Glucose Levels as a Mediator of the Detrimental Effect of Abdominal Obesity on Relative Handgrip Strength in Older Adults.

Excess central adiposity accelerates the decline of muscle strength in older people. Additionally, hyperglycemia, independent of associated comorbidities, is related to the loss of muscle mass and strength, and contributes to functional impairment in older adults. We studied the mediation effect of glucose levels, in the relationship between abdominal obesity and relative handgrip strength (HGS). A total of 1571 participants (60.0% women, mean age 69.1 ± 7.0 years) from 86 municipalities were selected following a multistage area probability sampling design. Measurements included demographic and anthropometric/adiposity markers (weight, height, body mass index, and waist circumference). HGS was measured using a digital dynamometer for three sets and the mean value was recorded. The values were normalized to body weight (relative HGS). Fasting glucose was analyzed by enzymatic colorimetric methods. Mediation analyses were performed to identify associations between the independent variable (abdominal obesity) and outcomes (relative HGS), as well as to determine whether fasting glucose levels mediated the relationship between excess adiposity and relative HGS. A total of 1239 (78.8%) had abdominal obesity. Abdominal obesity had a negative effect on fasting glucose (ß = 9.04, 95%CI = 5.87 to 12.21); while fasting glucose to relative HGS was inversely related (ß = -0.003, 95%CI = -0.005 to -0.001), p < 0.001. The direct effect of abdominal obesity on relative HGS was statistically significant (ß = -0.069, 95%CI = -0.082 to -0.057), p < 0.001. Lastly, fasting glucose levels mediates the detrimental effect of abdominal obesity on relative HGS (indirect effect ß = -0.002, 95%CI = -0.004 to -0.001), p < 0.001. Our results suggest that the glucose level could worsen the association between abdominal obesity status and lower HGS. Thus, it is plausible to consider fasting glucose levels when assessing older adults with excess adiposity and/or suspected loss of muscle mass.

Surface Behavior of BSA/Water/Carbohydrate Systems from Molecular Polarizability Measurements.

The effect of the presence of glucose and sucrose on the nonintrinsic contribution to partial molar volume ⟨Θ⟩ni of bovine serum albumin (BSA) is determined by means of static and dynamic electronic polarizability measurements. For that aim, a combined strategy based on high-resolution refractometry, high exactitude densitometry, and synchronous fluorescence spectroscopy is applied. Both static and dynamic mean electronic molecular polarizability values are found to be sensitive to the presence of glucose. In the case of sucrose, the polarizability of BSA is not appreciably affected. In fact, our results revealed that the electronic changes observed occurred without a modification of the native conformation of BSA. On the contrary, a nonmonotonous behavior with the concentration is observed in presence of glucose. These results advocate the influence of the electronic polarization on the repulsive and attractive protein-carbohydrate interactions. An analysis using the scaled particle theory indicates that the accumulation of glucose on the protein surface promotes dehydration. Inversely, hydration and preferential exclusion occur in the vicinity of the protein surface for sucrose-enriched systems.

Caracterización fenotípica de cepas de Staphylococcus aureus productoras de ß-lactamasas y resistente a la meticilina / Phenotypic characterization of Staphylococcus aureus strains that produce ß-lactamases and are resistant to methicillin / Caracterização fenotípica de cepas de Staphylococcus aureus pro-dutoras de ß-lactamases e resistentes à meticilina

Introducción.Staphylococcus aureus resistente a la meticilina (SARM) es una bacteria Gram positiva que hace parte de la microbiota normal y es causa importante de infecciones de origen hospitalario o adquiridas en la comunidad.Objetivo. Caracterizar fenotípicamente los aislamientos de cepas de S. aureus productoras de ß-lacta-masas y resistentes a la meticilina (SARM), aisladas en infecciones asociadas con la atención en salud en un centro hospitalario de tercer nivel.Métodos. Se llevó a cabo un estudio observacional, descriptivo y de corte transversal, que incluyó 141 cepas aisladas de 1.761 muestras clínicas que presentaban crecimiento bacteriano, en una insti-tución de salud de II nivel de complejidad de Duitama (Boyacá). En la identificación bacteriana y en las pruebas de sensibilidad, se utilizó el método automatizado Phoenix 100™ Becton Dickinson (BD). Los fenotipos de resistencia por ß-lactamasas y a la meticilina se confirmaron siguiendo la metodología del Clinical and Laboratory Standards Institute del 2017.Resultados. De 1.761 muestras clínicas que presentaron crecimiento bacteriano, se obtuvieron 141 cepas de S. aureus, de las cuales 40 presentaron el fenotipo de resistencia por betalactamasas y 19 fueron resistentes a meticilina. Conclusión. Se revela una importante prevalencia de fenotipos de resistencia circulantes en Duitama (Boyacá), con mayor prevalencia de producción de betalactamasas y menor prevalencia del fenotipo resistente a meticilina (SARM). Esto corrobora que a nivel regional y en el municipio de Duitama, S. aureus es una importante causa de infección y constituye un problema de salud pública, el cual debe continuar siendo objeto de futuras investigaciones.

Introduction: Methicillin resistant Staphylococcus aureus (MRSA) is a Gram positive bacteria that is part of the normal flora and a major cause of infections related to medical care and associated with the community.Objective: To characterize phenotypically the resistance of S. aureus with ß-lactamases resistance and methicillin-resistant strains isolated in infections associated with health care in a tertiary hospital center.Materials and methods: An observational, descriptive cross-sectional study was carried out by analy-sis of 141 S. aureus isolates obtained from a III level health institution of Duitama (Boyacá). Bacterial identification and sensitivity tests were determined by the automated method Phoenix 100™ Becton Dickinson (BD). The phenotypes of resistance to ß-lactamases or methicillin were confirmed following the 2017methodology of the Clinical and Laboratory Standards Institute.Results: One hundred and forty-one S. aureus cultures were collected, of these 40 strains were de-termined with the resistance phenotype type ß-lactamases extended spectrum and 19 resistant to methicillin (MRSA). Conclusions: High prevalence of circulating resistance phenotypes is revealed in Duitama, with a higher prevalence of ß-lactamases and a lower prevalence of the methicillin-resistant S. aureus phe-notype (MRSA), that in the region and in the municipality Duitama is an important cause of infection and constitutes a public health problem, which should continue to be the subject of future research.

Introdução. Staphylococcus aureus resistente à meticilina (MRSA) é uma bactéria Gram-positiva que faz parte da microbiota normal e é uma causa importante de infecções de origem hospitalar ou ad-quiridas na comunidade.Objetivo. Caracterizar fenotipicamente isolados de cepas de S. aureus produtoras de ß-lactamases e resistentes à meticilina (MRSA), isolados em infecções relacionadas à assistência à saúde em um centro hospitalar de terceiro nível.Materiais e métodos. Foi realizado um estudo observacional, descritivo e transversal, que incluiu 141 cepas isoladas de 1.761 amostras clínicas que evidenciaram crescimento bacteriano, em uma ins-tituição de saúde do nível II de complexidade de Duitama (Boyacá). Na identificação bacteriana e nos testes de sensibilidade, foi utilizado o método automatizado Phoenix 100 ™ Becton Dickinson (BD). Os fenótipos de resistência para ß-lactamases e meticilina foram confirmados seguindo a metodologia do Clinical and Laboratory Standards Institute de 2017.Resultados. Das 1.761 amostras clínicas que apresentaram crescimento bacteriano, foram obtidas 141 cepas de S. aureus, das quais 40 tiveram o fenótipo de resistência às beta-lactamases e 19 resis-tiram à meticilina.Conclusão. Foi revelada uma importante prevalência de fenótipos de resistência circulante em Duitama (Boyacá), com maior prevalência de produção de beta-lactamases e menor prevalência do fenótipo resistente à meticilina (MRSA). Isso corrobora que, ao nível regional e no município de Duitama, S. aureus é uma importante causa de infecção e constitui um problema de saúde pública, que deve con-tinuar sendo objeto de pesquisas futuras.

Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension.

Hypertension affects one-third of the adult population of the world. The causes of hypertension are incompletely understood, but relative impairment of sodium excretion is central to its pathogenesis. Immune cell infiltration in the kidney is a constant finding in hypertension that in association with local angiotensin and oxidants causes a defect in sodium excretion. However, it is unclear if the T cell influx into the kidney responds to nonspecific chemokine cues or is due to antigen-driven immune attraction. We found that T cells in experimentally induced salt-driven hypertension present a CD4 clonal response to heat shock protein 70 (HSP70) that is overexpressed in the kidney. We used a highly preserved amino acid sequence within the HSP molecule to induce immune tolerance associated with the generation of IL-10 producing regulatory T cells. Immune tolerant rats to HSP70 developed minimal renal inflammation and were protected from the development of salt-sensitive hypertension. Adoptive transfer of T lymphocytes isolated from spleen of tolerized rats also reversed hypertension. HSP70 gene delivery to the renal vein of the kidneys of rats sensitized to HSP70 caused an increment in blood pressure in response to a high-salt diet. The HSP70 peptide used in this work induces a strong proliferative response in peripheral blood lymphocytes of patients with essential hypertension. These studies provide evidence that autoimmunity plays a role in salt-sensitive hypertension and identifies HSP70 expressed in the kidney as one key antigen. These findings raise the possibility of novel approaches to the treatment of this condition.

Chronic sildenafil treatment corrects endothelial dysfunction and improves hypertension.

BACKGROUND: Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothelial function and arterial structure. Many of the biological actions of NO are mediated by 3'5'-guanosine monophosphate (cGMP), which is rapidly degraded by cGMP phosphodiesterase (PDE). Short-term cardiovascular effects of PDE inhibitors have been studied but the changes resulting from their chronic administration in hypertension have not been evaluated. We investigated if retarding the degradation of cGMP by long-term inhibition of PDE-5 would have beneficial consequences in spontaneously hypertensive rats (SHR), a commonly used experimental model of human essential hypertension. METHODS: Subgroups of hypertensive 13-week-old male SHR and normotensive Wistar-Kyoto rats were treated with sildenafil, 2.5 mg/kg/day, or vehicle, by gastric gavage for 6 months. RESULTS: As expected, the untreated SHR had endothelial dysfunction and a steady increment of the blood pressure. In contrast, chronic sildenafil administration reversed endothelial dysfunction, reduced renal oxidative stress and renal macrophage accumulation, and ameliorated the severity of hypertension in SHR. CONCLUSIONS: These results demonstrate beneficial effects of long-term PDE-5 inhibition in SHR and suggest that its use as an adjunct therapy in essential hypertension should be investigated.

Effect of chronic antioxidant therapy with superoxide dismutase-mimetic drug, tempol, on progression of renal disease in rats with renal mass reduction.

Oxidative stress and inflammation play a major role in the progression of renal damage and antioxidants are potentially useful therapeutic options in chronic renal disease. We investigated if treatment with tempol, a superoxide dismutase mimetic that has beneficial effects in several experimental models of hypertension and acute kidney injury, ameliorates the chronic renal damage resulting in renal mass reduction. Rats with surgical 5/6 nephrectomy were randomly assigned to receive no treatment (CRF group, n = 10) or tempol, 1 mmol/l in the drinking water (CRF-tempol group, n = 10). Sham-operated rats (n = 10) served as controls. All rats were followed for 12 weeks post-nephrectomy. Tempol treatment reduced plasma malondialdehyde (MDA) levels and halved the number of superoxide-positive cells in the remnant kidney; however, the number of hydrogen peroxide-positive cells increased and the overall renal oxidative stress (MDA and nitrotyrosine abundance) and inflammation (interstitial p65 NF-kappaB, macrophage and lymphocyte infiltration) were unchanged. Proteinuria, renal function and glomerular and tubulointerstitial damage in the remnant kidney were similar in the CRF and CRF-tempol groups. In conclusion, tempol administration, at the dose used in these studies, decreased plasma MDA and heightened superoxide dismutation in the kidney, but was incapable of reducing renal oxidative stress or improving renal function or structure in the remnant kidney model.

Melatonin ameliorates oxidative stress, inflammation, proteinuria, and progression of renal damage in rats with renal mass reduction.

The progressive deterioration of renal function and structure resulting from renal mass reduction are mediated by a variety of mechanisms, including oxidative stress and inflammation. Melatonin, the major product of the pineal gland, has potent_antioxidant and anti-inflammatory properties, and its production is impaired in chronic renal failure. We therefore investigated if melatonin treatment would modify the course of chronic renal failure in the remnant kidney model. We studied rats followed 12 wk after renal ablation untreated (Nx group, n = 7) and treated with melatonin administered in the drinking water (10 mg/100 ml) (Nx + MEL group, n = 8). Sham-operated rats (n = 10) were used as controls. Melatonin administration increased 13-15 times the endogenous hormone levels. Rats in the Nx + MEL group had reduced oxidative stress (malondialdehyde levels in plasma and in the remnant kidney as well as nitrotyrosine renal abundance) and renal inflammation (p65 nuclear factor-kappaB-positive renal interstitial cells and infiltration of lymphocytes and macrophages). Collagen, alpha-smooth muscle actin, and transforming growth factor-beta renal abundance were all increased in the remnant kidney of the untreated rats and were reduced significantly by melatonin treatment. Deterioration of renal function (plasma creatinine and proteinuria) and structure (glomerulosclerosis and tubulointerstitial damage) resulting from renal ablation were ameliorated significantly with melatonin treatment. In conclusion, melatonin administration improves the course of chronic renal failure in rats with renal mass reduction. Further studies are necessary to define the potential usefulness of this treatment in other animal models and in patients with chronic renal disease.

Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension.

Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis.

Evidence that was obtained in several experimental models and in strains of hypertensive rats indicates that infiltration of inflammatory cells and oxidative stress in the kidney play a role in the induction and maintenance of hypertension. Similar evidence is lacking in human hypertension, at least in part, because immunosuppressive treatment is unjustified in patients with hypertension. For addressing this issue, patients who were prescribed by their private physicians mycophenolate mofetil (MMF) for the treatment of psoriasis or rheumatoid arthritis and had, in addition, grade I essential hypertension and normal renal function were studied. Eight patients were studied before MMF was started, during MMF treatment, and 1 mo after MMF treatment had been discontinued. Other treatments and diet were unchanged in the three phases of the study. MMF therapy was associated with a significant reduction in systolic, diastolic, and mean BP. Urinary excretion of TNF-alpha was reduced progressively by MMF treatment and increased after MMF was discontinued. Reduction of urinary malondialdehyde, TNF-alpha, and RANTES excretion during MMF administration did not reach statistical significance but had a direct positive correlation with the BP levels. These data are consistent with the hypothesis that renal immune cell infiltration and oxidative stress play a role in human hypertension.

Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage.

BACKGROUND: Chronic renal disease is associated with oxidative stress and reduced nitric oxide availability which, in turn, promotes hypertension and further progression of renal damage. Most actions of nitric oxide are mediated by cyclic 3',5' guanosine monophosphate (cGMP) which is rapidly degraded by phosphodiesterases (PDE). Therefore, we investigated if inhibition of PDE-5 would retard the progression of chronic renal failure. METHODS: We studied rats with 5/6 nephrectomy treated with sildenafil (2.5 mg/kg(-1)/day(-1)) in two experimental protocols. In the first protocol, we started sildenafil therapy immediately after renal ablation and continued treatment for 8 weeks. Control groups consisted of rats with renal ablation treated with drug-free vehicle and sham-operated rats with and without sildenafil treatment. RESULTS: In these studies, sildenafil treatment prevented hypertension and deterioration of renal function, reduced histologic damage, inflammation and apoptosis, delayed the onset of proteinuria, and preserved renal capillary integrity. In the second protocol we compared sildenafil with losartan (7.5 mg/kg(-1)/day(-1)) and the combination of both drugs in established renal disease, starting these drugs 4 weeks after 5/6 nephrectomy. Delayed sildenafil treatment failed to improve proteinuria and glomerulosclerosis but ameliorated hypertension and azotemia. CONCLUSION: These observations suggest that currently available PDE-5 inhibitors have potential clinical value in the treatment of chronic renal disease.

Hypertension in Page (cellophane-wrapped) kidney is due to interstitial nephritis.

BACKGROUND: Cellophane wrapping of the kidneys (Page kidney) induces perinephrits and hypertension, assumed to be due to renal ischemia resulting from parenchymal compression by the fibrous hull surrounding the kidneys. We investigated if interstitial nephritis, rather than plasma angiotensin activity, played a role in the development of hypertension in the Page kidney model. METHODS: We followed for 7 weeks rats with bilateral cellophane wrapping of the kidneys that received 20 mg/kg/day of the immunosuppressive antiproliferative drug mycophenolate mofetil (MMF) (two-kidney wrap/MMF) (N = 10) or vehicle (two-kidney wrap) (N = 10), and sham-operated rats (N = 10). RESULTS: The two-kidney wrap group had progressive increment in blood pressure, inflammatory damage occupying 25% to 50% of the renal tubulointerstitial region and increased number of angiotensin II-positive cells, angiotensin II content, and oxidative stress in the kidney. MMF treatment prevented the development of hypertension and renal inflammation without modifying the perinephritic hull or the increment it induced in the intrarenal pressure. The plasma levels of angiotensin II were similar in the two-kidney wrap group, the two-kidney wrap/MMF group and the sham-operated animals and unchanged from baseline, despite the blood pressure increase in the two-kidney wrap group. CONCLUSION: Our results indicate that renal wrap hypertension is unrelated to plasma angiotensin II levels and related to the inflammatory damage caused by the external compression of the kidney.

Early and sustained inhibition of nuclear factor-kappaB prevents hypertension in spontaneously hypertensive rats.

Compelling evidence has emerged pointing to the interaction of oxidative stress and renal interstitial inflammation and their mutual contribution to the pathogenesis of hypertension in experimental animals. Renal interstitial inflammation in spontaneously hypertensive rats (SHR) is accompanied by and largely due to activation of redox-sensitive, proinflammatory nuclear transcription factor-kappaB (NF-kappaB). Therefore, the present study was designed to test the hypothesis that long-term inhibition of NF-kappaB, beginning early in the course of the disease, may attenuate renal interstitial inflammation and hypertension in SHR. To this end, we administered the reputed NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) (100 mg/kg daily intraperitoneally) to SHR from 7 to 25 weeks of age and compared the results with vehicle-treated SHR. Vehicle-treated and PDTC-treated Wistar Kyoto (WKY) rats served as controls. The untreated SHR exhibited a significant rise in arterial pressure; increased NF-kappaB activation, elevated intercellular adhesion molecule (ICAM)-1 and in situ mRNA macrophage chemoattractant molecule-1 (MCP-1) expressions; and interstitial accumulation of lymphocytes, macrophages, and angiotensin-II-positive cells. PDTC administration prevented the rise in blood pressure, and normalized renal cortical NF-kappaB activity as well as ICAM-1 and MCP-1 expressions. This was accompanied by a significant reduction in infiltration of immune cells, angiotensin II-expressing cells, and renal tissue malondialdehyde content to values that matched those found in the control WKY rats. Results suggest that NF-kappaB-driven intrarenal inflammatory reactivity play a major role in the pathogenesis of hypertension in the SHR.

Evolution of renal interstitial inflammation and NF-kappaB activation in spontaneously hypertensive rats.

Lymphocytes and macrophages infiltrate the kidney of spontaneously hypertensive rats (SHR) and interventions leading to their reduction are associated with improvement of the hypertension. The present studies examined the evolution of the interstitial inflammation in the natural course of the SHR to gain insight on the potential role of interstitial immune cell accumulation in the development of hypertension. We studied SHR and control WKY rats at 3 weeks (SHR-3 wk group, n = 11 and WKY-3 wk group, n = 10), 11 weeks (SHR-11 wk group, n = 5 and WKY-11 wk group, n = 5) and 24 weeks (SHR-24 wk group, n = 10 and WKY-24 wk group, n = 10). The SHR-3 wk group was normotensive and older SHR developed hypertension that was severe in the SHR-24 wk group. Tubulointerstitial accumulation of lymphocytes, macrophages, angiotensin II-positive cells, cells expressing the p65 DNA-binding subunit of NF-kappaB and activation of NF-kappaB in the kidney were all significantly increased (p < 0.01) in the prehypertensive SHR-3 wk group and augmented progressively, with the highest values in the SHR-24 wk group. The SHR-24 wk group showed increased (p < 0.001) helper (CD4) T cell infiltration and a high CD4/CD8 ratio. These findings are consistent with the possibility that activation of NF-kappaB and renal interstitial infiltration of immune cells may be part of the pathophysiologic process that drives hypertension in the SHR.