A xenograft model to evaluate the bone forming effects of sclerostin antibody in human bone derived from pediatric osteogenesis imperfecta patients.
Osteogenesis imperfecta (OI) is a rare and severe skeletal dysplasia marked by low bone mass and poor bone quality which is especially burdensome during childhood. Since clinical trials for pediatric OI are difficult, there is a widespread reliance on genetically modified murine models to understand the skeletal effects of emerging therapeutics. However a common model does not yet exist to understand how patient-specific genotype may influence treatment efficacy. Recently, sclerostin antibody (SclAb) has been introduced as a novel putative anabolic therapy for diseases of low bone mass, but effects in pediatric patients remain unexplored. In this study, we aim to establish a direct xenograft approach using OI patient-derived bone isolates which retain patient-specific genetic defects and cells residing in their intrinsic extracellular environment to evaluate the bone-forming effects of SclAb as a bridge to clinical trials. OI and age matched non-OI patient bone typically discarded as surgical waste during corrective orthopaedic procedures were collected, trimmed and implanted subcutaneously (s.c.) on the dorsal surface of 4-6-week athymic mice. A subset of implanted mice were evaluated at short (1 week), intermediate (4 week), and long-term (12 week) durations to assess bone cell survival and presence of donor bone cells in order to determine an appropriate treatment duration. Remaining implanted mice were randomly assigned to a two or four-week SclAb-treated (25mg/kg s.c. 2QW) or untreated control group. Immunohistochemistry determined osteocyte and osteoblast donor/host relationship, TRAP staining quantified osteoclast activity, and TUNEL assay was used to understand rates of bone cell apoptosis at each implantation timepoint. Longitudinal changes of in vivo μCT outcomes and dynamic histomorphometry were used to assess treatment response and ex vivo μCT and dynamic histomorphometry of host femora served as a positive internal control to confirm a bone forming response to SclAb. Human-derived osteocytes and lining cells were present up to 12 weeks post-implantation with nominal cell apoptosis in the implant. Sclerostin expression remained donor-derived throughout the study. Osterix expression was primarily donor-derived in treated implants and shifted in favor of the host when implants remained untreated. μCT measures of BMD, TMD, BV/TV and BV increased with treatment but response was variable and impacted by bone implant morphology (trabecular, cortical) which was corroborated by histomorphometry. There was no statistical difference between treated and untreated osteoclast number in the implants. Host femora confirmed a systemic bone forming effect of SclAb. Findings support use of the xenograft model using solid bone isolates to explore the effects of novel bone-targeted therapies. These findings will impact our understanding of SclAb therapy in pediatric OI tissue through establishing the efficacy of this treatment in human cells prior to extension to the clinic.


Pesticide-induced changes in hepatic microsomal enzyme systems: further studies on the effects of 1,1,-di(p-chlorophenyl)-2-chloroethylene (DDMU) in the Japanese quail.
Changes in the liver resulting from the low level dietary administration of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU),p,p'-DDT, o,p'-DDT, p,p'-DDD and p,p'-DDE to Japanese Quail have been monitored. DDMU was exceptional in causing substantial increases in relative liver wt. and hepatic glucose-6-phosphatase after feeding at 100 ppm for 28 days. The time course of liver enzyme induction by DDMU has also been studied in Japanese Quail after periods of dietary administration ranging from 1--28 days with particular reference to changes in hepatic cytochrome P-450 and relative liver wt. Structural changes in the liver have been followed by reference to protein and lipid components. The hepatic response to DDMU appears to be biphasic. Initially there are substantial increases in hepatic cytochrome P-450 and relative liver wt., but the latter is largely due to accumulation of triglycerides. After approximately 20 days the level of hepatic cytochrome P-450 remain at a high 'plateau' level. This secondary phase of liver induction probably involves cell proliferation. It is concluded that DDMU causes major changes in the avian liver and either directly or through a metabolite causes pronounced microsomal enzyme induction.


Stability of genetic and environmental influences on P300 amplitude: a longitudinal study in adolescent twins.
This study examined the stability of genetic and environmental influences on individual differences in P300 amplitude during adolescence. The P300 component is an event-related brain potential (ERP) that has attracted much attention as a biological marker for disturbed cognitive processing in psychopathology. Understanding the genetics of this biological marker may contribute to understanding the genetics of the associated psychopathologies. In a group of 213 adolescent twin pairs, the P300 component was measured twice, the first time at age 16 and the second time 18 months later. A large part of the variance of the P300 amplitude could be explained by familial factors, with estimates ranging from 30% to 81%. Whether the familial resemblance was due to genetic or shared environmental factors depended on sex. For males, genetic factors explained familial resemblance in P300 amplitude, but for females such resemblance was likely due to shared environmental factors. The phenotypic stability of the P300 amplitude from 16 to 18 years was high in both sexes, and stability could be attributed largely to the same familial factors. There was no evidence that new familial influences emerged at age 18.


Paradoxical reactions to rectal midazolam as premedication in children.
Eighty healthy children, between the ages of 2 and 7 years, who were to undergo oral surgical procedures under general anaesthesia, were allocated randomly to 4 groups. Three groups received rectal midazolam, and the other group a placebo (saline) as premedication 30 min prior to induction of anaesthesia. Group A children received midazolam 0.25 mg/kg, Group B 0.35 mg/kg and Group C 0.45 mg/kg. No statistically significant difference was found between the treatment groups as to the effect on systolic- (p = 0.6920) and diastolic (p = 0.8701) blood pressures, respiration (p = 0.0505) and pulse (p = 0.6192) rates at either pre- or post-sedation levels. However, the results indicate that levels of anxiolysis and sedation were significantly associated with midazolam dosage (p less than 0.0001).


The importance of the concept and histological criteria of "intraepithelial squamous cell carcinoma" of the esophagus: in comparison between Western and Japanese criteria.
There are differences in the histological diagnostic criteria for early stage gastrointestinal carcinoma between Western and Japanese pathologists. Western histological criteria of carcinoma are "presence of stromal invasion of neoplastic cells", while Japanese criteria are "the degree of cytological and structural abnormality of neoplastic cells, regardless of stromal invasion". The aim of the present study is to clarify and review the present status of the Western and Japanese histological criteria of early stage esophageal squamous cell carcinoma (SCC) and also to clarify their significance and accuracy. Twenty-nine Polish, German, and Japanese pathologists participated in this study. A total of 18 histological slides of biopsy, endoscopic submucosal dissection (ESD), and surgical resection of esophageal squamous lesions were diagnosed using a virtual slide system. Most of noninvasive (intraepithelial) carcinomas diagnosed by Japanese pathologists were diagnosed as high- or low-grade dysplasia (intraepithelial neoplasia) or reactive atypia by the majority of Polish and German pathologists. Diagnoses of not only high-grade dysplasia but also low-grade dysplasia or reactive lesion by Western criteria were given for many biopsy specimens of cases in which the corresponding ESD or surgical specimens showed definite stromal invasion. There still exist differences in the histological diagnostic criteria for early stage esophageal carcinoma between Western and Japanese pathologists. The Japanese diagnostic criteria could improve agreement of diagnoses between biopsy and resected specimens of esophageal SCC. Moreover, diagnostic approaches using Western criteria may cause delay in the early diagnosis and treatment of esophageal SCC.


Developmental changes in [3H]kainate binding in human brainstem sites vulnerable to perinatal hypoxia-ischemia.
The human brainstem is especially susceptible to hypoxia-ischemia in early life. To test the hypothesis that the period of vulnerability of the developing human brainstem to hypoxia-ischemia correlates with a transient elevation in kainate receptor binding, we compared the quantitative distribution of [3H]kainate binding in brainstem nuclei between four fetuses (19-26 gestational weeks), four infants (one to nine months), and three "mature" individuals (one child and two adults) without neurological disease. Quantitative tissues autoradiography was used. [3H]Kainate binding decreased in all brainstem regions from early life to maturity with the most significant decreases occurring in nuclei thought to be especially vulnerable to perinatal hypoxia-ischemia (e.g. principal inferior olive, griseum pontis, inferior colliculus and reticular core). The highest binding in the fetal and infant period was found primarily in the major cerebellar-relay nuclei. In the inferior olive and arcuate nucleus, binding increased from the fetal to the infant period, and then fell 50-61% to low mature levels. In the griseum pontis, binding decreased 60% between the fetal and mature periods. In the reticular formation, binding fell 67-78% from the fetal to mature period. These data support a correlation between the period of brainstem vulnerability to hypoxia-ischemia in early life to transient elevation in kainate binding, and are particularly relevant to the topographic brainstem patterns in perinatal hypoxia-ischemia of infantile olivary gliosis, pontosubicular necrosis and reticular core damage. Striking localization of [3H]kainate binding to rhombic lip derivatives further suggests that kainate receptors may be involved in the development and function of human brainstem-cerebellar circuitry.


Clinical experience of endovascular laser intervention in cardiovascular disease.
The authors studies laser angioplasty for patients with obstructive arterial diseases since the 1980s. Usefulness of laser angioplasty for endovascular surgery was recognized especially for patients having short segments of severe atherosclerotic changes in vessels. The authors retrospectively reviewed clinical experience of angioplasty by argon laser for 113 patients (103 peripheral, 10 coronary artery). Using an argon laser optimal conditions were (a) 6W in output and 3 sec in irradiation time or (b) metal tip temperature of 200 degrees C and 5 sec of ablation time for the peripheral artery. On the other hand, 4-5 W in output and 2 sec in irradiation time were optimal conditions for the same procedure on the coronary artery. The initial success rate of laser angioplasty for the peripheral artery was 92% in the stenotic lesions and 73% in the occlusive lesions. However, cumulative patency rate was 85% in the stenotic lesions and 74% in the occlusive lesions in the long-term follow-up study of 106 months among the patients with clinical success. On the basis of the excellent results in the peripheral arterial diseases, coronary laser angioplasty and coronary artery bypass grafting was intraoperatively performed in 10 patients with anginal attack. Patency rate was 90% in this series. Laser angioplasty for endovascular surgery was a useful procedure for patients with stenotic and occlusive changes of the peripheral and coronary arteries. Consequently, this method should be recommended especially for high-risk patients with atherosclerosis.


BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.
Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes. ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs. See related commentary by Phelan and Oellerich, p. 1844. This article is highlighted in the In This Issue feature, p. 1825.


The effects of angiotensin II and angiotensin-(1-7) in the rostral ventrolateral medulla of rats on stress-induced hypertension.
We have shown that angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] increased arterial blood pressure (BP) via glutamate release when microinjected into the rostral ventrolateral medulla (RVLM) in normotensive rats (control). In the present study, we tested the hypothesis that Ang II and Ang-(1-7) in the RVLM are differentially activated in stress-induced hypertension (SIH) by comparing the effects of microinjection of Ang II, Ang-(1-7), and their receptor antagonists on BP and amino acid release in SIH and control rats. We found that Ang II had greater pressor effect, and more excitatory (glutamate) and less inhibitory (taurine and γ-aminobutyric acid) amino acid release in SIH than in control animals. Losartan, a selective AT₁ receptor (AT₁R) antagonist, decreased mean BP in SIH but not in control rats. PD123319, a selective AT₂ receptor (AT₂R) antagonist, increased mean BP in control but not in SIH rats. However, Ang-(1-7) and its selective Mas receptor antagonist Ang779 evoked similar effects on BP and amino acid release in both SIH and control rats. Furthermore, we found that in the RVLM, AT₁R, ACE protein expression (western blot) and ACE mRNA (real-time PCR) were significantly higher, whereas AT₂R protein, ACE2 mRNA and protein expression were significantly lower in SIH than in control rats. Mas receptor expression was similar in the two groups. The results support our hypothesis and demonstrate that upregulation of Ang II by AT₁R, not Ang-(1-7), system in the RVLM causes hypertension in SIH rats by increasing excitatory and suppressing inhibitory amino acid release.


Integration of linear and dendritic actin nucleation in Nck-induced actin comets.
The Nck adaptor protein recruits cytosolic effectors such as N-WASP that induce localized actin polymerization. Experimental aggregation of Nck SH3 domains at the membrane induces actin comet tails--dynamic, elongated filamentous actin structures similar to those that drive the movement of microbial pathogens such as vaccinia virus. Here we show that experimental manipulation of the balance between unbranched/branched nucleation altered the morphology and dynamics of Nck-induced actin comets. Inhibition of linear, formin-based nucleation with the small-molecule inhibitor SMIFH2 or overexpression of the formin FH1 domain resulted in formation of predominantly circular-shaped actin structures with low mobility (actin blobs). These results indicate that formin-based linear actin polymerization is critical for the formation and maintenance of Nck-dependent actin comet tails. Consistent with this, aggregation of an exclusively branched nucleation-promoting factor (the VCA domain of N-WASP), with density and turnover similar to those of N-WASP in Nck comets, did not reconstitute dynamic, elongated actin comets. Furthermore, enhancement of branched Arp2/3-mediated nucleation by N-WASP overexpression caused loss of the typical actin comet tail shape induced by Nck aggregation. Thus the ratio of linear to dendritic nucleation activity may serve to distinguish the properties of actin structures induced by various viral and bacterial pathogens.


A new method to detect cerebral blood flow waveform in synchrony with chest compression by near-infrared spectroscopy during CPR.
The objective of the study is to demonstrate the utility of near-infrared spectroscopy (NIRS) in evaluating chest compression (CC) quality in cardiac arrest (CA) patients as well as determine its prognosis predictive value. We present a nonconsecutive case series of adult patients with CA whose cardiopulmonary resuscitation (CPR) was monitored with NIRS and collected the total hemoglobin concentration change (ΔcHb), the tissue oxygen index (TOI), and the ΔTOI to assess CC quality in a noninvasive fashion. During CPR, ΔcHb displayed waveforms monitor, which we regarded as a surrogate for CC quality. Total hemoglobin concentration change waveforms responded accurately to variations or cessations of CCs. In addition, a TOI greater than 40% measured upon admission appears to be significant in predicting patient's outcome. Of 15 patients, 6 had a TOI greater than 40% measured upon admission, and 67% of the latter were in return of spontaneous circulation after CPR and were found to be significantly different between return of spontaneous circulation and death (P = .047; P < .05). Near-infrared spectroscopy reliably assesses the quality of CCs in patients with CA demonstrated by synchronous waveforms during CPR and possible prognostic predictive value, although further investigation is warranted.


C-fos mediates antipsychotic-induced neurotensin gene expression in the rodent striatum.
The ubiquitous inducibility of the immediate-early gene c-fos in the central nervous system has led to the search for downstream genes which are regulated by its product, Fos. Recent evidence suggests that c-fos induction by a single injection of the classical antipsychotic haloperidol may contribute to the subsequent increase in neurotensin gene expression in the rodent striatum. Consistent with this proposal, in the present study haloperidol-induced Fos-like immunoreactivity and neurotensin/neuromedin N messenger RNA were found to be expressed by the same population of striatal neurons. Moreover, inhibition of haloperidol-induced c-fos expression by intrastriatal injection of antisense phosphorothioate oligodeoxynucleotides complimentary either to bases 109-126 or 127-144 of c-fos attenuated the subsequent increase in neurotensin/neuromedin N messenger RNA. However, injection of a sense phosphorothioate oligodeoxynucleotide corresponding to bases 127-144 of c-fos did not reduce haloperidol-induced c-fos or neurotensin/neuromedin N expression. Furthermore, constitutive expression of Jun-like immunoreactivity in the striatum was not reduced by either the sense or antisense phosphorothioate oligodeoxynucleotides. Similarly, the sense and antisense phosphorothioate oligodeoxynucleotide failed to reduce proenkephalin messenger RNA, which is located in the same striatal neurons that express haloperidol-induced neurotensin/neuromedin N messenger RNA, which is located in the same striatal neurons that express haloperidol-induced neurotensin/neuromedin N messenger RNA. Lastly, haloperidol-induced increases in nerve growth factor I-A-, JunB- and FosB-like immunoreactivity and fosB messenger RNA were not decreased by intrastriatal injection of either the sense or antisense phosphorothioate oligodeoxynucleotides. These results indicate that the antisense phosphorothioate oligodeoxynucleotides attenuated haloperidol-induced neurotensin/neuromedin N expression by selectively reducing c-fos expression and emphasize the potential importance of immediate-early gene induction in the mechanism of action of this antipsychotic drug.


Locating the anterior interosseous nerve in relation to the surgically relevant landmarks of the forearm: A cadaveric study.
This study emphasizes locating the anterior interosseous nerve (AIN) related to its level of origin, number, and lengths of its muscular branches and relation to surgically important landmarks such as the bi-epicondylar line, pronator teres, and Gantzer muscles. The study was undertaken at a private Medical school in south India during 2019-20. The level of origin of AIN was measured from the bi-epicondylar line and its length was measured up to the upper border of the pronator quadratus using 44 cadaveric upper limbs. The number of branches given to flexor digitorum profundus (FDP) and flexor pollicis longus (FPL) was quantified and their lengths were measured. The nerve originated at a mean distance of 41.56 mm from the bi-epicondylar line. In 12 upper limbs, FDP received two branches and in two limbs, it received three branches. In 13 upper limbs, FPL received two branches from AIN. It was observed that the muscular branches for FDP were shorter than those for FPL. Gantzer muscle was observed in 18 (40%) specimens and was found superficial to the nerve. The muscular branches of AIN had a variable pattern of innervation. Multiple muscular branches to the FPL and FDP were observed in the upper 2/3rds of the forearm. These branches to FPL and FDP would aid as a source of nerve grafting and nerve transfer in the cases of upper extremity nerve palsies.


Cross-talk between bioactive lipid mediators and the unfolded protein response in ischemic stroke.
Ischemic cerebral stroke is a severe medical condition that affects about 15 million people every year and is the second leading cause of death and disability globally. Ischemic stroke results in neuronal cell death and neurological impairment. Current therapies may not adequately address the deleterious metabolic changes and may increase neurological damage. Oxygen and nutrient depletion along with the tissue damage result in endoplasmic reticulum (ER) stress, including the Unfolded Protein Response (UPR), and neuroinflammation in the affected area and cause cell death in the lesion core. The spatio-temporal production of lipid mediators, either pro-inflammatory or pro-resolving, decides the course and outcome of stroke. The modulation of the UPR as well as the resolution of inflammation promotes post-stroke cellular viability and neuroprotection. However, studies about the interplay between the UPR and bioactive lipid mediators remain elusive and this review gives insights about the crosstalk between lipid mediators and the UPR in ischemic stroke. Overall, the treatment of ischemic stroke is often inadequate due to lack of effective drugs, thus, this review will provide novel therapeutical strategies that could promote the functional recovery from ischemic stroke.


Temporomandibular joint and psychosocial evaluation of patients after orthognathic surgery: a preliminary study.
The purpose of this study was to evaluate the psychological and psychosocial status of patients prior to and after orthognathic surgery. Twenty-two patients (13 males and 9 females) who underwent orthognathic surgery were examined in this study. The bilateral sagittal split ramus osteotomy (BSSRO) group included 10 patients, and the Le Fort I osteotomy and BSSRO group included 12 patients. We continued RDC/TMD Axis II research for 12 patients who had preoperative temporomandibular joint disorder (TMD). The RDC/TMD Axis II charts were recorded preoperatively and 6 months after surgery. The Wilcoxon signed rank test was used for statistical analysis. Overall, there was no significant difference between the preoperative and 6-month postoperative depression indices. The non-specific physical symptoms score (NPS) with pain score decreased significantly (p < 0.05), but the NPS without pain score decreased insignificantly. In terms of the graded pain score for the preoperative group, 75.0% of the patients were in the low disability group, whereas 25.0% were in the high disability group. In contrast, patients in the postoperative group only fell into the low disability group (p < 0.05). The RDC/TMD Axis II was developed to diagnose TMD, but we believe the RDC/TMD Axis II can help to establish postoperative treatment plans by evaluating a patient's psychological and psychosocial state.


Deglycosylation of the chymotryptic collagen-binding fragment of human plasma fibronectin does not modify its affinity to denatured collagen.
N-Glycanase deglycosylation of purified 44 kDa chymotryptic collagen-binding domain from human plasma fibronectin does not significantly modify its behavior on gelatin affinity chromatography. This indicates that carbohydrates do not play any role in the binding affinity of fibronectin to collagen. The influence of changes in glycosylation on the biological functions of fibronectin is discussed.


The contribution of cell phenotype to the behavior of gastric cancer.
Several histochemical studies suggest a role of tumor cell phenotype and related differentiation markers in the prognostic assessment of gastric cancer. Unfortunately, most studies have dealt with single or a few markers and have paid limited attention to their interplay with tumor histological types, which are potentially informative of prognosis. In this study, 292 invasive (T1b to T4) gastric cancers with prolonged follow-up and carefully analyzed histotype, inclusive of histotype-based grade, were investigated histochemically with a panel of 14 phenotypic markers known to be expressed in normal gut tissues and gastric cancer. Three of seven intestinal type markers investigated showed a trend for improved prognosis, one of which, CDX2, was stage independent. Three among gastric and pancreatobiliary duct markers (MUC1, MUC6, and pepsinogen II), predicted more severe prognosis stage independently, as did a combination of eight potentially informative (p < 0.1 at univariable Cox analysis) markers. Cancers with predominantly intestinal phenotype had significantly better prognosis than those with predominantly gastric, mixed, or poorly defined phenotypes; among the latter, those with high lymphocyte response, with favorable outcome, were separated from anaplastic cancers, with ominous prognosis. At multivariable analysis, CDX2 and the eight marker combination proved to be stage- and grade-independent predictors. When individually considered, and with the exception of CDX2, the biomarkers investigated gave an appreciable, although moderate, contribution to the prognostic evaluation of gastric cancer. Combined analysis of all potentially informative markers gave more important information, highly additive to both stage and histotype-based grade.


Initial tumor cell arrest in animals of defined coagulative status.
Experiments were made to evaluate the potential role played by thrombogenic factors on the hematogenous arrest of circulating tumor cells in mice with demonstrable coagulopathies associated with the presence of a primary tumor, by administration of "therapeutic" doses of anticoagulants. The effects of warfarin, aspirin and heparin administration on the early arrest patterns of 125IdUrd-labelled TA3 carcinoma and Gardner lymphosarcoma cells injected intravenously into tumor-bearing mice were examined. Several hematologic parameters of carcinoma- and lymphosarcoma-bearing animals were measured prior to anticoagulation experiments and the results indicated that mice had coagulopathies similar to those found in cancer patients with disseminated intravascular coagulation syndrome, i.e., thrombocytopenia and elevated fibrinogen levels. Despite the presence of coagulation abnormalities and effective anticoagulation in recipient animals, all three agents were without effect on localization patterns of both tumor types. It was concluded that the proposed involvement of thrombogenesis in metastasis was probably not due to any role played by those clotting factors inhibited by aspirin, warfarin and heparin in early intravascular tumor cell arrest.


Fetal echocardiography. Management of suspected congenital heart disease.
As prenatal ultrasound and echocardiographic imaging become more common-place, prenatal diagnosis of serious cardiac conditions becomes possible. A case report points out the importance of establishing a firm diagnosis before undertaking definitive treatment after birth.


Integrated breast massage versus traditional breast massage for treatment of plugged milk duct in lactating women: a randomized controlled trial.
Plugged milk duct during lactation is a common problem in breastfeeding. Traditional breast massage (TBM) has been performed in Thailand with reasonable outcomes, but several follow-up sessions are often required. A new massage technique, the integrated breast massage (IBM), was subsequently developed. This study aimed to compare resolution time, reduction in mass size, and pain score after breast massage between the IBM and TBM techniques. This randomized controlled trial was conducted at the Lactation Clinic of the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand during February 2019-July 2020. Women presenting with acute plugged milk duct were enrolled and randomly allocated to the IBM or TBM/control groups. Mass size in square centimeters (cm2) was calculated by multiplying the perpendicular axes of the mass. Pain score was self-scored by participants using a numerical rating scale. Median time (95% confidence interval [CI]) to resolution of plugged milk duct was derived using Kaplan-Meier survival analysis. Intention-to-treat analysis was performed. Eighty-four women (42 per group) were included. All enrolled study participants completed the study and were included in the final analysis. Twenty-six (61.9%) and 25 (59.5%) participants from IBM and TBM, respectively, had mass diameter > 5 cm. The median (interquartile range [IQR]) mass size was 30 (20-48) and 20 (12-14) cm2 in IBM and TBM (p = 0.05), respectively. The median (95% CI) time to resolution of plugged duct was 0 (not available) and 1 (0.47-1.53) day in IBM and TBM, respectively (p < 0.01). After the first breast massage, the median (IQR) size of mass reduction was 30 (20-48) and 10 (10-26) cm2 in IBM and TBM, respectively (p = 0.01). The median (IQR) reduction in pain score was 8 (7-8) and 6 (4-7) in IBM and TBM, respectively (p = 0.01). No participants developed skin bruising or hematoma after breast massage. The IBM technique resolved plugged milk duct significantly faster, with significantly less pain, and with significantly greater reduction in mass size after the first massage compared to TBM. Retrospectively registered in the Thai Clinical Trials Registry on 25 September 2019 ( TCTR20190925001 ).


A case of autoimmune glial fibrillary acidic protein astrocytopathy presenting with magnetic resonance imaging mimics of multiple sclerosis.
Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an inflammatory disorder of the central nervous system. On magnetic resonance imaging, the neuroradiological signature is a linear radial enhancement pattern of cerebral white matter (MRI). Dawson's fingers, on the other hand, and ovoid lesions with open-ring enhancement have long been recognized as distinct features of multiple sclerosis (MS). We herein report a case of autoimmune GFAP astrocytopathy presenting with these MRI findings specific to MS. Autoimmune GFAP astrocytopathy could mimic the MRI features of MS and should be included in the differential diagnosis of MS.


Constructing Z-scheme NiMoO4@Co3O4 core-shell heterogeneous architectures with prominent photoelectrocatalytic performance toward water purification.
Photoelectrocatalysis (PEC) oxidation is an efficient and eco-friendly advanced oxidation process (AOP), which is a hot research topic in the treatment of organic wastewater. The selection of superior photoelectrode materials is the critical factor affecting PEC efficiency and the main challenge in practical application. In this work, novel NiMoO4@Co3O4 hierarchical core-shell heterogeneous photoanodes were prepared through a two-step hydrothermal method and exhibited superior catalytic performance in the degradation of reactive brilliant blue KN-R. The wrapping of NiMoO4 nanosheets on Co3O4 nanowires electrode can enlarge its contact area with electrolyte, enable fast redox reaction and improve the long-term durability. The unique Z-scheme heterojunction structure between the two components ensured the effective separation of photo-generated carriers, facilitating the generation of OH and O2- during the PEC degradation process. The optimal firstname.lastname@example.com hierarchical architecture anode catalyst exhibited the highest removal rate of 83.65% of reactive brilliant blue KN-R in 120 min with long-term stability (∼12000 s) in 1.0 mol·L-1 H2SO4 solution. This report may inspire the design and fabrication of heterostructure photoanode in water purification.


Emotional Communication in Advanced Pediatric Cancer Conversations.
Cancer is a life-changing diagnosis accompanied by significant emotional distress, especially for children with advanced disease. However, the content and processes of discussing emotion in advanced pediatric cancer remain unknown. To describe the initiation, response, and content of emotional communication in advanced pediatric cancer. We audiorecorded 35 outpatient consultations between oncologists and families of children whose cancer recently progressed. We coded conversations based on Verona Coding Definitions of Emotional Sequences. About 91% of conversations contained emotional cues, and 40% contained explicit emotional concerns. Parents and clinicians equally initiated cues (parents: 48%, 183 of 385; clinicians: 49%) and concerns (parents: 51%; clinicians: 49%). Children initiated 3% of cues and no explicit concerns. Emotional content was most commonly related to physical aspects of cancer and/or treatment (28% of cues and/or concerns, present in 80% of conversations) and prognosis (27% of cues and/or concerns, present in 60% of conversations). Clinicians mostly responded to emotional cues and concerns implicitly, without specifically naming the emotion (85%). Back channeling (using minimal prompts or words that encourage further disclosure, e.g., uh-huh) was the most common implicit response that provided space for emotional disclosure (32% of all responses). Information advice was the most common implicit response that reduced space for further emotional disclosure (28%). Emotional communication in advanced pediatric cancer appears to be a subtle process where parents offer hints and clinicians respond with non-emotion-laden statements. Also, children were seldom engaged in emotional conversations. Clinicians should aim to create an environment that allows families to express emotional distress if and/or when ready.


Bile acids in cholestasis: bad for the liver, not so good for the kidney.
The elegant paper by Fickert et al. on bile duct ligated mice provides convincing evidence for the hypothesis that bile acids retained in the serum during cholestasis and excreted through the kidneys are toxic to collecting duct cells. The authors propose that bile acids initiate a chain of reactions leading to tubulointerstitial nephritis and fibrosis. Mice with cholestasis were protected by prefeeding with the hydrophilic bile acid norursodeoxycholic acid, an observation which suggests a potential therapeutic option for cholemic nephropathy.


Conserved sequence preference in DNA binding among recombination proteins: an effect of ssDNA secondary structure.
Repetitive sequences have been proposed to be recombinogenic elements in eukaryotic chromosomes. We tested whether dinucleotide repeats sequences are preferential sites for recombination because of their high affinity for recombination enzymes. We compared the kinetics of the binding of the scRad51, hsRad51 and ecRecA proteins to oligonucleotides with repeats of dinucleotides GT, CA, CT, GA, GC or AT. Since secondary structures in single-stranded DNA (ssDNA) act as a barrier to complete binding we measured whether these oligonucleotides are able to form stable secondary structures. We show that the preferential binding of recombination proteins is conserved among the three proteins and is influenced mainly by secondary structures in ssDNA.


Kinetic Potentiometry as a Method for Studying the Interactions of Antioxidants with Peroxyl Radicals.
This work presents a new method using kinetic potentiometry to study the thermodynamic and kinetic parameters of the reactions of antioxidants with peroxyl radicals. The rate constants of the reaction of antioxidants with radicals have been determined, and the groups of "fast" and "slow" antioxidants have been conventionally distinguished. Fast antioxidants include ascorbic, uric, gallic, chlorogenic, caffeic acids, glutathione, L-cysteine, and catechol with constant values from (1.05-9.25) × 103 M·s-1; "slow" antioxidants are α-tocopherol (in aqueous media), ionol, 2,6-ditretbutylphenol, and compounds of the azoloazine series, modified with polyphenolic fragments, with constant values from (4.00-8.50) × 102 M·s-1. It is shown that the value of the rate constant is directly related to the type of kinetic dependence of the potential recorded when an antioxidant is introduced into the solution of the radical initiator. It is shown that the method with the determination of the induction period is difficult in the study of "slow" antioxidants. It has been established that the area above the curve of the kinetic dependence Exp(∆E) is directly related to the amount of inhibited peroxyl radicals and can be used to assess the inhibitory properties of an antioxidant from a thermodynamic point of view. "Fixed time method" and "Initial rate method" were used. Positive correlations between the described method have been established. The utility of the parameter of the area above the curve of the kinetic dependence Exp(∆E) in the study of objects of complex composition is shown.


Response to thyrotropin-releasing hormone (TRH) in a horse with hyperthyroidism associated with a functional thyroid adenoma.
A 16-year-old American Paint Horse gelding was presented for evaluation of weight loss and high serum thyroid hormone concentrations resulting from a functional thyroid adenoma. The horse showed no response to a thyrotropin-releasing hormone (TRH) stimulation test. Clinical signs resolved following surgical removal of the adenoma.


Ethnicity and socioeconomic status influence use of primary angioplasty in patients presenting with acute myocardial infarction.
Primary percutaneous coronary intervention (PCI) has become an important treatment for patients (pts) with acute myocardial infarction (AMI). Whether ethnic and socioeconomic disparities exist in use of primary PCI for AMI is unknown. Patients hospitalized for transmural AMI in Pennsylvania from January 2003 through June 2004 (n = 16985) were studied. Patient clinical characteristics, insurance status, and hospital type were analyzed using multiple logistic regression analysis to assess the independent correlates of PCI on the day of admission for AMI. Among 16,985 pts, primary PCI was performed in 6934 (46%) of 14,944 whites, 363 (40%) of 910 African Americans, and 618 (55%) of 1131 other ethnicities. Primary PCI was associated positively with younger age, male sex, known dyslipidemia, and prior PCI (all P < .03), and negatively with diabetes, renal failure, prior myocardial infarction or bypass surgery, and higher predicted death by the Mediqual Atlas Outcomes score (all P < .01). After adjustment for these variables, African American ethnicity (odds ratio 0.78, 95% confidence interval 0.67-0.91), lowest income quintile, (odds ratios 0.87, 95% confidence interval 0.80-0.94), lack of commercial insurance, and nonurban and for-profit hospital status were independently associated with not undergoing primary PCI (all P < .003). In a large statewide database of pts with ST-segment elevation AMI, primary PCI was used less often in African American and in lower-income pts, independent of clinical, hospital, and insurance characteristics, identifying persisting disparities in application of advanced cardiac care in traditionally underserved segments of the population.


The Dialogue Between Neuroinflammation and Adult Neurogenesis: Mechanisms Involved and Alterations in Neurological Diseases.
Adult neurogenesis occurs mainly in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles. Evidence supports the critical role of adult neurogenesis in various conditions, including cognitive dysfunction, Alzheimer's disease (AD), and Parkinson's disease (PD). Several factors can alter adult neurogenesis, including genetic, epigenetic, age, physical activity, diet, sleep status, sex hormones, and central nervous system (CNS) disorders, exerting either pro-neurogenic or anti-neurogenic effects. Compelling evidence suggests that any insult or injury to the CNS, such as traumatic brain injury (TBI), infectious diseases, or neurodegenerative disorders, can provoke an inflammatory response in the CNS. This inflammation could either promote or inhibit neurogenesis, depending on various factors, such as chronicity and severity of the inflammation and underlying neurological disorders. Notably, neuroinflammation, driven by different immune components such as activated glia, cytokines, chemokines, and reactive oxygen species, can regulate every step of adult neurogenesis, including cell proliferation, differentiation, migration, survival of newborn neurons, maturation, synaptogenesis, and neuritogenesis. Therefore, this review aims to present recent findings regarding the effects of various components of the immune system on adult neurogenesis and to provide a better understanding of the role of neuroinflammation and neurogenesis in the context of neurological disorders, including AD, PD, ischemic stroke (IS), seizure/epilepsy, TBI, sleep deprivation, cognitive impairment, and anxiety- and depressive-like behaviors. For each disorder, some of the most recent therapeutic candidates, such as curcumin, ginseng, astragaloside, boswellic acids, andrographolide, caffeine, royal jelly, estrogen, metformin, and minocycline, have been discussed based on the available preclinical and clinical evidence.


Associating portal embolization and artery ligation to induce rapid liver regeneration in staged hepatectomy.
Insufficient volume of the future liver remnant (FLR) is a major cause of unresectability in patients with bilobar colorectal liver metastases (CLM). The objective of this study was to evaluate the safety and efficacy of the novel associating portal embolization and artery ligation (APEAL) technique before extended right hepatectomy during a two-stage procedure for CLM. All patients who had undergone extended right hepatectomy during two-stage surgery for CLM between 2012 and 2014 were identified retrospectively from a prospectively maintained database. In the first stage, right portal vein embolization, partial right hepatic artery ligation and devascularization of segment IVb along the round ligament without parenchymal transection were associated with clearance of the FLR and/or primary tumour resection. Liver volumetry was performed using OsiriX software on postoperative day (POD) 7 and 30. Ten patients underwent the APEAL procedure. During the first stage, APEAL was combined with colorectal resection in seven patients. The median (range) interval between the two stages was 45 (31-71) days. The FLR volume increased from 327 (214-537) cm(3) before surgery to 590 (508-1072) cm(3) on POD 7 and 701 (512-1018) cm(3) on POD 30. This corresponded to a FLR regeneration rate of 104 (42-185) and 134 (53-171) per cent respectively. There were no deaths. The overall morbidity rate was 60 per cent (6 of 10) after each procedure, with severe morbidity occurring in two and three of ten patients after the first and second procedures respectively. APEAL induces fast, safe, reproducible and effective FLR growth when an extended right hepatectomy is scheduled in patients with multiple bilobar CLM.


Pulsed-field gel electrophoresis typing of Campylobacter fetus subsp. fetus from sheep abortions in the Hawke's Bay region of New Zealand.
To type Campylobacter isolates from sheep abortions from the Hawke's Bay region of New Zealand. Campylobacter isolates were collected from aborted sheep fetuses from commercial farms in the Hawke's Bay region. Information on the Campylobacter vaccination status of flocks in the study was collected. Isolates were identified to species level using standard phenotypic tests, then typed using pulsed-field gel electrophoresis (PFGE). Eighty-one C. fetus subsp. fetus isolates were cultured from aborted sheep fetuses from 25 farms and four C. jejuni isolates were cultured from fetuses from three farms. The C. fetus subsp. fetus isolates were classified into six PFGE groups. A single pulsed-field type predominated amongst isolates from 19 of the 25 farms. The C. jejuni isolates comprised two types. A range of C. fetus subsp. fetus PFGE types was identified, and one type, B1, was found most frequently. Campylobacter fetus subsp. fetus was only isolated from samples from sheep that had not been vaccinated with C. fetus subsp. fetus vaccine that season.


Radioactivity in gastric juice-a simple adjunct to the Yb-169 DTPA cisternographic diagnosis of CSF rhinorrhea: concise communication.
A new method is offered as an adjunct to radionuclide cisternography and the measuring of radioactivity in nasal pledgets. The activity in gastric juice following the intrathecal injection of Yb-169-DTPA is measured and the ratio of gastric juice to blood is calculated. In patients suffering from CSF rhinorrhea the ratios significantly exceed the normal range. This method can be used to detect CSF leakage at the back of the nasopharynx, and in patients with head injuries too severe to permit the use of nasal pledgets.


Adenoid 'ameloblastoma': Clinicopathological description of 4 additional BRAF-negative cases.
Adenoid ameloblastoma (AA) is an epithelial odontogenic tumor that was recognized as a separate entity in the last odontogenic classification of WHO in 2022. The etiology is unknown, and the pathogenesis remains controversial. The objective of this study is to contribute the clinicopathological features of 4 additional BRAF-negative cases to the existing literature, aiming to enhance the molecular understanding of this unique tumor in the forthcoming classification. This study consists of a case series of four patients diagnosed with AA. The patients' demographic and clinical information were collected from the universities' medical achieves. Histopathologically, all cases were reexamined according to the latest update of the WHO odontogenic tumor classification. In addition to H&E and immunohistochemical stains, cytogenetics was also evaluated. Well-defined unilocular radiolucent lesions were observed in all cases. Ameloblastoma-like components exhibited reserved nuclear polarity, suprabasal stellate reticulum-like epithelium, duct-like structure, whorls/morules, and cribriform architecture were common features. Variable immunoreactivity to CK7, CK19, CK14, p63, and p40 were determined, and proliferative activity was greater than 15%. The BRAF molecular study revealed no mutations. When diagnosing AA, the essential histopathological characteristics must be rigorously applied, and a significant portion of the lesion should contain these features. Additionally, despite limited molecular data, since the BRAF mutation commonly observed in ameloblastomas is not present in the majority of AA cases, we propose changing the term "ameloblastoma" to "ameloblastic" and referring to it as "adenoid ameloblastic tumor" in the forthcoming classification.


Are they being used safely? A retrospective cross-sectional tertiary health care survey of selective serotonin reuptake inhibitors prescribing practice in Singapore.
To determine the prescribing pattern of the SSRIs and to evaluate the safety of current utilization of SSRIs associated with concomitant psychotropic medications in Singapore. The average prescribed daily dose (PDD) for each SSRI was calculated and compared with the defined daily dose (DDD). Pearson's chi2 test, one-way analysis of covariance (ANCOVA) and multinomial logistic regression were performed to examine the impacts of variables such as age, gender, patient type and concomitant psychotropic medications on the utilization of SSRIs. Safety issues were discussed by examining the potential metabolic drug interactions between the SSRIs and concomitant psychotropic medications. The most frequently prescribed SSRI was fluoxetine and the PDDs were slightly more than the DDDs for all these SSRIs except fluvoxamine. The SSRIs were mainly prescribed to the patients who were younger, female and outpatients. Psychotropics were more likely concomitantly used with fluvoxamine, sertraline and paroxetine, relative to fluoxetine. The prescribing pattern of SSRIs in a tertiary health center in Singapore is generally consistent with the accepted practices, although some safety concerns in terms of metabolic drug interactions were raised. This study provides useful baseline information for further in-depth studies for SSRIs usage both locally and for international comparison.


Sixty-year follow-up in an untreated patient with Kienböck disease.
Kienböck disease can be treated either conservatively or by various operations. We describe the findings of the progression of Kienböck disease over 60 years in an 84-year-old man who had had no surgical treatment. This is the longest follow-up ever reported to our knowledge of a patient with avascular necrosis of the lunate.


Injury patterns of medial patellofemoral ligament and correlation analysis with articular cartilage lesions of the lateral femoral condyle after acute lateral patellar dislocation in adults: An MRI evaluation.
The purpose of this study was to investigate the injury characteristics of medial patellofemoral ligament (MPFL), and to analyse the correlations between the injury patterns of MPFL and articular cartilage lesions of the lateral femoral condyle in adults with acute lateral patellar dislocation (LPD). Magnetic resonance (MR) images were prospectively obtained in 121 consecutive adults with acute LPD. Images were acquired using standardised protocols and these were independently evaluated by two radiologists. Forty-eight cases of partial MPFL tear and 71 cases of complete MPFL tear were identified. Injuries occurred at an isolated femoral attachment (FEM) in 48 cases, an isolated patellar insertion (PAT) in 36 cases and an isolated mid-substance (MID) in five cases. More than one site of injury to the MPFL (COM) was identified in 30 cases. The prevalence rate of chondral and osteochondral lesions of the lateral femoral condyle were 4.2% (2/48) and 6.3% (3/48) in the FEM subgroup, 19.4% (7/36) and 22.2% (8/36) in the PAT subgroup and 6.7% (2/30) and 13.3% (4/30) in the COM subgroup, respectively. The PAT subgroup showed significantly higher prevalence rate of chondral and osteochondral lesions in the lateral femoral condyle when compared with the FEM subgroup. The prevalence rate of chondral and osteochondral lesions of the lateral femoral condyle were 8.5% (6/71) and 19.7% (14/71) in the complete MPFL tear subgroup and 10.4% (5/48) and 4.2% (2/58) in the partial MPFL tear subgroup, respectively. The subgroup of the complete MPFL tear showed significantly higher prevalence rate of osteochondral lesions in the lateral femoral condyle when compared with the subgroup of the partial MPFL tear. Firstly, the MPFL is most easily injured at the FEM, and secondly at the PAT in adults after acute LPD. The complete MPFL tear is more often concomitant with osteochondral lesions of the lateral femoral condyle than the partial MPFL tear. The isolated patellar-sided MPFL tear is more easily concomitant with chondral lesions and osteochondral lesions of the lateral femoral condyle than the isolated femoral-sided MPFL tear.


Psychosocial support of the pediatric cancer patient: lessons learned over the past 50 years.
Advances in pediatric cancer treatment over the past 50 years have dramatically improved survival rates. Once considered almost uniformly fatal, pediatric cancer's overall survival rates now approach 85%. Formerly, little psychosocial support existed for the child with cancer other than that provided by nurses and family. The prospect for long-term survival was so remote that plans for the future (eg, school, social relationships, late effects of treatment, and emotional adjustment) were abandoned. As the survival rate for children with cancer improved, so did the need for and quality of psychosocial care, largely because of hope for a cure. Today children with cancer benefit from comprehensive behavioral pediatric psychosocial support programs in psychiatry, psychology, neuropsychology, child life, education (school), creative arts, chaplaincy, social work, and career and vocational counseling. Pediatric psycho-oncology research has provided insights into clinical care and the psychosocial adaptation of children and families to cancer treatment and survivorship.


Fundamental principles of cortical organization reflected in a new study.
In an exciting new finding by Gordon et al., the human motor cortex does not show a traditional body map. Instead, body-part-specific zones are separated by integrative zones, possibly reflecting the statistical structure of the human motor repertoire.


The manual stress test may not be sufficient to differentiate ankle ligament injuries.
To assess the accuracy of stress tests (anterior drawer, talar tilt) in the diagnosis of lateral ligament injuries.Design. Stress tests were performed in vitro, and rotation and displacement of the calcaneus relative to the tibia were measured. Stress tests are commonly used to diagnose ankle injuries. However, it is controversial as to whether stress tests can accurately differentiate between isolated anterior talofibular ligament injuries and combined anterior talofibular and calcaneofibular ligament injuries. Stress tests were performed in vitro under three conditions with both ligaments intact, after sectioning the anterior talofibular ligament, and after sectioning the anterior talofibular and calcaneofibular ligament. Motion of the calcaneus relative to the tibia was measured in neutral and in 20 degrees of plantarflexion at the ankle. There were statistically significant differences among cadavers, examiners and positions. There was a difference between isolated anterior talofibular ligament sectioning and combined anterior talofibular and calcaneofibular ligament sectioning in lateral tilt but not in anterior displacement. In contrast, a difference was found between intact and anterior talofibular ligament sectioned specimens in anterior displacement but not in lateral tilt. However the differences were not great enough to differentiate between the two conditions. Each of the stress tests provides reasonable hindfoot displacement but neither is sufficient for accurate diagnosis of specific ligament involvement due to the large amount of individual variation. Many clinicians rely on stress tests to diagnose lateral ligament injuries and to assess the extent of anatomic disruption. This in vitro study has demonstrated poor correlation between clinical stress tests and the degree of ligamentous disruption.


Potentialization of IL-2 effects on immune cells by oyster extract (JCOE) in normal and HIV-infected individuals.
Peripheral blood mononuclear cells (PBMCs) are physiologically activated by interleukin (IL)-2. We found that oyster extract (JCOE) currently used as a functional nutrient enhanced in vitro the IL-2 dependent activation as measured by cell count. 3H-thymidine uptake and up-regulation of a IL-2 receptor. In human immunodeficiency virus (HIV) seropositive individuals, this oyster extract-induced effect was marked in asymptomatic individuals with quasi-normal CD4 cell counts, but was weakly reflected in acquired immunodeficiency syndrome (AIDS) patients.


Nuclear tomographic phase analysis: localization of accessory conduction pathway in patients with Wolff-Parkinson-White syndrome.
The purpose of this study was to evaluate the usefulness of tomographic phase analysis in detecting the site of the accessory conduction pathway (ACP) in patients with Wolff-Parkinson-White (WPW) syndrome. Gated emission computed tomography and planar gated blood pool scintigraphy were performed in 20 patients with WPW syndrome, 14 with delta waves and six without delta waves (two intermittent types and four concealed types). The abnormal initial contractions in both planar and tomographic phase images were compared with the sites of ACPs confirmed by epicardial mapping and surgery. The atrioventricular ring was divided into eight segments on each side, and the identification of the initial phase in the segment in which the ACP was located, or that adjacent to it, was considered to be the correct diagnosis. In planar phase analysis, the abnormal initial phase was identified correctly in 8 of 14 patients (57%), whereas in tomographic phase analysis, the site of the ACP was detected in 12 of 14 patients (86%). Tomographic phase analysis can be a helpful adjunctive method in patients with WPW syndrome.


Drug repositioning for cancer in the era of AI, big omics, and real-world data.
Drug repositioning in cancer has been pursued for years because of slowing drug development, increasing costs, and the availability of drugs licensed for other indications with anticancer effects in the laboratory. Repositioning has encountered obstacles due to generally insufficient single-agent clinical anticancer effects of licensed drugs and a subsequent reluctance by pharmaceutical companies to invest in phase III combination studies with them. Here we review potential machine learning/artificial intelligence (ML/AI) approaches for using real-world data (RWD) that could overcome the limitations of clinical trials and retrospective analyses. We outline a two-tiered filtering approach of identifying top-ranked drugs based on their drug-target binding affinity scores while considering their challenges and matching the top-ranked drugs with their top-ranked specific scenarios from among the multitude of real-world scenarios for efficacy and safety. This approach will generate RWD scenario-specific hypotheses that can be tested in randomized clinical trials with high probabilities of success.


A study of patients who go to a psychology clinic seeking treatment.
In order to characterize a typical clinical context, as opposed to an academic or research context, this article will analyze the sociodemographic and clinical characteristics of patients who turn to a psychology clinic in need of professional help. This study was conducted using an initial sample of 1,305 patients at the Universidad Complutense de Madrid (UCM) Clínica Universitaria de Psicología. Of the sociodemographic characteristics studied, it is noteworthy that the majority of patients were women (65%) and relatively young (the average age is 29.7 years-old). The disorders for which psychological help was most often needed were anxiety and mood disorders and relationship problems, which together made up 50% of cases. In 17.70% of cases, patients had at least one comorbid disorder in addition to the one that brought them to the clinic. The generalizability and implications of the results are discussed.


Symmetries and cluster synchronization in multilayer networks.
Real-world systems in epidemiology, social sciences, power transportation, economics and engineering are often described as multilayer networks. Here we first define and compute the symmetries of multilayer networks, and then study the emergence of cluster synchronization in these networks. We distinguish between independent layer symmetries, which occur in one layer and are independent of the other layers, and dependent layer symmetries, which involve nodes in different layers. We study stability of the cluster synchronous solution by decoupling the problem into a number of independent blocks and assessing stability of each block through a Master Stability Function. We see that blocks associated with dependent layer symmetries have a different structure to the other blocks, which affects the stability of clusters associated with these symmetries. Finally, we validate the theory in a fully analog experiment in which seven electronic oscillators of three kinds are connected with two kinds of coupling.


Refined Feature-based Multi-frame and Multi-scale Fusing Gate network for accurate segmentation of plaques in ultrasound videos.
The accurate segmentation of carotid plaques in ultrasound videos will provide evidence for clinicians to evaluate the properties of plaques and treat patients effectively. However, the confusing background, blurry boundaries and plaque movement in ultrasound videos make accurate plaque segmentation challenging. To address the above challenges, we propose the Refined Feature-based Multi-frame and Multi-scale Fusing Gate Network (RMFG_Net), which captures spatial and temporal features in consecutive video frames for high-quality segmentation results and no manual annotation of the first frame. A spatial-temporal feature filter is proposed to suppress the noise of low-level CNN features and promote the detailed target area. To obtain a more accurate plaque position, we propose a transformer-based cross-scale spatial location algorithm, which models the relationship between adjacent layers of consecutive video frames to achieve stable positioning. To make full use of more detailed and semantic information, multi-layer gated computing is applied to fuse features of different layers, ensuring sufficient useful feature map aggregation for segmentation. Experiments on two clinical datasets demonstrate that the proposed method outperforms other state-of-the-art methods under different evaluation metrics, and it processes images with a speed of 68 frames per second which is suitable for real-time segmentation. A large number of ablation experiments were conducted to demonstrate the effectiveness of each component and experimental setting, as well as the potential of the proposed method in ultrasound video plaque segmentation tasks. The codes can be publicly available from https://github.com/xifengHuu/RMFG_Net.git.


Modulating the development of E. coli biofilms with 2-aminoimidazoles.
The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC(50) of 13μM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400μM.


Economic Burden and Healthcare Resource Use of Alopecia Areata in an Insured Population in the USA.
Comparative data on the economic burden of alopecia areata relative to the general population are limited. The objective of this retrospective database analysis was to evaluate healthcare resource utilization and direct medical costs among patients with alopecia areata from the US payer perspective compared with matched controls. Validated billing codes were used to identify patients with alopecia areata from the IQVIA PharMetrics Plus (2016-2018) who had continuous pharmacy and medical enrollment for 365 days both before (baseline period) and after (evaluation period) the index date. Demographic and clinical characteristics were characterized, and baseline comorbidities were assessed with the Quan Charlson Comorbidity Index. Using the exact matching feature from Instant Health Data, 14,340 patients with alopecia areata were matched with 42,998 control patients aged ≥ 12 years. Patients with alopecia areata had higher healthcare resource utilization and adjusted total all-cause mean medical costs versus matched controls ($8557 versus $6416; p < 0.0001), because of higher inpatient costs, emergency department visits, ambulatory visits, number of prescriptions and prescription costs, and other costs such as durable medical equipment and home healthcare. The number of inpatient visits did not significantly differ between the two groups. Mean ambulatory costs were $3640 for patients with alopecia areata and $2062 for controls, and mean pharmacy costs were $3287 and $1843, respectively (p < 0.0001 for both). Pharmacy costs related to immunologic agents represented 50.0% of the total difference in pharmacy spending between patients with alopecia areata and controls. Surgery on the integumentary system accounted for 9.5% of the total difference in ambulatory costs. Alopecia areata is associated with significant incremental healthcare resource utilization and costs relative to matched controls due to increased spending in areas such as surgical procedures and psychological and pharmacological interventions. Costs are primarily driven by ambulatory and pharmacy spending.


Surface characteristics and the interaction of colloidal particles with mouse peritoneal macrophages.
The effect of surface characteristics on the interaction of sterically stabilized polystyrene particles with mouse peritoneal macrophages was studied using a range of poloxamers and poloxamine as coating agents. The coated particles were characterized in terms of thickness of coating layer, surface charge and critical flocculation temperature. The relative phagocytic uptake was found to decrease with increasing adsorbed layer thickness i.e. longer hydrophilic polymer chains of the coating agent and consequently a greater steric stabilization effect.


A comparison of patient recovery following unilateral and bilateral endoscopic preperitoneal herniorrhaphy.
The advantage of using minimally invasive techniques over open techniques in the repair of inguinal hernias remains unclear. One of the more established indications for the performance of minimally invasive (e.g. endoscopic preperitoneal) herniorrhaphy is the presence of bilateral hernias. However, no prior study has compared the recovery following unilateral and bilateral endoscopic preperitoneal hernia repairs. From July 15, 1994 through August 16, 1996 one primary surgeon performed 373 hernia repairs on 250 patients. Unilateral herniorrhaphy (UH) was performed on 114 males and 13 females with an average age of 58 (range 18-89). Bilateral herniorrhaphy (BH) was performed on 121 males and 2 females with an average age of 53 (range 18-86) (p > 0.05). Within the UH group there were 105 virgin hernias and 22 recurrent hernias. The BH group included 212 virgin hernias and 34 recurrent (p > 0.05). Bilateral repairs took longer to perform than unilateral repairs (65 minutes vs. 45 minutes) (p < 0.05). At the time of discharge, all patients were given a postoperative survey and asked to record their level of pain, narcotic use and level of activity on the day of surgery and postoperative days 1, 2, 3, 7, 14, and 28. No differences were found in pain perception, narcotic use or level of activity on any of the days measured between the two groups (p > 0.05). In addition, both groups returned to work at a similar time (UH: 6.32 +/- 3.29 days, BH: 6.68 +/- 4.13 days) (p > 0.05). Bilateral endoscopic preperitoneal herniorrhaphy can be performed with the same expected patient recovery as unilateral repairs.


Concurrent right diaphragmatic hernia and esophageal atresia.
The occurrence of a coexisting congenital diaphragmatic hernia (CDH) and esophageal atresia (EA) with distal tracheoesophageal fistula is extremely rare and is considered highly lethal. Only 19 cases of CDH with EA have been reported in the world literature to date. This is a very challenging clinical problem, and the neonate is likely to deteriorate rapidly. Such a case is reported with a successful outcome, probably the first survivor with a right CDH and EA. Management guidelines for such a case are discussed.


Effect of copper, nutrient nitrogen, and wood-supplement on the production of lignin-modifying enzymes by the white-rot fungus Phlebia radiata.
Production of the oxidoreductive lignin-modifying enzymes - lignin and manganese peroxidases (MnPs), and laccase - of the white-rot basidiomycete Phlebia radiata was investigated in semi-solid cultures supplemented with milled grey alder or Norway spruce and charcoal. Concentrations of nutrient nitrogen and Cu-supplement varied also in the cultures. According to extracellular activities, production of both lignin peroxidase (LiP) and MnP was significantly promoted with wood as carbon source, with milled alder (MA) and low nitrogen (LN) resulting with the maximal LiP activities (550 nkat l(-1)) and noticeable levels of MnP (3 μkat l(-1)). Activities of LiP and MnP were also elevated on high nitrogen (HN) complex medium when supplemented with spruce and charcoal. Maximal laccase activities (22 and 29 μkat l(-1)) were obtained in extra high nitrogen (eHN) containing defined and complex media supplemented with 1.5 mM Cu(2+). However, the nitrogen source, either peptone or ammonium nitrate and asparagine, caused no stimulation on laccase production without Cu-supplement. This is also the first report to demonstrate a new, on high Cu(2+) amended medium produced extracellular laccase of P. radiata with pI value of 4.9, thereby complementing our previous findings on gene expression, and cloning of a second laccase of this fungus.


Evaluation of baicalein, chitosan and usnic acid effect on Candida parapsilosis and Candida krusei biofilm using a Cellavista device.
Biofilms are often the cause of chronic human infections and contaminate industrial or medical equipment. The traditional approach has been to use increasing concentrations of antibiotics, but microorganisms rapidly develop multiresistance to them. Therefore, we investigated the use of natural substances as an alternative solution. The quantification of the biofilms based on the colonized areas was measured using a Cellavista automatic microscope equipped with image analysis software. Using the Cellavista device brings new possibilities for qualification and quantification of sessile cells. In our study, this feature was documented by exploring the antifungal/anti-biofilm activity of amphotericin B, baicalein, chitosan and usnic acid against yeast biofilm formation. The influence of these substances on the formation and eradication of opportunistic pathogenic yeasts Candida parapsilosis and Candida krusei biofilms was studied in 96-well polystyrene microtiter plates. While amphotericin B was not very efficient, the use of baicalein and chitosan, even in minimum inhibitory concentrations, was found to rapidly decrease the colonized areas in the wells. The usnic acid did not display any significant antibiofilm properties even at concentration 300μgml(-1). Our results propose that Cellavista is a promising tool for the study of yeast biofilm formation and the effects of antimicrobial agents.


Lysophosphatidic acid stimulates osteoclast fusion through OC-STAMP and P2X7 receptor signaling.
Bone is continuously remodeled by bone formation and resorption, and cooperative bone metabolism is precisely regulated to maintain homeostasis. Osteoclasts, which are responsible for bone resorption, are differentiated through multiple steps that include cell fusion at the last step of differentiation, yielding multinuclear cells. However, the factors involved in and the precise mechanism of cell fusion are still unknown. To determine the molecules involved in osteoclast fusion, we examined the effect of lysophosphatidic acid (LPA), which has been reported to participate in the progression of cancer bone metastasis. LPA had no effect on osteoclast formation and bone resorption under receptor activator of nuclear factor kappa B ligand (RANKL) conditions, whereas LPA stimulated osteoclast fusion, thereby causing increased osteoclast diameter and bone resorptive capacity under a RANKL-limited condition. This result encouraged us to assess what molecules are needed for LPA-stimulated osteoclast fusion. Interestingly, LPA stimulated osteoclast stimulatory transmembrane protein (OC-STAMP) and P2X7 receptor mRNA expression during osteoclast fusion under a RANKL limiting condition. siRNA-induced OC-STAMP or P2X7 receptor knockdown significantly suppressed the LPA-stimulated increase in osteoclast diameter and bone resorptive capacity in differentiating cultures. Using cyclosporin A as an inhibitor, we revealed that NF-ATc1 directly regulates OC-STAMP and P2X7 receptor expression during LPA-stimulated osteoclast fusion. These results suggest that LPA is a critical regulator of osteoclast fusion by inducing the OC-STAMP and P2X7 receptor. Therefore, LPA signaling might be useful to help understand their effects on osteoclast formation and as a therapeutic target for patients with pathologically increased osteoclast formation.


Role of Therapeutic Drug Monitoring in the Treatment of Persistent Mycobacterium abscessus Central Nervous System Infection: A Case Report and Review of the Literature.
A patient presenting with recurrent ventriculoperitoneal shunt infection was found to have Mycobacterium abscessus growing from cerebrospinal fluid (CSF), which remained persistently positive. Therapeutic monitoring of clarithromycin, imipenem, and linezolid in CSF and plasma revealed lower than expected concentrations, prompting alternative therapy and culture clearance on hospital day 42.


Reduced-dose influenza vaccine.
To evaluate the effectiveness and safety of reduced-dose trivalent inactivated influenza vaccine in adults. A MEDLINE search was conducted (1966-May 2006) using the key search terms inactivated, trivalent, influenza vaccine, dose, and intradermal. Four recent studies evaluated the safety and effectiveness of reduced-dose, inactivated, trivalent influenza vaccine. Reduced doses had immunogenicity similar to that of standard dose vaccination in healthy individuals less than 60 years old. Intramuscular administration caused fewer local adverse effects compared with the other routes of administration. The differences in vaccine administration and dosing used in these studies limit the comparison of their results. The Centers for Disease Control and Prevention does not recommend vaccinating with reduced-dose influenza vaccine. If reduced-dose vaccination is to be employed during times of vaccine shortage, it should be administered only to healthy adults under the age of 60, and the intramuscular route is preferred.


[Anesthetic management of a patient with spinal muscular atrophy type III].
We report a 38-year-old man with Kugelberg-Welander disease who underwent triple arthrodesis for talipes equinovarus under combined spinal-epidural anesthesia supplemented with continuous intravenous infusion of propofol. There was no ventilatory disturbance, muscle weakness, or neurologic untoward event during perioperative period.


Differential exposure of the urban population to vehicular air pollution in Hong Kong.
This study aims to characterize the spatial variations in, and examine the influence of socio-economic class on, the exposure of urban population of Hong Kong to air pollution from vehicular sources. Hong Kong provides a unique and interesting case for an in-depth study of environmental inequality because of its dense environment and housing provision mechanism through which about half of the population is accommodated in public housing estates provided by the government. To estimate the exposure of the urban population to vehicular air pollution, the IMMIS(net) air dispersion model developed for city-wide air quality assessment was used. The annual mean concentrations of CO, NO(x), SO(2) and PM(10) were estimated for various assessment points of 275 public and 295 private building groups. The results show more pronounced inequality among residents living in private than in public housing estates. Elderly people and those of lower socio-economic status were found to be exposed to relatively higher levels of vehicular air pollution compared with groups of higher socio-economic status. However, when all the residents in Hong Kong were pooled together for analysis, no distinct class-biased patterns were found. This could be ascribed to the housing provision mechanism, in which less well-off people are accommodated in public housing estates where the air quality is relatively better. This study highlights the importance of government intervention in housing provision, through which the deprived groups in Hong Kong are inadvertently more protected from air pollution exposure.


Alkyl Polyglucosides as Components of Water Based Lubricants.
Water can be used as an ecological lubricant base if it is possible to select additives which can beneficially modify its tribological and corrosion properties. Additionally, those additives should not be harmful to human health and the natural environment. These conditions limit or even eliminate the possibility for the application of the additives used in traditional oil bases as they are insoluble in water and often toxic. Alkyl polyglucosides (APGs) have been suggested as additives improving lubricating properties of water. They are biodegradable and do not have to be recycled. They exhibit surface activity. They produce micelles at low concentration and lyotropic liquid crystals at high concentration. Two types of alkyl polyglucosides differing in alkyl chain lengths and degrees of polymerization were used in this investigation. Tribological tests were carried out using a ball-on-disc T-11 tester. The balls were made of steel, whereas the discs were made of steel, aluminium oxide, zirconium oxide, polyamide and poly(methyl methacrylate). The description of the device and the methods has been given in the literature (Szczerek and Tuszyński in TriboTest 8:273-284, 2002). The addition of APGs improves the lubricating properties of water. The relative decrease in motion resistance and wear depends both on the type of friction couple and on the kind of alkyl polyglucoside used. The tribological test results obtained were correlated with the activity of APGs measured as wettability of friction couples by their solutions.


CdSe/ZnS quantum dots based electrochemical immunoassay for the detection of phosphorylated bovine serum albumin.
A CdSe/ZnS quantum dot (QD) based electrochemical immunoassay of phosphorylated bovine serum albumin (BSA-OP) as a protein biomarker is presented. The QDs were used as labels for amplifying electrochemical signals and were conjugated with a secondary anti-phosphoserine antibody in a heterogeneous sandwich immunoassay. In this assay, the model phosphorylated protein BSA-OP was added to the primary BSA antibody coated polystyrene microwells, and then the QD labeled anti-phosphoserine antibody was added for completing immunorecognition. Finally, the bound QD was dissolved in an acid-dissolution step and was detected by electrochemical stripping analysis. The measured current responses were proportional to the concentration of BSA-OP. Under optimal conditions, the voltammetric response was linear over the range of 0.5-500 ngmL(-1) of BSA-OP, with a detection limit of 0.5 ngmL(-1). It also shows good reproducibility with a relative standard deviation of 8.6%. This QD-based electrochemical immunoassay offers great promise for simple and cost-effective analysis of protein biomarkers.


Endoscopic ultrasound-guided fine-needle aspiration in the evaluation of gallbladder masses.
There are very few data on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of gallbladder masses. The aim of this study was to assess the utility and safety of EUS-FNA in the evaluation of patients with gallbladder masses. Six patients who underwent EUS-FNA of gallbladder masses over a 2-year period between 2002 and 2004 were studied retrospectively. Reports of endoscopic ultrasound (EUS) procedures, EUS images, cytology results, and clinical records were reviewed. Abdominal computed tomography (CT) prior to EUS had revealed a definitive gallbladder mass in only one of the six patients and no gallbladder masses were identified in any of the patients who had undergone prior transabdominal ultrasound. At EUS, all the patients were found to have an echo-poor mass arising from the gallbladder wall or within the lumen of the gallbladder. EUS-FNA of the gallbladder masses revealed adenocarcinoma in five patients and benign disease in one patient. After a mean follow-up period of 127 days (range 90 - 187 days), three patients had died, two were undergoing palliative chemoradiotherapy, and one had been confirmed as having chronic cholecystitis at surgery. No complications occurred. In patients with obstructive jaundice and equivocal ultrasound or CT findings, evaluation of the gallbladder for the presence of a primary malignancy by EUS is useful. In patients with gallbladder masses, EUS-FNA can be performed safely and can help to make a definitive diagnosis.


Quantitative determination of butylated hydroxyanisole, butylated hydroxytoluene, and tert-butyl hydroquinone in oils, foods, and biological fluids by high-performance liquid chromatography with fluorometric detection.
Concentrations of synthetic antioxidants butylated hydroxyanisole, butylated hydroxytoluene, and tert-butyl hydroquinone were quantified using a high-performance liquid chromatograph with spectrofluorometric detector. The antioxidants were separated and eluted on a reversed-phase column by gradient of a mixture of H2O/acetonitrile/acetic acid (66.5: 28.5:5, by vol) and a mixture of acetonitrile/acetic acid (95:5, vol/vol). The eluants were monitored at emission and excitation wavelengths of 310 and 280 nm, respectively. Calibration curves obtained using peak areas against concentration showed high coefficients of multiple determination (R2 > 0.99) for all antioxidants. Known concentrations of added antioxidant standards were recoverable within 98-99% from oils and over 93% from mouse blood. This method requires minimum sample extraction and purification before analysis and provides a relatively high percentage recovery. The method has been applied successfully for the measurement of antioxidant concentrations in oils, dried foods, and biological fluids.


Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.
In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.


Current and future pharmacotherapies for obesity in children and adolescents.
Obesity is a common chronic disease in children and adolescents and its prevalence is increasing worldwide. The causes are multifactorial but involve biological predisposition towards a specific body-weight set point and defended adipose tissue mass converging with an obesogenic environment. Comprehensive treatment of paediatric obesity includes lifestyle modification therapy, anti-obesity medications (AOMs) and/or metabolic surgery. Lifestyle modification therapy used alone produces fairly modest weight loss for most youth with obesity. The emergence of new AOMs has changed the landscape of paediatric weight management, improving the outlook for youth with obesity. This Review briefly highlights obesity development pathways in youth and the role that pharmacotherapy can play in counteracting these pathophysiological forces. Here, results from adolescent AOM clinical trials published since 2020 are reviewed, including the safety, efficacy and tolerability of the newest treatments (glucagon-like peptide 1 receptor agonists and phentermine-topiramate). The importance of a comprehensive and chronic care model, including both lifestyle modification and ongoing pharmacotherapy, will be discussed in the context of maximizing long-term health outcomes. Finally, insight will be provided into the emerging pipeline of AOMs (for example, incretin receptor co-agonists and tri-agonists) and how future therapies might fundamentally change the prognosis for youth with obesity.


Exploration of the barriers of reporting nursing errors in intensive care units: A qualitative study.
The aim of this study was to explore the barriers to reporting nursing errors in intensive care units in Iranian hospitals. A descriptive qualitative analysis design was used. The data were collected through in-depth semi-structured interviews with a purposive sample of 16 nurses working in four general intensive care units in Kurdistan province, Iran. Interviews were transcribed and finally analysed through conventional content analysis. There are four major barriers to the reporting of errors by nurses working in Iranian critical care units: (a) saving professional reputation and preventing stigma; (b) fear of consequences - punishment, legal problems and organisational misconduct; (c) feelings of insecurity - pointing a finger at nurses and lack of managerial support and (d) not investigating the root cause of error. The findings revealed the need to support and provide security to nurses and to consider and find the cause of error occurrence. Managers must provide the required personal, professional and legal support for nurses to encourage them to effectively report errors, discover the root cause of errors and take measures to prevent them.


Synthesis of pyridine-based 1,3,4-oxadiazole derivative as fluorescence turn-on sensor for high selectivity of Ag+.
An oxadiazole derivative(OXD) containing symmetrical pyridine-2-formamidophenyl-binded moiety was synthesised as fluorescence turn-on sensor OA1. Its ultraviolet-visible(UV-vis) and fluorescent spectra(FS) gave prominent fluorescence enhancement only for monovalent silver ion(Ag(+)) in HEPES buffer solution (10 mM, pH = 7.0, DMF-H2O, 9:1, v/v), which indicated the photo-induced electron transfer(PET) occurred from the donor of pyridine-2-formamidophenyl group to oxadiazole fluorophore. The present study demonstrated that OA1 was a viable candidate as fluorescent receptor for a new Ag(+) sensor. And the results of fluorescent spectral titration showed this sensor formed 1:1 complex with Ag(+).


Automated pre-column high-performance liquid chromatographic method for the investigation of adibendan metabolism.
An automated pre-column high-performance liquid chromatographic method has been developed for the isolation of adibendan and metabolites from biological fluids and for their simultaneous quantitative assay. High sensitivities were obtained by the use of a multiple-injection device allowing solid-phase extraction from several successive sample injections with enrichment of metabolite traces on the pre-column. Two metabolites in dog urine were identified as N-oxypyridine (M1) and 2-hydroxypyridine (M2) derivatives of adibendan, while the structure of M3 is still unknown. M1 and M2 are also metabolites in rats, rabbits and humans, and contribute to cardiovascular efficacy. The metabolic profiles were determined in plasma, urine and bile, as a function of dose, route of administration and sex, using radioactivity and ultraviolet detection of the eluates.


Development of biocompatible aqueous polyurethane dispersions using chitosan and curcumin to improve physicochemical properties of textile surfaces.
The present research work aims to synthesize a blend of chitosan (CSN) and curcumin (CRN) based aqueous polyurethane dispersions (CSN-CRN APUDs) for the modification of textile surfaces. A series of anionic CSN-CRN APUDs were prepared by the reaction of isophorone diisocyanate (IPDI) with polyethylene glycol (PEG) and extended with chain extenders (CSN and CRN). Structural characterizations of prepared materials were examined through a fourier transformed infrared (FTIR) spectrophotometer. The performances of coated CSN-CRN APUDs on the colorfastness properties (washing, rubbing and perspiration) and the mechanical properties like tensile strength and tearing strength of plain weaved poly/cellulosic textiles (dyed, printed and white) were examined before and after the application of CSN-CRN APUDs. The findings showed that the mechanical and colorfastness properties of all the CSN-CRN APUDs treated poly/cellulosic textile samples were improved significantly as compared with untreated poly/cellulosic textile samples. The newly synthesized CSN-CRN APUD coating materials are sustainable and greener products, particularly derivatized from bio-resources. These coating materials can be utilized as outstanding eco-friendly substitutes for poly/cellulosic textile coatings for surface modifications.


The effect of question order on evaluations of test performance: how does the bias evolve?
Weinstein and Roediger (Memory & Cognition 38:366-376, 2010) found that manipulating the order of questions on a general knowledge quiz resulted in differing evaluations of performance at the end of the quiz: Irrespective of their actual performance, participants were consistently more optimistic about their performance when questions were given in an easy-to-hard order. In the present experiment, the participants were stopped 10 times throughout a 100-item test and asked to evaluate their performance on the last 10 questions they had answered, as well as rating their impressions of the test so far and predicting their final performance. Arranging the questions from the easiest to the hardest produced more optimistic performance evaluations on each block than did an analogous hard-easy question order, even though performance on the two versions did not differ significantly as a function of question order. Furthermore, the ratings of item difficulty on each block of 10 questions were asymmetrical in the two conditions, with a higher sensitivity to increasing as compared to decreasing question difficulty. On the other hand, the item-by-item ratings and predictions remained unaffected by question order. Our findings are best explained by an anchoring interpretation, which suggests that students fail to adjust their evaluations of performance as the difficulty of the questions changes across the test.


Development of efficient protocol for rice transformation overexpressing MAP kinase and their effect on root phenotypic traits.
Exhaustive studies on mitogen-activated protein kinase (MAPK) have reported the importance in regulating a variety of responses during plant growth and development. In particular, the potential MAPK genes, MPK3 and MPK6, seem to regulate a plethora of responses, conferring tolerance to varied abiotic, biotic, and developmental stimuli. This makes both MPK3 and MPK6 potential targets for further studies. It would be an important concern to overexpress and knock out these pivotal proteins and then, in turn, to monitor the plant response which is expected to correlate action of a gene to a trait in cellular and organismal contexts. However, overexpression of MAPK genes has remained a puzzle in plants. In the present study, we report the generation of stable transgenic lines overexpressing OsMPK3 in indica and japonica cultivars and OsMPK6 in japonica cultivar under the control of an inducible promoter. We also establish the crucial steps and troubleshooting for each of the indicated rice transformation medium components. Later, we study the potential role of these MAPKs in high-throughput analysis of root system architectural (RSA) traits. It was observed that OsMPK6 overexpression lines had a more robust and spread out root architectural system while OsMPK3 overexpression lines had a typical bushy phenotype.


Design and synthesis of pyrrolo[2,3-d]pyrimidine linked hybrids as α-amylase inhibitors: molecular docking, MD simulation, ADMET and antidiabetic screening.
Novel pyrrolo[2,3-d]pyrimidine-based analogues were designed, synthesized, and evaluated for their ability to inhibit the α-amylase enzyme in order to treat diabetes. In vitro antidiabetic analysis demonstrated excellent antidiabetic action for compounds 5b, 6c, 7a, and 7b, with IC50 values in the 0.252-0.281 mM range. At a 200 μg/mL concentration, the exceptional percent inhibition values for compounds 5a, 5b, 5d, and 6a varied from 97.79 ± 2.86% to 85.56 ± 4.13% overperforming the standard (acarbose). Molecular docking of all compounds performed with Bacillus paralicheniformis α-amylase enzyme. The most active compounds via in vitro and non-toxic via in silico ADMET and molecular docking analysis, hybrids 6c, 7a, and 7b displayed binding affinity from - 8.2 and - 8.5 kcal/mol. Molecular dynamic simulations of most active compound 5b and 7a investigated into the active sites of the Bacillus paralicheniformis α-amylase enzyme for a 100-ns indicating the stability of hybrid-protein complex. Consistent RGyr values for the two complexes under study further suggest that the system's proteins are closely packed in the dynamic state. Synthesized analogs' in vitro biological assessments, ADMET, molecular docking, and MD modelling reveal that 5b, 6c, 7a, and 7b hybrid analogs may be employed in the development of future antidiabetic drugs.


Insight into the dimer dissociation process of the Chromobacterium violaceum (S)-selective amine transaminase.
One of the main factors hampering the implementation in industry of transaminase-based processes for the synthesis of enantiopure amines is their often low storage and operational stability. Our still limited understanding of the inactivation processes undermining the stability of wild-type transaminases represents an obstacle to improving their stability through enzyme engineering. In this paper we present a model describing the inactivation process of the well-characterized (S)-selective amine transaminase from Chromobacterium violaceum. The cornerstone of the model, supported by structural, computational, mutagenesis and biophysical data, is the central role of the catalytic lysine as a conformational switch. Upon breakage of the lysine-PLP Schiff base, the strain associated with the catalytically active lysine conformation is dissipated in a slow relaxation process capable of triggering the known structural rearrangements occurring in the holo-to-apo transition and ultimately promoting dimer dissociation. Due to the occurrence in the literature of similar PLP-dependent inactivation models valid for other non-transaminase enzymes belonging to the same fold-class, the role of the catalytic lysine as conformational switch might extend beyond the transaminase enzyme group and offer new insight to drive future non-trivial engineering strategies.


Extra-gastrointestinal stromal tumor of the pancreas: case report and a review of the literature.
Gastrointestinal (GI) stromal tumors are mesenchymal tumors that arise from the GI tract. In rare cases, these tumors are found in intra-abdominal sites unrelated to the GI tract and are immunohistochemically similar to their GI tract counterparts. Primary pancreatic GI stromal tumors are very rare, with only 4 previous cases reported.