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.

Consent for cataract surgery training: a national trainers' survey.

AIMS: To evaluate current trainers' attitudes and practices for informing patients about the trainee participation in cataract surgery within the United Kingdom. METHODS: An anonymous online survey was distributed to current cataract surgery trainers via all Royal College of Ophthalmologists' tutors within the United Kingdom. Trainers were asked specific questions about their current consent practice regarding trainee participation in the cataract surgery. Questions also targeted experiences of patient complaints about training. RESULTS: One hundred and twenty-three trainers completed the survey. Ninety-three percent (n=114) of responders were consultants and 7% (n=8) were non-consultant career-grade doctors or other grades. A total of 34% (n=42) of responders stated that consent was usually taken by themselves or the trainee assigned to the list, whereas 26% (n=32) always took consent themselves. Sixty percent of responders (n=74) stated that consent is taken on the day of surgery; 59% (n=73) indicated consent is taken where listing takes place. Thirty-three percent (n=41) of trainers indicated that they had experienced patient dissatisfaction or complaints. Surgical complications, length of surgery, and discussions during surgery were the leading causes of complaints. Thirty-nine percent (n=48) would operate themselves if patients requested no trainee participation. CONCLUSIONS: There is a wide variety in the current practice of disclosure and level of information given regarding trainee participation in surgery. This will influence patients' expectations, experiences, and satisfaction.

Hepatitis C seropositivity is not a risk factor for sensory neuropathy among patients with HIV.

BACKGROUND: Sensory neuropathy (SN) is common in patients with HIV. Hepatitis C (HCV) coinfection is often cited as an HIV-SN risk factor, but data to support this are lacking. This collaboration aimed to examine the association between HCV serostatus and SN risk among ambulatory HIV-positive patients. METHODS: Patients with HIV were assessed in cross-sectional studies in Baltimore, Jakarta, Johannesburg, Kuala Lumpur, Melbourne, and Sydney for SN (defined by both supportive symptoms and signs). HCV seropositivity was assessed as an SN risk using a chi(2) test, followed by logistic regression modeling to correct for treatment exposures and demographics. RESULTS: A total of 837 patients of African, Asian, and Caucasian descent were studied. HCV seroprevalence varied by site (Baltimore n = 104, 61% HCV+; Jakarta 96, 51%; Johannesburg 300, 1%; Kuala Lumpur 97, 10%; Melbourne 206, 16%; Sydney 34, 18%). HCV seropositivity was not associated with increased SN risk at any site, but was associated with reduced SN risk in Melbourne (p = 0.003). On multivariate analyses, the independent associations with SN were increasing age, height, and stavudine exposure. HCV seropositivity was not independently associated with an increased SN risk at any site, but associated independently with reduced SN risk in Baltimore (p = 0.04) and Melbourne (p = 0.06). CONCLUSIONS: Hepatitis C (HCV) seropositivity was not associated with increased sensory neuropathy risk among HIV-positive patients at any site. While we were unable to assess HCV RNA or liver damage, the data suggest that HCV coinfection is not a major contributor to HIV-SN. HCV = hepatitis C; SN = sensory neuropathy.

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.

Age and height predict neuropathy risk in patients with HIV prescribed stavudine.

OBJECTIVE: Sensory neuropathy is a common problem in HIV-infected patients and is the dose-limiting toxicity of stavudine. Affordable methods of predicting neuropathy risk are needed to guide prescribing in countries where some use of stavudine remains an economic necessity. We therefore aimed to identify factors predictive of neuropathy risk before antiretroviral use. METHODS: A total of 294 patients attending clinics in Melbourne, Kuala Lumpur, and Jakarta were enrolled in a cross-sectional neuropathy screening program in 2006. Neuropathy was defined by the presence of symptoms and signs on the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Demographic, laboratory, and treatment details were considered as possible risk factors for neuropathy. The role of patient demographics in predicting stavudine neuropathy were then assessed in 181 patients who reported that they were free of neuropathy symptoms when first prescribed this drug. RESULTS: The prevalence of neuropathy was 42% in Melbourne (n = 100), 19% in Kuala Lumpur (n = 98), and 34% in Jakarta (n = 96). In addition to treatment exposures, increasing age (p = 0.002) and height (p = 0.001) were independently associated with neuropathy. Age and height cutoffs of > or=170 cm or > or =40 years predicted neuropathy. Among 181 patients who were asymptomatic before stavudine exposure, the risk of neuropathy following stavudine was 20% in younger, shorter patients, compared with 66% in older, taller individuals. CONCLUSIONS: Stavudine neuropathy risk increases with patient age and height. Prioritizing older and taller patients for alternative agents would be an inexpensive strategy to reduce neuropathy rates in countries where the burden of HIV disease limits treatment options.

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.

Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993-2006.

OBJECTIVES: The aim of the study was to describe the prevalence of and risk factors for HIV-associated sensory neuropathy (HIV-SN) in 2006 [the era of stavudine, didanosine and zalcitabine (dNRTI)-sparing highly active antiretroviral therapy (HAART)] and to compare our findings with data obtained in the same clinic in 1993 (pre-HAART) and 2001 (frequent use of dNRTI-containing HAART). METHODS: This was a cross-sectional comparative study using convenience sampling. HIV-positive adults attending a tertiary referral clinic over a 2-week period were screened for HIV-SN using the AIDS Clinical Trials Group screening tool. HIV-SN was defined as present if the patient had both neuropathic symptoms and abnormal signs. Demographic, clinical, laboratory and treatment data were considered as possible risk factors for HIV-SN, and results were compared with data obtained in the same clinic in 1993 and 2001. RESULTS: One hundred patients were screened. The prevalence of HIV-SN was 42%, which was unchanged since 2001 (44%) despite a significant reduction in the use of dNRTIs. HIV-SN remained much more common than in 1993 (42% vs 13%; P<0.0001). The only independent associations with HIV-SN in 2006 were increasing patient age and a history of exposure to either stavudine or indinavir. This compares with 1993 when neuropathy was increased in those with Mycobacterium avium complex infection, and 2001 when patient age and use of stavudine and didanosine were the independent associations with HIV-SN in this clinic. CONCLUSIONS: HIV-SN remained common among ambulatory patients in 2006 (42% prevalence) despite a significant reduction in the use of dNRTIs. In addition to patient age and stavudine exposure, indinavir use may be a risk factor for HIV-SN.

Does depression prior to caregiving increase vulnerability to depressive symptoms among caregivers of persons with Alzheimer's disease?

Based on the vulnerability model of depression, this study tested the hypothesis that caregivers with prior depression are more likely to be depressed during caregiving than caregivers without prior depression. We further hypothesized an interaction effect in which caregivers with prior depression would be affected more by care-recipient dependency in activities of daily living and care-recipient depressive symptoms than those without prior depression. In a sample of 111 caregivers of persons with Alzheimer's disease, in an additive regression model, neither 'prior depressive symptoms' nor the clinically more serious 'prior depressive syndrome' was related to depressive symptoms during caregiving. In an interaction model, for caregivers with either 'no prior depression' or 'prior depressive symptoms,' the greater the care-recipient dependencies in instrumental activities of daily living (IADL), the greater were the depressive symptoms during caregiving. For caregivers with a 'prior depressive syndrome', however, the greater the IADL dependency, the fewer were the depressive symptoms during caregiving. This unexpected finding suggests that caregivers with a history of clinically significant depression are not necessarily more prone to depressive symptoms when caregiving responsibilities, at least for instrumental activities, are high. This result questions the vulnerability model of depression when applied to older caregivers.

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.

Worker functions and traits associated with occupations and the development of AD.

OBJECTIVE: To investigate the association between Alzheimer disease (AD) and worker functions and traits associated with occupations. BACKGROUND: Studies have reported that occupational attainment is related to AD. However, most have not identified specific worker functions and traits (i.e., occupational demands) of occupations that may explain the association, nor have they accounted for changing occupational demands over time. METHODS: Within- and between-group differences in mental, motor, physical, and social occupational demands of 122 AD cases and 235 control subjects were compared across four decades of life (20s, 30s, 40s, and 50s) using repeated-measures analyses of covariance adjusted for race, gender, year of birth, and education. RESULTS: Overall, mental occupational demands were significantly lower and physical occupational demands were significantly higher for cases than for control subjects. Case/control differences in mental demand scores were not found in their 20s but only in later decades. Differences in physical demands were found in all decades but their 30s. Social and motor demands did not differ between cases and control subjects. Among cases only, there were no significant occupational demand score differences across decades. In contrast, mental and social demand scores of control subjects increased in later decades, and motor demand scores declined. Like cases, physical demand scores of control subjects remained stable across the decades. CONCLUSIONS: The authors' results may indicate a relatively early influence of Alzheimer disease neuropathology on capacity to pursue mentally demanding occupations. However, results also are consistent with the notion that mentally demanding occupations have a direct influence on Alzheimer disease neuropathology.

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.

A longitudinal study of the relationship between levels of depression among persons with Alzheimer's disease and levels of depression among their family caregivers.

The purpose of this study was to examine the effects, over time, of depressive symptoms in persons with Alzheimer's disease on depression in their family caregivers. In a sample of 353 patients and caregivers, multilevel longitudinal analysis was used to accommodate an observational design in which the number of observation points and the intervals between points varied across caregivers. The rate of change (increase) in caregiver depression was predicted by the rate of change (increase) in patient depressive symptoms and by increase in patient dependency in instrumental activities of daily living (ADLs). Acceleration of the increase in caregiver depression was predicted by acceleration in patient dependency in instrumental and basic ADLs but not by acceleration in patient depressive symptoms. These findings indicate the importance of measuring the rate and acceleration of change in patient characteristics in order to understand caregiver depression. They also support early interventions for caregivers.

Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members.

The development of Alzheimer's disease (AD) later in life may be reflective of environmental factors operating over the course of a lifetime. Educational and occupational attainments have been found to be protective against the development of the disease but participation in activities has received little attention. In a case-control study, we collected questionnaire data about 26 nonoccupational activities from ages 20 to 60. Participants included 193 people with probable or possible AD and 358 healthy control-group members. Activity patterns for intellectual, passive, and physical activities were classified by using an adaptation of a published scale in terms of "diversity" (total number of activities), "intensity" (hours per month), and "percentage intensity" (percentage of total activity hours devoted to each activity category). The control group was more active during midlife than the case group was for all three activity categories, even after controlling for age, gender, income adequacy, and education. The odds ratio for AD in those performing less than the mean value of activities was 3.85 (95% confidence interval: 2.65-5.58, P < 0.001). The increase in time devoted to intellectual activities from early adulthood (20-39) to middle adulthood (40-60) was associated with a significant decrease in the probability of membership in the case group. We conclude that diversity of activities and intensity of intellectual activities were reduced in patients with AD as compared with the control group. These findings may be because inactivity is a risk factor for the disease or because inactivity is a reflection of very early subclinical effects of the disease, or both.

Effects of educational attainment on the clinical expression of Alzheimer's disease: results from a research registry.

The "reserve" hypothesis suggests that education should affect the clinical expression of Alzheimer's disease (AD), but results from studies examining this idea are not consistent. In a single study, we evaluated the effects of educational attainment on three aspects of the clinical expression of AD: age at symptom onset, rate of cognitive decline, and survival. Subjects were 258 persons with mild- or moderate-stage Alzheimer's, drawn from our AD Research Registry. With statistical adjustment for confounding variables present in a clinic-based design, we found that higher educational attainment was associated with slightly earlier reports of symptom onset and a slower rate of cognitive decline on the Mini-Mental State Exam (MMSE). Education did not affect time of survival until death. We conclude that, for subjects in our sample, education had modest effects on aspects of the clinical expression of AD. These effects were not fully consistent with predictions derived from the "reserve" hypothesis.

MCE activities and malathion resistances in field populations of the australian sheep blowfly (Lucilia cuprina).

Malathion resistance has been shown to be the result of a single point mutation in the LcalphaE7 gene in four independently isolated chromosomes of Lucilia cuprina. The resultant amino acid substitution specifies high malathion carboxylesterase (MCE) activity. We have assayed MCE activities and resistance to malathion in three sets of field-derived samples, two sets of isogenic lines and five mass populations, and show that resistance to malathion in these samples is associated with high MCE activity in both sets of isogenic lines and four of the five mass populations. Additional mechanisms contributing to MCE activity or malathion resistance may be present in one of the mass populations. A second point mutation in LcalphaE7 is responsible for conferring diazinon resistance by encoding an increased organophosphate (OP) hydrolase activity. We also assayed diazinon resistances from the same three samples and show that diazinon and malathion resistances were in complete disequilibrium, with two exceptions. One exception involves the mass population with additional resistance mechanism(s) and the other involves three isogenic lines that are resistant to both insecticides. The molecular data for these lines suggest that they carry a duplication of the LcalphaE7 gene.