The electrophysiologic basis for the use of amiodarone for treatment of cardiac arrhythmias.
The electrophysiologic basis for the use of amiodarone in the treatment of cardiac arrhythmias is outlined, with reference to studies in isolated cardiac tissues, whole animal, and human studies. Amiodarone appears to have the distinctive property of directly prolonging action potential duration (and hence refractory periods) in nearly all cardiac tissues. Independent of its effects on refractory periods, conduction may also be impaired in the His-Purkinje system, possibly due to depression of phase 0 of the action potential. Sinus node and atrial automaticity, as well as that arising from diseased Purkinje fibers, may be depressed. Normal ventricular escape pacemakers appear relatively unaffected, however. A nonspecific anti-adrenergic action may contribute to its observed effects. These electrophysiological effects are more obvious and predictable after several weeks of oral treatment than after intravenous administration, suggesting a time-dependent mechanism of action. The drug appears well suited to the prevention of enhanced automaticity in the ventricle and re-entry throughout the heart, and its frequent clinical success in a broad spectrum of cardiac arrhythmias attests to this. Unwanted side effects include sinus node depression, His-Purkinje conduction delay or block, and ventricular arrhythmias enhanced by QT prolongation. However, the frequency of clinically significant examples of unwanted arrhythmic effects appears to be acceptably low.


Natural orifice translumenal endoscopic surgery (NOTES) transvaginal cholecystectomy in a morbidly obese patient.
Transvaginal natural orifice translumenal endoscopic surgery (NOTES) is a new diagnostic and potentially therapeutic method of surgical endoscopy. The first case of NOTES transvaginal cholecystectomy in a morbid obese patient in the literature is described. IRB approval was obtained at the institution for transvaginal NOTES clinical trials. A 58-year-old female patient with cholelithiasis, hypertension, and type II diabetes, and BMI of 35.8 kg/m(2) was submitted to the technique. After transvaginal access, a two-channel gastroscope was introduced into the abdominal cavity along with a laparoscopic trocar. There were 2 umbilical punctures for use of 3 mm laparoscopic equipment. Operative time was 85 min. There was no use of postoperative analgesia, and the patient was discharged on the third postoperative day. Transvaginal NOTES is a feasible alternative method for cholecystectomy in the morbidly obese, although available technology is limited for natural orifice surgery.


Evoked potential measurement and analysis on a small laboratory computer.
A program is described for the collection and subsequent analysis of somatosensory evoked potentials using a LINC-8 computer. The program allows simple evoked-potentials analysis in centers where a small laboratory computer may be available but sophisticated instrumentation such as a computer of average transients is not available. This program provides an efficient method of easily obtaining information concerning the conduction pathways of the nervous system as well as the cerebral function; the program can be implemented on small laboratory computers which most hospitals currently own, without the associated cost or complexity of additional hardware in the laboratory. Combining utilization of a small laboratory computer with an easily programmable method provides an approach for evoked potential analysis which is well within the financial and technical scope of most neurophysiology laboratories.


Human preformed IgG combining with membrane-bound porcine serotransferrin lyse porcine endothelial cells through antibody-dependent cellular cytotoxicity.
Preformed antibodies are involved in xenograft rejection. The purpose of this work was to characterize porcine xenoantigens recognized by human preformed IgG (hpIgG), and to investigate the role of hpIgG in xenogeneic rejection. IgG eluted from porcine livers perfused with human plasma, human sera and total human IgG were immunoblotted on porcine aortic endothelial cell extracts. The amino acid sequence of a 76-kDa antigen constantly revealed was 100% homologous with porcine serotransferrin (psTf). hpIgG from human sera, human IgG1 and IgG2 and F(ab')2gamma specifically bound to psTf. Neutralization by psTf abolished that binding. Although alpha1,3-linked galactose residues (Gal(alpha)1,3Gal) is the dominant epitope recognized by preformed antibodies in the swine-to-human combination, the analysis of carbohydrate composition of psTf showed that the molecule was devoid of Gal(alpha)1,3Gal moieties and that preformed anti-psTf IgG bound to epitopes localized on the peptide core of the molecule. Purified human anti-psTf IgG antibodies were able to bind to psTf linked to its receptor on porcine endothelial cells, and to kill those cells through antibody-dependent cellular cytotoxicity.


Natural Products & Bioactivity Inspired Synthetic Pursuits Interfacing with Carbohydrates: Ongoing Journey with C-Glycosides.
Natural products, remains the most important source for the discovery of new drugs for the treatment of human diseases. This has inspired the synthetic community to design and develop mimics of natural products either to answer important questions in biology or to explore their therapeutic potentials. Glycosides present themselves abundantly in nature, right from the cell surface receptors to natural products of any origin. The O-Glycosides are hydrolytically less stable compared to C-glycosides and this feature has presented a great opportunity for drug discovery. The discovery of Dapagliflozin, an SGLT inhibitor and C-glucoside, for the treatment of diabetes is one such example. Aryl acyl-anion chemistry has been explored for the synthesis of 2-deoxy-C-aryl furanoside/pyranoside/septanosides. Besides success, the studies have provided valuable insight into the natural propensities of the architectural framework for the cascade to furan derivatives. The aryl acyl-anion chemistry has also enabled the synthesis of biologically active diaryl heptanoids. Inspired from sucesss of Dapagliflozin, new analogues have been synthesized with pyridine and isocoumarin heterocycle as the proximal ring. C-glucosides of isoliquiritigenin have been synthesized for the first time and evaluated as an efficient aldose reductase inhibitor. The synthesis and evaluation of acyl-C-β-D-glucosides and benzyl-C-β-D-glucoside as glucose-uptake promoters has revealed promise in small molecules. The concept of building blocks has been used to obtain natural oxylipins, D-xylo and L-xylo-configured alkane tetrols and novel lipophilic ketones with erythro/threo configured trihydroxy polar head-group as possible anti-mycobacterial agents.


The fructose tolerance test in patients with chronic kidney disease and metabolic syndrome in comparison to healthy controls.
Fructose acutely raises serum uric acid in normal subjects, but the effect in subjects with metabolic syndrome or subjects with chronic kidney disease is unknown. The aim of the study was to evaluate changes in serum uric acid during the fructose tolerance test in patients with chronic kidney disease, metabolic syndrome with comparison to healthy controls. Studies were performed in 36 subjects with obesity (body mass index >30) and metabolic syndrome, 14 patients with stage 3 chronic kidney disease, and 25 healthy volunteers. The fructose tolerance test was performed in each patient. The change in serum uric acid during the fructose challenge was correlated with baseline ambulatory blood pressure, serum uric acid, metabolic, and inflammatory markers, and target organ injury including carotid intima media thickness and renal resistive index (determined by Doppler). Absolute serum uric acid values were highest in the chronic kidney disease group, followed by the metabolic syndrome and then healthy controls. Similar increases in serum uric acid in response to the fructose tolerance test was observed in all three groups, but the greatest percent rise was observed in healthy controls compared to the other two groups. No significant association was shown between the relative rise in uric acid and clinical or inflammatory parameters associated with kidney disease (albuminuria, eGFR) or metabolic syndrome. Subjects with chronic kidney disease and metabolic syndrome have higher absolute uric acid values following a fructose tolerance test, but show a relatively smaller percent increase in serum uric acid. Changes in serum uric acid during the fructose tolerance test did not correlate with changes in metabolic parameters, inflammatory mediators or with target organ injury. These studies suggest that acute changes in serum uric acid in response to fructose do not predict the metabolic phenotype or presence of inflammatory mediators in subjects with obesity, metabolic syndrome or chronic kidney disease. The study was registered in ClinicalTrials.gov. Identifier : NCT01332526. www.register.clinicaltrials.gov/01332526.


Awareness is the first step: What Ghanaian community pharmacists know about cancer.
The goal of this study was to access the knowledge of a representative sample of community pharmacists in Ghana on general cancer, risk factors, signs and symptom and most common cancer counseling points known to community pharmacists. A structured online questionnaire was administered to 435 registered community pharmacists in the sixteen regions of Ghana.Key findings: Mean score for knowledge of cancer among community pharmacists was 6.8 ± 1.61 points out of a maximum score of 15 points, categorizing the overall knowledge as inadequate. The overall assessment of pharmacists' knowledge revealed that 74.6% of the participants had inadequate level of knowledge on cancer. Mean score for knowledge of cancer signs and symptoms among community pharmacists was 3.55 ± 1.85 out of a maximum score of 7 points, categorizing the overall knowledge as inadequate. The overall evaluation indicated that 79.03% of pharmacists had inadequate knowledge of signs and symptoms cancer. Mean score for knowledge of risk factors of cancer among community pharmacists was 5.25 ± 1.15 out of a maximum score of 12 points, categorizing the overall knowledge as inadequate. The overall assessment of the knowledge score indicates that 70.34% of pharmacists had inadequate knowledge about causes and risk factors of cancer. Almost all participating pharmacists (96.5%) recommended counselling point was avoidance of smoking as a cancer preventive measure. An inverse significant correlation was found between age and knowledge scores of signs and symptoms of cancer (r = -0.077, P = 0.038). There was a statistically significant relationship between pharmacists' level of knowledge on cancer (whether adequate or inadequate) and the cancer items. Knowledge of cancer, its signs and symptoms and its risk factors were inadequate among community pharmacists in Ghana. Efforts should be made to improve knowledge of community pharmacists on cancer through continuous education. Also, undergraduate pharmacy training in oncology should encourage to close knowledge gap of community pharmacists on cancer.


The application of ultrasound shear wave elastography in the prediction of paradoxical upgrading reaction in tuberculous lymphadenitis. a pilot study.
Paradoxical upgrading reaction (PUR) indicates the unanticipated deterioration during therapy in patients with tuberculous lymphadenitis. We investigated the diagnostic performance of the ultrasonography and shear wave elastography (SWE) in predicting the therapeutic response of peripheral tuberculous lymphadenitis. A prospective observational study was conducted from December 2017 to August 2020. Participants diagnosed with peripheral tuberculous lymphadenitis were included for a longitudinal follow-up utilizing ultrasonography with two-dimensional SWE to record sonographic features and the maximum elasticity value (Emax). We defined PUR as the development of any worsening symptoms of the pre-existing lymphadenitis within one month after the previous ultrasonography. A total of 108 sonographic and SWE examinations were performed in 20 enrollees (75% woman), and their mean ( ± standard deviation) age was 49.6 ( ± 22.7) years. The area under the receiver operating characteristic curve of Emax to predict the next-month PUR was 0.906 at the cut-point of 85 kPa, with an accuracy of 87.0%, a sensitivity of 81.1% and a specificity of 87.9%. Multivariate analysis indicated that Emax > 85 kPa (OR: 24.85, 95% CI: 4.01-154.08, p < 0.001), Emax increment rate >2 kPa/month (OR: 15.14, 95% CI: 4.24-54.06, p < 0.001), and heterogeneous echogenicity (OR: 4.37, 95% CI: 1.16-16.43, p = 0.029) were independent sonographic predictors for PUR in the coming month. A high and non-declining Emax level and heterogeneous echogenicity were associated with the next-month PUR of tuberculous lymphadenitis. Ultrasonography with SWE may be a potential radiologic marker to predict the therapeutic response of tuberculous lymphadenitis.


Natural Genetic Variation for Growth and Development Revealed by High-Throughput Phenotyping in Arabidopsis thaliana.
Leaf growth and development determines a plant's capacity for photosynthesis and carbon fixation. These morphological traits are the integration of genetic and environmental factors through time. Yet fine dissection of the developmental genetic basis of leaf expansion throughout a growing season is difficult, due to the complexity of the trait and the need for real time measurement. In this study, we developed a time-lapse image analysis approach, which traces leaf expansion under seasonal light variation. Three growth traits, rosette leaf area, circular area, and their ratio as compactness, were measured and normalized on a linear timescale to control for developmental heterogeneity. We found high heritability for all growth traits that changed over time. Our study highlights a cost-effective, high-throughput phenotyping approach that facilitates the dissection of genetic basis of plant shoot growth and development under dynamic environmental conditions.


Gated three-terminal device architecture to eliminate persistent photoconductivity in oxide semiconductor photosensor arrays.
The composition of amorphous oxide semiconductors, which are well known for their optical transparency, can be tailored to enhance their absorption and induce photoconductivity for irradiation with green, and shorter wavelength light. In principle, amorphous oxide semiconductor-based thin-film photoconductors could hence be applied as photosensors. However, their photoconductivity persists for hours after illumination has been removed, which severely degrades the response time and the frame rate of oxide-based sensor arrays. We have solved the problem of persistent photoconductivity (PPC) by developing a gated amorphous oxide semiconductor photo thin-film transistor (photo-TFT) that can provide direct control over the position of the Fermi level in the active layer. Applying a short-duration (10 ns) voltage pulse to these devices induces electron accumulation and accelerates their recombination with ionized oxygen vacancy sites, which are thought to cause PPC. We have integrated these photo-TFTs in a transparent active-matrix photosensor array that can be operated at high frame rates and that has potential applications in contact-free interactive displays.


A new method for antimony speciation in plant biomass and nutrient media using anion exchange cartridge.
A selective separation method based on anion exchange cartridge was developed to determine antimony (Sb) speciation in biological matrices by graphite furnace atomic absorption spectrophotometry (GFAAS). The selectivity of the cartridge towards antimonite [Sb(III)] and antimonate [Sb(V)] reversed in the presence of deionized (DI) water and 2mM citric acid. While Sb(V) was retained by the cartridge in DI water, Sb(III) was retained in citric acid media. At pH 6, Sb(III) and Sb(V) formed Sb(III)- and Sb(V)-citrate complexes, but the cartridge had higher affinity towards the Sb(III)-citrate complex. Separation of Sb(III) was tested at various concentrations in fresh and spent growth media and plant tissues. Our results showed that cartridge-based Sb speciation was successful in plant tissues, which was confirmed by HPLC-ICP-MS. The cartridge retained Sb(III) and showed 92-104% Sb(V) recovery from arsenic hyperaccumulator Pteris vittata roots treated with Sb(III) and Sb(V). The cartridge procedure is an effective alternative for Sb speciation, offering low cost, reproducible results, and simple Sb analysis using GFAAS.


[Exposure therapy for panic disorder and agoraphobia in the context of existing antidepressive medication].
Cognitive behavioral therapy (CBT) and pharmacotherapy with antidepressants are both a highly effective treatment for agoraphobia and/or panic disorder; however, a combination of CBT and antidepressants is under debate due to potentially unfavorable interference effects. The associations of existing antidepressant medication with panic and agoraphobia symptom burden and their change in the context of a structured 5‑week day hospital and exposure-focused treatment in a naturalistic setting were investigated. Out of a total of n = 488 patients medication use during treatment was retrospectively determined for n = 380: n = 100 (26.3%) were taking antidepressants of different drug classes. Calculations were performed using multiple linear regression analysis, t‑tests, response analyses, and χ2-tests. Patients with existing antidepressant medication more often met the criteria for comorbid depressive disorder (p < 0.001). The measure of symptom change and treatment response rates did not differ between patients with and without antidepressants with respect to anxiety symptoms. In the context studied, patients with and without existing antidepressant medication benefited equally from CBT with respect to anxiety symptoms.


Monitoring phospholipids for assessment of ion enhancement and ion suppression in ESI and APCI LC/MS/MS for chlorpheniramine in human plasma and the importance of multiple source matrix effect evaluations.
Biological matrix effects are a source of significant errors in both electrospray (ESI) and atmospheric pressure chemical ionization (APCI) LC/MS. Glycerophosphocholines (GPChos) and 2-lyso-glycerophosphocholines (2-lyso GPChos) are known to fragment to form ions at m/z 184 and m/z 104, respectively. Phospholipids were used as markers to evaluate matrix effects resulting in both ion suppression and enhancement using ESI and APCI modes in the determination of chlorpheniramine in human plasma. Results revealed that GPChos and 2-lyso GPChos demonstrated very low ionization efficiency in the APCI mode, post-column infusion experiments were performed to confirm that suppression and enhancement matrix ionization effects coincided with the elution profiles of the phospholipids. The mean matrix effect for chlorpheniramine using APCI was 75% less than the mean matrix effect in ESI, making APCI the ionization method of choice initially even though the absolute response was lower than in the ESI mode. The resulting APCI method showed acceptable results according to the FDA guidelines; however, a multiple source relative matrix effects study demonstrated variability. It was concluded that an absolute matrix effects study in one source of biological fluid may be not sufficient to ensure the validity of the method in various sources of matrix. In order to obviate the multiple matrix source variability, we employed an isotopically labeled internal standard for quantification of chlorpheniramine in the ESI mode. An additional validation was completed with the use of chlorpheniramine-d(6) as the internal standard. This method met all acceptance criteria according to the FDA guidelines, and the relative matrix affects study was successful.


Topography of the C terminus of cytochrome b5 tightly bound to dimyristoylphosphatidylcholine vesicles.
Cytochrome b5 holoenzyme was bound asymmetrically in the tightly bound form to small unilamellar dimyristoylphosphatidylcholine vesicles. [3H]Taurine, a membrane-impermeant nucleophile, was added to the external medium and was then cross-linked to cytochrome carboxyl residues by the addition of a water-soluble carbodiimide. Nonpolar peptide was isolated after trypsin digestion of taurine-labeled apocytochrome b5 and contained 1.7-1.9 residues of taurine. The C-terminal tetrapeptide containing residues Thr130-Asn133 was generated by chymotryptic hydrolysis of radiolabeled nonpolar peptide and was purified by gel filtration and ion exchange chromatography. Amino acid analysis of the C-terminal tetrapeptide showed that about 1.6 mol of taurine was cross-linked per mol of peptide. When the experiment was performed with taurine trapped inside the vesicles, no cross-linking was observed. The results suggest that when cytochrome b5 holoenzyme is bound to vesicles in the tight binding form, the C terminus is located on the external surface of the vesicles.


A success targeted nano delivery to lung cancer cells with multi-walled carbon nanotubes conjugated to bromocriptine.
In this research, a new nano drug-based multi-walled carbon nanotubes (MWCNTs) was prepared and evaluated qualitatively. Bromocriptine (BRC) was conjugated to functionalized carbon nanotubes. Then, the CHNS, FT-IR, SEM, and RAMAN tests for characterization of the conjugated drug were done. The nanofluid-containing nano-drug was evaluated on lung cancer cells (A549 & QU-DB) and MRC5 by MTT and flow cytometry tests. Then, the gene expression studies of dopamine receptor genes were done before and after nano-drug treatment. After that, a western blotting test was carried out for further investigation of dopamine receptors protein production. Finally, Bax and Bcl-2 secretion were measured by the ELISA method in cells affected by MWCNTs-BRC Nf compared to untreated cells. The results showed that the nano-drug had a significant lethal effect on cancer cells, while it had no toxicity on MRC5. Also, the nano-drug could significantly induce apoptosis in lung cancer cells at a lower dose compared to the drug alone. In this study, a targeted nano-drug delivery system was designed, and its performance was evaluated based on neurotransmitter pathways, and the results showed that it may be useful in the treatment of lung cancer. However, additional studies on animal models are underway.


Hyaluronic acid carrier-based photodynamic therapy for head and neck squamous cell carcinoma.
Conventional photosensitizers for photodynamic therapy (PDT) typically have wide tissue distribution and poor water solubility. A hyaluronic acid (HA) polymeric nanoparticle with specific lymphatic uptake and highly water solubility was developed to deliver pyropheophorbide-a (PPa) for locally advanced head and neck squamous cell carcinoma (HNSCC) treatment. PPa was chemically conjugated to the HA polymeric nanoparticle via an adipic acid dihydrazide (ADH) linker. The conjugates were injected subcutaneously in a region near the tumor. Near-infrared (NIR) imaging was used to monitor distribution, and diode laser was used to activate PPa. The singlet oxygen generation efficiency of PPa was not affected by conjugation to HA nanoparticles at a PPa loading degree of 1.89 w.t.%. HA-ADH-PPa inhibited human HNSCC MDA-1986 cell growth only when photo-irradiation was applied. After HA-ADH-PPa treatment and radiation, NU/NU mice bearing human HNSCC MDA-1986 tumors showed reduced tumor growth and significantly enhanced survival time compared with an untreated group (p < 0.05). These results demonstrate that HA-ADH-PPa could be useful for in vivo locoregional photodynamic therapy of HNSCC.


New method of sentinel node detection using a combination of contrast-enhanced ultrasound and dye guidance: an animal study.
To determine whether a combination of contrast-enhanced ultrasound-guided methods and dye-guided methods can identify sentinel lymph nodes in animals. Seven pigs were put under general anesthesia and injected subcutaneously in the neck: three with 2 ml saline and four with 2 ml fluid comprising 0.4 ml 5% patent blue violet solution and 1.6 ml of hydroxyethylated starch (Salinhes) solution (PB + HS). The regional lymph nodes were observed by ultrasound; blue-stained regional lymph nodes found after the skin was cut were situated as ultrasound had shown they would be. The regional lymph nodes of the pigs given saline were unchanged, but in the pigs receiving PB + HS, the echo level in the lymph nodes nearest the injection site was altered, producing a clear contrast with the surrounding tissues. The area of the relevant regional lymph node in each PB + HS-injected pig increased significantly (t-test, P < 0.01; from 25.7, 39.6, 9.36, 70.2 mm(2), and mean, 36.2 mm(2); to 50.7, 65.5, 21.1, 98.3 mm(2), and mean, 58.9 mm(2), respectively). These enlarged regional lymph nodes were easily found by contrast-enhanced ultrasonography. When excised under ultrasound guidance, all were stained blue, indicating that they were sentinel lymph nodes. These results suggest that this combination of contrast-enhanced ultrasound-guided and dye-guided methods warrants use as a quick, simple procedure for detecting sentinel lymph nodes.


Functional discrepancies between tumor necrosis factor and lymphotoxin alpha explained by trimer stability and distinct receptor interactions.
Tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) are closely related cytokines which bind with nearly identical affinities to the same pair of cell surface receptors, p55 and p75TNFR. Therefore it is assumed that TNF and LT alpha are redundant cytokines. This study, however, demonstrates that TNF and LT alpha differ significantly with regard to their mitogenic and cytotoxic potentials. LT alpha's superior mitogenic effect could be explained by its formation of a more stable trimer. In contrast to the TNF trimer, which disintegrated under physiological conditions into biologically inactive monomers, the LT alpha trimer remained stable for several days. Accordingly, LT alpha more effectively induced fibroblast growth which demands long-term presence of the cytokine. TNF's superior cytotoxicity, which requires only short-term impact of the cytokine, could be attributed to a distinct interaction with the human p55TNFR. This was demonstrated in NIH 3T3 cells transfected with the human p55TNFR, where cytotoxicity is mediated exclusively by the transfected receptor. Although the p55ATNFR had virtually identical affinities for TNF and LT alpha, as defined by Scatchard analysis, it nevertheless discriminated between binding of each cytokine and showed a 200-fold enhanced cytotoxicity mediated by TNF.


Contribution of atmospheric N deposition to riverine N load in a forest-dominated watershed through field monitoring for three years.
Increased atmospheric nitrogen (N) deposition significantly impacts N cycling in freshwater ecosystems. Relative to lakes, the importance of N deposition in riverine N load is less studied. Thus, this study monitored N deposition and riverine N load for three years and then used the export coefficient model to explore N deposition's contribution to riverine N load in a forest-dominated watershed. It is found that the annual export of total N (TN) deposition could explain 17.4%-19.2% of riverine TN load. The contribution of TN deposition to riverine TN load was significantly higher (P < 0.05) during the crop production period (recorded as CPP, lasting from June to September, 22.7%) than the non-crop production period (Non-CPP, 13.8%). The application of chemical fertilizer and manure and the high precipitation were assumed as the primary reason for the increased N deposition and increased riverine TN load during CPP. This study shows that inland plain agriculture practices might considerably influence the nearby forest-dominated watershed, and it is necessary to develop sustainable agriculture programs for reducing riverine N load.


Radial microcolumnar cortical architecture: maturational arrest or cortical dysplasia?
The fetal neocortical plate, from initiation of radial migration at 5 weeks' gestation until midgestation, exhibits radial microcolumnar architecture. Horizontal histologic layering or lamination becomes superimposed in the second half of gestation, although residua of the columnar pattern persist postnatally, particularly where the cortex bends: at the crowns of gyri and in the depths of sulci. Columnar architecture of the cortical plate in the first half of gestation mostly results from radial migration of neuroblasts, but the Cajal-Retzius neurons and GABAergic neuroblasts from tangential migration regulate a transition to horizontal lamination of the mature cortex. In children and adults, prominent columnar architecture is a feature of many focal cortical dysplasias and is now recognized as a distinctive pattern of focal cortical dysplasias in the new International League Against Epilepsy classification. It also occurs, however, in many genetic syndromes and chromosomopathic conditions, including 22q12 deletions (DiGeorge syndrome), in several primary cerebral malformations, in the contralateral cingulate gyrus in hemimegalencephaly, in cortical tubers of tuberous sclerosis, in the margins of porencephalic cysts resulting from prenatal infarcts, and in some inborn metabolic defects such as methylmalonic acidemia. Synaptophysin demonstrates both radial and horizontal lamination of synaptic layers. Persistent fetal cortical architecture is potentially epileptogenic. We conclude that columnar architecture is a maturational arrest in histogenesis of the neocortical plate and becomes a component of cortical dysplasia in the perinatal period. An initially physiological process thus becomes pathologic by virtue of advancing age, but traces of it persist in normal mature brains. It also occurs in many genetic and inborn metabolic diseases and after acquired ischemic insults of the fetal brain.


Requests for electromyography from general practitioners and specialists: critical evaluation.
In order to improve the quality of service and limit costs of a local electromyographic service, the requests for electromyographic (EMG) examination issued by general practitioners and specialists were critically evaluated. The diagnoses suspected by referring doctors were compared with medical history and clinical data to analyze (1) the utility of EMG for the final diagnosis and (2) the concordance with that of the neurophysiologist and with the EMG results. In 1994 and 1995, there were 3482 patients referred to the EMG service. Only patients undergoing EMG for the first time (2706 subjects) were considered. In 76.6% of cases, the referring doctor had indicated the suspected diagnosis in the request. This diagnosis was compatible with medical history, symptoms and the results of neurological examination in 57.6% of cases. In 77.2%, the neurophysiologist considered the EMG useful in confirming the clinical diagnosis. The suspected diagnosis was confirmed by the clinical diagnosis of the neurophysiologist and by the EMG results in 54.2% and 45.4% of cases, respectively. When the request was issued by neurosurgeons, neurologists, orthopedists, rheumatologists and physiatrists, the suspected diagnosis was more accurate; as a consequence the EMG was more correctly oriented than when the request was issued by other specialists or by general practitioners. It is recommended that neurological examination be a prerequisite for EMG requests issued by general practitioners.


Advances toward Diagnostic Tools for Managing Zoonotic Visceral Leishmaniasis.
Visceral leishmaniasis (VL) is a life-threatening outcome of Leishmania infantum or Leishmania donovani infection. Dogs are the primary domestic reservoir of L. infantum parasites, and ownership of infected dogs increases the risk of human VL. Controlling infection within dog populations is regarded as critical to VL management in endemic countries, both preventing progression of canine disease and limiting parasite transmission to humans and dogs. Here we discuss various strategies that are used to diagnose canine visceral leishmaniasis (CVL) and the possibilities of adapting these for use within population screening and control programs. In addition, given the variable transmissibility of L. infantum to the sand fly vector, we outline some possibilities for the preferential identification of 'super-spreader' dogs among the overall infected population.


Conditioned taste avoidance induced by the combination of heroin and cocaine: Implications for the use of speedball.
Speedball (heroin + cocaine) is a prevalent drug combination among intravenous drug users. Although its use is generally discussed to be a function of changes in the rewarding effects of either or both drugs, changes in the aversive effects of either drug may also be impacted (weakened) by the combination. To address this latter possibility and its potential role in the use of speedball, the present studies examined the interaction of cocaine and heroin in taste avoidance conditioning. In Experiment 1, male Sprague-Dawley rats were given access to a novel saccharin solution and then injected with either vehicle or heroin (3.2 mg/kg, IP) followed immediately by various doses of cocaine (10, 18 or 32 mg/kg, SC). At the two lowest doses of cocaine, only animals injected with the drug combination (H + C) displayed a taste avoidance relative to control subjects (taste avoidance was induced with both the combination and the high dose of cocaine). At no dose did animals injected with the combination of heroin and cocaine drink more than animals injected with cocaine alone. In Experiment 2, male Sprague-Dawley rats were similarly treated but injected with vehicle or cocaine (10 mg/kg) followed by injections of various doses of heroin (1.8, 3.2, 5.6 or 10 mg/kg). At the three highest doses of heroin, only animals injected with the drug combination (C + H) displayed significant avoidance relative to control subjects (no avoidance was evident with the combination of cocaine and the low dose of heroin). At no dose did animals injected with the combination of cocaine and heroin drink more than animals injected with heroin alone. Together, these results suggest that the aversive effects of heroin and cocaine are not attenuated by co-administration by cocaine and heroin, respectively. The importance of this for the use of speedball was discussed.


Lenticonus anterior and Alport's syndrome.
Six patients, from five families, five males and one female, suffering from lenticonus anterior are presented. Furthermore, all suffered from chronic nephritis and nerve deafness and must be considered cases of Alport's syndrome. As all cases with lenticonus anterior which have been published within the last 13 years likewise were affected with nerve deafness and/or chronic nephritis, the assumption is submitted that lenticonus anterior exists exclusively as a part of Alport's syndrome. It is pointed out that four patients had a weakened bilateral macula reflex with changes in pigmentation. Attention is drawn to the fact that patients with lenticonus anterior often have a cornea astigmatism of 2-3 D. A complete table of all reported patients with anterior lenticonus is presented.


Automatic model-based contour detection of left ventricle myocardium from cardiac CT images.
For accurate evaluation of myocardial perfusion on computed tomography images, precise identification of the myocardial borders of the left ventricle (LV) is mandatory. In this article, we propose a method to detect the contour of LV myocardium automatically and accurately. Our detection method is based on active shape model. For precise detection, we estimate the pose and shape parameters separately by three steps: LV coordinate system estimation, myocardial shape estimation, and transformation. In LV coordinate system estimation, we detect heart features followed by the entire LV by introducing machine-learning approach. Since the combination of two types feature detection covers the LV variation, such as pose or shape, we can estimate the LV coordinate system robustly. In myocardial shape estimation, we minimize the energy function including pattern error around myocardium with adjustment of pattern model to input image using estimated concentration of contrast dye. Finally, we detect LV myocardial contours in the input images by transforming the estimated myocardial shape using the matrix composed of the vectors calculated by the LV coordinate system estimation. In our experiments with 211 images from 145 patients, mean myocardial contours point-to-point errors for our method as compared to ground truth were 1.02 mm for LV endocardium and 1.07 mm for LV epicardium. The average computation time was 2.4 s (on a 3.46 GHz processor with 2-multithreading process). Our method achieved accurate and fast myocardial contour detection which may be sufficient for myocardial perfusion examination.


Interferon (IFN)-alpha 2 genotype analysis of Chinese chronic hepatitis B patients undergoing recombinant IFN-alpha 2a therapy.
Sixteen Chinese chronic hepatitis B virus (HBV)-infected patients were treated with recombinant interferon-alpha 2a (rIFN-alpha 2a). Of these, 8 made a response to IFN, with titers of neutralizing antibody of 141-4525 as determined by an antiviral neutralization bioassay. To determine whether the immunogenicity of the IFN was directly linked to the patients' genotype, their genomic DNA was analyzed for the presence of the human IFN-alpha 2a gene. None of the patients possessed the gene for IFN-alpha 2a, but only 50% developed neutralizing antibodies. The hypothesis, therefore, of a direct link between antibody formation and genotype cannot be sustained. Alternative explanations of the immunogenicity of IFN-alpha 2a must be sought.


Methods of Assessing Ovarian Masses: International Ovarian Tumor Analysis Approach.
There are many diagnostic methods to assist clinicians in assessing adnexal masses on ultrasound. After suggesting a standardized terminology and measurement technique to evaluate adnexal masses, the International Ovarian Tumor Analysis (IOTA) group has developed different strategies such as the Simple Rules and Assessment of Different Neoplasias in the adneXa (ADNEX) model, which have been shown to outperform other available methods. Besides differentiating between benign neoplasms and malignancies, the ADNEX model can also give the predicted risk for different subtypes of malignant adnexal masses, which is clinically very relevant for guiding patient management.


Lopinavir/ritonavir monotherapy as maintenance treatment in HIV-infected individuals with virological suppression: results from a pilot study in Brazil.
The aim of the study was to evaluate the possibility of using lopinavir/ritonavir (LPV/RTV) alone as maintenance therapy in HIV-infected individuals with virological suppression. This was a single-armed single-centre pilot trial. Asymptomatic HIV-infected patients on highly active antiretroviral therapy (HAART) including LPV/RTV, and with plasma HIV RNA <40 copies/mL for at least 6 months, were enrolled in the study, during which they continued with LPV/RTV alone. The intention was to recruit 25 patients to be followed for 2 years. Viral failure was defined as two consecutive HIV RNA measurements >40 copies/mL. Nadir and baseline CD4 cell counts, highest ever HIV RNA load, time with undetectable viraemia before monotherapy, number of previous antiretroviral (ARV) regimens, and gene polymorphism at CYP3A4 and CYP3A5 were evaluated. All patients (27) completed the study. Their median age was 43 years, and 66% were men. Ten patients (37%) failed to maintain virological suppression (the median time to HIV rebound was 10.5 months, with a range of 4-23 months). One patient developed full resistance to LPV and another developed neurocognitive impairment while on LPV/RTV which improved after HAART reintroduction. There were no differences between failures and nonfailures according to the analysed parameters. Patients with viral failure were successfully resuppressed. LPV/RTV maintenance therapy was associated with 37% failure, a higher than expected failure rate. In order to ensure that unnecessary risks are not being taken in patients on LPV/RTV, this finding should be further evaluated in large randomized trials for longer periods of follow-up.


Early renal recovery after acute kidney injury in patients on venoarterial extracorporeal membrane oxygenation: A retrospective study.
The impact of VA-ECMO on early renal recovery (within 7 days after ECMO onset) in patients with pre-ECMO acute kidney injury and cardiogenic shock is unknown. This retrospective single-center study included adult patients with cardiogenic shock rescued by VA-ECMO and severe AKI occurring before ECMO implantation (pre-ECMO AKI). Patients with early renal recovery (defined as at least a 50% decrease in peak serum creatinine or weaning from renal replacement therapy) were compared to patients without early renal recovery. During 7 years, 145 patients with severe pre-ECMO AKI were included. Eighty-two patients had no early renal recovery whereas 63 had early renal recovery within 7 days after VA-ECMO onset. The median time to early renal recovery was 4 (3,6) days. Nephrotoxic antibiotics (HR = 0.35 [95% CI, 0.21-0.59], p < 0.001), median fluid balance during the first 7 days of VA-ECMO (HR = 0.77 [95% CI, 0.64-0.93], p = 0.008), pre-ECMO AKI stage 3 (HR = 0.36 [95% CI, 0.20-0.64], p < 0.001) and median vasoactive-inotropic score (HR = 0.99 [95% CI, 0.98,1.00], p = 0.035) were independently associated with no early renal recovery. Only 43% of patients with severe pre-ECMO AKI had early renal recovery after VA-ECMO initiation.


The physical significance of Km in the prothrombinase reaction.
Key kinetic parameters for the prothrombinase complex formed on membranes of phosphatidylserine (PS)/phosphatidylcholine (PC) (40/60) (Km = 0.12 microM, kcat = 11 s-1) or PS/PC (2/98) (Km = 0.40 microM, kcat = 11 s-1) differed only slightly. In contrast, the density of proteins on the membrane surface at the km differed greatly for the two membranes. The kinetics appeared unaffected by conditions where the number of phospholipid vesicles (2% PS) exceeded the number of protein molecules. These results establish that the Km for the prothrombinase reaction is determined by the concentration of prothrombin in solution rather than its density at the membrane surface. This system can be treated as a dissociable enzyme acting on a soluble substrate.


Tumor-targeted drug delivery using MR-contrasted docetaxel - carboxymethylcellulose nanoparticles.
A carboxymethylcellulose-based polymer conjugate with nanoparticle forming properties (Cellax) has been shown to enhance the pharmacokinetics, specificity of biodistribution, anti-tumor efficacy and safety of docetaxel (DTX) in comparison to the Taxotere™ formulation. We examined Cellax and Taxotere efficacy in four tumor models (EMT-6, B16F10, PC3, and MDA-MB-231), and observed variances in efficacy. To explore whether differences in tumor uptake of Cellax were responsible for these effects, we incorporated superparamagnetic iron oxide nanoparticles (SPIONs) into Cellax particles to enable magnetic resonance (MR) imaging (Cellax-MR). In the EMT-6 tumor model, Cellax-MR nanoparticles exhibited peak tumor accumulation 3-24 h post intravenous injection, and 3 days post-treatment, significant MR contrast was still detected. The amount of Cellax-MR deposited in the EMT-6 tumors was quantifiable as a hypointense volume fraction, a value positively correlated with drug content as determined by LC/MS analysis (R(2) = 0.97). In the four tumor models, Cellax-MR uptake was linearly associated with anti-tumor efficacy (R(2) > 0.9), and was correlated with blood vessel density (R(2) > 0.9). We have affirmed that nanoparticle uptake is variable in tumor physiology, and that this efficacy-predictive parameter can be non-invasively estimated in real-time using a theranostic variant of Cellax.


[Preliminary study on genotype of hepatitis B virus detected from Tibetans in China].
To determine the main genotype of hepatitis B virus (HBV) detected from Tibetans in China and provide basic data for hepatitis control and prevention. The S gene and C gene were amplified by PCR from the sera of HBsAg positive Tibetans. After sequencing, the gene sequences were analyzed and the phylogenetic trees were drawn by the software MEGA3. In trees based on S gene, the sequences of most samples clustered at genotype D, while in trees based on C gene, the sequences of all samples clustered at genotype C. The dominant genotype of HBV detected from Tibetans in China is a C/D hybrid.


Ubiquitin--conserved protein or selfish gene?
The posttranslational modifier ubiquitin is encoded by a multigene family containing three primary members, which yield the precursor protein polyubiquitin and two ubiquitin moieties, Ub(L40) and Ub(S27), that are fused to the ribosomal proteins L40 and S27, respectively. The gene encoding polyubiquitin is highly conserved and, until now, those encoding Ub(L40) and Ub(S27) have been generally considered to be equally invariant. The evolution of the ribosomal ubiquitin moieties is, however, proving to be more dynamic. It seems that the genes encoding Ub(L40) and Ub(S27) are actively maintained by homologous recombination with the invariant polyubiquitin locus. Failure to recombine leads to deterioration of the sequence of the ribosomal ubiquitin moieties in several phyla, although this deterioration is evidently constrained by the structural requirements of the ubiquitin fold. Only a few amino acids in ubiquitin are vital for its function, and we propose that conservation of all three ubiquitin genes is driven not only by functional properties of the ubiquitin protein, but also by the propensity of the polyubiquitin locus to act as a 'selfish gene'.


A short note on the Taeuber paradox.
When the force of mortality is reduced by a constant fraction delta at every age, the relative increase in life expectancy e(0) can be measured by deltaH, where H is determined by the l(a) values of the life table. Although H is not easily reducible in terms of the well-known life table parameters, it has been shown that it can be approximately estimated by 2 - e(0)/a in which a is the average age of the stationary population. It has been found that, for a given value of delta, the relative gain in life expectancy is less appreciable in countries with larger values of e(0).


Lymph node dissection in uterine leiomyosarcomas: A matched-pair study.
To assess the impact of the lymph node dissection (LND) in the disease-free (DFS) and overall survival (OS) of the women treated surgically of uterine leiomyosarcoma (ULMS). A multicentric retrospective study was conducted among European countries collecting patients diagnosed of uterine sarcoma (SARcoma of the UTerus - SARCUT study). A total of 390 ULMS were selected for the present study to compare patients who underwent LND and those who did not. A further matched-pair subanalysis identified 116 women, 58 pairs (58 with LND and 58 without it) comparable in age, tumor size, surgical procedures, extrauterine disease and adjuvant treatment. Demographic data, pathology results and follow-up were abstracted from medical records and analyzed. Disease-free (DFS) and overall survival (OS) were studied using Kaplan-Meier curves and Cox regression analysis. Among the 390 patients, the 5-year DFS was significantly higher in no-LDN group comparing to the LDN group (57.7% vs. 33.0%; HR 1.75, 95% CI 1.19-2.56; p = 0.007), but not the 5-year OS (64.6% vs. 64.3%; HR 1,10 95% CI 0,77-1,79; p = 0.704). In the matched-pair subanalysis, there were no statistical differences between the study groups. The 5- year DFS was 50.5% in the no-LND and 33.0% in the LND group (HR 1.38; 95% CI 0,83-2.31; p = 0,218) and the 5-year OS was 59.7% and 64.3% respectively (HR 0.81; 95% CI 0,45-1,49; p = 0,509). LND performed in women diagnosed of ULMS have no impact neither in the disease-free nor in the overall survival compared to patients without LDN in a complete homogeneous group.


Association between urinary manganese and pulmonary function in young adults: A cross-sectional design with a longitudinal cohort validation.
The impact of heavy metals on pulmonary function among young adults has been scarcely studied, especially by a longitudinal cohort study. We prospectively enrolled 974 young adults (aged 20-45 years) during 2017-2019 and measured pulmonary function and urinary heavy metals, including manganese, copper, chromium, iron, nickel, zinc, cadmium, and lead. Among them, 461 participants had examination of the same urinary heavy metals during 2006-2008, which could be used as a cohort for long-term effect of urinary metals on pulmonary function. In the 974 enrolled participants, urinary heavy metals were within normal range. The urinary manganese level was the only significant factor for the observed/predicted ratios of forced vital capacity (FVC %)(β coefficient: -1.217, p = 0.030), forced expiratory volume in one second (FEV1%)(β: -1.664, p < 0.001), and FEV1/FVC% of predicted (β: -0.598, p = 0.047) in multivariable linear regression under cross sectional design. In cohort analysis, the urinary manganese level was also negatively associated with the FEV1% (β: -1.920, p = 0.021). There was no significance between other urinary heavy metals and pulmonary function for all participants. The urinary manganese significantly negatively correlated with FVC%, FEV1% and FEV1/FVC% in female subgroup whereas copper and iron were significantly negatively correlated with FVC% in male subgroup. Among urinary heavy metals, urinary manganese level was associated with pulmonary function negatively, even the level was within normal range. In addition, women might be more susceptible to manganese. There is emergent need to conduct further investigation to confirm the respiratory hazardous effects of manganese.


Hepatic role in an early glucose-lowering effect by a novel dipeptidyl peptidase 4 inhibitor, evogliptin, in a rodent model of type 2 diabetes.
Although multiple dipeptidyl peptidase 4 (DPP4) inhibitors have shown glucose-lowering effects by preserving pancreatic cells in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice, the hepatic role in regulation of glucose homeostasis by DPP4 inhibitors in HFD/STZ mice remains elusive. In herein study, parallel comparison of effects on the liver (expression of gluconeogenic genes and the linked signaling molecules) and pancreas (islet morphology and relative area of alpha or beta cells) in combination with glucose-lowering effects were made at the end of 2- and 10-week of evogliptin treatment in HFD/STZ mice. Significant control of hyperglycemia was observed from the second week and persisted during 10-week treatment of 0.3% evogliptin in HFD/STZ mice. This effect was accompanied by increased level of plasma glucagon-like peptide-1 and preserved pancreas islet structure. Furthermore, the hepatic increases in gluconeogenic gene expression in HFD/STZ mice was significantly reduced by evogliptin treatment, which was accompanied by the suppression of cAMP response element-binding protein (CREB) phosphorylation and expression of transducer of regulated CREB protein 2. This hepatic effect of evogliptin treatment was reproduced in 2-week study, however, pancreatic beta-cell area was not altered yet although the expression of pancreatic and duodenal homeobox protein 1 was increased. We conclude that the suppression of hepatic gluconeogenesis by evogliptin is followed by preservation of pancreatic islet, leading to remarkable and persistent glucose-lowering effect in HFD/STZ mice. Our findings provide further insight for the hepatic role in DPP4 inhibitor-mediated glucose control in diabetes.


Infliximab exerts no direct hepatotoxic effect on HepG2 cells in vitro.
Infliximab-induced hepatotoxicity is reported in several case studies involving patients with inflammatory bowel disease (IBD) and a direct hepatotoxic effect has been proposed. The aim of this study was to determine the direct in vitro toxicity of infliximab. As a proof of principle the in vitro toxicity of thiopurines and methotrexate was also determined. Cell survival curves and the half maximal inhibitory concentrations (IC(50)) were obtained after 24, 48 and 72 h of incubation in HepG2 cells with the IBD drugs azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate or infliximab by using the WST-1 cytotoxicity assay. No in vitro hepatotoxicity in HepG2 cells was seen with infliximab, while concentration-dependent cytotoxicity was observed when HepG2 cells were incubated with increasing concentrations of azathioprine, 6-mercaptopurine and 6-thioguanine. Infliximab alone or given in combination with azathioprine showed no direct hepatotoxic effect in vitro, indicating that the postulated direct hepatotoxicity of infliximab is unlikely.


Effects of diet consistency on the myosin heavy chain mRNAs of rat masseter muscle during postnatal development.
To study the effects of diet consistency on the fiber phenotypes of rat masseter (1-70 days of age), the mRNAs of myosin heavy chain isoforms (MHC embryonic, neonatal, I, IIa, IId/x and IIb) were measured in total RNA preparations from masseters of hard-diet group (HDG) and soft-diet group (SDG) by competitive reverse transcriptase-polymerase chain reaction (RT-PCR). With respect to the time course of the transition of each MHC mRNA expressed as a percentage relative to the maximum mean, the soft diet facilitated early (9 days after weaning) expression of IId/x and IIb isoforms, and also a decline in the expression of neonatal and IIa isoforms. The expression of neonatal, IIa and IId/x isoforms at 70 days of age was significantly (P<0.05, P<0.01, P<0.01, respectively) lower in SDG than in HDG, indicating a higher relative composition of the IIb isoform in the SDG. Embryonic MHC mRNA had disappeared by 14 days of age (i.e. before weaning at 19 days). No MHC I mRNA was observed in any masseter studied. These results suggest that in the rat a soft diet facilitates an even more MHC IIb-rich phenotype in the masseter muscle than a hard diet.


Modulation of uncoupler-induced sugar uptake in isolated adult rat heart cells by isoproterenol.
When cells (2.4 mg/ml) in the presence of glucose were exposed to 0.15 microM p-trifluoromethoxyphenylhydrazone (FCCP), the time until 50% of the rod-shaped cells had undergone contracture was more than twice as long for cells without isoproterenol as for cells with isoproterenol. The cause of this large effect was revealed in experiments without glucose where 3-O-methylglucose entry, ATP levels, and cellular configuration were measured simultaneously. It was found that the onset of contracture was almost coincident with the decline in total measured ATP, suggesting that, in any cell, contracture was accompanied by a sudden and total ATP loss. In control cells, FCCP stimulated 3-O-methylglucose entry at or before the time this ATP catastrophe occurred. In cells exposed to isoproterenol, however, the stimulation of 3-O-methylglucose entry by FCCP did not occur until after the ATP catastrophe, and the extent of stimulation was reduced. This suggests that, when glucose was present, the FCCP-induced glucose influx was sufficient to significantly delay the onset of contracture in control cells but not in cells treated with isoproterenol. This conclusion was borne out by the observation that the effect of isoproterenol on contracture could be overcome with insulin.


Characterization of undecaprenol kinase from Lactobacillus plantarum.
A membrane-bound undecaprenol kinase from Lactobacillus has been identified by observing the ATP-dependent phosphorylation of [14C]undercaprenol. The product of this reaction was shown to be [14C]undecaprenyl monophosphate by comparison of its chromatographic mobilities with authentic undecaprenyl monophosphate. It was shown that 32P from [gamma-32P]ATP was incorporated into undecaprenyl monophosphate. The kinase was partially solubilized by a variety of methods utilizing Triton X-100. Both the membrane-associated and solubilized enzymes required Mg2+, Triton X-100 and dimethylsulfoxide for activity. The enzyme preferentially phosphorylated the C34, C50 AND C 55 polyprenols. Geranylgeraniol (C20) and dolichol (C100), however, were utilized only 6% and 13% as well as undecaprenol, respectively. Despite the 8-fold difference in apparent V values, the apparent Km values for dolichol and undecaprenol were both 14 microM. The apparent Km for the nucleotide cosubstrate, ATP, was 2 mM. No other nucleoside triphosphate could substitute for ATP.


Characteristics of unbuffered gel-immobilized urease particles. I. Internal pH.
The overall rate of reaction of a gel-immobilized urease particle necessarily depends upon the hydrogen ion concentrations within the particle. When the particle is unbuffered, the internal hydrogen ion concentrations are a consequence of the local rates of reaction and the rate of egress of the products of hydrolysis. A simple apparatus has been devised which allows a fairly rapid determination of the hydrogen ion concentration in the center of a particle for any given size, enzyme concentration, substrate concentration, and external pH. The products of urea hydrolysis are self-buffering in the region of pH 8.83 and for an external pH less than the self-buffering pH, the pH within the particle is increased because of the reaction. When the external pH is greater than the self-buffering pH, the converse occurs. The pH at the center of the particle approaches the self-buffering pH with an increase in particle size and enzyme concentration. The external increase in the external substrate concentration has a limited effect, simply rendering the local rates of reaction to be of zero order. The center-line pH and therefore all internal hydrogen ion concentrations depend upon the parameter L square root pe and the external pH. Differences between the external and center-line pH values of the order of units are unexceptional. The implications of the internal pH profiles on the local and overall rates of reaction are explored.


Verrucous carcinoma of the penis (Buschke-Lowenstein tumour): a clinico-pathological study.
The variant of squamous carcinoma of the penis known as verrucous carcinoma is an uncommon but distinct clinical and pathological condition which has a significantly better prognosis than the more common infiltrative type. We report seven cases from a continuing larger study of the disease and discuss the clinical features, the histological criteria for diagnosis and the methods of treatment available.


NW Iberian Peninsula coastal upwelling future weakening: Competition between wind intensification and surface heating.
Climate change will modify the oceanographic future properties of the NW Iberian Peninsula due to the projected variations in the meteorological forcing, that will intensify local winds and promote surface heating. The Delft3D-Flow model forced with atmospheric conditions provided within the framework of the CORDEX project under the RCP 8.5 greenhouse emission scenario was used to analyse changes in upwelling. Numerical experiments were conducted under high-extreme upwelling conditions for the historical (1976-2005) and future (2070-2099) period. This study also innovates through the exploitation of a numerical modelling approach that includes both shelf and estuarine processes along the coastal zone. Coastal upwelling will be less effective in the future despite the enhancement of upwelling favorable wind patterns previously predicted for this region. Upwelling weakening is due to the future sea surface warming that will increase the stratification of the upper layers hindering the upward displacement of the underlying water, reducing the surface input of nutrients.


Important interventions in the operating room to prevent bacterial contamination and surgical site infections.
The aim of this study was to explore interventions that Swedish operating room (OR) nurses considered important for the prevention of bacterial contamination and surgical site infections (SSIs). A web-based cross-sectional survey with an open-ended question was answered by OR nurses and analyzed using summative content analysis and descriptive statistics. The OR nurses (n = 890) worked within 11 surgical specialties and most of them worked at university hospitals (37%) or county hospitals (53%). The nurses described twelve important interventions to prevent bacterial contamination and SSI: skin disinfection (25.9%), the OR environment (18.2%), aseptic technique (16.4%), OR clothes (13.4%), draping (9.8%), preparation (6.1%), dressing (3.6%), basic hygiene (3.4%), normothermia (2.1%), communication (0.7%), knowledge (0.3%), and work strategies (0.2%). Skin disinfection was considered the most important intervention in order to prevent bacterial contamination and SSI. The responses indicated that many OR nurses believed the patients' skin to be sterile after the skin disinfection process. This is not a certainty, but skin disinfection does significantly decrease the amount of bacterial growth. This study shows that many OR nurses' interventions are in line with recommendations. Although, knowledge regarding the effect of skin disinfection needs further research, and continued education.


A pilot and feasibility study of a cognitive behavioural therapy-based anxiety prevention programme for junior high school students in Japan: a quasi-experimental study.
There is a good deal of evidence that cognitive behavioural therapy is effective for children and adolescents with anxiety-related problems. In Japan, an anxiety prevention programme based on cognitive behavioural therapy called 'Journey of the Brave' has been developed, and it has been demonstrated to be effective for elementary school students (aged 10-11 years). The purpose of this study was to have classroom teachers deliver the programme to junior high school students (aged 12-13 years) and to test the feasibility and efficacy of the programme in this setting. This study was a prospective observational study and was approved by the Chiba University Review Board. An intervention group consisting of six classes of students in their first year of junior high school at two different schools (n = 149; 81 boys, 68 girls) received seven 50-min programme sessions. Participants in the control group were recruited from four classes of students in their second year of junior high school at one school (n = 89; 51 boys, 38 girls). All participants completed the Spence Children's Anxiety Scale at pre-test, post-test, and 2-3 month follow-up. Statistical analysis was conducted using a mixed-effects model for repeated measures model. Mean total anxiety scores indicated a non-significant decrease at the 2-3 month follow-up for the intervention group compared to the control group. The group differences on the SCAS from baseline to post-test was - .71 (95% CI - 2.48 to 1.06, p = .43), and the 2-3 month follow-up was - .49 (95% CI - 2.60 to 1.61, p = .64). In this pilot study, implementation of the programme confirmed the partial feasibility of the programme but did not elicit a significant reduction in anxiety scores. In addition, there are several methodological limitations to this study. In the future, we propose to test the feasibility and efficacy of the programme with the required sample size and by comparing groups with equal characteristics as well as by carrying out additional follow-up assessments.Trial registration UMIN000032517.


Clonal karyotype abnormalities and clinical progress in the myelodysplastic syndrome.
Clonal karyotype abnormalities in 124 patients with myelodysplastic syndrome are reviewed. 36% of patients had abnormalities at referral, the most common being 5q-, +8 and lesions of chromosomes 7 and 20. Reduced survival was associated with the presence of either single or multiple clonal abnormalities at referral, abnormalities of chromosome 7 or 8 (either alone or with other lesions) and exclusively abnormal metaphases. The presence of 5q- alone did not appear to affect survival. Sequential studies were carried out in 77 patients of whom 12 showed karyotypic evolution. Reduced survival was observed in patients with an evolving karyotype but appeared to be due almost entirely to evolution in those patients whose initial karyotype was normal. Leukaemic transformation occurred more commonly in patients with an abnormal karyotype, particularly those with multiple abnormalities, and in patients with an evolving karyotype. Although the first appearance of an abnormal karyotype or an apparent evolution are important phenomena, it is probable that in some cases they merely represent expansion of a previously existing clone that has escaped detection. The distinction between true karyotypic evolution or clonal expansion and statistical variations due to small sample size and variability of samples may be difficult but needs to be taken into account in considering clinical significance.


Updating the evidence for an association between anxiety and risk of Alzheimer's disease: A meta-analysis of prospective cohort studies.
Anxiety is postulated to be a modifiable risk factor for Alzheimer's disease (AD). Our primary aim was to conduct a meta-analysis of prospective cohort studies investigating the association between anxiety and AD risk. We searched multiple scientific databases to identify relevant papers published up to March 2019. Inclusion criteria were: prospective cohort studies with a minimum follow-up period of 1 year, baseline anxiety assessment, absence of dementia at baseline, investigated the association between anxiety and AD incidence, and reporting Relative Risks (RRs), or equivalents (HRs and SHRs), for the association between anxiety and AD risk. We excluded studies that: focused on subjective memory or mild cognitive impairment samples, review and meta-analyses, not reporting original, published peer-reviewed results. We used a random-effects model that accommodated the differences in association statistics. 7 prospective cohorts (reported in 6 studies), with a total of 24,528 participants, were included in our meta-analysis. A marginally significant association between anxiety and AD risk was found, with a pooled RR of 1.45 (95% CI: 1.00-2.12), and a population attributable fraction for AD of 2.8% (95% CI: 1.2%-4.3%). There was a high level of heterogeneity across the studies, which may be associated with differences in the covariates adjusted for. Studies also differed considerably in how they measured anxiety. Anxiety is marginally associated with an increased risk of AD in this meta-analysis. Future research is needed to determine the extent to which anxiety might be a cause of AD rather than a prodrome or marker.


Analysis of human mini-exome sequencing data from Genetic Analysis Workshop 17 using a Bayesian hierarchical mixture model.
Next-generation sequencing technologies are rapidly changing the field of genetic epidemiology and enabling exploration of the full allele frequency spectrum underlying complex diseases. Although sequencing technologies have shifted our focus toward rare genetic variants, statistical methods traditionally used in genetic association studies are inadequate for estimating effects of low minor allele frequency variants. Four our study we use the Genetic Analysis Workshop 17 data from 697 unrelated individuals (genotypes for 24,487 autosomal variants from 3,205 genes). We apply a Bayesian hierarchical mixture model to identify genes associated with a simulated binary phenotype using a transformed genotype design matrix weighted by allele frequencies. A Metropolis Hasting algorithm is used to jointly sample each indicator variable and additive genetic effect pair from its conditional posterior distribution, and remaining parameters are sampled by Gibbs sampling. This method identified 58 genes with a posterior probability greater than 0.8 for being associated with the phenotype. One of these 58 genes, PIK3C2B was correctly identified as being associated with affected status based on the simulation process. This project demonstrates the utility of Bayesian hierarchical mixture models using a transformed genotype matrix to detect genes containing rare and common variants associated with a binary phenotype.


In vitro immunotoxicological effects of heavy metals on European sea bass (Dicentrarchus labrax L.) head-kidney leucocytes.
The knowledge about the direct effects of heavy metals on fish leucocytes is still limited. We investigate the in vitro effects of heavy metals (Cd, Hg, Pb or As) on oxidative stress, viability and innate immune parameters of head-kidney leucocytes (HKLs) from European sea bass (Dicentrarchus labrax). Production of free oxygen radicals was induced by Cd, Hg and As, mainly after 30 min of exposure. Cd and Hg promoted both apoptosis and necrosis cell death while Pb and As did only apoptosis, in all cases in a concentration-dependent manner. Moreover, expression of genes related to oxidative stress and apoptosis was significantly induced by Hg and Pb but down-regulated by As. In addition, the expression of the metallothionein A gene was up-regulated by Cd and Pb exposure though this transcript, as well as the heat shock protein 70, was down-regulated by Hg. Cd, methylmercury (MeHg) and As reduced the phagocytic ability, whereas Hg and Pb increased it. Interestingly, all the heavy metals decreased the phagocytic capacity (the number of ingested particles per cell). Leucocyte respiratory burst changed depending on the metal exposure, usually in a time- and dose-manner. Interestingly, the expression of immune-related genes was slightly affected by Cd, MeHg, As or Pb being Hg the form producing the greatest alterations, which included down-regulation of immunoglobulin M and hepcidin, as well as the up-regulation of interleukin-1 beta mRNA levels. This study provides an in vitro approach for elucidating the heavy metals toxicity, and particularly the immunotoxicity, in fish leucocytes.


Death investigation in colonial South Australia: the early years 1836-1839.
An account is given on the basis of contemporary records, of the investigation of violent or other unnatural deaths during the first three years of the colony of South Australia.


A structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors.
Killer cell immunoglobulin-like receptors (KIR) play a critical role in the regulation of natural killer (NK) cell activity through their recognition of class I MHC molecules expressed on target cells. KIR recognition provides vital information to NK cells about whether a target cell should be lysed or spared. Understanding the molecular mechanism of this recognition has remained a strong focus of investigation. This has resulted in the crystal structures of several members of the KIR family and more recently the determinations of the three dimensional structures of KIR2DL2 and KIR2DL1 complexed with their respective ligands, HLA-Cw3 and HLA-Cw4. A strong structural conservation has been revealed both in the receptor design and in the overall mode of KIR binding to class I molecules. Nevertheless, distinct differences in the receptor binding sites allow for high specificity between ligands. Furthermore, unexpected similarities with T-cell receptor (TCR) recognition of MHC molecules are also observed. The detailed interactions between KIR and HLA-C molecules and their functional implications will be reviewed here.


Patient navigation through the cancer care continuum: an overview.
Technologic advances, medical specialization, novel payment structures, and an increased scientific knowledge base have resulted in a health care system requiring trained experts to deliver guidance as patients complete care plans: Enter the concept of patient navigation.


Efficacy and safety of iliofemoral bypass using arm veins as an alternative conduit for chronic limb-threatening ischemia.
The use of basilic vein in iliofemoral revascularizations was previously described in the literature as an autologous option for the treatment of vascular prosthesis infection and as a primary conduit in patients at high risk of infectious surgical complications. However, the publications available include several different indications and are limited to case reports. Therefore, the aim of this study was to evaluate the outcomes of the use of arm veins as a safe and effective autologous alternative for iliofemoral reconstruction in patients with chronic limb-threatening ischemia (CLTI) and at high risk of prosthesis infection. We performed a multicenter, retrospective cohort study with 53 consecutive iliofemoral bypasses using arm veins as an alternative conduit. The procedures were performed between November 2013 and November 2021, exclusively for patients with CLTI classified as TASC aortoiliac C or D with increased risk of postoperative surgical infection. Demographic, clinical variables, and outcomes were collected from a prospective database. Main endpoints were amputation-free survival (AFS) and major adverse cardiovascular events. Secondary endpoints included primary and secondary patencies and overall survival. Cox regression analysis was used to identify the predictors of AFS. Postoperative surgical complications and 30-day mortality were also assessed. The mean age was 64.2 ± 8.4 years, with a predominance of male gender. The median follow-up period was 615 days. All patients had CLTI, with a predominance of tissue loss (n = 51; 96.2%) and a median ankle-brachial index of 0.28. The basilic vein was utilized in most procedures (69.8%). Thirty-day major adverse cardiovascular events occurred in five cases (9.4%), and the 30-day mortality rate was 3.8%. The AFS, primary patency, secondary patency, and overall survival in 720 days were 71%, 72%, 89%, and 75%, respectively. Cox regression analysis revealed no association between the variables analyzed for AFS. There was no graft late infection nor pseudoaneurysmal degeneration. Iliofemoral bypass using arm veins as an autologous conduit proved to be an effective and safe procedure with low incidence of postoperative cardiovascular complications and high rates of AFS in patients with CLTI. Also, this suggests that arm veins can be an interesting and suitable autologous alternative conduit for iliofemoral reconstructions, especially in cases in which a prosthesis should be avoided or when it is not available.


Evidence of Large Vestibulo-Ocular Reflex Reduction in Patients With Menière Attacks.
To examine the high frequency horizontal vestibular ocular-reflex (hVOR) during acute attacks of vertigo in Menière's disease (MD). Retrospective case series and literature review. Tertiary academic medical center. Patients with clinical diagnosis of unilateral "definite MD." Review of medical records. Spontaneous nystagmus and the dynamic hVOR gain change at different stages of an acute episode of MD attack. We studied 10 vertigo attacks during the unique stages of the episode. During the acme stage of the attack, lower hVOR gain was recorded on the affected side (mean 0.48 ± 0.23), which was associated with a paralytic nystagmus (beating away from the affected ear). Additionally, the mean hVOR gain remained significantly (p < 0.05) reduced during each of the other stages of the attack as compared with the unaffected side and a control group. After the attack, mean hVOR gains normalized in the affected ear. Mean hVOR gain of the unaffected ear remained normal during all stages. Vestibular function during an attack of MD is a dynamic process associated with fluctuation of the dynamic (hVOR gain) and static (spontaneous nystagmus) processes, which exist in parallel with the perception of vertigo. Our data support vHIT monitoring during an episode to provide objective and accurate evidence of the ear with active disease. This would be particularly useful for those patients with MD presentations of unreliable hearing or assisting to identify the ear to be treated in the case of bilateral MD.


A prospective, randomized trial of Roux-en-Y reconstruction with isolated pancreatic drainage versus conventional loop reconstruction after pancreaticoduodenectomy.
Postoperative pancreatic fistula (POPF) is a major and serious complication after pancreaticoduodenectomy (PD). There have been no prospective randomized trials evaluating POPF rates in Roux-en-Y reconstruction (RYR) with isolated pancreatic drainage versus conventional loop reconstruction (CLR). The authors hypothesized that RYR decreases the incidence and severity of POPF in patients after PD. Between January 2006 and April 2012, the findings for 216 patients were analyzed in this multicenter, prospective trial in China. After providing appropriate preoperative informed consent, patients were randomly assigned to either RYR or CLR after completion of pancreaticoduodenal resection. We referred to the Johns Hopkins fistula definition and classified POPF as grade A, B, or C according to the International Study Group of Pancreatic Fistula classification. The incidence of POPF was similar in the RYR (15.7%, 17/107) and CLR (17.6%, 19/109) groups. Both univariate and multivariate logistic regression analyses revealed that the factor most highly associated with POPF was ampullary or duodenal disease (P < .05). The incidence of type B POPF was higher in the CLR than in the RYR group. Furthermore, patients with POPF in the CLR group had a significantly longer postoperative hospital stay (31.9 ± 6.9 days) and higher total hospital costs than did the patients in the RYR group (P < .05). These data do not support the hypothesis that RYR is associated with a lower incidence of POPF than is CLR. However, they do indicate that RYR may contribute to decreasing fistula severity, duration of stay, and hospital expense.


Selective segregation of DNA strands persists in long-label-retaining mammary cells during pregnancy.
During pregnancy the mammary epithelial compartment undergoes extreme proliferation and differentiation, facilitated by stem/progenitor cells. Mouse mammary epithelium in nonpregnant mice contains long label-retaining epithelial cells (LREC) that divide asymmetrically and retain their template DNA strands. The role of LREC during alveogenesis has not been determined. We performed immunohistochemistry and autoradiography on murine mammary glands that had been labeled with 5-bromodeoxyuridine (5BrdU) during allometric ductal growth to investigate the co-expression of DNA label retention and estrogen receptor-alpha or progesterone receptor during pregnancy. A second DNA label ([3H]-thymidine) was administered during pregnancy to identify label-retaining cells (LRC), which subsequently enter the cell cycle. Use of this methodology allowed us to investigate the co-localization of 5BrdU with smooth muscle actin, CD31, cytokeratin, and desmin in periductal or peri-acinar LRC in mammary tissue from pregnant mice subsequent to a long chase period in order to identify LRC. Estrogen receptor-alpha positive and progesterone receptor positive cells represented approximately 30% to 40% of the LREC, which is under 1.0% of the epithelial subpopulation. Pregnancy altered the percentage of LREC expressing estrogen receptor-alpha. LRC situated in periductal or peri-acinar positions throughout the gland do not express epithelial, endothelial, or myoepithelial markers, and these undefined LRCs persist throughout pregnancy. Additionally, new cycling LREC ([3H]-thymidine retaining) appear during alveologenesis, and LRC found in other tissue types (for example, endothelium and nerve) within the mammary fat pad become double labeled during pregnancy, which indicates that they may also divide asymmetrically. Our findings support the premise that there is a subpopulation of LREC in the mouse mammary gland that persists during alveologenesis. These cells react to hormonal cues during pregnancy and enter the cell cycle while continuing to retain, selectively, their original template DNA. In addition, nonepithelial LRC are found in periductal or peri-acinar positions. These LRC also enter the cell cycle during pregnancy. During alveologenesis, newly created label-retaining ([3H]-thymidine) epithelial cells appear within the expanding alveoli and continue to cycle and retain their original template DNA ([3H]-thymidine) strands, as determined by a second pulse of 5BrdU.


Determinants of bone gamma-carboxyglutamic acid-containing protein in plasma of healthy aging subjects.
The gamma-carboxy glutamic acid (Gla)-containing protein of mammalian bone (BGP, also called osteocalcin) is a 49 amino acid polypeptide containing two to three residues of gamma-carboxyglutamic acid. BGP is synthesized by osteoblastlike cells, and plasma BGP in laboratory animals is derived principally from recently synthesized BGP. These data, taken together with observations that plasma BGP levels are elevated in patients with disorders of high bone turnover, suggest that plasma BGP is a marker of osteoblast activity. Since low bone formation rates may play an important role in the loss of bone mass with age, we have examined the determinants of plasma BGP levels in aging subjects, using a region-specific radioimmunoassay for human BGP based on the synthetic C-terminal peptide hBGP37-49. In 147 carefully screened healthy subjects, aged 23-91, BGP did not change with age, whereas alkaline phosphatase (AP) showed a significant positive correlation (r = 0.30, P less than 0.001). Creatinine clearance (GFR) declined by 0.9 ml/min/yr and correlated with both BGP (r = -0.21, P less than 0.001) and AP (r = -0.21, P less than 0.001). However, correlation of AP with age persisted after controlling for GFR. BGP was not correlated with serum PTH, urine Ca/GFR, or urine cAMP/GFR. In 48 patients with known parenchymal renal disease studied for comparison, plasma BGP was increased at a serum creatinine of greater than or equal to 1.8 mg/dl. Our results indicate that plasma BGP, a specific marker of bone metabolism, is not predictably related to age per se. This result is in contrast to the age-related rise in total AP. Subtle changes in renal function can affect plasma BGP levels.


Effect of sumac (Rhus Coriaria) on blood lipids: A systematic review and meta-analysis.
Cardiovascular diseases (CVD) are the prominent cause of mortality worldwide. Hypercholesterolemia is a chief risk factor for the progress of atherosclerotic vascular disease. Complementary and alternative medicine (CAM) such as herbal interventions has received much attention in literature. Rhus Coriaria (RC) with the general name Sumac is a medicinal spice, especially in Middle Eastern countries which is well known as an anti-lipid spice. This study aimed to summarize the existing findings regarding the effect of RC on the lipid profile. In this review randomized controlled trials (RCTs) assessing the effect of RC on blood lipids were included. Electronic searches using the MeSH terms were conducted in the following databases: Medline, Embase, Scopus, Web of Science and The Cochrane Library. The effect of RC on serum lipid concentration were measured as standardized mean difference (SMD) and 95% confidence intervals (CI) by the random-effects model. The initial search extracted 119 potentially relevant articles. After studying these publications, 4 were potentially eligible and retrieved in full text (four RCTs). Based on the results of the systematic review, RC has positive effects on different indices of the lipid profile including increasing Apo A-I and HDL; decreasing Apo B, Apo B/ Apo A1 ratio, total cholesterol, LDL and triglyceride. However the meta-analysis conducted on three studies on total cholesterol, HDL, LDL and triglyceride individually did not show any significant difference between intervention and control groups. No definite conclusion could be made on the effect of RC on serum blood lipids due to lack of sufficient clinical trials and variable inconsistency. Future trials with desirable designs that would eliminate the limitations in the current evidence are needed before conclusive claims can be made about the effect of RC on the lipid profile.


Psychometric properties of the Care Dependency Scale in stroke survivors in Indonesian hospitals.
This study aimed to evaluate the psychometric properties of the Indonesian version of the Care Dependency Scale (CDS) among stroke survivors. The study was undertaken in four hospitals. We analysed datasets obtained from 109 stroke survivors on inpatient wards and in outpatient clinics, who were rated by nurses to determine the CDS reliability coefficients. The Cronbach's α and Cohen's kappa coefficients were applied. Concurrent validity was conducted for the data on care dependency, which werecollected from 49 of these 109 participants on inpatient wards by nurses using the CDS and the Barthel Index. A Spearman's rank correlation analysis was conducted to measure the association between the CDS and the Barthel Index results. An analysis of the results of the CDS tested on the inpatient ward and in the outpatient clinic revealed a high level of internal consistency. The reliability analysis yielded the same Cronbach's α coefficient of 0.98 for both the inpatient and outpatient data. A significant, moderate correlation was observed between the CDS and Barthel Index results. The CDS can be recommended for use as a tool for the assessment and evaluation of stroke survivors who are receiving acute or long-term care.


Influences of impervious surfaces on ecological risks and controlling strategies in rapidly urbanizing regions.
Reducing ecological risks is important for promoting regional sustainable development. However, studies on the influence of impervious surfaces on ecological risks and risk control strategies in regions undergoing rapid urbanization are limited. Therefore, this study aimed to demonstrate the spatial-temporal dynamics of regional ecological risks using Beijing as a case study to reveal the influence of impervious surfaces and explore the controlling strategies of risks. We first characterized the ecological risks in Beijing based on the ecosystem service values and mapped the risk levels and temporal variations in risks. We then identified the ecological risk increases caused by impervious surface expansion and built linear regression models for impervious surface coverage (ISC) and risk index. Finally, we formulated ecological risk control strategies for the strategy categories identified based on the ISC thresholds. The results show that the mountainous areas mainly exhibited low ecological risk levels, and the plain areas mainly showed high levels. The expansion of impervious surface was the main cause of the relatively large temporal increase in ecological risks from 2005 to 2015. Moreover, the strategies for ecological risk control can be divided into four categories based on the division of ISC, with 30%, 70%, and 90% as the thresholds. For risk control strategies, reducing ISC is the most important measure to reduce ecological risks for the category with an ISC range of 90%-100%, and increasing the area proportions of forests and water bodies is the most effective measure for the category with an ISC range of 0%-30%. For the other two categories, controlling the ISC and other strategies are required. Our study can increase the understanding of the influences of impervious surfaces on ecological risks in rapidly urbanizing regions and help inform the formulation of strategies for controlling the ecological risks in Beijing.


Learning Representations to Predict Intermolecular Interactions on Large-Scale Heterogeneous Molecular Association Network.
Molecular components that are functionally interdependent in human cells constitute molecular association networks. Disease can be caused by disturbance of multiple molecular interactions. New biomolecular regulatory mechanisms can be revealed by discovering new biomolecular interactions. To this end, a heterogeneous molecular association network is formed by systematically integrating comprehensive associations between miRNAs, lncRNAs, circRNAs, mRNAs, proteins, drugs, microbes, and complex diseases. We propose a machine learning method for predicting intermolecular interactions, named MMI-Pred. More specifically, a network embedding model is developed to fully exploit the network behavior of biomolecules, and attribute features are also calculated. Then, these discriminative features are combined to train a random forest classifier to predict intermolecular interactions. MMI-Pred achieves an outstanding performance of 93.50% accuracy in hybrid associations prediction under 5-fold cross-validation. This work provides systematic landscape and machine learning method to model and infer complex associations between various biological components.


An ice- air-water-NAPL multiphase model for simulating NAPL migration in subsurface system under freeze-thaw condition.
Non-aqueous phase liquid (NAPL) leakage poses serious threats to human health and the environment. Understanding NAPL migration and distribution in subsurface systems is crucial for developing effective remediation strategies. Multiphase flow modeling is an important tool to quantitatively describe the NAPL migration process in the subsurface. However, most multiphase flow models are built for temperatures typical of warmer climates and above freezing conditions, only considering two phases (water-NAPL) or three phases (air-water-NAPL). To date, few studies simulate NAPL migration in a four-phase system (ice-air-water-NAPL), which would be more appropriate for cold regions. In this study, we developed a coupled non-isothermal multiphase transport model to quantitatively describe NAPL migration in a four-phase (ice, gas, water, NAPL) system. The ice phase was added in the continuity equations and the constitutive relationship between unfrozen water content and temperature was applied to solve the energy and flow equations. The developed mathematical model was evaluated using a two-dimensional experiment under freeze-thaw cycles (FTCs) with an R2 = 0.8803 between the simulated and observed NAPL saturation. Next, we evaluated the effect of freezing-induced changes in pressure and density between LNAPL and DNAPL on NAPL distribution under freeze-thaw condition. Simulation results show that ignoring the impact of ice formation and thawing during freeze-thaw cycles for LNAPL and DNAPL transport simulations can result in up to a 48% and 13% difference in model predictions of local NAPL saturations respectively, affecting model predictions of overall NAPL spatial distributions and potentially predicted remediation effectiveness.


Acute pulmonary paracoccidioidomycosis in an immunosuppressed patient.
A case of an acute pulmonary paracoccidioidomycosis following the use of immunosuppressive therapy in a solid cancer patient is reported.


Corticobasal syndrome etiologies in a young Filipino patient: A case report and literature review.
While corticobasal syndrome (CBS) has long been associated with corticobasal degeneration (CBD), only 24-57% of CBS patients will have the classic histopathologic findings of CBD postmortem. Here, we present a 28-year-old male who had a 3-year history of progressive right sided predominant, atypical parkinsonism, limb dystonia, stimulus sensitive myoclonus, apraxia, aphasia, alien limb phenomenon, and cognitive impairment, typical of CBS, who, based on Armstrong criteria will qualify as possible CBD. In conclusion, among young patients presenting with CBS, tauopathies are still the most common causes, but inherited metabolic and white matter diseases as well as other non-tau associated neurodegenerative conditions should also be ruled out. Nevertheless, since most of these are diagnosed histopathologically, accurate and complete clinical findings, in addition to extensive metabolic work ups, imaging and genetic tests may be needed to clinch the cause of this syndrome.


Monolayers of charged particles in a Langmuir trough: Could particle aggregation increase the surface pressure?
The effect of aggregation on the surface pressure, Π, of monolayers from charged micrometer-sized colloidal particles on the air/water interface is investigated. Π is completely due to the long-range electrostatic repulsion between the particles mediated by their electrostatic field in the air. The most probable origin of particle aggregation is the attraction between capillary quadrupoles due to undulated contact lines on particle surfaces. Aggregates have higher charge and repel each other stronger than single particles. The data analysis by means of a theoretical model implies that Π linearly increases with n(1/2); n is the mean aggregation number, which can be determined from the experimental Π vs. area curves. The presence of electrolyte promotes aggregation, which tends to increase Π, but simultaneously reduces the surface charge that leads to lower Π. For our system, the first effect prevails and apparently paradoxical behavior is observed: the addition of salt in water enhances the electrostatic surface pressure. The data indicate limited aggregation: the rise of the electrostatic barrier prevents the further coalescence of aggregates if they have become sufficiently large. The results contribute for a better understanding of the factors that control the interactions in monolayers of charged particles at liquid interfaces.


Permuting input for more effective sampling of 3D conformer space.
SMILES strings and other classic 2D structural formats offer a convenient way to represent molecules as a simplistic connection table, with the inherent advantages of ease of handling and storage. In the context of virtual screening, chemical databases to be screened are often initially represented by canonicalised SMILES strings that can be filtered and pre-processed in a number of ways, resulting in molecules that occupy similar regions of chemical space to active compounds of a therapeutic target. A wide variety of software exists to convert molecules into SMILES format, namely, Mol2smi (Daylight Inc.), MOE (Chemical Computing Group) and Babel (Openeye Scientific Software). Depending on the algorithm employed, the atoms of a SMILES string defining a molecule can be ordered differently. Upon conversion to 3D coordinates they result in the production of ostensibly the same molecule. In this work we show how different permutations of a SMILES string can affect conformer generation, affecting reliability and repeatability of the results. Furthermore, we propose a novel procedure for the generation of conformers, taking advantage of the permutation of the input strings--both SMILES and other 2D formats, leading to more effective sampling of conformation space in output, and also implementing fingerprint and principal component analyses step to post process and visualise the results.


A randomized trial comparing web-based decision aids on prostate cancer knowledge for African-American men.
Few decision aids are tailored for African-American men. We sought to determine if web-based decision aids increased knowledge of prostate cancer screening among African men. This postintervention, quasiexperimental research measured knowledge of prostate cancer screening among African-American men following receipt of 1 of 2 web-based decision aids: enhanced or usual care. Men ages 40-65 were recruited at the annual convention of the Prince Hall Masons in the summer of 2007, which was attended by 1170 masons. The primary outcome was knowledge of prostate cancer screening. There were 87 participants in the sample with a mean age of 52 years (standard deviation = 6.9). Forty-six masons were randomized to the enhanced decision aid, and 41 masons were randomized to the usual care decision aid. Knowledge scores were statistically significantly higher among the men receiving the enhanced decision aid compared to the usual care decision aid after simultaneously adjusting for age, educational level, marital status, family history, previous prostate specific antigen test and digital rectal exam (p = 0.01). We found evidence that the enhanced web decision aid was significantly more effective than the usual care decision aid in promoting knowledge of the benefits, limitations and risks of prostate cancer screening. Web-based sites may be effective in facilitating discussions about screening between patients and health care providers.


[Morphological characteristics and the degree of somatic maturity in children of short stature].
An auxological investigation involved 199 children with short stature ( hypostatura simplex) in preschool and school age. The analysis of the material showed that eight anthropometrical patterns and five somatometric indices, with the evaluation of the level of skeletal maturity, were all lower in children under study in comparison to the mean growth standard for Warsaw children. In all features differences were statistically significant. The biggest differences however, were found in the length of the upper extremities and the trunk. Observed differences increase with age. The authors concluded that the children under study were harmoniously delayed in morphological age which was confirmed by the level of the index of biological maturity based on skeletal age. It was found that the level of biological maturation was delayed but not to such a great extent as in growth pathology.


Spinosin, a C-glycoside flavonoid from semen Zizhiphi Spinozae, potentiated pentobarbital-induced sleep via the serotonergic system.
Semen Zizhiphi Spinozae has been used extensively for the treatment of insomnia. This study investigated the effect and possible mechanism of action of spinosin (also known as 2''-beta-o-glucopyranosyl swertisin), a major constituent of semen Zizhiphi Spinozae, on sleep in mice. The present results showed that spinosin significantly and dose-dependently augmented pentobarbital (45 mg/kg, i.p.)-induced sleep, reflected by increased sleep time and reduced sleep latency assessed with the loss-of-righting reflex, and these effects were potentiated by the 5-hydroxytryptamine (serotonin) precursor 5-hydroxytryptophan (5-HTP, 2.5 mg/kg,i.p.). With a subhypnotic dose of pentobarbital (28 mg/kg, i.p.), spinosin significantly increased the rate of sleep onset and exhibited a synergistic effect with 5-HTP (2.5 mg/kg, i.p.). Pretreatment with p-chlorophenylalanine (PCPA, 300 mg/kg, s.c.), an inhibitor of tryptophan hydroxylase, significantly decreased pentobarbital-induced sleep time, and spinosin significantly reversed this effect. The dopamine precursor L-3-(3, 4-dihydroxyphenylalanine (L-DOPA) reduced pentobarbital-induced sleep, an effect not significantly affected by spinosin. These results suggest that spinosin potentiated pentobarbital-induced sleep via a serotonergic mechanism.