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Depression, stress, and blood pressure in urban African-American women.

African-American women have disturbingly high rates of hypertension, exceeding those of African-American men and other ethnic groups. Reasons for these disparities are not understood. Depression, more common in women than men, has been linked to endothelial dysfunction, inflammation, metabolic and hematologic abnormalities, and increased sympathetic nervous system activity--all factors associated with cardiovascular disease. A descriptive correlational design was used to test the following hypotheses: 1) African-American women with higher levels of depression will have higher blood pressure (BP) levels, more cardiovascular risk factors, greater stress, and lower social support; and 2) depression will mediate the relationship between stress and BP. A convenience sample of 245 hypertensive African-American women (mean age, 61+/-12.7 years) was recruited through free BP screenings offered in the community. All data were collected during a structured interview and brief physical examination. Pearson r correlation coefficients, analysis of variance, and multiple regression analyses were used to analyze the hypotheses. Women with higher levels of depression had higher diastolic BP and were more likely to smoke, eat fewer fruits and vegetables, and have more stress and less social support. Depression mediated the relationship between stress and diastolic BP. The findings emphasize the importance of assessing both behavioral and psychosocial factors in urban African-American women with hypertension.

Black or African American↗

Relationship between plasma and hippocampal lipid peroxidation in obese and hypertensive SHR/NDmcr-cp rats.

1. It has been suggested that hypertension, hyperlipidaemia and diabetes participate in the onset and development of dementia. 2. To understand cognitive dysfunction in metabolic syndrome, the relationship between the plasma and the hippocampus regarding fatty acid composition and lipid peroxidation was estimated in genetically hypertensive and obese SHR/NDmcr-cp rats (SHR-cp) aged 7-9 and 18-20 weeks. 3. Levels of total fatty acids and lipid peroxide in the plasma were much higher (by 200-500%) in SHR-cp compared with age-matched control rats (Wistar-Kyoto rats). However, in the hippocampus these levels were not significantly different between the two groups of rats. 4. Levels of hippocampal lipid peroxide in both groups increased significantly with ageing. 5. These results indicate that, in SHR-cp, lipid peroxidation in the hippocampus would not be affected even if plasma levels of fatty acids and lipid peroxide increased markedly, when ageing is not a predicative factor.

Aging↗

Congenital renal tubular dysfunction associated with maternal sniffing of organic solvents.

Two cases of neonatal renal tubular dysfunction and metabolic acidosis due to maternal sniffing of a product containing toluene are reported. Both mothers had been sniffing regularly throughout their pregnancies. The infants were dysmature and had some dysmorphic features. They had hyperchloraemic acidosis and exhibited amino-aciduria. The metabolic changes were however transient. It is suggested that the sniffing of toluene containing solvents during pregnancy may change membrane permeability in both the proximal as well as distal renal tubules and may also enhance liver enzyme activity in the foetus.

Abnormalities, Drug-Induced↗

[Clinical analysis of the prognosis of severe pneumonia requiring mechanical ventilation].

To determine which factors are important in predicting the outcome of patients with severe pneumonia requiring mechanical ventilation, we compared 43 surviving pneumonic patients with 37 non-surviving pneumonic patients. The following results were obtained. The following characteristics were noted in the non-surviving patients as compared with surviving patients; 1. a worsening of performance status in the background, 2. presence of physical signs such as hypotension and trachycardia, 3. abnormal laboratory data such as leukocytosis, lymphocytopenia, hypoalbuminemia, hepatorenal dysfunction and metabolic acidosis, 4. presence of massive pulmonary infiltrations on chest roentgenograms, 5. a prevalence of resistant microorganisms for many antibiotics such as MRSA (Methicillin resistant Staphylococcus aureus). These results suggest that the most important factor affecting the prognosis of patients with severe pneumonia requiring mechanical ventilation may by the condition of the host and of the microorganisms rather than antibiotic treatment.

Aged↗

[Arterial thrombosis and genetic polymorphisms: too many actors, complex scenario].

Arterial thrombosis results from complex gene-gene and gene-environment interactions. While Vichow's triad was traditionally referred to venous thrombosis, the same process has been applied to arterial thrombosis: abnormalities of hemorrheology, abnormal blood constituents and abnormal vessel wall/endothelial dysfunction. Research carried out in the past decade has identified several polymorphisms in genes related to coagulation and fibrinolytic factors, platelet receptors, endothelial dysfunction, homocysteine metabolism, endothelial nitric oxide synthase, abnormal blood flow and oxidative stress. Whereas the individual contribution of each polymorphism to the overall cardiovascular risk seems to be modest, multiple gene-gene and gene-environment interactions appear more relevant in the pathogenesis of arterial thrombosis.

Blood Coagulation Factors↗

Acute pancreatitis: when and how to operate.

Patients with proved necrotizing pancreatitis should be treated in an intensive care unit. Surgical management of necrotizing pancreatitis is indicated if an acute abdomen or persistent or increasing signs of organ complications develop, such as pulmonary or renal insufficiency, cardiocirculatory dysfunction or metabolic disorders, and these do not respond to maximum intensive care treatment over at least 72 h. Besides these so-called non-responders to ICU treatment, operative management is clearly indicated in patients who develop signs of sepsis on the basis of a bacteriologically positive fine-needle aspiration of pancreatic necroses. In patients with minor necroses without any bacterial contamination and without extensive retroperitoneal fatty tissue necroses intensive care therapy can be successful without the necessity of a surgical intervention. The gold standard of surgical management of necrotizing pancreatitis is careful removal of necrotic tissue, drainage of bacterially infected area, elimination of the pancreatogenic ascites in order to prevent systemic spread of vasoactive and toxic substances and interruption of the inflammatory process. For the treatment of pancreatic necrosis we strongly support surgical debridement (necrosectomy), supplemented by postoperative closed continuous lavage of the lesser sac and the adjacent necrotic cavities. In 152 patients suffering from severe necrotizing pancreatitis the hospital mortality was 12.5% (19/152) by this surgical approach.

Acute Disease↗

Quality of life of patients with advanced and metastatic prostatic carcinoma.

The quality of life of patients with advanced prostate cancer may be profoundly affected by local infiltration into adjacent organs and the occurrence of distant metastases. Secondary manifestations of advanced stages of prostate cancer include urinary retention, ureteric obstruction, rectal obstruction, chronic bone pain, compression of the spinal cord, hematological dysfunction and metabolic abnormalities. This review discusses the management of these patients in order to optimize their quality of life. Suitable palliative treatment for each secondary manifestation is recommended.

Bone and Bones↗

Left ventricular filling profiles in young white-coat hypertensive patients without hypertrophy.

This study was to assess left ventricular diastolic function in young white-coat hypertensive subjects < 50 years of age without hypertrophy. Hypertensive patients (systolic or diastolic blood pressure > or = 140 or > or = 90 mm Hg on all three visits) were defined as white coat if their average 24-hour blood pressure was < 127/81 mm Hg and at least 18/16 mm Hg lower than their average office values. We chose three groups balanced for sex, age, and body mass index: 50 sustained hypertensives, 25 white-coat hypertensives, and 25 normotensives. Office blood pressure was similar in white-coat and sustained hypertensives. Ambulatory blood pressure was comparable in white-coat hypertensives and normotensives. Compared with normotensives, white-coat hypertensives had more impaired diastolic function: increased ratio of late to early filling velocities, raised ratio of late to early time-velocity integral, prolonged deceleration time, and lengthened isovolumic relaxation time (P<.001, P<.001, P=.002, and P<.001, respectively). No difference was noticed between white-coat and sustained hypertensives. Compared with normotensives, white-coat hypertensives had higher values of plasma and urine norepinephrine (P<.001 and P<.001, respectively), plasma and urine aldosterone (P<.001 and P=.002, respectively), plasma renin activity (P=.04), total cholesterol (P=.001), and LDL cholesterol (P<.001). No difference was observed between white-coat and sustained hypertensives. Within white-coat hypertensives, 24-hour urinary aldosterone closely correlated with the ratio of late to early filling velocities (P=.008), and plasma and 24-hour urinary norepinephrine correlated well with total cholesterol (P=.037 and P=.006, respectively). No correlation was detected within the sustained hypertensives and normotensives. Heightened neurohumoral activity clearly supported the progression of diastolic dysfunction and metabolic abnormality in white-coat hypertensives.

Adult↗

Uric acid: role in cardiovascular disease and effects of losartan.

A substantial body of epidemiological and experimental evidence suggests that serum uric acid is an important, independent risk factor for cardiovascular and renal disease especially in patients with hypertension, heart failure, or diabetes. Elevated serum uric acid is highly predictive of mortality in patients with heart failure or coronary artery disease and of cardiovascular events in patients with diabetes. Further, patients with hypertension and hyperuricemia have a 3- to 5-fold increased risk of experiencing coronary artery disease or cerebrovascular disease compared with patients with normal uric acid levels. Although the mechanisms by which uric acid may play a pathogenetic role in cardiovascular disease is unclear, hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation. Xanthine oxidase inhibitors (e.g., allopurinol) or a variety of uricosuric agents (e.g., probenecid, sulfinpyrazone, benzbromarone, and benziodarone) can lower elevated uric acid levels but it is unknown whether these agents reversibly impact cardiovascular outcomes. However, the findings of the recent LIFE study in patients with hypertension and left ventricular hypertrophy suggest the possibility that a treatment-induced decrease in serum uric acid may indeed attenuate cardiovascular risk. LIFE showed that approximately 29% (14% to 107%, p = 0.004) of the treatment benefit of a losartan-based versus atenolol-based therapy on the primary composite endpoint (death, myocardial infarction, or stroke) may be ascribed to differences in achieved serum uric acid levels. Overall, serum uric acid may be a powerful tool to help stratify risk for cardiovascular disease. At the very least, it should be carefully considered when evaluating overall cardiovascular risk.

Angiotensin Receptor Antagonists↗

Statin-induced expression of CD59 on vascular endothelium in hypoxia: a potential mechanism for the anti-inflammatory actions of statins in rheumatoid arthritis.

Hypoxia, which leads to dysfunctional cell metabolism, and complement activation both play central roles in the pathogenesis of rheumatoid arthritis (RA). Recent studies have reported that mice deficient for the complement-inhibitory protein CD59 show enhanced susceptibility to antigen-induced arthritis and reported that statins have anti-inflammatory effects in RA. We hypothesized that the anti-inflammatory effect of statins in RA relates in part to their ability to increase CD59 expression in hypoxic conditions and therefore to reduce complement activation. Flow-cytometric analysis showed that CD59 expression on endothelial cells (EC) was unaffected by atorvastatin in normoxia (21% O2), whereas in hypoxic conditions (1% O2) an up to threefold dose-dependent increase in CD59 expression was seen. This effect of hypoxia was confirmed by treatment of EC with chemical mimetics of hypoxia. The upregulation of CD59 protein expression in hypoxia was associated with an increase in steady-state mRNA. L-Mevalonate and geranylgeraniol reversed the response, confirming a role for inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and geranylgeranylation. Likewise, inhibition by NG-monomethyl-L-arginine and NG-nitro-L-arginine methyl ester confirmed that CD59 upregulation in hypoxia was nitric oxide dependent. The expression of another complement-inhibitory protein, decay-accelerating factor (DAF), is known to be increased by atorvastatin in normoxia; this response was also significantly enhanced under hypoxic conditions. The upregulation of CD59 and DAF by atorvastatin in hypoxia prevented the deposition of C3, C9 and cell lysis that follows exposure of reoxygenated EC to serum. This cytoprotective effect was abrogated by inhibitory anti-CD59 and anti-DAF mAbs. The modulation of EC CD59 and DAF by statins under hypoxic conditions therefore inhibits both early and late complement activation and may contribute to the anti-inflammatory effects of statins in RA.

Anti-Inflammatory Agents↗

Differential expression of plasma proteins and pathway enrichments in pediatric diabetic ketoacidosis.

BACKGROUND: In children with type 1 diabetes (T1D), diabetic ketoacidosis (DKA) triggers a significant inflammatory response; however, the specific effector proteins and signaling pathways involved remain largely unexplored. This pediatric case-control study utilized plasma proteomics to explore protein alterations associated with severe DKA and to identify signaling pathways that associate with clinical variables. METHODS: We conducted a proteome analysis of plasma samples from 17 matched pairs of pediatric patients with T1D; one cohort with severe DKA and another with insulin-controlled diabetes. Proximity extension assays were used to quantify 3072 plasma proteins. Data analysis was performed using multivariate statistics, machine learning, and bioinformatics. RESULTS: This study identified 214 differentially expressed proteins (162 upregulated, 52 downregulated; adj P&#x2009;<&#x2009;0.05 and a fold change&#x2009;>&#x2009;2), reflecting cellular dysfunction and metabolic stress in severe DKA. We characterized protein expression across various organ systems and cell types, with notable alterations observed in white blood cells. Elevated inflammatory pathways suggest an enhanced inflammatory response, which may contribute to the complications of severe DKA. Additionally, upregulated pathways related to hormone signaling and nitrogen metabolism were identified, consistent with increased hormone release and associated metabolic processes, such as glycogenolysis and lipolysis. Changes in lipid and fatty acid metabolism were also observed, aligning with the lipolysis and ketosis characteristic of severe DKA. Finally, several signaling pathways were associated with clinical biochemical&#xa0;variables. CONCLUSIONS: Our findings highlight differentially expressed plasma proteins and enriched signaling pathways that were associated with clinical features, offering insights into the pathophysiology of severe DKA.

Humans↗

ADMA and oxidative stress may relate to the progression of renal disease: rationale and design of the VIVALDI study.

The renin angiotensin system has been shown to be involved in the pathogenesis of vascular and renal sequelae of diabetes mellitus. In type 2 diabetes mellitus, angiotensin receptor blockers have been shown to exert clinical benefit by reducing the progression of diabetic nephropathy. They also improve endothelium-mediated vascular function. The latter effect is partly due to the reduction of angiotensin II-associated oxidative stress. Moreover, small clinical studies have shown that treatment with angiotensin receptor blockers also reduces the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. In the VIVALDI trial, the ability of the angiotensin receptor blocker telmisartan to reduce the progression of diabetic nephropathy (associated with proteinuria) in comparison with valsartan in more than 800 patients with type 2 diabetes during 1 year of treatment is being studied. In order to gain more detailed insight into the potential pathomechanisms associated with this effect, further end-points have been defined. Among these are the circulating levels of ADMA and the urinary excretion rate of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). The former is an endogenous inhibitor of NO-mediated vascular function(s) and a prospectively determined marker of major cardiovascular events and mortality; the latter is a lipid peroxidation product resulting from the nonenzymatic peroxidation of arachidonic acid, which exerts detrimental vascular effects similar to those of thromboxane A2. Urinary 8-iso-PGF2alpha has been shown in clinical studies to be an independent marker of cardiovascular disease. Highlighting the effects of telmisartan on ADMA and 8-iso-PGF levels in such a large cohort of diabetic patients will enhance our understanding of the roles of dysfunctional NO metabolism and redox mechanisms in the pathogenesis of end-organ damage and its prevention by pharmacotherapy with angiotensin receptor blockers.

Adult↗

Pattern of distribution of calcitonin gene-related Peptide in the dorsal root ganglion of animal models of diabetes mellitus.

This article examined the pattern of distribution of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG) of normal and diabetic Wistar, Zucker lean, and Goto-Kakizaki (GK) rats to determine whether there are changes in the number and pattern of distribution of CGRP-positive neurons after the onset of latent or overt diabetes. Type 1 diabetes mellitus was induced in Wistar rats by a single dose of streptozotocin (STZ) given intraperitoneally (60 mg/kg body weight). Four weeks after the induction of diabetes mellitus, diabetic (n = 6) and normal (n = 6), Zucker lean (n = 6), and GK (n = 6) rats were anesthetized with chloral hydrate and their DRGs were removed and processed for immunohistochemistry. CGRP-positive neurons were observed in the DRG of normal and diabetic Wistar, Zucker lean (nondiabetic), and GK (animal model of type 2 diabetes) rats. CGRP was present in small-, medium-, and large-sized neurons of the DRG in these three animal models. Only a small percentage of large-sized neurons contains CGRP. The number of CGRP-positive neurons was significantly (P < 0.05) reduced in STZ-induced diabetic Wistar and GK rats compared to normal Wistar and Zucker lean rats. Moreover, the quantity of CGRP-containing varicose nerves was less in diabetic Wistar and GK rats compared to control Wistar and Zucker lean rats. The reduced number of CGRP-positive neurons in the DRG of GK rats indicated that subjects with latent diabetes may already have dysfunctional CGRP metabolism and thus diabetic neuropathy.

Animals↗

The relationship of cardiac diastolic dysfunction to concurrent hormonal and metabolic status in type I diabetes mellitus.

The presence of diabetic cardiomyopathy and its relationship to concurrent hormonal and metabolic status have not been defined in patients with uncomplicated type I diabetes mellitus. Accordingly, radionuclide left ventricular angiograms and simultaneous metabolic profiles were obtained in 8 type I diabetic patients who had no major diabetic complications and in 11 normal subjects. Occult coronary artery disease was excluded by electrocardiogram exercise testing. Hemodynamics and systolic function did not differ between the groups. However, the peak filling rate (PFR; end-diastolic volumes per s) was less in the diabetic patients at rest [mean, 4.1 +/- 0.2 (+/- SE) vs. 4.8 +/- 0.2; P less than 0.05] and during aerobic (6.8 +/- 0.2 vs. 8.30 +/- 0.3; P less than 0.01) and anaerobic exercise (8.8 +/- 0.3 vs. 9.8 +/- 0.4; P less than 0.05). The time to PFR was prolonged in the diabetic patients at rest (174 +/- 10 vs. 133 +/- 7 ms; P less than 0.01) and during anaerobic exercise (126 +/- 5 vs. 103 +/- 6 ms; P less than 0.01). Plasma glucose and insulin levels were elevated in the diabetic patients at rest and during exercise. Otherwise, the metabolic and hormonal levels did not differ between the groups. In the diabetic patients, no single metabolic or hormonal parameter correlated with PFR or time to PFR. Impairment of diastolic filling also did not correlate with level of glycosylated hemoglobin or duration of diabetes. The alteration in diastolic filling present in type I diabetic patients who have no other diabetic complications may represent the earliest functional effect of diabetic cardiomyopathy.

Adult↗

Targeted disruption of the pituitary adenylate cyclase-activating polypeptide gene results in early postnatal death associated with dysfunction of lipid and carbohydrate metabolism.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hormone belonging to the glucagon superfamily of hormones. These hormones are known to play important roles in metabolism and growth. PACAP is a neuropeptide that causes accumulation of cAMP in a number of tissues and affects the secretion of other hormones, vasodilation, neural and immune functions, as well as the cell cycle. To determine whether PACAP is essential for survival and to evaluate its function(s), we have generated mice lacking the PACAP gene via homologous recombination. We found that most PACAP null mice died in the second postnatal week in a wasted state with microvesicular fat accumulation in liver, skeletal muscle, and heart. Gas chromatography-mass spectrometry showed that fatty acid beta-oxidation in liver mitochondria of PACAP(-/-) mice was not blocked based on the distribution of 3-hydroxy-fatty acids (C6-16) in the plasma. Instead, increased metabolic flux through the beta-oxidation pathway was suggested by the presence of ketosis. Also, serum triglycerides and cholesterol were significantly higher (2- to 3-fold) in PACAP null mice than littermates. In the fed state, both serum insulin and blood glucose were normal in 5-d-old null mice compared with their littermates. In contrast, fasted PACAP null pups had a significant increase in insulin, but a decrease in blood glucose compared with littermates. Glycogen in the liver was reduced. These results suggest PACAP is a critical hormonal regulator of lipid and carbohydrate metabolism.

Adipose Tissue↗

Impact of maternal undernutrition on hypothalamo-pituitary-adrenal axis and adipocyte functions in male rat offspring.

Malnutrition induces profound deleterious effects on several metabolic and neuroendocrine functions. In the present study, we examined the impact of maternal food restriction, during gestation and lactation, on the metabolic-neuroendocrine function of their male offspring at 21 and 60 d of age. Well-nourished (WN) and undernourished (UN) pregnant rats were used, during gestation and lactation, until pups were weaned. Twenty-one-day-old WN and UN male pups were studied in basal and postinsulin conditions. Additional groups of weaned (WN and UN) male rats were fed either ad libitum (WN-WN and UN-WN) or in a restricted fashion (WN-UN and UN-UN) until experimentation at age 60 d. Body weights of mothers and their male offspring were monitored. Basal and postinsulin plasma concentrations of several metabolic fuels were evaluated. Our results indicate that 21-d-old UN male rats exhibited (vs their WN counterparts), decreased body weights, similar basal and postinsulin glycemia, similar basal plasma adrenocorticotropic hormone (ACTH) and corticosterone levels but diminished ACTH response to insulin treatment, and basal hypoleptinemia and significant insulin-induced leptin release. Finally, at 60 d of age, long-term UN (WN-UN and UN-UN) rats showed lower plasma (basal and postinsulin) glucose, and basal triglyceride levels than their counterparts (WN-WN and UN-WN). Sixty-day-old rats submitted to either food restriction protocol also showed a reduced hypothalamo-pituitary-adrenal axis response to insulin-induced hypoglycemia and basal hypoleptinemia, in spite of restoration of normal body weights. These results further indicate a clear metabolic-neuroendocrine dysfunction in male pups of UN mothers, with the abnormality partially present at weaning and deteriorated by adulthood, even after the recovery of normal body weight. Our study strongly supports the importance of the irreversibility of a deleterious allostatic state resulting from fetal and early postnatal undernutrition.

Adipocytes↗

A mitochondrial oscillator dependent on reactive oxygen species.

We describe a unique mitochondrial oscillator that depends on oxidative phosphorylation, reactive oxygen species (ROS), and mitochondrial inner membrane ion channels. Cell-wide synchronized oscillations in mitochondrial membrane potential (Delta Psi(m)), NADH, and ROS production have been recently described in isolated cardiomyocytes, and we have hypothesized that the balance between superoxide anion efflux through inner membrane anion channels and the intracellular ROS scavenging capacity play a key role in the oscillatory mechanism. Here, we formally test the hypothesis using a computational model of mitochondrial energetics and Ca(2+) handling including mitochondrial ROS production, cytoplasmic ROS scavenging, and ROS activation of inner membrane anion flux. The mathematical model reproduces the period and phase of the observed oscillations in Delta Psi(m), NADH, and ROS. Moreover, we experimentally verify model predictions that the period of the oscillator can be modulated by altering the concentration of ROS scavengers or the rate of oxidative phosphorylation, and that the redox state of the glutathione pool oscillates. In addition to its role in cellular dysfunction during metabolic stress, the period of the oscillator can be shown to span a wide range, from milliseconds to hours, suggesting that it may also be a mechanism for physiological timekeeping and/or redox signaling.

Animals↗