Specificity of the fivefold increase in AD in mothers of adults with Down syndrome.

BACKGROUND: In a previous study, the authors found that the risk of AD among mothers who were 35 years or younger when their children with Down syndrome (DS) were born was five times that of mothers of children with other forms of mental retardation. The current study investigated the specificity of the familial aggregation of DS and AD by examining whether mothers who gave birth to children with DS before age 35 are also at increased risk of other age-related neurologic or medical disorders. METHODS: The authors used survival methods to compare cumulative incidence and relative risk of AD, other dementias, and common age-related disorders in parents of 200 adults with DS and parents of 252 adults with other forms of mental retardation. RESULTS: Mothers who were < or =35 years of age when their children with DS were born were four to five times as likely to develop AD as control mothers (rate ratio = 4.8, 95% CI 2.1, 11.2), whereas risk of AD among mothers who were >35 years when their children with DS were born was not significantly increased (rate ratio = 1.8, 95% CI 0.6, 5.1). Risk of AD among fathers of probands with DS was similar to that of control fathers, and did not vary by age at proband birth. Risk of other dementias and of other age-related medical condition was similar among mothers and fathers of probands with DS and control parents, regardless of age at proband birth. CONCLUSION: These findings suggest that the increased risk of AD among mothers who gave birth to children with DS before age 35 appears to represent a specific vulnerability to AD, as opposed to other age-related degenerative disorders.

Atopy, anergic status, and cytokine expression in HIV-infected subjects.

BACKGROUND: In HIV infection T-cell dysfunction resulting in anergy and hypersensitivity reactions precedes T-cell depletion. A shift in the cytokine profile from a type 1 to a type 2 response has been postulated. OBJECTIVE: We sought to examine the cytokine expression patterns in HIV infection and the relationship to allergy, stage of HIV disease, and other laboratory parameters. METHODS: A cross-sectional analysis of IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p35, IL-13, and IFN-gamma mRNA expression in PBMCs by noncompetitive dot-blot PCR was performed on blood obtained from 18 HIV-infected subjects. Delayed-type hypersensitivity multitests to detect anergy, skin prick testing and in vitro assay for specific IgE antibodies, assay for total IgE, and enumeration of eosinophils, CD4(+), and CD8(+) T cells were also performed on all subjects. RESULTS: We found evidence of a decline in type 1 cytokines (IL-2, IL-12p35, and IFN-gamma) associated with AIDS, CD4(+) T cells less than 200/microL, anergy, and atopy, although this only reached statistical significance in anergy. There was no associated significant alteration in type 2 cytokines. CONCLUSIONS: This is the first report of an association between low constitutive in vivo expression of IL-12 mRNA and anergy, which supports earlier data from in vitro stimulation studies. The presence of atopy was associated with a more global reduction in cytokine expression. Because the decline in type 1 cytokines was not accompanied by a similar decline in type 2 cytokines, this does suggest a shift in the type 1/type 2 balance.

ADH genotypes and alcohol use and dependence in Europeans.

We have tested for effects of alcohol dehydrogenase (ADH) genotypes on self-reported alcohol consumption and symptoms of alcohol dependence, recorded on three occasions up to 15 years apart, in 377 male and female subjects of European descent. ADH2 genotype had significant effects on both consumption and dependence in the men, but not in the women. The effects of ADH3 genotype were considerably less than those of ADH2, but significant results could be demonstrated when the combined genotypes were considered. The direction of the effects on alcohol consumption and dependence risk were consistent with reports on Asian subjects, and with the in vitro properties of ADH isoenzymes. As with previous studies on the relationship between ADH type and alcohol use, population stratification cannot be excluded as a contributing factor in these results.

Molecular biology of alcohol dependence, a complex polygenic disorder.

Alcohol dependence, and the medical conditions which arise from prolonged excessive alcohol use, have no single cause. Like other complex diseases, they result from a combination of social, personal and genetic contributions; but within any society genetic variation has a substantial influence on individual risk. The genes presently known to affect alcohol dependence produce variation in alcohol metabolism; other genes which affect personality or susceptibility to intoxication are likely to be significant but so far reproducible evidence is scanty. Designs which include related subjects have advantages for the study of complex diseases, because any association effects can be placed in the context of overall heritability and because linkage analysis can also be included. Examples of our studies of alcohol metabolism, consumption and dependence are presented.

Prevalence of chronic medical conditions in adults with mental retardation: comparison with the general population.

We interviewed caregivers and reviewed medical records of 278 adults with mental retardation with and without Down syndrome, 45 to 74 years of age. Standardized morbidity ratios were used to compare frequency of medical disorders in these adults to frequency in the general population. In adults with mental retardation, the frequency of common age-related disorders was comparable to that in the general population, but there was an increased frequency of thyroid disorders, nonischemic heart disorders, and sensory impairment. Surveillance of health status and increased access to health care for screening and treatment of age-related disorders that are more frequent in adults with mental retardation would be important to prevent the development or delay the impact of these conditions and to promote healthy aging.

Earlier onset of Alzheimer's disease in men with Down syndrome.

BACKGROUND: Virtually all individuals with Down syndrome (DS) have neuropathologic changes characteristic of Alzheimer's disease (AD) beginning at 40 years of age. Few studies have examined factors that influence age at onset of AD in DS. We investigated whether sex differences in age at onset and risk of AD among adults with DS are similar to those observed in the general population and whether the effect of sex on risk of AD is modified by apolipoprotein E (APOE) genotype. METHODS: A community-based sample of 111 adults with cytogenetically confirmed DS (34 to 71 years of age) was ascertained through the New York State Developmental Disabilities system. A semistructured interview with caregivers and review of medical records was used to ascertain the presence or absence of AD. APOE genotyping was carried out without knowledge of the subject's medical history or clinical diagnosis. RESULTS AND CONCLUSIONS: Both male gender and the presence of an APOE epsilon4 allele were associated with an earlier onset of AD. Compared with women, men with DS were three times as likely to develop AD. Compared with those with the APOE 3/3 genotype, adults with DS with the 3/4 or 4/4 genotypes were four times as likely to develop AD. No individual with an APOE epsilon2 allele developed AD. No evidence of interaction of sex and APOE genotype was found in risk of AD. The higher risk of AD in men may be related to differences in hormonal function between men and women with DS that are distinct from those in the general population.

Accuracy of e-codes assigned to emergency department records.

OBJECTIVE: To determine the accuracy of ICD-9-CM external-cause-of-injury codes (e-codes) assigned to the medical records of injured patients treated in an ED and released. METHODS: A comparison was made of routine coding and expert recoding of medical records generated in the ED for a convenience sample of patients treated for injuries within 24 hours of injury occurrence and subsequently released from the ED. The medical record was handwritten and subsequently coded by three medical records coders (MRCs). The e-coded charts were sent to an external medical record consultant (expert), who was blinded to the codes previously assigned. The expert reading was used as the criterion standard. Accuracy was measured using a kappa statistic, and errors were described. RESULTS: Of 126 available patient charts, 108 (85.7%) were assigned e-codes by MRCs. The expert assigned two codes to (double-coded) 67 patients, while the MRCs double-coded only one patient. The additional code was usually a "place of occurrence code." In 60 cases (55.6%), the expert code exactly matched the MRC code; kappa = 0.462. Of the 48 mismatches (44.4%), 20 (41.7%) were e-coded in the wrong category, 20 (41.7%) were e-coded in the correct category but with incorrect specificity of information, either too specific or not specific enough, and eight (16.6%) had combined coding errors. CONCLUSION: The accuracy of e-codes assigned to ED records was moderate in this single institution analysis. Errors were predominantly related to the specificity of the code, but some e-codes were in the wrong category. There are implications for injury surveillance and research. E-code assignment must be standardized and applied uniformly to obtain accurate codes. Automation of e-coding could improve accuracy and consistency of codes. National and international epidemiologic studies of cause of injury among ED patients will be severely hampered until e-code assignment can be better standardized.

Fourier transform infrared spectroscopy of dysplastic, papillomavirus-positive cervicovaginal lavage specimens.

To assess the utility of a new, rapid, economical procedure that may prove valuable in cervical screening, Fourier transform infrared (ir) spectroscopy was performed on 25 cervicovaginal lavage specimens from women referred for colposcopy on the basis of a cytological abnormality detected on their Pap smear and whose lavage specimen was positive for human papillomavirus. Of the 18 classed as CIN I or less by histopathology, 11 showed band frequencies that deviated only slightly from spectra that characterize normal cervical cells and 3 of 5 "atypia" specimens had spectra identical to normal. Two of 3 classed as CIN II had spectra only slightly more abnormal to these 11. In the case of 2 graded as CIN I, several bands were similarly altered in the direction of the pattern seen for 4 CIN III specimens. A further CIN I sample gave a spectrum that was even further shifted toward the latter and the remaining CIN I sample had a pattern that matched the 4 CIN IIIs. The most obvious change in each of the CIN IIIs was an additional peak at 972 cm-1 and this has been suggested as a key indicator for malignancy. One of the 3 CIN IIs had this peak. Other characteristic spectral changes were seen as well in the CIN III samples. High-risk HPV18 was present in 3 of the CIN III samples, as well as in one specimen classed as atypia, but having an abnormal ir spectrum. Low-risk HPV 6 or 11 was seen along in samples with a normal or slightly abnormal ir spectrum, but never in those that showed an ir pattern that was abnormal. The current study has therefore shown complete concordance between ir spectral findings and histopathology result in the case of CIN III specimens, but less precise matching for other grades of CIN. The spectral differences revealed by ir spectroscopy are likely to characterize molecular abnormalities in cervical cells during progression to cancer and may therefore have potential in assisting with clinical decision making. More studies will, however, be required to establish the place of this technique in cervical screening.

Assessment of HIV status using the polymerase chain reaction in antibody-positive patients and high-risk antibody-negative haemophiliacs.

The polymerase chain reaction (PCR) was used to identify the presence of DNA sequences homologous to HIV-1 in the buffy-coat leukocytes of antibody-positive and antibody-negative individuals in a haemophiliac population. The presence of HIV sequences was demonstrated in all of the antibody-positive haemophiliacs with the exception of one patient who was repeatedly negative. None of the seronegative haemophiliacs gave an overall positive result, although there were clear differences between this population and the negative controls who were examined. We conclude that, in our hands, PCR represents a reliable test which represents a useful diagnostic advance in HIV medicine.

Automated polymerase chain reaction for papillomavirus screening of cervicovaginal lavages: comparison with dot-blot hybridization in a sexually transmitted diseases clinic population.

The aim of the present study was to compare the recently developed polymerase chain reaction (PCR) technique with conventional dot-blot DNA hybridization for human papillomavirus (HPV) detection. Cells were collected by cervicovaginal lavage from a study group of 109 women attending a sexually transmitted diseases clinic. Using a machine that we developed for alternation of temperature cycles, HPV was detected in 51% of patients by PCR. By dot-blot hybridization, 44% of the patients were positive. Concordance of combined positive and negative results between PCR and dot blot was 69%. The greater sensitivity of PCR may have accounted for 19% of specimens that were PCR positive but dot-blot negative. Unexpectedly, however, 12% of specimens were dot-blot positive but negative by PCR, and several specimens were discordant for type of HPV. Both HPV DNA tests agreed with cytology in 41% of women, and in 33% cytology was negative in the face of positive PCR and dot blot. Concordance of cytology with just PCR was 59%, and only with dot blot was 56%. Cervicography agreed with both HPV DNA tests in 41% of patients, with PCR alone in 55%, and with dot blot alone in 58%. Biopsy results did not reveal a strong correlation between histopathological criteria of HPV infection and detection of HPV DNA by either PCR or dot-blot hybridization. Thus the present study has shown that PCR is a slightly more sensitive indicator of HPV infection than dot-blot hybridization. Agreement of HPV DNA results with conventional screening tests was not strong, an observation consistent with many comparative studies by others. In conclusion, PCR is slightly more sensitive than DNA hybridization for detection of HPV, it can be used in conjunction with specimen collection by gentle lavage of the cervicovaginal epithelium, and the possibility remains that it may prove suitable as a screening test.

Randomised controlled trial of recombinant human interferon -alpha A for chronic active hepatitis B.

The efficacy of interferon treatment for Australian patients with chronic active hepatitis B (CAH-B) was assessed by a three-centre randomised controlled trial in Sydney and Brisbane. Thirty patients (29 with histologically-proven CAH-B with and without cirrhosis and one with chronic persistent hepatitis) were allocated to receive either thrice weekly intramuscular injections of recombinant human leucocyte interferon -alpha A (either 2.5, 5.0 or 10.0 million units/m2) for six months followed by 12 months of observation, or to be observed for 18 months without active treatment. Three of 23 treated patients but none of seven controls underwent clinical, biochemical and histological resolution of their disease with loss of HBsAg, HBeAg and HBV-DNA from serum. An additional six treated and two control patients underwent a sustained partial remission of their disease. This was characterised by resolution of symptoms and serum aminotransferase abnormalities in association with seroconversion from HBeAg positive to negative, loss of HBV-DNA from serum but persistent hepatitis B surface antigenaemia. In such patients, there was significant improvement in histological appearances but some necroinflammatory activity remained and fibrosis was unchanged. Although total response rates were similar in treated and control subjects, they appeared to occur earlier after interferon treatment. Treatment with interferon was associated with predictable but minor side effects that usually did not necessitate dose reduction and rarely compromised the patient's life style. Interferon is thus a feasible treatment for CAH-B. Complete responses occurred only in treated patients and partial responses appeared to occur earlier in treated than in untreated patients. However, differences in the partial response rate at 18 months were not significant and seroconversion from HBeAg positive to negative was not associated with complete histological resolution of disease activity. Hence, while interferon is a promising agent for treatment of CAH-B, efforts must continue to define more optimal treatment regimes and to identify those patients most likely to respond to this agent.

The effect of concurrent human immunodeficiency virus infection on chronic hepatitis B: a study of 150 homosexual men.

To determine the influence of concurrent human immunodeficiency virus (HIV) infection on chronic hepatitis B virus (HBV) infection, 150 male homosexual chronic hepatitis B surface antigen (HBsAg) carriers were studied. Of these, 82 subjects (55%) tested positive for antibodies to HIV. They were more likely to express hepatitis B "e" antigen (HBeAg) (P less than .001) and HBV-DNA (P less than .0005) in serum than were HIV-seronegative individuals. However, the degree of immune suppression did not influence HBeAg-HBV-DNA expression. In HBeAg-seropositive subjects, concurrent HIV infection was associated with lower serum alanine transferase levels (P less than .001). This effect increased with the degree of immune suppression as determined by CD4+ lymphocyte counts. Conversely, in patients negative for HBeAg, there was a weak trend towards higher alanine transferase levels with concurrent HIV. This study suggests that chronic hepatitis B may be less severe when accompanied by HIV infection; however, greater viral replication may make it more contagious and resistant to antiviral therapy. These data support an immune-mediated pathogenesis for hepatitis B and have implications for its control.

Polymerase chain reaction for fast, nonradioactive detection of high- and low-risk papillomavirus types in routine cervical specimens and in biopsies.

A polymerase chain reaction (PCR) procedure capable of amplifying specific DNA sequences by up to a millionfold was developed for detection of infection by human papillomaviruses (HPVs) of low (HPV6, HPV11) or high (HPV16, HPV18, HPV33) oncogenic potential. For high-risk HPVs the region chosen was within the E6 open reading frame, which can become integrated into genomic DNA. A region corresponding to this was chosen for low-risk HPVs. After repeated cycles of specific oligonucleotide-primed extension of viral DNA with Klenow or thermophilic DNA polymerase, the type of HPV present was then determined on the basis of the size of the ethidium-bromide-stained band visible after polyacrylamide gel electrophoresis: for HPV6 or 11 the band was approximately 120 bp, for HPV 16 or 33 it was approximately 200 bp, and for HPV18 it was approximately 100 bp. Specific hybridization to the relevant band was seen using radioactive or nonradioactive (alkaline-phosphatase-linked) target oligonucleotide probes. Using the PCR method, we have determined, within as little as a few hours, the infection status of a variety of clinical specimens, including cervical scrapes and lavages, anal scrapes, and anogenital biopsies. The PCR steps can be automated, adding to the potential of PCR for widespread use in the detection of HPV, which is becoming increasingly popular in cervical screening.

Papillomavirus and cervical cancer: a clinical and laboratory study.

It is now widely accepted that HPV types 16, 18, 31, and 33 are associated with the development of high grade intraepithelial neoplasia and malignant lesions in the cervix. On this basis, the identification of HPV types in cervical scrape samples has been advocated as a supplement to cytological screening tests. However, little is known of the distribution of the virus at different sites in the lower female genital tract or of how this distribution may change during the natural course of HPV infection. In this survey, HPV DNA dot hybridizations and, in some instances, Southern blot hybridizations with mixed HPV 6/11 and 16/18 probes were undertaken to detect HPV DNA in cervical scrapes and biopsies of the cervix, vagina, and vulva. A total of 92 women attending a Sydney hospital were screened: 59 of these patients had cervical disease, either invasive cervical carcinoma (CaCx) or cervical intraepithelial neoplasia (CIN), grades I-III. A group of 33 women who lacked evidence of cervical abnormalities served as controls. HPV DNA, predominantly type 16/18, was detected in the cervical biopsies of 96% of the CaCx patients, 80% of the CIN III patients, and 65% of the CIN I-II patients. In contrast only 9% of the cervical biopsies from the control group contained detectable HPV 6, 11, 16, or 18 DNA. A high proportion of the women with cervical abnormalities had evidence of concurrent vaginal and/or vulval papillomavirus involvement. The significance of these findings for routine screening and subsequent management of patients with HPV-associated cervical disease is discussed.

Human papillomavirus: the untreated male reservoir.

Human papillomavirus infection currently is accepted as a major factor in the etiology of carcinoma of the cervix, vagina and vulva. While the nature of genital human papillomavirus infection in women is well documented, detailed knowledge of the disease in the male partners is lacking. Therefore, a prospective study was done to define the disease in the genitals of heterosexual men and to formulate an appropriate plan of management. We studied 52 men during an 8-month period for evidence of genital human papillomavirus infection. The majority of the lesions occurred on the shaft of the penis and on the foreskin of uncircumcised men. Deoxyribonucleic acid dot hybridization of biopsies of macroscopic warts and suspected warty lesions with mixed human papillomavirus types 6 and/or 11 and 16 and/or 18 probes revealed that 87 and 55 per cent, respectively, were positive for 1 or more of these human papillomavirus types. Of the macroscopic warts and subclinical lesions 52 and 29 per cent, respectively, contained the more potentially oncogenic types 16 and/or 18, either alone or in combination with types 6 and/or 11. There was no evidence of human papillomavirus in any semen or urine sample but human papillomavirus deoxyribonucleic acid sequences were detected in 31 per cent of the biopsies from apparently normal penile skin and in 18 per cent of the urethral mucosal biopsies. We suggest that management of human papillomavirus infection be directed toward prevention and contact screening, together with ablation of localized lesions.

Are specimens with "at risk" biochemical profiles more likely to be infectious for hepatitis B virus?

The potential infectivity of 640 plasma specimens with various biochemical profiles was directly assessed by hepatitis B virus (HBV) DNA dot-hybridization. We found that specimens with "at risk" biochemical profiles typical of various forms of liver disease were not significantly more likely to carry HBV than the general patient population. Specimens containing HBV cannot be distinguished from non-infectious specimens by any simple biochemical tests, including aminotransferases and bilirubin. The only predictive feature of HBV-positive samples was that they were more likely to be labeled as "biohazardous" by the medical staff, but even this was not always the case.