Beneficial effects of insulin-like growth factor I on epithelial structure and function in parenterally fed rat jejunum

BACKGROUND & AIMS: The functional significance of intestinal hyperplasia stimulated by insulin-like growth factor (IGF)-I is unclear and has not been studied in a model of mucosal atrophy induced by total parenteral nutrition (TPN). The aim of this study was to determine how IGF-I affects intestinal structure and epithelial function in the absence of luminal nutrition caused by TPN. METHODS: Rats were maintained with TPN with or without IGF-I (800 micrograms/day), and jejunal histology and epithelial ion transport were measured after 5 days. In a third TPN group without IGF-I, a short-term dose of IGF-I was added during in vitro flux chamber experiments. RESULTS: Rats given TPN with IGF-I had greater jejunal mucosal weight, greater protein and DNA content, and increased villus height and crypt depth compared with rats given TPN only. TPN increased ionic permeability and ion transport responses to secretory and absorptive agents. IGF-I in vivo reversed most of these changes; IGF-I in vitro enhanced sodium-dependent glucose absorption but had no other effects. CONCLUSIONS: Coinfusion of recombinant human IGF-I with TPN solution stimulates intestinal hyperplasia and attenuates transport changes induced by TPN. The latter effect seems to be primarily associated with the growth state of the epithelium. (Gastroenterology 1996 Dec;111(6):1501-8)     

The major histocompatibility complex region marked by HSP70-1 and HSP70- 2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat- shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.     

Effect of Different Irrigation Solutions on the Diffusion of MTA Cement into the Root Canal Dentin

(1) Aim: This study aims to analyze the in vitro infiltration of a silicate root canal sealer into dentinal tubules after using different endodontic irrigating solutions. (2) Methods: Twenty-nine teeth with single roots were separated into three groups according to the final irrigation protocol: G1 n = 10) = 17% EDTA (ethylenediaminetetraacetic acid) + 3.0% sodium hypochlorite (NaOCl), G2 (n = 10) = 17% EDTA + 2.0% chlorhexidine and G3 (Control group, n = 9) = 17% EDTA + saline solution. Root canals were filled using cold lateral compaction technique with MTA Fillapex sealer and gutta-percha. The sealer was labeled with rhodamine B. The teeth were segmented at the middle and third apical sections, which were visualized using 10× confocal laser microscopy to determine the sealer penetration percentage. (3) Results: In the apical section, no statistically significant differences were found between the groups regarding sealer penetration. In the middle section, Group 1 obtained the highest percentage, and Group 2 the lowest (p = 0.004). Group 1 also presented statistically significant differences in the Control Group (p = 0.031) and had close sealer penetration values. Meanwhile, the Control Group (p = 0.023) and Group 2 (p = 0.029) revealed a significant decrease of sealer penetration between the apical and middle sections. (4) Conclusion: The obtained results support that final irrigation with NaOCl promoted similar sealer penetration in the apical and middle sections. On the other hand, a significant decrease in the sealer penetration of the middle section was observed for the chlorhexidine and saline groups. Compared to other irrigant solutions, NaOCl promotes more uniform sealer penetration, which can correlate with better sealing and, consequently, higher endodontic treatment success.     

Analysis of ASPM in an ethnically diverse cohort of 400 patient samples: perspectives of the molecular diagnostic laboratory

Primary Autosomal Recessive Microcephaly (MCPH) is characterized by congenital microcephaly usually without additional clinical findings. The most common gene implicated in MCPH is ASPM and a large percentage of mutations described have been homozygous and in consanguineous families primarily of East Asian and Middle Eastern origin. ASPM sequencing was performed on 400 patients between the years 2009 and 2012. Seventy of the patient samples were also analyzed for copy number changes in the ASPM gene. Forty protein truncating mutations, including 29 novel mutations, were identified in 39 patients with MCPH. Approximately one third of patients were compound heterozygotes, indicative of non‐consanguinity in these patients. In addition, 46 non‐synonymous variants were identified and interpreted as variants of uncertain significance. No deletion/duplication in ASPM was identified in the patients analyzed. A wide ethnic distribution was observed, including the first reported patients with ASPM‐related MCPH of Hispanic descent. Clinical information was collected for 26 of the ASPM‐positive patients and 41 of the ASPM‐negative patients. As more individuals are identified with MCPH, we anticipate that we will continue to identify ASPM mutation‐positive patients from all ethnic origins supporting the occurrence of this genetic condition beyond that of consanguineous families of certain ethnic populations.     

Active tuberculosis in inflammatory bowel disease patients under treatment from an endemic area in Latin America

BACKGROUNDThere has been an increase in cases of inflammatory bowel disease (IBD) in recent years. There is also greater access and availability of immunosuppressive and biological agents, which increase the risk of opportunistic infection despite improving the quality of life and promoting mucosal healing. Tuberculosis (TB) remains a public health problem, and it has a high incidence in several countries. Therefore, knowledge of the risk of developing TB in patients with IBD is important.AIMTo evaluate the risk of active TB in patients with IBD under treatment from an endemic area in Latin America.METHODSA standard questionnaire included demographic variables, clinical aspects of IBD disease, history of active TB during treatment, active TB characteristics and evolution, initial screening and results and time from the start of anti-tumor necrosis factor alpha (TNFα) to TB development.RESULTSAzathioprine, anti-TNFα and the combination of these two drugs were associated with a higher risk of active TB incidence. The TNFα blockers increased the relative risk of developing active TB compared to other treatments. All four multivariable models showed that the use of TNFα blockers alone or in combination with azathioprine was an important risk factor for the incidence of active TB. After adjustment for sex, age, type of IBD and latent TB, anti-TNFα with azathioprine increased the relative risk to 17.8 times more than conventional treatment. Late TB, which was diagnosed 3 mo after the start of anti-TNFα, was the most frequent.CONCLUSIONTreatment with anti-TNFα increased the risk of active TB in IBD patients from an endemic area in Latin America. This risk was increased when anti-TNFα was combined with azathioprine. The time from the beginning of the treatment to the active TB diagnosis suggests a new TB infection.     

Securing sustainable funding for viral hepatitis elimination plans

The majority of people infected with chronic hepatitis C virus (HCV) in the European Union (EU) remain undiagnosed and untreated. During recent years, immigration to EU has further increased HCV prevalence. It has been estimated that, out of the 4.2 million adults affected by HCV infection in the 31 EU/ European Economic Area (EEA) countries, as many as 580 000 are migrants. Additionally, HCV is highly prevalent and under addressed in Eastern Europe. In 2013, the introduction of highly effective treatments for HCV with direct‐acting antivirals created an unprecedented opportunity to cure almost all patients, reduce HCV transmission and eliminate the disease. However, in many settings, HCV elimination poses a serious challenge for countries’ health spending. On 6 June 2018, the Hepatitis B and C Public Policy Association held the 2nd EU HCV Policy summit. It was emphasized that key stakeholders should work collaboratively since only a few countries in the EU are on track to achieve HCV elimination by 2030. In particular, more effort is needed for universal screening. The micro‐elimination approach in specific populations is less complex and less costly than country‐wide elimination programmes and is an important first step in many settings. Preliminary data suggest that implementation of the World Health Organization (WHO) Global Health Sector Strategy on Viral Hepatitis can be cost saving. However, innovative financing mechanisms are needed to raise funds upfront for scaling up screening, treatment and harm reduction interventions that can lead to HCV elimination by 2030, the stated goal of the WHO.     

Assessment of inhaler techniques employed by patients with respiratory diseases in southern Brazil: a population-based study

OBJECTIVE:

To identify incorrect inhaler techniques employed by patients with respiratory diseases in southern Brazil and to profile the individuals who make such errors.

METHODS:

This was a population-based, cross-sectional study involving subjects ≥ 10 years of age using metered dose inhalers (MDIs) or dry powder inhalers (DPIs) in 1,722 households in the city of Pelotas, Brazil.

RESULTS:

We included 110 subjects, who collectively used 94 MDIs and 49 DPIs. The most common errors in the use of MDIs and DPIs were not exhaling prior to inhalation (66% and 47%, respectively), not performing a breath-hold after inhalation (29% and 25%), and not shaking the MDI prior to use (21%). Individuals ≥ 60 years of age more often made such errors. Among the demonstrations of the use of MDIs and DPIs, at least one error was made in 72% and 51%, respectively. Overall, there were errors made in all steps in 11% of the demonstrations, whereas there were no errors made in 13%.Among the individuals who made at least one error, the proportion of those with a low level of education was significantly greater than was that of those with a higher level of education, for MDIs (85% vs. 60%; p = 0.018) and for DPIs (81% vs. 35%; p = 0.010).

CONCLUSIONS:

In this sample, the most common errors in the use of inhalers were not exhaling prior to inhalation, not performing a breath-hold after inhalation, and not shaking the MDI prior to use. Special attention should be given to education regarding inhaler techniques for patients of lower socioeconomic status and with less formal education, as well as for those of advanced age, because those populations are at a greater risk of committing errors in their use of inhalers.