Depression in Mexican Americans with diagnosed and undiagnosed diabetes.

BACKGROUND: Depression and diabetes commonly co-occur; however, the strength of the physiological effects of diabetes as mediating factors towards depression is uncertain. METHOD: We analyzed extensive clinical, epidemiological and laboratory data from n = 2081 Mexican Americans aged 35-64 years, recruited from the community as part of the Cameron County Hispanic Cohort (CCHC) divided into three groups: Diagnosed (self-reported) diabetes (DD, n = 335), Undiagnosed diabetes (UD, n = 227) and No diabetes (ND, n = 1519). UD participants denied being diagnosed with diabetes, but on testing met the 2010 American Diabetes Association and World Health Organization definitions of diabetes. Depression was measured using the Center for Epidemiological Studies - Depression (CES-D) scale. Weighted data were analyzed using dimensional and categorical outcomes using univariate and multivariate models. RESULTS: The DD group had significantly higher CES-D scores than both the ND and UD (p ⩽ 0.001) groups, whereas the ND and UD groups did not significantly differ from each other. The DD subjects were more likely to meet the CES-D cut-off score for depression compared to both the ND and UD groups (p = 0.001), respectively. The UD group was also less likely to meet the cut-off score for depression than the ND group (p = 0.003). Our main findings remained significant in models that controlled for socio-demographic and clinical confounders. CONCLUSIONS: Meeting clinical criteria for diabetes was not sufficient for increased depressive symptoms. Our findings suggest that the 'knowing that one is ill' is associated with depressive symptoms in diabetic subjects.

Hepatitis C virus in Mexican Americans: a population-based study reveals relatively high prevalence and negative association with diabetes.

This study aimed to estimate the prevalence and risk factors for hepatitis C virus (HCV) infection in Mexican Americans living in South Texas. We tested plasma for the presence of HCV antibody from the Cameron County Hispanic Cohort (CCHC), a randomized, population-based cohort in an economically disadvantaged Mexican American community on the United States/Mexico border with high rates of chronic disease. A weighted prevalence of HCV antibody of 2·3% [n = 1131, 95% confidence interval (CI) 1·2-3·4] was found. Participants with diabetes had low rates of HCV antibody (0·4%, 95% CI 0·0-0·9) and logistic regression revealed a statistically significant negative association between HCV and diabetes (OR 0·20, 95% CI 0·05-0·77) after adjusting for sociodemographic and clinical factors. This conflicts with reported positive associations of diabetes and HCV infection. No classic risk factors were identified, but important differences between genders emerged in analysis. This population-based study of HCV in Mexican Americans suggests that national studies do not adequately describe the epidemiology of HCV in this border community and that unique risk factors may be involved.

Persisting role of healthcare settings in hepatitis C transmission in Pakistan: cause for concern.

Transmission of hepatitis C (HCV) in Pakistan is a continuing public health problem; 15 years ago it was linked to the practice of reusing therapeutic instruments in healthcare settings. We sought to examine current risk factors for HCV transmission in a hospital population in Karachi, Pakistan. We enrolled 300 laboratory-confirmed HCV-positive participants and 300 laboratory confirmed HCV-negative participants from clinics at Indus Hospital. Independent and significant risk factors for both men and women were: receiving o12 injections in the past year, blood transfusions, having had dental work performed, and delivery in hospital or transfusion for women. Interestingly, being of Mohajir origin or born in Sindh province were protective.Encouragingly, a strong protective effect was observed for those that reported bringing their own needle for injections (59%). The widespread reuse of therapeutic needles in healthcare settings in Karachi remains a major driver of the HCV epidemic.

Host susceptibility to tuberculosis: insights from a longitudinal study of gene expression in diabetes.

Tuberculosis (TB) remains a major global disease, and diabetes, which is documented to increase susceptibility to TB threefold, is also becoming pandemic. This susceptibility has been attracting extensive research interest. The increased risk of TB in diabetes may serve as a unique model to understand host susceptibility to specific pathogens in humans. To examine this rationale, we investigated the expression of reported TB candidate genes in a longitudinal diabetes study. Two genes, HK2 and CD28, emerged as potential culprits in diabetes-increased TB susceptibility.

The sensitivity of interferon-gamma release assays is not compromised in tuberculosis patients with diabetes.

SETTING AND OBJECTIVES: the sensitivity of the interferon-gamma release assays (IGRAs) in the detection of Mycobacterium tuberculosis infection or disease may be affected by immune dysregulation in diabetes. As millions of type 2 diabetes patients are at risk for tuberculosis (TB) worldwide, it is important to determine if the sensitivity of IGRAs is compromised in this vulnerable population. DESIGN: the sensitivity of the IGRAs QuantiFERON®-TB Gold (QFT-G) and T-SPOT®.TB was evaluated among specimens from newly diagnosed adults with microbiologically confirmed TB with and without diabetes. We also evaluated the association between QFT-G results and diabetes-associated conditions (dyslipidemia, obesity). RESULTS: QFT-G sensitivity was 70% among TB patients. Patients with diabetes, chronic hyperglycemia or overweight/obesity were more than twice as likely to have positive test results in multivariate models (P < 0.05). Low high-density lipoprotein cholesterol or high triglycerides were not associated with assay results. In a separate group of TB patients (n = 43), T-SPOT.TB was 93% sensitive, with similar performance in patients with and without diabetes. CONCLUSION: IGRA sensitivity is not compromised by diabetes in TB patients. Accordingly, IGRAs may also be suitable for diagnosing TB infection in diabetes patients, which is required to assess TB risk.

Type 2 diabetes and tuberculosis in a dynamic bi-national border population.

The epidemic of type 2 diabetes in the United States prompted us to explore the association between diabetes and tuberculosis (TB) on the South Texas-Mexico border, in a large population of mostly non-hospitalized TB patients. We examined 6 years of retrospective data from all TB patients (n=5049) in South Texas and northeastern Mexico and found diabetes self-reported by 27.8% of Texan and 17.8% of Mexican TB patients, significantly exceeding national self-reported diabetes rates for both countries. Diabetes comorbidity substantially exceeded that of HIV/AIDS. Patients with TB and diabetes were older, more likely to have haemoptysis, pulmonary cavitations, be smear positive at diagnosis, and remain positive at the end of the first (Texas) or second (Mexico) month of treatment. The impact of type 2 diabetes on TB is underappreciated, and in the light of its epidemic status in many countries, it should be actively considered by TB control programmes, particularly in older patients.

Towards a human Lassa fever vaccine.

Arenaviruses, such as Lassa fever, establish chronic infections in rodents, leading to incidental transmission to humans. Lassa fever is a clinically severe disease, yet the absence of second attacks implies life-long immunity. The aim of this review is to consider whether such immunity could be provided by vaccines. The South American arenaviruses are controlled by neutralising antibody and a clinical trial of live, attenuated vaccine for Argentinian haemorrhagic fever provided 84% protection. In contrast, there is no evidence for protective humoral immunity against Old World arenaviruses which are controlled by cell-mediated immune responses. Nevertheless, vaccination with Lassa glycoproteins can protect monkeys from disease, implying that protection may be achievable, even though the immunological mechanisms are distinct. Recombinant vaccinia viruses expressing various forms of Lassa glycoproteins can protect both guinea-pigs and primates, while additional protective responses can be mounted against nucleocapsid genes. However, vaccines based upon vaccinia constructs are no longer tenable for African populations with a high seroprevalence of HIV infection. The scientific challenge now remains to find alternative methods of delivering T-cell immunity against glycoproteins from Lassa virus in ways which can overcome the local economic and political hurdles to vaccine development.

Human asymptomatic Ebola infection and strong inflammatory response.

BACKGROUND: Ebola virus is one of the most virulent pathogens, killing a very high proportion of patients within 5-7 days. Two outbreaks of fulminating haemorrhagic fever occurred in northern Gabon in 1996, with a 70% case-fatality rate. During both outbreaks we identified some individuals in direct contact with sick patients who never developed symptoms. We aimed to determine whether these individuals were indeed infected with Ebola virus, and how they maintained asymptomatic status. METHODS: Blood was collected from 24 close contacts of symptomatic patients. These asymptomatic individuals were sampled 2, 3, or 4 times during a 1-month period after the first exposure to symptomatic patients. Serum samples were analysed for the presence of Ebola antigens, virus-specific IgM and IgG (by ELISA and western blot), and different cytokines and chemokines. RNA was extracted from peripheral blood mononuclear cells, and reverse transcriptase-PCR assays were done to amplify RNA of Ebola virus. PCR products were then sequenced. FINDINGS: 11 of 24 asymptomatic individuals developed both IgM and IgG responses to Ebola antigens, indicating viral infection. Western-blot analysis showed that IgG responses were directed to nucleoprotein and viral protein of 40 kDa. The glycoprotein and viral protein of 24 kDa genes showed no nucleotide differences between symptomatic and asymptomatic individuals. Asymptomatic individuals had a strong inflammatory response characterised by high circulating concentrations of cytokines and chemokines. INTERPRETATION: This study showed that asymptomatic, replicative Ebola infection can and does occur in human beings. The lack of genetic differences between symptomatic and asymptomatic individuals suggest that asymptomatic Ebola infection did not result from viral mutations. Elucidation of the factors related to the genesis of the strong inflammatory response occurring early during the infectious process in these asymptomatic individuals could increase our understanding of the disease.

Effective vaccine for lassa fever.

Lassa fever has been estimated to cause 5,000 deaths annually in West Africa. Recently, war in the zone where Lassa fever is hyperendemic has severely impeded control and treatment. Vaccination is the most viable control measure. There is no correlation between antibody levels and outcome in human patients, and inactivated vaccines produce high titers of antibodies to all viral proteins but do not prevent virus replication and death in nonhuman primates. Accordingly, we vaccinated 44 macaques with vaccinia virus-expressed Lassa virus structural proteins separately and in combination, with the object of inducing a predominantly TH1-type immune response. Following Lassa virus challenge, all unvaccinated animals died (0% survival). Nine of 10 animals vaccinated with all proteins survived (90% survival). Although no animals that received full-length glycoprotein alone had a high titer of antibody, 17 of 19 survived challenge (88%). In contrast, all animals vaccinated with nucleoprotein developed high titers of antibody but 12 of 15 died (20% survival). All animals vaccinated with single glycoproteins, G1 or G2, died, but all those that received both single glycoproteins (G1 plus G2) at separate sites survived, showing that both glycoproteins are independently important in protection. Neither group had demonstrable antibody levels prior to challenge. We demonstrate that in primates, immune responses to epitopes on both glycoproteins are required to protect against lethal challenge with Lassa virus without having untoward side effects and that this protection is likely to be primarily cell mediated. We show that an effective, safe vaccine against Lassa virus can and should be made and that its evaluation for human populations is a matter of humanitarian priority.

Diagnosis of Ebola haemorrhagic fever by RT-PCR in an epidemic setting.

This study reports the first field evaluation of a new diagnostic technique for Ebola virus disease with sensitivity and specificity. Ebola virus causes rare but fulminating outbreaks in Equatorial Africa. Rapid differentiation from other infections is critical for timely implementation of public health measures. Patients usually die before developing antibodies, necessitating rapid virus detection. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay was developed, implemented and evaluated at Centre International de Recherches Médicales de Franceville (CIRMF) in Gabon, to detect Ebola viral RNA in peripheral blood mononuclear cells (PBMC). Twenty-six laboratory-confirmed patients during and 5 after the acute phase of Ebola haemorrhagic fever, 15 healthy controls and 20 febrile patients not infected with Ebola virus were studied. RT-PCR results were compared with ELISA antigen capture, and Ebola specific IgM and IgG antibody detection. Ebola virus RNA was amplified from 26/26 specimens from the acute phase, 3/5 during recovery, 0/20 febrile patients and 1/15 negative controls. Sensitivity of RT-PCR in identifying acute infection and early convalescence compared with antigen or IgM detection was 100% and 91% respectively, and specificity compared with antigen detection and IgM assay combined was 97%. Antigen capture detected only 83% of those identified by PCR, and IgM only 67%. Ebola virus RNA was detected in all 13 fatalities, only 5 of whom had IgM and none IgG. RT-PCR detected Ebola RNA in PBMC one to three weeks after disappearance of symptoms when antigen was undetectable. RT-PCR was the most sensitive method and able to detect virus from early acute disease throughout early recovery.

Apoptosis in fatal Ebola infection. Does the virus toll the bell for immune system?

In fatal Ebola virus hemorrhagic fever massive intravascular apoptosis develops rapidly following infection and progressing relentlessly until death. While data suggest that T lymphocytes are mainly deleted by apoptosis in PBMC of human fatal cases, experimental Ebola infection in animal models have shown some evidence of destruction of lymphocytes in spleen and lymph nodes probably involving both T and B cells. Nevertheless, we are able to conclude from the accumulated evidence that early interactions between Ebola virus and the immune system, probably via macrophages, main targets for viral replication, lead to massive destruction of immune cells in fatal cases.

Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients.

Ebola virus is very pathogenic in humans. It induces an acute hemorrhagic fever that leads to death in about 70% of patients. We compared the immune responses of patients who died from Ebola virus disease with those who survived during two large outbreaks in 1996 in Gabon. In survivors, early and increasing levels of IgG, directed mainly against the nucleoprotein and the 40-kDa viral protein, were followed by clearance of circulating viral antigen and activation of cytotoxic T cells, which was indicated by the upregulation of FasL, perforin, CD28 and gamma interferon mRNA in peripheral blood mononuclear cells. In contrast, fatal infection was characterized by impaired humoral responses, with absent specific IgG and barely detectable IgM. Early activation of T cells, indicated by mRNA patterns in peripheral blood mononuclear cells and considerable release of gamma interferon in plasma, was followed in the days preceding death by the disappearance of T cell-related mRNA (including CD3 and CD8). DNA fragmentation in blood leukocytes and release of 41/7 nuclear matrix protein in plasma indicated that massive intravascular apoptosis proceeded relentlessly during the last 5 days of life. Thus, events very early in Ebola virus infection determine the control of viral replication and recovery or catastrophic illness and death.

Household members of hepatitis C virus-infected people in Hafizabad, Pakistan: infection by injections from health care providers.

Household members of people with hepatitis C are at increased risk of HCV infection. The prevalence and routes of transmission of HCV to household members in Hafizabad, Pakistan were investigated. Household members of 24 index cases were given a risk factor questionnaire, tested for HCV infection, and the risk factors between the infected and uninfected were compared. Twelve of 74 household members (16.2%) were seropositive for HCV antibody. This was 2(1/2) times the rate of infection in the general population (OR = 2.8; P = 0.01). None of the routes of transmission studied within the household was associated with an increased risk. Household members who received more than 4 injections per year were 11.9 times more likely to be infected than those who had not (P = 0.016). In Hafizabad, the greatest risk for HCV infection to household members of infected people is injections given by health-care workers rather than household contact with infected persons.

Expansion of epidemic dengue viral infections to Pakistan.

OBJECTIVES: Antibodies to dengue viruses have occasionally been reported in individuals in Pakistan, but the frequency of occurrence of dengue infection in Pakistan is unclear. The first confirmed dengue hemorrhagic fever outbreak in Pakistan occurred in 1994. In October 1995, the authors investigated an outbreak of a febrile illness among employees of a construction contractor at a power generation plant in Baluchistan, Pakistan, to determine the cause of illness and recommend appropriate preventive measures. METHODS: The work site and living arrangements were inspected, a questionnaire was administered, and serum samples were collected from all consenting contractor employees and their families if they lived at the camp. Sera were analyzed for IgM against dengue virus, using an enzyme-linked immunosorbent assay. RESULTS: Interviews were conducted with 76 persons (mean age, 42y); 95% were men. Forty-two persons (55%) reported having experienced fever, headache, or myalgia in the preceding 6 weeks. Fifty-seven subjects (75%) had IgM antibodies against at least one dengue serotype; 45 subjects (59%) had IgM antibodies against dengue serotype 2. CONCLUSION: This was an outbreak of dengue fever due to multiple serotypes of dengue virus. This confirms that epidemic dengue infection was present in southern Pakistan for 2 consecutive years.

Risk factors for typhoid fever in an endemic setting, Karachi, Pakistan.

We conducted a study to evaluate risk factors for developing typhoid fever in a setting where the disease is endemic in Karachi, Pakistan. We enrolled 100 cases with blood culture-confirmed Salmonella typhi between July and October 1994 and 200 age-matched neighbourhood controls. Cases had a median age of 5.8 years. In a conditional logistic regression model, eating ice cream (Odds ratio [OR] = 2.3; 95% confidence interval [CI] 1.2-4.2, attributable risk [AR] = 36%), eating food from a roadside cabin during the summer months (OR = 4.6, 95% CI 1.6-13.0; AR = 18%), taking antimicrobials in the 2 weeks preceding the onset of symptoms (OR = 5.7, 95% CI 2.3-13.9, AR = 21%), and drinking water at the work-site (OR = 44.0, 95% CI 2.8-680, AR = 8%) were all independently associated with typhoid fever. There was no difference in the microbiological water quality of home drinking water between cases and controls. Typhoid fever in Karachi resulted from high-dose exposures from multiple sources with individual susceptibility increased by young age and prior antimicrobial use. Improving commercial food hygiene and decreasing unnecessary antimicrobial use would be expected to decrease the burden of typhoid fever.

Cholera in a developing megacity; Karachi, Pakistan.

Despite rapid urbanization and increasing affluence in Karachi, cases of cholera are frequent. We analysed computerized isolation data from the AKUH Clinical Microbiology Laboratory, Karachi, from 1990-6 to examine microbiological, temporal and demographic trends in Vibrio cholerae infections. During this period 888 strains of V. cholerae (566 V. cholerae serogroup O1, and 204 V. cholerae serogroup O139) were isolated from specimens from 886 patients; 214/464 were adult inpatients, and 250/464 paediatric inpatients, the remaining 422 outpatients. Isolations peaked between June and August. Overlapping epidemics occurred in 1993 and 1994 of serogroup O1 (May to August), and serogroup O139 (August to October). All ages and social and economic strata were affected. Forty-four percent of all isolates were from children under the age of 5 years. The mean age of all patients with serogroup O1 infections was 19.6 years (+/-0.9) compared with 367 (+/-1.7) for serogroup O139 infections (P < 0.0001, t test). More than a quarter (27%) of all serogroup O1 isolates were from babies under 2 years of age. One patient had a serogroup O1 infection followed by a serogroup O139 infection 1 year later. Another patient was infected with serogroup O1 strains 5 years apart. Emergence of resistant strains was observed, but by 1996 serogroup O139 had disappeared. An aquatic organism, cholera nevertheless continues to take its toll in this city of 11 million situated in a desert.

PIP: An analysis of computerized isolation data from the Aga Khan University Hospital Clinical Microbiology Laboratory (Karachi, Pakistan) for the 1990-96 period was performed to identify microbiologic, temporal, and demographic trends in Vibrio cholerae infections. During the study period, 888 strains of V. cholerae (566 V. cholerae serogroup O1 and 204 serogroup O139) were isolated in specimens from 886 patients (214 adult inpatients, 250 child inpatients, and 442 adult and child outpatients). Overlapping epidemics occurred in 1993 and 1994 of serogroup O1 (May-August) and serogroup O139 (August-October). 44% of all isolates involved children under 5 years of age and 27% of serogroup O1 isolates were from those under 2 years of age. There were no differences in cholera infection by socioeconomic status. The mean age of patients with serogroup O1 infections was 19.6 years compared with 36.7 years for those with serogroup O139 infections (p 0.0001). 1 patient had a serogroup O1 infection followed by a serogroup O139 infection 12 months later. Another patient was infected with serogroup O1 strains 5 years apart. Although emergence of resistant strains was observed, serogroup O139 had disappeared by 1996. These findings confirm the continuing presence of cholera in Karachi--a desert community with infrequent rainfall--and document its seasonal and temporal periodicity.

Opportunistic candidiasis: an epidemic of the 1980s.

Hospital discharge data from 1980 to 1989 from the National Center for Health Statistics, National Hospital Discharge Survey (NHDH), and two commercially generated hospital discharge data sources (PAS and McAuto) were analyzed to document nationally the increased rate of opportunistic candidal infections among hospitalized patients in the 1980s and to identify the major risk factors. National projections were made by year. Age-, sex-, race-, and disease-specific denominators were generated from NHDS data. ICD-9-CM codes derived from discharge diagnoses were used to identify patients with oropharyngeal candidiasis, disseminated candidiasis, human immunodeficiency virus (HIV) infection/AIDS, or malignancies and transplants. Between 1980 and 1989, rates of oropharyngeal candidiasis increased 4.7 times (from 0.34 to 1.6 cases per 1,000 admissions per year), and the number of deaths among patients with oropharyngeal candidiasis increased fivefold. Although the highest rates were among pediatric patients (3 cases per 1,000 pediatric admissions), the greatest rate increases were among 15- to 44-year-old patients (13-fold) and males (fivefold). Between 1983 and 1989, the rates of oropharyngeal candidiasis among patients with HIV infections/AIDS rose more than 22 times (from 0.02 to 0.45 case per 1,000 admissions; NHDS data). Over the whole decade, the rates of disseminated candidiasis increased 11 times (from 0.013 to 0.15 case per 1,000 admissions). Between 1985 and 1989, the rate of this complication among patients with HIV infection/AIDS increased 10-fold, compared with only a twofold rate increase among patients with malignancies or transplants. The rate of debilitating and life-threatening candidiasis among hospitalized patients increased considerably over the 1980s. This rate increase was significant among patients with HIV infection/AIDS and patients undergoing transplantation or immunosuppressive therapy for malignancies.

Review of cases of nosocomial Lassa fever in Nigeria: the high price of poor medical practice.

OBJECTIVE: To investigate two hospital outbreaks of Lassa fever in southern central Nigeria. SETTING: Hospitals and clinics in urban and rural areas of Imo State, Nigeria. DESIGN: Medical records were reviewed in hospitals and clinics in both areas. Patients with presumed and laboratory confirmed Lassa fever were identified and contracts traced. Hospital staff, patients, and local residents were questioned, records were carefully reviewed, and serum samples were taken. Serum samples were assayed for antibody specific to Lassa virus, and isolates of Lassa virus were obtained. RESULTS: Among 34 patients with Lassa fever, including 20 patients, six nurses, two surgeons, one physician, and the son of a patient, there were 22 deaths (65% fatality rate). Eleven cases were laboratory confirmed, five by isolation of virus. Most patients had been exposed in hospitals (attack rate in patients in one hospital 55%). Both outbreak hospitals were inadequately equipped and staffed, with poor medical practice. Compelling, indirect evidence revealed that parenteral drug rounds with sharing of syringes, conducted by minimally educated and supervised staff, fuelled the epidemic among patients. Staff were subsequently infected during emergency surgery and while caring for nosocomially infected patients. CONCLUSION: This outbreak illustrates the high price exacted by the practice of modern medicine, particularly use of parenteral injections and surgery, without due attention to good medical practice. High priority must be given to education of medical staff in developing countries and to guidelines for safe operation of clinics and hospitals. Failure to do so will have far reaching, costly, and ultimately devastating consequences.