Low frequency transcranial magnetic stimulation in subacute ischemic stroke: Number of sessions that altered cortical excitability.
Cortical reorganization between both cerebral hemispheres plays an important role in regaining the affected upper extremity motor function post-stroke. The purpose of the current study was to investigate the recommended number of contra-lesion low frequency repetitive transcranial magnetic stimulation (LF-rTMS) sessions that could enhance cortical reorganization post-stroke. Forty patients with right hemiparetic subacute ischemic stroke with an age range between 50-65 yrs were randomly assigned into two equal groups: control (GA) and study (GB) groups. Both groups were treated with a selected physical therapy program for the upper limb. Sham and real contra-lesion LF-rTMS was conducted for both groups daily for two consecutive weeks. Sequential changes of cortical excitability were calculated by the end of each session. The significant enhancement in the cortical excitability was observed at the fourth session in favor of the study group (GB). Sequential rate of change in cortical excitability was significant for the first eight sessions. From the ninth session onwards, no difference could be detected between groups. The pattern of recovery after stroke is extensive and not all factors could be controlled. Application of LF-rTMS in conjugation with a selected physical therapy program for the upper limb from four to eight sessions seems to be efficient.


Blockade of CTLA-4 signals inhibits Th2-mediated murine chronic graft-versus-host disease by an enhanced expansion of regulatory CD8+ T cells.
CTLA-4 (CD152) is thought to be a negative regulator of T cell activation. Little is known about the function of CTLA-4 in Th2-type immune responses. We have investigated the effect of initial treatment with anti-CTLA-4 mAb on murine chronic graft-vs-host disease. Transfer of parental BALB/c splenocytes into C57BL/6 x BALB/c F1 mice induced serum IgE production, IL-4 expression by donor CD4+ T cells, and host allo-Ag-specific IgG1 production at 6-9 wk after transfer. Treatment with anti-CTLA-4 mAb for the initial 2 wk significantly reduced IgE and IgG1 production and IL-4 expression. Analysis of the splenic phenotype revealed the enhancement of donor T cell expansion, especially within the CD8 subset, and the elimination of host cells early after anti-CTLA-4 mAb treatment. This treatment did not affect early IFN-gamma expression by CD4+ and CD8+ T cells and anti-host cytolytic activity. Thus, blockade of CTLA-4 greatly enhanced CD8+ T cell expansion, and this may result in the regulation of consequent Th2-mediated humoral immune responses. These findings suggest a new approach for regulating IgE-mediated allergic immune responses by blockade of CTLA-4 during a critical period of Ag sensitization.


Exclusion and diagnosis of pulmonary embolism by a rapid ELISA D-dimer test and noninvasive imaging techniques within the context of a clinical model.
A negative rapid ELISA D-dimer test alone in out-patients with a low to moderate clinical probability (CP) on pulmonary embolism (PE) is predicted to safely exclude pulmonary embolism. The combination of a negative rapid ELISA D-dimer test and a low to moderate CP on PE followed by compression ultrasonography (CUS) for the detection of deep vein thrombosis (DVT) is safe and cost-effective as it reduces the need for noninvasive imaging techniques to about 50% to 60% of outpatients with suspected PE. A high probability ventilation-perfusion (VP) scan or a positive spiral CT consistent with PE and the detection of DVT by CUS are currently considered to be clear indications for anticoagulant treatment. Subsequent pulmonary angiography (PA) is the gold standard diagnostic strategy to exclude or diagnose PE in suspected outpatients with a negative CUS, a positive rapid ELISA D-dimer test, and a nondiagnostic VP scan or negative spiral CT to prevent overtreatment with anticoagulants. However, the willingness of clinicians and the availability of resources to perform PA is restricted, a fact that has provided an impetus for clinical investigators to search for alternative noninvasive strategies to exclude or detect venous thromboembolism (VTE). Serial CUS testing for the detection of DVT in patients with a low to moderate CP on PE and a nondiagnostic VP scan or negative spiral CT is predicted to be safe and will reduce the need for PA to less than 10% or even less than 5%. This noninvasive serial CUS strategy restricts the need for invasive PA to a minor group of patients (< 5%) with the combination of a low CP on PE and high probability VP scan or the combination of a nondiagnostic VP scan or negative spiral CT and a high CP on PE. Prospective evaluations are warranted to implement and to validate the advantages and the disadvantages of the various combinations of noninvasive strategies and to compare serial CUS testing versus PA in randomized clinical management studies of outpatients with suspected pulmonary embolism.


Self-assembly in supramolecular systems.
The complex structural and functional properties of many natural molecules have spawned innumerable attempts to understand and mimic biological activity. This has often involved preparing extremely complex structures of carefully designed geometries. In natural systems the primary structure of a protein (the amino acid sequence) establishes all of the structural relationships within the molecule, although many of these are not apparent until the molecule folds, coils, or otherwise adopts the appropriate conformation. Nature has selected suitable amino acid sequences for various applications during eons of evolution. In this paper, we report our efforts to achieve similar results by providing all of the required structural elements on a flexible framework. This concept is illustrated in three ways: the design and preparation of a redox-switched vesicle and a small-molecule molecular receptor (both based on the ferrocene system) and of a functional cation channel.


On the value of CTIS imagery for neural-network-based classification: a simulation perspective.
The computed tomography imaging spectrometer (CTIS) is a snapshot hyperspectral imaging system. Its output is a 2D image of multiplexed spatiospectral projections of the hyperspectral cube of the scene. Traditionally, the 3D cube is reconstructed from this image before further analysis. In this paper, we show that it is possible to learn information directly from the CTIS raw output, by training a neural network to perform binary classification on such images. The use case we study is an agricultural one, as snapshot imagery is used substantially in this field: the detection of apple scab lesions on leaves. To train the network appropriately and to study several degrees of scab infection, we simulated CTIS images of scabbed leaves. This was made possible with a novel CTIS simulator, where special care was taken to preserve realistic pixel intensities compared to true images. To the best of our knowledge, this is the first application of compressed learning on a simulated CTIS system.


Flavokawain B, a kava chalcone, induces apoptosis in synovial sarcoma cell lines.
Synovial sarcomas (SS) are soft tissue sarcomas with poor prognosis, displaying a lack of response to conventional cytotoxic chemotherapy. Although SS cell lines have moderate chemosensitivity to isofamide and doxorubicin therapy, the clinical prognosis is still poor. In this article, we showed that flavokawain B (FKB), a novel chalcone from kava extract, potently inhibits the growth of SS cell lines SYO-I and HS-SY-II through induction of apoptosis. Treatment with FKB increased caspase 8, 9, and 3/7 activity compared to vehicle-treated controls, indicating that both extrinsic and intrinsic apoptotic pathways were activated. Furthermore, FKB treatment of both cell lines resulted in increased mRNA and protein expression of death receptor-5 and the mitochondrial pro-apoptotic proteins Bim and Puma, while down-regulating the expression of an inhibitor of apoptosis, survivin in a dose-dependent manner. Our results suggest the natural compound FKB has a pro-apoptotic effect on SS cell lines. FKB may be a new chemotherapeutic strategy for patients with SS and deserves further investigation as a potential agent in the treatment of this malignancy.


[Doppler ultrasound monitoring of cerebral circulation during neonatal intensive care with special reference to artificial respiration].
Doppler sonographic data from routine cerebral ultrasonic examination of mechanically ventilated premature neonates were analyzed in order to find out which intensive care influence factors take effect on the cerebral circulation. It was to be demonstrated if Doppler sonographic results are changed by current intensive medical influences especially mechanically ventilation. In 24 premature neonates (mean gestational age 29.6 +/- 4 weeks, mean birth weight 1367 +/- 660 g) treated with mechanical ventilation for IRDS cerebral blood flow parameters were assessed by pulsed Doppler sonography. A single Doppler sonographic investigation was performed during the first week of life (median: day 5). Doppler flow velocity waveforms were obtained, and resistance index (RI) and pulsatility index (PI) values were calculated from the anterior cerebral arteries (ACA) as well as from the internal carotid artery (ACI). Oscillometrically measured blood pressure, pH, pCO2, and parameters of mechanical ventilation were registered. Besides the well established influence of pCO2 and blood pressure parameters of mechanical ventilation PEEP and time of inspiration have an influence on cerebral blood flow. Our results demonstrate the impact of mechanical ventilation on cerebral blood flow and therefore indicate the necessity of Doppler sonographic monitoring during mechanical ventilation. To our knowledge this is the first report about the influence of mechanical ventilation on cerebral blood flow in neonates.


Subpopulation-specific machine learning prognosis for underrepresented patients with double prioritized bias correction.
Many clinical datasets are intrinsically imbalanced, dominated by overwhelming majority groups. Off-the-shelf machine learning models that optimize the prognosis of majority patient types (e.g., healthy class) may cause substantial errors on the minority prediction class (e.g., disease class) and demographic subgroups (e.g., Black or young patients). In the typical one-machine-learning-model-fits-all paradigm, racial and age disparities are likely to exist, but unreported. In addition, some widely used whole-population metrics give misleading results. We design a double prioritized (DP) bias correction technique to mitigate representational biases in machine learning-based prognosis. Our method trains customized machine learning models for specific ethnicity or age groups, a substantial departure from the one-model-predicts-all convention. We compare with other sampling and reweighting techniques in mortality and cancer survivability prediction tasks. We first provide empirical evidence showing various prediction deficiencies in a typical machine learning setting without bias correction. For example, missed death cases are 3.14 times higher than missed survival cases for mortality prediction. Then, we show DP consistently boosts the minority class recall for underrepresented groups, by up to 38.0%. DP also reduces relative disparities across race and age groups, e.g., up to 88.0% better than the 8 existing sampling solutions in terms of the relative disparity of minority class recall. Cross-race and cross-age-group evaluation also suggests the need for subpopulation-specific machine learning models. Biases exist in the widely accepted one-machine-learning-model-fits-all-population approach. We invent a bias correction method that produces specialized machine learning prognostication models for underrepresented racial and age groups. This technique may reduce potentially life-threatening prediction mistakes for minority populations.


Biochemical and Structural Characterization of the Carbohydrate Transport Substrate-binding-protein SP0092.
Development of new antimicrobials and vaccines for Streptococcus pneumoniae (pneumococcus) are necessary to halt the rapid rise in multiple resistant strains. Carbohydrate substrate binding proteins (SBPs) represent viable targets for the development of protein-based vaccines and new antimicrobials because of their extracellular localization and the centrality of carbohydrate import for pneumococcal metabolism, respectively. Described here is a rationalized integrated protocol to carry out a comprehensive characterization of SP0092, which can be extended to other carbohydrate SBPs from the pneumococcus and other bacteria. This procedure can aid the structure-based design of inhibitors for this class of proteins. Presented in the first part of this manuscript are protocols for biochemical analysis by thermal shift assay, multi angle light scattering (MALS), and size exclusion chromatography (SEC), which optimize the stability and homogeneity of the sample directed to crystallization trials and so enhance the probability of success. The second part of this procedure describes the characterization of the SBP crystals using a tunable wavelength anomalous diffraction synchrotron beamline, and data collection protocols for measuring data that can be used to resolve the crystallized protein structure.


Effects of gait rehabilitation with a footpad-type locomotion interface in patients with chronic post-stroke hemiparesis: a pilot study.
We developed a footpad-type locomotion interface called the GaitMaster. The purpose of this pilot study was to examine the effects of gait rehabilitation using the GaitMaster in chronic stroke patients. Randomized cross-over design. An outpatient department. Twelve patients with chronic post-stroke hemiparesis. In group A, patients underwent an 'intervention phase' followed by a 'non-intervention phase', whereas in group B, patients underwent the non-intervention phase first, followed by the intervention phase. In the four- or six-week intervention phase, participants underwent twelve 20-minute sessions of gait rehabilitation using the GaitMaster4. We measured gait speed and timed up-and-go test. No differences between the two groups were observed in the baseline clinical data. For the combined groups A and B, the maximum gait and timed up-and-go test speeds improved significantly only in the intervention phase (P = 0.0001 and P = 0.003, respectively). The percentages of improvement from baseline at the end of GaitMaster training were 16.6% for the maximum gait speed and 8.3% for the timed up-and-go test. The effect size for GaitMaster4 training was 0.58 on the maximum gait speed and 0.43 on the timed up-and-go test. This pilot study showed that gait rehabilitation using the GaitMaster4 was a feasible training method for chronic stroke patients. Calculation of the sample size indicated that a sample size of 38 participants would be adequate to test a null hypothesis of nil benefit additional to routine rehabilitation for chronic stroke patients in a future randomized controlled trial.


Cutaneous and Mucosal Melanomas of Uncommon Sites: Where Do We Stand Now?
Melanomas arising at uncommon sites include a group of lesions related to unusual localizations in specific ethnic groups. The rarity of the disease often represents a limit to the participation of patients in specific trials. However, this peculiar genetic scenario has important therapeutic implications regarding new oncologic therapies. The aim of this article is to review the clinical features, somatic alterations and therapeutic options for melanomas of uncommon sites. They can be classified as cutaneous and mucosal lesions affecting the nail apparatus, palms/soles, oral mucosa, genital area and scalp. The prognosis may be worse compared to melanomas of other districts, and a prompt diagnosis may dramatically influence the outcome. Dermatologists and oncologists should therefore distinguish this melanoma subgroup in terms of surgical intervention and medical treatment. Due to the lack of mutations in genes usually found in cutaneous melanomas, the discovery of novel targets is required to develop new strategies and to change the prognosis of non-responders or wild-type patients.


Population-based rates of revision of primary total hip arthroplasty: a systematic review.
Most research on failure leading to revision total hip arthroplasty (THA) is reported from single centers. We searched PubMed between January 2000 and August 2010 to identify population- or community-based studies evaluating ten-year revision risks. We report ten-year revision risk using the Kaplan-Meier method, stratifying by age and fixation technique. Thirteen papers met the inclusion criteria. Cemented prostheses had Kaplan-Meier estimates of revision-free implant survival of ten years ranging from 88% to 95%; uncemented prostheses had Kaplan-Meier estimates from 80% to 85%. Estimates ranged from 72% to 86% in patients less than 60 years old and from 90 to 96% in older patients. Data reported from national registries suggest revision risks of 5 to 20% ten years following primary THA. Revision risks are lower in older THA recipients. Uncemented implants may have higher ten-year rates of revision, regardless of age.


Accessing single nucleotide polymorphisms in genomic DNA by direct multiplex polymerase chain reaction amplification on oligonucleotide microarrays.
This study introduces a DNA microarray-based genotyping system for accessing single nucleotide polymorphisms (SNPs) directly from a genomic DNA sample. The described one-step approach combines multiplex amplification and allele-specific solid-phase PCR into an on-chip reaction platform. The multiplex amplification of genomic DNA and the genotyping reaction are both performed directly on the microarray in a single reaction. Oligonucleotides that interrogate single nucleotide positions within multiple genomic regions of interest are covalently tethered to a glass chip, allowing quick analysis of reaction products by fluorescence scanning. Due to a fourfold SNP detection approach employing simultaneous probing of sense and antisense strand information, genotypes can be automatically assigned and validated using a simple computer algorithm. We used the described procedure for parallel genotyping of 10 different polymorphisms in a single reaction and successfully analyzed more than 100 human DNA samples. More than 99% of genotype data were in agreement with data obtained in control experiments with allele-specific oligonucleotide hybridization and capillary sequencing. Our results suggest that this approach might constitute a powerful tool for the analysis of genetic variation.


The effects of hypotonic and isotonic negative contrast agent on gastrointestinal distention and physiological intake of 18F-FDG.
The objective of this study was to explore the effects of hypotonic and isotonic oral mannitol on intestinal distention and fluorine-18 fluorodeoxyglucose ((18)F-FDG) intake in PET/computed tomography (CT) imaging. A total of 124 patients without gastrointestinal disease were evaluated with PET/CT imaging and divided into four groups using a random number table. Group 1 drank plain water, group 2 drank 2.5% mannitol, group 3 drank 2.5% mannitol and also received 10 mg of scopolamine butylbromide, and group 4 drank 2.5% mannitol and also received 20 mg of scopolamine butylbromide. The patients in each group underwent PET/CT imaging 50 min after (18)F-FDG injection. In these groups, differences such as age, sex, disease distribution, oral liquid amount, and adverse reactions were compared. Gastrointestinal distention and F-FDG intake were analyzed by two experts in nuclear medicine by visual observation. Data were statistically analyzed using a rank-sum test, R×C contingency table, one-way analysis of variance, and a paired t-test. There were no significant differences in blood glucose levels after oral administration of 2.5% mannitol (t=0.62, P>0.05). Gastrointestinal distention of patients in groups 2, 3, and 4 was superior to that of patients in group 1 (P<0.05/6). In addition to the sigmoid colon and rectum, (18)F-FDG intake in each part of the gastrointestinal tract in groups 2, 3, and 4 was less than that in group 1 (P<0.05/6). Patients in group 4 experienced significantly more adverse reactions compared with patients in the other groups (P<0.05). Oral negative contrast agent and hypotonic bowel preparation decreased the physiological intake of (18)F-FDG, increased the distention of the gastrointestinal tract, and thus improved the image quality.


An innovative fixation technique by osteosuture in a young athletic female patient with coracoid process fracture: a case report.
Coracoid process fractures are uncommon lesions but are frequently associated with an acromioclavicular dislocation. The aim of this article is to report our experience of an innovative fixation technique by osteosuture in a young athletic female patient presenting a displaced fracture of the coracoid process on the insertion footprint of coracoclavicular ligaments, with no breach of continuity of the lower coracoid cortex. She also had a roockwood type 3 acromioclavicular dislocation. After a deltopectoral approach, the fracture was reduced to the anatomical position and stabilized by a first lacing, using a non-absorbable large caliber thread passing under the mid part of the coracoid process between the 2 coracoclavicular ligaments. A second lacing passing under the coracoid process and through the trapezoid ligament, and a third one through the conoïd ligament. At 6 months, the fracture was consolidated and the constant score was 100/100. This innovative fixation provides good clinical and radiological results in the short and medium term.


NSAIDs and gastrointestinal complications: new clinical challenges.
The use of NSAIDs is associated with significant risk of upper gastrointestinal ulcer, bleeding, perforation and stricture. NSAIDs vary in their analgesic and anti-inflammatory properties; choice of NSAID, dosage and duration are the cornerstone of rationale therapy. Proton pump inhibitors are widely used to reduce the risk of serious events, despite the paucity of data that indicates that they are effective for this indication. The existing recommendations for prevention of gastrointestinal toxicity are reviewed in this article, in light of new clinical challenges posed by the emerging data regarding competing cardiovascular risk. Strategies are proposed for common clinical prescribing dilemmas, new clinical risk groups are identified and preventative strategies for these special populations are recommended.


The ORF I and II proteins of Commelina yellow mottle virus are virion-associated.
Antibodies were prepared against bacterially expressed Commelina yellow mottle badnavirus (CoYMV) proteins. Antiserum against purified virions and antiserum against the C-terminus of the putative coat protein-encoding region of ORF III detected the same virus-specific proteins, indicating that the CoYMV coat protein is encoded in ORF III. In addition to the two major forms of the coat protein (37 and 39 kDa), several high molecular weight virus-specific proteins were detected when virions were isolated without chloroform treatment. These proteins are possible ORF III polyprotein processing intermediates and might be associated with "immature" virions which are eliminated by chloroform treatment. As predicted by the genomic sequence, a 20-kDa virus-specific protein was detected by an antiserum raised against the C-terminus of the putative ORF I protein. Results of filtration experiments suggest that the ORF I protein is equally associated with virions and with plant component(s). The association between the ORF I protein and the virions was further confirmed using immunosorbent electron microscopy and immunogold labeling. The ORF I protein was not detected in virus preparations treated with chloroform, and colocalized with virions containing immature coat protein on sucrose-cesium sulfate density gradients, suggesting that it is associated with immature virions. An antiserum raised against the putative ORF II gene product detected a 15-kDa virus-specific protein whose association with the virions was unaffected by chloroform treatment. The ORF II protein was found to be sensitive to some protease(s) that copurified with the virions, and protease inhibitors preventing this degradation have been identified.


Numerical simulations of perforated plate liners: Analysis of the visco-thermal dissipation mechanisms.
In the linear regime and in the absence of mean flow, the impedance of perforated liners is driven by visco-thermal effects. In this paper, two numerical models are employed for predicting these visco-thermal losses. The first model is the linearized compressible Navier-Stokes equations (LNSE), solved in the frequency domain. The second model is the Helmholtz equation with a visco-thermal boundary condition, accounting for the influence of the acoustic boundary layers. These models are compared and validated against measurements. The quantitative analysis of the dissipation rate due to viscosity, computed from the LNSE solutions of four perforated plates, highlights significant differences between the edge effects of a macro- and a micro-perforated plate. In the latter case, a jet is present at the entrances of the perforation. In contrast, the proposed numerical method to calculate the impedance of perforated liners, based on the Helmholtz equation and a visco-thermal boundary condition, is found to be computationally cheaper and to provide reliable predictions.


Improvement of nitrogen retention by arginine and glycine supplementation and its relation to collagen synthesis in traumatized mature and aged rats.
The effect of arginine and glycine supplementation on reducing body protein losses and on enhancing wound healing after trauma was studied in two age groups. Mature (4 month) and aged (24 month) Fischer 344 male rats were fed a diet containing 25% casein and 0.4% methionine with or without supplementation with 2.4% arginine . HCl and 1.0% glycine for 7 days before and after laparotomy. Nitrogen (N) balance studies (N intake - urinary N) were carried out during the last three pretrauma days and seven posttrauma days. The supplemented rats retained significantly more N than the controls and the mature rats significantly more than the aged rats. Polyvinyl alcohol sponges, implanted during surgery and removed from the rats on day 3 or 7 after surgery, were analyzed for hydroxyproline content and for the ratios of type III/type I collagen synthesized. Sponges obtained from the supplemented and the mature rats had more hydroxyproline and higher ratios of type III/type I collagen than those from the control and the aged rats. The beneficial effect of arginine and glycine supplementation on improving N retention in traumatized rats appears to be due, at least in part, to increased collagen synthesis in wounds.


Expression of a recombinant breast tumor-associated mucin fusion protein in Escherichia coli exposes the tumor-specific epitope.
Mucins are highly immunogenic glycoproteins that are abundantly expressed by breast carcinomas and other carcinomas. The fact that deglycosylated normal mucin can induce tumor-specific monoclonal antibodies indicates that tumor-specific epitopes are hidden in the fully glycosylated form. Using recombinant DNA techniques, a fragment of mucin tandem repeats was inserted into pMal-p, an Escherichia coli expression vector, and resulted in the expression of an unglycosylated maltose-binding protein-mucin fusion protein. This fusion protein has been purified and showed strong affinity to breast tumor-specific monoclonal antibody SM3. The antisera against this recombinant mucin fusion protein recognized all breast tumor cell lines we tested. Competition assay with monoclonal antibody SM3 shows that anti-recombinant mucin fusion protein binds the epitope that SM3 binds. These results confirm the hypothesis that unglycosylated mucin contains a tumor-specific epitope. This leads to the possibility that recombinant mucin may be used to develop vaccines against breast cancer and cytotoxic T-lymphocyte lines for immunotherapy of breast cancer.


A modification of Peto's nonparametric estimation of survival curves for interval-censored data.
Peto (1973, Applied Statistics, 22, 86-91) gave a nonparametric generalized maximum-likelihood estimate of the survival function for interval-censored data. His method has a tendency to concentrate probability masses at the endpoints of the intervals, even for the ordinary grouped data, instead of spreading them through the intervals, as one might expect them to be in the underlying distribution. We describe a modification that overcomes this. The new estimate reduces to the standard binomial estimate when applied to grouped data. It also reduces to the Kaplan-Meier estimate when applied to survival data that consist of only exact or right-censored observations. Both estimates are maximum-likelihood estimates but are based on different interpretations of the endpoints of the intervals.


Malignant melanoma in the penguin: characterization of the clinical, histologic, and immunohistochemical features of malignant melanoma in 10 individuals from three species of penguin.
Malignant melanomas are aggressive neoplasms that are relatively common in penguins compared to other avian species. In this study, the clinical and pathologic characteristics of melanocytic neoplasms in five macaroni (Eudyptes chrysolophus), three rock hopper (Eudyptes chrysocome), and two Humboldt (Spheniscus humboldti) penguins are described. Tumors most commonly occurred in the skin of the foot or hock, and were seen in the subcutaneous muscle, especially near the beak/oral cavity. Gross lesions were usually heavily pigmented, becoming raised and ulcerated over time. Humboldt penguins had a unique presentation, forming variably pigmented, cornified lesions in the inguinal area. Original case materials were obtained from all but two cases, and were assessed to define the characteristics of malignancy, evaluate four immunohistochemical markers for melanoma, and look for factors useful to informing prognosis and clinical decisions. Diagnosis was made histologically, based on morphologic features and pigmentation. Though not necessary for diagnosis, PNL-2 was found to be a useful immunohistochemical marker. HMB-45 showed unreliable positive labelling and S-100, Melan-A and Ki67 were not useful. Several factors were associated with prognosis, including gross surface dimension, mitotic index, depth of neoplastic cell invasion, and degree of surface ulceration. Metastatic spread occurred to the liver, lung, adrenal gland, brain, and bone; all lesions showed positive labelling to PNL-2. The average survival after diagnosis was 7 mo, though complete surgical excision of tumors less than 2.0 cm was curative in two cases and radiation therapy prolonged survival in one penguin. The underlying pathogenesis associated with the high prevalence of melanocytic neoplasms in captive penguins could not be identified. Three different molecular methods were performed to look for viral particles and results were negative. Advanced age is the most probable associated risk factor; ultraviolet light and chlorine exposure, viral induction, and genetic predisposition were ruled out or considered unlikely.


Severe Dizziness and Hypereosinophilia: Coincidence or Complication? A Case Report.
Hypereosinophilia is a common issue in medicine. One rare cause is myeloproliferative neoplasm with PDGFRA rearrangement. In these patients, the gold standard for therapy is low-dose imatinib. We present the case of a patient with a new diagnosis of myeloproliferative neoplasm following an unconventional diagnostic pattern, which developed clinically relevant unexplained dizziness a week after starting treatment. Our case presented with lower back pain and multiple bone lesions at MRI investigation. Bone marrow and cytogenetic analysis led to the diagnosis of myeloproliferative neoplasm with PDGFRA rearrangement. We started a treatment with a tyrosine kinase inhibitor (imatinib), and the patient noticed an onset of severe, persistent and intense dizziness, which was more intense with closed eyes. Diagnostic tests were not conclusive, and dizziness persisted at 48 months of follow-up. In conclusion, clinically relevant dizziness was never described in patients with myeloproliferative neoplasm. Even if the exact physiopathological mechanism is not clear, clinicians should know that hypereosinophilia could lead to central nervous system damage.


Determination of the cuticula thickness of human and porcine hairs and their potential influence on the penetration of nanoparticles into the hair follicles.
An efficient penetration and long-term storage of topically applied substances is important for drug delivery in medical treatment and cosmetics. It has recently become apparent that the hair follicles represent an efficient and long-term reservoir for topically applied substances. It was found that particles sized 300-600 nm penetrate more efficiently into the hair follicles than smaller or larger particles. In the present paper, the hair surface structure of human and porcine hairs was analyzed by electron microscopy. It could be observed that the thickness of the cuticula corresponds to the optimal size of the nanoparticles for penetration into the hair follicles. Additionally, it could be demonstrated that the cuticula of human vellus and terminal hairs were of similar thickness (approx. 530 nm), while the thickness of the cuticula obtained from porcine ear bristles were slightly thinner (approx. 320 nm).


Carbohydrate counting-1: South Asian framework.
Carbohydrate counting or "carb counting" is a meal planning technique for persons with diabetes for managing blood glucose levels by tracking the grams of carbohydrate consumed at meals. It has shown to improve glycaemic control and glycaemic variability and decreases risk of hypoglycaemia in persons with diabetes especially on insulins. It needs basic education of the patient regarding meal plan, assessment of carbohydrate content of various foods and also exchange lists. It also gives flexibility of food choice, helps to identify patterns in blood glucose levels and adjustment of pre meals short acting insulins as related to food intake. In this short review we have summarised basic principles of carbohydrate counting, its application in clinical practice and also exchange lists primarily pertaining to South Asian population.


Automated gamma knife radiosurgery treatment planning with image registration, data-mining, and Nelder-Mead simplex optimization.
Gamma knife treatments are usually planned manually, requiring much expertise and time. We describe a new, fully automatic method of treatment planning. The treatment volume to be planned is first compared with a database of past treatments to find volumes closely matching in size and shape. The treatment parameters of the closest matches are used as starting points for the new treatment plan. Further optimization is performed with the Nelder-Mead simplex method: the coordinates and weight of the isocenters are allowed to vary until a maximally conformal plan specific to the new treatment volume is found. The method was tested on a randomly selected set of 10 acoustic neuromas and 10 meningiomas. Typically, matching a new volume took under 30 seconds. The time for simplex optimization, on a 3 GHz Xeon processor, ranged from under a minute for small volumes (<1000 cubic mm, 2-3 isocenters), to several tens of hours for large volumes (>30,000 cubic mm, >20 isocenters). In 8/10 acoustic neuromas and 8/10 meningiomas, the automatic method found plans with conformation number equal or better than that of the manual plan. In 4/10 acoustic neuromas and 5/10 meningiomas, both overtreatment and undertreatment ratios were equal or better in automated plans. In conclusion, data-mining of past treatments can be used to derive starting parameters for treatment planning. These parameters can then be computer optimized to give good plans automatically.


Disparity in Utilization of Multiagent Therapy for Acute Promyelocytic Leukemia in the United States.
Despite high rate of cure in acute promyelocytic leukemia (APL) in clinical trials, outcomes in real-world practice are dismal. We utilized National Cancer Database (NCDB) to explore utilization of multiagent therapy in APL and identify any disparities in treatment in real-world practices. NCDB categorizes use of systemic chemotherapy into single agent versus multiagent therapy. Some patients received hormonal therapy, immunotherapy, and unknown therapy; details of these treatments could not be ascertained. We therefore used multiple logistic regression analysis to evaluate effects of covariates on the probability of multiagent therapy use in 6678 patients. Compared to patients >60 years, patients aged 0 to 18 years (hazard ratio[HR] 3.2, 95% confidence interval [CI] 1.8-5.5, P< .0001), 19 to 40 years (HR 1.6, 95% CI 1.03-2.54, P= .03), and 41 to 60 years (HR 1.6, 95% CI 1.3-1.9, P< .0001) were more likely to receive multiagent therapy. Patients with Charlson comorbidity index (CCI) of 0 (HR 1.6, 95% CI 1.2-2.3, P= .001) and CCI of 1 (HR 1.4, 95% CI 1.0-1.9, P= .04) had a higher likelihood of receiving multiagent therapy than patients with CCI ≥ 3. Patients treated at academic cancer centers, compared to those treated at community cancer center (HR 0.5, 95% CI 0.3-0.7, P= .001), comprehensive community cancer center (HR 0.7, 95% CI 0.6-0.8, P< .0001), and integrated network cancer center (HR 0.8, 95% CI 0.6-0.9, P= .02) were more likely to be treated with multiagent therapy. Compared to the patients with private insurance, those with Medicaid had increased likelihood (HR 1.2, 95% CI 1.0-1.4, P= .04) whereas uninsured patients had a lower likelihood of receiving multiagent therapy (HR 0.6, 95% CI 0.5-0.8, P= .0005). To our knowledge, this study is the first and the largest scale analysis of treatment practices in APL in real-world practices. Our findings highlight significant disparities in treatment of APL based on age, insurance, and health-system factors.


Estimating Pavement Roughness by Fusing Color and Depth Data Obtained from an Inexpensive RGB-D Sensor.
Measuring pavement roughness and detecting pavement surface defects are two of the most important tasks in pavement management. While existing pavement roughness measurement approaches are expensive, the primary aim of this paper is to use a cost-effective and sufficiently accurate RGB-D sensor to estimate the pavement roughness in the outdoor environment. An algorithm is proposed to process the RGB-D data and autonomously quantify the road roughness. To this end, the RGB-D sensor is calibrated and primary data for estimating the pavement roughness are collected. The collected depth frames and RGB images are registered to create the 3D road surfaces. We found that there is a significant correlation between the estimated International Roughness Index (IRI) using the RGB-D sensor and the manual measured IRI using rod and level. By considering the Power Spectral Density (PSD) analysis and the repeatability of measurement, the results show that the proposed solution can accurately estimate the different pavement roughness.


Marketing in the HMO industry: an analysis of spending patterns and enrollment growth results.
The purpose of this paper is to assess the level of marketing spending in the HMO industry and the enrollment growth HMOs have achieved in return for their marketing dollars. This study identifies industry norms that are designed to assist HMOs in the evaluation of their marketing performance. The study is based on data from 1985 to 1986 covering approximately half the HMOs in the country and comprising a substantial proportion of industry-wide enrollment (Table 1). The analyses are designed to allow operational HMOs to compare their marketing efforts, enrollment growth, and marketing costs per new member with industry norms within similar age, model type, enrollment level, and geographic categories. The marketing expenses provided by each HMO are an aggregate figure including sales staff salaries, benefits and commissions, advertising, costs for the production and printing of marketing materials, and all other expenses directly related to the marketing effort. Components of the aggregate marketing expenses, such as the amount spent on advertising versus sales staff compensation, were not available.


Laparotomy Closure: A Review of Available Education Training Models.
As studies continue to provide advanced knowledge concerning abdominal wall closure after laparotomy, there have been many improvements in surgical techniques and recommended closure materials. However, there continues to be a high rate of incisional hernias following exploratory laparotomies. The goal of this review is to provide a comprehensive assessment of available educational models for laparotomy closure. A comprehensive literature review was made using PubMed, Cochrane, and NCBI MeSH databases to find the most relevant articles associated with various abdominal closure models using specific keywords. Human cadaver, animal, synthetic, and virtual reality models were reviewed. Strengths and limitations of each model were described. Each model has practical benefits in its ability to mimic in vitro anatomy and the experiential similarities to actual laparotomy closure. However, there are also limitations and potential cost-prohibitive factors for individual models. Overall, while there have been some advances in synthetic and virtual models, human cadaver and porcine models remain the most similar to human abdominal wall closures.


Hepatic fibrogenesis.
The main pathogenic mechanism of the progress of chronic hepatitis into cirrhosis is represented by fibrogenesis. Stopping this progress is the subject of much research and would. The hepatic stellate cells play a central role based on their ability to undergo activation following liver injury from any cause is important. On the basis of improved knowledge of the pathophysiology of fibrogenesis, the development of new therapeutic approaches will become possible. (Fig. 3, Ref. 50.)


Lack of autocrine effects of IL-6 on human bone marrow stromal osteoprogenitor cells.
Interleukin-6 (IL-6) produced by osteoblastic cells plays an important role in the regulation of bone remodeling, mainly by stimulating osteoclast action. Although the IL-6 receptor is also found in osteoblastic cells, whether IL-6 exerts autocrine effects on osteoblastic cells is a matter of debate. This led us to study the effects of IL-6 on proliferation, osteoblastic activity as well as mRNA expression of various osteoblastic proteins in human bone marrow stromal osteoprogenitor cells (hBMSC). IL-6 did not affect cell proliferation assessed by [3H]-thymidine incorporation and osteoblastic activity determined by alkaline phosphatase activity and 45Ca incorporation. The expression of mRNAs for alkaline phosphatase, alpha 1 (I)-collagen, osteopontin and decorin also did not change significantly by IL-6 treatment. These results show that IL-6 does not have a significant autocrine role in regard to proliferation and osteoblastic activity of hBMSC.


[Effects of residues of organochlorine pesticides on reproductive endocrine in human].
To explore effects of residues of organochlorine pesticides on reproductive endocrine in human. The accumulative levels of the pesticides in the pregnant women's venous blood were determined and were grouped to understand the associations among the pesticides, hormones, and genes. (1) With the increase of blood burden of organochlorine pesticides, levels of the hormones such as follicle stimulating hormone (FSH), estradiol (E2) and progesterone (P) in the maternal blood and FSH, luteinizing hormone (LH) and E2 in the umbilical cord blood increased in dose-effect manner, respectively. However, the hormones, for example, LH in the women blood and P in the cords blood decreased respectively with the rising pesticides' levels and an obvious dose-effect relationship was found. (2) The expressional abundances of alpha-estrogen receptor (alpha-ER), beta-endorphin (beta-EP) and gonadotropin releasing hormone (GnRH) in the placentae and alpha-ER and beta-EP in the cord tissues went up respectively in dose-effect manner following the rising pesticides' burdens. (3) The times of the previous adverse pregnancy outcomes increased with the increase of the residues' burdens and there were significant differences between the control and various residue groups, but the times in the high-residue was smaller than that in the mid-residue group (P < 0.01). The average weights of the newborn in various residue groups were heavier comparing to the control. There was no significant difference between the high residue group and the control. However, significances existed among the low, intermediate, and control group (P < 0.05). Moreover, the rank from high to low was the low-residue, mid-residue and high residue group. The residues of organochlorine pesticides (DDT and BHC and their metabolites) possess reproductive and developmental toxicities, and present mostly the estrogenic activity under the joint exposure in which the total BHC concentration was higher than that of the total DDT in maternal blood.


The self-reported likelihood of patient delay in breast cancer: new thoughts for early detection.
Delayed presentation of self-discovered breast symptoms influences stage of cancer at diagnosis and decreases breast cancer survival. A total of 699 asymptomatic women (black, white, and Latino), recruited in community settings and stratified by age, income, and educational level, were surveyed for their likelihood to delay (J-Delay scale) in the event of a breast symptom discovery. Models of likelihood were tested with logistic regression analyses. A total of 166 women (23.7%) reported likelihood to delay. Lower income, lower educational level, self identification as Latino or black, experienced prejudice in care delivery, perceived lack of access to health care, fatalism about breast cancer, poor health care utilization habits, self-care behavior, spouse/partner and employer perceived constraints, problem-solving style, and a lack of knowledge of breast cancer's presenting symptoms were associated with likelihood to delay. A combined sample multiple logistic regression model correctly predicted 40.6% of women reporting a likelihood to delay, 94.9% of those not likely to delay, and 82.4% (551 of 669) of cases overall. Self-reported likelihood of patient delay is measurable in advance of symptom occurrence, and this measure is consistent with behavioral and knowledge variables previously linked with advanced breast cancer at diagnosis.


Precise definitions of some terminology for longitudinal clinical trials: subjects, patient populations, analysis sets, intention to treat, and related terms.
Biostatisticians recognize the importance of precise definitions of technical terms in randomized controlled clinical trial (RCCT) protocols, statistical analysis plans, and so on, in part because definitions are a foundation for subsequent actions. Imprecise definitions can be a source of controversies about appropriate statistical methods, interpretation of results, and extrapolations to larger populations. This paper presents precise definitions of some familiar terms and definitions of some new terms, some perhaps controversial. The glossary contains definitions that can be copied into a protocol, statistical analysis plan, or similar document and customized. The definitions were motivated and illustrated in the context of a longitudinal RCCT in which some randomized enrollees are non-adherent, receive a corrupted treatment, or withdraw prematurely. The definitions can be adapted for use in a much wider set of RCCTs. New terms can be used in place of controversial terms, for example, subject. We define terms specifying a person's progress through RCCT phases and that precisely define the RCCT's phases and milestones. We define terms that distinguish between subsets of an RCCT's enrollees and a much larger patient population. 'The intention-to-treat (ITT) principle' has multiple interpretations that can be distilled to the definitions of the 'ITT analysis set of randomized enrollees'. Most differences among interpretations of 'the' ITT principle stem from an RCCT's primary objective (mainly efficacy versus effectiveness). Four different 'authoritative' definitions of ITT analysis set of randomized enrollees illustrate the variety of interpretations. We propose a separate specification of the analysis set of data that will be used in a specific analysis. Copyright © 2016 John Wiley & Sons, Ltd.


[Prevalence of nonalcoholic fatty liver disease in patients with polycystic ovary syndrome: a case-control study].
To explore the prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with polycystic ovary syndrome (PCOS). A case-control study employing 60 nonpregnant patients with PCOS and 60 non-pregnant patients without PCOS as control was conducted to compare the prevalence of NAFLD. The aminotransferase (ALT), fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels were (29 +/- 15) U/L, (19 +/- 12) mU/L and 0.47 +/- 0.29 in PCOS group, which were significantly higher (P < 0.05) than corresponding parameters in control group [(15 +/- 13) U/L, (11 +/- 8) mU/L and 0.31 +/- 0.21)]. The occurrence of insulin resistance and NAFLD was63% (38/60) and 42% (25/60), higher than those in control group [35% (21/60) and 20% (12/60), P < 0.05]. The increment of ALT was 40% (24/60) in PCOS group, higher than that of 3% (2/60) in control group (P < 0.01). Compared with patients without NAFLD, patients with NAFLD had significantly increased body mass index (P < 0.01), waist-hip ratio, ALT, C-reaction protein, fasting insulin, insulin and HOMA-IR levels 2 hours after oral glucose tolerance test (P < 0. 05). The increased prevalence of NAFLD in PCOS patients suggests an association between these two conditions and the necessity of hepatic screening among PCOS patients for potential NAFLD.


A comparison of Goldmann III, V and spatially equated test stimuli in visual field testing: the importance of complete and partial spatial summation.
Goldmann size V (GV) test stimuli are less variable with a greater dynamic range and have been proposed for measuring contrast sensitivity instead of size III (GIII). Since GIII and GV operate within partial summation, we hypothesise that actual GV (aGV) thresholds could predict GIII (pGIII) thresholds, facilitating comparisons between actual GIII (aGIII) thresholds with pGIII thresholds derived from smaller GV variances. We test the suitability of GV for detecting visual field (VF) loss in patients with early glaucoma, and examine eccentricity-dependent effects of number and depth of defects. We also hypothesise that stimuli operating within complete spatial summation ('spatially equated stimuli') would detect more and deeper defects. Sixty normal subjects and 20 glaucoma patients underwent VF testing on the Humphrey Field Analyzer using GI-V sized stimuli on the 30-2 test grid in full threshold mode. Point-wise partial summation slope values were generated from GI-V thresholds, and we subsequently derived pGIII thresholds using aGV. Difference plots between actual GIII (aGIII) and pGIII thresholds were used to compare the amount of discordance. In glaucoma patients, the number of 'events' (points below the 95% lower limit of normal), defect depth and global indices were compared between stimuli. 90.5% of pGIII and aGIII points were within ±3 dB of each other in normal subjects. In the glaucoma cohort, there was less concordance (63.2% within ±3 dB), decreasing with increasing eccentricity. GIII found more defects compared to GV-derived thresholds, but only at outermost test locations. Greater defect depth was found using aGIII compared to aGV and pGIII, which increased with eccentricity. Global indices revealed more severe loss when using GIII compared to GV. Spatially equated stimuli detected the greatest number of 'events' and largest defect depth. Whilst GV may be used to reliably predict GIII values in normal subjects, there was less concordance in glaucoma patients. Similarities in 'event' detection and defect depth in the central VF were consistent with the fact that GIII and GV operate within partial summation in this region. Eccentricity-dependent effects in 'events' and defect depth were congruent with changes in spatial summation across the VF and the increase in critical area with disease. The spatially equated test stimuli showed the greatest number of defective locations and larger sensitivity loss.


Therapeutic Effects and Mechanism of Liraglutide in Rats with Type 2 Diabetes and Metabolic-associated Fatty Liver Disease.
SREBP-1c/Insig/SCAP acts as a lipid de novo synthesis pathway, and its factors are highly expressed in the endoplasmic reticulum. At present, this pathway has become a research hotspot in the development of metabolic-associated fatty liver disease. However, there are few studies on how various factors in this pathway change after endoplasmic reticulum stress; in particular, the role of the insulin-inducing gene-1 (Insig-1) has not been elucidated in detail. The aim of the study was to investigate whether liraglutide has a therapeutic effect on rats with T2DM and MAFLD, and to further study its possible mechanism. Rats in the control group and modeling group were fed with normal diet and high-sugar and high-fat diet, respectively. After one month, the mice in the modeling group were injected with 35mg/kg STZ intraperitoneally to establish the model of type 2 diabetes mellitus. T2DM and MAFLD rats were randomly divided into three groups: model group, low-dose liraglutide group, and high-dose liraglutide group. Fasting blood glucose, fasting insulin, blood lipid profile, alanine aminotransferase, and aspartate aminotransferase were measured at the end of 8th week. Paraffin sections were obtained from the same part of the liver of rats in each group and observed by electron microscope after HE staining. Western blot was used to detect the expression of endoplasmic reticulum stress index (GRP78) and negative feedback index of lipid synthesis (Insig-1) in each group. Liver tissue from the drug intervention groups demonstrated a decrease in lipid droplet vacuoles, and the hepatocytes were arranged neatly again. While the expression of GRP78 rose, that of Insig-1 declined. There were differences observed with different doses of liraglutide; the higher the dose was, the more obvious the effect. No such changes were observed in T2DM and MAFLD rats after injection of saline. In this study, we show that liraglutide may have a therapeutic effect on rats with T2DM and MAFLD by reducing endoplasmic reticulum stress in the liver and increasing the expression of Insig-1.


miR-22 targets YWHAZ to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival.
Many miRNAs are associated with the carcinogenesis of hepatocellular carcinoma (HCC) and some exhibit potential prognostic value. In this study, to further confirm the prognostic value of miRNAs in HCC, we employed miRNA-sequencing data of tumor tissues of 372 HCC patients released by The Cancer Genome Atlas (TCGA) and identified 3 miRNAs including miR-22, miR-9-1 and miR-9-2 could be used as independent predictors for HCC prognostic evaluation. As a tumor-suppressive miRNA, miR-22 was down-regulated in HCC tissues. This down-regulation correlated with tumor vascular invasion, Edmondson-Steiner grade, TNM stage, and AFP level. Moreover, biofunctional investigations revealed that miR-22 significantly attenuated cellular proliferation, migration and invasion of HCC cells. Additionally, through gene expression profiles and bioinformatics analysis, YWHAZ was identified to be a direct target of miR-22 and its overexpression partially counteracted the inhibitory effects of miR-22 on HCC cells. Finally, molecular studies further confirmed that miR-22 promoted the accumulation of FOXO3a in nucleus and subsequently reversed invasive phenotype of HCC cells by repressing YWHAZ-mediated AKT phosphorylation. Taken together, these data demonstrate that miR-22 exhibits tumor-suppressive effects in HCC cells by regulating YWHAZ/AKT/FOXO3a signaling and might be used as an independent prognostic indicator for HCC patients.


No increasing risk of a limnic eruption at Lake Kivu: Intercomparison study reveals gas concentrations close to steady state.
Lake Kivu, East Africa, is well known for its huge reservoir of dissolved methane (CH4) and carbon dioxide (CO2) in the stratified deep waters (below 250 m). The methane concentrations of up to ~ 20 mmol/l are sufficiently high for commercial gas extraction and power production. In view of the projected extraction capacity of up to several hundred MW in the next decades, reliable and accurate gas measurement techniques are required to closely monitor the evolution of gas concentrations. For this purpose, an intercomparison campaign for dissolved gas measurements was planned and conducted in March 2018. The applied measurement techniques included on-site mass spectrometry of continuously pumped sample water, gas chromatography of in-situ filled gas bags, an in-situ membrane inlet laser spectrometer sensor and a prototype sensor for total dissolved gas pressure (TDGP). We present the results of three datasets for CH4, two for CO2 and one for TDGP. The resulting methane profiles show a good agreement within a range of around 5-10% in the deep water. We also observe that TDGP measurements in the deep waters are systematically around 5 to 10% lower than TDGP computed from gas concentrations. Part of this difference may be attributed to the non-trivial conversion of concentration to partial pressure in gas-rich Lake Kivu. When comparing our data to past measurements, we cannot verify the previously suggested increase in methane concentrations since 1974. We therefore conclude that the methane and carbon dioxide concentrations in Lake Kivu are currently close to a steady state.


Perinatal Arterial Ischemic Stroke.
Perinatal arterial ischemic stroke (PAIS) is a common cause of seizures, encephalopathy, altered mental status, and focal neurologic deficits in the neonatal period. It is the leading known cause of cerebral palsy. Other long-term risks include the development of epilepsy and impairment in cognition, language, and behavior. This article will review the known risk factors for PAIS, as well as the evaluation, management, and prognosis. Long-term neurodevelopmental surveillance is recommended, along with intensive therapies to reduce morbidity.


Seizures and early onset dementia: D2HGA1 inborn error of metabolism in adults.
D-2-hydroxyglutaric aciduria type 1 (D2HGA1) is a rare inherited metabolic disorder usually manifesting in infancy/early childhood with seizures and significant central nervous system involvement. We report two siblings with D2HGA1 presenting with mild intellectual disability, and the onset of seizures in adulthood. One of them was misdiagnosed as tuberous sclerosis due to her presentation and the presence of subependymal nodules on brain imaging. Both further developed early onset dementia. This report expands the phenotype of D2HGA1 to include late-onset seizures and early onset dementia in adults.


Gene expression alterations from reversible to irreversible stages during coral metamorphosis.
For corals, metamorphosis from planktonic larvae to sedentary polyps is an important life event, as it determines the environment in which they live for a lifetime. Although previous studies on the reef-building coral Acropora have clarified a critical time point during metamorphosis when cells are committed to their fates, as defined by an inability to revert back to their previous states as swimming larvae (here referred to as the "point of no return"), the molecular mechanisms of this commitment to a fate remain unclear. To address this issue, we analyzed the transcriptomic changes before and after the point of no return by inducing metamorphosis of Acropora tenuis with Hym-248, a metamorphosis-inducing neuropeptide. Gene Ontology and pathway enrichment analysis of the 5893 differentially expressed genes revealed that G protein-coupled receptors (GPCRs) were enriched, including GABA receptor and Frizzled gene subfamilies, which showed characteristic temporal expression patterns. The GPCRs were then classified by comparison with those of Homo sapiens, Nematostella vectensis and Platynereis dumerilii. Classification of the differentially expressed genes into modules based on expression patterns showed that some modules with large fluctuations after the point of no return were biased toward functions such as protein metabolism and transport. This result suggests that in precommitted larvae, different types of GPCR genes function to ensure a proper environment, whereas in committed larvae, intracellular protein transport and proteolysis may cause a loss of the reversibility of metamorphosis as a result of cell differentiation.


Muscle cell apoptosis is responsible for the body weight loss in tumor-bearing rabbits.
In order to elucidate the cause of body weight loss in the early stage of tumor progression, morphological changes of striated muscle were investigated in rabbits every 10 days after VX2 carcinoma implantation. The lean body mass started to decrease in the tumor-bearing rabbits 10 days after implantation, and body fat ratio showed a significant decrease from 30 days, different from the starved rabbits, whose lean body mass and body fat ratio started to decrease from 10 days. Morphological hallmarks of apoptosis in muscle cells were detected in tumor-bearing animals prior to the tumor growth but not in starved animals. These findings suggest that muscle cell apoptosis may be responsible for the body weight loss in the early tumor-bearing.


UN conference reaffirms reproductive rights.
The United Nations Conference on Human Settlements, also known as the Habitat II conference, met in Istanbul from June 3 to 14. It was the last major UN gathering of this millennium and the first major UN meeting since 1995's Fourth World Conference on Women (the "Beijing Conference")--and thus an important opportunity for a wider international community to weigh in on agreements reached in Beijing and at the International Conference on Population and Development, held in Cairo in 1994. The final document that emerged from Habitat II, the "Global Plan of Action," affirmed crucial elements of those earlier accords. The Habitat documents calls for action to "[d]evelop and implement programmes to ensure universal access for women throughout their life-span to a full range of affordable health care services, including those related to reproductive health care, which includes family planning and sexual health, consistent with the Report of the International Conference on Population and Development." Language adopted at the Cairo meeting is also affirmed in Habitat's call for "universal access to the widest range of primary health care services." Perhaps most significantly, the Istanbul document reiterated an important declaration from the Beijing conference: "While the significance of national and regional particularities and various historical, cultural, and religious backgrounds must be borne in mind, it is the duty of all States to promote and protect all human rights and fundamental freedoms." Most of the 189 UN members and observer states that attended the conference upheld all three of these provisions. Only a small group of states--Argentina, Guatemala, Iran, Jordan, Lebanon, Malta, Qatar, Saudi Arabia, Sudan, Syria, United Arab Emirates, Yemen, and the Holy See--filed reservations on the health care sections.


Lateral Prefrontal Cortex Contributes to Fluid Intelligence Through Multinetwork Connectivity.
Our ability to effectively adapt to novel circumstances--as measured by general fluid intelligence--has recently been tied to the global connectivity of lateral prefrontal cortex (LPFC). Global connectivity is a broad measure that summarizes both within-network connectivity and across-network connectivity. We used additional graph theoretical measures to better characterize the nature of LPFC connectivity and its relationship with fluid intelligence. We specifically hypothesized that LPFC is a connector hub with an across-network connectivity that contributes to fluid intelligence independent of within-network connectivity. We verified that LPFC was in the top 10% of brain regions in terms of across-network connectivity, suggesting it is a strong connector hub. Importantly, we found that the LPFC across-network connectivity predicted individuals' fluid intelligence and this correlation remained statistically significant when controlling for global connectivity (which includes within-network connectivity). This supports the conclusion that across-network connectivity independently contributes to the relationship between LPFC connectivity and intelligence. These results suggest that LPFC contributes to fluid intelligence by being a connector hub with a truly global multisystem connectivity throughout the brain.


Antigen detection in the diagnosis of viral infections.
The value of viral antigen detection from nasopharyngeal secretion (NPS) by enzyme immunoassay (EIA) in everyday clinical practice was evaluated in 570 children hospitalized because of infections. NPS-EIA gave a positive result in 32% of all cases. Virus isolation was positive in the NPS in 25%, virus isolation in stool samples in 14%, and virus serology in 28% of the cases. NPS-EIA was superior for detecting adenovirus, respiratory syncytial (RS) and parainfluenza viruses. In a series of 124 patients in whom 3 methods were compared, NPS-EIA was the only positive method in 48% of all findings positive for adenoviruses, in 73% for RSV, and in 58% for parainfluenza viruses. Antigen detection by NPS-EIA markedly increased the diagnostic potential in everyday clinical practice, especially for viral respiratory diseases.


Orally Administrated Whole Yeast Vaccine Against Porcine Epidemic Diarrhea Virus Induced High Levels of IgA Response in Mice and Piglets.
The mucosal immune response against the porcine epidemic diarrhea virus (PEDV) is very important in piglets. To develop a PEDV vaccine suitable for inducing high levels of intestinal IgA in piglets, recombinant yeast expressing the PEDV S1 gene was constructed and tested by oral immunization of mice and piglets. The S1-specific IgG and IgA were tested at 0, 14, and 28 days postimmunization (dpi) in mice. Compared to the control group, the mice treated with S1 expressing yeast, demonstrated significantly higher levels of IgG and IgA against PEDV from 14 dpi onward. The recombinant yeast inducing a fecal IgA response in piglets was also tested. PEDV-specific IgA could be detected at 7 dpi and increased to 28 dpi. We demonstrated that whole recombinant yeast can be used as a PEDV vaccine vector for inducing high levels of IgA against PEDV in piglets. This could be a good vaccine candidate for PEDV control in piglets.


Brain natriuretic peptide (nesiritide) in the treatment of heart failure.
Over the last decade brain natriuretic peptide (BNP) emerged as a cardiac hormone of clinical interest in diagnosis, prognosis and treatment of patients with Heart Failure (HF). The diagnostic potential of BNP is now well established both in patients with suspected HF as well as in patients with asymptomatic left ventricular systolic dysfunction. The prognostic information obtained from BNP levels in HF and acute myocardial infarction patients seems even more promising. Nesiritide is a synthetic peptide, homologous to endogenous BNP. It is a balanced vasodilator with diuretic and natriuretic properties. It decreases the elevated levels of neurohormones resulting from activation of the sympathetic and renin-aldosterone systems in HF. The results of clinical trials involving more than 2000 patients with decompensated HF are now available. In these trials nesiritide was administered by single or repeated bolus injections, as well as by sustained infusions. Nesiritide has been shown to produce a potent, dose-related vasodilator effect that is rapid in onset and sustained during infusion. Balanced vasodilation is reflected by decreases in systemic vascular resistance, pulmonary artery wedge pressure and right atrial pressure. No tachyphylaxis has been observed in these trials. Efficacy of nesiritide in the treatment of decompensated HF has been demonstrated. Trials comparing nesiritide with conventional treatment of decompensated HF showed that nesiritide compares favorably to standard agents. The safety profile has been excellent with a dose-dependent hypotension as the major side effect. Ventricular arrhythmia was not more frequent in patients treated with nesiritide than with placebo. Thus, nesiritide appears to be useful as a first-line agent in the treatment of patients with decompensated HF.


[Circular insanity, 150 years on].
On January 31 1854, Jules Baillarger delivered a lecture to the French Imperial Academy of Medicine describing a new variety of insanity, "la folie à double forme", whose main feature was the occurrence of both manic and depressive episodes in the same patient. Immediately his colleague Jean-Pierre Falret pointed out that he had already published a description of the same disorder, that he had named "folie circulaire" and, on February 14, presented a lecture on the subject to the Academy. Baillarger accused him of plagiarism, contending that Falret had used the two weeks between the two lectures to attribute the main characteristics of la folie à double forme to his folie circulaire, whose description now bore little relation to the (very short) previous report that Falret had evoked as proof of his priority. Falret subsequently showed great restraint in the controversy, while Baillarger reiterated and extended his accusations until his death. An objective study of the printed material not only establishes Falret's clear priority, but also demonstrates that Baillarger's accusations of plagiarism are unfounded, as the descriptions of la folie circulaire and la folie à double forme differ on many important points, the first being much closer than the second to our present conceptions. Falret's discovery is thus a landmark in the nosology of mental disorders. Contrary to the then-widespread belief in the existence of a single entity--" mental alienation"--with several symptomatic manifestations, Falret affirmed that, in psychiatry as in the rest of medicine, separate disease entities existed. While their etiology was still unknown, they could be distinguished by their syndromic expressions and their outcome; on this basis, Falret considered that la folie circulaire was, together with general paralysis, the only true mental disorder so far identified. His principles were subsequently adopted by Kraepelin, whose main nosological concepts, established around 1900, are still in use today. Kraepelin attributed most psychotic manifestations to two diseases, namely dementia praecox (later renamed schizophrenia) and manic-depressive psychosis; the two differed mainly by the progression of the former to a final state of mental deterioration. Falret's folie circulaire was incorporated in the second disease, as one of its many symptomatic forms. It regained its autonomy only in 1966 when Angst and Perris demonstrated the specificity of its heredity and named it bipolar disorder. Recent studies suggest that the boundaries of this disorder extend far beyond those of its classical description. The so-called bipolar spectrum now includes, on the basis of clinical, biological, genetic and therapeutic arguments, the manic and hypomanic, and even purely depressive manifestations of mood disorder. One hundred and fifty years after its inception, Falret's concept of folie circulaire has become one of the main focuses of psychiatric research.


Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2.
The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.


[Erratic divergent evolution in fish from the Northern Pacific].
The mtDNA divergence was examined in some families of anadromous and semi-anadromous fish. Heterogeneous distribution of the divergence values along the scale was demonstrated. Statistically significantly higher number of the species pairs were characterized by divergence values ranging from 2 to 4% and 5 to 12% of nucleotide substitutions. These results suggest that in different monophyletic groups occupying common historical ranges, divergence-associated speciation often happened within similar time intervals. Comparison of the species divergence time calculated using the molecular clock pointed to the coincidence of the radiation periods in the taxa with paleogeological and paleoclimatic global changes in the history of Northern Pacific.


Osteoarthritis of the peripheral joints.
Osteoarthritis (OA) is a complex process affecting many different joint areas in the body. From a pathophysiological point of view some features are crucial for the diagnosis, such as cartilage fibrillation and thinning, subchondral sclerosis and the presence of osteophytes. From a clinical perspective, OA is the most prevalent rheumatic joint disorder, causing pain and stiffness of the joints and, for the individual, impaired function and health status. The aim of this chapter is to present current knowledge of definitions of OA, its presence in different populations and in different joint areas (the back excluded). Furthermore, methods of diagnosing and delineating clinically relevant forms of OA, now and in the future, are presented as well as current knowledge of the risk factors for developing and the factors for preventing OA.


The Concept of Contexts in Pain: Generalization of Contextual Pain-Related Fear Within a de Novo Category of Unique Contexts.
The experience of unpredictable pain fluctuations can trigger anticipatory pain-related fear. When discrete predictors for pain are lacking, fear typically accrues to the broader environmental context: a phenomenon referred to as contextual pain-related fear. We examined whether conceptual similarity between discrete contexts facilitates pain-related fear generalization; this mechanism is known as category-level fear generalization. Using a voluntary joystick movement paradigm, pain-free participants performed movements in 2 contexts (within-subjects design); context was manipulated by varying background color screens. In the predictable context, one movement predicted pain and another did not. In the unpredictable context, 2 other movements never predicted pain but pain was unpredictably delivered during the context. Participants subsequently learned to categorize novel background colors (ie, generalization contexts) as being similar to either the unpredictable or predictable pain context. Then we tested fear generalization to these novel contexts. We measured self-reported pain-related fear, expectancy, and eyeblink startle. Results indicated higher pain-related fear reports, but no elevated startle responses, for generalization contexts that were trained to be similar to the original unpredictable context rather than the predictable pain context. This highlights a potential pathway through which neutral contexts can elicit pain-related fear and motivate avoidance behavior associated with chronic pain disability. Self-reported pain-related fear and expectancy of painful outcome in response to a context associated with unpredictable pain generalizes to perceptually distinct contexts that are trained to be conceptually similar to the unpredictable pain context. Category-level generalization may be a pathway contributing to spreading of fear and avoidance in chronic pain.


Correction: The evolution of spiropyran: fundamentals and progress of an extraordinarily versatile photochrome.
Correction for 'The evolution of spiropyran: fundamentals and progress of an extraordinarily versatile photochrome' by Luuk Kortekaas et al., Chem. Soc. Rev., 2019, 48, 3406-3424, DOI: 10.1039/C9CS00203K.


Non Vascular Congenital Brain Malformations. An MR Study of 5000 Patients.
Central nervous system (CNS) malformations are frequently severe and often fatal. Diagnosis during pregnancy is of fundamental importance for a correct clinical evaluation and pharmacological management or, where possible, surgery. Modern imaging technology, pre and post-natal ultrasound scans, but above all magnetic resonance (MR) imaging have revolutionized the diagnostic study of cerebral malformations. In particular, MR provides images of the various brain sections by means of a multidisciplinary non invasive study that today is particularly rapid. MR allows an accurate assessment of cortical development, normal myelinization and the evolution of malformations. We report here our experience with MR carried out after birth on 5000 patients for the study of non vascular cortical anomalies. In only one case was the examination carried out during pregnancy, following ultrasound investigations that showed a developmental anomaly of the corpus callosum. We confirmed 112 malformations with an incidence of 2.24%, greater in males and affecting principally the anatomy of the supratentorial encephalic structures. These cases were selected and MR was carried out based on the clinical picture present at the time of the examination or a suspected diagnosis formulated following ultrasound. The ultrasound investigations were carried out principally in the obstetrics department; only a few were carried out in our unit, together with most of the postnatal ultrasound scans. The percentage of the various malformations was higher than those reported in the literature.


Bone Mineral Density in Adolescent Girls with Hypogonadotropic and Hypergonadotropic Hypogonadism.
Deficiency of sex steroids has a negative impact on bone mineral content. In studies conducted on postmenopausal women and animal studies, elevated follicle-stimulating hormone (FSH) levels were found to be correlated with a decrease in bone mineralization and osteoporosis. The aim of the present study was to evaluate bone mineral density (BMD) in adolescent girls with hypogonadotropic and hypergonadotropic hypogonadism and also to investigate the correlation between FSH level and BMD. The study group included 33 adolescent girls with hypogonadism (14 with hypogonadotropic hypogonadism and 19 with hypergonadotropic hypogonadism). FSH, luteinizing hormone, estradiol levels, and BMD (using dual energy x-ray absorptiometry) were measured. There were no statistically significant differences between the chronological age and bone age of the two patient groups, namely, with hypogonadotropic and hypergonadotropic hypogonadism. There was also no significant difference between BMD z-score values obtained from measurements from the spine and the femur neck of patients in the two groups (p-values were 0.841 and 0.281, respectively). In the hypergonadotropic group, a moderately negative correlation was detected between FSH level and BMD z-score measured from the femur neck (ρ=-0.69, p=0.001), whilst no correlation was observed between FSH levels and height adjusted BMD-z scores measured from the spine (ρ=0.17, p=0.493). FSH level was not found to be an independent variable affecting BMD z-score. BMD z-scores were detected to be similar in adolescent girls with hypogonadotropic and hypergonadotropic hypogonadism, and FSH levels were not found to have a clinically relevant impact on BMD.


Genetic manipulation in Δku80 strains for functional genomic analysis of Toxoplasma gondii.
Targeted genetic manipulation using homologous recombination is the method of choice for functional genomic analysis to obtain a detailed view of gene function and phenotype(s). The development of mutant strains with targeted gene deletions, targeted mutations, complemented gene function, and/or tagged genes provides powerful strategies to address gene function, particularly if these genetic manipulations can be efficiently targeted to the gene locus of interest using integration mediated by double cross over homologous recombination. Due to very high rates of nonhomologous recombination, functional genomic analysis of Toxoplasma gondii has been previously limited by the absence of efficient methods for targeting gene deletions and gene replacements to specific genetic loci. Recently, we abolished the major pathway of nonhomologous recombination in type I and type II strains of T. gondii by deleting the gene encoding the KU80 protein(1,2). The Δku80 strains behave normally during tachyzoite (acute) and bradyzoite (chronic) stages in vitro and in vivo and exhibit essentially a 100% frequency of homologous recombination. The Δku80 strains make functional genomic studies feasible on the single gene as well as on the genome scale(1-4). Here, we report methods for using type I and type II Δku80Δhxgprt strains to advance gene targeting approaches in T. gondii. We outline efficient methods for generating gene deletions, gene replacements, and tagged genes by targeted insertion or deletion of the hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) selectable marker. The described gene targeting protocol can be used in a variety of ways in Δku80 strains to advance functional analysis of the parasite genome and to develop single strains that carry multiple targeted genetic manipulations. The application of this genetic method and subsequent phenotypic assays will reveal fundamental and unique aspects of the biology of T. gondii and related significant human pathogens that cause malaria (Plasmodium sp.) and cryptosporidiosis (Cryptosporidium).


Comparative studies of genetic diversity in kenaf (Hibiscus cannabinus L.) varieties based on analysis of agronomic and RAPD data.
Kenaf (Hibiscus cannabinus L.) is a fiber crop classified in the genus Hibiscus (Malvaceae), and has a great potential for its multipurpose utilization, in addition to its traditional usage. Varietal identification of kenaf is always problematic and knowledge on genetic diversity of kenaf varieties is also limited, which significantly hindered our effective utilization and conservation of the valuable kenaf germplasm. In order to find a proper method for identifying kenaf varieties and studying their variation, morpho-agronomic characters and random amplified polymorphic DNA (RAPD) markers were analyzed among 14 kenaf varieties commonly used in Japan. Data from morphological analysis showed that the included kenaf varieties could be divided into three major groups. The characters, such as middle stem diameter, whole stalk weight, and days to 50% flowering, are highly responsible for the variation of the kenaf varieties, but it is difficult to identify individual varieties merely by the morpho-agronomic characters. On the other hand, clearly separation of the kenaf varieties was achieved based on the RAPD variation patterns. Genetic relationship of the kenaf varieties can also be traced through the analysis of RAPD and morph-agronomic variation. It is concluded from the present study that RAPD analysis is an effective tool in identifying of kenaf varieties and determining their genetic relationships, particularly when combined with the analysis of morpho-agronomic characters.


Reiterative use of the notch signal during zebrafish intrahepatic biliary development.
The Notch signaling pathway regulates specification of zebrafish liver progenitor cells towards a biliary cell fate. Here, using staged administration of a pharmacological inhibitor of Notch receptor processing, we show that activation of the Notch pathway is also important for growth and expansion of the intrahepatic biliary network in zebrafish larvae. Biliary expansion is accompanied by extensive cell proliferation and active remodeling of the nascent ductal network, as revealed by time lapse imaging of living zebrafish larvae that express a Notch responsive fluorescent reporter transgene. Together, these data support a model in which the Notch signal functions reiteratively during biliary development; first to specific biliary cells and then to direct remodeling of the nascent biliary network. As the Notch pathway plays a comparable role during mammalian biliary development, including humans, these studies also indicate broad conservation of the molecular mechanisms directing biliary development in vertebrates.


Catalytic cracking of polystyrene pyrolysis oil: Effect of Nb2O5 and NiO/Nb2O5 catalyst on the liquid product composition.
The catalytic cracking of polystyrene pyrolysis oil was investigated over a Nb2O5 and a NiO/Nb2O5 catalyst in a fixed bed reactor. First, the pyrolysis of two different polystyrene feedstock (polystyrene foam and polystyrene pellet) was carried out in a semi-batch reactor, and the resulting polystyrene pellets pyrolysis oil was selected for catalytic cracking reaction because of its high liquid yield (85%). Catalytic cracking experiments were then performed at different temperatures (350-500 °C) using Nb2O5 or NiO/Nb2O5 catalyst. Gas chromatography-mass spectrometry analysis of liquid product obtained from the catalytic cracking process showed that the dimers in the pyrolysis oil were converted to monomers during the catalytic cracking process. The catalytic cracking results also showed that the NiO/Nb2O5 catalyst (having slightly higher acidic sites) had slightly higher activity for monomer conversion than the Nb2O5 catalyst (having less acidic sites). X-ray diffraction, transmission electron microscopy, pyridine Fourier transform infrared spectroscopy, NH3 Temperature Programmed Desorption and X-ray photoelectron spectroscopy were used to characterize the catalyst. The highest catalytic cracking activity was observed at 400 °C with the Nb2O5 catalyst with 4% toluene, 6% ethylbenzene, approximately 50% styrene, 13% α-methyl styrene, and only 6% of dimers in the liquid oil. The increase in temperature positively affected the yield of gases during catalytic cracking process.


Comparison of mammography sensitivity after reduction mammoplasty targeting the glandular and fat tissue.
Mammography may have some limitations in the diagnosis and screening of breast cancer for women who have previously undergone breast reduction surgery. This study aimed to investigate how the structural defects in the breast tissue formed by postoperative changes are reflected on mammography. The records of patients who had previously undergone breast reduction surgery and who were requested to undergo mammography for breast cancer screening by the general surgery clinic were retrospectively studied. The patients' ages, surgical procedures, postoperative follow-up periods, amount of removed material, and histopathological and mammographic results were studied. The patients were classified into 3 groups: those older than 40 years who underwent reduction mammoplasty targeting predominantly the glandular tissue (group 1), those younger than 40 years who underwent reduction mammoplasty targeting predominantly the fat tissue (group 2), and those older than 40 years who were diagnosed with breast hypertrophy and were not operated (group 3). The mean follow-up period of the patients was 6 (2-10) years. The mean value of resected tissue was 1120 g (680-2070) in group 1 and 1220 g (720-1980) in group 2. The mean age at the time of surgery was 45 (40-70) years for group 1 and 35 (24-40) years for group 2. All patients in group 1 were classified in Breast Imaging-Reporting and Data System (BI-RADS) category 1-2; 28 patients in group 2 were classified in BI-RADS 1-2, 4 were classified in BI-RADS 3, and 8 were classified in BI-RADS 0. In group 3, 35 patients were classified in BI-RADS 1-2, 4 were classified in BI-RADS 3, and 1 was classified in BI-RADS 0. We believe that breast reduction surgery targeting predominantly the glandular tissue in patients older than 40 years increases mammographic sensitivity.


Sedation for the critically ill neurologic patient.
To review the scientific basis for sedation of critically ill neurologic patients by summarizing the distinct neurophysiologic disturbances present in this population and presenting the central nervous system effects of sedative agents to permit optimal drug therapy. Review of the English language clinical and scientific literature using MEDline data search. Literature references were selected through a key word search of sedative therapy, drugs used for sedation, and specific neurologic disorders and processes to provide an in-depth overview of sedative drug mechanisms of action, effects on neurophysiology and intracranial dynamics, pharmacokinetics, and toxicity profile. Special emphasis was placed on neurologic side effects. Clinical and scientific literature was reviewed and data relevant to neurophysiologic effects of sedative drug therapy were summarized. Recommendations for institution of sedative therapy and of particular agents were made as a result of analysis of all pooled data. Critically ill patients with neurologic pathology present as a unique subset of individuals cared for in an acute care setting. Because monitoring of neurologic patients requires frequent assessment of the neurologic examination, the goal of sedative therapy should be to enhance, or to minimally perturb elicitation of the examination. Neurophysiologic disturbances introduce distinct risks for sedation and require their identification and understanding before the initiation of any sedative therapy. Sedative drugs, in particular, act to disturb central nervous system function and their effects may result in diagnostic confusion and further neurologic deterioration. The pharmacokinetic and neurophysiologic actions of the common classes of sedative agents, such as benzodiazepines, opioids, barbiturates, and neuroleptics, as well as ketamine, propofol, and clonidine are discussed. Recommendations are presented based on the specific type of sedation required and the underlying neurologic disturbance. Several specific examples, including head trauma, neuromuscular disease, and alcohol withdrawal, are provided. Preservation of the neurologic examination is paramount in documenting clinical improvement or deterioration in the critically ill neurologic patient. Pharmacologic sedation in this unique population of acute care patients requires careful consideration of the underlying neurophysiologic disturbances and potential adverse effects introduced by sedative drugs.


[Hydroxyethyl starch-induced transient renal failure in preexisting glomerular damage].
Hemorheological therapy through hemodilution has been gaining importance for several years and been applied to an ever increasing degree in stationary as well as in ambulant treatment. While renal insufficiency without previously established nephropathy is known to be a side effect of dextrans, cases of HES-induced nephropathy have so far not been reported. Two cases are presented in which in the course of stationary hemodilution therapy with HES an acute deterioration of an already exiting nephropathy was noted. Possible pathophysiological causes for such a deterioration are most likely to be found in an increased permeability of the glomerular basal lamina. Hydroxyethyl starch molecules are filtered above the physiological renal threshold which increases the viscosity of the primary urine. This can be counteracted by increasing diuresis. This conclusion can be drawn from our own observations which proved that renal insufficiency can be avoided through sufficient fluid intake (approx. 3 liters/day). In patients with creatinine values above 1.5/dl and arterial hypertension the indication for hemodilution therapy must be analysed carefully. If hemodilution therapy proves to be necessary, sufficient fluid intake must be guaranteed. Retention parameters must be controlled every other day in the course of the therapy. As an alternative, the administration of gelatin preparations should be considered as it does not cause cumulation.


Representation of women at American Psychiatric Association annual meetings over 10 years (between 2009 and 2019).
Sex disparity is a major societal issue. The aim of this paper was to describe changes in the representation of women among speakers of the American Psychiatric Association (APA) annual meeting over 10 years, between 2009 and 2019 and to compare them to changes in the proportion of women among American psychiatrists. Data were collected from the programs of the APA annual meetings of 2009 and 2019, and from the Association of American Medical Colleges. Descriptive and comparative statistical analyses were performed. There were 1,138 distinct speakers at the 2009 conference and 1,784 at the 2019 conference. The number of distinct female speakers increased from 413 (36.3%) to 813 (45.6%). The proportion of female speakers at the meetings was almost equivalent to the proportion of women in the American psychiatrists' workforce. The number of female chairs increased from 158 (39.6%) to 322 (46.4%). There were 38 female speakers in child and adolescent psychiatry in 2009 (51.4% of 74 speakers) and 74 in 2019 (51.0% of 155 speakers). The representation of women at the APA annual meetings increased between 2009 and 2019. At the same time, the growth in the percentage of women in the American psychiatrists' workforce was slower. The APA appears to promote female representation during its annual meetings.


Synthesis of Enantiomeric Polyhydroxyalkylpyrrolidines from 1,3-Dipolar Cycloadducts. Evaluation as Inhibitors of a β-Galactofuranosidase.
Enantiomeric 2,3,4-tris(hydroxyalkyl)-5-phenylpyrrolidines have been synthesized from the major cycloadducts obtained by the 1,3-dipolar cycloaddition of sugar enones with azomethine ylides derived from natural amino acids. Reduction of the ketone carbonyl group of the cycloadducts, which possess a basic structure of bicyclic 6-(menthyloxy)hexahydropyrano[4,3-c]pyrrol-7(6H)one, afforded a number of pyrrolidine-based bicyclic systems. A sequence of reactions, which involved hydrolysis of the menthyloxy substituent, reduction, N-protection, and degradative oxidation, afforded varied pyrrolidine structures having diverse configurations and patterns of substitution; in particular, polyhydroxylated derivatives have been obtained. The unprotected products were isolated as pyrrolidinium trifluoroacetates. Because of the furanose-like nature of the target trihydroxyalkyl pyrrolidines, these molecules have been evaluated as inhibitors of the β-galactofuranosidase from Penicillium fellutanum. The compounds showed practically no inhibitory activity for concentration of pyrrolidines in the range of 0.1-1.6 mM.


The cost of treating patients with COPD in Denmark--a population study of COPD patients compared with non-COPD controls.
This paper describes a population-based study of health care resource use of patients with chronic obstructive pulmonary disease (COPD) compared to non-COPD controls. Through a screening of the Danish Patient Registry for patients admitted with COPD diagnoses for a 5-year period, 1998-2002, 66,000 individuals with COPD still alive at the beginning of 2002 were identified. Their use of health care resources in 2002 were compared with equivalent data, stratified for age, sex and mortality rates, for a control population without COPD based on data for the 300,000 remaining patients on the Danish Patient Registry in 2002. Results indicated that the gross cost of treating patients with COPD in the Danish somatic hospital and primary health care sector corresponded to 10% of the total cost of treating patients of 40 years or more. The net cost for COPD patients was 1.9 billion DKK (256 million euro), 6% of the total annual costs of treating the population of 40 years or more. The gross cost related to any disease and the net cost reflected the resource use which could be attributed to COPD and its related diagnoses. The incidence of inpatient hospital admissions was almost four times higher in the COPD population than in the control group. COPD patients contacted their general practitioner 12 times more per year than non-COPD controls, but for specialist and paramedic treatment in the primary care sector there was no significant difference between COPD patients and non-COPD controls. Only one third of the COPD costs were due to treatment of COPD as the primary diagnosis. The remaining two-thirds of the COPD-related costs were mainly due to admissions for other diseases such as cardio-vascular diseases, other respiratory diseases, and cancer.