Expedited blood pressure control with initial angiotensin II antagonist/diuretic therapy compared with stepped-care therapy in patients with ambulatory systolic hypertension

OBJECTIVES: The present study investigated whether initiating therapy with a combination of losartan (L) and hydrochlorothiazide (HCTZ) allows for faster blood pressure (BP) control and fewer medications than the usual stepped-care approach in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension. METHODS: Patients with a mean daytime systolic ambulatory BP (ABP) of 135 mmHg or higher were randomly assigned to receive L 50 mg plus HCTZ 12.5 mg titrated to L 100 mg plus HCTZ 25 mg versus HCTZ 12.5 mg plus atenolol 50 mg. Amlodipine 5 mg was then added, if needed, to achieve a BP goal of less than 130 mmHg. Treatment titration was based on ABP. RESULTS: Significantly more patients randomly assigned to L/HCTZ (63.5%) than stepped-care (37.5%; P=0.008) achieved the primary end point (daytime systolic BP of less than 130 mmHg). Initial L/HCTZ induced significantly greater decreases in ABP during each 24 h period after six weeks of therapy. Although reductions in systolic and diastolic ABP were not statistically different at the end of the study, ABP reduction was significantly greater (P<0.001) with the L/HCTZ-based regimen. Twice as many patients in the L/HCTZ group achieved the goal ABP with no more than two drugs (30.0% versus 14.7%; P=0.03). Moreover, tolerability was significantly better (P=0.006) in the L/HCTZ group, with a 40.0% incidence of adverse events, versus 65.6% in the stepped-care group. CONCLUSION: Initiating antihypertensive therapy with the combination of L/HCTZ in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension reaches a target BP faster in a higher proportion of patients, with fewer adverse events and less need for a third drug regimen than the conventional stepped-care approach.     

Beneficial effects of statin therapy on survival in hypertensive patients with acute myocardial infarction: data from the RICO survey

BACKGROUND: Randomized studies have shown a reduction in cardiovascular events associated with low doses of statin among hypertensive patients at only moderate cardiovascular risk. The hypothesis of the present study was that statin therapy initiated during hospitalization could improve the long-term outcome after acute myocardial infarction (MI) in hypertensive patients. METHODS: From the French regional obserRvatoire des Infarctus de C?te d'Or (RICO) survey, 1076 patients with a history of hypertension, surviving acute MI were included. Patients on statin therapy initiated before their hospitalization were excluded from the study. Patients were categorized into two groups based on whether or not statin treatment was initiated during the hospital stay. RESULTS: Patients in the statin group were younger (70 years [range, 58 to 77 years] v 75 years [range, 65 to 82 years], P < .001) and were more likely to have hypercholesterolemia (42% v 28 %, P < .001). No differences were observed between the two groups for LDL-cholesterol levels on admission. At 1-year follow-up, cardiovascular mortality and rehospitalization for heart failure were lower in the statin group (respectively, 5% v 15%, P < .001; 5% v 7%, P < .001). Multivariate analysis showed that statin therapy was associated with decreased mortality (hazard ratio [95% confidence interval; CI]: 0.58 [0.32-0.98], P = .035) independently of either hypercholesterolemia, the use of beta-blockers, angiotensin-converting enzyme inhibitors, or diuretics, but not with a decreased incidence of heart failure (hazard ratio [95% CI]: 0.88 [0.55-1.23], P = .152). CONCLUSIONS: In this observational study, the long-term benefits of statin therapy initiated in-hospital in hypertensive patients after acute MI was demonstrated. These findings may have implications for treatment optimization of hypertensive patients in secondary prevention.     

Uso de glucocorticoides en la artritis reumatoide. ¿Cuándo y cómo deben usarse los esteroides en la artritis reumatoide?

Glucocorticoids (GC) are a mainstay of the therapy in rheumatoid arthritis (RA). Currently, and despite their extensive use, the discussion about the benefits and adverse effects of low dose GC in the management of RA persists. In recent years, a number of clinical trials have attempted to establish the benefits of long-term GC use as a disease-modifying antirheumatic drug in RA, and to define their side effects. Results of these clinical trials provide solid evidence that low-dose GC can inhibit radiographic damage in early RA, and that side effects of GC, when used in that clinical framework, are limited to hyperglycaemia, cataracts, and transient weight gain.     

Intracellular pH regulates amyloid precursor protein intracellular domain accumulation

The amyloid precursor protein (APP) metabolism is central to pathogenesis of Alzheimer's disease (AD). Parenchymal amyloid deposits, a neuropathological hallmark of AD, are composed of amyloid-beta peptides (Abeta). Abeta derives from the amyloid precursor protein (APP) by sequential cleavages by beta- and gamma-secretases. Gamma-secretase cleavage releases the APP intracellular domain (AICD), suggested to mediate a nuclear signaling. Physiologically, AICD is seldom detected and thus supposed to be rapidly degraded. The mechanisms responsible of its degradation remain unknown. We used a pharmacological approach and showed that several alkalizing drugs induce the accumulation of AICD in neuroblastoma SY5Y cell lines stably expressing APP constructs. Moreover, alkalizing drugs induce AICD accumulation in naive SY5Y, HEK and COS cells. This accumulation is not mediated by the proteasome or metallopeptidases and is not the result of an increased gamma-secretase activity since the gamma-secretase cleavage of Notch1 and N-Cadherin is not affected by alkalizing drug treatments. Altogether, our data demonstrate for the first time that alkalizing drugs induce the accumulation of AICD, a mechanism likely mediated by the endosome/lysosome pathway.     

The bidirectional communication between neurons and mast cells within the gastrointestinal tract

Normal or disordered behaviour of the gastrointestinal tract is determined by a complex interplay between the epithelial barrier, immune cells, blood vessels, smooth muscle and intramurally located nerve elements. Mucosal mast cells (MMCs), which are able to detect noxious and antigenic threats and to generate or amplify signals to the other cells, are assigned a rather central position in this complex network. Signal input from MMCs to intrinsic enteric neurons is particularly crucial, because the enteric nervous system fulfils a pivotal role in the control of gastrointestinal functions. Activated enteric neurons are able to generate an alarm program involving alterations in motility and secretion. MMC signalling to extrinsic nerve fibres takes part in pathways generating visceral pain or extrinsic reflexes contributing to the disturbed motor and secretory function. Morphological and functional studies, especially studies concerning physiological stress, have provided evidence that, apart from the interaction between the enteric nervous system and MMCs, there is also a functional communication between the central nervous system and these mast cells. Psychological factors trigger neuronal pathways, which directly or indirectly affect MMCs. Further basic and clinical research will be needed to clarify in more detail whether basic patterns of this type of interactions are conserved between species including humans.     

Thermoregulation during exercise in the heat: strategies for maintaining health and performance

As a result of the inefficiency of metabolic transfer, >75% of the energy that is generated by skeletal muscle substrate oxidation is liberated as heat. During exercise, several powerful physiological mechanisms of heat loss are activated to prevent an excessive rise in body core temperature. However, a hot and humid environment can significantly add to the challenge that physical exercise imposes on the human thermoregulatory system, as heat exchange between body and environment is substantially impaired under these conditions. This can lead to serious performance decrements and an increased risk of developing heat illness. Fortunately, there are a number of strategies that athletes can use to prevent and/or reduce the dangers that are associated with exercise in the heat. In this regard, heat acclimatisation and nutritional intervention seem to be most effective. During heat acclimatisation, the temperature thresholds for both cutaneous vasodilation and the onset of sweating are lowered, which, in combination with plasma volume expansion, improve cardiovascular stability. Effective nutritional interventions include the optimisation of hydration status by the use of fluid replacement beverages. The latter should contain moderate amounts of glucose and sodium, which improve both water absorption and retention.     

Synthesis and evaluation of a (99m)Tc-MAMA-propyl-thymidine complex as a potential probe for in vivo visualization of tumor cell proliferation with SPECT

INTRODUCTION: Cytosolic thymidine kinase (TK1) catalyzes phosphorylation of thymidine to its monophosphate. TK1 activity is closely related with DNA synthesis, and thymidine analogs derivatized with bulky carboranylalkyl groups at the N-3 position were reported to be good substrates for TK1. Accordingly, we have synthesized (99m)Tc-MAMA-propyl-thymidine and evaluated it as a potential tumor tracer. METHODS: The bis(S-trityl)-protected MAMA-propyl-thymidine precursor (3-N-[S-trityl-2-mercaptoethyl]-N-[N'-(S-trityl-2-mercaptoethyl)amidoacetyl]-aminopropyl-thymidine) was prepared in three steps, and its structure was confirmed with (1)H NMR and mass spectrometry. Deprotection of the thiols and labeling with (99m)Tc were done in a two-step, one-pot procedure, yielding (99m)Tc-MAMA-propyl-thymidine, which was analyzed with high-performance liquid chromatography, radio-LC-MS analysis (ESI+) and electrophoresis, and its log P was determined. The biodistribution in normal mice was evaluated, and its biodistribution in a radiation-induced fibrosarcoma (RIF) tumor mouse was compared with that of 3'-deoxy-3'-[(18)F] fluorothymidine [(18)F]FLT. RESULTS: (99m)Tc-MAMA-propyl-thymidine was obtained with a radiochemical yield of 70%. Electrophoresis indicated that the complex is uncharged, and its log P was 1.0. The molecular ion mass of the Tc complex was 589 Da, which is compatible with the hypothesized N(2)S(2)-oxotechnetium structure. Tissue distribution showed fast clearance from plasma primarily by the hepatobiliary pathway. Whole-body planar imaging after injection of (99m)Tc-MAMA-propyl-thymidine in an RIF tumor-bearing mouse showed high uptake in the liver and the intestines. No uptake was observed in the tumor, in contrast to the clear uptake observed for [(18)F] FLT visualized with muPET. CONCLUSIONS: Although it has been reported that TK1 accepts large substituents at the N-3 position of the thymine ring, the results of this study show that (99m)Tc-MAMA-propyl-thymidine cannot be used as a single photon emission computed tomography tumor tracer, probably because the (99m)Tc-MAMA ligand is too bulky to be tolerated by TK1.     

Treatment of chronic static scapholunate dissociation with the modified Brunelli technique: preliminary results

A series of 10 patients with reducible chronic post-traumatic scapholunate dissociation, treated with the modified Brunelli technique, is presented. The general outcome was good with a mean DASH score of 12, a range of motion of 69% and gripping force of 77% compared with the contralateral side.