Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene

Human surfactant protein C (hSP-C(1-197)) is synthesized as a 197 amino acid proprotein and cleaved to a mature 3.7 kD form. Although interstitial lung disease in patients with mutations of the hSP-C gene is becoming increasingly recognized, the mechanisms linking molecular events with clinical pathogenesis are not fully defined. We describe a full-term infant with respiratory insufficiency associated with a spontaneous heterozygous mutation resulting in a substitution of lysine for glutamic acid at position 66 (= E66K) of the proximal hSP-C COOH flanking propeptide. Lung histology and biochemical studies of the index patient (hSP-C(E66K)) revealed nonspecific interstitial pneumonia, increased alveolar total phospholipid lacking phosphatidylglycerol, and increased surfactant protein A. Localization of proSP-C from lung sections prepared from this patient using immunofluorescence and immunogold electron microscopy revealed abnormal proSP-C staining in endosomal-like vesicles of type II cells distinct from SP-B. To evaluate the effect of the E66K substitution on intracellular trafficking of proSP-C, fusion proteins consisting of enhanced green fluorescent protein (EGFP) and hSP-C(1-197) (wild type) or mutant hSP-C(E66K) were generated and transfected into A549 cells. EGFP/hSP-C(1-197) was expressed within CD-63-positive, EEA-1-negative vesicles, whereas EGFP/hSP-C(E66K) localized to EEA-1 positive vesicles. The E66K substitution is representative of a new class of SP-C mutation associated with interstitial lung disease that is diverted from the normal biosynthetic pathway. We propose that, similar to other storage disorders, lung injury results from induction of a toxic gain of function induced by the mutant product that is subject to genetic modifiers and environmental influences.     

Loss of muscarinic M4 receptors in spinal cord of arthritic rats: implications for a role of M4 receptors in pain response

Changes in the levels of muscarinic M4 receptors in spinal cord of acute and chronic arthritic rats (animal models of pain) were studied by receptor autoradiography using muscarinic M4 receptor subtype selective ligand. Arthritis was induced in female Lewis rats by single intradermal injection of heat-killed Mycobacterium butyricum and sacrificed 12 days (acute group) and 30 days (chronic and control groups) after induction of arthritis. Our results demonstrate significant reduction in the level of M4 receptors in the spinal cord (Rexed laminae I-X) of acute and chronic arthritic rats compared to controls. These findings suggest that the muscarinic M4 receptor subtype may be involved in cholinergic mechanisms of analgesia.     

Dual-energy CT of the heart for diagnosing coronary artery stenosis and myocardial ischemia-initial experience

We aimed to evaluate the feasibility of diagnosing coronary stenosis and myocardial ischemia with a single dual-energy CT (DECT) acquisition. Thirty-five patients underwent contrast-enhanced, ECG-gated DECT of the heart while independently operating the two tubes of a dual-source CT system at high- and low-energy X-ray spectra. From the same raw data, coronary CTA (cCTA) studies were reconstructed for stenosis detection, and the myocardial blood-pool was analyzed by determining the tissue iodine content. Two independent observers analyzed all studies for stenosis and myocardial blood-pool deficits. Results were correlated with SPECT, coronary catheterization and cCTA on a segmental basis. cCTA had 98% sensitivity, 88% specificity and 92% accuracy for detection of >50% stenosis. DECT detected myocardial ischemia with 84% sensitivity, 94% specificity and 92% accuracy. Our initial experience may warrant further exploration of DECT as a possibly feasible single imaging investigation for the comprehensive diagnosis of coronary stenosis and myocardial ischemia. Electronic Supplementary Material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Differential Fos expression in the paraventricular nucleus of the hypothalamus, sacral parasympathetic nucleus and colonic motor response to water avoidance stress in Fischer and Lewis rats

The responsiveness of hypothalamic CRF to various stressors is reduced in the young female Lewis relative to the histocompatible Fischer rat. Whether such a difference impacts the brain-gut response to water avoidance stress was investigated by monitoring Fos immunoreactivity in the brain and sacral spinal cord and fecal pellet output. Exposure for 60 min to water avoidance stress increased the number of Fos positive cells in the paraventricular nucleus of the hypothalamus (PVN), nucleus tractus solitarius (NTS), and the parasympathetic nucleus of the lumbo-sacral spinal cord (L6-S1) in both Lewis and Fischer rats compared with non stress groups. The Fos response was lower by 32.0% in the PVN, and 63% in sacral parasympathetic nucleus in Lewis compared with Fischer rats while similar Fos expression was observed in the NTS. Stress-induced defecation was reduced by 52% in Lewis compared with Fischer rats while colonic motor response to CRF injected intracisternally resulted in a similar pattern and magnitude of defecation in both strains. The CRF receptor antagonist [ -Phe12,Nle^21,38C^aMeLeu³⁷]-CRF_12–41 injected intracisternally antagonized partly the defecation response in Lewis and Fischer rats. These data indicate that a lower activation of PVN and sacral parasympathetic nuclei in Lewis compared with Fisher rats may contribute to the differential colonic motor response and that the blunted CRF hypothalamic response to stress, unlike responsiveness to central CRF plays a role.     

Significant hospitalization cost savings to the payer with a pharmacist-led mobile health intervention to improve medication safety in kidney transplant recipients

This was an economic analysis of a 12-month, parallel arm, randomized controlled trial in adult kidney recipients 6 to 36 months posttransplant (NCT03247322). All participants received usual posttransplant care, while the intervention arm received supplemental clinical pharmacist-led medication therapy monitoring and management, via a smartphone-enabled mHealth app, integrated with risk-based televisits. Hospitalization charges were captured from the study institution accounts payable and non-study institution hospitalization charges were estimated using multiple imputation. Multivariable modeling was used to assess the impact of the intervention on charges. The intervention significantly reduced rates of hospitalization (1.08 per patient-year in the control arm vs 0.65 per patient-year in the intervention arm, p = .007). The control arm had estimated hospitalization costs of $870,468 vs $390,489 in the intervention arm. Modeling demonstrated a 49% lower hospitalization charge risk in the intervention arm (RR 0.51, 95% CI 0.28-0.91; p = .022). From a payer or societal perspective, the net estimated cost savings, after accounting for intervention delivery costs, was $368,839, with a return on investment (ROI) of $4.30 for every $1 spent. These results demonstrate that a mHealth-enabled, pharmacist-led intervention significantly reduced hospitalization costs for payers over a 12-month period and has a positive ROI.     

Somalia: supporting the child survival agenda when routine health service is broken

Somalia, one of the most unstable countries in the world, has been without a permanent government for nearly 2 decades. With a health system in total disarray, coverage of basic health interventions remains low and, maternal and child mortality is among the highest in the world. Health partners jointly outlined an integrated package of critical child survival interventions to be delivered through a population-based delivery strategy known as Child Health Days (CHDs), to reduce child mortality. Using this strategy, key child survival interventions are delivered to the community with an objective of reaching children <5 years and women of childbearing age in all districts of Somalia every 6 months. Through this strategy, immunization services were reached in remote areas, and coverage disparity between the urban and rural areas was reduced from 17% (42% urban and 25% rural) to 10% (50% urban and 60% rural). In addition, infants were reached with a third dose of diphtheria-pertussis-tetanus vaccine, achieving 51% coverage during 2009 and 66% in 2010. This paper summarizes the challenges of scaling up child interventions in the troubled context of Somalia by reviewing the planning, implementation, and achievements of CHDs as well as reflecting on challenges for the future of child survival in Somalia.     

Racial and Ethnic Differences in Cardio-Metabolic Risk in Individuals with Undiagnosed Diabetes: National Health and Nutrition Examination Survey 1999–2008

Background

Although early recognition and treatment of diabetes may be essential to prevent complications, roughly one-fifth of diabetes remains undiagnosed.

Objective

Examine cardio-metabolic risk factors and their control in non-Hispanic white (NHW), non-Hispanic black (NHB) and Mexican American (MA) individuals with undiagnosed diabetes.

Design

Nationally representative cross-sectional study of participants in the National Health and Nutrition Examination Survey (NHANES) continuous cycles conducted 1999 through 2008.

Participants

Of 22,621 non-pregnant individuals aged ≥20 years, 2521 had diagnosed diabetes. Of the remaining 20,100 individuals, 17,963 had HbA1c measured, 551 of whom were classified as having undiagnosed diabetes and comprise the study population.

Main Measures

Undiagnosed diabetes was defined as HbA1c ≥ 6.5% without a self-report of physician diagnosed diabetes. Cardio-metabolic risk factor control was examined using regression methods for complex survey data.

Key Results

Among individuals with undiagnosed diabetes, mean HbA1c level was 7.7% (95% CI: 7.5, 7.9), 19.3% (95% CI: 14.2, 24.3) smoked, 59.7% (95% CI: 54.5, 64.8%) had hypertension and 96.5% (95% CI: 94.6, 98.4%) had dyslipidemia. Lipid profiles were remarkably different across racial-ethnic groups: NHB had the highest LDL- and HDL-cholesterol, but the lowest triglycerides, while MA had the highest triglycerides and the lowest LDL-cholesterol. After adjusting for age, sex, NHANES examination cycle and use of either blood pressure or lipid medication, the odds of having blood pressure ≥130/80 mmHg was higher in NHB [1.92 (95% CI: 1.09, 3.55)] than NHW, while the odds of having LDL-cholesterol >100 mg/dl was higher in NHW[2.93 (95% CI: 1.37, 6.24)] and NHB[3.34 (95% CI: 1.08, 10.3)] than MA.

Conclusions

In a nationally representative sample of individuals with undiagnosed diabetes, cardio-metabolic risk factor levels were high across all racial/ethnic groups, but NHB and MA had poorer control compared to NHW. Interventions that target identification of diabetes and treatment of cardio-metabolic risk factors are needed.KEY WORDS: undiagnosed diabetes, disparities, cardio-metabolic risk, HbA1c     

Prevalence and antibiogram of bacterial isolates from urinary tract infections at Dessie Health Research Laboratory,Ethiopia

Objective

To determine the prevalence and antimicrobial susceptibility of bacteria from suspected urinary tract infections.

Methods

A retrospective analysis of bacterial pathogens and their antimicrobial susceptibility was done on urine samples at Dessie Regional Laboratory in the period 2003 to 2010. Antimicrobial susceptibility tests were done using disc diffusion technique as per the standard of Kirby-Bauer method.

Results

The male to female ratio of the patients was 1:1.96. Of the total 1 404 samples, 319 (22.7%) were culture positive. Escherichia coli was the dominant isolate (63.6%) followed by Klebsiella spp. (8.5%) and Proteus spp. (8.2%). The overall resistance rates to erythromycin, amoxycillin, and tetracycline were 85.6%, 88.9% and 76.7%, respectively. The three most frequently isolated bacteria had resistance rates of 80.1%-90.0% to, amoxycillin, and tetracycline and sensitivity rates of 0 to 25% to nitrofurantoin, ciprofloxacin and gentamicin. Antibiogram of isolates showed that 152 (47.85%) isolates were resistance to two and more antimicrobials.

Conclusions

In the study area resistance rates to erythromycin, amoxycillin and tetracycline were high. Since most isolates were sensitive to nitrofurantoin and gentamicin, they are considered as appropriate antimicrobials for empirical treatment urinary tract infections.