The metabolic profile of early Huntington's disease--a combined human and transgenic mouse study

Huntington's disease (HD) is a debilitating autosomal dominant, neurodegenerative disease with a fatal prognosis. Classical symptoms include motor disturbances, subcortical dementia and psychiatric symptoms but are not restricted to this triad. Patients often experience other problems such as weight loss, although why and when this occurs in the disease course is not known. We studied metabolism using whole body indirect calorimetry in both early stage HD patients and in the R6/2 transgenic mouse model of HD, at times before and after they displayed signs of disease. Using this combined approach we found that patients with early HD tended to be in negative energy balance for reasons not related to their movement disorder, which was paralleled in the transgenic R6/2 mice. These mice had significantly elevated total energy expenditure as they developed overt disease with weight loss due primarily to a loss of muscle bulk. This study has shown for the first time that in HD there is the development of early negative energy balance, which in turn may cause weight loss with loss of muscle bulk in particular. The reason for this is not known but may reflect a catabolic state secondary to hypothalamic pathology, as abnormalities have been reported in the hypothalamus early in the disease course.     

A phase II study of days 1 and 8 combination of docetaxel plus gemcitabine for the second-line treatment of patients with advanced non-small-cell lung cancer and good performance status

OBJECTIVE: We conducted a phase II trial to evaluate the efficacy and toxicity of a combination consisting of second-line docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Eligibility criteria: histologically confirmed advanced NSCLC with progressive disease to platinum-based chemotherapy, ECOG performance status (PS) 0 or 1, and adequate kidney, liver and bone marrow function. Treatment consisted of docetaxel 36 mg/m(2) i.v. over 60 min followed by gemcitabine 1000 mg/m(2) i.v. over 30 min on days 1 and 8 of each 3-week cycle for a planned six cycles or unacceptable toxicity. RESULTS: Of the 52 patients enrolled, 50 were evaluable for response and toxicity. The mean age was 59 years (range 42-79), 46 male and 4 female. Histology subtypes were: adenocarcinoma 26 patients, bronchioloalveolar 1 patient, large cell carcinoma 5 patients, and squamous cell carcinoma 18 patients. Thirty-eight patients had ECOG PS 1 and 12 patients had PS 0. The median number of cycles administered was four (range 2-6). The overall response rate was 28%. The median follow-up was 9 months (range 5-34 months). The median survival time (MST) was 8.2 months (95% CI, 4-12%), and the 1-year survival was 25%. The median progression-free survival was 4.4 months (95% CI, 2-6%). In the Cox regression model, survival was only significantly affected by the PS. The median survival in patients with PS 0 was 17.8 months (95% CI, 18.8-21.8%) compared with a median survival for patients with PS 1 of 6.1 months (95% CI, 4.1-8.2%) (P=0.0057). Toxicity: three patients had grade 3 anemia, three patients had grade 3 thrombocytopenia, four patients had grade 3 neutropenia and only one patient developed grade 4 febrile neutropenia. Non-hematologic toxicity was also mild; the most frequent was asthenia, with grade 3 in eight patients (16%), and one patient with grade 4. CONCLUSION: This regimen of docetaxel in combination with gemcitabine in advanced second-line NSCLC is an active and safe regimen.     

Characterisation of NcGRA7 and NcSAG4 proteins: Immunolocalisation and their role in the host cell invasion by <Emphasis Type="Italic">Neospora caninum</Emphasis> tachyzoites

Neospora caninum negatively impacts bovine reproductive performance around the world. Addressing this problem requires a greater understanding of the parasite’s molecular biology. In this study, monoclonal antibodies against recombinant proteins were successfully developed and employed to characterise two different proteins of N. caninum: the acute phase-associated NcGRA7 and the chronic phase-associated NcSAG4. Immunofluorescence with the anti-rNcGRA7 monoclonal antibody suggested that NcGRA7 trafficks from tachyzoite dense granules to the matrix of the parasitophorous vacuole and parasite’s surroundings. Furthermore, NcGRA7 is also expressed in the bradyzoite stage and localised on the matrix of bradyzoite-positive vacuoles. NcGRA7 appears to be partially involved in the tachyzoite-invasion mechanisms, as an anti-rNcGRA7 monoclonal antibody partially inhibited in vitro tachyzoite-invasion. A monoclonal antibody specific for NcSAG4 confirmed this protein’s bradyzoitespecific expression both by western blot and immunofluorescence. However, some bradyzoite-positive vacuoles only weakly expressed NcSAG4, if it was expressed at all. The specificity of the anti-rNcSAG4 monoclonal antibody was confirmed by the recognition of the NcSAG4 in the membrane surface of Nc-1SAG4^c transgenic tachyzoites, which constitutively expresses NcSAG4. Blocking NcSAG4 of Nc-1SAG4^c tachyzoites with the monoclonal antibody did not affect host cell invasion. However, its implication on the host cell adhesion or host immune evasion should not be discarded.     

Echocardiographic estimation of pulmonary arterial systolic pressure in acute heart failure. Prognostic implications

BackgroundPrognostic implications of echocardiographic assessment of pulmonary hypertension (PH) in non-selected patients hospitalized for acute heart failure (AHF) are not clearly defined. The aim of this study was to evaluate the association between echocardiography-derived PH in AHF and 1-year all-cause mortality.MethodsWe prospectively included 1210 consecutive patients admitted for AHF. Patients with significant heart valve disease were excluded. Pulmonary arterial systolic pressure (PASP) was estimated using transthoracic echocardiography during hospitalization (mean time after admission 96 ± 24 h). Patients were categorized as follows: non-measurable, normal PASP (PASP ≤ 35 mm Hg), mild (PASP 36-45 mm Hg), moderate (PASP 46-60 mm Hg) and severe PH (PASP > 60 mm Hg). The independent association between PASP and 1-year mortality was assessed with Cox regression analysis.ResultsAt 1-year follow-up, 232 (19.2%) deaths were registered. PASP was measured in 502 (41.6%) patients with a median of 46 [38–55] mm Hg. The distribution of population was: 708 (58.5%), 76 (6.3%), 147 (12.1%), 190 (15.7%) and 89 (7.4%) for non-measurable, normal PASP, mild, moderate and severe PH, respectively. One-year mortality was lower for patients with normal PASP (1.32 per 10 person-years), intermediate for patients with non-measurable, mild and moderate PH (2.48, 2.46 and 2.62 per 10 persons-year, respectively) and higher for those with severe PH (4.89 per 10 person-years). After multivariate adjustment, only patients with PASP > 60 mm Hg displayed significant adjusted increase in the risk of 1-year all-cause mortality, compared to patients with normal PASP (HR = 2.56; CI 95%: 1.05–6.22, p = 0.038).ConclusionsIn AHF, severe pulmonary hypertension derived by echocardiography is an independent predictor of 1-year-mortality.     

Autoradiographic analysis of cannabinoid receptor binding and cannabinoid agonist-stimulated [S]GTPγS binding in morphine-dependent mice

The present study was designed to test the possible existence of changes in brain cannabinoid receptors in morphine-dependent mice. To this end, we compared cannabinoid receptor binding and WIN 55,212-2-stimulated [³⁵S]guanylyl-5′-O-(γ-thio)-triphosphate ([³⁵S]GTPγS) binding in several brain regions of mice chronically exposed to morphine or saline. The existence of opiate dependence in morphine-injected mice was assessed by analyzing the well-known jumping behavior induced by the blockade of opioid receptors with naloxone, whereas these animals were unresponsive to the blockade of cannabinoid receptors with SR141716. The different structures analyzed exhibited similar cannabinoid receptor binding levels in morphine-dependent and control mice, with the only exception of the globus pallidus, which exhibited a very small, but statistically significant, increase. In addition, the activation of cannabinoid receptors with WIN 55,212-2 increased [³⁵S]GTPγS binding in most of the structures examined. The increase was of similar magnitude in morphine-dependent and control mice, except in the substantia nigra, where morphine-dependent mice exhibited lesser [³⁵S]GTPγS binding levels in basal conditions, although a significantly higher WIN 55,212-2-stimulated binding. Other structures, such as the central gray substance, where there was a poor agonist-induced stimulation in control mice, exhibited, however, higher levels of WIN 55,212-2-stimulated [³⁵S]GTPγS binding in morphine-dependent mice, whereas these animals tended to exhibit a higher [³⁵S]GTPγS binding levels in basal conditions, although a lesser and not statistically significant WIN 55,212-2-stimulated binding, in the deep layers of the cerebral cortex. Thus, the data support the potential existence of a specific effect of morphine in the coupling of cannabinoid receptors to GTP-binding proteins, rather than on receptor binding, although this was observed only in the substantia nigra and central gray substance.     

Is advanced esophageal adenocarcinoma a distinct entity from intestinal subtype gastric cancer? Data from the AGAMENON-SEOM Registry

Gastric Cancer - Advanced esophageal adenocarcinoma (EAC) is generally treated similarly to advanced gastroesophageal junction (GEJ-AC) and gastric (GAC) adenocarcinomas, although GAC clinical...