Current perspectives of catabolic mediators of cancer cachexia.

The development of cancer cachexia is perhaps the most common manifestation of advanced malignant diseases and has been recognized as a poor prognostic sign. The abnormalities associated with the condition include progressive weight loss, anorexia, asthenia, and anemia. The degree of cachexia is inversely correlated with the survival time of the patient and always implies a poor prognosis. Currently there is no established mechanism for cancer cachexia, but the severe metabolic disturbances and marked alterations in carbohydrate, lipid, and protein metabolism in the host finally lead to an increased energy deficiency. Weight loss, the key feature of cachexia, is due to a reduction of food intake, an increase in energy expenditure, or a combination of the two. A variety of changes in nutrient metabolism have been described in patients with cancer cachexia. Patients frequently exhibit a relative glucose intolerance and insulin resistance with increased activity of the Cori cycle. The cancer-bearing state affects protein synthesis and breakdown in different tissues of the body in a different manner. An acute-phase protein response can be presented in a significant proportion of patients with cancer with disease progression. A variety of proinflammatory cytokines appears to play a role in aspects of cachexia and a complex network of cytokines in combination with other factors might be involved. Aside from potential humoral mediators of cachexia, tumor-derived biologically active molecules have been reported recently.     

Increasing pneumococcal vaccination for immunosuppressed patients: A cluster quality improvement trial

Objective

Pneumococcal vaccination is important for patients taking immunosuppressive medications, but prior studies suggest that most patients do not undergo vaccination. The aim of this study was to evaluate the effects of a point‐of‐care paper reminder form as a quality improvement (QI) strategy to increase the numbers of immunosuppressed patients being kept up‐to‐date with pneumococcal vaccination in a rheumatology practice.

Methods

Selected rheumatologists at 5 ambulatory practice sites received a point‐of‐care paper reminder form to be applied to patients who were not up‐to‐date with pneumococcal vaccination. Interrupted time‐series analyses were used to measure the effect of the intervention on the pneumococcal vaccination rates among patients, comparing the rates in the intervention group with those in a control group of rheumatologists who did not receive the intervention. Adjusted Cox proportional hazards models were examined to identify independent predictors of being up‐to‐date with pneumococcal vaccination.

Results

We evaluated a total of 3,717 patients (66.0% with rheumatoid arthritis) who were taking immunosuppressive medications (74.1% women, mean age 53.7 years). Rheumatologists who received the intervention had a significant increase in the rate of patients who were up‐to‐date with pneumococcal vaccination, from 67.6% to 80.0% (P = 0.006), in the time period following the intervention, compared to a rate that remained stable, from 52.3% to 52.0% (P = 0.90), among patients in the nonintervention control group during this same time period. In regression models, positive predictors of being up‐to‐date with pneumococcal vaccination at the patient level included the following: having received the intervention (hazard ratio [HR] 3.58, 95% confidence interval [95% CI] 2.46–5.20), having a primary care physician affiliated with Brigham and Women's Hospital (HR 1.68, 95% CI 1.44–1.97), having a diagnosis of diabetes mellitus (HR 1.57, 95% CI 1.02–2.41), and being age 56–65 years at baseline, compared to age ≤45 years (HR 1.24, 95% CI 1.01–1.51).

Conclusion

A QI strategy involving a simple point‐of‐care paper reminder form significantly increased the rate of being up‐to‐date with pneumococcal vaccination among patients receiving immunosuppressive medications in our rheumatology practices over a 6‐month period.

     

Sleep disorders and illness intrusiveness in patients on chronic dialysis.

BACKGROUND: The prevalence of sleep problems (insomnia, restless legs syndrome, periodic limb movements in sleep and sleep apnoea) has been shown to be high in patients with end-stage renal disease (ESRD) and might contribute to impaired quality of life in this population. METHODS: In a cross-sectional study using self-administered questionnaires, we examined the prevalence of sleep disorders and assessed their effect on different aspects of health-related quality of life in a sample of Hungarian patients on maintenance dialysis. RESULTS: Our data confirm that sleep problems are frequent in patients with ESRD; 65% of the patients reported symptoms of at least one specific sleep disorder; insomnia was the most common sleep complaint with 49%, the prevalence of sleep apnoea was 32% and the prevalence of restless legs syndrome was 15%. Co-morbidity, assessed by the End-Stage Renal Disease Severity Index, was shown to be an independent predictor of sleep disorders. Patients with sleep disorders reported higher illness intrusiveness and worse self-perceived health than those without sleep problems. The presence of sleep disorders was an independent predictor of illness intrusiveness, an important determinant of health-related quality of life. CONCLUSION: Sleep disorders are important determinants of illness intrusiveness and health-related quality of life in patients with ESRD. Sleep problems may be treated successfully; therefore, more attention should be paid to assessing these problems in this patient population.     

Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance

Up to 20% of serious vascular events in high-risk vascular patients is attributable to a failure of aspirin (ASA) to suppress platelet aggregation. Resveratrol is a cardioprotective phytoestrogen that can inhibit platelet aggregation in animal models. We hypothesized that resveratrol can also inhibit aggregation of platelets from ASA-resistant (ASA-R) patients. Thus, platelet-rich plasma was isolated from ASA-sensitive (ASA-S) and ASA-R patients (aspirin resistance was defined as higher-than-expected aggregation to collagen and epinephrine [>/=40%] after oral treatment with 100 mg/d ASA). Aggregation to adenosine diphosphate (ADP; 5 and 10 mumol/L), collagen (2 mug/mL), and epinephrine (10 mumol/L) in the absence and presence of resveratrol (10 mol/L) was measured by optical aggregometry. Maximal aggregation to 5 mumol/L ADP was only slightly affected by resveratrol. Similar results were obtained using 10 mumol/L ADP. Maximal aggregation of ASA-R platelets to collagen was significantly decreased by resveratrol, whereas resveratrol had only marginal effects in ASA-S platelets. Similar results were obtained with epinephrine as well. Collectively, resveratrol effectively inhibited collagen- and epinephrine-induced aggregation of platelets from ASA-R patients, which may contribute to its cardioprotective effects in high-risk cardiac patients.     

Vascular dysfunction in aging: potential effects of resveratrol, an anti-inflammatory phytoestrogen

Epidemiological studies demonstrated that even in the absence of other risk factors (e.g. diabetes, hypertension, hyperhomocysteinemia, hypercholesterolemia), advanced age itself significantly increases cardiovascular morbidity by enhancing vascular oxidative stress and inflammation. Because the population in the Western world is rapidly aging, there is a substantial need for pharmacological interventions that delay the functional decline of the cardiovascular system. Resveratrol is an atoxic phytoestrogen found in more than 70 plants including grapevine and berries. Recent data suggest that nutritional intake of resveratrol and other polyphenol compounds may contribute to the "French paradox", the unexpectedly low cardiovascular morbidity in the Mediterranean population. There is increasing evidence that resveratrol exerts multifaceted anti-oxidant and/or anti-inflammatory effects in various disease models. Importantly, resveratrol was reported to slow aging and increase lifespan in simple organisms and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to activate NAD-dependent histone deacetylases (sirtuins), which may contribute to its anti-aging effects. This review focuses on the role of oxidative stress and inflammation in cardiovascular dysfunction in aging, and on emerging anti-aging therapeutic strategies offered by resveratrol and other polyphenol compounds.     

The sensory nitrergic nature of the hepatic insulin sensitizing substance mechanism in conscious rabbits

Functional deterioration of sensory fibres in the anterior hepatic plexus or intraportal administration of 7-nitro indazole (1 mg/kg), a selective inhibitor of neural nitric oxide (NO) synthase, caused insulin resistance as determined by hyperinsulinaemic (100 micro U/ml) euglycaemic (5.5 mmol/l) glucose clamping in chronically instrumented conscious rabbits. Intraportal nitroglycerin restored insulin sensitivity in either case. We conclude that NO of sensory neural origin plays a major role in endogenous neurogenic insulin sensitizing mechanisms.     

Association of TLR-4 and TNF-alpha polymorphisms with clinical symptoms and cytokine levels in patients with allergic rhinitis

Our objective was to determine the frequency of TNF-alpha −238, −308 G/A promoter and TLR-4 299 D/G and 399 T/I polymorphisms in healthy population and in patients with seasonal allergic rhinitis, and to examine its influences on serum TNF-alpha, TNF receptor-1, Fas, Fas-ligand, IgE levels and on clinical symptoms. A pilot study was performed in 66 patients with seasonal allergic rhinitis to ragweed pollen and 161 non-allergic subjects using PCR–RFLP technique and ELISA. Carriers of the −238A and −308G alleles have significantly higher TNF-alpha and IgE levels, clinical score values and lower peak nasal flow (PNIF) values during and after ragweed pollen season. Patients with the 299G/399I alleles of the TLR-4 gene have significantly lower TNF-alpha, Fas, FasL and IgE levels, clinical scores and higher PNIF values during and after pollen season. The −238A and −308G polymorphisms of the TNF-alpha promoter and 299D/399T polymorphisms of the TLR-4 gene are associated with more pronounced clinical symptoms, higher cytokine and IgE levels, and low PNIF values. These polymorphisms are very likely to contribute to the heterogeneity of clinical and laboratory parameters of patients.     

Prolyl carboxypeptidase regulates energy expenditure and the thyroid axis

Hypothalamic α-melanocyte-stimulating hormone (α-MSH) plays a central role in regulating energy uptake and expenditure. Prolyl carboxypeptidase (PRCP), a protease expressed in the hypothalamus, is responsible for the degradation of α-MSH. PRCP null animals (PRCP(gt/gt) mice) display elevated α-MSH in the hypothalamus, lower body weight, and are protected from diet induced obesity. Here, we report that PRCP(gt/gt) mice have a significant decrease in fat mass, although an increase in lean mass was also observed. In agreement with low fat accumulation, reduced leptin levels were found. Consistent with the effect of α-MSH on energy metabolism, PRCP(gt/gt) mice had increased energy expenditure with elevated circulating thyroid hormone levels and brown adipose tissue uncoupling protein 1 mRNA levels compared with control mice when exposed to regular diet. TRH mRNA levels in the PVN were significantly higher in fed PRCP(gt/gt) animals compared with fed wild-type controls. Fasting significantly decreased TRH mRNA levels in both PRCP(gt/gt) and wild-type (WT) mice. However, TRH mRNA levels in fasted PRCP(gt/gt) animals were significantly higher than those of fasted WT mice. Refeeding analysis after fasting showed a reduced food intake in PRCP(gt/gt) compared with WT mice. Finally, TRH mRNA levels in T(3)-treated hypothyroid PRCP(gt/gt) mice showed a non significant reduction compared with those of hypothyroid PRCP(gt/gt) mice, supporting the impairment of the hypothalamo-pituitary-thyroid axis in PRCP(gt/gt) mice. All together, these data confirm that PRCP plays a role in the regulation of energy metabolism.     

Serum immunoreactive erythropoietin during pregnancy and in the early postpartum

We studied 209 women during normal pregnancy, at delivery, or in the early postpartum, to determine whether erythropoietin (EPO) response was appropriate for the degree of anaemia. Serum immunoreactive EPO was measured in 74 nonpregnant women, including 33 normal subjects (16.4 +/- 4.1 mU/ml) and 41 women with hypoplastic, haemolytic, dyserythropoietic, or iron-deficient anaemia. An inverse linear relationship (R = -0.88, P less than 0.0001) between log(EPO) and Hct was observed. Predicted EPO values were derived for each Hct and an O/P ratio of observed/predicted log(EPO) was calculated for each sample (1.00 +/- 0.10, range 0.80-1.20). Serum EPO levels (mU/ml) were significantly higher during pregnancy (30 +/- 16, n = 142), at delivery (31 +/- 16, n = 41), and on day 7 postpartum (37 +/- 35, n = 26) than in normal women (P less than 0.001). EPO levels increased steadily from 18 +/- 6 mU/ml in the first, to 26 +/- 14 mU/ml in the second, and to 35 +/- 18 mU/ml in the third trimester (P less than 0.0001). The O/P ratio was normal on day 7 postpartum (1.01 +/- 0.16), at delivery (1.03 +/- 0.16), and in the third trimester (0.96 +/- 0.15), but was significantly reduced in the first two trimesters (0.88 +/- 0.15, P less than 0.001). A significant negative correlation between log(EPO) and Hct was lacking in the first two trimesters, was present but with a reduced slope during the third trimester and at delivery, and was normal postpartum. We conclude that EPO response to anaemia is impaired in early pregnancy, recovers in late pregnancy, and normalizes rapidly in the postpartum.     

Sirolimus therapy in the treatment of pseudomyogenic hemangioendothelioma

Pseudomyogenic hemangioendothelioma (PMH) is a rare, mostly indolent vascular tumor. Extensive cases are treated with amputation as chemotherapy seems to be ineffective. Recently, promising results were published using mammalian target of rapamycin (mTOR) inhibitors in tumors of vascular origin. Here, we present a case of a child with advanced PMH relapsing after surgery and chemotherapy. Sirolimus achieved significant clinical improvement and stabilization of the lesions without any remarkable toxicity. This case contributes to the growing evidence regarding the efficacy of mTOR inhibitors, such as sirolimus, in multifocal PMH.