Miracle-dz/UniFAR-FTUs huggingface dataset:
Odanacatib: a review of its potential in the management of osteoporosis in postmenopausal women

Odanacatib is a cathepsin K inhibitor developed for the treatment of postmenopausal osteoporosis. It is a bone resorption inhibitor, but which preserves bone formation to some extent. It can be administered once a week, in tablets also containing vitamin D. In a large clinical development program, it has been shown that odanacatib reduces bone resorption, with a reduction of about 60–70% in biochemical markers of resorption, while bone formation decreases to a lesser magnitude. Odanacatib continuously increases bone mineral density (BMD) at the hip and lumbar spine over 5 years. Once it is stopped, a complete resolution of effect is observed, with declining BMD and increased bone turnover. Bone microarchitecture and bone strength have also been improved in clinical trials using quantitative computed tomography (QCT) at the lumbar spine and hip, and high resolution peripheral QCT at the distal radius and tibia. In a phase III trial involving 16,713 postmenopausal women ⩾65 years of age with low BMD, the risk of fragility fracture was significantly reduced at the spine, hip and other nonvertebral sites compared with the placebo group. Odanacatib has been generally well tolerated, with no observation of osteonecrosis of the jaw so far, but with exceptional observations of subtrochanteric atypical fracture and morphea-like lesions. Odanacatib appears a useful new option in the treatment of postmenopausal osteoporosis.
Effects of Age on Speech-in-Noise Identification: Subjective Ratings of Hearing Difficulties and Encoding of Fundamental Frequency in Older Adults

Background and Objectives Numerous studies have indicated deterioration of speech perception in noisy conditions among the elderly even those with normal hearing capabilities. The aim of this study was to investigate the effects of age on the speech-in-noise identification by speech-in-noise (SIN) test, subjective ratings of hearing difficulties by speech, spatial, and qualities of hearing scale (SSQ) questionnaire and encoding of fundamental frequency (F0) by Speech auditory brainstem response (ABR) in the elderly and comparing the results with young people. Subjects and Methods The present study was conducted on 32 elderly people aged over 60 years old (17 male and 15 female) with the mean age of 68.9 (standard deviation=6.33) possessing normal peripheral hearing and 32 young subjects (16 male and 16 female) aged 18-25 years old. Results Findings showed that the score of SIN test is lower among the elderly people as compared with young people in signal-to-noise ratios of 0 and -10 based on Iranian version of SSQ questionnaire (p<0.001). The range of F0 amplitude in the elderly people is also lower than young people (p<0.001) in Speech ABR. Conclusions It seems that speech processing in older people is deteriorated comparing with young people regardless of their normal peripheral auditory thresholds. This decrease will result in weaker perception and improper segregation of speech from other competing sources.
TGFβ‐TAZ/SRF signalling regulates vascular smooth muscle cell differentiation

Vascular smooth muscle cells (VSMCs) do not terminally differentiate; they modulate their phenotype between proliferative and differentiated states, which is a major factor contributing to vascular diseases. TGFβ signalling has been implicated in inducing VSMC differentiation, although the exact mechanism remains largely unknown. Our goal was to assess the network of transcription factors involved in the induction of VSMC differentiation, and to determine the role of TAZ in promoting the quiescent VSMC phenotype. TGFβ robustly induces VSMC marker genes in 10T1/2 mouse embryonic fibroblast cells and the potent transcriptional regulator TAZ has been shown to retain Smad complexes on DNA. Thus, the role of TAZ in regulation of VSMC differentiation was studied. Using primary aortic VSMCs coupled with siRNA‐mediated gene silencing, our studies reveal that TAZ is required for TGFβ induction of smooth muscle genes and is also required for the differentiated VSMC phenotype; synergy between TAZ and SRF, and TAZ and Myocardin (MyoC856), in regulating smooth muscle gene activation was observed. These data provide evidence of components of a novel signalling pathway that links TGFβ signalling to induction of smooth muscle genes through a mechanism involving regulation of TAZ and SRF proteins. In addition, we report a physical interaction of TAZ and MyoC856. These observations elucidate a novel level of control of VSMC induction which may have implications for vascular diseases and congenital vascular malformations.
Ebola virus disease in West Africa--the first 9 months of the epidemic and forward projections.

BACKGROUND On March 23, 2014, the World Health Organization (WHO) was notified of an outbreak of Ebola virus disease (EVD) in Guinea. On August 8, the WHO declared the epidemic to be a "public health emergency of international concern. " METHODS By September 14, 2014, a total of 4507 probable and confirmed cases, including 2296 deaths from EVD (Zaire species) had been reported from five countries in West Africa--Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. We analyzed a detailed subset of data on 3343 confirmed and 667 probable Ebola cases collected in Guinea, Liberia, Nigeria, and Sierra Leone as of September 14. RESULTS The majority of patients are 15 to 44 years of age (49.9% male), and we estimate that the case fatality rate is 70.8% (95% confidence interval [CI], 69 to 73) among persons with known clinical outcome of infection. The course of infection, including signs and symptoms, incubation period (11.4 days), and serial interval (15.3 days), is similar to that reported in previous outbreaks of EVD. On the basis of the initial periods of exponential growth, the estimated basic reproduction numbers (R0 ) are 1.71 (95% CI, 1.44 to 2.01) for Guinea, 1.83 (95% CI, 1.72 to 1.94) for Liberia, and 2.02 (95% CI, 1.79 to 2.26) for Sierra Leone. The estimated current reproduction numbers (R) are 1.81 (95% CI, 1.60 to 2.03) for Guinea, 1.51 (95% CI, 1.41 to 1.60) for Liberia, and 1.38 (95% CI, 1.27 to 1.51) for Sierra Leone; the corresponding doubling times are 15.7 days (95% CI, 12.9 to 20.3) for Guinea, 23.6 days (95% CI, 20.2 to 28.2) for Liberia, and 30.2 days (95% CI, 23.6 to 42.3) for Sierra Leone. Assuming no change in the control measures for this epidemic, by November 2, 2014, the cumulative reported numbers of confirmed and probable cases are predicted to be 5740 in Guinea, 9890 in Liberia, and 5000 in Sierra Leone, exceeding 20,000 in total. CONCLUSIONS These data indicate that without drastic improvements in control measures, the numbers of cases of and deaths from EVD are expected to continue increasing from hundreds to thousands per week in the coming months.
The long-term effects of semiconductor diode laser transscleral cyclophotocoagulation on the normal equine eye and intraocular pressure(a).

OBJECTIVE To describe the long-term histologic and intraocular pressure (IOP) lowering effects of diode laser transscleral cyclophotocoagulation (TSCP) on the normal equine eye. ANIMALS Eight normal adult horses. PROCEDURES TSCP was performed in one randomly assigned eye. Sixty spots were treated at settings of 1500 ms and 1500 mW. Two horses were randomly selected for euthanasia at 2, 4, 12, or 24 weeks post-TSCP. Both eyes were enucleated and histologically evaluated. Intraocular pressure was measured by applanation tonometry prior to TSCP, immediately post-TSCP, twice daily for 7 days post-TSCP and then monthly until study conclusion. A longitudinal model estimated the average IOP values for the treated and untreated eyes at 1 week, 1, 3, and 6 months post-TSCP. RESULTS All treated eyes at all time periods exhibited four characteristic histologic lesions: scleral collagen hyalinization, ciliary body pigment dispersion and clumping, focal disruption of the ciliary body epithelium, and focal ciliary process atrophy. After TSCP, there were no significant changes in IOP from baseline for the control eyes, while the IOP in treated eyes was significantly decreased from baseline (P < 0.05) at all time periods. The estimated decrease in IOP in the treated eyes compared to baseline IOP at 6 months was -3.76 mmHg for an average decrease in IOP of 20% from baseline. CONCLUSION Diode laser TSCP produces histologic lesions in the equine ciliary body that result in a significant and sustained decrease in IOP. TSCP may be an effective management for equine glaucoma.
Validation Study of Radio-Guided Sentinel Lymph Node Navigation in Esophageal Cancer

Background:Radio-guided detection of sentinel lymph nodes (SLN) has been used to predict regional lymph node metastasis in patients with melanoma and breast cancer. However, the validity of the SLN hypothesis is still controversial for esophageal cancer. The aim of this study is to evaluate the feasibility and accuracy of radio-guided SLN mapping for esophageal cancer. Methods:Seventy-five consecutive patients who were diagnosed preoperatively with T1N0M0 or T2N0M0 primary esophageal cancer were enrolled. Endoscopic injection of technetium-99m tin colloid was performed before surgery and radioactive SLNs were identified with preoperative lymphoscintigraphy and gamma probe. Standard radical esophagectomy with lymphadenectomy was performed in all patients and all resected nodes were evaluated by routine pathologic examination. Results:SLNs were identified successfully in 71 (95%) of 75 patients. The mean number of identified SLNs per case was 4.7. Twenty-nine (88%) of 33 cases with lymph node metastasis showed positive SLNs. The diagnostic accuracy based on SLN status was 94% (67/71). Distribution of identified SLNs was widely spread from the cervical to abdominal areas. Conclusions:This study reveals that radio-guided SLN mapping is an accurate diagnostic procedure for detecting lymph node metastasis in patients with early-stage esophageal cancer.
Clinical correlates of {18F}fluorodopa uptake in five grafted Parkinsonian patients

To assess the efficacy of fetal mesencephalic grafts in Parkinson's disease, it is important to know if the grafted cells survive and are functional. Positron emission tomography (PET) and {18F}fluorodopa ({18F}dopa) have been used to demonstrate the survival of the grafted cells, but the relationship of {18F}dopa uptake changes in the grafted striatum to motor function remains unclear. We investigated this question with 16 serial PET scan in 5 severe parkinsonian patients unilaterally grafted in whom we found a significant and progressive increase of the {18F}dopa uptake in the grafted putamen. The number of patients was too small to assess the sensitivity of {18F}dopa PET scans in individual patients. Yet, by analyzing the 16 serial PET scans we found a correlation between the {18F}dopa uptake (Ki) in the grafted putamen and the percentage of daily time spent “on,” suggesting that Ki changes have a functional meaning. In addition, the Ki values were correlated with the contralateral finger dexterity to the same extent in both the grafted and nongrafted putamen. These results indicate that {18F}dopa uptake reflects the motor function of the opposite side of the body, similarly in the grafted and ungrafted putamen, at least in terms of these tasks. Finally, extrapolating from these correlations offers the suggestion that clinical optimal results of the graft could be achieved if the graft brings the Ki values in the putamen to about two standard deviations of mean control values.
Pharmacologie moléculaire du sunitinib et du vandetanib, deux inhibiteurs d’activité kinase, dans le cancer médullaire de la thyroïde

Le cancer medullaire de la thyroide (CMT), qui represente 5 a 8% des cancers de la thyroide, est issu de la transformation maligne des cellules C du parenchyme thyroidien. Ce cancer, sporadique dans 70 a 80% des cas et familial pour les 20 a 30% restants, est essentiellement lie a des anomalies du proto-oncogene RET, codant un recepteur a activite tyrosine kinase. La frequence elevee des mutations activatrices de RET ont permis d’identifier ce recepteur comme une cible therapeutique majeure. Si la chirurgie est le traitement de reference pour les formes localisees, les formes localement avancees ou metastatiques, de pronostic plus pejoratif etaient avant le developpement des therapies moleculaires ciblees, dans une impasse therapeutique. La meilleure comprehension de la biologie des tumeurs a permis le developpement de ces therapies plus rationnelles et plus specifiques, en particulier des inhibiteurs d’activite tyrosine kinase (ITK). L’optimisation de leur utilisation en clinique necessite de mieux comprendre leurs mecanismes d’action.Dans ce contexte, les objectifs de cette these ont ete a la fois cognitifs et cliniques, visant a ameliorer la comprehension de la reponse moleculaire a deux ITKs, le sunitinib et la vandetanib,dans le CMT, et a identifier de nouveaux biomarqueurs de suivi therapeutique. Dans un premier temps, nous avons montre les effets antiproliferatifs, antitumoraux et antiangiogeniques du sunitinib et du vandetanib dans un modele de CMT mute RETC634W, mettant en evidence des profils d’activite proches entre les deux inhibiteurs. Puis, les principales voies de signalisation mises en jeu lors de la reponse a ces ITKs ont ete explorees par Reverse-Phase Protein Array(RPPA). Par une approche transcriptomique haut-debit menee sur des modeles precliniques, les principales fonctions cellulaires impliquees dans la reponse au sunitinib et au vandetanib ont ete identifiees. Le role de genes participant a l’invasion tissulaire et au pouvoir metastatique a ete mis en evidence. De nouveaux biomarqueurs potentiels de reponse au vandetanib et au sunitinib, tels que l’IL-8 et le TGF-2 dont les taux seriques sont significativement plus eleves chez les patients atteints de CMT, ont ete identifies. Enfin, l’interet de trois approches methodologiques dans lesuivi de la reponse antitumorale chez les patients a ete evalue. Ainsi, le developpement d’une methode de dosage du vandetanib par spectrometrie de masse a permis de suggerer un lien entre des taux seriques eleves et l’apparition de toxicites severes. L’evaluation de biomarqueurs dans le serum de patients traites par le vandetanib a souligne l’interet de l’IL-8 comme marqueur pronostic potentiel dans cette pathologie. Enfin les resultats preliminaires, evaluant la reponse au sunitinib par echographie doppler sur un modele preclinique de souris xenogreffees, ont confirme l’interet de l’imagerie fonctionnelle dans ce domaine.
THE OPTIMAL COMPLEX TRAINING REST INTERVAL FOR ATHLETES FROM ANAEROBIC SPORTS

Complex training research has indicated that 3–4 minutes may be an optimum intracomplex rest interval. The purpose of this study was to determine if a heavy resistive exercise causes performance enhancement of a slow stretch–shortening cycle exercise and if there is an optimal rest interval. Eighteen subjects performed countermovement jumps (CMJs) before and after a 5 repetition maximum back squat lifting protocol. This procedure was repeated 4 times over 2 days using rest intervals of 30 seconds and 2, 4, and 6 minutes. Flight time and peak ground reaction force (GRF) were the dependent variables. All jumps were performed on a specially constructed sledge and force platform apparatus. Repeated measures analysis of variance found a significant reduction in flight time at the 30-second and 6-minute interval (p ≤ 0.05). No significant difference was found between men and women. Only the men showed an enhancement in jump performance after the 4-minute interval. The improvement window was different for each subject, and an analysis of the greatest increase and decrease in flight time and peak GRF was conducted, showing a significant decrease for men and women and a significant increase in flight time for men and peak ground reaction force for women. The results suggest that complex training can benefit or inhibit CMJ performance depending on the rest interval. The individual determination of the intracomplex rest interval may be necessary in the practical setting.
Tenascin-C Is Associated with Cored Amyloid-&bgr; Plaques in Alzheimer Disease and Pathology Burdened Cognitively Normal Elderly

Tenascin-C (TN-C) is an extracellular matrix glycoprotein linked to inflammatory processes in pathological conditions including Alzheimer disease (AD). We examined the distribution of TN-C immunoreactivity (ir) in relation to amyloid-&bgr; (A&bgr;) plaques and vascular A&bgr; deposits in autopsy brain tissues from 14 patients with clinical and neuropathological AD and 10 aged-matched controls with no cognitive impairment; 5 of the controls had A&bgr; plaques and 5 did not. TN-C ir was abundant in cortical white matter and subpial cerebral gray matter in all cases, whereas TN-C ir was weak in blood vessels. In all cases with A&bgr; plaques but not in plaque-free controls, TN-C ir was detected as large (>100 µm in diameter) diffuse extracellular deposits in cortical grey matter. TN-C plaques completely overlapped and surrounded cored A&bgr; plaques labeled with X-34, a fluorescent derivative of Congo red, and they were associated with reactive astrocytes astrocytes, microglia and phosphorylated tau-containing dystrophic neurites. Diffuse A&bgr; plaques lacking amyloid cores, reactive glia or dystrophic neurites showed no TN-C ir. In cases with cerebral amyloid angiopathy, TN-C ir in vessel walls did not spread into the surrounding neuropil. These results suggest a role for TN-C in A&bgr; plaque pathogenesis and its potential as a biomarker and therapy target.
A Balanced Protocol for Return to School for Children and Youth Following Concussive Injury

Background. Few protocols exist for returning children/youth to school after concussion. Childhood concussion can significantly affect school performance, which is vital to social development, academic learning, and preparation for future roles. The goal of this knowledge translation research was to develop evidence based materials to inform physicians about pediatric concussion. Methods. The Return to School (RTS) concussion protocol was developed following the National Institute for Health and Care Excellence procedures. Results. Based on a scoping review, and stakeholder opinions, an RTS protocol was developed for children/youth. This unique protocol focuses on school adaptation in 4 main areas: (a) timetable/attendance, (b) curriculum, (c) environmental modifications, and (d) activity modifications. Conclusion. A balance of cognitive rest and timely return to school need to be considered for returning any student to school after a concussion. Implementation of these new recommendations may be an important tool in prevention of prolonged absence from school and academic failure while supporting brain recovery.
Biosimilars of filgrastim in autologous stem cell transplant: reduction in granulocyte-colony stimulating factor costs, but similar effects on bone marrow recovery

Abstract Granulocyte-colony stimulating factors (G-CSFs) enhance bone marrow (BM) recovery after autologous stem cell transplant (ASCT) in patients with lymphoma and myeloma. Few publications exist that discuss the use of filgrastim biosimilars after ASCT. We conducted a single-center retrospective study in patients with lymphoma and myeloma treated at Brest Hospital to assess the cost reductions related to and the efficiency and safety of filgrastim biosimilars. We identified 65 patients with lymphoma or myeloma treated with filgrastim biosimilars for ASCT and compared 19 parameters of these patients, including BM recovery, side effects, infectious complications and treatment costs, with published historical data on a cohort of 50 patients treated with classic filgrastim. We observed a significant reduction of G-CSF costs in both groups but did not observe a change in total hospitalization costs (representing less than 2% of the costs) between groups. Additionally, we did not observe differences between the two groups in BM recovery, infectious complications, side effects or the other studied parameters. In this retrospective study, the absence of differences between groups after ASCT in lymphoma and myeloma led us to believe that these drugs could be safely and effectively used for such indications without a significant impact on hospitalization costs. A prospective study should be conducted to confirm our results.
Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation.

RATIONALE The use of extracorporeal membrane oxygenation (ECMO) in patients who are awake and spontaneously breathing may represent a novel bridging strategy toward lung transplantation (LuTx). OBJECTIVES To evaluate the outcomes of patients treated with the "awake ECMO" concept as bridge to transplantation. METHODS We performed a retrospective, single-center, intention-to-treat analysis of consecutive LuTx candidates with terminal respiratory or cardiopulmonary failure receiving awake ECMO support. The outcomes were compared with a historical control group of patients treated with conventional mechanical ventilation (MV group) as bridge to transplant. MEASUREMENTS AND MAIN RESULTS Twenty-six patients (58% female; median age, 44 yr; range, 23-62) were included in the awake ECMO group and 34 patients (59% female; median age, 36 yr; range, 18-59) in the MV group. The duration of ECMO support or MV, respectively, was comparable in both groups (awake ECMO: median, 9 d; range, 1-45. MV: median, 15 d; range, 1-71; P = 0.25). Six (23%) of 26 patients in the awake ECMO group and 10 (29%) of 34 patients in the MV group died before a donor organ was available (P = 0.20). Survival at 6 months after LuTx was 80% in the awake ECMO group versus 50% in the MV group (P = 0.02). Patients in the awake ECMO group required shorter postoperative MV (P = 0.04) and showed a trend toward a shorter postoperative hospital stay (P = 0.06). CONCLUSIONS ECMO support in patients who are awake and nonintubated represents a promising bridging strategy, which should be further evaluated to determine its role in patients with end-stage lung disease awaiting LuTx.
Consistent Immunostaining for Cyclin D1 Can Be Achieved on a Routine Basis Using a Newly Available Rabbit Monoclonal Antibody

Rabbit monoclonal antibody (MAb), which has become available only recently, theoretically combines the advantage of the high affinity attributable to its rabbit origin and the high specificity due to its monoclonal nature. Since immunohistochemical demonstration of cyclin D1 is notoriously difficult, this study aims to assess whether a newly available rabbit MAb against cyclin D1 (SP4) can improve the consistency of immunostaining, especially for the diagnosis of mantle cell lymphoma (MCL). A total of 150 cases of lymphoproliferative lesions, including 30 cases of MCL, histologic mimickers of MCL, and various types of lymphomas and leukemias, were studied. Immunostaining was performed on formalin-fixed, paraffin-embedded tissue sections using a labeled streptavidin-biotin peroxidase system in an automated immunostainer. All cases of MCL expressed cyclin D1, with a higher median staining score (8 out of a maximum of 12) compared with mouse MAb DCS-6 (score 4). In addition, 2 of 15 cases of B-cell chronic lymphocytic leukemia (B-CLL), 3 of 12 cases of multiple myeloma, and 2 of 5 cases of hairy cell leukemia were also positive. Comparable staining results could also be achieved by an optimized manual staining protocol. This study thus confirms the superior performance of the rabbit MAb SP4, which should permit consistent immunostaining for cyclin D1 to be readily achieved. The value of cyclin D1 immunohistochemistry in the differential diagnosis of MCL from other low-grade B-cell lymphomas is also affirmed, but with the caveat that rare cases of B-CLL can also be cyclin D1 positive.