were similar in both cases. Basophilic fringes typical of IS covered the surfacing colonic epithelium and consisted of dense growths of spirochetes adherent to and oriented perpendicular to the plasma membranes of the surfacing epithelium. The spirochetes measured 3 to 5 μm in length and 0.2 (im in width, contained four to eight axial fibrils, and closely resembled Brachyspira aalborgi ultrastructurally. These cases are notable because the histopathologic changes of IS were more extensive than generally described. There was involvement of both the right colon and rectum by IS in case 2, and in both cases there was extension of the IS down into the crypts of Lieberkiihn, spirochetal invasion of the colonic mucosa, and a conspicuous inflammatory response by macrophages in the underlying lamina propria.     

Genes mediating programmed cell death: an immunohistochemical study of bcl-2, c-myc and p53 expression in colorectal neoplasia

Aims—To describe the expression of three genes involved in the regulation of cell proliferation and programmed cell death (apoptosis) in normal, dysplastic and malignant large bowel epithelium, and to relate any alterations to important biological and clinical variables.     

Acquired immune deficiency in Haitians: opportunistic infections in previously healthy Haitian immigrants

We describe acquired immune deficiency manifested by opportunistic infections in 10 previously healthy heterosexual Haitian men. The opportunistic pathogens included Toxoplasma gondii (in four patients), Cryptococcus neoformans (in one), Pneumocystis carinii (in four patients), and Candida albicans (in three). Six of the patients also had Mycobacterium tuberculosis. Immunologic studies of three patients showed a decrease in the numbers and activity of helper T cells, with normal or increased populations of suppressor T cells. Serologic markers for previous infections from hepatitis A, cytomegalovirus, and herpes simplex virus were detected in several patients. Six of the patients died despite specific antimicrobial therapy. The clinical and immunologic findings in these 10 Haitians are similar to those reported in drug addicts and homosexuals with the acquired immune-deficiency syndrome.     

Viral titers in nasal lining fluid compared to viral titers in nasal washes during experimental rhinovirus infection

BACKGROUND: The concentration of rhinovirus in nasal wash specimens from infected volunteers peaks at 48-72 h after inoculation. The volume of expelled nasal fluid peaks at the same time, raising the question of whether the viral concentration in nasal wash reflects viral replication in nasal cells or merely the production of an increased volume of nasal fluid during a cold. OBJECTIVES: To determine the amount of rhinovirus in nasal lining fluid during colds before the nasal fluid has been diluted in a nasal wash. STUDY DESIGN: Rhinovirus titers were determined in nasal wash specimens collected daily for five days from 14 subjects with type16 rhinovirus infection. The urea concentration in nasal lining fluid equals that in blood. By determining the urea concentration in a nasal wash and comparing it to the urea concentration in blood from the same subject, it was possible to determine the amount of dilution of the nasal lining fluid. The dilution factor (reciprocal of the dilution) was then used to calculate the viral concentration in undiluted nasal lining fluid. RESULTS: The dilution factor in 70 nasal washes varied from 5 to 64. The viral GMTs (+S.E.) in nasal washes were 1.79 (+0.3) TCID(50)/ml at 24 h, 3.11 (+0.15) at 48 h, and 2.61 (+0.3) at 72 h. The viral GMTs in nasal lining fluid, based on urea adjusted values, paralleled those in nasal washes but were approximately one log higher. Virus concentrations returned to near baseline values by day 5. CONCLUSIONS: The temporal pattern of rhinovirus shedding observed in nasal wash specimens, with a peak in virus concentration at 48-72 h after infection, is a true indication of virus production in nasal cells and not an artifact of the increased amount of nasal fluid produced during the early phase of a cold.     

Acoustic transmission in normal human hips: structural testing of joint symmetry

An acoustical technique has been developed for the measurement of structural symmetry of the hip joints. A mild vibratory force was applied to the sacrum and sound signals were picked up at both hips by a pair of microphones installed in two stethoscopes. These stethoscope–microphone assembles were calibrated to achieve a difference in relative sensitivity of less than 0.2 dB. The relative transmission of sound signals was analysed and compared between both hips by a dual-channel signal analyser. Twenty-seven healthy adults, 20 healthy pre-school children and 19 normal neonates were tested. Results from these three groups showed high coherence of the sound signals and that the discrepancy between both hips was smallest in the frequency range of 200–315 Hz. For normal neonates, the sound signals maintained a high coherence (γ²>0.97) and small discrepancy (D<1.25 dB) between both hips. This study has shown that the acoustical technique provides a practical structural testing for bony symmetry of the hips and the results offer a baseline for further investigation into developmental dysplasia of the hip (DDH) in neonates. Clinical screening for DDH is still problematic in developing countries.     

Thermal regulatory responses to submaximal cycling following lower-body cooling in humans

This study compared the effects of pre-exercise cooling with control water immersions on exercise-induced thermal loads derived from steady-state submaximal exercise. Eight healthy male participants [mean (SEM) age 29 (1) years, maximal oxygen uptake 3.81 (0.74) l·min^–1, and body surface area 1.85 (0.11) m²] took part in experiments that included 30 min of baseline data collection [ambient temperature 21.3 (0.2°C)], 30 min of immersion in water to the level of the supra-iliac crest [water temperatures of 35.1 (0.3)°C for thermoneutral and 17.7 (0.5)°C for precooled treatments], and 60 min of cycling exercise at 60% of maximal oxygen uptake. No significant differences were noted during exercise in net mechanical efficiency, metabolic rate, O₂ pulse, or ratings of perceived exertion between the two treatments. Precooling resulted in a significant negative body heat storage during immersion and allowed greater heat storage during exercise. However, net body heat storage for the entire protocol was no different between treatments. Cooling significantly lowered rectal, mean skin, and mean body temperatures as well as more than doubling the exercise time until a 0.5°C rectal temperature increase was observed. The cooling trial significantly delayed onset of sweating by 19.62 min and decreased sweat rate by 255 ml·h^–1 compared to control. Thermal and sweat sensation scores were lower after the cooling treatment compared to control. These data suggest that lower-body precooling is effective at decreasing body heat storage prior to exercise and decreases reliance on heat dissipation mechanisms during exercise. Therefore, this unique, well-tolerated cooling treatment should have a broader application than other precooling treatments. Electronic Publication     

Metabolic profile of the hippocampus of Zucker Diabetic Fatty rats assessed by in vivo 1H magnetic resonance spectroscopy

Localized in vivo 1H magnetic resonance spectroscopy (MRS) was used to investigate metabolite levels in the brain of adult Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes mellitus. This study focussed on the hippocampus, assumed to be one of the main brain areas affected by this disease. Together with an almost 5-fold increase in blood glucose concentration measured by glucose oxidation, significant increases were found in the hippocampal concentrations of glucose (4.93 vs 1.66 mM p < 0.001), myo-inositol (6.52 vs 4.30 mM; p < 0.05), and total creatine (12.71 vs 10.50 mM; p < 0.05) in ZDF rats (n = 5) compared with littermates (n = 5). Although no obvious alterations were detected in the hippocampal levels of other metabolites, including NAA + NAAG and choline-containing compounds in the ZDF rats, the increase in Glc and Ins levels is in line with elevated brain tissue contents of these metabolites in patients with diabetes mellitus.