A new assay of thermal-based avoidance test in freely moving mice.

The hot plate test is a standard way to measure nociceptive response latencies to a noxious thermal stimulus. Here we have modified the classic hot plate by allowing animals to escape to an adjacent chamber after exposure to the heated surface. In this test, the animals escape to the adjacent chamber after exposure to the hot plate set at 50 degrees C. Repeated exposure to the hot plate resulted in a facilitation of escape responses, as measured by a reduced latency to escape from the noxious thermal stimulus. Signs of nociceptive behavior, such as licking or jumping, were not affected in animals that received hot plate training. The reduction of escape latencies after repeated hot plate exposure might be a useful measure for studying the facilitation of escape responses. In addition, the modified hot plate described here might be useful in studying performance and memory deficits related to noxious thermal stimuli. PERSPECTIVE: We modified a hot plate to measure facilitation of escape responses to a noxious thermal stimulus. The measure of escape responses might be useful in the assessment of memory defects, evaluation of drug therapies, and the behavioral characterization of transgenic mice.     

Glioma apoptosis induced by macrophages involves both death receptor-dependent and independent pathways

Apoptosis of glioma may represent a promising intervention for tumor treatment. Macrophages are able to induce apoptosis in a number of tumor cells, including glioma. It is known that apoptosis of cells is executed on either a death receptor-dependent or independent pathway. Whether and how apoptosis of glioma cells induced by activated macrophages is involved in these two pathways simultaneously are not known. Using in vitro and in vivo experimental models, we investigated Bcl-2 system and Fas/FasL channel, representing the death receptor-dependent and independent pathways, respectively, in glioma cells treated with the supernatant from the activated macrophages, which was rich in tumor necrosis factor-alpha and interferon-gamma. We found that levels of Fas and FasL were up-regulated both in vitro and in vivo, accompanying an increase in the expression of caspase-8. The number of apoptotic cells was also increased significantly, although the percentage of death cells exceeded the number of tumor cells positive for Fas or FasL. It was also evident that the expression of Bax was increased, whereas the level of Bcl-2 was decreased, in glioma cells treated with the supernatant from the activated macrophages. The alteration of molecules related to both death pathways led to apoptosis of glioma and the inhibition of xenograft glioma growth in mice. Apoptosis of glioma induced by the activated macrophage is executed by way of both death receptor-dependent and independent pathways, and such an apoptosis-induced approach can effectively inhibit the growth of glioma in vivo.     

A randomised controlled trial comparing completeness of responses of three methods of collecting patient-reported outcome measures in men diagnosed with prostate cancer

Quality of Life Research - The purpose of the study was to compare completeness, timeliness and cost of patient-reported outcome measures (PROMs) collection using telephone, email and post in men...     

Meeting physical activity recommendations is associated with health-related quality of life in women before and after Roux-en-Y gastric bypass surgery

Quality of Life Research - Meeting physical activity (PA) recommendations is positively associated with health-related quality of life (HRQoL), but it is still unclear whether PA (specifically...     

The impact of intra-operative sternum vertical displacement on the sagittal curves of the spine

Patient positioning is an important step in spinal surgeries. Many surgical frames allow for lumbar lordosis modulation due to lower limb displacement, however, they do not include a feature which can modulate thoracic kyphosis. A sternum vertical displacer (SVD) prototype has been developed which can increase a subject’s thoracic kyphosis relative to the neutral prone position on a surgical frame. The kyphosis increase is obtained by lifting the subject’s torso off the thoracic cushions with a dedicated sternum cushion that can be displaced vertically. The objective of this study was to evaluate the impact of SVD utilization on the sagittal curves of the spine. Experimental testing was performed on six healthy volunteers. Lateral radiographs were taken in the neutral and sternum raised positions and then analyzed in order to compare the values of sagittal curves. The displacement of volunteers and surgical frame components between positions was recorded using an optoelectronic device. Finally, interface pressures between the volunteers and surgical frame cushions were recorded using a force sensing array. Average results show that passing from the neutral to sternum raised positions caused an increase of 53% in thoracic kyphosis and 24% in lumbar lordosis; both statistically significant. Sensors showed that the sternum was raised a total of 8 cm and that interface pressures were considerably higher in the raised position. The SVD provides a novel way of increasing a patient’s thoracic kyphosis intra-operatively which can be used to improve access to posterior vertebral elements and improve sagittal balance. It is recommended that its use should be limited in time due to the increase in interface pressures observed.     

Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study

Treatment options for patients suffering from indolent forms of mastocytosis remain inadequate with the hyperactivation of mast cells responsible for many of the disease's systemic manifestations. Masitinib is a potent and highly selective oral tyrosine kinase inhibitor. A combined inhibition of c-Kit and Lyn make it particularly efficient in controlling the activity of mast cells and therefore, of potential therapeutic benefit in mastocytosis. Masitinib was administered to 25 patients diagnosed as having systemic or cutaneous mastocytosis with related handicap (i.e., disabilities associated with flushes, depression, pruritus and quality-of-life) at the initial dose levels of 3 or 6 mg/kg/day over 12 weeks. In accordance with the AFIRMM study, response was based upon change of clinical symptoms associated with patient handicap at week 12 relative to baseline, regardless of disease subtype. Improvement was observed in all primary endpoints at week 12 including a reduction of flushes, Hamilton rating, and pruritus as compared with baseline by 64% (P = 0.0005), 43% (P = 0.0049), and 36% (P = 0.0077), respectively. An overall clinical response was observed in 14/25 patients (56%; [95%CI = 37%-75%]), with sustainable improvement observed throughout an extension phase (>60 weeks). Common adverse events were edema (44%), nausea (44%), muscle spasms (28%), and rash (28%), the majority of which were of mild or moderate severity with a significant decline in frequency observed after 12 weeks of treatment. One patient experienced a serious adverse event of reversible agranulocytosis. Masitinib is a promising treatment for indolent forms of mastocytosis with handicap and indicates acceptable tolerability for long-term treatment regimens.     

Drug-dependent inpatients reporting continuous absence of spontaneous drug craving for the main substance throughout detoxification treatment

Introduction and Aims. Drug craving is considered to be an essential component of substance dependence. We aimed to characterise drug‐dependent inpatients reporting continuous absence of subjective spontaneous drug craving. Design and Methods. This is a 3 year chart‐review study designed to compare drug‐dependent inpatients who did not report craving everyday (non‐cravers) and their counterparts who did (cravers). All participants were recruited consecutively and completed a 14 day detoxification treatment. Craving was defined as a desire to use the main detoxification substance. This substance was chosen by patients, who completed a craving visual analogue scale, the Beck Depression Inventory and the State‐Trait Anxiety Inventory daily. The Temperament and Character Inventory and the Addiction Severity Index were also used. Results. Of the 195 patients who completed the detoxification treatment, 45 (23.1%) were non‐cravers and 32 (16.4%) were cravers. The main detoxification substances were alcohol, benzodiazepines, cannabis, cocaine, heroin and methadone. Non‐cravers named methadone as the main detoxification substance more frequently than cravers, and benzoylecgonine was less frequently present in their urine at treatment entry. A decreased score on the Temperament and Character Inventory dimension of harm avoidance (i.e. trait anxiety) was the only independent predictor of absence of craving (odds ratio = 1.16, 95% confidence interval = 1.03–1.31). During admission, non‐cravers had lower Beck Depression Inventory and State‐Trait Anxiety Inventory scores than cravers. These differences were not accounted for by pharmacological treatment. Discussion and Conclusions. Drug ‐dependent inpatients who report absence of craving are characterised by relatively low levels of depression and anxiety throughout detoxification treatment, and relatively low levels of trait anxiety.[Pérez de los Cobos J, Siñol N, Trujols J, Bañuls E, Batlle F, Tejero A. Drug‐dependent inpatients reporting continuous absence of spontaneous drug craving for the main substance throughout detoxification treatment. Drug Alcohol Rev 2011;30:403–410]     

A retrospective analysis of the potential impact of IgG antibodies to agalsidase β on efficacy during enzyme replacement therapy for Fabry disease

Fabry disease results from a genetic deficiency of α-galactosidase A (αGAL) and the impaired catabolism of globotriasoylceramide (GL-3) and other glycosphingolipid substrates, which then accumulate pathogenically within most cells. Enzyme replacement therapy (ERT) with agalsidase β (Fabrazyme®), one of two available forms of recombinant human αGAL, involves regular intravenous infusions of the therapeutic protein. Immunoglobulin G (IgG) antibodies to recombinant αGAL develop in the majority of patients upon repeated infusion. To explore whether anti-αGAL IgG interferes with therapeutic efficacy, retrospective analyses were conducted using data obtained from a total of 134 adult male and female patients with Fabry disease who were treated with agalsidase β at 1 mg/kg every 2 weeks for up to 5 years during placebo-controlled trials and the corresponding open-label extension studies. The analyses did not reveal a correlation between anti-αGAL IgG titers and the onset of clinical events or the rate of change in estimated GFR during treatment, and no statistically significant association was found between anti-αGAL IgG titers and abnormal elevations in plasma GL-3 during treatment. However, a statistically significant association was found between anti-αGAL IgG titers and observation of some GL-3 deposition in the dermal capillary endothelial cells of skin during treatment, suggesting that GL-3 clearance may be partially impaired in some patients with high antibody titers. Determination of the long-term impact of circulating anti-αGAL IgG antibodies on clinical outcomes will require continued monitoring, and serology testing is recommended as part of the routine care of Fabry disease patients during ERT.     

Recombinant human luteinizing hormone, lutropin alfa, for the induction of follicular development and pregnancy in profoundly gonadotrophin-deficient women

OBJECTIVE: To provide evidence of efficacy and safety for use of lutropin alfa in inducing follicular development and pregnancy in hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency. DESIGN: An open-label, noncomparative extension of a randomized, double-blind, placebo-controlled study PATIENTS: A total of 31 hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency in 23 medical centres in four countries were studied. INTERVENTIONS: Lutropin alfa 75 IU and follitropin alfa (75-225 IU), individually based on each patient's response as is consistent with usual medical practice. MEASUREMENTS: Follicular development as defined by (i) at least one follicle >or= 17 mm; (ii) preovulatory serum oestradiol level >or= 109 pg/ml on the day of hCG administration; and (iii) midluteal phase P(4) level >or= 7.9 ng/ml. Pregnancy and over-response leading to cycle cancellation were considered treatment successes. Pregnancy rates were assessed. RESULTS: In a total of 54 cycles, 27 of 31 (87.1%) profoundly gonadotrophin-deficient patients achieved follicular development within three cycles. Twenty of 27 patients (74.1%) who achieved follicular development and received hCG became pregnant; 16 (59.3%) continued to clinical pregnancy. One patient was hospitalized for severe ovarian hyperstimulation syndrome. Lutropin alfa was well tolerated. CONCLUSIONS: Coadministration of lutropin alfa 75 IU and follitropin alfa is safe and effective in inducing follicular development and pregnancy in hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency in a setting consistent with established medical practice.     

A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs’ disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs'' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.