LSD1/KDM1A is essential for neural stem cell differentiation in mice.

The proper regulation of neural stem cell differentiation is required for the proper specification of the central nervous system. Here we investigated the function of the H3K4me1/2 demethylase LSD1/KDM1A during neural stem differentiation in mice. Conditional deletion of LSD1 in nestin- positive neural stem cells results in 100% perinatal lethality after birth with severe motor coordination deficits, retarded growth and defects in brain morphology. Despite these severe defects, motor neuron progenitors and the initial motor neuron population are specified normally and motor neurons with normal morphology can be cultured from these mice in vitro. However, motor neurons cultured from mice lacking LSD1 in neural stem cells continue to inappropriately maintain critical neural stem cell proteins. Taken together these results suggest that, as in other mouse stem cell populations, LSD1 is required to deactivate the stem cell program to enable normal neural stem cell differentiation. However, unlike in other mouse stem cell populations, the inappropriate maintenance of the stem cell program during neural stem cell differentiation may compromise neuronal function rather than neuronal specification.

Evaluation of point-of-care algorithms to detect diabetes during screening for latent TB infection.

BACKGROUND: Individuals with both diabetes mellitus (DM) and TB infection are at higher risk of progressing to TB disease.OBJECTIVE: To determine DM prevalence in populations at high risk for latent TB infection (LTBI) and to identify the most accurate point-of-care (POC) method for DM screening.METHODS: Adults aged ≥25 years were recruited at health department clinics in Hawaii and Arizona, USA, and screened for LTBI and DM. Screening methods for DM included self-report, random blood glucose (RBG), and POC hemoglobin A1c (HbA1c). Using HbA1c ≥6.5% or self-reported history as the gold standard for DM, we compared test strategies to determine the most accurate method while keeping test costs low.RESULTS: Of 472 participants, 13% had DM and half were unaware of their diagnosis. Limiting HbA1c testing to ages ≥30 years with a RBG level of 120-180 mg/dL helped identify most participants with DM (sensitivity 85%, specificity 99%) at an average test cost of US$2.56 per person compared to US$9.56 per person using HbA1c for all patients.CONCLUSION: Self-report was insufficient to determine DM status because many participants were previously undiagnosed. Using a combination of POC RBG and HbA1c provided an inexpensive option to assess DM status in persons at high risk for LTBI.

Risk factors for transmission of tuberculosis among United States-born African Americans and Whites.

SETTING: Tuberculosis (TB) patients and their contacts enrolled in nine states and the District of Columbia from 16 December 2009 to 31 March 2011. OBJECTIVE: To evaluate characteristics of TB patients that are predictive of tuberculous infection in their close contacts. DESIGN: The study population was enrolled from a list of eligible African-American and White TB patients from the TB registry at each site. Information about close contacts was abstracted from the standard reports of each site. RESULTS: Close contacts of African-American TB patients had twice the risk of infection of contacts of White patients (adjusted risk ratio [aRR] 2.1, 95%CI 1.3-3.4). Close contacts of patients whose sputum was positive for acid-fast bacilli on sputum smear microscopy had 1.6 times the risk of tuberculous infection compared to contacts of smear-negative patients (95%CI 1.1-2.3). TB patients with longer (>3 months) estimated times to diagnosis did not have higher proportions of infected contacts (aRR 1.2, 95%CI 0.9-1.6). CONCLUSION: African-American race and sputum smear positivity were predictive of tuberculous infection in close contacts. This study did not support previous findings that longer estimated time to diagnosis predicted tuberculous infection in contacts.

Using mobile technology to overcome language barriers in medicine.

Australia has a large migrant population with variable fluency in English. Interpreting services help ensure that healthcare services are delivered appropriately to these populations. However, the use of professional interpreters in hospitals is expensive. There are also issues with service availability and convenience. Mobile devices containing software with translating abilities have promising potential to improve communication between patients and hospital staff as an adjunct to professional interpreters. It is highly convenient and inexpensive. There are concerns about the accuracy of the interpretation done with such software and more research needs to be carried out to support or allay these concerns. For now, clinically important and medicolegal related interpretation should be undertaken by professional interpreters whereas less crucial tasks may be performed with the help of interpreting software on mobile devices.

Isolated vasculitis of the bladder.

We describe a case of isolated vasculitis involving the bladder that presented with severe irritative voiding and hematuria. This case presented a diagnostic problem, because malignancy was suspected, but not confirmed by biopsies. Once the vasculitis was diagnosed, secondary systemic causes were excluded, and successful treatment was subsequently undertaken using systemic steroids. It is important to differentiate this rare pathologic entity from the much more frequent tumors of the bladder because the treatment is medical rather than surgical.

An assessment of the ability of routine restaurant inspections to predict food-borne outbreaks in Miami-Dade County, Florida.

OBJECTIVES: This study sought to determine the usefulness of restaurant inspections in predicting food-borne outbreaks in Miami-Dade County, Fla. METHODS: Inspection reports of restaurants with outbreaks in 1995 (cases; n = 51) were compared with those of randomly selected restaurants that had no reported outbreaks (controls; n = 76). RESULTS: Cases and controls did not differ by overall inspection outcome or mean number of critical violations. Only 1 critical violation--evidence of vermin--was associated with outbreaks (odds ratio = 3.3; 95% confidence interval = 1.1, 13.1). CONCLUSIONS: Results of restaurant inspections in Miami-Dade County did not predict outbreaks. If these findings are representative of the situation in other jurisdictions, inspection practices may need to be updated.

A prevalence study of hepatitis A virus infection in a migrant community: Is hepatitis A vaccine indicated?

BACKGROUND: The Advisory Committee on Immunization Practices recommends routine hepatitis A vaccination of children living in communities with high rates of hepatitis A. Rates among children living in migrant farm worker families are unknown. METHODS: Participants recruited from the 1243 migrant children aged 2 to 18 years in Okeechobee County, Florida, were administered a questionnaire. A blood sample was taken for testing for antibodies to hepatitis A virus (anti-HAV), and hepatitis A vaccine was administered. RESULTS: Of 244 (20%) participating children, 125 (51%) were anti-HAV-positive. Seropositivity increased with age from 34% (2- to 5-year-olds) to 81% (>/=14-year-olds) (P <.0001). In multivariate analysis, age (odds ratio [OR] = 1.2/year; 95% CI = 1.1 to 1.3), having a Mexican-born father (OR = 12.2; 95% CI = 2.2 to 227.9), and age on moving to the United States (OR = 1.3/year; 95% CI = 1.0 to 1.6) were independently associated with anti-HAV positivity. Among US-born children aged 2 to 5 years who had never left the United States, 33% were anti-HAV-positive. CONCLUSIONS: Anti-HAV prevalence among migrant children in Okeechobee County, including the youngest US-born children, is high, indicating ongoing transmission of HAV. Children in this and other US migrant communities may benefit from hepatitis A vaccination.

CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.

The Insulin-like growth factor 2 (Igf2) and H19 genes are imprinted, resulting in silencing of the maternal and paternal alleles, respectively. This event is dependent upon an imprinted-control region two kilobases upstream of H19 (refs 1, 2). On the paternal chromosome this element is methylated and required for the silencing of H19 (refs 2-4). On the maternal chromosome the region is unmethylated and required for silencing of the Igf2 gene 90 kilobases upstream. We have proposed that the unmethylated imprinted-control region acts as a chromatin boundary that blocks the interaction of Igf2 with enhancers that lie 3' of H19 (refs 5, 6). This enhancer-blocking activity would then be lost when the region was methylated, thereby allowing expression of Igf2 paternally. Here we show, using transgenic mice and tissue culture, that the unmethylated imprinted-control regions from mouse and human H19 exhibit enhancer-blocking activity. Furthermore, we show that CTCF, a zinc finger protein implicated in vertebrate boundary function, binds to several sites in the unmethylated imprinted-control region that are essential for enhancer blocking. Consistent with our model, CTCF binding is abolished by DNA methylation. This is the first example, to our knowledge, of a regulated chromatin boundary in vertebrates.

An outbreak of cyclosporiasis in Florida in 1995: a harbinger of multistate outbreaks in 1996 and 1997.

Before 1995, only one outbreak of cyclosporiasis had been reported in the United States. To identify risk factors for Cyclospora infection acquired in Florida in 1995, we conducted a matched case-control study (24 sporadic cases and 69 controls) and retrospective cohort studies of clusters of cases associated with two May social events (attack rates = 15.4% [8 of 52] and 54.5% [6 of 11]). In univariate analysis of data from the case-control study, consumption of fresh raspberries (odds ratio [OR] = 6.0, 95% confidence interval [CI] = 1.1-31.7) and bare-handed contact with soil (OR = 5.4, 95% CI = 1.4-20.7) were associated with infection; soil contact was also implicated in multivariate analysis. For the events, mixed-fruit items that had only fresh raspberries and strawberries in common had elevated relative risks (3.7 and 4.2), but the confidence intervals overlapped 1.0. The raspberries eaten at the events and by sporadic case-patients were imported. Given the cumulative evidence of the three studies and the occurrence in 1996 and 1997 of outbreaks in North America associated with consumption of Guatemalan raspberries, food-borne transmission of Cyclospora was likely in 1995 in Florida as well.

Platinum group element enrichments and possible chondritic Ru:Ir across the Frasnian-Famennian boundary, western New York State.

The Frasnian-Famennian boundary is recognized as the culmination of a global mass extinction in the Late Devonian. In western New York State the boundary is a distinct horizon within a pyritic black shale bed of the upper Hanover Shale defined by the first occurrence of Palmatolepis triangularis in the absence of Frasnian conodonts. The boundary is characterized by a minor disconformity marked by a lag concentration of conodonts. Iridium at the boundary is 0.11-0.24 ng/g, two to five times background levels of <0.05 ng/g; other Ir enrichments of 0.38 ng/g and 0.49 ng/g occur within 50 cm of the conodont-constrained boundary. Numerous Ir enrichments in the boundary interval suggest extraterrestrial accretion and platinum group element (PGE) concentration at disconformities, or mobilization and concentration in organic-rich/pyritic-rich laminations from cosmic or terrestrial sources. PGE ratios of Pt/Pd and Ku/Ir at the boundary horizon approximate chondritic ratios and are suggestive of an unaltered extraterrestrial source. These values do not conclusively establish a single extraterrestrial impact as the ultimate cause of the Frasnian-Famennian mass extinction, especially given the presence of similar Ir enrichments elsewhere in the section and the absence at the boundary of microtektites and shocked mineral grains.

Gender differences in abdominal aortic aneurysm prevalence, treatment, and outcome.

PURPOSE: The purpose of this study was to investigate gender differences in the management of and outcome of surgery for abdominal aortic aneurysms (AAA). METHODS: Hospital discharge data from all acute care hospitals in Michigan, as compiled in the Michigan Inpatient Data Base, were retrospectively analyzed to assess sex differences in regard to AAA prevalence, treatment, and surgical outcome from 1980 to 1990. This population database included 11,512 women and 29,846 men 50 years of age and older with diagnoses of intact or ruptured AAA. RESULTS: Hospitalizations for intact or ruptured AAA were approximately five times more common among men compared with women. After controlling for age and year of surgery, men were 1.8 times as likely as women to have an intact AAA treated surgically and 1.4 times as likely to have a ruptured AAA treated surgically (95% confidence intervals, 1.7 to 1.9 and 1.2 to 1.7, respectively). Women who had operations for intact AAA had a 1.4 times greater risk of dying compared with men, and women who had operations for ruptured AAA had a 1.45 times greater risk of dying, after controlling for other predictors of death (95% confidence intervals, 1.14 to 1.73 and 1.10 to 1.90, respectively). CONCLUSIONS: In a population-based statewide experience, women who had intact or ruptured AAA were less likely than men to undergo aortic reconstruction and, when they did, were less likely than men to survive to discharge.

Abdominal aortic aneurysms.

Certain biological differences between men and women are relevant to the problem of AAA, and are widely accepted. Women unequivocally have smaller aortas. The size difference correlates with a variety of anthropomorphic measurements, but is most strongly associated with body surface area. In women the compliance of the aorta decreases in linear fashion with age, whereas in men the decrease in compliance is exponential with age. Women appear to be underrepresented in AAA surgical series (typically 18% to 20% of operative cases) compared with autopsy studies (29% to 32%), ultrasound screening studies (19% to 25%), and mortality studies (34% of the 14,982 deaths due to AAA in the US in 1988). Several lines of evidence suggest that women with AAA are less likely than men to be referred for surgery, and that, when referred, they have higher mortality rates. The reasons for these differences are unclear. The very factors that allow increased longevity in women may have an adverse effect on the ability to tolerate a major surgical stress. Wenger et al have suggested that psychosocial and economic factors may affect women's decisions to seek care, or their choice of therapeutic options. Lack of knowledge among practitioners of gender-related aortic size differences and overreliance on simplistic clinical paradigms that dictate operations for 5-cm diameter aneurysms and watchful waiting for 4- to 5-cm AAAs may result in unintended bias in patient selection. It may be that a 5-cm diameter AAA in a woman with a predicted normal aortic size of 1.4 cm represents a more advanced stage of disease than a 5-cm diameter AAA in a man with a normal aortic diameter of 2.5 cm. More precise and detailed algorithms are needed to permit clinicians to tailor decisions to patients' size, sex, and risk factors. Development of such algorithms requires expansion of clinical and epidemiological studies to include enough women to make precise risk estimates.

Electron-beam CT: use of a calibration phantom to reduce variability in calcium quantitation.

PURPOSE: To measure scanner and patient variation in computed tomographic (CT) numbers for electron-beam CT and to determine the ability of calibration phantoms to reduce variability in calcium quantitation. MATERIALS AND METHODS: Two calibration phantoms were imaged to ensure longitudinal homogeneity and to determine the short-term intrascanner variation in CT numbers. Each phantom set was imaged twice a day for 14 weeks to determine intra- and interscanner variation. Data from examinations of 167 patients that included the phantom were analyzed to determine the intra- and interpatient variation in CT numbers of objects with known calcium concentrations. RESULTS: The calibration reduced scanner variations by approximately 25%. The calcium concentration associated with a CT number of 130 HU varied from 77.1 to 136.4 mg/cm3 and was dependent on patient girth, sex, smoking history, and image level. CONCLUSION: Scanner and patient variations in CT numbers in electron-beam CT can be reduced with a calibration phantom. In vitro and in vivo estimates of calcium concentration had a precision of 2% and 7%, respectively.

Operative mortality rates for intact and ruptured abdominal aortic aneurysms in Michigan: an eleven-year statewide experience.

PURPOSE: The purposes of this study were (1) to determine the current population-based mortality rate for the surgical treatment of abdominal aortic aneurysms (AAA) in Michigan, (2) to document changes in mortality rates over 11 years, and (3) to identify risk factors for operative mortality. METHODS: A statewide database provided clinical information on all Michigan hospital admissions with a diagnosis of AAA from 1980 to 1990. The mortality rate analysis included all admissions with a primary diagnosis of AAA that underwent repair. Determination of diagnoses and comorbidities were based on International Classification of Diseases-ninth revision-Clinical Modification codes. RESULTS: Conventional surgical repairs were performed on 8185 intact and 1829 ruptured AAA. Hospital mortality rates accompanying operation for intact AAA decreased from 13.6% in 1980 to 5.6% in 1990 (p < 0.001). Mortality rates over the 11 years averaged 10.7% in women and 6.8% in men (p < 0.001). Mortality rates averaged 10.7% in 4170 admissions of patients 70 years old or older and 4.2% in 4015 admissions of patients 69 years old or younger. Preexistent kidney failure was associated with an average mortality rate of 41.2% compared with 6.2% without this comorbidity. Preexistent dysrhythmia increased mortality rates from 6.6% to 13.6%. Uncomplicated hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, diabetes, arterial occlusive disease, and ischemic heart disease in recent years were not associated with increased mortality rates. Hospitals with an annual volume of 21 or more intact AAA repairs had a surgical mortality rate of 6.2%, compared with 8.9% in hospitals with lower surgical volume (p < 0.001). Mortality rates for surgical repair of ruptured AAA averaged 49.8% and did not improve significantly over the 11 years studied. CONCLUSION: Despite a dramatic drop in surgical mortality rates, repair of intact AAA remains a formidable undertaking. This population-based series documents a substantially higher mortality rate than most selected series. The unchanged mortality rate for ruptured AAA suggests that development of better algorithms to identify those AAA most apt to rupture and earlier intervention in those instances is likely to improve patient survival rates.

HIV testing in patients with tuberculosis. Physician response to national recommendations.

The epidemic of human immunodeficiency virus (HIV) disease has contributed to the resurgence of tuberculosis in the United States. For clinical and public health reasons, the Advisory Council for the Elimination of Tuberculosis has recommended that all patients with tuberculosis be tested for HIV antibodies. We reviewed the medical records of all patients with tuberculosis in whom a diagnosis was made at a Detroit medical center from July 1, 1986 to June 30, 1990, before and after recommendations were issued. Of 195 patients, 69 (35.4%) were tested for HIV antibodies: 73.7% of 57 patients whose medical records documented risk behaviors for HIV infection, and 19.6% of 138 patients who denied high-risk behaviors or whose medical records contained no risk information (relative risk of testing among patients with documented risk factors compared with others, 3.8; 95% confidence interval, 2.6 to 5.5). Testing of patients who denied risk behaviors or had no information in their records increased from 14.9% in the first 12 months to 30.4% in the last (p = 0.08, test for trend). In this population, national recommendations appear to have stimulated HIV testing, although most patients still are not being tested.

Synthesis of pyridazine analogues of the naturally occurring nucleosides cytidine, uridine, deoxycytidine, and deoxyuridine.

The condensation of 4,5-dichloro-3-[(trimethylsilyl)oxy]pyridazine (5) with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (6) was accomplished by the stannic chloride procedure to yield 4,5-dichloro-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)pyridazin-6-one (7). Procedures used to unequivocally determine the site of ribosylation and anomeric configuration of 7 are discussed. Treatment of 7 with liquid ammonia effected a concomitant removal of the blocking groups and selective nucleophilic displacement of the 4-chloro group. Subsequent dehalogenation yielded 4-amino-1-(beta-D-ribofuranosyl)pyridazin-6-one (11, 6-aza-3-deazacytidine). Treatment of 7 with methanolic sodium methoxide, followed by dehalogenation and hydrolysis with aqueous alkali, yielded 4-hydroxy-1-beta-D-ribofuranosylpyridazin-6-one (6-aza-3-deazauridine, 15). The syntheses of various nucleosides derived from 7, 11, and 15 are described. Condensation of 5 with 3,5-di-O-p-toluoyl-2-deoxy-D-erythro-pentofuranosyl chloride (27) gave a mixture of the blocked anomeric 2'-deoxynucleosides 28 and 29. Nucleoside 28, the beta anomer, was treated in the same manner as 7 to yield 4-amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)pyridazin-6-one (32, 6-aza-3-deaza-2'-deoxycytidine) and 4-hydroxy-1-(2-deoxy-beta-D-erythro-pentofuranosyl)pyridazin-6-one (32, 6-aza-3-deaza-2'-deoxycytidine) and 4-hydroxy-1-(2-deoxy-beta-D-erythro-pentofuranosyl)pyridazin-6-one (34, 6-aza-3-deaza-2'-deoxy-uridine). 6-Aza-3-deazauridine (15) was found to inhibit the growth of L1210 cells with an ID50 of about 7 x 10(-5) M.

Conformation of pyridazine nucleosides: the molecular structure of 4-hydroxy-1-(beta-D-ribofuranosyl)pyridazin-6-one (3-deaza-6-azauridine).

The glycosyl torsiona angle in 4-hydroxy-1-(beta-D-ribofuranosyl)-pyridazin-6-one (or 3-deaza-6-azauridine) is in the "high-anti" region. This is similar to the torsional angles observed for 6-azapyrimidine and 8-azapurine nucleosides, but in marked contrast to those found in uridine, 3-deazauridine and other pyrimidine nucleosides.

Diagnosis and management of arterial mural thromboemboli.

If ischemic lesions or cerebral dysfunction appear without obvious cause, aneurysm, stenosing, or ulcerative plaques in proximal arteries are suspected. Diagnostic methods are outlined. Treatment by removal of the embolic source is preferred and exclusion of the lesion and bypass is reserved for inacessible lesions or poor operative risks.