Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of a head-to-head study of lisdexamfetamine dimesylate and atomoxetine

Here, we evaluate a report of a head-to-head study of the prodrug stimulant lisdexamfetamine dimesylate (LDX) and the non-stimulant atomoxetine hydrochloride (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). An inadequate response to previous methylphenidate (MPH) treatment was a notable inclusion criterion. The primary efficacy outcome of a more rapid clinical response to LDX than to ATX was predictable from the known properties of the two drugs. However, secondary efficacy outcomes indicated that LDX was significantly more effective than ATX in relieving investigator-rated symptoms of ADHD, with an effect size of 0.56. Safety and tolerability profiles were consistent with the known properties of LDX and ATX. Despite some issues with the study design, the conclusion that LDX is more effective than ATX over the short term appears robust. In addition, the magnitude of improvement with both treatments indicated that previous MPH treatment is not a factor affecting the potential for patients to benefit from LDX or ATX. The results may help to inform clinical practice in Europe, where LDX is approved for treating children and adolescents with ADHD and a previous inadequate response to MPH, and in other regions where generic MPH formulations are typically the first-line therapeutic option.
Altering Intracellular pH Disrupts Development and Cellular Organization in Preimplantation Hamster Embryos1

Abstract In early cleavage stage hamster embryos, the inability to regulate intracellular pH (pHi) properly is associated with reduced developmental competence in vitro. The disruption of mitochondrial organization is also correlated with reduced development in vitro. To determine the relationship between pHi and the disruption of cytoplasmic organization, we examined the effects of altering pHi on hamster embryo development, mitochondrial distribution, and cytoskeletal organization. The weak base trimethylamine was used to increase pHi and was found to reduce embryo development and disrupt the perinuclear organization of mitochondria. The weak acid 5,5-dimethyl-2,4-oxazolinedione was used to decrease pHi and was also found to reduce development and disrupt the perinuclear organization of mitochondria. With either treatment, the microfilament organization was perturbed, but the microtubule cytoskeleton was not. However, the temporal progression of the disruption of mitochondrial distribution was more rapid in alkalinized embryos than acidified embryos, as revealed by two-photon imaging of living embryos. Additionally, the disruption of the microfilament network by the two treatments was not identical. The cytoplasmic disruptions observed were not due to acute toxicity of the compounds because embryos recovered developmentally when the treatment compounds were removed. These observations link ionic homeostasis, structural integrity and developmental competence in preimplantation hamster embryos.
Ultrasound Score Is More Predictive than Serum Creatinine in Assessment of Cellular Rejection in Cynomolgus Monkey Renal Allografts

Gaschen L, Schuurman HJ. Ultrasound score is more predictive than serum creatinine in assessment of cellular rejection in cynomolgus monkey renal allografts. Invest Radiol 2002;37:376–380. rationale and objectives. To investigate whether ultrasound (US), in particular the use of an ultrasound scoring system, can provide more diagnostic information than clinical parameters, such as serum creatinine, for the diagnosis and determination of the degree of cellular rejection in renal allografts in the cynomolgus monkey (Macaca fascicularis). methods. Sixty-eight cynomolgus monkeys with life-supporting renal allografts were examined with a 7.5MHz linear ultrasound transducer. One-hundred fifty two-dimensional, spectral, and power Doppler examinations were performed and four ultrasound parameters, percentage increase in graft volume, cortical thickness, resistive index (RI) of the renal arcuate artery, and power Doppler (PD) scores were recorded from serial examinations. An ultrasound score was assigned to each graft based on the number of those parameters that were abnormal; a score of 1 indicated that all four were normal, and a score of 5 that all four were abnormal. Each parameter and the combined score were compared with serum creatinine values and histology and evaluated statistically using Spearman rank correlation. results. In animals with dysfunctioning allografts (serum creatinine elevations >200 &mgr;mol/L), Spearman rank correlation showed a significant correlation between the US score and the histology score: between 200 and 500 &mgr;mol/L, r = 0.309, P = 0.046, n = 31 and if > 500 &mgr;mol/L, r = 0.486, P = 0.005, n = 30. In those same animals, no correlation could be shown between serum creatinine values and the US score or between the serum creatinine values and the histologic diagnosis. In contrast to the US score, single ultrasound parameters were not found to correlate to histologic findings. conclusion. The application of ultrasound imaging in nonhuman primate renal transplant models provides valuable information concerning the presence and severity of cellular rejection in cases of graft dysfunction and the US score has a better predictive value of histology than serum creatinine values alone.
Intracellular compartmentation of pyruvate in primary cultures of cortical neurons as detected by 13C NMR spectroscopy with multiple 13C labels

The intracellular compartmentation of pyruvate in primary cultures of cortical neurons was investigated by high resolution 13C NMR using mixtures of different pyruvate precursors conveniently labeled with 13C or unlabeled. Cells were incubated with 1–5 mM (1‐13C, 1,2‐13C2 or U‐13C6) glucose only or with mixtures containing 1.5 mM (1‐13C or U‐13C6) glucose, 0.25–2.5 mM (2‐13C or 3‐13C) pyruvate and 1 mM malate. Extracts from cells and incubation media were analyzed by 13C NMR to determine the relative contributions of the different precursors to the intracellular pyruvate pool. When (13C) glucose was used as the sole substrate fractional 13C enrichments and 13C isotopomer populations in lactate and glutamate carbons were compatible with a unique intracellular pool of pyruvate. When mixtures of (13C) glucose, (13C) pyruvate and malate were used, however, the fractional 13C enrichments of the C2 and C3 carbons of lactate were higher than those of the C2 and C3 carbons of alanine and depicted a different 13C isotopomer distribution. Moreover, neurons incubated with 1 mM (1,2‐13C2) glucose and 0.25–5 mM (3‐13C) pyruvate produced exclusively (3‐13C) lactate, revealing that extracellular pyruvate is the unique precursor of lactate under these conditions. These results reveal the presence of two different pools of intracellular pyruvate; one derived from extracellular pyruvate, used mainly for lactate and alanine production and one derived from glucose used primarily for oxidation. A red‐ox switch using the cytosolic NAD+/NADH ratio is proposed to modulate glycolytic flux, controlling which one of the two pyruvate pools is metabolized in the tricarboxylic acid cycle when substrates more oxidized or reduced than glucose are used. © 2001 Wiley‐Liss, Inc.
Statistical properties of the traditional algorithm-based designs for phase I cancer clinical trials.

Although there are several new designs for phase I cancer clinical trials including the continual reassessment method and accelerated titration design, the traditional algorithm-based designs, like the '3 + 3' design, are still widely used because of their practical simplicity. In this paper, we study some key statistical properties of the traditional algorithm-based designs in a general framework and derive the exact formulae for the corresponding statistical quantities. These quantities are important for the investigator to gain insights regarding the design of the trial, and are (i) the probability of a dose being chosen as the maximum tolerated dose (MTD); (ii) the expected number of patients treated at each dose level; (iii) target toxicity level (i.e. the expected dose-limiting toxicity (DLT) incidences at the MTD); (iv) expected DLT incidences at each dose level and (v) expected overall DLT incidences in the trial. Real examples of clinical trials are given, and a computer program to do the calculation can be found at the authors' website approximately linyo" locator-type="url">http://www2.umdnj. edu/ approximately linyo.
Effect of phoshpodiesterase 4 (PDE4) inhibibtors on eotaxin expression in humen bronchial epithelial cells.

UNLABELLED The increasing number of eosinophils into bronchoaelvolar space is observed during noninfectious inflammatory lung diseases. Eotaxins (eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26) are the strongest chemotactic agents for eosinophils. Inhibitors of phosphodiesterase 4 (PDE4), the enzyme decomposing cAMP, are anti-inflammatory agents which act through cAMP elevation and inhibit numerous steps of allergic inflammation. The effect of PDE4 inhibitors on eotaxin expression is not known in details. The aim of our study was to evaluate the influence of PDE4 inhibitors: rolipram and RO-20-1724 on expression of eotaxins in bronchial epithelial cell line BEAS-2B. Cells were preincubated with PDE4 inhibitors or dexamethasone for 1 hour and then stimulated with IL-4 or IL-13 alone or in combination with TNF-α. After 48 hours eotaxin protein level was measured by ELISA and mRNA level by real time PCR. RESULTS PDE4 inhibitors decreased CCL11 and CCL26 expression only in cultures co-stimulated with TNF-α. In cultures stimulated with IL-4 and TNF-α rolipram and RO-20-1724 diminished CCL11 mRNA expression by 34 and 37%, respectively, and CCL26 by 43 and 47%. In cultures stimulated with IL-13 and TNF-α rolipram and RO-20-1724 decreased expression of both eotaxins by about 50%. These results were confirmed at the protein level. The effect of PDE4 inhibitors on eotaxin expression in BEAS-2B cells, in our experimental conditions, depends on TNF-α contribution.
Evaluation of Limb Alignment, Component Positioning, and Function in Primary Total Knee Arthroplasty Using a Pinless Navigation Technique Compared with Conventional Methods

Abstract The purpose of this study was to examine component positioning, limb alignment, and the early functional range of motion of a pinless image-free computer-assisted navigation system, and compare it to conventional intramedullary component alignment methods. A total of 72 patients underwent cemented total knee arthroplasty. The pinless navigation group consisted of 40 knees in 39 patients, while the conventional group comprised 33 knees in 33 patients. Preoperative and postoperative radiographs were evaluated for coronal and sagittal alignment. Functional assessment was evaluated by early postoperative range of motion. There was no statistical significance when examining individual component alignment or early functional range of motion. When evaluating ability to achieve overall anatomic tibiofemoral alignment within a range of 4 to 7 degrees valgus, the conventional group was able to accomplish this 39% of the time, whereas the pinless navigation group succeeded in 65% of cases (p < 0.03). The tourniquet time was mean 59.5 minutes (range: 48 to 77 minutes) for the conventional group, compared with mean 71.9 minutes (range: 54 to 97 minutes) for the navigation group (p < 0.0001, 95% CI). The pinless navigation technique improved coronal anatomic alignment without complications that have been cited with use of femoral or tibial reference tracker pins or intramedullary alignment guides.
Effect of Prior Statin Use on Functional Outcome and Delayed Vasospasm after Acute Aneurysmal Subarachnoid Hemorrhage: A Matched Controlled Cohort Study

OBJECTIVE:Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), which exhibit beneficial cerebrovascular effects by modulating inflammation and nitric oxide production, have not been evaluated in acute aneurysmal subarachnoid hemorrhage (SAH) patients. The effect of prior statin use on 14-day functional outcome and on prevention of vasospasm-induced delayed cerebral ischemia (DCI) or stroke during hospitalization was analyzed. METHODS:We conducted a 1:2 matched (age, admission Hunt and Hess grade, vascular disease/risk history) cohort study of 20 SAH patients on statins and 40 SAH controls. The primary outcome was functional outcome at 14 days (Modified Lawton Physical Self-Maintenance Scale and Barthel Index scale scores). Secondary outcomes were 14-day mortality, Modified Rankin Scale score, DCI, DCI supported by angiography/transcranial Doppler [TCD], cerebral infarctions of any type, and TCD highest mean velocity elevation. RESULTS:Statin users demonstrated a significant protective effect on 14-day Barthel Index scale and Modified Lawton Physical Self-Maintenance Scale scores (77 ± 10 versus 39 ± 8, P = 0.003; 12 ± 7 versus 19 ± 9, P = 0.03, respectively). Moreover, statin users demonstrated a significantly lower incidence of DCI and DCI supported by angiography/TCD (10% versus 43%, P = 0.02; 5% versus 35%, P = 0.01, respectively), cerebral infarctions of any type (25% versus 63%, P = 0.01), and baseline-to-final TCD highest mean velocity change of 50 cm/s or greater (18% versus 51%, P = 0.03). CONCLUSION:SAH statin users demonstrated significant improvement in 14-day functional outcome, a significantly lower incidence of DCI and cerebral infarctions of any type, as well as prevention of TCD highest mean velocity elevation. However, we did not find a significant statin impact on mortality or global outcome (Modified Rankin Scale) in this small sample. This study provides clinical evidence for the potential therapeutic benefit of statins after acute SAH.
Nine- to fourteen-year follow-up of implant treatment. Part II: presence of peri-implant lesions.

OBJECTIVES The aim of this study was to analyse the proportions of peri-implant lesions at implants after 9-14 years of function. MATERIAL AND METHODS Two hundred and ninety-four patients underwent implant therapy during the years 1988-1992 in Kristianstad County. These individuals were recalled to the speciality clinic 1 and 5 years after placement of the suprastructure. Between 2000 and 2002, 218 patients with 999 implants were examined clinically and radiographically. RESULTS Forty-eight per cent of the implants had probing depth > or =4 mm and bleeding on probing (peri-implant mucositis). In 20.4% of the implants, the bone level was located 3.1 mm apical to the implant shoulder. Progressive bone loss (> or =1.8 mm) during the observation period was found in 7.7% of the implants. Peri-implantitis defined as bone loss > or =1.8 mm compared with 1-year data (the apical border of the bony defect located at or apical to the third thread, i.e. a minimum of 3.1 mm apical to the implant shoulder), combined with bleeding on probing and or pus, were diagnosed among 16% of the patients and 6.6% of the implants. CONCLUSION After 10 years in use without systematic supportive treatment, peri-implant lesions is a common clinical entity adjacent to titanium implants.
Osteoblast‐Like Cells From Estrogen Receptor α Knockout Mice Have Deficient Responses to Mechanical Strain

Osteoblast‐like cells in primary cultures derived from ERα−/− mice do not proliferate in response to mechanical strain, unlike those from their ERα+/+ littermates. ERα−/− cells also lack strain‐related NO production and responsiveness to IGFs. Proliferative responsiveness to strain is rescued by transfection with functional ERα. ERα number or function in bone cells may limit bones' adaptability to mechanical loading.
Acidic pH weakens the microhardness and microstructure of three tricalcium silicate materials.

AIM To investigate the microhardness and microstructural features of three tricalcium silicate materials: mineral trioxide aggregate (MTA), Endosequence Root Repair Material Putty (ERRM Putty) and Endosequence Root Repair Material Paste (ERRM Paste), after exposure to a range of acidic environments in comparison with intermediate restorative material (IRM). METHODOLOGY Endosequence Root Repair Material Putty (Brasseler, Savannah, GA, USA), ERRM Paste (Brasseler, Savannah, GA, USA), MTA (ProRoot; Dentsply Tulsa Dental, Johnson City, TN, USA) and IRM (Dentsply Caulk, Milford, DE, USA) were set in cylindrical rubber moulds as four groups containing twenty specimens each. Fifteen specimens per each material were randomly distributed into three groups (n = 5) to be exposed to butyric acid buffered at three different pH levels (5.4, 6.4 and 7.4) for 7 days. The remaining five specimens were exposed to distilled water as a control group. The surface microhardness after exposure either to acid or to water was measured after 7-days at 37 °C. The morphology of the internal microstructure was observed using a scanning electron microscope (SEM). Two-way univariate analysis of variance (anova) was applied to evaluate the Vickers microhardness value (VHN). RESULTS The microhardness values of the materials were significantly higher in the neutral environment of butyric acid at pH 7.4 compared to those in the acidic condition of pH 5.4 for all groups (P < 0.001). MTA, ERRM Putty and ERRM Paste had higher microhardness values than IRM at all pH levels (P < 0.001). Specimens exposed to distilled water displayed significantly higher microhardness values than those values obtained in the presence of butyric acid buffered to all pH levels (P < 0.001). A more porous microstructure was observed following exposure to butyric acid at pH 5.4 than at pH 7.4. Several types of crystalline structures were formed by recrystallization, especially at pH 7.4 in all groups except for IRM. CONCLUSIONS The microhardness values of ERRM Putty, ERRM Paste and MTA were reduced in an acidic environment, which resulted in these materials having more porous and less crystalline microstructures. MTA seems the most suitable material for application to an area of inflammation where a low pH value may exist.
Co(II) and Ni(II) binding of the Escherichia coli transcriptional repressor RcnR orders its N terminus, alters helix dynamics, and reduces DNA affinity

RcnR, a transcriptional regulator in Escherichia coli, derepresses the expression of the export proteins RcnAB upon binding Ni(II) or Co(II). Lack of structural information has precluded elucidation of the allosteric basis for the decreased DNA affinity in RcnR's metal-bound states. Here, using hydrogen–deuterium exchange coupled with MS (HDX-MS), we probed the RcnR structure in the presence of DNA, the cognate metal ions Ni(II) and Co(II), or the noncognate metal ion Zn(II). We found that cognate metal binding altered flexibility from the N terminus through helix 1 and modulated the RcnR–DNA interaction. Apo–RcnR and RcnR–DNA complexes and the Zn(II)–RcnR complex exhibited similar 2H uptake kinetics, with fast-exchanging segments located in the N terminus, in helix 1 (residues 14–24), and at the C terminus. The largest difference in 2H incorporation between apo- and Ni(II)- and Co(II)-bound RcnR was observed in helix 1, which contains the N terminus and His-3, and has been associated with cognate metal binding. 2H uptake in helix 1 was suppressed in the Ni(II)- and Co(II)-bound RcnR complexes, in particular in the peptide corresponding to residues 14–24, containing Arg-14 and Lys-17. Substitution of these two residues drastically affected DNA-binding affinity, resulting in rcnA expression in the absence of metal. Our results suggest that cognate metal binding to RcnR orders its N terminus, decreases helix 1 flexibility, and induces conformational changes that restrict DNA interactions with the positively charged residues Arg-14 and Lys-17. These metal-induced alterations decrease RcnR–DNA binding affinity, leading to rcnAB expression.
White Adipose Tissue: Getting Nervous

Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para‐ and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.
A novel approach to the determination of clinical decision thresholds

Our objective was to determine the test and treatment thresholds for common acute primary care conditions. We presented 200 clinicians with a series of web-based clinical vignettes, describing patients with possible influenza, acute coronary syndrome (ACS), pneumonia, deep vein thrombosis (DVT) and urinary tract infection (UTI). We randomly varied the probability of disease and asked whether the clinician wanted to rule out disease, order tests or rule in disease. By randomly varying the probability, we obtained clinical decisions across a broad range of disease probabilities that we used to create threshold curves. For influenza, the test (4.5% vs 32%, p<0.001) and treatment (55% vs 68%, p=0.11) thresholds were lower for US compared with Swiss physicians. US physicians had somewhat higher test (3.8% vs 0.7%, p=0.107) and treatment (76% vs 58%, p=0.005) thresholds for ACS than Swiss physicians. For both groups, the range between test and treatment thresholds was greater for ACS than for influenza (which is sensible, given the consequences of incorrect diagnosis). For pneumonia, US physicians had a trend towards higher test thresholds and lower treatment thresholds (48% vs 64%, p=0.076) than Swiss physicians. The DVT and UTI scenarios did not provide easily interpretable data, perhaps due to poor wording of the vignettes. We have developed a novel approach for determining decision thresholds. We found important differences in thresholds for US and Swiss physicians that may be a function of differences in healthcare systems. Our results can also guide development of clinical decision rules and guidelines.