The Staub-Traugott effect. Evidence for multifactorial regulation of a physiological function.
Previous exposure to large amounts of glucose facilitates the disposal of a subsequent load of the sugar (priming or Staub-Traugott effect). We have investigated whether, in man, the classical effect can also be induced by more physiological loads of glucose and whether a priming effect is accompanied by augmented insulin release. To facilitate interpretation of results, a second exposure to glucose was imposed at a time point following the first exposure when the subjects were again euglycaemic. Initial infusion of glucose significantly diminished the hyperglycaemia seen after the subsequent ingestion of 1.75 g/kg of glucose. The corresponding incremental insulin response was diminished while the integrated absolute levels of the hormone were unaffected by prior i.v. glucose. Initial ingestion of 0.5 g/kg of glucose slightly reduced the glycaemic but did not affect the insulin response to a second oral load. Initial ingestion of the same oral glucose load clearly facilitated the disposal of 12.5 g of glucose subsequently injected i.v. Again, this effect of priming with glucose was not accompanied by any priming effect on insulin levels. The lack of enhancement of peripherally measured insulin secretion seemed, if anything, to overestimate B-cell secretory rates since the ratio of insulin to C-peptide was increased (from 37 to 89) after priming with glucose, suggesting that the hepatic clearance of insulin was decreased during the second glucose challenge. It is concluded that (1) facilitation of glucose disposal by previous glucose administration can be induced by amounts of glucose equivalent to those associated with meal intake, (2) enhancement of insulin release is not an obligatory component of the facilitated glucose disposal, (3) decreased hepatic clearance of insulin may accompany the Staub-Traugott effect.


Incidental Thyroid Carcinoma in Patients Treated Surgically for Presumably Benign Thyroid Disease.
Incidental Thyroid Carcinoma (ITC) is quite high as been reported in the world's Journal. This study reviews the frequency of the ITC in patients treated surgically for otherwise benign Thyroid disease in one of the Endocrine surgery unit of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. This study was developed by the investigating the outcome of one hundred and twenty seven patient who underwent partial or total thyroidectomy for benign thyroid pathology in a single Endocrine Surgery Unit of BSMMU from January 2011 to July 2015. This observational study was done to find out the actual incidence of thyroid malignancy among the patients admitted for surgical management with thyroid pathology. All patients underwent at least FNAC and Ultrasonography of the Neck before surgery. Patients with undetermined cytology and follicular nodules were excluded from the study. Overall 19(14.96%) incidental thyroid carcinoma was recorded. Among the ITC 11(8.66%) Papillary Carcinoma, 7(5.51%) Follicular Carcinoma & 1(0.79%) is poorly differentiated carcinoma. The Overall incidence of papillary carcinoma is higher among the incidental carcinoma of Thyroid. Increased incidence associated with follicular adenoma present as an isolated thyroid nodules or multifocal lesion and should be considered malignant potential and total thyroidectomy would be the right choice as surgical management of the both cases. In case of multinodular goiter, total thyroidectomy is currently practiced in majority of the centers and our observations reinforced the attitude further.


Investigating Direct and Indirect Genetic Effects in Attention-Deficit/Hyperactivity Disorder Using Parent-Offspring Trios.
Attention-deficit/hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e., direct) and nontransmitted (i.e., indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is overtransmitted to ADHD probands. We also tested for indirect or genetic nurture effects by examining whether nontransmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population. Polygenic risk scores (PRSs) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, Tourette syndrome, and cognitive ability were calculated in UK control subjects (n = 5081), UK probands with ADHD (n = 857), their biological parents (n = 328 trios), and also a replication sample of 844 ADHD trios. ADHD PRSs were overtransmitted and cognitive ability and obsessive-compulsive disorder PRSs were undertransmitted. These results were independently replicated. Overtransmission of polygenic liability was not observed for other disorders. Nontransmitted alleles were not enriched for ADHD liability compared with control subjects. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status. The results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that nontransmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be nonrandom, in terms of demographic and clinical factors.


Neuropsychiatric sequelae of portal-systemic encephalopathy: a review.
Portal-systemic encephalopathy (PSE) is a common condition affecting individuals with chronic hepatic dysfunction. The clinical presentation of PSE often mimics a number of psychiatric disorders and, as discussed in the text, complicates the treatment of persons who suffer from both liver dysfunction and psychiatric illness. This review of the literature addresses the etiology, natural history and treatment of PSE. Special attention is devoted to clarifying the cognitive and affective manifestations of chronic low grade PSE.


Managing sternal osteomyelitis with antibiotic bead implantation.
Early, aggressive debridement followed by closure with muscle flaps is thought to improve the resolution of deep sternal wound infection that occurs after sternotomy. However, persistently discharging sternal osteomyelitis remains difficult to resolve. We successfully treated 2 patients who developed deep sternal wound infection after cardiac surgery by combining one-stage debridement with implantation of gentamicin beads to fill up the evacuated bone marrow space. This approach provides a simple and effective solution for sternal osteomyelitis.


[Recurrence of varicocele caused by renal tumour].
A 31-year-old man referred with six to seven years' history of a left-side WHO grade III varicocele and normal palpatory abdominal findings underwent microsurgical subinguinal varicocelectomy. At 3-month follow-up there was complete remission. The varicocele recurred after one year and abdominal ultrasound demonstrated a solid mass in the left kidney. A radical nephrectomy was performed and histology demonstrated renal cell carcinoma pT2. We recommend performing an abdominal ultrasound in adults if recurrence of a varicocele is detected following microsurgical subinguinal varicocelectomy.


Determinants of community members' willingness to donate stool for faecal microbiota transplantation.
Universal stool banks rely on, but face difficulties recruiting, community volunteers to donate stool for faecal microbiota transplantation (FMT) to effectively treat recurrent Clostridioides difficile. This study sought to identify determinants of community members' willingness to donate stool to guide donor recruitment. 397 Australian residents (52% male, 47% 21-30 years, 63% university educated) completed a survey to gauge willingness to donate stool, bowel habits, information needs, attitudes, barriers, and motives for donation. Most reported regular bowel movements (BMs; 90%), morning BMs (63%), BMs ≤5 minutes duration (67%), and some discomfort doing BMs in public restrooms (69%). Less than half were willing to donate stool in-centre (45% willing) or at home (48%). Important information needs identified by >80% were convenience and travel requirements associated with donation. Main barriers were logistics, capabilities to donate, disgust (e.g., donation process), and discomfort (e.g., privacy). The main motivator was altruism, with compensation secondary. Linear regression models identified less discomfort doing BMs in public restrooms (β = -0.15), understanding benefits to patients (β = 0.15), placing less importance on understanding the donation process (β = -0.13), and positive attitudes (β = 0.56) as determinants of willingness to donate in-centre. Understanding benefits to self (β = 0.11) and patients (β = 0.24), placing less importance on understanding the donation purpose (β = -0.19), and positive attitudes (β = 0.50) determined willingness to donate at home. Stool banks should consider donor's bowel habits, comfort donating in-centre, and information needs early in recruitment; and implement flexible logistics for potential donors who face time constraints and limited access to stool banks.


Oedematous malnutrition.
Oedematous malnutrition, represented by its most severe form kwashiorkor, is rampant in many parts of the world and is associated with a high case fatality rate. Despite being first described more than a century ago, the pathogenesis of kwashiorkor is still not clear. The traditional thinking is that it results from a deficiency of dietary protein and is usually associated with an infection. This has now been challenged by the finding that there is no difference in diets of children developing marasmus or kwashiorkor. Nutritional oedema is associated with an increased secretion of anti-diuretic substance (probably antidiuretic hormone) which prevents the normal excretory response to water administration. Experimental studies have shown that feeding low-protein, low-calorie diets results in delayed and incomplete response to a water load, and that the livers of the animals show a reduced capacity for inactivating anti-diuretic hormone. There is now evidence that links generation of free radicals and depletion of anti-oxidants with the development of oedema in kwashiorkor.


Immunohistochemical and ultrastructural study of ito cells (fat-storing cells) in response to extrahepatic bile duct ligation in broiler chickens.
The Ito cell (fat-storing cell) lies in perisinusoidal space of liver and has a variety of functions. We investigated the immunohistochemistry and ultrastructure of Ito cells in normal and cholestatic livers of broiler chickens. Immunohistochemistry demonstrated that Ito cells expressed HHF35 muscle actin, vimentin, desmin, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), chromogranin A and cytokeratins in normal livers. These cells were diffusely scattered throughout the lobules. Livers treated with extrahepatic bile duct ligation (BDL) showed cholestasis, fibrosis, proliferation of biliary ductules and Ito cells. The Ito cells were frequently found in fibrotic areas and were larger in size with more extensive immunoreactivity than those of normal livers. Ultrastructural study demonstrated that Ito cells were closely associated with the production of collagen fibers in BDL livers. These findings suggest that Ito cells actively react against hepatocytic injuries and play a major role in the hepatic fibrogenesis of cholestatic livers of chickens.


Comparison of vitamin E levels in plasma, bronchoalveolar lavage, and lung tissues of adult pulmonary patients.
Plasma, bronchoalveolar lavage fluids (BAL), and lung parenchyma were analyzed for vitamin E and polyunsaturated fatty acid (PUFA) concentrations in three groups of patients routinely receiving oxygen therapy--two with adult respiratory distress syndrome (ARDS and SARDS), a third with pneumonia (PNEU), as well as a fourth group of patients receiving little or no oxygen therapy (OTHER). Only plasma alpha- and gamma-tocopherols were significantly lower in patients receiving oxygen therapy compared to those not requiring oxygen. Among diagnosis groups, PNEU patients exhibited highest levels of alpha-tocopherol in BAL, though all groups on oxygen had greater amounts of alpha-tocopheryl quinone in BAL as compared to those of the OTHER group. No significant differences in BAL measures were observed between oxygen and non-oxygen groups, however. No statistical tests on lung measures could be performed between these groups because of insufficient sampling for the OTHER group. A highly significant relationship was observed (r = +0.73, p less than 0.004) between plasma vitamin E and lung vitamin E when expressed in terms of PUFA, whereas no significant relationship was observed if plasma vitamin E and lung vitamin E levels were compared directly. No relationship was obtained for BAL alpha-tocopherol (expressed per number of cells) and lung alpha-tocopherol. These findings support previous reports that in an appropriate setting plasma vitamin E:PUFA ratios along with smoking status may be used to evaluate lung vitamin E levels when also expressed in terms of PUFA.


On the HKUST-1/GO and HKUST-1/rGO Composites: The Impact of Synthesis Method on Physicochemical Properties.
The chemical stability and adsorptive/catalytic properties of the most widely studied metal-organic framework (MOF), which is HKUST-1, can be improved by its combination with graphene oxide (GO) or reduced graphene oxide (rGO). The chemistry of GO or rGO surfaces has a significant impact on their interaction with MOFs. In this work, we demonstrate that GO and rGO interaction with HKUST-1 influences the morphology and textural properties but has no impact on the thermal stability of the final composites. We also show that synthesis environment, e.g., stirring, to some extent influences the formation of HKUST-1/GO and HKUST-1/rGO composites. Homogeneous samples of the sandwich-type composite can be obtained when using reduced graphene oxide decorated with copper (Cu/rGO), which, owing to the presence of Cu sites, allows the direct crystallisation of HKUST-1 and its further growth on the graphene surface. This work is the first part of our research on HKUST-1/GO and HKUST-1/rGO and deals with the influence of the type of graphene material and synthesis parameters on the composites' physicochemical properties that were determined by using X-ray diffraction, scanning and transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis.


Quantification of Nineteen Bioactive Components in the Ancient Classical Chinese Medicine Formula of Wen-Dan Decoction and Its Commercial Preparations by UHPLC-QQQ-MS/MS.
A UHPLC-QQQ-MS/MS method was developed to quantify the significant constituents in Wen-Dan Decoction (WDD), a traditional Chinese medicine. Analysis of 19 compounds was conducted on an ACQUITY UPLC® BEH C18 Column (2.1 × 50 mm, 1.7 μm) using elution with a gradient elution of acetonitrile and 0.05% (v/v) formic acid in water. A triple quadrupole mass spectrometer was operated in negative ionization mode and positive ionization mode by multiple reaction monitoring (MRM), respectively. All calibration curves showed acceptable linearity (r ≥ 0.9950). The RSDs of intra- and inter-day precisions of low, mid and high concentrations were ≤ 8.88%. The repeatabilities (RSDs ≤ 7.17%) and stabilities (RSD ≤ 4.79%) of the samples were qualified. The recoveries were found in the range of 93.07 ± 3.86 to 103.98 ± 2.98% with the RSD varying between 1.30 and 7.86%. The final rapid, sensitive, precise, accurate and reliable UHPLC-QQQ-MS/MS method was used for the simultaneous quantification of 19 constituents in WDD and its commercial preparations. The strategy of combining the contents of the 19 chemicals in a daily dose of the WDD preparations with the hierarchical cluster analysis and the 3D principal component analysis was employed to effectively distinguish the WDD preparations provided by the different suppliers, which represents a contribution to the evaluation and control of the quality of WDD (or other decoctions consisting of the same herbs) and the preparations of WDD in other dosage forms such as tablets and granules.


Serous macular detachment, yellow macular deposits, and prominent middle limiting membrane in multiple myeloma.
Bone marrow-derived multiple myeloma is a type of plasma cell tumor that may be associated with ocular complications. A 52-year-old male patient was admitted to our eye clinic with the complaint of sudden visual loss and a visual acuity of 20/50 in the right eye and 20/800 in the left eye. Fundus examination revealed common flame-shaped hemorrhages, venous dilatation and tortuosity, Roth spots, serous macular detachment, and yellow macular deposits in both eyes. Evaluation with fundus fluorescein angiography, fundus autofluorescence, and spectral-domain optical coherence tomography resulted in suspicion of hyperviscosity retinopathy and referral to the hematology clinic. After hematology consultation confirmed a diagnosis of multiple myeloma, chemotherapy and plasmapheresis were initiated. Four months after presentation, best-corrected visual acuity was 20/20 in both eyes and improvement in hyperviscosity retinopathy, serous macular detachment, and yellow macular deposits was observed.


Management of spontaneous cerebrospinal fluid leaks of the sphenoid sinus: our experience.
Closure of spontaneous sphenoid sinus cerebrospinal fluid leaks can be challenging because of the relative inaccessibility of the lateral recess and the presence of intracranial hypertension. We present our experience of such cases and highlight factors associated with a successful outcome. Eleven patients with spontaneous, laboratory confirmed, sphenoid sinus cerebrospinal fluid leaks were included. All patients underwent endoscopic closure by either a three-layer technique or fat obliteration. In all but one patient, the leak was successfully sealed (success rate, 90.9 per cent; mean follow up, 37.1 months). Elevated intracranial pressure was measured in eight patients, two of whom did not exhibit relevant clinical or radiological characteristics. Five patients received diuretics and dietary advice for weight reduction. In one patient with recurrence two weeks after repair, successful revision was performed by additional placement of a ventriculoperitoneal shunt (follow up, 67 months). Long-lasting cerebrospinal fluid fistula sealing in the sphenoid sinus requires stable reconstruction of the defect in three layers or fat obliteration if the anatomy is unfavourable. All patients should be intra- and post-operatively screened for elevated intracranial pressure to identify those who need additional intracranial pressure reduction measures.


The Maize ABA Receptors ZmPYL8, 9, and 12 Facilitate Plant Drought Resistance.
Drought is one of the major abiotic stresses affecting world agriculture. Breeding drought-resistant crops is one of the most important challenges for plant biologists. PYR1/PYL/RCARs, which encode the abscisic acid (ABA) receptors, play pivotal roles in ABA signaling, but how these genes function in crop drought response remains largely unknown. Here we identified 13 PYL family members in maize (ZmPYL1-13). Changes in expression of these genes under different stresses indicated that ZmPYLs played important roles in responding to multiple abiotic stresses. Transgenic analyses of ZmPYL genes in Arabidopsis showed that overexpression of ZmPYL3, ZmPYL9, ZmPYL10, and ZmPYL13 significantly enhanced the sensitivity of transgenic plants to ABA. Additionally, transgenic lines overexpressing ZmPYL8, ZmPYL9, and ZmPYL12 were more resistant to drought. Accumulation of proline and enhanced expression of drought-related marker genes in transgenic lines further confirmed the positive roles of ZmPYL genes in plant drought resistance. Association analyses with a panel of 368 maize inbred lines identified natural variants in ZmPYL8 and ZmPYL12 that were significantly associated with maize drought resistance. Our results deepen the knowledge of the function of maize PYL genes in responses to abiotic stresses, and the natural variants identified in ZmPYL genes may serve as potential molecular markers for breeding drought-resistant maize cultivars.


Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.
Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.


Influence of Social Exclusion on the Inferiority Feeling of Community Youth.
Inferiority feeling leads to the negative reactions such as depression and anxiety among community youth, social exclusion also forms their negative emotions due to the alienation of social relations. We aimed to explore the effect of social exclusion on the inferiority feeling of community youth. In December 2021, a total of 681 community youth from Wuhan in China were selected as the research object. They were evaluated using a social exclusion scale, inferiority scale, and rumination scale, respectively. The mediating effect of rumination on the relationship between social exclusion and inferiority of community youth was tested by using structural equation model and bootstrap test. The scores of social exclusion, inferiority complex, and rumination were positively correlated (P<0.05). The mediation effect test showed that the mediation hypothesis model had a relatively good fitting index. Social exclusion was a positive predictor of rumination, and rumination was a positive predictor of inferiority. Ruminant thinking had a significant partial mediating effect in the relationship between social exclusion and inferiority feeling, the indirect effect was 0.078, the direct effect was 0.04, the total effect was 0.118, and the ratio of direct effect to indirect effect was approximately 1:2. Therefore, social exclusion exerted the influence on inferiority through rumination. Social exclusion positively affects the inferiority feeling of community youth through the mediating effect of rumination thinking. The health prevention of community youth's inferiority feeling should not only prevent the negative impact of social exclusion but also strengthen the cultivation of rumination thinking.


Leveraging unique structural characteristics of WNK kinases to achieve therapeutic inhibition.
The with-no-lysine (K) WNK kinases are master regulators of the Na+-(K+)-Cl- cotransporters, including the renal-specific NCC and NKCC2 cotransporters. The discovery of WNK463, an orally bioavailable pan-WNK kinase inhibitor that exploits unique structural properties of the WNK catalytic domain to achieve high affinity and kinase selectivity, illustrates a strategy of leveraging distinct kinase features to develop specific inhibitors and validates the genetic predictions of the in vivo pharmacology of WNK inhibition.


Attenuation of giant laser pulses by absorbing filters.
Three types of absorbing filters were tested for suitability as reproducible attenuators for a Q-switched ruby laser beam. None of the filters tested were irreversibly damaged when irradiated with pulses having peak powers up to 40 MW (beam cross section ~10(-4) M(2)). However, Tiffen Photar neutral density filters and Corning filters showed reversible photobleaching (optical saturation) at large pulse energies, while Kodak Wratten neutral density filters did not saturate.


Improvement of salt tolerance in transgenic potato plants by glyceraldehyde-3 phosphate dehydrogenase gene transfer.
In the previous experiment, we isolated and characterized glyceraldehyde-3-phosphate dehydrogenase (GPD) gene of the oyster mushroom, Pleurotus sajor-caju. Expression levels of the GPD gene in the mycelia of P sajor-caju was significantly increased by exposing the mycelia to abiotic stresses, such as salt, cold, heat, and drought. We also showed that GPD confers abiotic stress resistance when introduced into yeast cells. The survival rate of the transgenic yeast cell that harbored the GPD gene was significantly higher when the yeast cells were subjected to salt, cold, heat, and drought stresses, compared with the yeast that was transformed with the pYES2 vector alone. In order to investigate the functional role of the P. sajor-caju GPD gene in higher plant cells, the complete P. sajor-caju GPD cDNA was fused into the CaMV35S promoter and then introduced into potato plants. Putative potato transformants were screened by using PCR. Twenty-one transformants were further analyzed with RT-PCR to confirm the expression of P. sajor-caju GPD. A RT-PCR Southern blot analysis revealed that 12 transgenics induced the P. sajor-caju GPD gene expression. A bioassay of these transformants revealed that the P. sajor-caju GPD gene was enough to confer salt stress resistance in the potato plant cell system. Results showed that P. sajor-caju GPD, which was continuously expressed in transgenic potato plants under normal growing conditions, resulted in improved tolerance against salt loading.


Steroid-induced osteoporosis.
Prolonged administration of glucocorticoids causes accelerated loss of bone, which leads to osteopenia and an increased incidence of fractures. The clinical presentation of cortisol excess is one of progressive demineralization, primarily of trabecular bone, resulting in fractures of the vertebral bodies and ribs. Bone dissolution is greatest during the initiation of steroid therapy and can result in the loss of up to 20 per cent of trabecular bone in the first year. Bone loss slows with prolonged therapy; cortical bone is relatively spared so that appendicular skeleton fractures are not typically a part of this syndrome. The rate of bone loss is greatest in those individuals who have high bone remodeling rates. Histologically, one finds decreased trabecular volume and increased bone resorption with an increase in osteoclast number and activity, along with decreased bone formation and mineralization rate. Adjuvant medical therapies that block accelerated bone resorption may protect against steroid-induced osteoporosis.


Elevated eosinophil levels observed in infantile hemangioma patients from Kaifeng, China.
Infantile hemangioma (IH) is one of the most common soft-tissue neoplasms of infancy. Although clinical diagnosis for IH is well-established, the haematological parameters associated with IH are not well explored. In this short study, we observed significantly higher eosinophil (EO) numbers in IH patient blood compared to healthy controls. This contributed to the observed higher EO % in the peripheral blood of IH patients and was irrespective of age. This new haematological finding could carry a potential diagnostic/prognostic relevance for IH.


Tutorial dynamics and participation in small groups: a student perspective in a multicultural setting.
This study investigated the language and cultural backgrounds of medical students, and explored their perspectives of the influences on student participation in small-group tutorial settings. A task group of students and staff from a variety of cultural backgrounds designed a cross-sectional survey using an anonymous questionnaire. The survey was conducted at the Christchurch School of Medicine and Health Sciences (a campus of the University of Otago). Students attending a 4th-year and a 5th-year lecture were invited to participate. Seventy-five percent of students enrolled in the medical course responded to the survey. Half of the sample self-identified as New Zealand European or Maori. Sixty-four percent of students identified English as their first language. Ninety-one percent of students stated a preference for small-group tutorials rather than lectures. Most students reported that there was a 'lack of prior preparation' by students in these tutorials (no statistically significant difference between students with English as first or second language). Two thirds of students (66%) students felt there was a lack of full participation in small-group teaching. Personality, cultural, and language differences were perceived as contributing factors to the lack of participation. Lack of participation should not be assumed to be due to language difficulties. Barriers to participation are perceived differently by students from a variety of language and cultural backgrounds. Moreover, interactions between students who dominate and under-participate may influence student participation. Further research is needed to determine whether language and cultural backgrounds affect students' participation in small group teaching.


EORTC QLQ-BM22 quality of life evaluation and pain outcome in patients with bone metastases from breast cancer treated with zoledronic acid.
We assessed the effect of zoledronic acid on quality of life (QOL) and pain outcome in breast cancer patients with bone metastases using the European Organization for Research and Treatment of Cancer bone metastases module (EORTC QLQ-BM22). Three hundred sixty-six breast cancer patients receiving zoledronic acid for bone metastases from 13 Centers were prospectively enrolled. QOL was evaluated using the EORTC QLQ-BM22 and pain outcome were measured monthly with a Visual Analog Scale (VAS) score for 24 months. No significant change of functional scale (functional interference and psychosocial aspects) of the EORTC QLQ-BM22 was reported. Significant reduction of the symptom scale was noted after treatment compared with the baseline. The painful site subscale was significantly reduced during the first 12 months, with the exception the 6-month follow-up of point. Pain characteristics subscale was also significantly lower from the 2-month time point onwards. VAS scores indicated a significant reduction in pain over the course of the study to the 22-month time point follow-up compared to the baseline. Zoledronic acid treatment improved QOL of breast cancer patients with bone metastases by relieving bone pain.


Nano-biomimetics for nano/micro tissue regeneration.
Nanostructured biomimetics have recently shown great promise in the field of tissue engineering. They can be used as nanoscaffolds and tailored at the molecular level. The scaffold topography closely resembles the native extracellular matrix in terms of framing, porosity and bio-functionality. This review covers the approaches used for biomimetic fabrication, including soft lithography, the plasmonic nanohybrid matrix method and multilayer self-assembly scaffolds for tissue regeneration. It brings together knowledge from different arenas about the synthesis, characterization and functionalization of matrices to accelerate the tissue regeneration process. Every tissue in the body presents different challenges and requires a specific fabrication process designed to identify and mirror the particular organ. For example, microfluidics systems aim to mimic the extracellular matrix of vascular and cartilage tissue, and these systems have different parts with completely different mechanical strength, cellular adhesion and interplay between matrix and cells. A fully functional nanomatrix designed by a self-assembling methodology for use as a vascular tissue engineering scaffold needs to have intrinsic microvessels that facilitate the transportation of metabolites and nutrients. Similarly, in the case of peripheral nerve regeneration, a scaffold needs to have sufficient mechanical strength to protect the regenerating tissue, yet be biodegradable enough to avoid a possible second surgery. To enhance the functionality of scaffolds, increasing focus has been placed on in vitro and in vivo research to achieve optimal scaffold design. Nanobiomimetics unarguably offer the most suitable physicochemical scaffold properties for tissue regeneration.


Genetics of quantitative traits with dominance under stabilizing and directional selection in partially selfing species.
Recurrent self-fertilization is thought to lead to reduced adaptive potential by decreasing the genetic diversity of populations, thus leading selfing lineages down an evolutionary "blind alley." Although well supported theoretically, empirical support for reduced adaptability in selfing species is limited. One limitation of classical theoretical models is that they assume pure additivity of the fitness-related traits that are under stabilizing selection, despite ample evidence that quantitative traits are subject to dominance. Here, we relax this assumption and explore the effect of dominance on a fitness-related trait under stabilizing selection for populations that differ in selfing rates. By decomposing the genetic variance into additional components specific to inbred populations, we show that dominance components can explain a substantial part of the genetic variance of inbred populations. We also show that ignoring these components leads to an upward bias in the predicted response to selection. Finally, we show that when considering the effect of dominance, the short-term evolutionary potential of populations remains comparable across the entire gradient in outcrossing rates, and genetic associations can even make selfing populations more evolvable on the longer term, reconciling theoretical, and empirical results.


Variability in soman toxicity in the rat: correlation with biochemical and behavioral measures.
The inhibition of cholinesterase (ChE) activity in the central nervous system of the rat by the potent organophosphorus compound soman was examined. At soman doses greater than 55 micrograms/kg s.c. (0.5 LD50), there were: (1) dose-related inhibition of ChE activity in brain regions; (2) variability in the degree of ChE inhibition at each soman dose in each brain region; and (3) variability in the severity of signs of intoxication at each dose. These data suggest that measurements of ChE should be made directly or predicted individually in each animal for which the effects of soman are assessed. At the estimated ED50 soman dose for signs of intoxication (66 micrograms/kg s.c.), the remaining ChE activity in brain correlated poorly with ChE activity in plasma and red blood cells (R = 0.14-0.20), moderately with behavioral scores based on overt signs of intoxication (R = 0.63-0.94), and well with spinal cord ChE activity (R = 0.93-0.98). Finally, ChE activity in the thoracic and lumbosacral regions of spinal cord were not affected by headfocused microwave inactivation of brain enzymes, demonstrating that ChE activity in these regions of the cord can be used to predict the level of ChE inhibition in brain when direct measurement in brain is unfeasible.


Sequential onset of bilateral trigeminal neuralgia: clinical presentation and outcomes.
Sequential onset of bilateral trigeminal neuralgia (TN) is rare and not well-described in the literature. The objective of this study was to characterize demographic, clinical, and procedural characteristics of patients with sequential onset bilateral TN. We retrospectively reviewed patients presenting with sequential onset bilateral TN at our institution from 2007 to 2020. Patient demographics, clinical diagnoses, pain outcomes, and procedural characteristics were recorded and compared. Factors associated with pain recurrence were assessed using survival analyses and multivariate regressions. We identified 34 patients who presented with sequential onset bilateral TN. The average age of onset for the index case was 49.9 ± 15.5 years, and 58.0 ± 16.8 years for the contralateral case. In total for our cohort, 91 surgical procedures were performed for the index case, and 70 for the contralateral case. With each additional surgical intervention, pain-free survival was more likely to decrease, p = 0.05. When controlled for order of intervention, glycerin rhizotomy (p = 0.01) and glycerin-radiofrequency rhizotomy (p = 0.05) were more likely associated with pain recurrence compared to microvascular decompression. While pain outcomes were significantly decreased in our cohort at final follow-up, 82.4% of patients were still dependent on medication for pain management after an average of 5.03 ± 7.74 years. Our results represent one of the largest series of sequential onset bilateral TN in North America. Our study demonstrates the high treatment burden and chronicity of pain encountered in this population.


Studies on the sequence of the 3'-terminal region of turnip-yellow-mosaic-virus RNA.
A fragment representing the 3'-terminal 'tRNA-like' region of turnip yellow mosaic (TYM) virus RNA has been purified following incubation of intact TYM virus RNA with Escherichia coli 'RNase P'. This fragment, which is 112+3-nucleotides long has been completely digested with T1 RNase and pancreatic RNase and all the oligonucleotides present in such digests have been sequenced using 32P-end labelling techniques in vitro. The TYM virus RNA fragment is free of modified nucleosides and does not contain a G-U-U-C-R sequence. Using nuclease P1 from Penicillium citrinum, the sequence of 26 nucleotides from the 5' end and 16 nucleotides from the 3' end of this fragment has been deduced. The nucleotide sequence at the 5' end of the TYM virus RNA fragment indicates that this fragment includes the end of the TYM virus coat protein gene.


Serum CCL2 Is a Prognostic Biomarker for Non-Metastatic Castration-Sensitive Prostate Cancer.
Purpose: Prostate-specific antigen (PSA) is a useful prostate cancer (PC) biomarker, but some cases reported that PSA does not correlate with the Gleason score. Serum chemokine (CC motif) ligand 2 (CCL2) has been reported to be a potential complementary PSA biomarker, but it remains unclear whether it can be applied to non-metastatic castration-sensitive prostate cancer (nmCSPC) or each section of the stages. Serum CCL2′s usefulness was investigated as a prognostic nmCSPC biomarker in this study. Methods: Serum samples were collected from 379 patients who underwent prostate biopsy at Kanazawa University Hospital from 2007 to 2013. A total of 230 patients with nmCSPC were included in this study of the 255 patients with histologically diagnosed prostate cancer. The serum CCL2 efficacy as a prognostic nmCSPC biomarker was investigated retrospectively. Results: An independent significant predictor of worse OS was CCL2 ≥ 280 pg/dL and CRP ≥ 0.5 mg/dL in multivariate analysis. Gleason score ≥ 8 and CCL2 ≥ 280 pg/dL were independent significant predictors of CRPC-free survival (CFS) worsening in multivariate analysis. Serum CCL2 was a predictive biomarker for OS and CFS in nmCSPC. Furthermore, CCL2 ≥ 280 pg/mL patients had significantly worse visceral metastasis-free survival than those with CCL2 < 280 pg/mL. Conclusion: This study is the first to demonstrate serum CCL2 utility as a biomarker to predict OS and CFS in nmCSPC.


[Angio-CT in the staging of renal carcinoma].
The authors report the results about the staging of renal carcinoma using "angio-CT". The diagnostic accuracy, the sensibility, the specificity, in 42 patients, have been evaluated and compared with the subsequent operative or authoptic diagnosis. The meaning of this study is the comparison of the results obtained by this method in front of other examinations, especially artheriography.


Atlantoaxial malformation in a half-Arabian colt.
A 1-year-old half-Arabian colt was referred for evaluation of a cranial cervical abnormality. Physical examination revealed the left wing of the atlas to be more ventral than the right wing. A head tilt, with the pole deviated to the left, was present because of the malpositioned atlas. Neurologic examination identified symmetrical weakness, ataxia, and proprioceptive deficits in all four limbs. Radiographs of the cranial cervical region revealed fusion of the atlas and axis, and deviation of the atlantoaxial joint to the left of the median plane. Euthanasia was elected. Necropsy confirmed the radiographic findings. The atlas was rotated 20 degrees counterclockwise when viewed from the caudal aspect. Multifocal myelomalacia was present in the first and second cervical spinal cord segments. The malformation was believed to be due to a degenerative process or abnormal embryological development.


Deep learning identifies robust gender differences in functional brain organization and their dissociable links to clinical symptoms in autism.
Autism spectrum disorder (ASD) is a highly heterogeneous disorder that affects nearly 1 in 189 females and 1 in 42 males. However, the neurobiological basis of gender differences in ASD is poorly understood, as most studies have neglected females and used methods ill-suited to capture such differences. To identify robust functional brain organisation markers that distinguish between females and males with ASD and predict symptom severity. We leveraged multiple neuroimaging cohorts (ASD n = 773) and developed a novel spatiotemporal deep neural network (stDNN), which uses spatiotemporal convolution on functional magnetic resonance imaging data to distinguish between groups. stDNN achieved consistently high classification accuracy in distinguishing between females and males with ASD. Notably, stDNN trained to distinguish between females and males with ASD could not distinguish between neurotypical females and males, suggesting that there are gender differences in the functional brain organisation in ASD that differ from normative gender differences. Brain features associated with motor, language and visuospatial attentional systems reliably distinguished between females and males with ASD. Crucially, these results were observed in a large multisite cohort and replicated in a fully independent cohort. Furthermore, brain features associated with the motor network's primary motor cortex node predicted the severity of restricted/repetitive behaviours in females but not in males with ASD. Our replicable findings reveal that the brains of females and males with ASD are functionally organised differently, contributing to their clinical symptoms in distinct ways. They inform the development of gender-specific diagnoses and treatment strategies for ASD, and ultimately advance precision psychiatry.


Proficiency testing/external quality assessment: current challenges and future directions.
Proficiency testing (PT), or external quality assessment (EQA), is intended to verify on a recurring basis that laboratory results conform to expectations for the quality required for patient care. Key factors for interpreting PT/EQA results are knowledge of the commutability of the samples used and the process used for target value assignment. A commutable PT/EQA sample demonstrates the same numeric relationship between different measurement procedures as that expected for patients' samples. Noncommutable PT/EQA samples frequently have a matrix-related bias of unknown magnitude that limits interpretation of results. PT/EQA results for commutable samples can be used to assess accuracy against a reference measurement procedure or a designated comparison method. In addition, the agreement of the results between different measurement procedures for commutable samples reflects that which would be seen for patients' samples. PT/EQA results for noncommutable samples must be compared to a peer group mean/median of results from participants who use measurement procedures that are expected to have the same or very similar matrix-related bias. Peer group evaluation is used to asses whether a laboratory is using a measurement procedure in conformance to the manufacturer's specifications and/or in conformance to other laboratories using the same technology. A noncommutable PT/EQA sample does not give meaningful information about the relationship of results for patients' samples between different measurement procedures. PT/EQA provides substantial value to the practice of laboratory medicine by assessing the performance of individual laboratories and, when commutable samples are used, the status of standardization or harmonization among different measurement procedures.


Breastfeeding is associated with lower risk for multiple sclerosis.
Multiple sclerosis (MS) is an autoimmune disease with known genetic and environmental susceptibility factors. Breastfeeding has been shown to be protective in other autoimmune diseases. This case-control study analyzed the association of breastfeeding in infancy on the risk of developing MS. A case-control study was performed in Berlin of 245 MS patients and 296 population-based controls, who completed a standardized questionnaire on their history and duration of breastfeeding in infancy and demographic characteristics. Univariable and multivariable logistic regression analysis was performed to investigate the association between breastfeeding and MS. The multivariate model was adjusted for age, gender, number of older siblings, number of inhabitants in place of domicile between ages 0 and 6 (categorized in each case), and daycare attendance between ages 0 and 3. In multivariable analysis, breastfeeding showed an independent association with MS (adjusted OR 0.58; p = 0.028). However, with no breastfeeding as reference, the protective effect only emerges after four months of breastfeeding (multivariable analysis for ≤ four months adjusted OR 0.87; p = 0.614 and for > four months OR 0.51; p = 0.016). The results of this case-control study support the hypothesis that breastfeeding is associated with a lower risk of MS. These results are in line with findings of previous studies on other autoimmune diseases, in which breastfeeding was shown to have protective effects.


Integration of an online simulated prescription analysis into undergraduate pharmacy teaching using supplemental and replacement models.
To describe student use and perceptions of online simulated prescription analysis following integration of supplemental and replacement models into pharmacy practice teaching. Strathclyde Computerized Randomized Interactive Prescription Tutor (SCRIPT) is a simulated prescription analysis tool designed to support a pharmacy practice competency class. In 2008-2009, SCRIPT scenarios were released to coincide with timetabled teaching as the supplemental model. In 2009-2010, SCRIPT also replaced one-sixth of the taught component of the class as the replacement model. Student use and performance were compared, and their perceptions were documented. In both cohorts, the majority of use (over 70%) occurred immediately before assessments. Remote access decreased from 6409 (supplemental) to 3782 (replacement) attempts per 100 students. There was no difference in student performance between the cohorts, Students reported group and individual use and 4 targeted approaches using SCRIPT. E-learning can reduce the staff time in pharmacy practice teaching without affecting student performance. SCRIPT permits flexible learning that suits student preferences.


Overcoming the Warburg Effect: Is it the key to survival in sepsis?
Sepsis is a leading cause of mortality in the U.S. and Europe. Sepsis and septic shock are the results of severe metabolic abnormalities following infection. Aerobic glycolysis (the Warburg Effect) is as much a hallmark of sepsis as it is of cancer. Warburg observed that cancer cells generated energy through glycolysis (generation of ATP through degradation of glucose, usually associated with anaerobic conditions) rather than through oxidative phosphorylation (generation of ATP through the mitochondrial inner membrane via the tricarboxylic acid cycle, usually associated with aerobic conditions). Although the initial pathways of cancer and sepsis may be different, the mechanisms which allow aerobic glycolysis to occur, even in the presence of oxygen, are similar. This review provides some evidence that reversing these steps reverses the Warburg Effect in model systems and some pathological consequences of this effect. Therefore, this implies that these steps might be modifiable in sepsis to reverse the Warburg Effect and possibly lead to better outcomes.


[The efficiency of cutting balloon angioplasty in the treatment of in-stent restenosis].
Although stents reduce the restenosis rate, stent restenosis continues to be a major problem and the optimal treatment of stent restenosis is still controversial. In this study, we aimed to investigate the angiographic recurrent stent restenosis rate at 6-12 months after successful cutting balloon angioplasty (CBA) for the bare metal stent restenosis. Thirty patients (mean age: 57.9 ± 11.6, 22 males) undergoing successful CBA for the treatment of in-stent restenosis at our hospital were prospectively included in this study. Control coronary angiography was performed at 6-12 months after CBA. Lesion length, minimal lumen diameter (MLD), and reference vessel diameter were analyzed by computerized digital angiographic analysis. Recurrent restenosis was defined as the lesions obstructing the lumen more than 50%. We described the lesions shorter than 10 mm as to be focal and those longer than 10 mm as to be diffuse. We used Student t, Chi-square, and Mann-Whitney U tests for statistical analysis. Two patients had two distinct lesions; therefore, 32 lesions were assessed. There were 9 (28.1%) recurrent restenosis on the control coronary angiography. Recurrent restenosis developed in 3/21 (14.3%) of focal type lesions and 6/11(54.5%) of diffuse type lesions (p=0.035). Pre-procedural MLD was lower in the restenotic group compared to non-restenotic group (0.41 ± 0.29 vs. 0.64 ± 0.17 mm, p=0.048) while percent of stenosis was higher in the restenotic group (76.8 ± 12 vs. 69.6 ± 5.37%, p=0.029). In the selected patients, CBA is an effective and a safe method for the treatment of bare metal stent restenosis. CBA might be considered as a first-line treatment method in patients with focal type lesions.


Risk Assessment of Perioperative Respiratory Adverse Events and Validation of the COLDS Score in Children with Upper Respiratory Tract Infection.
Background and objectives: Children are at greater risk of upper respiratory tract infection (URTI), which can pose a higher risk of perioperative respiratory adverse events (PRAEs), than adults. The purpose of this study was to validate the COLDS score as a pre-anesthetic risk assessment tool for predicting the possibility of PRAEs. Materials and methods: Children aged under 18 years and undergoing elective surgery were retrospectively included. Logistic regression analysis and the area under the receiver-operating characteristic (ROC) curve (AUC) were used to estimate the ability of the COLDS score to predict PRAEs. Propensity-matched comparison was evaluated using the cut-off value from the ROC curve. Results: Among the 6252 children, 158 children had a recent URTI and 34 cases of PRAEs were reported. Age, current symptoms, and COLDS score were found to be significant variables in predicting PRAEs. From the ROC curve, values of 0.652 (p = 0.007) for AUC and 12.5 for the cut-off value of the COLDS score were calculated. Propensity-matched comparison revealed that each and every component of COLDS contributed to the higher COLDS score group. In addition to higher COLDS score, younger age and current URTI symptoms were found to be significant risk factors for PRAEs. Conclusions: This study validated the predictive power of COLDS score as a risk assessment tool for children with URTI undergoing elective surgery under general anesthesia.


Impaired stretch modulation in potentially lethal cardiac sodium channel mutants.
The presence of two slowly inactivating mutants of the cardiac sodium channel (hNa(V)1.5), R1623Q and R1626P, associate with sporadic Long-QT3 (LQT3) syndrome, and may contribute to ventricular tachyarrhythmias and/or lethal ventricular disturbances. Cardiac mechanoelectric feedback is considered a factor in such sporadic arrhythmias. Since stretch and shear forces modulate hNa(V)1.5 gating, detailed electrophysiological study of LQT-Na(V)1.5 mutant channel alpha subunit(s) might provide insights. We compared recombinant R1623Q and WT currents in control vs. stretched membrane of cell-attached patches of Xenopus oocytes. Macroscopic current was monitored before, during, and after stretch induced by pipette suction. In either mutant Na(+) channel, peak current at small depolarizations could be more than doubled by stretch. As in WT, R1623Q showed reversible and stretch intensity dependent acceleration of current onset and decay at all voltages, with kinetic coupling between these two processes retained during stretch. These two Na(V)1.5 channel alpha subunits differed in the absolute extent of kinetic acceleration for a given stretch intensity; over a range of intensities, R1623Q inactivation speed increased significantly less than did WT. The LQT3 mutant R1626P also retained its kinetic coupling during stretch. Whereas WT stretch-difference currents (I(Na)(V,t) without stretch minus I(Na)(V,t) with stretch) were mostly inhibitory (equivalent to outward current), they were substantially (R1623Q) or entirely (R1626P) excitatory for the LQT3 mutants. If stretch-modulated Na(V)1.5 current (i.e., brief excitation followed by accelerated current decay) routinely contributes to cardiac mechanoelectric feedback, then during hemodynamic load variations, the abnormal stretch-modulated components of R1623Q and R1626P current could be pro-arrhythmic.


Increased circulating monocyte MDSCs positively correlate with serum Interleukin-10 in metastatic melanoma patients.
Numerous immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and inhibitory cytokines identified in melanoma microenvironment have the important role in immune escape. Therefore, in this study we analyzed monocytic (m)MDSCs in peripheral blood of metastatic melanoma (MM) patients. In peripheral blood of 35 MM patients and 30 healthy controls we analyzed percentage of CD14 + HLA-DR- mMDSCs in monocyte gate and the mean fluorescence intensity of Foxp3 in CD25 + CD4 + regulatory T cells by Flow cytometry. Serum levels of transforming growth factor beta, interferon-gamma, interleukin (IL)-6, IL-8, IL-10 are measured by ELISA assays. In this study MM patients have significantly higher percentage of CD14 + HLA-DR- mMDSCs, as well as increased the baseline mMDSC/PBMC subset (NK, T, B cells, monocytes) ratio. Although there is no significant difference in the percentage of mMDSCs between groups of MM patients with different localization of distant metastasis, patients with elevated serum lactate dehydrogenase (LDH) have statistically significant higher percentage of these cells compared to LDH negative patients. Furthermore, in MM patients there is statistically significant positive correlation between values of IL-10 and the percentage of mMDSCs, only. Therefore, therapeutics that target circulating mMDSCs and IL-10 may have a big importance in the improvement of antitumor immunity in MM patients.


[Hemolytic activity of new hybrid antioxidants ichfans].
The hemolytic activity of new spatially screened hybrid antioxidants--ichfans--has been studied. The concentration-dependent hemolytic action of high concentrations of ichfans with 8, 10, 12 or 16 carbon atoms in the aliphatic chain has been revealed. A nonmonotonic dependence of the hemolytic activity on the hydrophobic properties of ichfans has been found.


[Cerebral activation during movement of both hands. A study with transcranial Doppler].
In healthy persons, the force carried out by a group of muscles doing bilateral exercise with maximum effort is less than that done during unilateral exercise. The nervous control of movement is probably different in these two cases. Our objective was to study and compare cerebral activation on movement of one and of both hands by means of transcranial Doppler (TCD). We studied 30 healthy volunteers (19 men and 11 women; average age 65.4 +/- 9.5 years). Using transtemporal TCD we assessed the relative changes in average velocity of flow in both middle cerebral arteries during the exercise of sequential opposition of the fingers of one hand and of both hands. The activity due to the exercise of the hand contralateral to the hemisphere being studied was greater than that due to exercise of both hands together, both on the right side (p < 0.001) and on the left (p < 0.001). The functional activity of each cerebral hemisphere is not necessarily greater when both hands are exercised than when the contralateral hand is used, and may even be less. The possible increase in activity due to the additional contribution to ipsilateral movement in the first case may be compensated by simultaneous transhemispherical inhibition.


Comparative analysis of single-stranded DNA donors to generate conditional null mouse alleles.
The International Mouse Phenotyping Consortium is generating null allele mice for every protein-coding gene in the genome and characterizing these mice to identify gene-phenotype associations. While CRISPR/Cas9-mediated null allele production in mice is highly efficient, generation of conditional alleles has proven to be more difficult. To test the feasibility of using CRISPR/Cas9 gene editing to generate conditional knockout mice for this large-scale resource, we employed Cas9-initiated homology-driven repair (HDR) with short and long single stranded oligodeoxynucleotides (ssODNs and lssDNAs). Using pairs of single guide RNAs and short ssODNs to introduce loxP sites around a critical exon or exons, we obtained putative conditional allele founder mice, harboring both loxP sites, for 23 out of 30 targeted genes. LoxP sites integrated in cis in at least one mouse for 18 of 23 genes. However, loxP sites were mutagenized in 4 of the 18 in cis lines. HDR efficiency correlated with Cas9 cutting efficiency but was minimally influenced by ssODN homology arm symmetry. By contrast, using pairs of guides and single lssDNAs to introduce loxP-flanked exons, conditional allele founders were generated for all four genes targeted, although one founder was found to harbor undesired mutations within the lssDNA sequence interval. Importantly, when employing either ssODNs or lssDNAs, random integration events were detected. Our studies demonstrate that Cas9-mediated HDR with pairs of ssODNs can generate conditional null alleles at many loci, but reveal inefficiencies when applied at scale. In contrast, lssDNAs are amenable to high-throughput production of conditional alleles when they can be employed. Regardless of the single-stranded donor utilized, it is essential to screen for sequence errors at sites of HDR and random insertion of donor sequences into the genome.


[Rapid quantitative detection of free cancer cells in the peritoneal cavity of gastric cancer patients with real-time RT-PCR, and its prognostic significance].
We have established a rapid and quantitative detection method using real-time RT-PCR on the LightCycler instrument. This method can reproducibly quantitate 10-10(5) CEA expressing colon carcinoma cells per 10(7) peripheral blood leukocytes, a sensitivity comparable with conventional RT-PCR with a wide linear measuring range. Analysis of peritoneal washes from 241 gastric cancer patients with this assay revealed relative values of CEA transcripts that correlate well with the depth of tumor invasion. The sensitivity and specificity of real-time RT-PCR with a cut-off value of 0.25 were 88% and 81%, respectively. At this cut-off value, patients in the real-time RT-PCR (+) group were found to suffer from peritoneal metastasis with a high frequency, while peritoneal recurrence was very rare among patients with real-time RT-PCR (-) results. These results indicate a positive correlation between CEA mRNA levels in peritoneal washes and patient prognosis. We conclude that real-time RT-PCR with hybridization probes is a sensitive, quantitative, specific and rapid method to detect free cancer cells in peritoneal washes.


Genetic background of systemic sclerosis: autoimmune genes take centre stage.
SSc is a complex multiorgan disease. The key steps in its pathogenesis include early endothelial damage, dysregulation of the immune system with abnormal autoantibody production and fibroblast activation resulting in hyperproduction of extracellular matrix. The disease is caused by an interaction between susceptibility genes and environmental triggers since epidemiological data, including family and twin studies, reveal a genetic component in the pathogenesis of SSc. The candidate gene approach has mainly been employed to identify SSc susceptibility genes. We will focus on data obtained through large samples of well-phenotyped patients and replicated in independent cohorts. These case-control association studies have enabled the identification of several genes that are shared with other connective tissue disorders, and for some of these, putative autoimmune susceptibility genes have been identified. Indeed, we will mainly focus on IRF5 (rs2004640), STAT4 (rs7574865), PTPN22 (rs2476601) and BANK1 (rs3733197 and rs10516487) data. Some of these genes/loci are common to several autoimmune diseases, indicating a shared genetic background also contributing to SSc. Among connective tissue disorders, similarities for genetic markers with SLE are noteworthy. Most likely, these immune-modifying genes could interact and influence both disease phenotype and severity. Less evidence is available yet with regard to genetic markers relating to the vascular and fibrotic aspects of the disease.


[Effects of miR-144 on proliferation, apoptosis and cisplatin resistance by targeting MYCN in pediatric neuroblastoma].
Objective: To investigate the effects and mechanisms of miR-144 on proliferation, apoptosis and cisplatin (DDP) resistance of neuroblastoma cells. Methods: Real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the mRNA expressions of miR-144 and MYCN in neuroblastoma cell lines, including SH-SY5Y and SK-N-SH, and human umbilical vein endothelial cells HUVEC. The miR-negative control, miR-144 mimics, si-negative control, si-MYCN, miR-144 mimics and pcDNA, miR-144 mimics and pcDNA-MYCN co-transfected SH-SY5Y cells were described as miR-NC, miR-144, si-NC, si-MYCN, miR-144+ pcDNA and miR-144+ pcDNA-MYCN group, respectively. The half maximal inhibitory concentration (IC(50)) and cell proliferation were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay. The protein expressions of MYCN, p21, cyclin D1, Bax, Bcl-2 were analyzed by western blot. Cell apoptosis was detected by flow cytometry. The cell fluorescence activity was detected by double luciferase reporter gene assay. Results: Compared with HUVEC cells, the expressions of miR-144 in neuroblastoma cells SH-SY5Y and SK-N-SH significantly decreased, while the mRNA and protein expression of MYCN significantly increased. The IC(50) of DDP was 9.16 μg/ml in SH-SY5Y cells. The absorbance value in 490nm (A(490) value) of miR-144 group was 0.30±0.03, significantly lower than 0.46±0.03 of miR-NC group. The cell apoptotic rate of miR-144 group was 26.94%±2.01%, significantly higher than 9.68%±0.52% of miR-NC group. The IC(50) value of DDP in miR-144 group was 2.95±0.26, significantly lower than 9.23±0.61 of miR-NC group. The expressions of p21, cyclin D1, Bax, Bcl-2 in miR-NC and miR-144 group were 2.67±0.19, 0.41±0.04, 2.12±0.21, 0.18±0.01 and 1.01±0.07, 1.00±0.06, 1.00±0.05, 1.00±0.06, respectively, with statistical significance (all P<0.05). Knockdown of MYCN showed the similar effects with those of miR-144 overexpression in SH-SYSY cells. MiR-144 significantly inhibited the fluorescence activity of ectopic MYCN expressing cells and negatively regulated the expression of MYCN. Overexpression of MYCN can reverse the effects of miR-144 on proliferation inhibition, apoptosis promotion and sensitization of SH-SY5Y cells to DDP. Conclusion: MiR-144 inhibits proliferation, promotes apoptosis and enhances the sensitivity of neuroblastoma cells to DDP through targeting MYCN, which provides a potential treatment for neuroblastoma.


Responsible research publication: international standards for editors.
Editors are accountable and should take responsibility for everything they publish. Editors should make fair and unbiased decisions independent from commercial consideration and ensure a fair and appropriate peer review process. Editors should adopt editorial policies that encourage maximum transparency and complete, honest reporting. Editors should guard the integrity of the published record by issuing corrections and retractions when needed and pursuing suspected or alleged research and publication misconduct. Editors should pursue reviewer and editorial misconduct. Editors should critically assess the ethical conduct of studies in humans and animals. Peer reviewers and authors should be told what is expected of them. Editors should have appropriate policies in place for handling editorial conflicts of interest.


Threephasic contractions in mammalian myocardium. Isolation and identification of a late component. Implications for rested-state contractions.
More than 100 years after Bowditch's discovery of the "Treppe" phenomenon the mechanism of the striking rate and rhythm dependence of cardiac contraction is not unequivocally established. Beside sophisticated techniques biphasic contractions seemed to be a promising approach. There was soon a general agreement that the first component of biphasic contractions is activated by Ca released from the sarcoplasmic reticulum. About the second component prevails confusion: It does not directly reflect the Ca current, but is somehow related to that. In addition, involvement of Na-Ca exchange is supposed. We produced threephasic contractions by the use of isoproterenol (0.5-.4 microM) in guinea pig papillary muscle. Either by the application of ryanodine (1 microM) or after long periods of rest a ryanodine resistant late component of contraction could be isolated. On reducing the transmembrane Na gradient either by reducing [Na]o or by experimental manoeuvres expected to increase [Na]i. (.5 mM [K]o; 2-8 microM ouabain) this component was found to be increased. The evidence suggests that this component is substantially activated by Ca entering the cell via the sarcolemmal Na-Ca exchange. The ryanodine sensitive first component of threephasic contractions was found to be sensitive to caffeine, isoproterenol and changes in stimulation as well. These findings support the view that it may be generated by Ca induced Ca release from the sarcoplasmic reticulum. The pharmacological properties of the second and third ryanodine sensitive component and its dependence on the stimulation pattern were similar to those of the aftercontraction. They were found to be sensitive to procaine, verapamil, Mg, Ni and isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)


Nomogram for Prediction of Diabetic Retinopathy Among Type 2 Diabetes Population in Xinjiang, China.
To establish an accurate risk prediction model of diabetic retinopathy (DR) using cost effective and easily available patients' characteristics and clinical biomarkers. Totally 18,904 cases diagnosed type 2 diabetes mellitus (T2DM) were collected, among which 13,980 cases were selected after quality screening. The least absolute shrinkage and selection operator (LASSO) regression models were used for univariate analysis and factors selection, and the multi-factor logistic regression analysis was used to establish the prediction model. Discrimination, calibration, and clinical usefulness of the prediction model were assessed using AUC/ Harrell's C statistic, calibration plot, and decision curve analysis. Both the development group and validation group were assessed. Candidate variables were selected by Lasso regression and multivariate logistic regression analysis. Finally, the candidate predictive variables were included diabetic peripheral neuropathy (DPN), age, neutrophilic granulocyte (NE), high-density lipoprotein (HDL), hemoglobin A1c (HbA1C), duration of T2DM, and glycosylated serum protein (GSP) were used to establish a nomogram model for predicting the risk of DR. In the development group, the area under the receiver operating characteristic curve (AUC) was 0.882 (95% CI, 0.875-0.888). In the validation group, the AUC was 0.870 (95% CI, 0.856-0.881). Meanwhile, the optimism-corrected Harrell's C statistic were 0.878 and 0.867 in the development group and the validation group, respectively. Decision curve analysis demonstrated that the nomogram was clinically useful. We constructed and verified nomograms that could accurately predict the risk of DR in T2DM patients, which could be used to predict the personalized risk of DR patients in Xinjiang, China.


Severe mental retardation after large prenatal exposures to bomb radiation. Reduction in oxygen transport to fetal brain: a possible abscopal mechanism.
Reasonable expectations, based on the normal physiology of the human fetus, cast new light on the possibilities of extrapolation from the finding of severe mental retardation (SMR) in Japanese bomb survivors after maternal exposure to 1.8-5.5 Gy T65DR Gy. After such large exposures the fetal haematopoietic tissues (DS86 dose 0.9-2.2 Gy) cannot escape severe damage and a consequent reduction in erythropoiesis. Diminished fetal erythropoiesis will diminish oxygen transport from placenta to fetus. Impaired oxygen transport to the developing forebrain will augment the localized forebrain damage caused directly by large radiation doses. Linear extrapolation of an observed linear dose response for SMR after large radiation exposures is unlikely to be a valid method for predicting the frequency of SMR after much smaller exposures causing minimal damage to the fetal haematopoietic tissues.


[Treatment of patellar instability of adolescence through arthroscopic reconstruction of medial patellofemoral ligament with trabs of medial soft tissues].
To explore the clinical effectiveness of arthroscopic reconstruction of medial patellofemoral ligament (MPFL) with trabs of medial soft tissues in the treatment of patellar instability of adolescence. From January 2005 to December 2006, 23 cases of patellar instability were treated, including 10 males and 13 females with an average age of 16 years old (13 to 20 years old). The locations were left knee in 11 cases, right knee in 12 cases. The disease course was 1-28 weeks (mean 15 weeks). All patients had patellar instability sense and knee arthralgia during strenuous exercise. Preoperative, the International Knee Documentation Committee (IKDC) score and Lysholm score were 48.30 +/- 5.77 and 50.80 +/- 7.61. The congruence angle, lateral patellar angle, and Q angle were (9.00 +/- 2.46), (2.94 +/- 2.55) and (19.10 +/- 4.16) degrees. All of the patients experienced the operation of reconstruction of MPFL with trabs of medial soft tissues (medial patellar retinaculum, joint capsule and vastus medialis oblique muscle fiber) through arthroscope. All the wounds healed by first intention, and no postoperative early complication occurred. All cases were followed up 19 months on average (12 to 24 months). Apprehensive test and patella tilt test were negative. The range of motion returned to normal. There was no recurrence of dislocation after operation. At 12 months after operation, the congruence angle, lateral patellar angle, and Q angle were (-7.03 +/- 0.60), (11.00 +/- 3.47) and (11.30 +/- 1.90) degrees; the IKDC score and Lysholm score were 93.20 +/- 3.51 and 94.10 +/- 4.26. There were statistically significant differences between preoperation and postoperation (P < 0.05). Arthroscopic reconstruction of MPFL with trabs of medial soft tissues can improved obviously the affected limb function in treatment of patellar instability of adolescence.


Synthesis and characterization of a new ZIF-67@MgAl2O4 nanocomposite and its adsorption behaviour.
Fabricating suitable adsorbents with low-cost and high efficiency extraction for measurement of very small amounts of agricultural pesticides in food and water is playing a vital key role in personal and environmental health. Here, a new composite of zeolitic imidazolate framework-67@magnesium aluminate spinel (ZIF-67@MgAl2O4) has been fabricated by a simple method at room temperature with different weight ratios. Several techniques such as FE-SEM, BET, XRD, and TGA have been used to confirm the structural characterization of the obtained materials. The obtained ZIF-67@MgAl2O4 was utilized as an adsorbent in the solid phase microextraction technique to extract and preconcentrate the herbicide molinate (as an analyte) in aqueous solution. Corona discharge ionization-ion mobility spectrometry (CD-IMS) was applied for quantification of the analyte molecules. Extraction temperature, extraction time, stirring rate, and sample pH as the main parameters that affected the extraction proficiency were chosen and considered. Under optimal conditions, the linear dynamic range (LDR) of the various concentrations of the molinate and correlation coefficient were 10.0-100.0 μg L-1 and 0.9961, respectively. The limit of quantification (LOQ) and method detection limit (MDL) were 10.0 μg L-1 and 3.0 μg L-1, respectively. The relative standard deviation (RSD) of the ZIF-67@MgAl2O4 for extracting the molinate molecules (molinate concentration; 50 μg L-1) was calculated to be 4% and the enrichment factor (EF) was ∼5.


FVB.129P2-Pde6b(+) Tyr(c-ch)/Ant, a sighted variant of the FVB/N mouse strain suitable for behavioral analysis.
Mice of the FVB/N strain are severely visual impaired as a result of tyrosinase gene defects, leading to a deficiency of the key enzyme for melanin synthesis in skin and eye and of cyclic guanosine monophosphate phosphodiesterase gene defects, which results in albinism (Tyr(c/c)) and retinal degeneration (Pde6b(rd1/rd1)), respectively. Nevertheless, FVB/N mice are commonly used for the generation of transgenic animals because of their large, strong pronuclei and high breeding performance. However, due to visual impairment of the FVB/N animals, the resulting transgenic animals cannot be used in tests that depend on vision, including tests of cognitive behavior. Therefore, we have bred a sighted version of the FVB/N strain by an outcross between FVB/N and 129P2/OlaHsd, followed by repeated backcrosses to FVB/N mice while selecting against albinism and homozygosity of the retinal degeneration mutation. After 11 generations of backcrossing, sighted animals were intercrossed to generate the congenic FVB.129P2-Pde6b(+) Tyr(c-ch)/Ant strain, which is pigmented (Tyr(c-ch)/(c-ch)) and devoid of the genetic predisposition to retinal degeneration. The accurate visual abilities of the FVB.129P2-Pde6b(+) Tyr(c-ch)/Ant mice, for which we propose the name FVBS/Ant, demonstrated a clear visual evoked potential in the presence of normal eye histology and improved performance in the Morris water maze test.


[Testing the susceptibility of cultured cells to infection with bovine leukemia virus].
Different cell cultures were studied for their susceptibility to bovine leucosis virus infection. Syncytial assay was used for this study. The FLS/BLV+ cell line served as virus source. Cell lines BHK-21 and ZP-1/58 were found to be susceptible to syncytium formation. Large cells with one to three large nuclei, and loose nuclei reaching the size of syncytium were observed to occur in the BHK-21 and ZP-1/58 cell lines, apart from the syncytial formations. The virus specificity of the syncytia arising in these two cell lines was confirmed by the immunofluorescence assay. In the case of the immunoperoxidase assay, a positive result was obtained only in the BHK-21 cell line. The occurrence of syncytia and large nuclei was observed even in the cases when the BHK-21 cells were infected with the lymphocytes of leucotic cows.


[Lee Jungsook, a Korean independence activist and a nurse during the Japanese colonial period].
This article examines the life of Lee Jungsook, a Korean nurse, as a independence activist during the Japanese colonial period. Lee Jungsook(1896-1950) was born in Bukchung in Hamnam province. She studied at Chungshin girl's high school and worked at Severance hospital. The characteristics and culture of her educational background and work place were very important factors which influenced greatly the life of Lee Jungsook. She learned independent spirit and nationalism from Chungshin girls' high school and worked as nurse at the Severance hospital which were full of intense aspiration for Korea's independence. Many of doctors, professors and medical students were participated in the 3.1 Independence Movement. Lee Jungsook was a founding member of Hyulsungdan who tried to help the independence activists in prison and their families and worked as a main member of Korean Women's Association for Korean Independece and Kyungsung branch of the Korean Red Cross. She was sent to jail by the Japanese government for her independence activism. After being released after serving two years confinement, she worked for the Union for Women's Liberation as a founding member. Lee Joungsook was a great independence activist who had a nursing care spirit as a nurse.


Pulmonary venous flow determinants of left atrial pressure under different loading conditions in a chronic animal model with mitral regurgitation.
The aim of our study was to quantitatively compare the changes and correlations between pulmonary venous flow variables and mean left atrial pressure (mLAP) under different loading conditions in animals with chronic mitral regurgitation (MR) and without MR. A total of 85 hemodynamic conditions were studied in 22 sheep, 12 without MR as control (NO-MR group) and 10 with MR (MR group). We obtained pulmonary venous flow systolic velocity (Sv) and diastolic velocity (Dv), Sv and Dv time integrals, their ratios (Sv/Dv and Sv/Dv time integral), mLAP, left ventricular end-diastolic pressure, and MR stroke volume. We also measured left atrial a, x, v, and y pressures and calculated the difference between v and y pressures. Average MR stroke volume was 10.6 +/- 4.3 mL/beat. There were good correlations between Sv (r = -0.64 and r = -0.59, P <.01), Sv/Dv (r = -0.62 and r = -0.74, P <.01), and mLAP in the MR and NO-MR groups, respectively. Correlations were also observed between Dv time integral (r = 0.61 and r = 0.57, P <.01) and left ventricular end-diastolic pressure in the MR and NO-MR groups. In velocity variables, Sv (r = -0.79, P <.001) was the best predictor of mLAP in both groups. The sensitivity and specificity of Sv = 0 in predicting mLAP 15 mm Hg or greater were 86% and 85%, respectively. Pulmonary venous flow variables correlated well with mLAP under altered loading conditions in the MR and NO-MR groups. They may be applied clinically as substitutes for invasively acquired indexes of mLAP to assess left atrial and left ventricular functional status.


Actin guides filamentous rhizoid growth and morphogenesis in the zoosporic fungus Chytriomyces hyalinus.
The advantage of filamentous growth to the fungal lifestyle is so great that it arose multiple times. Most zoosporic fungi from phylum Chytridiomycota exhibit a monocentric thallus form consisting of anucleate filamentous rhizoids that anchor reproductive sporangia to substrata and absorb nutrients. Actin function during polarized growth and cytokinesis is well documented across eukaryotes, but its role in sculpting nonhyphal, nonyeast fungal cells is unknown. We sought to provide a basis for comparing actin organization among major fungal lineages and to investigate the effects of actin disruption on morphogenesis in a monocentric thallus. Using fluorescence microscopy, we observed fixed, rhodamine phalloidin-stained actin in chemically fixed Chytriomyces hyalinus, exemplifying monocentric thallus development within the diverse, zoosporic phylum Chytridiomycota. We also compared rhizoid lengths and rhizoid branching of thalli incubated with the actin inhibitor latrunculin B to determine the effects of actin disruption on morphology. Actin was concentrated at the tips of growing rhizoids. Actin cables typically formed cortical, parallel arrays in hyphae, but in mature sporangia they were concentrated in a funnel-shaped array in the central region. Thalli treated with latrunculin B had shorter rhizoids with fewer branches than controls. In both hyphae and monocentric thalli, actin localization coincides with active, polarized growth and cytokinesis. Specific actin localization patterns are largely shared between monocentric species but differ significantly from patterns observed in hyphae. Actin integrity is critical for sustaining filamentous growth in all fungi.


High-resolution CT of complications of idiopathic fibrotic lung disease.
Idiopathic pulmonary fibrosis (IPF) has a more variable clinical course than has been traditionally recognised. Many patients will remain stable over time while others experience relatively rapid deterioration. The prognosis and clinical course of patients with other fibrosing lung diseases is also variable. A number of conditions may complicate the clinical course of the idiopathic fibrosing lung diseases, which results in morbidity and mortality, but also represents potentially treatable causes of worsening symptoms. Infection and malignancy have a long-recognised association with IPF while other conditions, particularly pulmonary hypertension and acute exacerbation of IPF, are being increasingly recognised in this patient population. Many of these patients have serial high-resolution CT (HRCT) examinations that may demonstrate one or more of these supervening conditions. In this article we review the more common conditions that may complicate the course of idiopathic fibrosing lung disease with an emphasis on the HRCT appearance, which the reporting radiologist should be aware of.


Diabetic foot ulcer, the effect of resource-poor environments on healing time and direct cost: A cohort study during Syrian crisis.
Diabetic foot ulcer (DFU) is one of the slowest healing wounds that hurt the human body. Many studies from developed countries are concerned about materials, procedures, and equipment that accelerate the healing time. In Sweden, the diabetic foot management costs around 24965$/patient. In this review, we would evaluate the healing time of DFUs during what is considered one of the worst humanitarian crisis of the 21st century. 1747 DFUs were studied from the main diabetic foot clinic in Damascus (2014-2019). We predicted many variables that could prolong the healing time. The cost according to these variables was also reported. The SINBAD Classification was performed to grade the severity of ulcers. We noticed that the median healing time for DFUs was 8 weeks. Almost half of these ulcers healed between 3 and 12 weeks. The time of healing for men was significantly longer than that for women. While the presence of infection doubled the median time of healing, the presence of peripheral artery disease doubled the mean of the direct health care cost. The location of the ulcer acted as another independent risk factor. In conclusion, DFUs face many barriers to heal during a crisis.The environment with resource-poor settings should be added to the traditional risk factors that delay the healing of DFUs for months or even years. More studies from disaster are as are needed to evaluate low-cost materials that could be cost effective in applying standard care of the diabetic foot.


Choreography of the Mycobacterium replication machinery during the cell cycle.
It has recently been demonstrated that bacterial chromosomes are highly organized, with specific positioning of the replication initiation region. Moreover, the positioning of the replication machinery (replisome) has been shown to be variable and dependent on species-specific cell cycle features. Here, we analyzed replisome positions in Mycobacterium smegmatis, a slow-growing bacterium that exhibits characteristic asymmetric polar cell extension. Time-lapse fluorescence microscopy analyses revealed that the replisome is slightly off-center in mycobacterial cells, a feature that is likely correlated with the asymmetric growth of Mycobacterium cell poles. Estimates of the timing of chromosome replication in relation to the cell cycle, as well as cell division and chromosome segregation events, revealed that chromosomal origin-of-replication (oriC) regions segregate soon after the start of replication. Moreover, our data demonstrate that organization of the chromosome by ParB determines the replisome choreography. Despite significant progress in elucidating the basic processes of bacterial chromosome replication and segregation, understanding of chromosome dynamics during the mycobacterial cell cycle remains incomplete. Here, we provide in vivo experimental evidence that replisomes in Mycobacterium smegmatis are highly dynamic, frequently splitting into two distinct replication forks. However, unlike in Escherichia coli, the forks do not segregate toward opposite cell poles but remain in relatively close proximity. In addition, we show that replication cycles do not overlap. Finally, our data suggest that ParB participates in the positioning of newly born replisomes in M. smegmatis cells. The present results broaden our understanding of chromosome segregation in slow-growing bacteria. In view of the complexity of the mycobacterial cell cycle, especially for pathogenic representatives of the genus, understanding the mechanisms and factors that affect chromosome dynamics will facilitate the identification of novel antimicrobial factors.


Multilabel Deep Visual-Semantic Embedding.
Inspired by the great success from deep convolutional neural networks (CNNs) for single-label visual-semantic embedding, we exploit extending these models for multilabel images. We propose a new learning paradigm for multilabel image classification, in which labels are ranked according to its relevance to the input image. In contrast to conventional CNN models that learn a latent vector representation (i.e., the image embedding vector), the developed visual model learns a mapping (i.e., a transformation matrix) from an image in an attempt to differentiate between its relevant and irrelevant labels. Despite the conceptual simplicity of our approach, the proposed model achieves state-of-the-art results on three public benchmark datasets.


Fragment of Japanese encephalitis virus envelope protein produced in Escherichia coli protects mice from virus challenge.
A fragment from the N-terminal part (E(A)) and a fragment from the C-terminal part (E(B)) of the envelope (E) protein of Japanese encephalitis virus (JEV) was synthesized in Escherichia coli. These two fragments were overlapping with each other by nine amino acids, however, they were not cross-reacting with each other at the antisera level. Both E(A)and E(B)are antigenic by themselves when injected into mice, but when tested against sera from mice, rabbit, swine and human that had been immunized or naturally infected with JEV, E(B)acted as a better antigen than E(A)by ELISA assays. E(B)also proved to be a better immunogen in protection against lethal JEV infection than E(A). The protection appears to be correlated with the neutralizing titres of the anti-JEV sera. The response elicited by E(B)is a Th1 response and the antibody produced contained higher neutralizing titre than E(A)fragment. The major difference between E(A)and E(B)fragments is the solubility during expression in E. coli, while E(B)fragment is soluble, E(A)was isolated from the insoluble inclusion bodies. Therefore the antigenicity and immunogenicity expressed by the E(B)fragment may probably be due to its proper folding to assume a correctly assembled form during expression in E. coli, a quality that is important for a protein to qualify as a good vaccine candidate.


Can curriculum innovations create incentives for young veterinarians to practise in remote rural areas?
Research on the problem of decreasing numbers of rural veterinarians has identified that rural practice employment periods following graduation are getting shorter and replacing the graduates who leave is becoming increasingly difficult. One way of addressing these problems would be to develop a Bachelor of Veterinary Science (BVSc) curriculum that motivates young graduates to seek work in rural and remote communities and ensures they are more 'practice-ready' as soon as they leave university and start working. Developments in a series of curriculum initiatives to address this strategy are discussed, including: encouraging deeper learning in livestock health and production, provision of extramural rotations in rural locations in the final year, offering opportunities to study abroad and emphasising the global impact of farm animal medicine, developing rural support enhancements for students on rural placements, and adjusting admission requirements to increase access for rural students.


Thymosins, lymphokines, and the immunology of aging.
Recent data point to a significant role for thymosins, lymphokines, and other soluble mediators in the senescence of the immune response that occurs with aging. In recent years, considerable progress has been made in the isolation and physiochemical characterization of several of these soluble mediators. We are now beginning to define the mechanisms by which these molecules regulate and mediate immune responses. In this paper we review the properties of the best characterized thymic hormones and lymphokines and focus on the role of the endocrine thymus in modulating immune responses. Of particular interest is the recent observation that thymosin fraction 5 can enhance production of interleukin-2 (IL-2) and colony-stimulating factor (CSF), and that IL-2 production, but not CSF production, is selectively diminished in aging mice. Several of the products of the immune system also can act as neuroactive immunotransmitters and modulate a number of neuroendocrine responses. Current studies point to an important role for these molecules in modulating neuroendocrine function, suggesting a broader role for the endocrine thymus in the aging process.


Carboxyhydrazides of the aglycone of teicoplanin. Synthesis and antibacterial activity.
The condensation of the terminal carboxyl group of the deglucoteicoplanin (TD) with various substituted hydrazines produced hydrazide derivatives having different physico-chemical properties. This chemical modification of the carboxyl function does not affect the ability of teicoplanin antibiotics to interfere in bacterial cell-wall synthesis. The antibacterial activity of deglucoteicoplanin hydrazides (V) were found to depend mostly on their ionic character. All the hydrazides were slightly more active than TD on Escherichia coli. Those possessing an additional basic group were more in vitro active than TD against Gram-negative microorganisms. In Experimental Streptococcus pyogenes septicemia in the mouse, basic hydrazides were more active than other derivatives when administered subcutaneously although they are as potent as TD.


Cerebroplacental Ratio Versus Nonstress Test in Predicting Adverse Perinatal Outcomes in Hypertensive Disorders of Pregnancy: A Prospective Observational Study.
In developing countries, nonstress test (NST) is the most widely used method for antenatal fetal surveillance.Lately, cerebroplacental ratio (CPR) has emerged as a predictor for adverse perinatal outcomes, especially in hypertensive disorders in pregnancy (HDP). Against this background, the present study was conducted with the primary objective of quantifying the diagnostic accuracy of cerebroplacental ratio (CPR) versus nonstress test (NST) in predicting adverse perinatal outcomes in women with HDP. This was a prospective observational cohort study conducted in a tertiary care institute in eastern India. All consecutive women with hypertension in pregnancy at a gestational age of ≥32 weeks were recruited into the study. Both CPR and NST were performed at baseline and repeated weekly till delivery. The parameters obtained within one week of delivery were entered for analysis. Sixty-two of the 65 women completed the study. There were 22 women (35.5%) in group A (both CPR and NST normal), 17 (27.4%) in group B (CPR abnormal, NST normal), 14 (22.6%) in group C (CPR normal and NST abnormal), and nine (14.5%) in group D (both CPR and NST abnormal). CPR had greater sensitivity (93.33% versus 46.67%), with higher positive predictive value (53.85% versus 30.43%), specificity (74.47% versus 65.91%), and negative predictive value (97.22% versus 79.49%) than NST for predicting neonatal intensive care unit admission. CPR also had higher sensitivity (84.62% versus 61.54%) and specificity (91.34% versus 69.39%) than NST in predicting neonatal complications. The negative predictive value (NPV) of CPR was 100% for predicting requirement of bag and mask ventilation and continuous positive airway pressure. CPR had greater diagnostic accuracy in terms of both higher sensitivity and greater specificity than NST in predicting adverse perinatal outcomes in women with hypertensive disorders of pregnancy.


COVID-19 Disease Outcomes: Does Gastrointestinal Burden Play a Role?
The novel coronavirus disease 2019 presents an urgent threat to global health. As the epidemic grows, prognosis prediction is essential for monitoring risky patient. It is thus important to consider gastrointestinal manifestations and the duration of symptoms as predictors of prognosis. Our aim was to determine the correlation of gastrointestinal symptoms and laboratory markers with disease outcomes and whether symptom duration varies substantially between patients. We also undertook this study to determine the optimal time to predict COVID-19 outcome. A total of 190 patients with polymerase chain reaction-confirmed COVID-19 were followed up until recovery. We proposed a correlation between gastrointestinal symptoms and disease severity (based on clinical data, and diagnostic investigations) to estimate the duration of symptoms as a predictor of COVID-19 prognosis. The prevalence of gastrointestinal symptoms was 49.5%, consisting mainly of diarrhea in 27.9% of patients. In addition, a longer disease duration and higher temperature were observed in patients with diarrhea. Symptom duration was variable, with a median of 12 days and a range of 1-55 days. Statistical analysis indicated that patients with a duration of symptoms ≥12 day had more severe symptoms and a worse prognosis. Patients who complained of diarrhea had 2.7 times the odds of a longer duration of symptoms, and those with a history of chronic lung disease have 7.2 times the odds of a longer duration of symptoms. GIT manifestations (mainly diarrhea) and the duration of symptoms of COVID-19 provide prognostic evidence of COVID-19 outcomes, irrespective of earlier categorization by the World Health Organization. Thus, patients with mild symptoms who present with diarrhea and a duration of symptoms longer than 12 days are expected to have a worse prognosis.


Comparison of maxillary arch dimensional changes with passive and active self-ligation and conventional brackets in the permanent dentition: a multicenter, randomized controlled trial.
The purpose of this study was to compare maxillary arch dimensional and inclination changes during alignment with conventional brackets and self-ligation. Ninety-six patients, ages 16 years and above, were included in this multicenter, 3-group parallel randomized trial. The main outcome measures were changes in maxillary intercanine, interpremolar, and intermolar dimensions, and molar and incisor inclination changes. The patients were randomly allocated in permuted blocks of 12 subjects into 3 equal groups with the allocations concealed in opaque sealed envelopes. Each participant underwent alignment with a standard Damon Q (Ormco, Orange, Calif) wire sequence for a minimum of 34 weeks. Blinding of clinicians and patients was not possible. Data were analyzed on a per-protocol basis, since losses to follow-up were minimal. Complete data were obtained from 87 subjects. Bracket type had no significant effect on any of the transverse dimensional changes. No difference in molar inclination was found between passive self-ligation and conventional brackets (0.67°; 95% CI, -2.24, 3.58; P = 0.65) or active self-ligation (0.91°; 95% CI, -1.95, 3.78; P = 0.53). Similarly, incisor inclination changes with the Damon Q could not be differentiated from those developing with either conventional system (0.44°; 95% CI, -1.93, 2.8; P = 0.71) or In-Ovation C (-0.22°; 95% CI, -2.58, 2.14; P = 0.85). No harms were encountered. No difference in the arch dimensional or inclination changes during alignment can be expected between conventional brackets and either active or passive self-ligation.