Miracle-dz/UniFAR-FTUs huggingface dataset:
Mucolipidosis II: a single causal mutation in the N‐acetylglucosamine‐1‐phosphotransferase gene (GNPTAB) in a French Canadian founder population

Mucolipidosis (ML) II (I‐cell disease) is a lysosomal storage disorder caused by a deficiency of UDP‐N‐acetylglucosamine:lysosomal enzyme N‐acetylglucosamine‐1‐phosphotransferase. MLII is an autosomal recessive disease with a carrier rate estimated at 1/39 in Saguenay–Lac‐Saint‐Jean (SLSJ) (Quebec, Canada), which is the highest frequency documented worldwide. To identify the causing mutation, we sequenced GNPTAB exons in 27 parents of 16 MLII‐deceased children from the SLSJ region as obligatory and potential carriers. We also performed a genealogical reconstruction for each parent to evaluate consanguinity levels and genetic contribution of ancestors. Our goal was to identify which parameters could explain the high MLII frequency observed in the SLSJ population. A single mutation (c.3503_3504delTC) was found in all obligatory carriers. In addition, 11 apparent polymorphisms were identified. The mutation was not detected in genomic DNA of 50 unrelated controls. Genealogical data show six founders (three couples) with a higher probability of having introduced the mutation in the population. The frequency of the mutation was increased as a consequence of this founder effect and of the resulting population structure. We suggest that c. 3503_3504delTC is the allele causing MLII in the SLSJ population, and its high carrier rate is most likely explained by a founder effect.
The phenomenology of carryover effects between show-up and line-up identification

This study explored carryover effects from show-ups to subsequent line-up identifications using a novel paradigm in which participants rendered multiple identification judgements. A total of 160 participants studied a series of faces and subsequently viewed a series of target-absent and target-present show-ups. Following a retention interval, participants then made identification judgements from a series of target-absent and target-present line-ups. Remember-Know-Guess judgements were collected to assess the phenomenological basis of carryover effects in face identification. Our results indicated clear carryover effects from show-ups to line-ups, such that repeated exposure to a face increased the likelihood that it would later be identified, regardless of whether or not it had been presented at the time of study. The phenomenological basis for these carryover effects is discussed, as are the implications of these findings for police conduct of multiple eyewitness identification procedures.
The Intrathecally Administered Kappa-2 Opioid Agonist GR89696 and Interleukin-10 Attenuate Bone Cancer–Induced Pain Through Synergistic Interaction

BACKGROUND:Although bone cancer–related pain is one of the most disruptive symptoms in patients with advanced cancer, patients are often refractory to pharmacological treatments; thus, more effective treatments for bone cancer pain are needed. We evaluated the analgesic efficacy of and interaction between intrathecal GR89696, a &kgr;2-opioid receptor agonist, and interleukin (IL)-10 in a rat model of bone cancer pain. METHODS:The rat model of bone cancer pain was produced by right tibia intramedullary injection of rat breast cancer cells, and an intrathecal catheterization was performed. Ten days later, a paw-withdrawal threshold to mechanical stimulus by von Frey hairs was measured using the up-down method, after intrathecal administration of GR89696 and IL-10. The interaction between the 2 drugs was also evaluated using an isobolographic analysis. RESULTS:Intrathecal GR89696 and IL-10 significantly increased the paw withdrawal threshold of the cancer cell–implanted rat, in a dose-dependent manner, with 50% effective dose values (95% confidence interval) of 50.78 &mgr;g (31.80–80.07&mgr;g) and 0.83 &mgr;g (0.59–1.15 &mgr;g), respectively. Isobolographic analysis revealed a synergistic interaction between intrathecal GR89696 and IL-10. CONCLUSIONS:Intrathecally administered GR89696 and IL-10 attenuated bone cancer–induced pain, and the 2 drugs interacted synergistically in the spinal cord. These results raise the intriguing possibility of &kgr;2-opioid receptor agonists and IL-10 as a new therapeutic approach for the management of bone cancer–associated pain.
Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study

We conducted a randomized, controlled study to assess the need for hydroxychloroquine (HCQ) during lupus pregnancy and to assess safety. Twenty consecutive pregnant patients with similar characteristics were enrolled. The HCQ group included eight patients with systemic lupus erythematosus (SLE) and two with discoid lupus erythematosus (DLE). The placebo (PL) group included nine patients with SLE and one with DLE. The HCQ group had no flare-ups. SLEPDAI scores were similar at study entry, and at conclusion the placebo group had significantly higher scores. One patient had improvement of skin lesions and another of arthritis, allowing a decrease of prednisone dose. There were no retinal effects. Three patients in the PL group flared up, two with skin rashes, one also with arthritis and uveitis, and one (previously in remission on HCQ) with hemolytic anemia, polyserositis and anti-dsDNA antibody. Toxemia was diagnosed in only three patients in the PL group (one fetal death). Comparing prednisone dosage change, we noted a decrease in the HCQ and an increase in the PL group. Delivery age and Apgar scores were higher in the HCQ group. Neonatal examination did not reveal congenital abnormalities, nor did a neuroophthalmological and auditory evaluation at 1.5–3 y of age. In spite of the small number of patients studied, we noted beneficial effects of HCQ during lupus pregnancy, as measured by SLEPDAI and decrease in prednisone dose with no detriment to patients' health.
Effects of modafinil on simulator driving and self‐assessment of driving following sleep deprivation

While it has been suggested that the novel wake promoting drug modafinil may have some utility with respect to drowsy driving in healthy adults, this has not been investigated until now. The present study was designed to assess the effects of modafinil on objective and self‐assessed driving simulator performance during an overnight period of sleep loss.
Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study.

BACKGROUND Patients with diabetes mellitus (DM) have a marked increase in coronary heart disease (CHD) events relative to those without DM. In a previous report from the Scandinavian Simvastatin Survival Study using a clinical case definition of DM (n = 202), simvastatin-treated patients had significantly fewer CHD events compared with placebo-treated control subjects. OBJECTIVE To examine the effect of simvastatin therapy on CHD in patients with DM and impaired fasting glucose levels. METHODS Using the 1997 American Diabetes Association diagnostic criteria, we assessed the effect of simvastatin therapy post hoc for an average of 5.4 years in Scandinavian Simvastatin Survival Study patients with normal fasting glucose (n = 3237), impaired fasting glucose (n = 678), and DM (n = 483). RESULTS Simvastatin-treated patients with DM had significantly reduced numbers of major coronary events (relative risk [RR] = 0.58; P = .001) and revascularizations (RR = 0.52; P = .005). Total (RR = 0.79; P = .34) and coronary (RR = 0.72; P = .26) mortality were also reduced in DM, but not significantly, due to small sample size. In impaired fasting glucose (IFG) subjects, simvastatin use significantly reduced the number of major coronary events (RR = 0.62; P = .003), revascularizations (RR = 0.57; P = .009), and total (RR = 0.57; P = .02) and coronary (RR = 0.45; P = .007) mortality. CONCLUSION Our results extend previous findings in patients with DM to a larger cohort, confirming the benefit of cholesterol lowering with simvastatin treatment on CHD events. In addition, significant decreases in total mortality, major coronary events, and revascularizations were observed in simvastatin-treated patients with impaired fasting glucose levels. These results strongly support the concept that cholesterol lowering with simvastatin therapy improves the prognosis of patients with elevated fasting glucose levels (> or =6.0 mmol/L [> or =110 mg/ dL]) or DM and known CHD.
Long Residence Times Revealed by Aurora A Kinase‐Targeting Fluorescent Probes Derived from Inhibitors MLN8237 and VX‐689

We report the development of three fluorescent probes for protein kinase Aurora A that are derived from the well‐known inhibitors MLN8237 and VX‐689 (MK‐5108). Two of these probes target the ATP site of Aurora A, and one targets simultaneously the ATP and substrate sites of the kinase. The probes were tested in an assay with fluorescence polarisation/anisotropy readout, and we demonstrated slow association kinetics and long residence time of the probes (kon 105–107 M−1 s−1, koff 10−3–10−4 s−1; residence time 500–3000 s). The presence of the Aurora A activator TPX2 caused a significant reduction in the on‐rate and increase in the off‐rate of fluorescent probes targeting ATP site. These observations were supported by Aurora A inhibition assays with MLN8237 and VX‐689. Overall, our results emphasise the importance of rational design of experiments with these compounds and correct interpretation of the obtained data.
The slow wave does not propagate across the gastroduodenal junction in the isolated feline preparation

Detailed spatial analysis of the propagation of individual slow waves was performed in the isolated gastroduodenal preparation of the cat. Use was made of a system that allowed the simultaneous recordings from 240 extracellular electrodes, which were positioned across the gastroduodenal region. Reconstructions of the spread of propagation (n = 31) revealed that (a) the antral slow wave never propagated into the duodenum but was blocked at the pyloric ring, (b) the duodenal slow wave did not activate the antral tissue, and (c) a quiescent zone in which no slow waves could be recorded was always present at the most proximal part of the duodenum immediately distal to the pyloric ring. Furthermore, phase density distributions of duodenal cycles revealed that antral activity had no influence on the rate of discharge of duodenal pacemakers. Light microscopic study of sections of the duodenum close to the pyloric ring and further away did not show any structural differences between the quiescent zone and the active areas. In conclusion, slow waves do not propagate across the gastroduodenal junction in the isolated feline preparation and therefore do not seem to play a role in the electro‐mechanical integration between the stomach and the duodenum.
Estimating the Effect of Discretionary Spending on Corruption: Evidence from Brazilian Municipalities

This paper analyzes the relationship between discretion of public spending and corruption in answering to the following research question: tighter procurement rules, as a proxy to discretion in spending, result in lower prevalence of corruption in Brazilian municipalities? The empirical strategy conducted here draws from a two-stage least squares (2SLS) regression approach locally estimated in each cutoff of procurement categories. Results show, however, that lower discretion is associated with higher corruption prevalence to most cutoffs of Law 8.666/93 in both purchases and works subgroups.
Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.

BACKGROUND Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.
The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer

Purpose. Radiation-induced oral mucositis is an acute morbidity seen in patients undergoing treatment for head and neck cancers. In this study, we evaluated the efficacy of turmeric in preventing radiation-induced mucositis. Methods. This was a single-blinded, randomized, controlled clinical trial and was conducted with head and neck cancer patients requiring 70 Gy of radiation or chemoradiotherapy (daily radiotherapy plus carboplatin once a week). Eligible patients (n = 80) were randomly assigned to receive either turmeric gargle (n = 40) or povidone-iodine ([n = 40] active comparator condition) during chemo/radiotherapy during the period of treatment. Oral mucositis was assessed using the RTOG (Radiation Therapy Oncology Group) grading system before the start, during, and at the end of the treatment by an investigator unaware of the treatment. The primary endpoint of this study was the incidence of mucositis every week during the 7-week period. The secondary endpoint was the effect of turmeric gargle on the incidence of treatment breaks, loss of scheduled treatment days, and decrease in body weight at the end of the treatment. Results. This study clearly suggests that when compared with the cohorts using povidone-iodine gargle, the group using turmeric as a mouthwash had delayed and reduced the levels of radiation-induced oral mucositis and was statistically significant at all time points (P < 0.001 to P < 0.0001). Additionally, the cohorts using turmeric had decreased intolerable mucositis (P < 0.001) and lesser incidence of treatment breaks in the first half of the treatment schedule before 4 weeks (P < 0.01) and reduced change in body weight (P < 0.001). Conclusions. Gargling with turmeric by head and neck cancer patients undergoing radiation therapy provided significant benefit by delaying and reducing the severity of mucositis. Turmeric is readily available, relatively inexpensive, and highly accepted making it useful in cancer treatment.
Integration Strategy for Free-form Lithium Ion Battery: Material, Design to System level Applications

Integration Strategy for Free-form Lithium-Ion Battery: Material, Design to System-level Applications Arwa Kutbee Power supply in any electronic system is a crucial necessity. Especially so in fully compliant personalized advanced healthcare electronic self-powered systems where we envision seamless integration of sensors and actuators with data management components in a single freeform platform to augment the quality of our healthcare, smart living and sustainable future. However, the status-quo energy storage (battery) options require packaging to protect the indwelling toxic materials against harsh physiological environment and vice versa, compromising its mechanical flexibility, conformability and wearability at the highest electrochemical performance. Therefore, clean and safe energy storage solutions for wearable and implantable electronics are needed to replace the commercially used unsafe lithium-ion batteries. This dissertation discusses a highly manufacturable integration strategy for a freeform lithium-ion battery towards a genuine mechanically compliant wearable system. We sequentially start with the optimization process for the preparation of all solid-state material comprising a ‘’Lithium-free’’ lithium-ion microbattery with a focus on thin film texture optimization of the cathode material. State of the art complementary metal oxide semiconductor technology was used for the thin film based battery. Additionally, this thesis reports successful development of a transfer-less scheme for a flexible battery with 5 small footprint and free form factor in a high yield production process. The reliable process for the flexible lithium-ion battery achieves an enhanced energy density by three orders of magnitude compared to the available rigid ones. Interconnection and bonding procedures of the developed batteries are discussed for a reliable back end of line process flexible, stretchable and stackable modules. Special attention is paid to the advanced bonding, handling and packaging strategies of flexible batteries towards system-level applications. Finally, this work shows seamless integration of the developed battery module in an effective strategy to incorporate them into a complex architecture such as orthodontic domain in the human body. The developed optoelectronic system embedded in a 3D printed smart dental braces for enhanced enamel healthcare protection and overall healthcare cost reduction. These findings complement and provide power solution options in which flexibility of electronics is an added beneficial dimensionality to wearable biomedical and implantable devices.
Myogenic vascular regulation in skeletal muscle in vivo is not dependent of endothelium-derived nitric oxide.

The hypothesis, based on in vitro experiments on large conduit arteries, that endothelium-derived nitric oxide is a mediator of vascular myogenic reactivity was tested in cat gastrocnemius muscle in vivo. This was done by comparing, in the absence and presence of effective endothelium-derived nitric oxide blockade by the specific inhibitors NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester, myogenic responses in defined consecutive vascular sections to dynamic vascular transmural pressure stimuli, to arterial occlusion (reactive hyperaemia), and to arterial pressure changes (autoregulation of blood flow and capillary pressure). The results demonstrated that the myogenic vascular reactivity to quick ramp transmural pressure stimuli was not attenuated by endothelium-derived nitric oxide blockade, but rather reinforced. The amplitude of the reactive hyperaemia response was unaffected by endothelium-derived nitric oxide blockade, but its duration was shortened because of faster myogenic constriction, especially of large-bore arterial resistance vessels greater than 25 microns, in the recovery phase. Both the improved myogenic responsiveness to transmural pressure stimuli and the shortening of the reactive hyperaemia by endothelium-derived nitric oxide blockade suggested that endothelium-derived nitric oxide released in vivo acts as a 'metabolic' factor which certainly does not improve, but rather depresses myogenic vascular reactivity. Autoregulation of blood flow and capillary pressure were well preserved in the presence of endothelium-derived nitric oxide blockade. It was concluded from the results of these multifaceted tests that myogenic vascular regulation in skeletal muscle in vivo seems independent of endothelium-derived nitric oxide. (ABSTRACT TRUNCATED AT 250 WORDS)
The Premature Fetus: Not as Defenseless as We Thought, but Still Paradoxically Vulnerable?

Traditionally, it has been believed that the cardiovascular and hormonal responses to asphyxia in preterm fetuses are immature, and this immaturity contributes to their apparent vulnerability to neural injury. However, these data were derived from studies using relatively mild insults, which did not allow for the greater cardiac glycogen reserves and anaerobic capacity of the brain near midgestation. Here, we review the maturation of the cardiovascular and cerebrovascular and cerebral responses to asphyxia in experimental animals and how these relate to the apparent vulnerability of the human premature brain. Most such investigations have been performed in the chronically instrumental fetal sheep. Recent studies have demonstrated that the premature fetus has highly adaptive and relatively mature responses to asphyxia, and that in absolute terms the preterm brain is very resistant to asphyxial injury. These data suggest that the premature fetus is able to survive much more prolonged periods of asphyxia than the near- term fetus, but that, paradoxically, such survival is associated with exposure to prolonged periods of hypotension and hypoperfusion and consequently greater risk of severe neural damage.
Captopril and its time of administration in myocardial ischaemic-reperfusion injury.

The present study was designed to investigate the role of captopril in an in vivo model of myocardial ischaemic-reperfusion injury with respect to its time of administration. In open-chest pentobarbitone anaesthetized cats, the left anterior descending coronary artery was occluded for 15 min followed by 60 min of reperfusion. Vehicle (saline) or captopril (4 mg kg(-1)) was administered 10 min before instituting ischaemia (pre-treatment) or 5 min before reperfusion (post-treatment). In the vehicle-treated group, ischaemic-reperfusion injury (IRI) was evidenced by enhanced plasma renin activity, depression of global haemodynamic function (mean arterial pressure, left ventricular-end-diastolic-pressure, peak positive and negative dP/dt) along with depletion of myocardial high energy phosphate (HEP) compounds. Oxidant stress in IRI was evidenced by raised levels of myocardial thiobarbituric acid reactive substances (TBARS) and depletion of endogenous myocardial antioxidants (glutathione, superoxide dismutase and catalase). Pre-treatment with captopril prevented (i) loss of myocardial haemodynamic function, (ii) rise in TBARS and (iii) depletion of myocardial HEP compounds. However, in the post-treatment group, only partial recovery of myocardial haemodynamic function, with no significant reduction in TBARS, was observed. Glutathione, superoxide dismutase and catalase were unaffected by either treatment schedules. The results of the present study suggest that captopril is more effective in attenuating ischaemic-reperfusion injury when administered before ischaemia rather than before reperfusion.