Miracle-dz/UniFAR-FTUs huggingface dataset:
Contribution to the Somatology of Periodic Catatonia

This is Age Action Year, just 30 years after the first geriatric departments were established in our hospitals, and the British Geriatrics Society makes its contribution to the Year in the form of this book. Members of the Society give an account of their personal views and experiences, and the reader gains a vivid impression of the enthusiasm of those who practise in this field, which is often poorly understood by doctors in other specialties. The first chapter is by the president of the Society, Sir Ferguson Anderson, who describes the considerable progress made in geriatric medicine since its beginning. Authors of subsequent chapters deal with the clinical aspects from the viewpoint of the physician and the psychiatrist, organisational aspects of hospital and community services, the prospects for research in gerontology, the clinical medicine ofold age, and the psychology, epidemiology, and sociology of ageing. The chapter on attitudes focuses attention on the need for more enlightened educational policies, and it is followed by an account of the educational experiences of the three youngest contributors, a medical student, a vocational trainee in general practice, and a pre-registration house physician. Not only doctors and members of the health professions will find many points of interest in this book. Politicians and social administrators should be looking harder for solutions to the problems presented by an ageing population. The policies current in western civilisation today, as Professor Grimley Evans points out, tend to compound the diminished capacity for physiological and psychological adjustment due to ageing by also reducing social and economic adaptability of older people. The editor has made a wise choice of contributors. They have presented succinctly some fascinating views on the problems and opportunities for increasing our knowledge of medical practice in old age.
Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of the Soluble Guanylate Cyclase Activator Cinaciguat (BAY 58‐2667) in Healthy Male Volunteers

Preclinical data indicate that the nitric oxide—independent soluble guanylate cyclase activator cinaciguat (BAY 58–2667), which is a new drug in development for patients with heart failure, induces vasodilation preferentially in diseased vessels. This study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat. Seventy‐six healthy volunteers were included in this randomized, placebo‐controlled study. Cinaciguat (50–250 μg/h) was administered intravenously for up to 4 hours in a maximum of 6 individuals per dose group. No serious adverse events were reported. Four‐hour infusions (50–250 μg/h) decreased diastolic blood pressure and increased heart rate (all P values < .05) versus placebo, without significantly reducing systolic blood pressure (P between 0.07 and 0.56). At higher doses (150–250 μg/h), 4‐hour infusions decreased mean arterial pressure and increased plasma cyclic guanosine monophosphate levels (all P values < .05). Pharmacokinetics showed dose‐proportionality with low interindividual variability. Plasma concentrations declined below 1.0 μg/L within 30 minutes of cessation of infusion. Cinaciguat had potent cardiovascular effects reducing preload and afterload, warranting further investigation in patients with heart failure.
In vivo confocal microscopy in dermatology: from research to clinical application

Abstract. Confocal laser scanning microscopy (CLSM) represents an emerging technique for the noninvasive histomorphological analysis of skin in vivo and has shown its applicability for dermatological research as well as its value as an adjunct tool in the clinical management of skin cancer patients. Herein, we aim to give an overview on the current clinical indications for CLSM in dermatology and also highlight the diverse applications of CLSM in dermatological research.
Population Pharmacokinetic Analysis of Ibuprofen Enantiomers in Preterm Newborn Infants

The aim of this pharmacokinetic analysis was to develop and validate a population pharmacokinetic model for R‐ and S‐ibuprofen from samples obtained after 3 successive administrations of ibuprofen (10–5–5 mg/kg) at 24‐hour intervals to preterm newborn infants aged from <6 hours to 8 days of life. A model including unilateral bioconversion of R‐ibuprofen into S‐ibuprofen was developed using the software NONMEM. R‐ and S‐ibuprofen plasma concentrations were adequately fitted by this model. Estimated clearance and volume of distribution were 3.5 mL/h/kg and 173 mL/kg, respectively, with a calculated half‐life (t1/2) of 34.3 hours for S‐ibuprofen. Estimated clearance at birth and volume of distribution were 25.5 mL/h/kg and 306 mL/kg with a t1/2 at birth of 8.3 hours for R‐ibuprofen. R‐ibuprofen elimination increased during the first week of life, whereas S‐ibuprofen pharmacokinetics were weakly modified. Therefore, because the activity of the 2 enantiomers differs, it is important that subsequent studies consider R‐ and S‐enantiomers separately. Mean simulated ibuprofen concentrations at various dose regimens were in agreement with observed concentrations. The present analysis allows a more accurate estimation of the ibuprofen pharmacokinetics as parameters could be estimated separately for each enantiomer and the effect of postnatal age on the elimination of R‐ibuprofen was elicited.
Gender Has a Small but Statistically Significant Effect on Clearance of CYP3A Substrate Drugs

The role of gender on the disposition of drugs metabolized by cytochrome P4503A (CYP3A) remains controversial. Some sources suggest that CYP3A activity in women exceeds that in men, but evidence to support this position is inconsistent at best. We evaluated 38 data sets in which clearance of CYP3A substrate drugs was studied in healthy young male and young female subjects. None of these drugs was a substrate for transport by P‐glycoprotein (P‐gp). The overall mean (±SE) for the female/male ratio of weight‐normalized clearance was 1.26 (±0.07) for parenteral dosage and 1.17 (±0.07) for oral dosage. Both ratios were significantly different (P < .05) from 1.0. For oral dosage studies, the female/male clearance ratio was unrelated to the drug's absolute oral bioavailability. Thus gender has a small and statistically significant, although most likely clinically unimportant, influence on CYP3A phenotype for substrates not transported by P‐gp.
Single‐Dose Pharmacokinetic Study of Clomiphene Citrate Isomers in Anovular Patients With Polycystic Ovary Disease

The pharmacokinetics of the zuclomiphene (Zu) and enclomiphene (En) isomers of clomiphene citrate following a single oral dose (50 mg) were characterized for the first time in patients receiving the drug (ie, infertile women with polycystic ovary syndrome). Plasma concentrations of Zu and En were measured in 9 patients from the second day of their menstrual cycle (day 1 of dosing) up to 21 days. The mean (± coefficient of variation) of Cmax, tmax, and AUC of Zu was 15 ± 41 ng/mL, 7 ± 87 h, and 1289 ± 34 ng/mL·h (AUC0–456 h), and that of En was 15 ± 18 ng/mL, 3 ± 68 h, and 65 ± 35 ng/ml·h (AUC0–72 h), respectively. These parameters appeared to be different for Zu from those reported previously in healthy participants, except for tmax. The pharmacokinetic parameters of En in patients with polycystic ovary syndrome were not generally different from the healthy subjects. The effect of obesity on Zu kinetics was stronger than that on En. The conventional model‐dependent pharmacokinetics of clomiphene citrate isomers could not be determined due to a very flat terminal half‐life and the long‐tailed residence time, signifying the lipophilic nature and potentially extensive distribution of the compound.
Multiple Feature-Enhanced SAR Imaging Using Sparsity in Combined Dictionaries

Nonquadratic regularization-based image formation is a recently proposed framework for feature-enhanced radar imaging. Specific image formation techniques in this framework have so far focused on enhancing one type of feature, such as strong point scatterers, or smooth regions. However, many scenes contain a number of such feature types. We develop an image formation technique that simultaneously enhances multiple types of features by posing the problem as one of sparse representation based on combined dictionaries. This method is developed based on the sparse representation of the magnitude of the scattered complex-valued field, composed of appropriate dictionaries associated with different types of features. The multiple feature-enhanced reconstructed image is then obtained through a joint optimization problem over the combined representation of the magnitude and the phase of the underlying field reflectivities.
Photodynamic effects of Photodithazine on cervical cancer model

Photodynamic therapy (PDT) has been reported to be effective for treating various tumors and induce apoptosis in many tumor cells. In this study, we examined a biological significance of PDT with a new photosensitizer, Photodithazine, in a cervical cancer model using TC-1 cells. Also, to see the accumulation level of Photodithazine in tumours, we measured the concentration of Photodithazine at indicated time points in tumours of the mice injected with Photodithazine. When the tumor bearing mice were exposed to varied doses of Photodithazine with laser irradiation (300 J/cm2), retarded tumor growth was significant in mice treated with PDT, as compared to the control group. On the other hand, in the uptake of Photodithazine experiments showed that the highest accumulation of Photodithazine in tumors was shown at 0·5 hr after injection and its concentration was decreased. Photodithazine keeps high concentration values during the first day, Photodithazine showed a rapid clearance from sera as it is relatively long kept by tumor tissue. Taken together, we propose that PDT after the application of Photodithazine may be effective in the mice system.
Over Their Dead Bodies: Yankee Epitaphs and History.

Tombstones and epitaphs have been collectors' cherished items for centuries. Not only are they full of conscious and unconscious whimsy, fancy, fantasy, and, I suppose we all would guess, a good deal of benignant prevarication; but they also serve as a commentary on the social kaleidoscope of the changing times and customs of a people. For the mass of inarticulate men, a tombstone often enough memorialized them as they might have been. Here is a logical place for one to say his say. Certainly it is the last word; but few write their own epitaphs. Occasionally one is jolted by the stunning frankness of the anonymous compositor, obviously not the one who is honored. Mann and Greene have collected epitaphs from sundry graveyards in New England and arranged them in sequence for the 300-year span which includes the pioneer and colonial life through 1775; War, Reason and Revivalism, 1776-1815; "The
Pharmacokinetics, Safety, and Tolerability of Doripenem After 0.5‐, 1‐, and 4‐Hour Infusions in Healthy Volunteers

The pharmacokinetics, safety, and tolerability of doripenem in healthy subjects were evaluated in 2 studies. Study 1 was a double‐blind, randomized, placebo‐controlled dose‐escalation study in which doripenem was administered for 7 days by infusion over 30 minutes (500 mg) or 1 hour (1000 mg). Study 2 was an open‐label, randomized, 3‐way crossover study in which each subject received a single dose of each of the following doripenem treatments on separate occasions: 500 mg infused over 1 hour, 500 mg infused over 4 hours, and 1000 mg infused over 4 hours. Doripenem exhibited linear pharmacokinetics with concordance between the studies for pharmacokinetic parameters. Doripenem did not accumulate with repeated dosing over 7 days. The area under the plasma concentration‐time curve (AUC) for doripenem 500 mg infused over 1 hour versus 4 hours was bioequivalent, and the AUC and Cmax increased proportionally with dose for the 500‐ and 1000‐mg doses administered over 4 hours. These results, along with the stability profile of doripenem, support its use as a prolonged infusion. All regimens of doripenem were safe and well tolerated.
Predicting the ischemic infarct volume at the first minute after occlusion in rodent stroke model by laser speckle imaging of cerebral blood flow

Abstract. Stroke is a worldwide medical emergency and an important issue in stroke research is looking for the early pathophysiological markers which can predict the severity of brain injury. Decreased cerebral blood flow (CBF) has been serving as the most important indicator of ischemic stroke. Particular attention is paid to study the spatio-temporal CBF changes immediately after the onset of stroke in a rat intraluminal filament middle cerebral artery occlusion (MCAO) model and investigation of its correlation with brain infarct volume after 24 h. We implement an on-line laser speckle imaging (LSI) system, which could provide real time high spatio-temporal resolution CBF information before, during, and immediately after the rat MCAO surgery. We found a significant correlation between the affected area with 50% CBF reduction (CBF50) at the first minute after occlusion with the infarct volume. To the best of our knowledge, this is the earliest CBF marker for infarct volume prediction. Based on such a CBF–infarct volume correlation, LSI may be used as a real time guidance for improving the consistency of intraluminal filament MCAO model since the depth of filament insertion could be adjusted promptly and those unsuccessful models could be excluded in the earliest stage.
Spatial-Attraction-Based Markov Random Field Approach for Classification of High Spatial Resolution Multispectral Imagery

This letter presents a novel spatial-attraction-based Markov random field (MRF) (SAMRF) approach for high spatial resolution multispectral imagery (HSRMI) classification. First, the initial class label and class membership for each pixel are obtained by applying the maximum likelihood classifier (MLC) classification for the HSRMI. Second, to reduce the oversmooth classification in the traditional MRF, an adaptive weight MRF model is introduced by integrating the spatial attraction model into the traditional MRF. Finally, the initial classification map, generated in the first step, will be refined though the SAMRF regularization. Two different experiments were performed to evaluate the performance of the SAMRF, in comparison with standard MLC and MRF. Experimental results indicate that the SAMRF method achieved the highest accuracy, hence, providing an effective spectral-spatial classification method for the HSRMI.
Multiple primary tumours following head and neck cancer in southern England during 1961-98.

BACKGROUND Successful initial treatment of oral and oro-phayngeal cancer has led to the emergence of second primary tumours (SPTs). Population data are meagre. METHODS Occurrence of multiple primary cancers following a malignancy in a head and neck site was computed using data from a population-based cancer registry covering a population of 14 million. RESULTS Among 59,958 subjects reported to the registry, 5.5% males and 3.6% females developed a second primary cancer. At the sites studied, a total of 2771 second primary cancers were found, compared with an expected number of 2341. The standardised incidence ratio (SIR) for contracting a new primary cancer was 1.14 (95% CI=1.09-1.19) for men and 1.34 (95% CI=1.24-1.44) for women. There was a significantly increased risk for a second cancer in most of the upper aerodigestive tract sites that are generally regarded as tobacco associated, with an SIR for subsequent oral cancer of 5.56 in men and 15.31 in women. Subjects first detected with a pharyngeal cancer experienced the highest SIR for a subsequent tumour. Excluding tobacco-associated sites, the risk of a subsequent cancer was not significantly raised in either sex (SIR 0.87 (95% CI 0.81-0.93) for men; SIR 0.99 (95% CI 0.90-1.09) for women). CONCLUSIONS The relative risk for multiple primary cancer was higher in younger subjects, those detected with a head and neck cancer during the 1990s as compared with earlier decades of the study, and among patients who received radiotherapy for their first tumour. By 20 years from the time of the first head and neck cancer, we estimate that approximately 30% of male patients and 20% of female patients will have developed an SPT.
Accuracy of Phase-Based Algorithms for the Estimation of the Specific Differential Phase Shift Using Simulated Polarimetric Weather Radar Data

The specific differential phase shift on propagation Kdp is widely employed in the study of precipitation, although little is known about the effective accuracy of its estimates. The aim of this letter is to analyze the quality of Kdp estimates, using realistic simulated fields of drop size distributions. Two classical and one recently proposed estimation algorithms are tested, which are chosen among the algorithms that use the measured and noisy total differential phase shift Ψdp as their main input. A data set of six simulated rain events, from which polarimetric radar variables can be derived, is employed in this letter. The mean normalized absolute error in the estimation of Kdp at the radar resolution volume scale ranges from 27% to 30% for all the algorithms proposed, and significant negative biases up to -50% emerge at the highest values of Kdp for the most biased algorithm. The new algorithm, which is based on Kalman filtering, is able to keep these localized bias values around -25% and outperforms the classical algorithms in terms of efficiency, correlation, and root-mean-square error.
Microdose Pharmacokinetics of IDX899 and IDX989, Candidate HIV‐1 Non‐Nucleoside Reverse Transcriptase Inhibitors, Following Oral and Intravenous Administration in Healthy Male Subjects

IDX899 and IDX989 are new non‐nucleoside reverse‐transcriptase inhibitors (NNRTIs) that exhibit potent inhibition of HIV‐1 replication, including NNRTI‐resistant mutants. This microdose study investigates the pharmacokinetics and determined oral bioavailability. For each compound, 4 healthy male subjects are randomized to receive via a crossover design a single 100‐μg oral and intravenous dose together with 100 nCi of [14C]‐labeled drug. Plasma and urine samples are obtained over a period of 168 hours postdose and analyzed for total, unchanged drug and major metabolites using an accelerator mass spectrometry method. Based on total radioactivity, oral absorption is near complete. For the parent drug, mean absolute bioavailability is 61% and 65% for IDX899 and IDX989, respectively. Both compounds are extensively metabolized especially after oral dosing. Observed terminal phase half‐lives after oral and intravenous doses range from 4 to 10 hours and are comparable for the 2 compounds. Urine excretion of radioactivity for both compounds is less than 10%. These data show for the first time that IDX899 and IDX989 possess favorable pharmacokinetic properties in humans, including high mean absolute bioavailability and long half‐life. IDX899 has been selected based on these initial pharmacokinetic assessments and other criteria as the candidate for further clinical development.
Use of Enantiomeric Bupropion and Hydroxybupropion to Assess CYP2B6 Activity in Glomerular Kidney Diseases

Chronic kidney disease affects more than 50 million people in the U.S.1. The top three etiologies for end-stage kidney disease are diabetes mellitus (45% of patients), hypertension (29% of patients), and glomerulonephritis (19% of patients). 2 While it is well established that chronic kidney diseases can result in decreased elimination of drugs via the kidneys, the effects of kidney disease on non-renal clearance processes, especially specific metabolic routes, are less well described. Experimental models of chronic kidney disease have reported reductions in hepatic cytochrome P450 (CYP) enzymes including 3A1, 3A2, 2C11, and N-acetyltransferases.3–5 Reductions in nonrenal clearance ranging from 30% to 67% have been reported for substrates of the CYP3A4, CYP2D6, CYP2B6, and CYP2C9 enzymes in patients with kidney disease.6 In order to fully understand the clinical significance of altered metabolic routes associated with kidney disease, it will be necessary to evaluate the effects that specific forms of kidney diseases have on these pathways and whether these processes effect drug disposition. Numerous studies have reported various probe drugs or cocktail approaches to evaluate the in vivo function of various drug metabolizing enzymes and transporters in patients.7, 8 However, only a few studies9–12 were actually conducted in chronic kidney disease patients, and hence applicability of most of the published studies beyond the healthy control population remains to be established. As chronic kidney disease patients are commonly prescribed ~10–12 different daily medications13, studies that evaluate metabolic pathway alterations should address requirements for modifications in drug regimens as well as drug interaction potential. While studies designed to assess and report the pharmacokinetics of bupropion exist14, 15, studies designed specifically to assess the influence of chronic kidney diseases on CYP2B6 activity are currently nonexistent. CYP2B6 is responsible for the metabolism of 3–8% of the currently marketed drugs16, 17 including bupropion, cyclophosphamide, efavirenz, selegiline, methadone, and sertraline18–22 and several drugs, including clopidrogrel, ticlopidine, clotrimazole, itraconazole, sertraline, and raloxifene have been purported to inhibit CYP2B6.23 Data from healthy subjects demonstrate that both the R and S enantiomers of bupropion and its hydroxy-metabolite are present in plasma, but only stereoselective S bupropion and (S,S) hydroxybupropion formation clearance have been shown to be a phenotypic probe for CYP2B624, complicating the assessment of in vivo activity. The purpose of the current study was to evaluate the pharmacokinetics of enantiomeric bupropion and its hydroxybupropion metabolite in patients with kidney diseases affecting the glomerulus in order to provide an assessment of CYP2B6 activity in this disease state.
Computational segmentation of collagen fibers from second-harmonic generation images of breast cancer

Abstract. Second-harmonic generation (SHG) imaging can help reveal interactions between collagen fibers and cancer cells. Quantitative analysis of SHG images of collagen fibers is challenged by the heterogeneity of collagen structures and low signal-to-noise ratio often found while imaging collagen in tissue. The role of collagen in breast cancer progression can be assessed post acquisition via enhanced computation. To facilitate this, we have implemented and evaluated four algorithms for extracting fiber information, such as number, length, and curvature, from a variety of SHG images of collagen in breast tissue. The image-processing algorithms included a Gaussian filter, SPIRAL-TV filter, Tubeness filter, and curvelet-denoising filter. Fibers are then extracted using an automated tracking algorithm called fiber extraction (FIRE). We evaluated the algorithm performance by comparing length, angle and position of the automatically extracted fibers with those of manually extracted fibers in twenty-five SHG images of breast cancer. We found that the curvelet-denoising filter followed by FIRE, a process we call CT-FIRE, outperforms the other algorithms under investigation. CT-FIRE was then successfully applied to track collagen fiber shape changes over time in an in vivo mouse model for breast cancer.