Health effects of mold in children

Mold is ubiquitous, and exposure to mold and its products of metabolism is unavoidable, whether indoors or outdoors. Mold can produce a variety of adverse health outcomes by four scientifically validated pathophysiologic mechanisms: hypersensitivity, toxicity, infection, and irritation. Some adverse health outcomes have been attributed to mold for which mechanisms of injury are not well defined or are implausible. This article discusses these adverse health outcomes, focusing predominantly on those for which valid associations have been established.     

Characterization of novel Mycobacterium tuberculosis pncA gene mutations in clinical isolates from the Ukraine

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis cases in the Ukraine are increasing. Pyrazinamide (PZA) is critically important for first- and second-line tuberculosis (TB) treatment regimes. However, PZA drug susceptibility testing is time consuming and technically challenging. The present study utilized Next-generation sequencing (NGS) to identify mutations in the pncA gene from clinical isolates and to assess the prevalence of pncA gene mutations in MDR/XDR-TB patients. Clinical isolates were inactivated in molecular transport media and shipped from Kharkiv, Ukraine, to San Antonio, TX. Whole-genome and targeted pncA gene sequencing was carried out using Illumina MiSeq instrumentation. Mutations were noted in 67 of 91 (74%) clinical isolates comprising substitutions, insertions, and deletions in the pncA coding and upstream promoter region. Of 45 mutation types, there were 11 novel, i.e., to date unknown, pncA mutations identified of which 3 were confirmed PZA resistant. Seven isolates contained mixed base mutations, whereas 4 harbored doubled mutations. Data reported here further support use of NGS for pncA gene characterization and may contribute in significant fashion to PZA therapy, especially in MDR- and XDR-TB patients.     

National Survey of Clerkship Directors in Internal Medicine on the Competencies That Should Be Addressed in the Medicine Core Clerkship

PURPOSE: To prioritize competencies that should be addressed in the medicine core clerkship, assess factors influencing this prioritization, and estimate the percentage of clerkship time that should be devoted to inpatient versus outpatient care.METHODS: A national survey of the Clerkship Directors in Internal Medicine (CDIM) was used. Using explicit criteria, respondents assigned priority scores, on a 1 to 5 scale, to 17 general competencies and 60 disease-specific clinical competencies pertinent to care of adult patients in inpatient. ambulatory, intensive care, and emergency settings.RESULTS: Ninety-three (75%) of 124 CDIM members responded. The highest mean priority scores were assigned to 6 general competencies: case presentation skills (4.65), diagnostic decision-making (4.64), history and physical diagnosis (4.61), test interpretation (4.47), communication with patients (4.35), and therapeutic decision-making (4.12). Disease-specific clinical competency areas receiving the highest mean priority scores were: hypertension (4.57), coronary disease (4.53), diabetes mellitus (4.45), heart failure (4.42), pneumonia (4.39), chronic obstructive pulmonary disease (4.26), acid-base/electrolyte disorders (4.19), and acute chest pain (4.08). Priorities for general competencies were moderately correlated with importance to the practice of general internists (mean Spearman rho 0.49) and with importance to students pursuing careers outside internal medicine (mean Spearman rho 0.45), but only weakly correlated with the adequacy with which a competency was addressed in other parts of the curriculum. Respondents' mean recommended allocation of clerkship time was: 52% inpatient, 33% ambulatory care, 8% intensive care, and 7% emergency medicine. This time allocation did not differ by any characteristics of respondents.CONCLUSION: There is consensus among medicine clerkship directors that the medicine core clerkship should emphasize fundamental competencies and devote at least one third of the time to clinical competencies pertinent to ambulatory care.     

Combined procoagulant activity and proteolytic activity of acute promyelocytic leukemic cells: reversal of the bleeding disorder by cell differentiation

In the human promyelocytic cell line HL60, we observed both a strong procoagulant activity (PCA) on the cell membrane and proteolytic activity in the lysate of these cells. Because these cell-line cells are susceptible to differentiation to either a more mature granulocytic or monocytic form, we were able to study the hypothesis that the combination of PCA and proteolytic activity is confined to the promyelocyte. This may explain the severe coagulopathy seen in patients with acute promyelocytic leukemia. Cell differentiation in a myeloid direction induced by retinoic acid or DMSO led to a diminished PCA, while not affecting the fibrinolytic activity. On the other hand, monocytic differentiation obtained by culturing the cells in the presence of 1; 25 dihydroxy vitamin D3 led to the complete disappearance of the proteolytic activity of the cell lysate, although the procoagulant activity was still present. Furthermore, we found that the elastase activity almost disappeared after monocytic differentiation. We also studied the PCA, proteolytic activity, and elastase activity of blast cells of patients with acute myeloid leukemia. Only in patients with acute promyelocytic leukemia did we observe both a strong PCA and fibrinolytic activity. This supports our hypothesis that the combination of these activities is unique to the promyelocyte and may explain the observed bleeding complications in patients with acute promyelocytic leukemia.     

Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin

Ferroportin Q248H mutation has an allele frequency of 2.2–13.4% in African populations and is associated with a mild tendency to increased serum ferritin in the general population. Some investigators have reported that ferroportin Q248H is degraded after exposure to hepcidin in exactly the same manner as wild-type ferroportin, but supraphysiological concentrations of hepcidin were used. The aim of our study was to determine whether ferroportin Q248H may have reduced sensitivity to physiological concentrations of hepcidin. The sensitivity of ferroportin Q248H to hepcidin was determined in 293T cells transiently expressing ferroportin using immunoblotting and fluorescence analysis. Ferritin concentrations were measured in these cells and also in human primary monocytes derived from humans with different ferroportin genotypes. The effect of Q248H on serum iron measures was examined in patients with sickle cell anemia. Immunoblotting and fluorescence analysis showed decreased sensitivity of ferroportin Q248H to physiological concentrations of hepcidin. Lower ferritin concentrations were observed after incubation with iron and hepcidin in 293T cells expressing ferroportin Q248H and in primary monocytes from ferroportin Q248H subjects. In sickle cell anemia, ferroportin Q248H heterozygotes had lower serum ferritin concentrations than wild-type subjects, consistent with enhanced iron release by macrophage ferroportin Q248H. A clinical benefit of ferroportin Q248H was suggested by lower echocardiographic estimates of pulmonary artery pressure in patients carrying mutant alleles. In conclusion, our results suggest that ferroportin Q248H protein is resistant to physiological concentrations of hepcidin and that this mutation has discernible effects on iron metabolism-related clinical complications of sickle cell anemia. They provide a mechanistic explanation for the effect of ferroportin Q248H on iron status in individuals of African descent and suggest that these changes in iron metabolism may be beneficial under certain disease-specific circumstances.(ClinicalTrials.gov Identifier:{"type":"clinical-trial","attrs":{"text":"NCT00011648","term_id":"NCT00011648"}}NCT00011648).