Human immunodeficiency virus 1 expression in the female genital tract in association with cervical inflammation and ulceration

OBJECTIVES: Determining the source of human immunodeficiency virus 1 in the female genital tract and identifying factors that influence the amount of virus shed are important in the understanding of heterosexual human immunodeficiency virus 1 transmission. STUDY DESIGN: Cervicovaginal human immunodeficiency virus 1 ribonucleic acid shedding was quantified before and after treatment of cervical squamous intraepithelial lesions in 14 women. Genotypic analysis was performed on peptide HIV-1 env gp120 of the major human immunodeficiency virus 1 species in plasma and cervicovaginal lavage of selected samples. RESULTS: At 2 to 4 weeks after treatment, when cervices were inflamed and ulcerated, human immunodeficiency virus 1 ribonucleic acid in lavage samples increased 1.0 to 4.4 log 10. Genotypic analysis showed significant differences between the predominant human immunodeficiency virus 1 species in paired plasma and lavage samples from 2 of 4 women, suggesting that the increase in human immunodeficiency virus 1 was the result of local viral replication. CONCLUSIONS: Cervical inflammation and ulceration are associated with local human immunodeficiency virus 1 expression, which increases as much as 10,000-fold the amount of human immunodeficiency virus 1 shed into genital secretions. This may explain why sexually transmitted diseases are important risk factors for human immunodeficiency virus transmission.     

Atrial natriuretic factor-potentiating and antihypertensive activity of SCH 34826. An orally active neutral metalloendopeptidase inhibitor

The effects of SCH 34826, an orally active neutral metalloendopeptidase inhibitor, on responses to atrial natriuretic factor-(103-125) or -(99-126) and on blood pressure were evaluated in rats. SCH 34826 (10, 30, and 90 mg/kg s.c. and 90 mg/kg p.o.) potentiated the antihypertensive action of atrial natriuretic factor (30 micrograms/kg i.v.) in conscious spontaneously hypertensive rats. SCH 34826 (90 mg/kg) also potentiated the diuretic and natriuretic responses to atrial natriuretic factor (30 micrograms/kg i.v.) as well as the plasma levels achieved after peptide injection. SCH 34826 significantly reduced blood pressure in the conscious deoxycorticosterone acetate-salt hypertensive rat, at doses of 90 mg/kg s.c. (-35 +/- 12 mm Hg), 10 mg/kg p.o. (-30 +/- 7 mm Hg), and 90 mg/kg p.o. (-45 +/- 6 mm Hg). SCH 34826 was devoid of acute antihypertensive activity in the spontaneously hypertensive rat but reduced blood pressure by day 3 of a 5-day treatment schedule. SCH 34826 (90 mg/kg s.c.) enhanced urine volume output in the deoxycorticosterone acetate-salt rat (2.78 +/- 0.6 vs. 1.27 +/- 0.3 ml/100 g/3 hr in vehicle-control rats, p less than 0.05). SCH 34826 (90 mg/kg s.c.) increased plasma levels of atrial natriuretic factor at 1 hour (753 +/- 89 vs. 451 +/- 79 pg/ml in vehicle-treated rats, p less than 0.05) but not 3 hours after dosing. The renal excretion of atrial natriuretic factor (3,092 +/- 1,089 vs. 21 +/- 6 pg/100 g/3 hr in vehicle-treated rats, p less than 0.05) and cyclic guanosine monophosphate (2,131 +/- 509 vs. 879 +/- 168 pg/100 g/3 hr in vehicle-treated rats, p less than 0.05) was markedly elevated by SCH 34826 in deoxycorticosterone acetate-salt rats. These studies suggest that neutral endopeptidase inhibition may represent a new approach to treatment of some forms of hypertension.     

Vaccination with Live Escherichia coli Expressing Brucella abortus Cu/Zn Superoxide Dismutase Protects Mice against Virulent B. abortus

Vaccination of mice with Escherichia coli expressing Brucella Cu/Zn superoxide dismutase (SOD) [E. coli(pBSSOD)] induced a significant level of protection against virulent Brucella abortus challenge, although this level was not as high as the one reached with B. abortus vaccine strain RB51. In addition, vaccination with E. coli(pBSSOD) induced antibodies to Cu/Zn SOD and a strong proliferative response of splenocytes when stimulated in vitro with a thioredoxin-Cu/Zn SOD fusion protein.     

Post laryngectomy rehabilitation the case for planned early speech therapy

This study reflects the efficacy of planned early speech therapy on post laryngectomy rehabilitation. Not only do a larger number of laryngectomees acquire intelligible esophageal speech where therapy is instituted early but also the pace of development and quality of the speech is far superior when compared to those laryngectomees in whom speech therapy was delayed. This paper unequivocally supports the institution of planned early speech therapy in the successful rehabilitation of the laryngectomee. Such therapy can proceed simultaneously with the post operative radiation therapy sans deleterious effects and without prolonging hospital stay with its attendant overheads.     

Macromolecules reduce abnormal microvascular permeability in rat limb ischemia-reperfusion injury

We studied the effect of iv administration of biodegradable macromolecules on microvascular permeability after ischemia-reperfusion injury in a rat gastrocnemius model. After 2 h of tourniquet ischemia of the rats' hind limb, groups of animals were given iv lactated Ringer's solution (RL), serum albumin 5%, or varying MW fractions of biodegradable macromolecules of hydroxyethyl starch (HES), glycogen, and dextran. At the conclusion of the 24-h reperfusion period, the rat gastrocnemius muscles were collected. Water and K+ differences between the ischemic and control muscles were compared. Rats given a 100,000 to 300,000-dalton fraction of HES had significantly decreased water content (5.1 +/- 3.4%) when compared to rats receiving RL (8.3 +/- 2.2, p less than .01), less than 100,000 dalton HES (8.3 +/- 3.2, p less than .05), less than 300,000 glycogen (7.9 +/- 2.5, p less than .01), or dextran 150,000 (8.3 +/- 1.5, p less than .05). Rats given 100,000 to 300,000-dalton HES also had significantly higher ischemic muscle K+ content as compared to the nontourniquet control (difference 14.2 +/- 9.7 mEq/g) than rats receiving any of the other solutions (range 32.5 to 39.3) except the 300,000 to 1,000,000-dalton fraction of HES. Regression analysis comparison of K+ difference to the histologic evaluation of the muscles on the criteria of polymorphonuclear infiltration and interstitial edema (0, best; 3, worst) had a Pearson correlation coefficient of r = .73. Reduction of abnormally increased microvascular permeability may be accomplished by the iv use of appropriate sized biodegradable macromolecules.     

A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families

Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two‐thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity. Pathogenicity of the 18 novel missense variants was analyzed functionally by determining the ability of the mutant cDNA to improve the survival of a FANCA‐null cell line when treated with MMC. Overexpressed pathogenic missense variants were found to reside in the cytoplasm, and nonpathogenic in the nucleus. RNA analysis demonstrated that two variants (c.522G > C and c.1565A > G), predicted to encode missense variants, which were determined to be nonpathogenic by a functional assay, caused skipping of exons 5 and 16, respectively, and are most likely pathogenic. We report 48 novel FANCA sequence variants. Defining both variants in a large patient cohort is a major step toward cataloging all FANCA variants, and permitting studies of genotype–phenotype correlations.