TGF-betal/Smad signaling in prostate cancer

Adenocarcinoma of the prostate is the most common type of cancer, excluding skin cancer, and the second leading cause of cancer death in adult men in the United States. The lifetime risk for developing symptomatic prostate cancer is one in five for an American man. A pivotal step in carcinogenesis is a shift in the balance between proliferation, differentiation, and apoptosis that favors cell proliferation. Transforming growth factor-beta (TGF-beta) is a key negative growth regulator in the normal prostate. Although TGF-beta) inhibits the proliferation of normal prostate cells and functions as a tumor suppressor in early tumorigenesis, it acts as a tumor promoter in later stages of tumor progression. Elevated expression of TGF-beta in prostate cancer cells is associated with poor clinical outcome. Over-expression of TGF-beta aids tumorigenesis by not only stimulating angiogenesis and suppressing the immune system, but also by acting directly on the prostate tumor cells. While prostate cancer cells become resistant to TGF-beta-induced growth inhibition and apoptosis, they retain other TGF-beta-induced responses that enhance tumorgenicity. such as induction of extracellular matrix proteins, cell adhesion proteins and proteases. These direct tumor effects are mediated primarily through Smad signaling. This review addresses the mechanisms by which prostate cancer cells may acquire TGF-beta resistance and promote tumorgenicity. Understanding the mechanisms underlying TGF-beta resistance is important for the identification and development of better diagnostic markers and more effective strategies for treating prostate cancer.     

Quality improvement for pressure ulcer care in the nursing home setting: the Northeast Pressure Ulcer Project

OBJECTIVES: The objectives of this study were to evaluate the impact of a collaborative model of quality improvement in nursing homes on processes of care for the prevention and treatment of pressure ulcers. STUDY DESIGN: The study design was experimental. SETTING: We studied 29 nursing homes in New Jersey, Pennsylvania, and Rhode Island. PARTICIPANTS: Participants consisted of pressure ulcer quality improvement teams in 29 nursing homes. INTERVENTION: Quality improvement teams attended a series of workshops to review clinical guidelines and quality improvement principles and to share best practices, and worked one-on-one with mentors to implement quality improvement techniques and to collect data independently. MEASUREMENTS: We calculated process measures based on the Agency for Healthcare Research and Quality (AHRQ) guidelines. Process measures addressed each facility's processes of care for the prevention and treatment of pressure ulcers at baseline and after 12 months of intervention. Prevention measures focused on recent admissions and high-risk residents; treatment measures focused on patients newly diagnosed with pressure ulcers and all patients with pressure ulcers. RESULTS: Overall, 6 of 8 prevention process measures improved significantly, with percent difference between baseline and follow up ranging from 11.6% to 24.5%. Three of 4 treatment process measures improved significantly, with 5.0%, 8.9%, and 25.9% difference between baseline and follow up. For each process measure, between 5 and 12 facilities demonstrated significant improvement between baseline and follow up, and only 2 or fewer declined for each process measure. CONCLUSION: Improvement in processes of care after the use of a structured collaborative quality improvement approach is possible in the nursing home setting.     

Effects of cataractogenesis on the CDP-choline pathway: changes in ATP concentration and phosphocholine synthesis during and after exposure of rat lenses to sugars in vitro and in vivo

We measured choline influx and phosphorylation, ATP concentration ([ATP]), choline kinase activity and lens swelling during formation and partial reversal of sugar cataracts in rat lenses incubated with xylose or galactose and in lenses of galactosemic rats. [ATP] and phosphocholine (P-Cho) synthesis decreased about 60 and 40% after 4 h in normal rat lenses incubated up to 24 h in medium containing 30 mM xylose and partially recovered when the lenses were then removed from the xylose. Incubation with the somewhat less cataractogenic sugar galactose decreased P-Cho synthesis but had little effect on [ATP]. P-Cho synthesis decreased rapidly in the lenses of rats fed a 50% galactose diet, but began recovery by the third day on this diet. [ATP] decreased for at least 10 days during the galactose diet and did not recover, even with resumption of the control diet (50% starch) after 4 or 7 days. The results of in vitro and in vivo sugar cataractogenesis differed from each other in several respects, including effects on choline influx and the degree to which the changes were reversible. The in vitro and in vivo sugar cataracts, however, could both produce swelling and opacification of the lens and decreased P-Cho synthesis and [ATP]. Neither model caused a substantial change in the choline kinase activity (as measured in cell-free assays). The data did not generally support the hypothesis that decreased [ATP] causes decreased P-Cho synthesis.     

Heparin-induced antiheparin-platelet antibody associated with retinal venous thrombosis

OBJECTIVE: To report a case of a 33-year-old white woman in whom retinal venous thromboses developed secondary to heparin-induced antiheparin-platelet antibodies. DESIGN: Interventional case report. METHODS: The patient underwent complete ophthalmic and medical examinations. Laser Doppler measurement of retinal blood circulation also was performed. INTERVENTION: Prolonged anticoagulation with thrombin inhibitors and warfarin. MAIN OUTCOME MEASURES: Visual symptoms, retinal appearance on clinical examination, and measurement of retinal blood flow by laser Doppler technique. RESULTS: The patient experienced a scotoma in the visual field of the left eye, left retinal venous thrombosis, decreased venous blood flow in the left eye, and heparin-induced antiheparin-platelet antibodies in serum. After intervention, the visual symptoms and retinal appearance improved, and retinal blood flow normalized. CONCLUSIONS: Heparin-induced antiheparin-platelet antibody can lead to thrombosis of the ocular circulation. This index case, which is the first one ever reported in association with antiheparin-platelet antibodies, further illustrates the potential side effects of heparin and widens the spectrum of complications of heparin-induced thrombocytopenia (HIT) and HIT thrombosis syndrome (HITTS).     

Optimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compounds

Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (INa) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position alpha [N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide (To5)] or beta [N-(2,6-dimethylphenyl)pyrrolidine-3-carboxamide (To9)] in a proline-like cycle and/or linked to a lipophilic benzyl moiety as in N-benzyl-tocainide (Benzyl-Toc), 1-benzyl-To5 (Benzyl-To5), and 1-benzyl-To9 (Benzyl-To9). INa were elicited with pulses to -20 mV from different holding potentials (-140, -100, and -70 mV) and stimulation frequencies (2 and 10 Hz). All compounds were voltage-dependent and use-dependent channel blockers. The presence of a proline-like cycle increased the potency; i.e., To5 was 3- and 10-fold more effective than Toc in blocking INa at the holding potential of -140 and -70 mV, respectively. The benzyl group on the amine further enhanced drug effectiveness with the following scale: Benzyl-To9 >/= Benzyl-Toc > Benzyl-To5. At a holding potential of -100 mV and 10-Hz stimulation, Benzyl-To9 blocked INa with a half-maximal concentration of 0.5 microM, being 60 and 400 times more potent than To9 and Toc, respectively. The similar effectiveness of Benzyl-Toc and Benzyl-To9 was paralleled by a similar spatial arrangement by equilibrium geometry modeling. In addition, the latter had a higher pKa value that probably contributed to a slow kinetic during its high use-dependent behavior. Benzyl-To5 had its lowest energy level at a more folded conformation that justifies the less favorable profile among the N-benzylated analogs. The new compounds are the most potent tocainide-like sodium channel blockers so far described and have high therapeutic potentials.     

Different ability of clenbuterol and salbutamol to block sodium channels predicts their therapeutic use in muscle excitability disorders

Activation of muscle beta(2)-adrenergic receptors successfully counteracted sarcolemma inexcitability in patients suffering from hyperkalemic periodic paralysis (HPP), a hereditary disease caused by mutations in the gene encoding the skeletal muscle sodium channel. Looking for potential modulation of these channels by beta(2)-adrenergic pathway using patch-clamp technique, we found that clenbuterol blocked sodium currents (I(Na)) in rat skeletal muscle fibers and in tsA201 cells transfected with the human channel isoform, whereas salbutamol did not. The effects of clenbuterol were independent of beta-adrenoceptor stimulation. Instead, clenbuterol structure and physicochemical characteristics as well as I(Na) blocking properties resembled those of local anesthetics, suggesting direct binding to the channels. Similar experiments with the chemically similar beta-antagonists propranolol and nadolol, suggested the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. Importantly, clenbuterol use-dependently inhibited action potential firing in rat skeletal muscle fibers, owing to beta-adrenoceptor-independent I(Na) block. From a clinical point of view, our study defines the rationale for the safe use of salbutamol in HPP patients, whereas clenbuterol may be more indicated in patients suffering from myotonic syndromes, a condition characterized by sarcolemmal overexcitability, because use-dependent I(Na) block can inhibit abnormal runs of action potentials.