Effect of periconceptional nutrition on the growth, behaviour and survival of the neonatal lamb.

Periconceptional nutrition (PCN) can influence foetal hypothalamo-pituitary adrenal (HPA) axis function and alter cortisol secretion with possible consequences for maturation and growth of major organs, gestation length and behaviour. We examined effects of PCN on phenotype and survival of the neonatal lamb in 466 Merino ewes allocated to treatments providing 70%, 100% and 150% respectively, of maintenance requirements for 17 days prior and 6 days after insemination. Gestation length and birth weight for lambs in PCN treatment groups was similar (P > 0.05) but low PCN decreased the size of the neonate (crown-rump-length and metacarpal length P < 0.05). A subset of lambs euthanased at 5 days of age further showed that low PCN decreased the amount of peri-renal fat (P < 0.05) and increased liver mass (P < 0.05) while high PCN increased neck thymus and ovary mass (P < 0.05). Neonatal lambs from low PCN ewes returned faster to their mothers after release (P < 0.05) and contacted the udder in the shortest time (P < 0.05). Significant interactions between PCN treatment and sex (P < 0.05) and between PCN treatment and ewe age (P < 0.05) were also observed for time lambs took to follow the ewe. Survival of lambs was similar but potential differences may have been masked by favourable weather conditions. In conclusion, this study provides evidence of significant changes in lamb growth and development dependent on PCN and, for the first time, links these changes with significant changes in behaviour of the neonate. The impact of these effects on lamb survival and potential reproductive capacity of female offspring remains to be determined.

Electromagnetic fields and breast cancer on Long Island: a case-control study.

The EMF and Breast Cancer on Long Island Study (EBCLIS) was a case-control study designed to evaluate the possible association between exposure to electromagnetic fields (EMFs) and breast cancer. Eligible women were participants in the population-based Long Island Breast Cancer Study Project, were under 75 years of age at enrollment, were residentially stable, and were identified between August 1, 1996, and June 20, 1997. Of those eligible, 576 cases and 585 controls participated in EBCLIS (87% and 83%, respectively). In-home data collection included various spot and 24-hour EMF measurements, ground-current magnetic field measurements, wire mapping of overhead power lines servicing the home, and an interview. Odds ratios and 95% confidence intervals were based on multivariate logistic regression analyses. All odds ratios were close to 1 and nonsignificant. For the highest quartile of 24-hour EMF measurements, the odds ratio was 0.97 (95% confidence interval (CI): 0.69, 1.37) in the bedroom and 1.09 (95% CI: 0.78, 1.51) in the most lived-in room. For the highest exposure category of ground-current measurements, the odds ratio was 1.13 (95% CI: 0.88, 1.44) in the bedroom and 1.08 (95% CI: 0.85, 1.38) in the most lived-in room. These and other EBCLIS results agree with other recent reports of no association between breast cancer and residential EMF exposures.

Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial.

OBJECTIVE: To determine whether post Lyme syndrome (PLS) is antibiotic responsive. METHODS: The authors conducted a single-center randomized double-masked placebo-controlled trial on 55 patients with Lyme disease with persistent severe fatigue at least 6 or more months after antibiotic therapy. Patients were randomly assigned to receive 28 days of IV ceftriaxone or placebo. The primary clinical outcomes were improvement in fatigue, defined by a change of 0.7 points or more on an 11-item fatigue questionnaire, and improvement in cognitive function (mental speed), defined by a change of 25% or more on a test of reaction time. The primary laboratory outcome was an experimental measure of CSF infection, outer surface protein A (OspA). Outcome data were collected at the 6-month visit. RESULTS: Patients assigned to ceftriaxone showed improvement in disabling fatigue compared to the placebo group (rate ratio, 3.5; 95% CI, 1.50 to 8.03; p = 0.001). No beneficial treatment effect was observed for cognitive function or the laboratory measure of persistent infection. Four patients, three of whom were on placebo, had adverse events associated with treatment, which required hospitalization. CONCLUSIONS: Ceftriaxone therapy in patients with PLS with severe fatigue was associated with an improvement in fatigue but not with cognitive function or an experimental laboratory measure of infection in this study. Because fatigue (a nonspecific symptom) was the only outcome that improved and because treatment was associated with adverse events, this study does not support the use of additional antibiotic therapy with parenteral ceftriaxone in post-treatment, persistently fatigued patients with PLS.

An educational approach to improving physician breast cancer screening practices and counseling skills.

A multifaceted, individualized, physician education program designed to increase the breast cancer screening practices of community-based primary care physicians is described and the results are evaluated. Community-based surveys identified primary care providers with breast cancer screening educational needs who were assigned, using a factorial design, to an intervention or control condition. The sample included 154 control and 128 intervention physicians. The intervention consisted of a 1-2h in-office training program and/or self-study workbook. Self-reported overall breast cancer screening need scores improved for a greater proportion of intervention than control physicians, particularly those receiving the in-office intervention (P=0.03). Clinical breast examination (CBE) need declined (P=0.01); use of provider reminder systems increased (P=0.02); preparedness to counsel about CBE (P=0.04) and recognition that age is an important risk factor for breast cancer (P=0.02) improved in more intervention compared to control physicians.

Low levels of cell cycle inhibitor p27kip1 combined with high levels of Ki-67 predict shortened disease-free survival in T1 and T2 invasive breast carcinomas.

Breast cancer is the second leading cause of cancer death in North American women. There is considerable need for better prognostic markers to identify those subsets of patients who would benefit from more aggressive therapy because their tumors show an increased risk of poor clinical behavior. p27kip1 is an important inhibitor of the cell cycle that acts by binding and inactivating cyclin-dependent kinases (CDKs). The aim of this study was to determine the prognostic value of loss of p27 protein in invasive breast cancer. We performed an immunohistochemical study of 147 patients with T1 and T2 invasive breast cancers and compared survival in the high p27 expressing group with that of the low p27 expressing group. On univariate analysis comparing tumor size, nodal status, Ki-67, c-erbB-2, p53 and estrogen receptor, low or absent p27kip1 is a strong predictor of reduced disease-free survival. Importantly, on multivariate analysis, the combined effect of low p27 with high Ki-67 is a stronger predictor of reduced disease-free survival than either marker alone. This simple, reliable and inexpensive assay, particularly when used in combination with Ki-67, improves the ability to predict disease recurrence and could become a useful adjunct of breast cancer evaluation to better identify high risk patients.

A method for detecting current temporal clusters of toxic events through data monitoring by poison control centers.

BACKGROUND: Poison control centers have become a widely recognized source of data for chemical and other environmental exposures. Concurrently, increased emphasis on early identification of temporal clustering of toxic exposures has stimulated development of sensitive statistical methods to detect clusters at the time of occurrence. METHOD: This paper discusses the scan test which has been applied to retrospective data to detect carbon monoxide poisoning clusters. We propose a more sensitive method, based on the binomial distribution to detect current clusters of only 1 or more days duration during the ongoing data collection and monitoring process. RESULTS: Applied to daily carbon monoxide poisoning incidence data on which the scan test has been applied, the new test for current clustering evidently has much more power. For retrospective identification of previous clusters lasting more than 1 day, the scan test is recommended. However, for previous daily clusters, a third method is recommended. CONCLUSION: Certain toxic events such as carbon monoxide poisoning occasionally occur in daily clusters, or in clusters lasting a few days. Timely detection of clusters requires application of early intervention strategies fostered by sensitive statistical methods of detection, as presented here.

Magnetic field exposure assessment: a comparison of various methods.

The accurate and valid measurement of personal exposure to magnetic fields poses a major challenge for epidemiologic studies. When considering the various methods to assess exposure, it is unclear which measures are most relevant for studies of human disease, if any. Given these uncertainties, the Electromagnetic Fields and Breast Cancer on Long Island Study (EBCLIS) undertook a pilot study to develop the data collection protocol for a case-control study of breast cancer and magnetic fields. The pilot study used and compared various methods to assess residential exposures to magnetic fields, and related these measures to personal exposures. It included 31 women without breast cancer (mean age, 63+/-7 yr) who lived in their present homes for at least 15 yr. The pilot study consisted of an in-home interview, spot and 24-h magnetic field waveforms and broadband recordings, ground currents, wire coding, and personal 24-h broadband measurements. From the regression analyses, the model that best predicted personal magnetic field exposures included 24-h measurements in the bedroom and in the most lived-in room; as well as ground current test loads taken at the center of this most lived in room (r(2)=86%). The addition of other variables in this regression model yielded only small and nonsignificant increases in r(2). As a direct result of this pilot, EBCLIS will include ground current measurements in its protocol, which have not previously been collected as part of an epidemiologic study. Ground currents may be important because they may be richer in 180 Hz components than are the other currents in a power system. EBCLIS will have the opportunity to examine the ground-current hypothesis in the context of female breast cancer.

CCR5 genotype and resistance to vertical transmission of HIV-1.

A human gene has been identified that affects susceptibility to HIV-1 infection. The gene codes for CCR5, the coreceptor for macrophage-tropic strains of HIV-1. Individuals who are homozygous for a deleted, mutant form of the gene, delta32, display a high degree of natural resistance to sexual and parenteral transmission of HIV-1. To investigate whether delta32 plays a role in vertical transmission, we determined the CCR5 genotype of 552 children born to infected mothers in the United States and correlated the genotypes with HIV-1 infection status. Of these children, 13% were white, 30% Latino, and 56% African American, reflecting the ethnic makeup of infected women in the United States. The delta32 gene frequency varied among these groups, ranging from 0.08 in whites to 0.02 in both Latinos and African Americans. Approximately 27% of the children in each ethnic group were infected. Four children were identified as delta32 homozygotes, two uninfected whites (3.77%) and two uninfected Latinos (1.68%). None of the infected children displayed the delta32 homozygous genotype. Among Latinos and whites, the number of uninfected children who carried the homozygous delta32 mutation was significantly greater than that predicted by the Hardy-Weinberg equilibrium (p < .001 for Latinos, p = .044 for whites). This association was noted in Latino and white children whose mothers were either treated or untreated with zidovudine. These data document the occurrence of the homozygous delta32 genotype among children of HIV-1-infected mothers and suggest that this mutant genotype may confer protection from mother-to-child transmission of HIV-1. They also suggest that sexual, parenteral, and vertical transmission all involve processes that use CCR5 as a coreceptor for primary HIV-1 infection. Therefore, blocking the CCR5 receptor may provide an additional strategy to prevent HIV-1 vertical transmission.

Increased serum stromelysin-1 levels in systemic lupus erythematosus: lack of correlation with disease activity.

OBJECTIVE: In view of evidence that stromelysin-1 and collagenase-1 are involved in tissue injury in inflammatory joint diseases, we sought to determine whether matrix metalloproteinases (MMP) are implicated in the pathophysiology of systemic lupus erythematosus (SLE). METHODS: Seventy-three patients with SLE and 39 healthy subjects were evaluated. Serum levels of MMP and tissue inhibitor of metalloproteinases were measured. RESULTS: Serum stromelysin-1 levels were significantly increased in patients with SLE (416+/-252 ng/ml) compared to healthy subjects (125+/-93 ng/ml). No correlation between serial measurements of stromelysin-1 and disease activity in SLE patients was noted. Serum collagenase-1, gelatinase A, and TIMP-1 levels were not increased in SLE. CONCLUSION: Serum concentrations of stromelysin-1 are increased in SLE, but the levels do not correlate with disease activity.

Hypertension in nursing home patients.

There have been few studies of hypertension in nursing home patients. To assess the prevalence, demographic characteristics, comorbidity and drug therapy in hypertensive nursing home patients compared with those who are normotensive, we reviewed all medical charts of patients in three nursing home facilities. Of the 804 patients, 355 (44.2%) have hypertension. Calcium channel blockers were the most frequently prescribed anti-hypertensive (30.3%) and together with diuretics (28.4%) and ACE inhibitors (27.7%) account for more than 85%. Hypertensive patients take more cardiac, hypoglycaemic, and analgesic drugs (P = <0.001, <0.001, and 0.004, respectively) than those who are normotensive. Overall patients take an average of 8.68 medications daily. In hypertensive patients, the average number of comorbid conditions (excluding hypertension) is 5.02 compared with 3.23 in normotensive patients. Hypertension is significantly associated with diabetes, heart disease, cerebrovascular disease, neoplasms, endocrine disorders, gastrointestinal diseases, psychiatric disorders, dementia, other central nervous system diseases, skin problems, blood diseases and inversely with hip fracture. Blood pressure control (<140/90 mm Hg) is achieved in 88.8%, is not related to age and is significantly more frequent in males than females (91.8% vs 82.6% P = 0.025). The problem of hypertension in nursing home patients is complex and has received insufficient study. Since studies demonstrating benefit from anti-hypertensive therapy in the elderly excluded the very elderly and those with significant comorbid conditions, additional research is needed.

RhDNase I aerosol deposition and related factors in cystic fibrosis.

To identify factors influencing lung dose of aerosolized recombinant human deoxyribonuclease (rhDNase I), we used gamma camera and filter techniques to measure deposition in 15 clinically stable patients with cystic fibrosis (CF) (five males and 10 females, age 6-31 yr, mean 16.9) who were on chronic daily therapy. Total and regional deposition were correlated with breathing pattern, pulmonary function, demographic factors, and disease severity. In addition, the effects of each patient's measured lung dose on pulmonary function was estimated by stopping the drug and observing changes in spirometry over a 2-wk follow-up period. After discontinuance of the drug, all patients reported worsening of dyspnea and difficulty producing sputum. There was a significant decrease in FEV1 (% predicted, mean +/- SE, 86.9% +/- 5.57 to 77.8% +/- 5.73, p < 0.005), but all patients completed the study. In some patients, as much as 48% of the deposited aerosol was found in the pharynx (range 0.0 to 0.30 mg, mean 0.089 mg +/- 0.029), and pharyngeal deposition correlated negatively with tidal volume (r = -0.696, p < 0.006) and age (r = -0.743, p < 0.005). For the lungs, deposition ranged between 0.16 mg and 0.78 mg of the 2.5 mg nebulizer dose (mean 0.47 +/- 0.04 mg) and correlated negatively with FEV1 (% predicted, r = -0.611, p = 0.0152). However, the spirometric decrements following cessation of therapy did not correlate with the lung dose of the drug. Analysis of regional deposition within the lungs indicated a wide range of distribution between central and peripheral zones. In conclusion, the deposition pattern of rhDNase I aerosols in patients with CF is largely influenced by respiratory physiology, which itself depends upon age and severity of lung disease. As the patients grow there is a decrease in upper airway deposition and more particles are presented to the lungs where those patients with more airways disease have enhanced pulmonary deposition. Upper airway deposition of rhDNase I is significant, especially in younger patients, and may be related to laryngeal side effects.

Cerebrospinal fluid findings in children with Lyme disease-associated facial nerve palsy.

OBJECTIVE: To determine the relative frequency of abnormal cerebrospinal fluid (CSF) findings in children with Lyme disease-associated facial nerve palsy. DESIGN: A clinical series. A prospective evaluation was undertaken of the condition of children seen between 1988 and 1996 at a single medical center in a Lyme disease endemic area. PATIENTS: Forty children (24 boys and 16 girls, aged 3-19 years) with new onset facial nerve palsy who met the Centers for Disease Control and Prevention case definition of Lyme disease. INTERVENTIONS: Neurologic examinations. Cerebrospinal fluid analysis. MAIN OUTCOME MEASURES: Rates of abnormal CSF findings: white blood cell count, protein level, and Borrelia burgdorferi-specific CSF assays. RESULTS: Cerebrospinal fluid white blood cell count, protein level, or both were abnormal in 27 (68%) of the children. Thirty-six (90%) of the 40 children had a CSF abnormality consistent with central nervous system infection or immune involvement by B burgdorferi. Of the 22 children with CSF pleocytosis, only 7 (32%) had headache and none had meningeal signs. CONCLUSIONS: Most children with Lyme disease-associated facial nerve palsy have CSF abnormalities. Our studies indicate that, in endemic areas, facial nerve palsy in children may be a marker of Lyme disease and occult meningitis. When Lyme disease is suspected, CSF should be examined; in some cases, it may be helpful to expand beyond routine CSF studies to look at a battery of B burgdorferi-specific assays.

Effect of high and intermediate ligation on survival and recurrence rates following curative resection of colorectal cancer.

PURPOSE: How wide excision of the regional mesenteric lymphatic drainage influences survival and recurrence rates following curative resection of colorectal cancers needs to be more clearly defined. METHODS: A series of 2,409 consecutive patients undergoing curative resections with detailed descriptions of the operative procedure and the lymphatic drainage in the surgical specimens provided a unique database to provide meaningful comparisons between high and intermediate level ligation. RESULTS: High ligation made a statistically significant difference in the death rate from recurrent cancer in patients with Dukes B, AC, and C1 cancers. Based on cancer-related deaths, the probability of five-year survival rate increased with high ligation from 73.9 to 84 percent in patients with Dukes B colon cancers and from 49.0 to 58.6 percent in patients with Dukes C1 colon cancers. In patients with Dukes AC cancers, high ligation increased the five-year survival rate from 64.9 to 80.4 percent. In patients with Dukes C cancers with involved middle level lymph nodes, the five-year survival rate increased from 20.5 to 33 percent and the death rate from recurrent cancer fell from 77 to 59 percent with high ligation. In patients with Dukes AC cancers with four or less involved nodes, the five-year survival rate was increased by high ligation from 50 to 78.6 percent in the colon and from 40 to 71.4 percent in the rectum. When more than four lymph nodes were involved, the survival rate was unaffected by the level of ligation. Although high ligation reduced distant recurrences, its greatest effect was observed in the incidence of local and suture line recurrence. The five-year local recurrence rate in patients with Dukes B who were managed by high ligation was 11.4 percent compared with 18.7 percent with intermediate ligation. In patients with Dukes C cancer, the local recurrence rate was 20.8 percent five years following high ligation compared with 30.7 percent for intermediate ligation. In patients with Dukes B cancer who were undergoing curative resections, the incidence of suture line recurrence was 3.9 percent following high ligation compared with 5.5 percent following intermediate ligation. In patients with Dukes C cancer, the incidence of suture line recurrence was 6.9 percent with high ligation and 11.4 percent with intermediate ligation. CONCLUSION: In certain stages of colorectal cancer, the more extensive resection of mesenteric lymphatic drainage associated with high ligation appears to increase the survival rate and reduce the recurrence rate following curative resections.

Withdrawal of antihypertensive medications.

BACKGROUND: Pharmacologic treatment of hypertension reduces risks of stroke, congestive heart failure, renal failure, and mortality, but whether medications, once begun, need to be continued for life is uncertain. METHODS: Several search strategies on MEDLINE using key words "medication," "withdrawal," "discontinuance," and "therapy" in several combinations, nested within "hypertension," were not productive. Accordingly, articles known to the authors and citations within them were reviewed. A survey of a random sample of members of the New York Academy of Family Practice was conducted to ascertain current practice of practicing physicians. RESULTS: Eighteen studies of antihypertensive medication withdrawal were located and all were reviewed. In 12 trials average success rates of 40.3 percent after 1 year of follow-up and 27.7 percent after 2 years were achieved. In six studies limited to elderly patients, an average success rate of 26.2 percent was obtained for periods of 2 or more years. The trials, however, were heterogeneous in design, patient selection criteria, and follow-up. The survey of family physicians indicated that 79.1 percent attempt withdrawal of antihypertensive medications in hypertensive patients whose blood pressure is controlled and who are without symptoms from medication. CONCLUSIONS: We conclude that successful withdrawal of antihypertensive medications can have substantial benefits with few or no adverse consequences and might be successful in about one third of patients. Additional research is required to substantiate rates of successful medication withdrawal, to define the best method of withdrawing medications, and to delineate characteristics of patients in whom withdrawal is most likely to succeed.

Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia.

Brain structural deviation is known to be present in chronic patients with schizophrenia when compared with normal age-matched individuals. While the assumption is that these differences are based on a neurodevelopmental disturbance, whether they are static or continue to change throughout the disease process remains unknown. The following report describes a prospective follow-up study of first episode cases of schizophrenic illness. Analyses of MRI evaluations on an approximate annual basis for a minimum of four years are presented on 50 patients and 20 controls. Computer-assisted image analysis measuring the volume of several brain regions, using the program ANALYZE (Mayo Clinic), was performed on all scans. Patients were compared with controls for the rate of change over time in size of structures. No differences were found for the volumes of the caudate nucleus, temporal lobes, or hippocampus; and no changes in the degree of cerebral laterality were detected. However, there was a significant difference in the rate of change in the overall volumes of left and right hemispheres (P < 0.0004 and 0.001, respectively), right cerebellum (P < 0.02) and area of the isthmus of the corpus callosum (P < 0.05). The left cerebral ventricle had significantly greater enlargement over time when measured on coronal slice sequences (P < 0.02), but was not detected by axial views. These findings suggest that a subtle active brain process may be continuing through the first few years of a schizophrenic illness causing greater than the normal adult cortical deterioration. Further studies using other methods of image analysis and over a longer period of time are needed to determine the course and nature of this biologic process.

Maternal serum vitamin A levels are not associated with mother-to-child transmission of HIV-1 in the United States.

HIV-1 transmission from mother to child has been associated with maternal vitamin A status in studies of women living in Africa. This finding has raised the question of whether vitamin A supplementation might help reduce transmission in the United States as well as worldwide. In industrialized nations, however, both the vitamin A nutritional status of HIV-1-infected pregnant women and the association of vitamin A levels with vertical transmission were unknown. Furthermore, vitamin A is teratogenic, and supplements during pregnancy have caused birth defects. To investigate whether maternal serum levels of vitamin A (retinol) and three other micronutrients correlate with vertical transmission of HIV-1 in the United State, we studied 95 HIV-1-infected pregnant women and followed their infants to determine whether transmission occurred. Sera were obtained during the third trimester of pregnancy from 95 HIV-1-infected women living in the New York and Los Angeles metropolitan areas. The two cohorts were established to study vertical transmission of HIV-1 and to reflect the racial, ethnic, and socioeconomic status of HIV-1-infected in women in the United States. We measured serum levels of vitamin A (retinol) and three other micronutrients, vitamin E (alpha-tocopherol), beta-carotene, and lycopene, in the mothers using reverse-phase high-performance liquid chromatography and determined the HIV-1 infection status of their infants using virus cultivation and polymerase chain reaction. Sixteen of the 95 women transmitted HIV-1 to their infants. Statistical analysis of the data indicated that low maternal serum retinol levels during the third trimester of pregnancy were not associated with mother-to-child transmission of HIV-1. None of the women had retinol levels so low as to have clinical symptoms of vitamin A deficiency. The serum levels of alpha-tocopherol, beta-carotene, and lycopene, three micronutrients that act as antioxidants and enhance immune function, were also measured. Statistical analysis of the data revealed no association of the levels of these three micronutrients with vertical transmission of HIV-1. Analysis of the data obtained from 95 women in the United States indicates that vitamin A deficiency is rare, and serum retinol levels are not associated with risk of vertical HIV-1 transmission. In view of the teratogenic effects of vitamin A when taken as a supplement during pregnancy, pregnant HIV-1-infected women living in nations where vitamin A deficiency is not a public health problem should not be advised to take extra vitamin A supplements.

Alcohol abuse and stage of HIV disease in intravenous drug abusers.

Our objective was to identify factors that might correlate with human immunodeficiency virus (HIV) disease stage in intravenous drug abusers (IVDA). Particular attention was given to alcohol abuse. We accordingly explored in a cross-sectional study the relation between stage of HIV disease and age, sex, needle sharing, ethnicity, self-reported history of alcohol consumption and CAGE scores. IVDA from a single municipal hospital were subdivided into three groups according to HIV disease status. Group 1 comprised 42 individuals with AIDS; group 2 comprised 114 who were HIV positive but without AIDS; and group 3 comprised 52 who were HIV negative. Information on alcohol consumption and CAGE responses were obtained by questionnaire and interview. Discriminant analysis indicated that alcohol abuse, assessed either by self-reported consumption or by CAGE scores, was significantly more common in the AIDS group than in either the HIV positive or the HIV negative groups, when controlled for age, sex, and needle sharing status. The relative risk of AIDS was 3.8 times higher in the heavy drinkers than in moderate drinkers. Needle sharing was also more common in the AIDS group than in the HIV positive or HIV negative groups when the other factors were controlled for. AIDS was more common in black than white IVDA, and this increased frequency did not appear related to alcohol consumption since the distribution of heavy drinkers within each category of HIV disease did not differ within the ethnic groups. These data indicate that a history of heavy alcohol consumption is more common in IVDA with AIDS than in IVDA at earlier stages of HIV disease.