Seasonal variations in maternal serum and mammary immunity to RS virus

We have recorded the systemic and mammary/mucosal immune responses of women following natural infection with RS virus during the second and third trimesters of pregnancy. Anti-RS virus IgG antibody levels in the sera of women collected in the first trimester of pregnancy showed a bimodal distribution with high and low antibody groups. Antibody levels increased after exposure to the winter RS virus epidemic in the second trimester of pregnancy, probably as a result of infection but only for women in the low antibody group. Despite the increases, antibody levels for these women remained well below those of the high antibody group. There was no rise in mean antibody levels after exposure in the third trimester, even among women with low antibody, suggesting a degree of immunosuppression in late pregnancy. There was no evidence that infection during pregnancy was associated with adverse consequences for the infant. Exposure to RS virus in the first two trimesters, but not the third, was associated with high colostral IgA antibody levels that were maintained in the milk throughout the first 7 weeks of lactation. There was a significant correlation between colostral and maternal nasal IgA antibody levels at delivery. Levels of blood or colostral lymphocyte transformation responses at delivery were unaffected by exposure to RS virus in pregnancy. These observations upon natural infection suggest that vaccination during pregnancy is likely to achieve only marginal effects upon serum antibody levels but boost maternal mammary/mucosal immunity.     

Parental origin of de novo chromosome 9 deletions in del(9p) syndrome

Parental origin of de novo deletions in the short arm of chromosome 9 in patients with a clinical diagnosis of del(9p) syndrome was assessed in 13 patients using polymerase chain reaction (PCR) analysis of highly polymorphic dinucleotide repeat micro-satellite markers located in the putative deleted region. The deletion was found to be of paternal origin in 9 cases and of maternal origin in the remaining 4 cases, suggesting that the molecular event resulting in the deletion occurs in both male and female gametogenesis and that genomic imprinting does not appear to play a role in the patho-genesis of del(9p) syndrome. © 1995 Wiley-Liss, Inc.     

An enzyme-linked immunosorbent assay (ELISA) for IgG and IgA antibodies to respiratory syncytial virus in low dilutions of secretions of human serum and secretions

An enzyme-linked immunosorbent assay (ELISA) has been developed for titration of IgG and IgA antibodies to respiratory syncytial (RS) virus in low dilutions of human serum, colostrum, and nasopharyngeal secretions. Previously the sensitivity of RS virus ELISA on such specimens has been limited by nonspecific absorption of antibody, particularly IgA, to crude antigen preparations. For IgG antibody estimation in infant sera, this unwanted binding was reduced to workable levels by increasing the serum, salt, and detergent concentration of the diluent. Residual nonspecific binding of IgA in colostra appeared mainly due to antigen lipids or to lipoproteins. This was markedly reduced by partitioning Triton X-100-treated infected cell lysate antigens in Arklone. Using the modified ELISA technique for anti-RS virus IgA, good correlations were found with unfixed cell membrane immunofluorescence (MIF) for colostra (r = 0.81, P less than 0.001) and nasal secretions from adult volunteers. In several samples nonspecific absorption of antibody precluded MIF assay, but did not affect the ELISA. Although there was an overall correlation between ELISA for anti-RS IgG antibody in sera, the complement fixation test (r = 0.75, P less than 0.001), and MIF test (r = 0.82, P less than 0.001), the sensitivity of ELISA for antibody responses in convalescent sera of infants from 3 months to 2 years was poor. Conversely, the sensitivity of ELISA for antibody in the sera of older children and for transplacentally acquired antibody in very young infants was higher than that for the other two tests. ELISA was thus less reliable than either CF or MIF for detecting antibody rises in paired infant sera, particularly where maternally acquired antibody remained in the acute serum. The reasons for this apparent disparity are discussed.     

Bronchial vagal tone and responsiveness to histamine, exercise and bronchodilators in adult patients with cystic fibrosis.

Atopy and bronchial responsiveness to histamine, exercise and bronchodilators were investigated in 18 adult patients with cystic fibrosis (CF). Reversibility of airflow limitation was measured after ipratropium bromide and terbutaline, and histamine and exercise provocation tests were performed. Histamine hyperresponsiveness was observed in 10 out of 18 patients and was not confined to those with severe airway obstruction. The positive histamine responders showed significantly better bronchodilatation after terbutaline, when compared to negative histamine responders. Histamine responsiveness was not related to atopy or exercise responsiveness. Exercise challenge caused bronchodilatation without bronchoconstriction in all patients. The exercise-induced bronchodilatation correlated with bronchodilatation after ipratropium bromide. It is proposed that an increased vagal tone may lead to an increased resting bronchomotor tone which can be reduced by ipratropium bromide and by exercise in adult patients with cystic fibrosis.     

De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment,Spastic Paraparesis,Axonal Neuropathy,and Cerebellar Atrophy

KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.     

Risk of concomitant malignancy in hyperfunctioning adrenal incidentalomas

Background

Adrenal masses are common incidental findings on radiologic imaging. The association between malignancy and hormonal hyperactivity found in incidentally discovered adrenal tumors, however, remains unclear.

Methods

A retrospective analysis of prospectively collected data from patients who underwent adrenalectomy for incidentally discovered adrenal tumors at a single institution. Outcomes and operative data were compared by univariate analysis. Area under the curve was used to analyze the effect of tumor size in predicting malignancy.

Results

There were 49 patients who initially presented with adrenal incidentalomas that underwent adrenalectomy. Most patients were Caucasian women with an average age of 51 ± 14 years. Of this group, 24 patients underwent resection for hyperfunctioning adrenal glands. There were no significant differences in malignancy rates between hyperfunctional and nonfunctional tumors (4.1% vs. 12.0%, P = 0.32). On final histopathology, there were four patients with adrenal malignancies: two adrenocortical carcinomas and two metastatic from renal carcinoma. Only one patient with a hyperfunctioning adrenal tumor had underlying malignancy. Overall, invasion of adjacent structures (P < 0.001), presence of lymphadenopathy (P = 0.02), metastasis (P = 0.03), irregular tumor margins (P = 0.01), heterogeneity (P = 0.05), and tumor size >6 cm (P = 0.04) on radiologic imaging were strongly associated with malignancy in adrenal incidentalomas.

Conclusions

The risk of concomitant malignancy and hormonal hyperactivity in adrenal incidentalomas is very low. Tumor size (>6 cm) and radiographic features remain the most important predictors of adrenal malignancy, regardless of tumor function.     

Lower serum DHEAS levels are associated with a higher degree of physical disability and depressive symptoms in middle-aged to older African American women

BACKGROUND: Changes in androgen levels and associations with chronic disease, physical and neuropsychological function and disability in women over the middle to later years of life are not well understood and have not been extensively studied in African American women. AIMS: The present cross-sectional analysis reports such levels and associations in community dwelling, African American women aged 49-65 years from St. Louis, Missouri. METHODS: A home-based physical examination and a health status questionnaire were administered to randomly sampled women. Body composition (DEXA), lower limb and hand-grip muscle strength, physical and neuropsychological function and disability levels were assessed. Blood was drawn and assayed for total testosterone (T), sex hormone-binding globulin (SHBG), dehydroepiandrosterone-sulfate (DHEAS), oestradiol (E2), adiponectin, leptin, triglycerides, glucose, C-reactive protein (CRP) and cytokine receptors (sIL2r, sIL6r, sTNFr1 and sTNFr2). Multiple linear regression modelling was used to identify the best predictors of testosterone, DHEAS and free androgen index (T/SHBG). RESULTS: Seventy-four percent of women were menopausal and a quarter of these were taking oestrogen therapy. DHEAS and E2 declined between the ages of 49 and 65 years, whereas total T, SHBG and FAI remained stable. Total T and DHEAS levels were strongly correlated. In this population sample there were no independent associations of either total T or FAI with indicators of functional limitations, disability or clinically relevant depressive symptoms. Unlike total T and FAI, lower DHEAS levels were independently associated with both higher IADL scores (indicating a higher degree of physical disability) and higher CESD scores (indicating a higher degree of clinically relevant depressive symptoms). CONCLUSION: There is an age-related decline in serum DHEAS in African American women. Lower DHEAS levels appear to be associated with a higher degree of physical disability and depressive symptoms in this population.