Anticipatory postural adjustments and kinematic analysis of step ascent and descent in adults with Down syndrome.

BACKGROUND: Step ascent and descent is one of the most common daily tasks. Although it is generally considered a rather simple movement, it may not be so easy for participants with Down syndrome. METHODS: A kinematic analysis of step ascent and descent was conducted, and a comparison between 11 adult participants with Down syndrome and 23 healthy participants was carried out. This analysis was accompanied by a posturographic analysis with the aim of evaluating aspects relating to balance. The principal aim of postural control was to investigate the trajectory of the centre of pressure, while the kinematic analysis of movement included the following: (1) the analysis of anticipatory postural adjustments, (2) the calculation of spatiotemporal parameters and (3) the evaluation of articular range of motion. RESULTS: A general instability for participants with Down syndrome, highlighted in the postural control by an increased anteroposterior and mediolateral excursion, when the test was conducted with both open and closed eyes, was found out. Regarding anticipatory postural adjustments, this deficit in balance control was revealed by the execution of small steps before completing the movement and by a much longer preparation time anticipating the movement. In addition, the kinematic analysis reported a longer ascent and descent time and a lower velocity, accompanied by a greater rising of both limbs in ascent, which indicates an increased perception of the obstacle. Finally, a wider trunk range of motion in both the sagittal and frontal planes was revealed. CONCLUSIONS: All the data confirm a compromised balance control that could be associated with damage to the sensorimotor centre.

Legacy and emerging contaminants in the endangered filter feeder basking shark Cetorhinus maximus.

The status of contamination by chemical pollutants on large filter feeding sharks is still largely unknown. This study investigated for the first time the presence of legacy, emerging contaminants and trace elements in multiple tissues of basking sharks. In general, skin showed higher concentration of legacy and emerging contaminants probably due to pollutants being adsorbed onto the dermal denticles of the skin rather than accumulated in the tissue itself. Contaminants measured in both subcutaneous tissue and muscles appeared to strongly correlate with each other, indicating that the former might be a good proxy of muscle contamination in basking sharks. Considering the migratory nature of this species, longevity and feeding ecology, this species represents the perfect candidate to act as early warning bioindicator of regional contamination. In this context, non-lethal subcutaneous biopsies could allow the early detection of any temporal variation in the bioaccumulation of pollutants in the Mediterranean Sea.

Instrumental Timed Up and Go test discloses abnormalities in patients with Cervical Dystonia.

Background Cervical dystonia is a movement disorder characterized by involuntary and sustained contraction of the neck muscles that determines abnormal posture. The aim of this study was to investigate whether dystonic posture in patients with cervical dystonia affects walking and causes postural changes. Methods Patients with cervical dystonia and a group of age-matched healthy controls underwent an instrumental evaluation of the Timed Up and Go Test. Findings All the spatio-temporal parameters of the sub-phases of the Timed up and go test had a significantly higher duration in cervical dystonia patients compared to the control group while no differences in flection and extension angular amplitudes were observed. Indeed, we found that Cervical Dystonia patients had abnormalities in turning, as well as in standing-up and sitting-down from a chair during the Timed up and go test than healthy controls. Interpretation Impairment in postural control in cervical dystonia patients during walking and postural changes prompts to develop rehabilitation strategies to improve postural stability and reduce the risk of fall in these patients.

Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase II trial.

BACKGROUND: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. PATIENTS AND METHODS: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks). RESULTS: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001). CONCLUSIONS: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.

Sex and region-specific effects of high fat diet on PNNs in obesity susceptible rats.

Perineuronal nets (PNNs) are specialized extracellular matrix structures that primarily surround fast-spiking parvalbumin (PV)-containing interneurons within the PFC. They regulate PV neuron function and plasticity to maintain cortical excitatory/inhibitory balance. For example, reductions in PNN intensity are associated with reduced local inhibition and enhanced pyramidal neuron firing. We previously found that exposure to dietary high fat reduced PNN intensity within the PFC of male Sprague-Dawley (SD) rats. However, how high fat affects PNNs in the PFC of females or in obesity-vulnerable vs. -resistant models is unknown. Therefore, we gave male and female SD, selectively bred obesity-prone (OP), and obesity-resistant rats (OR) free access to standard lab chow or 60% high fat for 21 days. We then measured the number of PNN positive cells and PNN intensity (determined by Wisteria floribunda agglutinin [WFA] staining) as well as the number of PV positive neurons using immunohistochemistry. We found sex and region-specific effects of dietary high fat on PNN intensity, in the absence of robust changes in cell number. Effects were comparable in SD and OP but differed in OR rats. Specifically, high fat reduced PNN intensities in male SD and OP rats but increased PNN intensities in female SD and OP rats. In contrast, effects in ORs were opposite, with males showing increases in PNN intensity and females showing a reduction in intensity. Finally, these effects were also region specific, with diet-induced reductions in PNN intensity found in the prelimbic PFC (PL-PFC) and ventral medial orbital frontal cortex (vmOFC) of SD and OP males in the absence of changes in the infralimbic PFC (IL-PFC), and increases in PNN intensity in the IL-PFC of SD and OP females in the absence of changes in other regions. These results are discussed in light of roles PNNs may play in influencing PFC neuronal activity and the differential role of these sub-regions in food-seeking and motivation.

Enhanced anxiety-like behavior emerges with weight gain in male and female obesity-susceptible rats.

Epidemiological data suggest that body mass index and obesity are strong risk factors for depression and anxiety. However, it is difficult to separate cause from effect, as predisposition to obesity may enhance susceptibility to anxiety, or vice versa. Here, we examined the effect of diet and obesity on anxiety-like behaviors in male and female selectively bred obesity-prone and obesity-resistant rats, and outbred Sprague-Dawley rats. We found that when obesity-prone and obesity-resistant rats do not differ in weight or fat mass, measures of anxiety-like behavior in the elevated plus maze and open field are similar between the two groups. However, once weight and fat mass diverge, group differences emerge, with greater anxiety in obesity-prone relative to obesity-resistant rats. This same pattern was observed for males and females. Interestingly, even when obesity-resistant rats were "forced" to gain fat mass comparable to obesity-prone rats (via prolonged access to 60% high-fat diet), anxiety-like behaviors did not differ from lean chow fed controls. In addition, a positive correlation between anxiety-like behaviors and adiposity were observed in male but not in female obesity-prone rats. Finally, diet-induced weight gain in and of itself was not sufficient to increase measures of anxiety in outbred male rats. Together, these data suggest that interactions between susceptibility to obesity and physiological alterations accompanying weight gain may contribute to the development of enhanced anxiety.

Intracellular angiotensin-(1-12) changes the electrical properties of intact cardiac muscle.

In the present work, the influence of intracellular injection of angiotensin-(1-12) [Ang-(1-12)] on the electrical properties of the intact left ventricle of Wistar Kyoto rats was investigated with electrophysiological methods. Particular attention was given to the role of chymostatin on the effect of the peptide. The results indicated that intracellular administration of the peptide elicited a depolarization of the surface cell membrane and an increase of duration of the action potential followed by the generation of early afterdepolarizations. The increment of action potential duration caused by Ang-(1-12) (100 nM) was due to a decrease of total potassium current recorded from single cardiomyocytes using the whole cell configuration of pCAMP. The decrease of potassium current was related to the activation of protein kinase C (PKC) because the specific inhibitor of kinase C, Bis-1 (10-9 M), abolished Ang-(1-12) effects on the potassium current. The question of whether the effect of Ang-(1-12) was related to the formation of Ang II by chymase was investigated.The results revealed that the intracellular administration of chymostatin, a chymase inhibitor (10-9 M) abolished the effect of intracellular Ang-(1-12) on the potassium current. Moreover, intracellular Ang II (100 nM), by itself, reduced the potassium current, an effect decreased by intracellular valsartan (100 nM). Valsartan (10-9 M) dialyzed into the cell abolished the effect of Ang-(1-12) (100 nM). These observations demonstrate that the effect of Ang-(1-12) on potassium current was related to the formation of Ang II and that the peptide has arrhythmogenic properties.

The human gut microbiota and its interactive connections to diet.

The microbiota of the gastrointestinal tract plays an important role in human health. In addition to their metabolic interactions with dietary constituents, gut bacteria may also be involved in more complex host interactions, such as modulation of the immune system. Furthermore, the composition of the gut microbiota may be important in reducing the risk of contracting particular gut infections. Changes in the microbiota during an individual's lifespan are accompanied by modifications in multiple health parameters, and such observations have prompted intense scientific efforts aiming to understand the complex interactions between the microbiota and its human host, as well as how this may be influenced by diet.

The trastuzumab and vinorelbine combination: an alternative to taxane-based chemotherapy for early-stage and locally advanced her2-positive breast cancer.

BACKGROUND: Anthracyclines and taxanes have historically constituted the backbone of chemotherapy regimens for patients with breast cancer positive for the human epidermal growth factor receptor 2 (her2). For a subset of patients who categorically refuse alopecia, or for those with a contraindication to those drugs, there is an urgent need to define alternative regimens. Here, we report our institutional experience with trastuzumab and vinorelbine (tv), a combination with good clinical activity and a good side effect profile for patients with her2-positive breast cancer. METHODS: In a retrospective analysis, outcomes data were extracted for patients receiving tv as their only chemotherapy in the non-metastatic setting at the Jewish General Hospital. For the most part, tv was administered weekly for 6 months, followed by trastuzumab for 6 months. RESULTS: The analysis identified 46 patients (mean age: 64 years) who received tv between 2003 and 2012 (n = 36 adjuvant, n = 10 neoadjuvant). Of the patients in the adjuvant group, 81% had stage i disease. In the neoadjuvant group, 3 patients experienced a complete pathologic response. Only 1 patient experienced local recurrence after a short course (3 months) of adjuvant tv. Overall survival and breast cancer-specific survival were 94% and 98% respectively at a median 5 years of follow-up. Febrile neutropenia-induced sepsis resulted in the death of 1 patient with significant medical comorbidities; 2 other patients died of comorbidities unrelated to their cancer or treatment. Grades 3 or 4 adverse events included neutropenia (23%), febrile neutropenia (10%), fatigue (2%), and anemia (2%). CONCLUSIONS: For patients with non-metastatic breast cancer refusing alopecia, or for patients who are not candidates for standard chemotherapy, tv is a reasonable alternative to standard adjuvant chemotherapy.

A real-life experience using panitumumab in chemo-refractory metastatic colorectal cancer patients: a retrospective analysis at the Jewish General Hospital, 2009-2012.

BACKGROUND: Panitumumab is a fully human monoclonal antibody, directed against the epidermal growth factor receptor, that was shown to be effective in third-line metastatic colorectal cancer. We performed a retrospective analysis of patients with chemo-refractory non-KRAS-mutated metastatic colorectal cancer, who received panitumumab at the Jewish General Hospital in Montreal, Canada, between 2009 and 2012. METHODS: This chart review included 44 patients (median age: 60 years; performance status: 0-3), of whom 50% had already received three lines of treatment. The primary endpoint was progression-free survival (pfs). Secondary endpoints were overall survival and safety. Tumour progression was determined by radiologic assessments performed once every 3 months per clinical guidelines or by clinical deterioration as determined by the clinician-investigator. RESULTS: In our sample, median pfs was 21.86 ± 5.23 weeks (95% confidence interval: 12.9 to 36.9 weeks) and overall survival was 35.14 ± 7.75 weeks (95% confidence interval: 25.6 to 73.4 weeks) with a median of 5 cycles of panitumumab treatment. The most frequently reported toxicities with panitumumab were skin toxicity (16.2% grade 3) and hypomagnesemia (10.8% grade 3). No infusion reactions were reported. CONCLUSIONS: Despite a small sample size from a single institution, our survival and efficacy data are encouraging and comparable to results obtained from the registration panitumumab trial. Our findings suggest that panitumumab can be effective and tolerable in a real-world setting.

Species-specific DNA probe and development of a quantitative PCR assay for the detection of Morganella morganii.

AIMS: To develop a SYBR Green quantitative PCR assay (qPCR) for the specific detection of Morganella morganii, a fish pathogen responsible for the Histamine Fish Poisoning. METHODS AND RESULTS: A new primer set, amplifying a 179-bp fragment of the 16S rRNA gene, was selected for specificity, and 14 M. morganii strains and 32 non-Morganella strains were evaluated. The melting temperature of 84°C was consistently specific for the amplicon. Two standard curves were constructed: the minimum detection sensitivity was 0·563 pg of pure DNA, corresponding to DNA extracted from nine cells of M. morganii. The qPCR assay was evaluated in experiments with seeded fish samples, and the regression coefficient values were calculated. CONCLUSIONS: A highly specific and rapid assay was developed for the detection of M. morganii in tuna fish samples. SIGNIFICANCE AND IMPACT OF THE STUDY: This method represents the first study about the quantification of pathogenic M. morganii in fish products. This approach can be utilized to prevent the presence of this undesirable species in the food chain.

An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer.

Tumor-suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. TSGs containing nonsense mutations may not be expressed because of nonsense-mediated RNA decay (NMD). We combined inhibition of the NMD process, which clears transcripts that contain nonsense mutations, with the application of high-density single-nucleotide polymorphism arrays analysis to discriminate allelic content in order to identify candidate TSGs in five breast cancer cell lines. We identified ARID1A as a target of NMD in the T47D breast cancer cell line, likely as a consequence of a mutation in exon-9, which introduces a premature stop codon at position Q944. ARID1A encodes a human homolog of yeast SWI1, which is an integral member of the hSWI/SNF complex, an ATP-dependent, chromatin-remodeling, multiple-subunit enzyme. Although we did not find any somatic mutations in 11 breast tumors, which show DNA copy-number loss at the 1p36 locus adjacent to ARID1A, we show that low ARID1A RNA or nuclear protein expression is associated with more aggressive breast cancer phenotypes, such as high tumor grade, in two independent cohorts of over 200 human breast cancer cases each. We also found that low ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A re-expression in the T47D cell line results in significant inhibition of colony formation in soft agar. These results suggest that ARID1A may be a candidate TSG in breast cancer.

Ki 67 is a major, but not the sole determinant of Oncotype Dx recurrence score.

BACKGROUND: Immunohistological assessment of Ki 67 expression is less expensive than Oncotype Dx, which is currently used to identify patients with lymph node-negative breast cancer, who will benefit from adjuvant chemotherapy. METHODS: The relationship of immunohistologically measured Ki 67 to Oncotype DX recurrence score (RS) was examined in 53 cases of T1-2 N0 M0 (oestrogen receptor-positive, HER2/neu negative) breast cancer. RESULTS: There was a strong linear correlation between Ki 67 value and the Oncotype Dx RS. All patients in the low Ki 67 group (Ki 67 of ≤ 10%) had Oncotype Dx RSs of low or intermediate risk. The vast majority of patients (93.8%) in the high-Ki 67 group (Ki 67 ≥ 25%) had oncotype RSs of high or intermediate risk. CONCLUSION: Ki 67 proliferation value is a major, but not the sole determinant of Oncotype Dx score.

Trastuzumab and vinorelbine in early stages of HER2-positive breast cancer.

The combination of vinorelbine and trastuzumab (VH) is highly active and well tolerated in patients with metastatic HER2+ breast cancer. We assessed the efficacy and tolerability of VH as an alternative adjuvant treatment for patients with localized breast cancer refusing or ineligible for standard adjuvant trastuzumab-based chemotherapy. Twenty-eight patients with stage I-III breast cancer were treated only with VH as preoperative or postoperative chemotherapy. Fourteen patients received VH as adjuvant treatment for pT1a-b pN0 or eR+ pT1c pN0 cancers. VH was well tolerated, the only grade 3-4 toxicity being neutropenia with 2 cases of febrile neutropenia. At a median follow-up of 39 months, no breast cancer relapses were documented; moreover, overall and disease-free survival was 96.4%. In summary, our results indicate that VH is effective and well tolerated. VH should be prospectively tested as adjuvant treatment for pN0 pT1a-b breast cancer patients for which no standard treatment is well defined.

Therapeutic targets in liver transplantation: angiotensin II in nonsteatotic grafts and angiotensin-(1-7) in steatotic grafts.

Numerous steatotic livers are discarded as unsuitable for transplantation because of their poor tolerance of ischemia-reperfusion(I/R). The injurious effects of angiotensin (Ang)-II and the benefits of Ang-(1-7) in various pathologies are well documented. We examined the generation of Ang II and Ang-(1-7) in steatotic and nonsteatotic liver grafts from Zucker rats following transplantation. We also studied in both liver grafts the effects of Ang-II receptors antagonists and Ang-(1-7) receptor antagonists on hepatic I/R damage associated with transplantation. Nonsteatotic grafts showed higher Ang II levels than steatotic grafts, whereas steatotic grafts showed higher Ang-(1-7) levels than nonsteatotic grafts. Ang II receptor antagonists protected only nonsteatotic grafts against damage, whereas Ang-(1-7) receptor antagonists were effective only in steatotic grafts. The protection conferred by Ang II receptor antagonists in nonsteatotic grafts was associated with ERK 1/2 overexpression, whereas the beneficial effects of Ang-(1-7) receptor antagonists in steatotic grafts may be mediated by NO inhibition. Our results show that Ang II receptor antagonists are effective only in nonsteatotic liver transplantation and point to a novel therapeutic target in liver transplantation based on Ang-(1-7), which is specific for steatotic liver grafts.

[Endemic corridors: a useful tool for the epidemiological surveillance of influenza]. / Corredores endémicos: una herramienta útil para la vigilancia epidemiológica de la influenza.

Epidemiological surveillance provides updated information about health problems which allows for the establishment of health policy guidelines. The methods for detecting the epidemic frequency of disease require the systematic collection of data on the occurrence of specific diseases. Influenza has cyclic seasonal peaks and its endemic baseline rates are useful for identifying outbreaks: the comparison between baseline and current data supplies epidemiological evidence related to an ongoing outbreak. The upper and lower incidence curves were traced for the data referring to IA detection in the nasopharyngeal aspirates from children hospitalized for acute lower respiratory tract infection from 1996 to 2002. The arithmetic mean and the 95% confidence interval for upper and lower limits of weekly incidence were calculated. The highest incidence was observed between weeks 25 and 32. When analyzing the prepared endemic corridor, it was observed that the highest detection in 2003 occurred between weeks 19 and 25, whereas two peaks occurred in 2004, the first starting at week 20, at a lower level than the normal epidemic peak, and the second at week 26.

The rate of intravenous cocaine administration alters c-fos mRNA expression and the temporal dynamics of dopamine, but not glutamate, overflow in the striatum.

The rapid entry of drugs into the brain is thought to increase the propensity for addiction. The mechanisms that underlie this effect are not known, but variation in the rate of intravenous cocaine delivery does influence its ability to induce immediate early gene expression (IEG) in the striatum, and to produce psychomotor sensitization. Both IEG induction and psychomotor sensitization are dependent upon dopamine and glutamate neurotransmission within the striatum. We hypothesized, therefore, that varying the rate of intravenous cocaine delivery might influence dopamine and/or glutamate overflow in the striatum. To test this we used microdialysis coupled to on-line capillary electrophoresis and laser-induced fluorescence, which allows for very rapid sampling, to compare the effects of a rapid (5 s) versus a slow (100 s) intravenous cocaine infusion on extracellular dopamine and glutamate levels in the striatum of freely moving rats. An acute injection of cocaine had no effect on extracellular glutamate, at either rate tested. In contrast, although peak levels of dopamine were unaffected by infusion rate, dopamine levels increased more rapidly when cocaine was administered over 5 versus 100 s. Moreover, c-fos mRNA expression in the region of the striatum sampled was greater when cocaine was administered rapidly than when given slowly. These data suggest that small differences in the temporal dynamics of dopamine neurotransmission may have a large effect on the subsequent induction of intracellular signalling cascades that lead to immediate early gene expression, and in this way influence the ability of cocaine to produce long-lasting changes in brain and behavior.

Corredores endémicos: Una herramienta útil para la vigilancia epidemiológica de la influenza / Endemic corridors: a useful tool for the epidemiological surveillance of influenza

La vigilancia epidemiológica provee información actualizada y oportuna sobre los problemas de salud y sus condicionantes, lo que permite definir acciones de prevención y control. Para la detección de epidemias es útil disponer de corredores endémicos, que indican el número de casos esperados para un cuadro infeccioso en un momento determinado. Con datos de la sección Microbiología del Hospital de Niños "Dr. Pedro de Elizalde" acerca de pacientes internados con diagnóstico de infección respiratoria aguda baja (IRAB) entre el 1/1/96 y el 31/12/2002 se confeccionaron los corredores para influenza A (IA) por semanas epidemiológicas, correspondientes a un período de siete años. En ese período se internaron 10.473 niños con diagnóstico de IRAB y se identificó IA en 411 aspirados nasofaríngeos. Se calcularon la media y el intervalo de confianza de 95% para los límites superior e inferior de incidencia en períodos semanales, y se encontró que el pico estacional ocurre entre las semanas 25 y 32. Al analizar los datos del año 2003, se observó que el pico se produjo antes, entre las semanas 19 y 25, y con valores muy por encima de los esperados para esas semanas. En 2004 aparecen 2 picos, el primero en la semana 20 y sin superar los valores de fluctuación de la parte central de la curva, y el segundo en la semana 26.

Epidemiological surveillance provides updated information about health problems which allows for the establishment of health policy guidelines. The methods for detecting the epidemic frequency of disease require the systematic collection of data on the occurrence of specific diseases. Influenza has cyclic seasonal peaks and its endemic baseline rates are useful for identifying outbreaks: the comparison between baseline and current data supplies epidemiological evidence related to an ongoing outbreak. The upper and lower incidence curves were traced for the data referring to IA detection in the nasopharyngeal aspirates from children hospitalized for acute lower respiratory tract infection from 1996 to 2002. The arithmetic mean and the 95% confidence interval for upper and lower limits of weekly incidence were calculated. The highest incidence was observed between weeks 25 and 32. When analyzing the prepared endemic corridor, it was observed that the highest detection in 2003 occurred between weeks 19 and 25, whereas two peaks occurred in 2004 , the first starting at week 20, at a lower level than the normal epidemic peak, and the second at week 26.