Diabetes causes decreased osteoclastogenesis, reduced bone formation, and enhanced apoptosis of osteoblastic cells in bacteria stimulated bone loss

The most common cause of inflammatory bone loss is periodontal disease. After bacterial insult, inflammation induces bone resorption, which is followed by new reparative bone formation. Because diabetics have a higher incidence and more severe periodontitis, we examined mechanisms by which diabetes alters the response of bone to bacterial challenge. This was accomplished with db/db mice, which naturally develop type 2 diabetes. After inoculation of bacteria osteoclastogenesis and bone resorption was measured. Both parameters were decreased in the diabetic group. Diabetes also suppressed reparative bone formation measured histologically and by the expression of osteocalcin. The impact of diabetes on new bone formation coincided with the effect of diabetes on apoptosis of bone-lining cells. Within 5 d of bacterial challenge, apoptosis declined in the wild-type animals yet remained significantly higher in the diabetic group. Thus, diabetes may cause a net loss of bone because the suppression of bone formation is greater than the suppression of bone resorption. The uncoupling of bone formation and resorption may be due in part to prolonged apoptosis of bone lining cells.     

Diabetes enhances mRNA levels of proapoptotic genes and caspase activity, which contribute to impaired healing

We previously reported that after a bacteria-induced wound in the scalp, type 2 diabetic (db/db) mice had higher levels of apoptosis of fibroblasts and bone-lining cells that are critical for healing compared with normoglycemic controls. To investigate mechanisms by which this might occur, RNA profiling and caspase activity was measured after inoculation of Porphyromonas gingivalis. Diabetes caused a more than twofold induction of 71 genes that directly or indirectly regulate apoptosis and significantly enhanced caspase-8, -9, and -3 activity. The functional significance of diabetes-induced apoptosis was studied by treating diabetic mice with a pancaspase inhibitor, z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone). Inhibiting apoptosis significantly improved several parameters of healing, including fibroblast density, enhanced mRNA levels of collagen I and III, and increased matrix formation. Improvements were also noted in bone, with an increase in the number of bone-lining cells and new bone formation. Thus, diabetes-enhanced apoptosis represents an important mechanism through which healing is impaired, and this can be explained, in part, by diabetes-increased expression of proapoptotic genes and caspase activity.     

Diabetes-enhanced tumor necrosis factor-alpha production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy

Retinal microvascular cell loss plays a critical role in the pathogenesis of diabetic retinopathy. To examine this further, type 1 streptozotocin-induced diabetic rats and type 2 Zucker diabetic fatty rats were treated by intravitreal injection of the tumor necrosis factor-specific inhibitor pegsunercept, and the impact was measured by analysis of retinal trypsin digests. For type 2 diabetic rats, the number of endothelial cells and pericytes positive for diabetes-enhanced activated caspase-3 decreased by 81% and 86%, respectively, when treated with pegsunercept (P < 0.05). Similarly, the number of diabetes-enhanced terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive endothelial cells and pericytes decreased by 81% and 67% respectively when treated with pegsunercept (P < 0.05). Diabetes-increased activated caspase-3- and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive microvascular cell numbers were both reduced by 81% and 80%, respectively, in pegsunercept-treated type 1 diabetic rats (P < 0.05). Inhibition of tumor necrosis factor reduced type 1 diabetes-enhanced pericyte ghost formation by 87% and the number of type 2 diabetes-enhanced pericyte ghosts by 62% (P < 0.05). Similarly, increased acellular capillary formation caused by type 1 and type 2 diabetes was reduced by 68% and 67%, respectively, when treated with pegsunercept (P < 0.05). These results demonstrate a previously unrecognized role of tumor necrosis factor-alpha in promoting the early pathogenesis of diabetic retinopathy leading to loss of retinal microvascular cells and demonstrate the potential therapeutic benefit of modulating its activity.     

P. gingivalis and E. coli lipopolysaccharides exhibit different systemic but similar local induction of inflammatory markers

BACKGROUND: Porphyromonas gingivalis is a Gram-negative bacterium that is an important etiologic agent of human adult periodontitis. The goal of the study was to test the hypothesis that two isoforms of P. gingivalis lipopolysaccharide (PgLPS), PgLPS(1435)(/1449) and PgLPS(1690), exhibit differences in their capacity to stimulate systemic versus local responses compared to Escherichia coli lipopolysaccharide (LPS). METHODS: LPS was inoculated into the scalp of mice, and the response was measured locally at the site of inoculation and systemically in the heart/aorta. Vascular cell adhesion molecule (VCAM)-1 was assessed at the protein level by enzyme-linked immunosorbent assay, and VCAM-1, E-selectin, and intercellular adhesion molecule (ICAM)-1 were assessed at the RNA level of the RNase protection assay. Serum tumor necrosis factor-alpha (TNF-alpha) levels were also measured. RESULTS: E. coli LPS and both isoforms of P. gingivalis LPS were relatively potent in stimulating the expression of inflammatory markers, with E. coli LPS being more potent. In contrast, when the systemic response was measured in the heart/aorta, E. coli LPS, but not P. gingivalis LPS, significantly induced inflammatory markers. At moderate to low doses (1 and 10 microg per injection), serum TNF-alpha levels were minimally induced by P. gingivalis LPS compared to E. coli LPS. CONCLUSIONS: Both forms of P. gingivalis LPS stimulated an inflammatory response when injected into connective tissue but were minimally stimulatory when a systemic response was measured. In contrast, E. coli LPS was a potent stimulus at the systemic and local levels.     

The Role of Food Insecurity and Dietary Diversity on Recovery from Wasting among Hospitalized Children Aged 6–23 Months in Sub-Saharan Africa and South Asia

Background: Current guidelines for the management of childhood wasting primarily focus on the provision of therapeutic foods and the treatment of medical complications. However, many children with wasting live in food-secure households, and multiple studies have demonstrated that the etiology of wasting is complex, including social, nutritional, and biological causes. We evaluated the contribution of household food insecurity, dietary diversity, and the consumption of specific food groups to the time to recovery from wasting after hospital discharge. Methods: We conducted a secondary analysis of the Childhood Acute Illness Network (CHAIN) cohort, a multicenter prospective study conducted in six low- or lower-middle-income countries. We included children aged 6–23 months with wasting (mid-upper arm circumference [MUAC] ≤ 12.5 cm) or kwashiorkor (bipedal edema) at the time of hospital discharge. The primary outcome was time to nutritional recovery, defined as a MUAC > 12.5 cm without edema. Using Cox proportional hazards models adjusted for age, sex, study site, HIV status, duration of hospitalization, enrollment MUAC, referral to a nutritional program, caregiver education, caregiver depression, the season of enrollment, residence, and household wealth status, we evaluated the role of reported food insecurity, dietary diversity, and specific food groups prior to hospitalization on time to recovery from wasting during the 6 months of posthospital discharge. Findings: Of 1286 included children, most participants (806, 63%) came from food-insecure households, including 170 (13%) with severe food insecurity, and 664 (52%) participants had insufficient dietary diversity. The median time to recovery was 96 days (18/100 child-months (95% CI: 17.0, 19.0)). Moderate (aHR 1.17 [0.96, 1.43]) and severe food insecurity (aHR 1.14 [0.88, 1.48]), and insufficient dietary diversity (aHR 1.07 [0.91, 1.25]) were not significantly associated with time to recovery. Children who had consumed legumes and nuts prior to diagnosis had a quicker recovery than those who did not (adjusted hazard ratio (aHR): 1.21 [1.01,1.44]). Consumption of dairy products (aHR 1.13 [0.96, 1.34], p = 0.14) and meat (aHR 1.11 [0.93, 1.33]), p = 0.23) were not statistically significantly associated with time to recovery. Consumption of fruits and vegetables (aHR 0.78 [0.65,0.94]) and breastfeeding (aHR 0.84 [0.71, 0.99]) before diagnosis were associated with longer time to recovery. Conclusion: Among wasted children discharged from hospital and managed in compliance with wasting guidelines, food insecurity and dietary diversity were not major determinants of recovery.     

Prevalence of anemia and its associated factors in human immuno deficiency virus infected adult individuals in Ethiopia. A systematic review and meta-analysis

Background

Anemia is a common hematologic disorder among human Immunodeficiency virus (HIV) infected adult Individuals. However, there is no concrete scientific evidence established at national level in Ethiopia. Hence, this review gave special emphasis on Ethiopian HIV infected adult individuals to estimate pooled prevalence of anemia and its associated factors at national level.

Methods

Studies were retrieved through search engines in PUBMED/Medline, Cochrane Library, and the web of science, Google and Google scholar following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Joanna Briggs Institute Meta-Analysis of Statistical Assessment and Review Instrument (JBI-MAStARI) was used for critical appraisal of the included studies. Random effects meta-analysis was used to estimate the pooled prevalence of anemia and associated factors at 95% Confidence interval with its respective odds ratio (OR). Meta regression was also carried out to identify the factors. Moreover, Sub-group analysis, begs and egger test followed by trim-and-fill analysis were employed to assess heterogeneity and publication bias respectively.

Result

A total of 532 articles were identified through searching of which 20 studies were included in the final review with a total sample size of 8079 HIV infected adult individuals. The pooled prevalence of anemia was 31.00% (95% CI: 23.94, 38.02). Cluster of Differentiation 4 (CD4) count <= 200 cells/μl with OR?=?3.01 (95% CI: 1.87, 4.84), World Health Organization (WHO) clinical stage III&IV with OR?=?2.5 (95% CI: 1.29, 4.84), opportunistic infections (OIs) with OR?=?1.76 (95% CI: 1.07, 2.89) and body mass index (BMI) <?18.5 kg/M² with OR?=?1.55 ((95% CI: 1. 28, 1.88) were the associated factors.

Conclusion

This review demonstrates high prevalence of anemia among HIV infected adults. Low CD4 count, WHO clinical stage III&IV, OIs and low level of BMI were found to have significant association with the occurrence of anemia. Therefore, the responsible stockholders including anti retro viral treatment (ART) clinics should strengthen the system and procedures for the early diagnosis of opportunistic infection and screening of underlying problems. There should be also early screening for OIs and under nutrition with strict and frequent monitoring of HIV infected individuals CD4 count.

     

Diabetes alters the response to bacteria by enhancing fibroblast apoptosis

Diabetics suffer from both more frequent bacterial infections and greater consequences of infection. However, bacteria-induced tissue destruction and the subsequent response in diabetics have received relatively little attention. To investigate this issue, we inoculated the scalp of control or db/db diabetic mice, with the pathogen Porphyromonas gingivalis, which causes connective tissue destruction in humans. Both bacteria-induced cytokine expression and tissue loss were similar in diabetic and control mice. However, there was a significantly higher rate of fibroblast-specific apoptosis in the diabetic group, which was measured as cells that were double positive for the terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling assay and expression of vimentin. The higher rate of fibroblast apoptosis could be explained in the diabetic group by enhanced levels of activated caspase-3. Apoptosis was evident during the peak healing period and coincided with reduced numbers of fibroblasts, diminished collagen I and III expression, and significantly reduced formation of new connective tissue matrix in diabetic mice. Thus, diabetes may impair the healing response to bacteria-induced connective tissue loss by increasing the number of caspase-3-activated fibroblasts, leading to greater apoptosis and reduced numbers of fibroblastic cells.