Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin

Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle, yielding fragments that are substrates that are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF-1, and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin, which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting, suggesting that therapies that block myostatin could prevent muscle wasting in catabolic conditions.     

Age‐related changes in brain energetics and phospholipid metabolism

Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus (³¹P) MRS. ³¹P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21–84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (?0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using ³¹P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non‐demented and psychiatrically stable older adults and specifically analyzed gray‐white matter differences in brain metabolism. Copyright © 2009 John Wiley & Sons, Ltd.     

Starch as a renewable finish to improve the pesticide-protective properties of conventional workclothes

Because many pesticide handlers persist in wearing and reusing conventional workclothes, a renewable functional finish that enhances the pesticide-protective qualities of fabrics would be useful. This study investigated the ability of starch to act as a pesticide trap, preventing transfer and increasing removal by laundering, and the effect of carboxymethyl cellulose on release of pesticide in laundry. The retention and distribution of methyl parathion (MeP) on 65% polyester/35% cotton fabric was studied with four finishes: starch and carboxymethyl cellulose (CMC) as nondurable finishes; durable press resin (DP) and durable press/ carboxymethyl cellulose (DP/CMC) as durable finishes. Starching with an add-on of 8% (w/w) effectively reduced the area of contamination and enhanced the removal of methyl parathion from polyester/cotton fabrics. Residual pesticide values for CMC, DP, and DP/CMC finishes were similar to that of the unfinished fabric. While distribution profiles of methyl parathion throughout the yarn and fiber structures were similar for all the finishes, lower concentrations of pesticide were observed on the cotton fibers from the starched fabric. Starch reduced the pesticide transferring by rubbing from both 100% cotton and 65% polyester/cotton fabrics. These studies support the intriguing theory that starch can act as a pesticide trap on the fabric surface to decrease pesticide transfer and to enhance pesticide removal. Extensive penetration studies, field studies, and additional investigation of fiber, yarn, and fabric parameters are needed to further quantify the effects of starch.     

HIV associated systemic necrotizing vasculitis

The spectrum of HIV associated rheumatic syndromes continues to expand as does our experience with the disease. The following is a case of HIV associated systemic necrotizing vasculitis documented by rectal biopsy. The patient was treated successfully with corticosteroids alone, and after 9 months of followup has no evidence of progression to frank AIDS.     

Distribution of cytoplasmic phospholipase A2 in the normal rat brain.

The calcium-dependent cytoplasmic PLA2 (cPLA2) is an 85-kDa cytosolic enzyme that has been detected in cytosolic fractions from rat brain. With immunocytochemical methods, this cPLA2 is distributed throughout rat brain. Very dense immunostaining is observed in the superior olivary nucleus, periolivary nucleus, facial motor nucleus and dorsal cochlear nucleus in hindbrain whereas light immunostaining is seen in forebrain and midbrain areas. Assays of cPLA2 activity in forebrain, midbrain and hindbrain show the highest specific activity in the hindbrain. The distribution of cPLA2 coincides with that of protein kinase C activity in rat brain. The presence of cPLA2 and PKC in hindbrain suggests that these enzymes play a central role in neurotransmitter release, long-term potentiation and neuritogenesis in this area under normal conditions.     

Sustained activation of p38 mitogen-activated protein kinase contributes to the vascular response to injury

The vascular response to mechanical injury involves inflammatory and fibroproliferative processes that result in the formation of neointima and vascular remodeling. The complex cellular interactions initiated by vascular injury are coordinated and modulated by the elaboration of cytokines and growth factors. The production and transduction of many of these mediators require phosphorylation of p38 mitogen-activated protein kinase (MAPK). In the present investigation, we examined the pattern and localization of p38 MAPK activation following balloon vascular injury. The effects of long-term and selective inhibition of p38 MAPK with SB 239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[2-methoxy)pyrimidin-4-yl]imidazole) were also investigated in a model of vascular injury. Western blotting and immunohistochemical staining demonstrated that phospho-p38 MAPK was increased following balloon injury of the rabbit iliofemoral artery. The p38 MAPK activation was noted as early as 15 min after balloon injury and remained elevated for at least 28 days. Phospho-p38 MAPK immunoreactivity (IR) was localized primarily in regions of dedifferentiated, smooth muscle alpha-actin-positive cells in all lamina of the vessel wall. Phospho-p38 MAPK IR was not correlated with the localization of macrophage or proliferating cells (proliferating cell nuclear antigen; PCNA +). Long-term treatment (4 weeks) with SB 239063 (50 mg/kg/day, p.o.) reduced the vascular response to injury in the hypercholesterolemic rabbit. SB 239063 had no effect on platelet-derived growth factor (PDGF)-stimulated migration or proliferation of rabbit vascular smooth muscle cells (VSMCs) in culture. However, SB 239063 produced a concentration-dependent inhibition of transforming growth factor (TGF)-beta-stimulated fibronectin production in VSMCs. In conclusion, sustained activation of p38 MAPK plays an important role in the vascular response to injury and inhibition of p38 MAPK may represent a novel therapeutic approach to limit this response.     

A multidisciplinary approach to the management of breast cancer, part 2: therapeutic considerations

New approaches to breast cancer treatment have enhanced clinical outcomes and patient care. These approaches include advances in breast irradiation and hormonal and systemic adjuvant therapies. In addition to the identification of new drug targets and targeted therapeutics (eg, trastuzumab), there is renewed re-emphasis in the development of biomarkers for the prediction of response to therapy. One example is the pharmacogenetics of tamoxifen metabolism and the individualization of hormonal therapy. The current treatment of breast cancer continues to evolve rapidly, with new scientific and clinical achievements constantly changing the standard of care and leading to substantial reductions in breast cancer mortality. The goal of this article is to provide clinicians who care for women with breast cancer a multidisciplinary, state-of-the art approach to the treatment of these patients.     

Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease

We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.