IL-12 is required for mTOR regulation of memory CTLs during viral infection.

The induction of functional memory cytotoxic T lymphocytes (CTLs) is a major goal of vaccination against intracellular pathogens. Interleukin (IL)-12 is critical for the generation of memory CTLs, and inhibition of mammalian target of rapamycin (mTOR) by rapamycin can effectively enhance the memory CTL response. Yet, the role of IL-12 in mTOR's regulation of memory CTL is unknown. Here we hypothesized that the immunostimulatory effects of mTOR on memory CTLs requires IL-12 signaling. Our results revealed that rapamycin increased the generation of memory CTLs in vaccinia virus infection, and this enhancement was dependent upon the IL-12 signal. Furthermore, IL-12 receptor deficiency diminished the secondary expansion of rapamycin-regulated memory and resultant secondary memory CTLs were abolished. Rapamycin enhanced IL-12 signaling by upregulating IL-12 receptor ß2 expression and signal transducer and activator of transcription factor 4 phosphorylation in CTLs during early infection. In addition, rapamycin continually suppressed T-bet expression in both wild-type and IL-12 receptor knockout CTLs. These results indicate an essential role for IL-12 in the regulation of memory CTLs by mTOR and highlight the importance of considering the interplay between cytokines and adjuvants during vaccine design.

Use of transoesophageal echocardiography during the peri-operative period for trauma patients.

The medical facility at Camp Bastion continues to evolve as a consequence of the increased throughput of battlefield trauma patients. There is a requirement for rapid and accurate diagnosis of haemodynamic instability and continued haemodynamic monitoring throughout the peri-operative period. Transoesophageal echocardiography (TOE) has been used for this purpose in the arena of cardiac anaesthesia since the mid 1980s. It is being introduced to other peri-operative settings where severe haemodynamic instability is expected. The old proverb: 'There are none so blind as those who cannot see' (Jeremiah 5:21) is applicable to this topic, in that TOE is proven to be a rapid, portable, safe and effective tool in the assessment of the haemodynamically unstable patient. This paper explores the application of TOE for the assessment of the major causes of haemodynamic instability in the trauma population.

Chemistry of molecular growth processes in flames.

Chemical mechanisms of pyrolysis, growth, and oxidation processes in flames have traditionally been inferred from spatial profile measurements of species concentrations. Experimental investigations now include the detection of numerous minor species such as reactive radicals and intermediate hydrocarbons. In assessing a proposed mechanism important new constraints can be established when the detailed species profile data are combined with velocity and temperature measurements and analyzed to determine production and destruction rates for specific molecules. Recent results on hydrocarbon diffusion flames provide new information on the interplay between chemical and transport processes. These measurements have led to direct tests of proposed routes for the formation of aromatic hydrocarbons and the first, small soot particles. The inception chemistry of hydrocarbon growth reactions and initial particle formation is thought to control soot formation, flame radiation and energy transfer, and pollutant emission in combustion environments.

Active case finding of undetected tuberculosis among chronic coughers in a slum setting in Kampala, Uganda.

SETTING: Kisenyi slum in peri-urban Kampala, Uganda. OBJECTIVES: Using chronic cough (> or = 2 weeks) inquiry as a screening tool to identify undetected smear-positive tuberculosis (TB) cases and to describe the characteristics of smear-positive TB cases detected by active case finding. DESIGN: A house-to-house survey was conducted in five randomly selected villages in Kampala between June and August 2005. A sample of households was visited; adults aged > or = 15 years were consecutively interviewed to identify those with chronic cough. Three sputum specimens were collected and examined by smear microscopy. RESULTS: Among 930 individuals, we identified 189 (20%) chronic coughers. Of these, we found 33 (18%) undiagnosed smear-positive cases. The newly detected cases had an even sex distribution (P = 0.47), a median age of 30 years, a median cough duration of 1 month and 55% had acid-fast bacilli 1+ sputum smear grade. CONCLUSION: These findings suggest that active case finding could supplement DOTS to yield additional smear-positive TB cases, lead to early diagnosis and thus shorten the duration of infectiousness before effective chemotherapy is initiated. In communities such as Kisenyi, this is a feasible strategy that may prove useful for TB control, but its cost-effectiveness needs to be evaluated. Early health care seeking for cough should be emphasized.

The dominant temperature-sensitive lethal DTS7 of Drosophila melanogaster encodes an altered 20S proteasome beta-type subunit.

Proteasomes are multicatalytic complexes that function as the major proteolytic machinery in regulated protein degradation. The eukaryotic 20S proteasome proteolytic core structure comprises 14 different subunits: 7 alpha-type and 7 beta-type. DTS7 is a dominant temperature-sensitive (DTS) lethal mutation at 29 degrees that also acts as a recessive lethal at ambient temperatures. DTS7 maps to cytological position 71AB. Molecular characterization of DTS7 reveals that this is caused by a missense mutation in a beta-type subunit gene, beta2. A previously characterized DTS mutant, l(3)73Ai1, results from a missense mutation in another beta-type subunit gene, beta6. These two mutants share a very similar phenotype, show a strong allele-specific genetic interaction, and are rescued by the same extragenic suppressor, Su(DTS)-1. We propose that these mutants might act as "poison subunits," disrupting proteasome function in a dosage-dependent manner, and suggest how they may interact on the basis of the structure of the yeast 20S proteasome.

Variation in the use of do-not-resuscitate orders in patients with stroke.

OBJECTIVES: To identify sociodemographic and clinical characteristics associated with the use of do-not-resuscitate (DNR) orders in hospitalized patients with stroke. To examine whether the use of DNR orders varies across hospitals. METHODS: This observational cohort study used data collected for 13337 consecutive eligible patients with a primary diagnosis of stroke. These patients were discharged in 1991 through 1994 from 30 hospitals in a large metropolitan area. Study data were abstracted from patients' hospital records using standard forms. Admission severity of illness was measured using a validated multivariable model. Sociodemographic and clinical factors independently associated with the use of DNR orders were identified using stepwise logistic regression. RESULTS: Do-not-resuscitate orders were written for 2898 patients (22%). Patient characteristics independently (P < .01) associated with increased use of DNR orders included increasing age (odds ratio [OR], 1.06 per year); admission from a skilled nursing facility (OR, 2.44) or through the emergency department (OR, 1.49); cancer (OR, 2.73), intracerebral hemorrhage (OR, 2.12), coma (OR, 7.47), or lethargy or stupor on admission neurological assessment (OR, 3.38); and increasing admission severity (OR; 1.29 per decile). In contrast, African American race was associated with lower use of DNR orders (OR, 0.54). Although substantial variation in the use of DNR orders was observed across hospitals, with rates ranging from 12% to 32%, adjusting for the above patient characteristics eliminated much of this variation, including differences between major teaching and other hospitals and between hospitals with and without religious affiliations. CONCLUSIONS: In our community-based analysis of patients with stroke, the use of DNR orders was common and was strongly related to several patient characteristics. These factors explained much of the variation across hospitals. While our analysis did not account for differences in patient preferences for treatment, the differences we observed in the use of DNR orders across sociodemographic groups are suggestive of variations in care and may have important implications for the cost and quality of hospital care.

Patients perceived stigma associated with community-based directly observed therapy of tuberculosis in Uganda.

OBJECTIVE: To assess whether linkage of tuberculosis (TB) and HIV/AIDS increases the perception of stigma among TB patients on Community-Based Directly Observed Therapy (CB-DOT) compared to similar TB patients on self-administered therapy (SAT). DESIGN: A Cross-sectional study. SETTING: Kiboga (CB-DOT) and Mubende (SAT) districts, Uganda in 2000. SUBJECTS: One hundred and five tuberculosis patients on CB-DOT and 202 patients on SAT. One hundred and twenty one (39%) of these patients agreed to be tested for HIV. RESULTS: Patients on CB-DOT and patients on SAT were similar on most of the domains used to assess stigma associated with a TB diagnosis, except for the domain of TB diagnosis and general belief that TB and HIV/AIDS are linked. Patients on CB-DOT were more likely to believe that neighbours knew they had TB compared to patients on SAT (91% vs. 62%, p < 0.001), but the groups did not differ in their perception that neighbours thought they have HIV because of TB (46% vs. 46%, p = 0.954). HIV prevalence was similar in both groups. CONCLUSION: The study demonstrates that TB patients on CB-DOT did not differ from SAT patients in their perception of stigma as a result of TB. Therefore, HIV-related stigma may not limit wide implementation of CB-DOT in countries like Uganda.

Evolutionary conservation of a testes-specific proteasome subunit gene in Drosophila.

Proteasomes are large multisubunit particles that act as the proteolytic machinery for the ubiquitin-dependent proteolytic pathway. The core of this complex, the 20S proteasome, is made up of seven alpha-type and seven beta-type subunits, arranged in an (alpha1-alpha7)(beta1-beta7)(beta1-beta7)(alpha1-al pha7) configuration. Previous work had shown that there exist alternative isoforms of the Drosophila melanogaster alpha4-type subunit, encoded by two distinct genes, alpha4t1_dm and alpha4t2_dm, and that these are expressed exclusively in the germline of the testes. We sought to investigate the evolutionary conservation of this phenomenon by screening for orthologs of the alpha4-type gene family in the distantly related Drosophila species, D. virilis. We isolated the D. virilis orthologs of the somatically expressed gene, alpha4_dm, and the testes-specific gene, alpha4t2_dm. We failed to find an ortholog of the other testes-specific gene, alpha4t1_dm. The alpha4_dv gene maps to the X chromosome at 12A-C, its product shares 90% amino acid identity with alpha4_dm, and it is expressed at high levels in both males and females. The other gene, alpha4t_dv, encodes a protein most similar to the testes-specific alpha4t2_dm proteasome subunit (59% a.a. identity), and it maps to position 27 on chomosome 2. The expression of the alpha4t_dv gene is testes-specific, like that of alpha4t2_dm. The existence of testes-specific alpha4-type subunits in two widely diverged subgenera of Drosophila suggests that these subunit isoforms have important functional roles in spermatogenesis.

Complete amino acid sequence of fetal bovine serum acetylcholinesterase and its comparison in various regions with other cholinesterases.

The complete amino acid sequence of a mammalian acetylcholinesterase from fetal bovine serum (FBS AChE) is presented. This enzyme has a high degree of sequence identity with other cholinesterases, liver carboxyesterases, esterase-6, lysophospholipase, and thyroglobulin. The locations of 191 amino acids in 10 regions of the FBS enzyme were compared with corresponding sequences of Torpedo, human, and Drosophila AChEs and human serum butyrylcholinesterase (BChE). In one region there is a marked difference in both the number of amino acids and their sequence between mammalian AChE and other AChEs and the human serum BChE. The amino acid sequence of FBS AChE showed overall homologies of 90% with human AChE, 60% with T. california AChE, 50% with human serum BChE, and 39% with Drosophila AChE in these regions.

Personality changes in Alzheimer's disease.

How personality changes in Alzheimer's disease is not well understood. Accentuations of premorbid personality, systematic shifts in personality traits, and specific personality changes affecting subtypes of patients have been postulated. To investigate which of these alternatives occurs in Alzheimer's disease, caregivers were given a comprehensive personality inventory standardized for use by informants. Caregivers observed more neurotic, less extroverted, and less conscientious behavior. To a smaller extent, patients with Alzheimer's disease were reported as becoming less agreeable and less open. The changes in reports of neuroticism, extroversion, agreeableness, and openness suggested consistent systematic shifts across all patients. Patients with depressive features were reported to have been more neurotic; those with paranoid delusions were reported as having been more hostile. Premorbid personality traits may predispose to subsequent psychiatric symptoms in Alzheimer's disease.

Complex visual disturbances in Alzheimer's disease.

Although Alzheimer's disease (AD) involves visual association cortex, previous studies have not systematically investigated complex visual disturbances in AD. We examined 30 community-based AD patients, 13 (43%) of whom had complex visual complaints, and compared them with 30 controls on 7 types of complex visual tasks. Despite preserved visual acuity and color recognition, the AD patients were impaired in the visual evaluation of common objects, famous faces, spatial locations, and complex figures. In the AD patients, we found that all 30 had disturbances in figure-ground analysis; 17 (57%) had difficulties visually recognizing actual objects ("agnosia"); those with worse dementia disability had the most complex visual disturbances; and a subgroup (6) with Balint's syndrome performed the most poorly on the complex visual tasks. This study demonstrates that a range of complex visual disturbances are common in AD and suggests that they may result from the known neuropathology in the visual association cortex.

On the use of surrogate respondents for controls in a case-control study of Alzheimer's disease.

OBJECTIVE: To examine the presence and extent of bias introduced by using surrogate respondents for healthy controls in a case-control study of Alzheimer's disease (AD). DESIGN: Comparative study of matched responses to questionnaire ascertaining lifestyle issues. SETTING: University Hospitals/Case Western Reserve University Alzheimer Center. PARTICIPANTS: Controls (n = 50) were identified through the Research Registry. Surrogates (n = 50) were their healthy relatives or friends. MEASUREMENTS: Answers in the areas of demographic and occupational history, smoking habits, medical history, dietary intake, and leisure and work activities were recorded. The analysis was based on methods for paired data. Continuous variables were analyzed, focusing on paired differences between self and surrogate responses. RESULTS: For occupations and exposures, over 80% of the surrogates agreed with the subjects on over 80% of the questions. On smoking history, over 90% of the surrogates agreed with the subjects on over 70% of the questions. On leisure and work activities, over 70% of the surrogates agreed with the subjects on over 50% of the questions. There was less agreement regarding medical history. For continuous variables, most paired t-tests of zero mean difference between self and surrogate responses resulted in nonrejection of this hypothesis. Computed mean differences were not always positive or always negative. CONCLUSION: We did not find systematic under- or overreporting by the surrogates of the controls. Therefore, if there are biases in the responses of surrogates of the AD cases in our case-control study, they would not be canceled out by using surrogates for the controls.

The relationship of clinical psychopathologic rating and cognitive factors to clinical dementia staging.

1. Sixty-six patients were assessed by one of three physicians employing CERAD assessment and were staged by CDR criteria. 2. The same day, trained raters completed the Brief Psychiatric Rating Scale, the Cornell Scale for Depression in Dementia and the Mini-mental State Examination. 3. Clinician's Global Rating of the CDR is strongly related to the Mini-mental State Examination Score. 4. The CDR is insensitive to mild psychopathology in this population.

Relationships among the variables age, weight, A/B behaviour, cholesterol, ways of coping and blood pressure levels.

This study investigated the interrelationship between serum cholesterol levels, coping responses, type A/B behaviour and blood pressure. A convenience sample of 191 working women completed a health history which included sociodemographic data and a 'Ways of Coping' checklist. In addition, they underwent a structured interview--for type A/B behaviour and were monitored every minute for blood pressure changes, before, during and after the interview. A stepwise regression revealed that four variables; age, weight, A/B type and cholesterol, explained 22% of variance in blood pressure levels. Further analysis showed that type B's used 'Seeking Social Support' significantly more than type A's.

Relative risk of untreated hypertension in type-A employed African American women.

The purpose of this study was to determine the relative risk of hypertension in African American women with type A behaviour pattern. Of the 305 employed African American women, 147 (48.2%) were classified as type A and 158 (51.8%) as type B. The logistic regression procedure was used to calculate the adjusted relative risk of having an elevated SBP by controlling for age, weight and cholesterol. We found that the adjusted relative risk of type A African American women having an elevated SBP and DBP was 9.06 and 2.26 times that of type B, respectively.

Structure and functions of a dimeric form of surfactant protein SP-C: a Fourier transform infrared and surfactometry study.

Surfactant proteins SP-B (M(r) = 8700, reduced) and SP-C (M(r) = 3000-6000, major form, non-reduced) interact with surfactant phospholipids to enhance their surface active properties. In the present study, we describe the structural and functional characteristics of a novel dimeric form of bovine SP-C (M(r) = 9000, non-reduced), which is identified as [SP-C]2. Dimeric SP-C exhibits surface tension-lowering properties differing from those of monomeric SP-C and enhances the surface properties of bovine SP-B/phospholipid mixtures. Chemical analysis indicated that [SP-C]2 was not acylated at the cysteinyl residues. Fourier transform-infrared spectroscopy (FT-IR) was utilized to determine the secondary structures of [SP-C]2 in DPPC films. Relative percentages of alpha-helical, beta-sheet, beta-turn and random coil structures were calculated by peak fit analysis of the amide I band of the FT-IR spectra indicating that, in contrast to the helical structure of monomeric SP-C, [SP-C]2 exhibits almost exclusively beta-sheet structure. In addition, only 10% of the amide (backbone) hydrogens exchanged with deuterium of D2O, indicating that the remaining 90% of amide hydrogens were not accessible to D2O due to strong hydrogen bonding or their location in a hydrophobic environment. Dimerization of SP-C effects a major change in secondary structure, a factor which may play a role in the interaction of SP-C with phospholipids in pulmonary surfactant.

The factor structure of the Brief Psychiatric Rating Scale in Alzheimer's disease.

The factor structure of the Brief Psychiatric Rating Scale (BPRS) is well established with young psychiatric patients. A study by Overall and Beller showed, however, that its factor structure was different with geropsychiatric patients. Although the BPRS has been used in assessing the behavioral characteristics of patients with probable Alzheimer's disease (AD), its factor structure has not been established with these patients. The present study investigated the factor structure of the BPRS among patients with clinically diagnosed AD by (NINCDS/ADRDA) criteria. The scale had limited usefulness with outpatients with mild AD. The factor structure obtained was similar to that found with other patient groups, but a unique factor, including the items Tension and Uncooperativeness, probably reflects the behavioral and psychological agitation characteristic of some AD patients. We recommend caution be taken in generalizing data from younger psychiatric samples to older adult patients with dementia.

Assessment of behavioral and affective symptoms in Alzheimer's disease.

Noncognitive behavioral symptoms occurring during the prior week were studied in 34 Alzheimer's disease (AD) patients and 21 spousal control subjects via caregiver and patient interviews using the Behavioral Pathology in Alzheimer's Disease Rating Scale and the Cornell Scale for Depression in Dementia. Delusional or paranoid features were reported in 13 subjects (38%) and hallucinations in six (18%); patients with these psychoticlike symptoms had lower scores on the Folstein's Mini-Mental State Examination. Other behavioral symptoms reported in AD patients included anxiety (50%) and activity disturbances (44%). Six AD subjects (18%) and two controls (10%) showed mild to moderate symptoms of depression; AD subjects were more likely than controls to show behavioral signs and symptoms of depression, but the two groups did not differ in terms of mood-related, cyclical, or physical signs and symptoms.

A partial primary structure of squid hepatopancreas organophosphorus acid anhydrolase.

Earlier studies of OPA anhydrolase from the squid, Loligo pealei, report that the enzyme has a molecular weight near 26 kDa, despite the common observation that SDS-PAGE experiments do not support this conclusion. Recent results from protein sequencing and cloning experiments now suggest that the enzyme found in squid hepatopancreas has a molecular weight of about 42 kDa. The enzyme easily degrades into two fragments of 16 kDa and approximately 26 kDa. N-terminal sequence analyses of the intact enzyme and the 16 kDa fragment blotted from an SDS gel and sequenced from the blot have shown conclusively that the intact 42 kDa protein has a blocked N-terminus. Sequence data obtained previously are from the N-terminal portion of the 16 kDa fragment. Additional support for this interpretation has been obtained from PCR analysis of L. pealei mRNA and cDNA. The partial (30 residue) sequence presented here reveals no indication of similarity to any other OPA anhydrolase or aryldialkylphosphatase (EC 3.1.8.1.).

Using telecomputing to provide information and support to caregivers of persons with dementia.

The Alzheimer's Disease Support Center (ADSC) is a telecomputing-based project designed to provide information and support to caregivers of persons with dementia. Inherent features of telecomputing make computer-mediated information and support systems like the ADSC a viable complement to existing efforts to meet caregivers' needs. This article outlines the rationale for the ADSC and describes its context, structure, content, and operation.