Cerebrovascular reactivity is impaired in patients with non-insulin-dependent diabetes mellitus and microangiopathy

BACKGROUND: Cerebrovascular reactivity (CVR) is a hemodynamic parameter representing the increase in normal cerebral artery blood flow in response to a vasodilatory stimulus such as hypercapnia. MAIN PURPOSE: The aim of the study was to assess CVR using transcranial Doppler ultrasound and the breath-holding test (BHT) in normotensive patients with non-insulin-dependent diabetes mellitus (NIDDM). The cerebrovascular response to hypercapnia was evaluated in relation to risk factors for cerebral microangiopathy. METHODS: The study was carried out in a group of 34 normotensive NIDDM patients and a group of 31 sex- and age-matched normal controls. The NIDDM group was subdivided into 21 patients with microangiopathic complications (Group A, 12 men, 9 women; mean age 58.77 +/- 8.91 years) and 13 patients with no such complications (Group B, 8 men, 5 women; mean age 56.34 +/- 9.83 years). The control group comprised 17 men and 14 women (Group C, mean age 58.43 +/- 6.31 years). Exclusion criteria were hypertension and past or present symptomatic cerebrovascular disease. The BHT consisted of spontaneous hypercapnia induced by holding the breath for 20 seconds. CVR was estimated in relation to the increase in the mean flow velocity (MFV) compared with the basal velocity in both middle cerebral arteries during hypercapnia. RESULTS: In Group A, the CVR was significantly decreased in 71.42% of patients, whereas in Group B only 30.76% of patients presented with mildly to moderately impaired CVR. Predictors for impaired % increase in the MFV during the BHT demonstrated by univariate regression analysis were: duration of diabetes (r = 0.802; P < 0.0001), fibrinogen (r = 0.574; P < 0.0001), C-reactive protein (r = 0.525; P < 0.001), proteinuria (r = 0.924; P < 0.0001) and serum creatinine (r = 0.969; P < 0.0001). Multivariate regression analysis showed as predictors: duration of diabetes (P < 0.0001), proteinuria (P < 0.0001) and serum creatinine (P < 0.0001). CONCLUSION: CVR is impaired in normotensive NIDDM patients. These cerebral hemodynamic changes correlate significantly with the duration of DM, parameters of inflammation, proteinuria and serum creatinine.     

Live colonocytes in newborn stool: surrogates for evaluation of gut physiology and disease pathogenesis

Studies of gastrointestinal pathophysiology are not feasible by biopsies in human neonates. We examined the utility of live colonocytes in stool in studying cellular markers during early neonatal life. Expression of IgA, IgG, cluster of differentiation-45 cells (CD45), and toll-like receptors-2 and 4 (TLR2 and TLR4) were analyzed by flow cytometry. Colonocyte RNA extracts were used in quantitative real-time PCR (qRT-PCR) to examine the expression of cytokeratin-19, ribosomal protein-24, and tight-junction (Tj) protein zonula occludens-1 (ZO-1). Colonocyte yield varied between 5 × 10? to 2 × 10? cells/g of stool. Meconium samples yielded a highly enriched population of viable cells. Although low, all samples showed CD45-positive cells during the initial weeks of life. Starting as early as d 2, IgA expression was observed in 69% of the cells. Low to moderate expression of IgG was observed with a linear increase as the infants grew. There was an almost total lack of TLR2 staining; however, >55% of the colonocytes showed TLR4 expression. Although high levels of IgA in gut cells may serve as a natural protectant during neonatal period, increased TLR4 may provide a niche for lipopolysaccharide (LPS)-mediated epithelial damage. Use of stool colonocytes can be a valuable noninvasive approach for studying gut pathophysiology in the neonatal period.     

Antenatal maternal hypoxic stress: adaptations in fetal lung Renin-Angiotensin system

Antenatal maternal hypoxia (AMH) can lead to intrauterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult, the latter of which may be a consequence of alterations in the local pulmonary renin-angiotensin system (RAS). Little is known of these adaptations, however. Thus, we tested the hypothesis that antenatal maternal hypoxia is associated with alterations in gene and protein expression of the pulmonary renin-angiotensin system, which may play an important role in pulmonary disorders in the offspring. In FVB/NJ mice, we studied messenger RNA (mRNA) and protein expression, as well as promoter DNA methylation and microRNA (miRNA) levels in response to 48 hours hypoxia (10.5% O(2)) at 15.5 day post coitum (DPC). In response to AMH, the pulmonary mRNA levels of angiotensin-converting enzyme (ACE) 1.2, ACE-2, and angiotensin II type 1b (AT-1b) receptors were increased significantly, as compared to controls (N = 4). In response to antenatal hypoxia, pulmonary protein levels of renin and ACE-2 also were increased significantly, whereas ACE-1 protein expression was reduced. In fetal lungs, we also observed reduced expression of the miRNAs: mmu-mir -199b, -27b, -200b, and -468 that putatively increase the translation of renin, ACE-1, ACE-2, and AT-1 receptors, respectively. In response to AMH, promoter methylation of ACE was unchanged. We conclude that AMH leads to changes in expression of pulmonary RAS of fetal mice. The possible implications of these changes for the regulation of pulmonary vascular contractility in later life remain to be explored.     

Grafted α-hydroxyphosphonic acids onto polymeric supports: preparation,characterization, and antimicrobial effect

The paper deals with the preparation and characterization of compounds with antimicrobial activity: α-hydroxyphosphonic acids grafted onto styrene-12%–(15%)-divinylbenzene copolymer. These products proved to have antimicrobial effect against two species of gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and two species of gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) and a species of yeast (Candida albicans). Tests showed the reduction of bacterial load at different time intervals during the 18 h of contact.     

Autoantibodies to cytosolic 5′‐nucleotidase 1A in inclusion body myositis

The metabolic syndrome and neuropathy are common conditions, especially in the elderly, that are associated with significant morbidity. Furthermore, the metabolic syndrome is reaching epidemic proportions across the world. Current evidence supports the association of the metabolic syndrome and its individual components with neuropathy. Several clinical trials have demonstrated that treating hyperglycemia, a component of the metabolic syndrome, has a significant effect on reducing the incidence of neuropathy in those with type 1 diabetes. However, glucose control has only a marginal effect on preventing neuropathy in those with type 2 diabetes, suggesting that other factors may be driving nerve injury in these patients. Emerging evidence supports the metabolic syndrome as including risk factors for neuropathy. Interventions exist for treatment of all of the metabolic syndrome components, but only glucose control has strong evidence to support its use and is widely employed. Our understanding of the biology of metabolic nerve injury has rapidly expanded over the past several years. Mechanisms of injury include fatty deposition in nerves, extracellular protein glycation, mitochondrial dysfunction, and oxidative stress. Additionally, the activation of counter‐regulatory signaling pathways leads to chronic metabolic inflammation. Medications that target these signaling pathways are being used for a variety of diseases and are intriguing therapeutic agents for future neuropathy clinical trials. As we move forward, we need to expand our understanding of the association between the metabolic syndrome and neuropathy by addressing limitations of previous studies. Just as importantly, we must continue to investigate the pathophysiology of metabolically induced nerve injury. Ann Neurol 2013;74:397–403     

Could there be an interplay between periodontal changes and pancreatic malignancies?

The term periodontal disease refers to a group of chronic inflammatory illnesses caused by specific microorganisms from subgingival biofilm, that affect the tooth-supporting tissues. Recent research has also shown that periodontal infection plays a role in aggravating systemic disease states at distal sites, reinforcing the significance of the oral cavity for general health. Additionally, it has been suggested that gastroenterological malignancies may be promoted by hematogenous, enteral or lymphatic translocation of periopathogens. In the past 25 years, the global burden of pancreatic cancer (PC) has more than doubled, making it one of the major causes of cancer-related mortality. Periodontitis has been linked to at least 50% increased risk of PC and it could be considered a risk factor for this malignancy. A recent study performed on 59000 African American women with a follow up of 21 years showed that participants who had poor dental health had higher chances of PC. The findings, according to researchers, might be related to the inflammation that some oral bacteria trigger. Regarding the mortality of PC, periodontitis considerably raises the chance of dying from PC. Microbiome alterations in the gut, oral cavity and pancreatic tissues of PC patients occur when compared to healthy flora, demonstrating a link between PC and microecology. Inflammation may also contribute to PC development, although the underlying pathway is not yet known. The function of the microbiome in PC risk has drawn more focus over the last decade. Future risk of PC has been linked to the oral microbiome, specifically increased levels of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans and decreased relative abundance of Leptotrichia and Fusobacteria, suggesting that it may have an impact on the inflammatory condition by expanding, altering, and regulating the commensal microbiome. Patients who received periodontal treatment had significantly decreased incidence rate ratios for PC. By analyzing patterns in the microbiome composition throughout PC development and establishing strategies to enhance the cancer-associated microbial system, we can increase the efficacy of therapy and eventually find an application for the microbial system. The development of immunogenomics and gut micro-genomics in the life sciences will result in a significant advancement in our understanding of how microbial systems and immunotherapy interact, and it may also have intriguing therapeutic implications for extending the lifetime of PC patients.