Glycated haemoglobin (HbA1c ) and fasting plasma glucose relationships in sea-level and high-altitude settings.

AIM: Higher haemoglobin levels and differences in glucose metabolism have been reported among high-altitude residents, which may influence the diagnostic performance of HbA1c . This study explores the relationship between HbA1c and fasting plasma glucose (FPG) in populations living at sea level and at an altitude of > 3000 m. METHODS: Data from 3613 Peruvian adults without a known diagnosis of diabetes from sea-level and high-altitude settings were evaluated. Linear, quadratic and cubic regression models were performed adjusting for potential confounders. Receiver operating characteristic (ROC) curves were constructed and concordance between HbA1c and FPG was assessed using a Kappa index. RESULTS: At sea level and high altitude, means were 13.5 and 16.7 g/dl (P > 0.05) for haemoglobin level; 41 and 40 mmol/mol (5.9% and 5.8%; P < 0.01) for HbA1c ; and 5.8 and 5.1 mmol/l (105 and 91.3 mg/dl; P < 0.001) for FPG, respectively. The adjusted relationship between HbA1c and FPG was quadratic at sea level and linear at high altitude. Adjusted models showed that, to predict an HbA1c value of 48 mmol/mol (6.5%), the corresponding mean FPG values at sea level and high altitude were 6.6 and 14.8 mmol/l (120 and 266 mg/dl), respectively. An HbA1c cut-off of 48 mmol/mol (6.5%) had a sensitivity for high FPG of 87.3% (95% confidence interval (95% CI) 76.5 to 94.4) at sea level and 40.9% (95% CI 20.7 to 63.6) at high altitude. CONCLUSION: The relationship between HbA1c and FPG is less clear at high altitude than at sea level. Caution is warranted when using HbA1c to diagnose diabetes mellitus in this setting

An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses

Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients

Geographical variation in the progression of type 2 diabetes in Peru: The CRONICAS Cohort Study.

BACKGROUND: The study aims were to estimate the incidence and risk factors for T2D in four settings with different degree of urbanization and altitude in Peru. METHODS: Prospective cohort study conducted in urban, semi-urban, and rural areas in Peru. An age- and sex-stratified random sample of participants was taken from the most updated census. T2D was defined as fasting blood glucose ⩾7.0mmol/L or taking anti-diabetes medication. Exposures were divided into two groups: geographical variables (urbanization and altitude), and modifiable risk factors. Incidence, relative risks (RR), 95% confidence intervals (95%CI), and population attributable fractions (PAF) were estimated. RESULTS: Data from 3135 participants, 48.8% males, mean age 55.6years, was analyzed. Overall baseline prevalence of T2D was 7.1% (95%CI 6.2-8.0%). At follow-up, including 6207 person-years of follow-up, a total of 121 new T2D cases were accrued, equating to an incidence of 1.95 (95%CI 1.63-2.33) per 100 person-years. There was no urban to rural gradient in the T2D incidence; however, compared to sea level sites, participants living in high altitude had a higher incidence of diabetes (RR=1.58; 95%CI 1.01-2.48). Obesity had the highest attributable risk for developing T2D, although results varied by setting, ranging from 14% to 80% depending on urbanization and altitude. CONCLUSIONS: Our results suggest that the incidence of T2D was greater in high altitude sites. New cases of diabetes were largely attributed to obesity, but with substantial variation in the contribution of obesity depending on the environment. These findings can inform appropriate context-specific strategies to reduce the incidence of diabetes

El Niño adversely affected childhood stature and lean mass in northern Peru

El Niño is responsible for natural disasters and infectious disease outbreaks worldwide. During the 1997–1998 El Niño, northern Peru endured extreme rainfall and flooding. Since short stature may occur as a result of undernutrition or repeated infections during childhood, both of which are highly prevalent during natural disasters, we sought to determine if the 1997–1998 El Niño had an adverse effect on stature and body composition a decade later. In 2008–2009, we measured height, weight, and bioimpedance in a random sample of 2,095 children born between 1991 and 2001 in Tumbes, Peru

Rationing tests for drug-resistant tuberculosis - who are we prepared to miss?

BACKGROUND: Early identification of patients with drug-resistant tuberculosis (DR-TB) increases the likelihood of treatment success and interrupts transmission. Resource-constrained settings use risk profiling to ration the use of drug susceptibility testing (DST). Nevertheless, no studies have yet quantified how many patients with DR-TB this strategy will miss. METHODS: A total of 1,545 subjects, who presented to Lima health centres with possible TB symptoms, completed a clinic-epidemiological questionnaire and provided sputum samples for TB culture and DST. The proportion of drug resistance in this population was calculated and the data was analysed to demonstrate the effect of rationing tests to patients with multidrug-resistant TB (MDR-TB) risk factors on the number of tests needed and corresponding proportion of missed patients with DR-TB. RESULTS: Overall, 147/1,545 (9.5%) subjects had culture-positive TB, of which 32 (21.8%) had DR-TB (MDR, 13.6%; isoniazid mono-resistant, 7.5%; rifampicin mono-resistant, 0.7%). A total of 553 subjects (35.8%) reported one or more MDR-TB risk factors; of these, 506 (91.5%; 95% CI, 88.9-93.7%) did not have TB, 32/553 (5.8%; 95% CI, 3.4-8.1%) had drug-susceptible TB, and only 15/553 (2.7%; 95% CI, 1.5-4.4%) had DR-TB. Rationing DST to those with an MDR-TB risk factor would have missed more than half of the DR-TB population (17/32, 53.2%; 95% CI, 34.7-70.9). CONCLUSIONS: Rationing DST based on known MDR-TB risk factors misses an unacceptable proportion of patients with drug-resistance in settings with ongoing DR-TB transmission. Investment in diagnostic services to allow universal DST for people with presumptive TB should be a high priority

Prevalence and risk factors of restrictive spirometry in a cohort of Peruvian adults

INTRODUCTION: Few studies have described the prevalence of and lung function decline among those with a restrictive spirometric pattern (RSP) in low- and middle-income countries. METHODS: We analyzed prospective data from 3055 adults recruited across four diverse settings in Peru over a 3-year period. Multivariable logistic regression was used to study the association between the presence of restriction and associated risk factors. Multivariable linear mixed models were used to determine lung function decline. RESULTS: Among 3055 participants, the average age was 55.4 years (SD 12.4); 49% were male. Overall prevalence of RSP was 4.7%, ranging from 2.8% (Lima) to 6.9% (Tumbes). The odds of having RSP were higher among those who lived in a rural environment (OR 2.19, 95%CI 1.43–3.37), had a diagnosis of diabetes (OR 1.94, 95%CI 1.10–3.40) and among women (OR 2.09, 95%CI 1.41–3.09). When adjusting for baseline lung function, adults with RSP had accelerated decline in forced expiratory volume in 1 s (FEV1) compared with non-obstructed, non-restricted individuals. DISCUSSION: RSP is prevalent particularly among women and in individuals living in rural settings of Peru. When adjusted for baseline lung function, participants with RSP had accelerated rates of FEV1 decline. Our findings are consistent with the notion that RSP is an insidious inflammatory condition with deleterious effects of lung function decline

G Protein Activation without a GEF in the Plant Kingdom

Animal heterotrimeric G proteins are activated by guanine nucleotide exchange factors (GEF), typically seven transmembrane receptors that trigger GDP release and subsequent GTP binding. In contrast, the Arabidopsis thaliana G protein (AtGPA1) rapidly activates itself without a GEF and is instead regulated by a seven transmembrane Regulator of G protein Signaling (7TM-RGS) protein that promotes GTP hydrolysis to reset the inactive (GDP-bound) state. It is not known if this unusual activation is a major and constraining part of the evolutionary history of G signaling in eukaryotes. In particular, it is not known if this is an ancestral form or if this mechanism is maintained, and therefore constrained, within the plant kingdom. To determine if this mode of signal regulation is conserved throughout the plant kingdom, we analyzed available plant genomes for G protein signaling components, and we purified individually the plant components encoded in an informative set of plant genomes in order to determine their activation properties in vitro. While the subunits of the heterotrimeric G protein complex are encoded in vascular plant genomes, the 7TM-RGS genes were lost in all investigated grasses. Despite the absence of a Gα-inactivating protein in grasses, all vascular plant Gα proteins examined rapidly released GDP without a receptor and slowly hydrolyzed GTP, indicating that these Gα are self-activating. We showed further that a single amino acid substitution found naturally in grass Gα proteins reduced the Gα-RGS interaction, and this amino acid substitution occurred before the loss of the RGS gene in the grass lineage. Like grasses, non-vascular plants also appear to lack RGS proteins. However, unlike grasses, one representative non-vascular plant Gα showed rapid GTP hydrolysis, likely compensating for the loss of the RGS gene. Our findings, the loss of a regulatory gene and the retention of the “self-activating” trait, indicate the existence of divergent Gα regulatory mechanisms in the plant kingdom. In the grasses, purifying selection on the regulatory gene was lost after the physical decoupling of the RGS protein and its cognate Gα partner. More broadly these findings show extreme divergence in Gα activation and regulation that played a critical role in the evolution of G protein signaling pathways

Chagas Cardiomyopathy in the Context of the Chronic Disease Transition

Latin America is undergoing a transition from disease patterns characteristic of developing countries with high rates of infectious disease and premature deaths to a pattern more like industrialized countries, in which chronic conditions such as obesity, hypertension and diabetes are more common. Many rural residents with Chagas disease have now migrated to cities, taken on new habits and may suffer from both types of disease. We studied heart disease among 394 adults seen by cardiologists in a public hospital in the city of Santa Cruz, Bolivia; 64% were infected with T. cruzi, the parasite that causes Chagas disease. Both T. cruzi infected and uninfected patients had a high rate of hypertension (64%) and overweight (67%), with no difference by infection status. Nearly 60% of symptomatic congestive heart failure was due to Chagas disease; mortality was also higher for infected than uninfected patients. Males and older patients had more severe Chagas heart disease. Chagas heart disease remains an important cause of congestive heart failure in this hospital population, but often occurs in patients who also have obesity, hypertension and/or other cardiac risk factors

A Field Trial of Alternative Targeted Screening Strategies for Chagas Disease in Arequipa, Peru

In the wake of emerging T. cruzi infection in children of periurban Arequipa, Peru, we conducted a prospective field trial to evaluate alternative targeted screening strategies for Chagas disease across the city. Using insect vector data that is routinely collected during Ministry of Health insecticide application campaigns in 3 periurban districts of Arequipa, we separated into 4 categories those households with 1) infected vectors; 2) high vector densities; 3) low vector densities; and 4) no vectors. Residents of all infected-vector households and a random sample of those in the other 3 categories were invited for serological screening for T. cruzi infection. Subsequently, all residents of households within a 15-meter radius of detected seropositive individuals were invited to be screened in a ring case-detection scheme. Of 923 participants, 21 (2.28%) were seropositive. There were no significant differences in prevalence across the 4 screening strategies, indicating that household entomologic factors alone could not predict the risk of infection. Indeed, the most predictive variable of infection was the number of years a person lived in a location with triatomine insects. Therefore, a simple residence history questionnaire may be a useful screening tool in large, diverse urban environments with emerging Chagas disease