Urine dicarboxylic acids change in pre-symptomatic Alzheimer's disease and reflect loss of energy capacity and hippocampal volume.

Non-invasive biomarkers will enable widespread screening and early diagnosis of Alzheimer's disease (AD). We hypothesized that the considerable loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD. We examined urine dicarboxylic acids (DCA) of carbon length 3-10 to reflect products of oxidative damage and energy generation or balance that may account for changes in brain function in AD. Mean C4-C5 DCAs were lower and mean C7-C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4-C5 DCAs were lower and mean C7-C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of early AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aß42, while C7-C10 DCAs negatively correlated with CSF Aß42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7-C10 DCAs with hippocampal volume (p < 0.01), which was not found in the occipital volume. Urine measures of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau. These data suggest that urine measures of increased lipoxidation and dysfunctional energy balance reflect early AD pathology from brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness or monitor the efficacy of therapies in clinical trials.

Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure.

Adeno-associated virus serotype 1 (AAV1) has many advantages as a gene therapy vector, but the presence of pre-existing neutralizing antibodies (NAbs) is an important limitation. This study was designed to determine: (1) characteristics of AAV NAbs in human subjects, (2) prevalence of AAV1 NAbs in heart failure patients and (3) utility of aggressive immunosuppressive therapy in reducing NAb seroconversion in an animal model. NAb titers were assessed in a cohort of heart failure patients and in patients screened for a clinical trial of gene therapy with AAV1 carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a). AAV1 NAbs were found in 59.5% of 1552 heart failure patients. NAb prevalence increased with age (P=0.001) and varied geographically. The pattern of NAb titers suggested that exposure is against AAV2, with AAV1 NAb seropositivity due to crossreactivity. The effects of immunosuppression on NAb formation were tested in mini-pigs treated with immunosuppressant therapy before, during and after a single AAV1/SERCA2a infusion. Aggressive immunosuppression did not prevent formation of AAV1 NAbs. We conclude that immunosuppression is unlikely to be a viable solution for repeat AAV1 dosing. Strategies to reduce NAbs in heart failure patients are needed to increase eligibility for gene transfer using AAV vectors.

Diagnostic radiography and adult acute myeloid leukaemia: an interview and medical chart review study.

BACKGROUND: Aetiology of acute myeloid leukaemia (AML) is not well understood, perhaps because of its distinct subtypes. High-dose ionising radiation is a known risk factor, but less is known about risk from low-dose exposure such as from diagnostic radiography. METHODS: Subjects were 412 matched case-control pairs. Ten-year subject histories of diagnostic radiography were based on interview and medical records. RESULTS: There was no convincing association between AML risk and ionising radiation exposure from diagnostic imaging procedures, either for AML overall or for any AML subtype. CONCLUSION: The association between diagnostic radiography and AML risk remains uncertain.

Tuberculosis in the foreign-born population of Tarrant county, Texas by immigration status.

The epidemiology of tuberculosis is changing in the United States as a result of immigration, yet the extent to which different classes of immigrants contribute to overall morbidity is unknown. Tuberculosis in nonimmigrant visitors is of particular interest as they are currently exempt from screening requirements. We conducted a prospective survey of all culture-positive tuberculosis patients in Tarrant County, Texas from 1/98 to 12/00. Immigration status of foreign-born patients was classified as permanent residents, undocumented, or nonimmigrant visitors. Of 274 eligible participants, 114 (42%) were foreign-born; of these, 67 (59%) were permanent residents, 28 (25%) were undocumented, and 19 (17%) were nonimmigrant visitors. Among the foreign-born, we observed significant differences by immigration status in multidrug resistance (p = 0.02), human immunodeficiency virus (HIV) infection (p = 0.0007), and hospitalization (p = 0.03 for ever/never, 0.01 for duration). Compared with other immigrants, more nonimmigrant visitors were multi-drug-resistant (16 % versus 11% of undocumented residents and 1% of permanent residents), were HIV-positive (32% versus 0% of undocumented and 5% of permanent residents), were hospitalized (47% versus 36% of undocumented and 19% of permanent residents), and had lengthy hospitalizations (median [midspread] days = 87 [25 to 153] versus 8.5 [4 to 28] for undocumented and 10 [7 to 24 d] for permanent residents). We found nonimmigrant visitors to be an important source of tuberculosis morbidity in Tarrant County. Further studies in other regions of the U.S. are needed to determine if screening and treatment recommendations of persons who spend extended periods in the U.S. should be raised to the standards set for permanent residents.

Botulinum toxin type A (BOTOX) for treatment of migraine.

An open-label study and 2 double-blind, placebo-controlled studies have provided supporting evidence of botulinum toxin type A (BTX-A) as an effective, well-tolerated treatment for migraine. Observed durations of benefit were consistent with known properties of BTX-A. Findings suggest that response may vary by features of preinjection headaches, such as migraine frequency. The precise mechanism by which BTX-A provides pain relief is hypothesized to be related not only to acetylcholine inhibition but also to a blocking action on the parasympathetic nervous system. Additional studies that control factors likely to be related to response may lead to better understanding of the BTX-A effect on migraine and an optimal treatment protocol.

Maternal cured meat consumption during pregnancy and risk of paediatric brain tumour in offspring: potentially harmful levels of intake.

OBJECTIVE: To describe the relationship between specific levels of nitrite intake from cured meat consumption during pregnancy and the relative risk of paediatric brain tumours in the offspring. DESIGN: Exposure data were previously collected for a population-based case-control study of paediatric brain tumours; data on nitrite content were obtained by a comprehensive literature review of surveys of residual nitrite content in cured meats published in the USA and Canada. The level of nitrite intake for each mother was predicted by year of pregnancy based on survey results. Dose-response was evaluated both categorically and continuously using polynomial and quadratic spline regression. SETTING: The US west coast: Los Angeles County, the San Francisco-Oakland Bay Area and the Seattle-Puget Sound area. SUBJECTS: There were 540 cases diagnosed between 1984 and 1990 at ages varying from 0 to 19 years, and 801 controls frequency-matched by geographic area, age and birth year. RESULTS: In general, survey results suggest a trend of decreasing nitrite levels in cured meats over time. We observed a moderate increase in brain tumour risk in the offspring of mothers with relatively low levels of nitrite consumption from cured meats during pregnancy, and a two- to three-fold risk increase in offspring of mothers who consumed 3 mg day-1 nitrite from cured meats (about 125 g day-1 of cured meat consumption throughout the pregnancy). CONCLUSIONS: A substantial risk of paediatric brain tumour appears to be associated with relatively high levels of maternal cured meat consumption during pregnancy. A more scientifically valid approach than a literature review to estimate nitrite intake from cured meats and data from a large group of highly exposed subjects would be useful in determining potentially harmful levels.

Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study.

OBJECTIVE: The object of this clinical experience was to evaluate the correlation between pericranial botulinum toxin type A (BOTOX, Allergan Corp, Irvine, CA) administration and alleviation of migraine headache symptoms. STUDY DESIGN AND SETTING: A nonrandomized, open-label study was performed at 4 different test sites. The subjects consisted of 106 patients, predominantly female, who either (1) initially sought BOTOX treatment for hyperfunctional facial lines or other dystonias with concomitant headache disorders, or (2) were candidates for BOTOX treatment specifically for headaches. Headaches were classified as true migraine, possible migraine, or nonmigraine, based on baseline headache characteristics and International Headache Society criteria. BOTOX was injected into the glabellar, temporal, frontal, and/or suboccipital regions of the head and neck. Main outcome measures were determined by severity and duration of response. The degrees of response were classified as: (1) complete (symptom elimination), (2) partial > or =50% reduction in headache frequency or severity), and (3) no response [neither (1) nor (2)]. Duration of response was measured in months for the prophylactic group. RESULTS: Among 77 true migraine subjects treated prophylactically, 51% (95% confidence interval, 39% to 62%) reported complete response with a mean (SD) response duration of 4.1 (2.6) months; 38% reported partial response with a mean (SD) response duration of 2.7 (1.2) months. Overall improvement was independent of baseline headache characteristics. Seventy percent (95% confidence interval, 35% to 93%) of 10 true migraine patients treated acutely reported complete response with improvement 1 to 2 hours after treatment. No adverse effects were reported. CONCLUSIONS: BOTOX was found to be a safe and effective therapy for both acute and prophylactic treatment of migraine headaches. Further research is needed to explore and develop the complete potential for the neuroinhibitory effects of botulinum toxin.

Reliability of demographic, smoking and occupational data provided by mothers vs. fathers in a childhood cancer study.

A large case-control study of children was used to test mothers' reporting of information on fathers' background, lifestyle and occupational factors. For a subset (104) of 1341 enrolled families, both parents were interviewed about fathers' characteristics. Reliability of reporting was determined for fathers' race, education, smoking status, non-recent job history and use of occupational agents. The ability of mothers to report fathers' race, education and smoking status was high (kappa > 0.70). Mothers were generally able to report jobs held by the fathers in the 5 years preceding the birth of the child, but reliability was higher for jobs held for longer (kappa typically above 0.70), rather than shorter periods (kappa above 0.40). The finding that mothers' reporting on fathers' background, lifestyle and non-recent job history was reliable is encouraging, because many studies on childhood health rely exclusively on information from interviews with mothers. However, mothers were not reliably able to describe exposure to specific occupational agents.

Exposure stratified case-cohort designs.

A variant of the case-cohort design is proposed for the situation in which a correlate of the exposure (or prognostic factor) of interest is available for all cohort members, and exposure information is to be collected for a case-cohort sample. The cohort is stratified according to the correlate, and the subcohort is selected by stratified random sampling. A number of possible methods for the analysis of such exposure stratified case-cohort samples are presented, some of their statistical properties developed, and approximate relative efficiency and optimal allocation to the strata discussed. The methods are compared to each other, and to randomly sampled case-cohort studies, in a limited computer simulation study. We found that all of the proposed analysis methods performed well and were more efficient than a randomly sampled case-cohort study.

Evidence from molecular fingerprinting of limited spread of drug-resistant tuberculosis in Texas.

To determine the contribution of recent transmission to spread of drug-resistant tuberculosis in Texas, we performed IS6110-based and pTBN12-based restriction fragment length polymorphism (RFLP) analyses on Mycobacterium tuberculosis isolates. Isolates collected from 201 patients in Texas between 1992 and 1994 were studied. The distribution of cases was strikingly focal. All cases were reported from 35 of the 254 counties in Texas, and 74% (148 of 201) were reported from only 9 counties. One hundred sixty-one (80%) of the patients had M. tuberculosis isolates with unique RFLP patterns, and 41 (20%) patients were in 20 clusters, each comprising 2 to 3 patients. The largest number of cases of drug-resistant tuberculosis were reported in counties bordering Mexico, but the percentage of clustered cases was highest in northeast Texas and in counties that included the cities of Dallas, Fort Worth, and Houston. Compared to nonclustered patients, clustered patients were more likely to be African American and to have been born in the United States. Clustered patients were significantly more likely to be from the same geographic area, and clustered patients from the same geographic area were more likely to have isolates with identical drug susceptibility patterns, suggesting that they were linked by recent transmission. In 11 of 20 clusters, clustered patients were from geographically separate regions, and most isolates did not have identical drug susceptibility patterns, suggesting that tuberculosis was contracted from a common source in the remote past. Based on the low percentage of clustered cases and the small cluster size, we conclude that there is no evidence for the extensive transmission of drug-resistant tuberculosis in Texas.

Foci of tuberculosis transmission in central Los Angeles.

To identify sites of tuberculosis transmission and to determine the contribution of HIV-infected patients to tuberculosis morbidity in an urban area, we prospectively evaluated 249 patients with culture-proven tuberculosis in central Los Angeles. Restriction fragment length polymorphism (RFLP) analysis was performed on Mycobacterium tuberculosis isolates to identify patients infected with the same strain. Using RFLP and clinical and epidemiologic data, we identified the most likely source case and site of transmission for 79 patients. Homelessness, birth in the United States and Native American ethnicity were independent predictors of being a source case, but HIV infection was not. Three homeless shelters were sites of tuberculosis transmission for 55 (70%) of the 79 patients. HIV-infected patients constituted 27% (66/249) of the study population, but only 17% (13/79) of patients were infected by an HIV-infected source case. We conclude that transmission of tuberculosis in central Los Angeles was highly focal, and that the major transmission sites were three homeless shelters. HIV- infected tuberculosis patients did not play a major role in spread of tuberculosis. Tuberculosis control measures targeted at specific homeless shelters can reduce tuberculosis morbidity in urban areas where homelessness is common and the incidence of tuberculosis is high.

Prenatal vitamin supplementation and pediatric brain tumors: huge international variation in use and possible reduction in risk.

An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976-1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1051 cases and for 1919 controls in eight geographic areas of North America, Europe and Israel. While risk estimates varied by study center, combined results suggest that maternal supplementation for two trimesters may decrease risk of brain tumor [odds ratio (OR)=0.7; 95% confidence interval (CI)=0.5-0.9], with a trend toward less risk with longer duration of use (P trend= 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all three trimesters (OR=0.5; CI=0.3- 0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breast feeding. These findings are largely driven by data from the US, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied tremendously, from 3% in Israel and in France through 21% in Italy, 33% in Canada, 52% in Spain to 86-92% at the three US centers. The composition of the various multivitamin compounds taken also varied: daily dose of vitamin C ranged from 0 up to 600 mg; vitamin E from 0 to 70 mg; vitamin A from 0 to 30,000 IU and folate from 0 to 2000 mg. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine potential independent effects of these micronutrients.

An international case-control study of adult glioma and meningioma: the role of head trauma.

BACKGROUND: Increased brain tumour risk after head trauma suggested by case reports and clinical series has been previously studied epidemiologically with mixed results. An international multicentre case-control study investigated the role of head trauma from injury or sports participation in adult brain tumour risk. METHODS: In all, 1178 glioma and 330 meningioma cases were individually or frequency matched to 2236 controls. Only exposures that occurred at least 5 years before diagnosis and head injuries that received medical attention were considered. RESULTS: Risk for ever having experienced a head injury was highest for male meningiomas (odds ratio [OR] = 1.5, 95% confidence interval [CI] : 0.9-2.6) but was lower for 'serious' injuries, i.e. those causing loss of consciousness, loss of memory or hospitalization (OR = 1.2, 95% CI: 0.6-2.3). Among male meningiomas, latency of 15 to 24 years significantly increased risk (OR = 5.4, 95% CI: 1.7-16.6), and risk was elevated among those who participated in sports most correlated with head injury (OR = 1.9, 95% CI: 0.7-5.3). Odds ratios were lower for male gliomas (OR = 1.2, 95% CI : 0.9-1.5 for any injury; OR = 1.1, 95% CI: 0.7-1.6 for serious injuries) and in females in general. CONCLUSIONS: Evidence for elevated brain tumour risk after head trauma was strongest for meningiomas in men. Findings related to sports should be interpreted cautiously due to cultural variability in our data and our lack of complete data on physical exercise in general which appeared to be protective.

Results from an international case-control study of childhood brain tumors: the role of prenatal vitamin supplementation.

An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976 to 1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1051 cases and 1919 controls from eight geographic areas in North America, Europe, and Israel. Although risk estimates varied by study center, combined results suggest that maternal supplementation for two trimesters may decrease risk of brain tumor (odds ratio [OR] 0.7, 95% confidence interval [CI] 0.5-0.9), with a trend of less risk with longer duration of use (p trend = 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all three trimesters (OR 0.5, CI 0.3-0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breast feeding. These findings are largely driven by data from the United States, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied tremendously: from 3% in Israel and France, 21% in Italy, 33% in Canada, 52% in Spain and 86 to 92% at the three U.S. centers. The composition of the various multivitamin compounds taken also varied: the daily dose of vitamin C ranged from 0 to 600 mg, vitamin E ranged from 0 to 70 mg, vitamin A ranged from 0 to 30,000 IU, and folate ranged from 0 to 2000 micrograms. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine potential independent effects of these micronutrients.

Parental occupation and childhood brain tumors: astroglial and primitive neuroectodermal tumors.

Data from a population-based case-control study in 19 counties in California and Washington State were used to investigate the association between parental employment and childhood brain tumors. Parents of 540 cases (including 308 astroglial and 109 primitive neuroectodermal tumors) and 801 controls diagnosed from 1984 to 1991 were interviewed. Analysis was completed for parents' self-reported industry of employment and job tasks during the five years preceding the birth of the child. Parents who worked in the chemical industry were at increased risk of having had children with astroglial tumors (fathers' odds ratio [OR] = 2.1; 95% confidence interval [CI], 1.1-3.9); mothers' OR = 3.3; 95% CI, 1.4-7.7), but no trend by duration of employment was seen for mothers. Children of fathers employed as electrical workers were at increased risk of developing brain tumors of any histologic type (OR = 2.3; 95% CI, 1.3-4.0).

Prenatal vitamin supplementation and risk of childhood brain tumors.

An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976 to 1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1,051 cases and for 1,919 controls from 8 geographic areas in North America, Europe and Israel. While risk estimates varied by study center, combined results suggest that maternal supplementation for 2 trimesters decreased risk of brain tumor [odds ratio (OR) = 0.7; 95% confidence interval (CI) = 0.5, 0.9], with a trend of less risk with longer duration of use (p trend = 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all 3 trimesters (OR = 0.5; CI = 0.3, 0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breastfeeding. Our findings are largely driven by data from the United States, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied markedly from 3% in Israel and in France, 21% in Italy, 33% in Canada and 52% in Spain to 86-92% at the 3 U.S. centers. The composition of the various multivitamin compounds taken also varied: daily dose of vitamin C ranged from 0 to 600 mg; vitamin E from 0 to 70 mg; vitamin A from 0 to 30,000 IU; and folate from 0 to 2,000 micrograms. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine the potential independent effects of these micronutrients.

Chest radiographic findings in patients with tuberculosis with recent or remote infection.

To determine if chest radiographic findings differ in adult tuberculosis patients with recent and remote infection, we reviewed the chest radiographs of 103 patients with tuberculosis in Los Angeles and performed RFLP analyses of their Mycobacterium tuberculosis isolates. Patients whose isolates had identical or closely related RFLP patterns were considered a "cluster." Most patients in large clusters (more than seven patients) had tuberculosis from recent infection, whereas most unclustered patients had tuberculosis from remote infection. Mediastinal adenopathy or pleural effusions were classified as typical of recent infection, and upper lobe infiltrates, cavitation, or fibrosis were classified as characteristic of remote infection. Radiographic patterns were typical of remote infection in 62% of patients and were characteristic of recent infection in 23% of patients. The distribution of these radiographic patterns was similar in clustered and unclustered patients, both with or without human immunodeficiency virus (HIV) coinfection. However, mediastinal adenopathy and pleural effusions were significantly more common in HIV-infected patients. We conclude that: (1) chest radiographic findings in adults with tuberculosis of recent infection are similar to those in patients with remote infection; (2) the distinctive chest radiographic findings in HIV-infected patients with tuberculosis are not due to an increased frequency of recent infection.

Patterns of tuberculosis transmission in Central Los Angeles.

CONTEXT: Recent studies suggest that many tuberculosis cases in urban areas result from recent transmission. Delineation of the epidemiologic links between patients is important to optimize strategies to reduce tuberculosis transmission. OBJECTIVE: To identify epidemiologic links among recently infected urban patients with tuberculosis. DESIGN: Prospective evaluation of patients with tuberculosis. SETTING: Central Los Angeles, Calif. PATIENTS: A total of 162 patients who had culture-proven tuberculosis. INTERVENTIONS: Patients were prospectively interviewed to identify their contacts and whereabouts. The IS6110-based and pTBN12-based restriction fragment length polymorphism analyses were performed on Mycobacterium tuberculosis isolates. Patients whose isolates had identical or closely related restriction fragment length polymorphism patterns were considered a cluster. Unconditional logistic regression was used to identify independent predictors of clustering. MAIN OUTCOME MEASURES: Relationship of clinical and epidemiologic variables to clustering. RESULTS: A total of 96 (59%) of 162 patients were in 8 clusters. Only 2 of the 96 clustered patients named others in the cluster as contacts. The degree of homelessness was an independent predictor of clustering. Compared with nonclustered patients, patients in 6 clusters were significantly more likely to have spent time at 3 shelters and other locations when at least 1 patient in the cluster was contagious, and these locations were independent predictors of clustering. Among nonhomeless persons, clustered patients were significantly more likely than nonclustered patients to have used daytime services at 3 shelters. CONCLUSIONS: (1) Traditional contact investigation does not reliably identify patients infected with the same M tuberculosis strain, and (2) locations at which the homeless congregate are important sites of tuberculosis transmission for homeless and nonhomeless persons. Measures that reduce tuberculosis transmission should be based on locations rather than on personal contacts.

Potential role for estrogen replacement in the treatment of Alzheimer's dementia.

In light of evidence that estrogen replacement therapy (ERT) might affect cholinergic function, we examined possible effects of ERT on clinical and cognitive responses to the cholinesterase inhibitor tacrine in women with Alzheimer's disease (AD). In a previously reported 30-week, randomized, double-blind, placebo-controlled, multicenter clinical trial, 14.5% of 318 women with evaluable data had been receiving ERT prior to randomization. Patients were randomly assigned to receive placebo or one of three ascending dosages of tacrine (maximum dosages of 80 mg/day, 120 mg/day, or 160 mg/day). Women completing the trial receiving ERT and tacrine improved more than women not receiving ERT who were randomized to tacrine or to placebo as assessed by cognitive (p <0.01), clinical (p = 0.02), caregiver (p = 0.006), and mental status (p = 0.07) ratings. Using an intent-to-treat analysis, they improved significantly on cognitive ratings (p = 0.01). These results provide evidence that prior and continuing ERT may enhance response to tacrine in women with AD. Randomized trials are needed.