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The hydrogen/bromine flow battery is a promising candidate for large-scale energy storage due to fast kinetics, highly reversible reactions and low chemical costs. However, today's conventional hydrogen/bromine flow batteries use membrane materials (such as Nafion), platinum catalysts, and carbon-paper electrode materials that are expensive. In addition, platinum catalysts can be poisoned and corroded when exposed to HBr and Br2, compromising system lifetime. To reduce the cost and increase the durability of H2/Br2 flow batteries, new materials are developed. The new Nafion/polyvinylidene fluoride electrospun composite membranes have high perm-selectivity at a fraction of the cost of Nafion membranes; the new nitrogen-functionalized platinum-iridium catalyst possesses excellent activity and durability in HBr/Br2 environment; and the new carbon-nanotube-based Br2 electrodes can achieve equal or better performance with less materials when compared to baseline electrode materials. Preliminary cost analysis shows that the new materials reduce H2/Br2 flow-battery energy-storage system stack and system costs significantly. The resulting advanced H2/Br2 flow batteries offer high power, high efficiency, substantially increased durability, and expected reduced cost.

Abstract The mechanism of nonalcoholic fatty liver disease (NAFLD) has not been completely revealed. In this study, we investigated the association of liver histological changes and long noncoding RNAs (lncRNAs) in the NAFLD zebrafish model. Forty zebrafish were fed a high-cholesterol diet (1.5 g per day) for 8 weeks. We measured fatty liver changes in the zebrafish liver using oil red O staining and divided them into two groups based on high and low scores. We pooled each group of zebrafish livers and identified lncRNAs, miRNAs, and mRNAs using Next-generation sequencing. Human homologs of lncRNAs were identified using ZFLNC, Ensembl, and NONCODE. We found several significant genes, including 32 lncRNAs, 5 miRNA genes, and 8 protein-coding genes, that were associated with liver metabolism and NAFLD-related functions in zebrafish. In particular, eight conserved human homologs of lncRNAs were found. We discovered the human homologs of eight lncRNA candidates from fatty liver zebrafish for the first time. The spectrum of biological mechanisms by which lncRNAs mediate their functional roles in NAFLD in a high cholesterol diet adult zebrafish model remains to be uncovered.

Abstract Since its debut in the biomedical research fields in 1981, zebrafish have been used as a vertebrate model organism in more than 40,000 biomedical research studies. Especially useful are zebrafish lines expressing fluorescent proteins in a molecule, intracellular organelle, cell or tissue specific manner because they allow the visualization and tracking of molecules, intracellular organelles, cells or tissues of interest in real time and in vivo. In this review, we summarize representative transgenic fluorescent zebrafish lines that have revolutionized biomedical research on signal transduction, the craniofacial skeletal system, the hematopoietic system, the nervous system, the urogenital system, the digestive system and intracellular organelles.

Epidermal growth factor-like domain multiple 6 (Egfl6) is a basement membrane protein and plays an important role in hair follicle morphogenesis, angiogenesis, notochord development in vertebrates. Although egfl6 expression in the developing head was observed in zebrafish, its role for craniofacial development and the determination of the pharyngeal region expressing egfl6, have not been reported yet. Here, we report the expression patterns and function of egfl6 in craniofacial development in zebrafish. egfl6 was expressed sequentially in the developing pharyngeal pouches that are key epithelial structures governing the development of the vertebrate head. However, loss-of-function mutations in egfl6 did not cause any craniofacial defects, including the pouches as well as the thymus and facial cartilages whose development is contingent upon appropriate pouch formation. egfl6 was unlikely redundant with egfl7 expressed in a distinct pharyngeal region from that of egfl6 in craniofacial development because reduction of egfl7 with a MO in egfl6 mutants did not affect craniofacial development. In addition, we found that egfl6 carried an endogenous start loss mutation in the wild-type Tübingen strain, implying egfl6 would be a non-functional gene. Taken all together, we suggest that egfl6 expression in the pharyngeal pouches is not required for craniofacial development in zebrafish.

Background: The aim of this study was to determine whether immobilization of an arm has detrimental effects on driving performance.Methods: Thirty-six healthy officers-in-training were assigned a sequence of fiberglass splints (left and right-sided above-the-elbow thumb spica and below-the-elbow splints) with use of a randomized higher-order crossover design. Runs were scored on a cone-marked driving course used for officer certification with predetermined passing requirements. Driving time, the number of cones hit per course section, and the cone-adjusted total time (a five-second penalty per hit cone) were recorded. A linear mixed-effect model with random environmental and learning effects for cone-adjusted time analysis was used. Participants rated perceived driving difficulty and safety with each splint, and ratings were compared with the Wilcoxon signed-rank test.Results: Thirty participants completed the entire set of runs. Analysis of total cone-adjusted time revealed a significant performance decrease with the left arm in an above-the-elbow thumb spica splint (average, 22.2 seconds; p < 0.001) and with the left arm in a below-the-elbow splint (average, 16.2; p = 0.007). Analysis of forward-only course sections revealed poorer performance trends with all splints, with the worst performance with the left arm in an above-the-elbow thumb spica splint. Driving with the left arm in an above-the-elbow thumb spica splint had the highest perceived difficulty (median, 8.0) and lowest perceived safety (median, 3.0).Conclusions: Driving performance as measured with a standardized track and scoring system was significantly degraded with splint immobilization of the left arm. Further studies are required to determine the effect of arm immobilization on normal driving conditions. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore the attitudes toward the components of active aging and to examine the relationship of attitudes toward active aging with the impressions of older adults across different age groups and across Taiwan, South Korea and Japan. The sample was a total 1,619 individuals comprising of 615 Taiwanese people, 495 Koreans, and 509 Japanese people. Five factors of attitudes toward active aging were extracted by factor analysis: Health, Participation, Connectedness, Work, and Security. Taiwanese people emphasized more importance on health, social participation, and security; while Koreans and Japanese people emphasized more on social connectedness and work. The age group differences were not significant in the attitudes to active aging. Japanese reported more negative impressions to older adults than Taiwanese people, and Koreans were less willing to live with older adults than Taiwanese people. The older group also reported more positive impressions to older adults. Public stigma of aging may exist, implying that intergenerational mutual understanding would reduce ageism or age discrimination. An active aging policy may reduce the public stigma toward older adults and may reduce the burden of intergenerational redistribution.

The challenges of hip fracture care in Malaysia is scarcely discussed. This study evaluated the outcomes of older patients with hip fracture admitted to a teaching hospital in Malaysia. We found that one in five individuals was no longer alive at one year after surgery. Three out of five patients did not recover to their pre-fracture mobility status 6 months following hip fracture surgery., Purpose: With the rising number of older people in Malaysia, it is envisaged that the number of fragility hip fractures would also increase. The objective of this study was to determine patient characteristics and long-term outcomes of hip fracture in older individuals at a teaching hospital in Malaysia., Methods: This was a prospective observational study which included consecutive patients aged  ≥ 65 years old admitted to the orthopedic ward with acute hip fractures between March 2016 and August 2018. Patient socio-demographic details, comorbidities, pre-fracture mobility status, fracture type, operation and anesthesia procedure, and length of stay were recorded. Post-fracture mobility status was identified at 6 months. Cox proportional hazard analysis was used to assess the risk of death in all patients., Results: 310 patients (70% women) with the mean age of 79.89 years (SD 7.24) were recruited during the study period. Of these, 284 patients (91.6%) underwent surgical intervention with a median time to surgery of 5 days (IQR 3-8) days. 60.4% of patients who underwent hip fracture surgery did not recover to their pre-fracture mobility status. One year mortality rate was 20.1% post hip fracture surgery. The independent predictor of mortality included advanced age (hazard ratio, HR = 1.05, 95% CI = 1.01-1.08; p = 0.01), dependency on activities of daily living (HR = 2.08, 95% CI = 1.26-3.45; p = 0.01), and longer length of hospitalization (HR = 1.02, 95% CI = 1.01-1.04; p < 0.01)., Conclusion: One in 5 individuals who underwent hip fracture surgery at a teaching hospital in Kuala Lumpur was no longer alive at one year. A systematic approach to hip fracture management is crucial to improve outcomes and restore pre-fracture function of this vulnerable group of patients., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Coronavirus disease-19 (COVID-19) is caused by the newly discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the lung remains the primary target site of COVID-19 injury, damage to myocardium, and other organs also contribute to the morbidity and mortality of this disease. There is also increasing demand to visualize viral components within tissue specimens. Here we discuss the cardiac autopsy findings of 12 intensive care unit (ICU) naïve and PCR-positive COVID-19 cases using a combination of histological, Immunohistochemical/immunofluorescent and molecular techniques. We performed SARS-CoV-2 qRT-PCR on fresh tissue from all cases; RNA-ISH and IHC for SARS-CoV-2 were performed on selected cases using FFPE tissue from heart. Eight of these patients also had positive post-mortem serology for SARS-CoV-2. Histopathologic changes in the coronary vessels and inflammation of the myocardium as well as in the endocardium were documented which support the reports of a cardiac component to the viral infection. As in the pulmonary reports, widespread platelet and fibrin thrombi were also identified in the cardiac tissue. In keeping with vaccine-induced activation of virus-specific CD4 + and CD8 + T cells, and release of cytokines such as interferon-gamma (IFNγ), we observed similar immune cellular distribution and cytokines in these patients. Immunohistochemical and immunofluorescent localisation for the viral Spike (S-protein) protein and the nucleocapsid protein (NP) were performed; presence of these aggregates may possibly contribute to cardiac ischemia and even remodelling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chong, Iqbal, Yeong, Aw, Chan and Chui.)

Orthopaedic injuries of the upper extremity remain common, often requiring prolonged immobilization after surgical or nonsurgical management. Upper extremity immobilization often has a profound effect on a patient's daily life, including one's ability to safely operate a motor vehicle. Current literature on the safety of driving while immobilized is varied, although above-elbow immobilization of the upper extremity is generally thought to present a particular hazard to safe driving. Unfortunately, as common as this situation is, currently little to no guidance exists for patients, physicians, or lawmakers with regard to deciding whether a patient is safe to return to driving with upper extremity immobilization. Similar discord exists with the issue of patient and physician liability in such cases. In this review, we seek to present both historical precedent and a contemporary update of this complex, though a frequently encountered situation.

We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide- N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human pharmacokinetics and lower efficacious doses relative to 1.

The International Academy of Cytology (IAC) gathered together a group of cytopathologists expert in breast cytology who, working with clinicians expert in breast diagnostics and management, have developed the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytology. The project was initiated with the first cytopathology group meeting in Yokohama at the 2016 International Congress of Cytology. This IAC Yokohama System defines five categories for reporting breast cytology, each with a clear descriptive term for the category, a definition, a risk of malignancy (ROM) and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category will be presented more fully in a subsequent atlas. The System emphasizes that the crucial requirements for diagnostic breast FNAB cytology are a high standard for the performance of the FNAB and for the making of direct smears, and well-trained experienced cytopathologists to interpret the material. The performance indicators of breast FNAB, including specificity and sensitivity, negative predictive value, positive predictive value and ROM stated in this article have been derived from the recent literature. The current practice of breast FNAB has evolved with the increasing use of ultrasound guidance and rapid on-site evaluation. Two recent publications have shown a range of ROM for the insufficient/inadequate category of 2.6-4.8%, benign 1.4-2.3%, atypical 13-15.7%, suspicious of malignancy 84.6-97.1%, and malignant 99.0-100%. The management algorithm in the System provides options because there are variations in the management of breast lesions using FNAB and core-needle biopsy in those countries utilizing the "triple test" of clinical, imaging, and FNAB assessment, and also variations in the availability of CNB and imaging in low- and middle-income countries. The System will stimulate further discussion and research, particularly in the cytological diagnostic features of specific lesions within each category and in management recommendations. This will lead to continuing improvements in the care of patients with breast lesions and possible modifications to the IAC Yokohama System., (© 2019 S. Karger AG, Basel.)

The detection and identification of two endocytobiotic bacterial strains, one affiliated to the "Candidatus Caedibacter acanthamoebae"/"Ca. Paracaedimonas acanthamoeba", and another to the endosymbiont of Acanthamoeba UWC8 and "Ca. Jidaibacter acanthamoeba" are described. For endocytobiont screening, we developed a PCR method with a set of broad-range bacterial 16S rRNA primers to substitute the commonly used but technically demanding fluorescent in situ hybridization technique. Our PCR test alone without sequencing failed to discriminate the endocytobiont-containing and endocytobiont-free Acanthamoeba sp. due to the presence of mismatched primers to host mitochondrial DNA. We highlighted the need to perform bacterial primer checking against the Acanthamoeba genome to avoid false positive detection in PCR. Although the genetic aspect of "Ca. Caedibacter acanthamoebae"/"Ca. Paracaedimonas acanthamoeba" and the endosymbiont of Acanthamoeba UWC8/"Ca. Jidaibacter acanthamoeba" are well studied, knowledge pertaining to their morphologies are quite vague. Hence, we used transmission electron microscopy to examine our endocytobionts which are affiliated to previously described intracellular bacteria of Acanthamoeba sp. We used good-quality TEM images for the localization and the fate of the current endocytobionts inside different life stages of the hosts. Furthermore, to the best of our knowledge, our TEM findings are the first to provide morphological evidence for the clearance of defective Acanthamoeba endocytobionts via an autophagic-like process., Competing Interests: The authors have declared that no competing interests exist.

Signaling by serine/threonine phosphorylation controls diverse processes in bacteria, and identification of the stimuli that activate protein kinases is an outstanding question in the field. Recently, we showed that nutrients stimulate phosphorylation of the protein kinase G substrate GarA in Mycobacterium smegmatis and Mycobacterium tuberculosis and that the action of GarA in regulating central metabolism depends upon whether it is phosphorylated. Here we present an investigation into the mechanism by which nutrients activate PknG. Two unknown genes were identified as co-conserved and co-expressed with PknG: their products were a putative lipoprotein, GlnH, and putative transmembrane protein, GlnX. Using a genetic approach, we showed that the membrane protein GlnX is functionally linked to PknG. Furthermore, we determined that the ligand specificity of GlnH matches the amino acids that stimulate GarA phosphorylation. We determined the structure of GlnH in complex with different amino acid ligands (aspartate, glutamate, and asparagine), revealing the structural basis of ligand specificity. We propose that the amino acid concentration in the periplasm is sensed by GlnH and that protein-protein interaction allows transmission of this information across the membrane via GlnX to activate PknG. This sensory system would allow regulation of nutrient utilization in response to changes in nutrient availability. The sensor, signaling, and effector proteins are conserved throughout the Actinobacteria , including the important human pathogen Mycobacterium tuberculosis , industrial amino acid producer Corynebacterium glutamicum , and antibiotic-producing Streptomyces species. IMPORTANCE Tuberculosis (TB) kills 5,000 people every day, and the prevalence of multidrug-resistant TB is increasing in every country. The processes by which the pathogen Mycobacterium tuberculosis senses and responds to changes in its environment are attractive targets for drug development. Bacterial metabolism differs dramatically between growing and dormant cells, and these changes are known to be important in pathogenesis of TB. Here, we used genetic and biochemical approaches to identify proteins that allow M. tuberculosis to detect amino acids in its surroundings so that it can regulate its metabolism. We have also shown how individual amino acids are recognized. The findings have broader significance for other actinobacterial pathogens, such as nontuberculous mycobacteria, as well as Actinobacteria used to produce billions of dollars of amino acids and antibiotics every year., (Copyright © 2018 Bhattacharyya et al.)

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the Western world. It is becoming increasingly clear that CRC is a diverse disease, as exemplified by the identification of subgroups of CRC tumours that are driven by distinct biology. Recently, a number of studies have begun to define panels of diagnostically relevant markers to align patients into individual subgroups in an attempt to give information on prognosis and treatment response. We examined the immunohistochemical expression profile of 18 markers, each representing a putative role in cancer development, in 493 primary colorectal carcinomas using tissue microarrays. Through unsupervised clustering in stage II cancers, we identified two cluster groups that are broadly defined by inflammatory or immune-related factors (CD3, CD8, COX-2 and FOXP3) and stem-like factors (CD44, LGR5, SOX2, OCT4). The expression of the stem-like group markers was associated with a significantly worse prognosis compared to cases with lower expression. In addition, patients classified in the stem-like subgroup displayed a trend towards a benefit from adjuvant treatment. The biologically relevant and poor prognostic stem-like group could also be identified in early stage I cancers, suggesting a potential opportunity for the identification of aggressive tumors at a very early stage of the disease.

We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.

Breast cancer is a significant cause of morbidity and mortality in women with a high incidence of recurrence or treatment failure. Growing evidence suggests that cancer stem cells (CSCs) most likely contribute to tumour progression, spread and therapy failure. However, despite extensive research and the tremendous clinical potential of such cells in possible therapeutic management, the real nature of CSCs remains an enigma. In this review, we discuss the fundamental properties and molecular target of CSCs and focus on recent advances regarding the identification of CSC markers with emphasis on breast cancer and the underlying molecular mechanism of CSC phenotypes. We also discuss experimental evidence of targeting molecular pathways in order to modulate breast CSC behaviour in tumourigenesis and the controversies associated with it that potentially weaken the CSC model in breast cancer and other cancers as well.

Context: Nonspecific changes (nonspecific chronic inflammation) in patients with chronic diarrhea represent the commonest diagnosis in colorectal biopsy interpretation, but these changes are of little clinical significance., Objective: To find, within this group, histologic and immunohistologic diagnostic criteria to predict the duration and resolution of diarrhea., Design: Detailed clinical features and histologic findings were analyzed in a cohort of 47 patients with chronic diarrhea, with near-normal histology and no clear-cut known etiologic agent. Immunohistochemistry to mast cells (CD117) and Treg cells (FOXP3) was also assessed in 39 patients., Results: Increased number of lymphoid follicles and aggregates, increased number of mast cells, and paucity of Treg were the statistically significant key findings (P  =  .003, P  =  .008, and P  =  .04, respectively). The duration of diarrhea was correlated with the number of large lymphoid follicles and aggregates (P  =  .001, r  =  .48), number of total lymphoid follicles and aggregates (P  =  .003, r  =  .43), density of lymphoid follicles and aggregates (P  =  .009, r  =  .38), and total lymphoid follicles and aggregates per biopsy (P  =  .004, r  =  .42) and the number of mast cells (P  =  .001, r  =  .52). The number of mast cells and Treg cells showed significant difference between resolved and unresolved cases (P  =  .001 and P  =  .01 respectively)., Conclusions: Lymphocytic follicles and aggregates colitis, previously regarded as of negligible diagnostic significance, allows the prediction of the behavior of chronic diarrhea in a subset of patients with nonspecific changes on colonic biopsy. The increased number of mast cells and paucity of Treg cells further helps to identify such unresolved cases.

A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Progress in understanding the effects of dietary soy isoflavones on chronic disease prevention in the Hong Kong Chinese population has been hampered by the lack of a comprehensive soy isoflavone database. In this study, we determined the concentrations and distribution of isoflavones in 47 foods included in a soy food frequency questionnaire by reverse-phase HPLC. Results indicated that most soy products contained isoflavones ranging from 1 mg of aglucon equivalents/100 g of wet weight (bean strip noodle and egg bean curd) to 80 mg of aglucon equivalents/100 g of wet weight (oyster sauce soybean and sweet bean curd sheet). Among our food groups, mean isoflavone concentrations were lowest in the soy milk group (9.99 mg of aglucon equivalents/100 g of wet weight) and highest in the bean curd skin group (40 mg of aglucon equivalents/100 g of wet weight). The conjugation patterns of isoflavones varied within and between food groups as influenced by the types of soybeans and the processing or cooking techniques used. The isoflavone concentrations reported herein will be useful for ascertaining the relationship between exposure to dietary soy isoflavones and health effects in the Chinese population.

RUNX3 is believed to have tumour suppressor properties in several cancer types. Inactivation of RUNX3 has been shown to occur by methylation-induced transcriptional silencing and by mislocalization of the protein to the cytoplasm. The aim of this study was to examine the clinical significance of RUNX3 expression in a large series of colorectal cancers using immunohistochemistry and tissue arrays. With advancing tumour stage, expression of RUNX3 in the nucleus decreased, whereas expression restricted to the cytoplasmic compartment increased. Nuclear RUNX3 expression was associated with significantly better patient survival compared to tumours in which the expression of RUNX3 was restricted to the cytoplasm (P=0.025). These results support a role for RUNX3 as a tumour suppressor in colorectal cancer.

Objective: Pharmacogenetics suggests variants of genes involved in gemcitabine pharmacology could be useful markers for predicting inter-ethnic and inter-patient outcomes from treatment with the agent. Here, we have characterized the distribution of variants of genes involved in gemcitabine pharmacology in ethnic Asian populations and their association with non-small cell lung cancer (NSCLC) patient outcome., Methods: All genes involved in gemcitabine transport, metabolism and activity were screened for suitable variants for analysis using publications and public databases. By pyrosequencing, the frequency of qualifying variants was characterized from germline DNA of 94 healthy Asian donors and 53 NSCLC patients receiving gemcitabine-based chemotherapy., Results: Significant differences in genotype distribution between Caucasians and Asians were seen at 10/25 (45%) variant loci. In NSCLC patients, CDA+435 C>T variants were associated with response (p=0.026) and time to progression (p=0.016) and SLC28A1+1561 G>A variants were associated with neutropenia (p=0.030) and thrombocytopenia nadir (p=0.037)., Conclusions: Many genotypes in gemcitabine pharmacology vary in their frequency between Caucasians and Asians. CDA+435, and SLC28A1+1561 are worthy of further investigation as potential indicators of patient outcome after gemcitabine treatment.

Objective: The purpose of this study was (a) to describe HRCT findings for pulmonary tuberculosis before and after treatment, and (b) to evaluate the possible use of HRCT to assess disease activity., Patients and Methods: We prospectively studied 52 patients with newly diagnosed pulmonary tuberculosis that was proven bacteriologically. HRCT scans were performed before and after treatment., Results: Micronodules, nodules, tree-in-bud appearance, consolidation, and cavities were the most common HRCT findings seen in active pulmonary tuberculosis. The disappearance of tree-in-bud appearance, pleural effusion and the presence of fibrotic change appear to be indications of the effectiveness of treatment. HRCT can differentiate old fibrotic lesions from newly active tuberculous lesions., Conclusions: HRCT may be helpful in the diagnosis of pulmonary tuberculosis and may be useful in the assessment of the efficacy of anti-tuberculous treatment.

Substantial evidence suggests that soy isoflavones may protect against certain chronic diseases. This study aims to assess the reproducibility and validity of a 47-item semiquantitative soy FFQ (SFFQ) designed to measure the usual intake of soy isoflavones among 145 Chinese mid-life women in Hong Kong. Reproducibility of the SFFQ was assessed by the stability of dietary intake obtained at baseline (SFFQ0) and at 13-mo follow-up (SFFQ1). Relative validity was measured by comparing data collected from SFFQ1 with those derived from 23-d, 24-h dietary recalls (DR) collected during the same 1-y validation period. Isoflavone intake was calculated using analytical values from the Chinese University of Hong Kong Soy Isoflavone Database. A total of 3,217 DR were successfully obtained. The median (interquartile range) absolute intake estimated by the SFFQ1 was 0.91 (-2.7 to 6.8) mg aglucon equivalents/d higher than the 6.3 (3.7-10.7) mg aglucon equivalents/d measured by the DR (P < 0.0057; Wilcoxon's Signed Rank test). Bland-Altman analysis further demonstrated the presence of significant proportional bias between methods among Cantonese women with above-median intake (Spearman correlation coefficient; r = 0.44; P = 0.0005). Nonetheless, the intraclass and Pearson correlation coefficients, respectively, were 0.84 and 0.72 for non-Cantonese and 0.65 and 0.50 for Cantonese, showing moderate to good levels of reproducibility and validity of the SFFQ (difference between 2 intraclass correlation coefficients, P = 0.09; difference between 2 Pearson r, P = 0.16). The unadjusted and BMI-adjusted correlations were of similar magnitude. The SFFQ is a reasonably valid instrument for assessing dietary soy isoflavone exposure in Hong Kong Chinese mid-life women.

Cribriform-morular variant (C-MV) of papillary thyroid carcinoma (PTC) is a rare and unusual neoplasm composed of multiple histologic components, including cribriform, papillary, solid, tall columnar, and morular patterns. Analyses of gross C-MV of PTC lesions has linked adenomatous polyposis coli (APC) mutations to its pathogenesis; however, the extent of involvement of mutations in the development of individual components is unclear. We report on bidirectional sequencing of the mutation cluster region (codons 1032-1565) of the APC gene in individually laser-microdissected components of a previously unreported C-MV of PTC. A silent Thr1493Thr gene variant was found in all tumoral components, whereas a 5-base-pair frameshift deletion at codon 1309 was identified only in the morules. Neither variant was observed in matched normal thyroid tissue. These results show the histologic components of C-MV of PTC to have some common mutational background, although additional somatic mutations may be involved in the development of morular structures.

The dietary sources, intake levels, and determinants of soy isoflavone intake were examined using 3217 dietary recalls (DR) collected from 141 Hong Kong Chinese women aged 50-61 y. Multiple-pass 24-h DR were administered by phone by trained interviewers on 23 random, nonconsecutive days to participants over a 12-mo period from 2001 to 2002. We calculated isoflavone intake using analytical values in the Chinese University of Hong Kong Soy Isoflavone Database. Results indicated that the daily intake of total isoflavones was 7.8 +/- 5.6 mg in the study population. Non-Cantonese women had a higher intake of 10.7 +/- 7.6 mg compared with 7.3 +/- 5.0 mg in Cantonese women (P = 0.04). Altogether, 22 foods contributed approximately 90% of the total isoflavone intake. Soft tofu alone accounted for approximately 21% of the isoflavone intake, followed by bean curd skin (7.1%), name-brand soybean milk (6.3%), homemade soybean milk (6.2%), and generic soybean milk (5.8%). Combined, these 5 food items contributed 46% of the total dietary isoflavones. Multiple linear regression analysis indicated dialect group, self-reported health, and age group were significant independent predictors of soy isoflavone consumption. The data provide the basis for elucidating the patterns, determinants, and assessment of dietary soy isoflavone intake in Asian women.

Basal cell carcinomas (BCC), which are the most common form of skin malignancy, are invariably associated with the deregulation of the Sonic Hedgehog (Shh) signalling pathway. As such, BCC represent a unique model for the study of interactions of the Shh pathway with other genes and pathways. We constructed a tissue microarray (TMA) of 75 paired BCC and normal skin and analysed the expression of beta-catenin and RUNX3, nuclear effectors of the wingless-Int (Wnt) and bone morphogenetic protein/transforming growth factor-beta pathways, respectively. In line with previous reports, we observed varying subcellular expression pattern of beta-catenin in BCC, with 31 cases (41%) showing nuclear accumulation. In contrast, all the BCC cases tested by the TMA showed RUNX3 protein uniformly overexpressed in the nuclei of the cancer cells. Analysis by Western blotting and DNA sequencing indicates that the overexpressed protein is normal and full-length, containing no mutation in the coding region, implicating RUNX3 as an oncogene in certain human cancers. Our results indicate that although the deregulation of Wnt signalling could contribute to the pathogenesis of a subset of BCC, RUNX3 appears to be a universal downstream mediator of a constitutively active Shh pathway in BCC.

The coexistence of multiple and synchronous primary neoplasms in the genitourinary system has only rarely been described in the literature. We present the case of a 78-year-old man with haematuria as the initial presentation, finally proven to be transitional cell carcinoma (TCC) combined with renal cell carcinoma (RCC). Intravenous urography (IVU), CT and arterial angiography studies revealed a space-occupying nodule at the right upper renal pelvicalyces showing mild enhancement with contrast medium. Another strong contrast medium enhancing exophytic tumour was found at the lower pole of kidney; there were hypodense foci and calcified components in this lesion. A right nephroureterectomy was performed. Pathological diagnosis was a papillary TCC and a clear cell type RCC. This is a rare case of combined renal malignancies diagnosed by imaging.

Background and Objectives: Sacral amputations above the S2 body often involve increased surgical complexity leading to long-term morbidity. The purpose of this study was to determine whether proximal sacral amputations have substantially higher perioperative morbidity compared with more distal sacral amputations., Methods: We evaluated the effect of sacral amputation level on perioperative outcomes within 90 days of surgery. Outcome measures included blood loss, intensive care unit (ICU) and hospital stay, hospital cost, and incidence of a major and minor morbidity. Survival analyses were adjusted for the level of resection and histological appearance., Results: Thirteen proximal and 14 distal resections were performed. In comparing proximal versus distal resections, median estimated blood loss was 4 L versus 1 L (P < 0.001), ICU stay was 4 days versus 0 days (P = 0.012), hospital stay was 19 days versus 8 days (P = 0.001), hospital cost was 28,800 dollars versus 7,500 dollars (P = 0.003), with one or more major complications in 85% versus 29% (P = 0.011). Survival analysis demonstrated that the sacral resection level did not influence survival (P = 0.936), whereas the type of tumor did influence survival (P = 0.012)., Conclusion: Tumor resections above S2 demonstrate increased perioperative morbidity, suggesting that proximal osteotomies be reserved for patients with a realistic cure potential., (2006 Wiley-Liss, Inc.)

These studies attempt to understand more fully the host response and pathogenesis associated with severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) by monitoring gene expression using formalin-fixed paraffin-embedded (FFPE) pulmonary autopsy tissues. These tissues were from patients in different hospitals in Singapore who were diagnosed with various microbial infections, including SARS-CoV, that caused acute respiratory distress syndrome (ARDS). Global expression patterns showed limited correlation between end-stage ARDS and the initiating pathogen, but when focusing on a subset of genes implicated in pulmonary pathogenesis, molecular signatures of pulmonary disease were obtained and appeared to be influenced by preexisting pulmonary complications and also bacterial components of infection. Many factors detected during pulmonary damage and repair, such as extracellular matrix (ECM) components, transforming growth factor (TGF) enhancers, acute-phase proteins, and antioxidants, were included in the molecular profiles of these ARDS lung tissues. In addition, differential expression of cytokines within these pulmonary tissues were observed, including notable genes involved in the interferon (IFN) pathway, such as Stat1, IFN regulatory factor-1 (IRF-1), interleukin-6 (IL-6), IL-8, and IL-18, that are often characterized as elevated in ARDS patients.

Background: Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements., Methods: We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin., Results: The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype., Conclusions: Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.

[reaction: see text] A total synthesis of (+)-bullatacin has been accomplished via a diastereoselective [3+2] annulation reaction of the highly enantiomerically enriched allylsilane 3 and racemic aldehyde 4, which provides the key bis-tetrahydrofuran fragment 15 with > or = 20:1 ds.

Introduction: The aims of this study was to show the accuracy and clinical usefulness of endoscopic ultrasonography (EUS) with EUS-guided fine needle aspiration (FNA) in the diagnosis and staging of pancreatic cancer not obvious in computed tomographic (CT) scan abdomen imaging., Materials and Methods: Five male patients were evaluated; 4 presented with obstructive jaundice and 1 had unexplained loss of weight. The mean age was 66 years (range, 40 to 77). All had CT scan abdomen imaging which did not show any obvious pancreatic tumour. EUS with FNA was done for all cases when indicated. Surgical findings, if any, were obtained and compared to EUS findings., Results: EUS easily detected the pancreatic tumour in all 5 cases. The tumour sizes detected ranged from 27 to 40 mm in diameter. These corresponded fairly accurately with that of surgical findings for all 3 who had surgery. EUS reported 3 cases with pathological lymph node involvement. All 5 cases were confirmed by FNA or surgery. EUS was also accurate in 4 cases, which reported the absence of portal vein or superior mesenteric vein invasion. Surgical documentation could not verify the fifth case. There were no complications at all from the EUS with/without FNA., Conclusion: This case series showed that EUS with/without FNA appears to be useful and safe in diagnosing and staging pancreatic head tumours not detectable by CT scanning.

A case of a total hip arthroplasty infection with Staphylococcus aureus, co-infected with Salmonella choleraesuis was treated with two-stage exchange and administration of vancomycin and ciprofloxacin. No signs of re-infection have appeared fourteen months after surgery. Cases of salmonella infection of hip prostheses are quite rare, with only a handful of reports in the literature.

Context: An outbreak of severe acute respiratory syndrome (SARS), an infectious disease attributed to a novel coronavirus, occurred in Singapore during the first quarter of 2003 and led to 204 patients with diagnosed illnesses and 26 deaths by May 2, 2003. Twenty-one percent of these patients required admission to the medical intensive care unit. During this period, the Center for Forensic Medicine, Health Sciences Authority, Singapore, performed a total of 14 postmortem examinations for probable and suspected SARS. Of these, a total of 8 were later confirmed as SARS infections., Objective: Our series documents the difficulties encountered at autopsy during the initial phases of the SARS epidemic, when the pattern of infection and definitive diagnostic laboratory criteria were yet to be established., Design: Autopsies were performed by pathologists affiliated with the Center for Forensic Medicine, Health Sciences Authority, Singapore. Tissue was accessed and read at the Tan Tock Seng Hospital, Singapore, and at the Armed Forces Institute of Pathology, Washington, DC. Autopsy tissue was submitted to the Virology Department, Singapore General Hospital, for analysis, and in situ hybridization for the SARS coronavirus was carried out at the National Institute of Infectious Diseases, Tokyo, Japan., Results: Thirteen of 14 patients showed features of diffuse alveolar damage. In 8 patients, no precipitating etiology was identified, and in all of these patients, we now have laboratory confirmation of coronavirus infection. Two of the 8 patients presented at autopsy as sudden unexpected deaths, while the remaining 6 patients had been hospitalized with varying lengths of stay in the intensive care unit. In 3 patients, including the 2 sudden unexpected deaths, in situ hybridization showed the presence of virally infected cells within the lung. In 4 of the 8 SARS patients, pulmonary thromboemboli were also recognized on gross examination, while one patient had marantic cardiac valvular vegetations., Conclusions: It is unfortunate that the term atypical pneumonia has been used in conjunction with SARS. Although nonspecific by itself, the term does not accurately reflect the underlying dangers of viral pneumonia, which may progress rapidly to acute respiratory distress syndrome. We observed that the clinical spectrum of disease as seen in our autopsy series included sudden deaths. This is a worrisome finding that illustrates that viral diseases will have a spectrum of clinical presentations and that the diagnoses made for such patients must incorporate laboratory as well as clinical data.

Severe acute respiratory syndrome (SARS) is an infectious condition caused by the SARS-associated coronavirus (SARS-CoV), a new member in the family Coronaviridae. To evaluate the lung pathology in this life-threatening respiratory illness, we studied postmortem lung sections from 8 patients who died from SARS during the spring 2003 Singapore outbreak. The predominant pattern of lung injury in all 8 cases was diffuse alveolar damage. The histology varied according to the duration of illness. Cases of 10 or fewer days' duration demonstrated acute-phase diffuse alveolar damage (DAD), airspace edema, and bronchiolar fibrin. Cases of more than 10 days' duration exhibited organizing-phase DAD, type II pneumocyte hyperplasia, squamous metaplasia, multinucleated giant cells, and acute bronchopneumonia. In acute-phase DAD, pancytokeratin staining was positive in hyaline membranes along alveolar walls and highlighted the absence of pneumocytes. Multinucleated cells were shown to be both type II pneumocytes and macrophages by pancytokeratin, thyroid transcription factor-1, and CD68 staining. SARS-CoV RNA was identified by reverse transcriptase-polymerase chain reaction in 7 of 8 cases in fresh autopsy tissue and in 8 of 8 cases in formalin-fixed, paraffin-embedded lung tissue, including the 1 negative case in fresh tissue. Understanding the pathology of DAD in SARS patients may provide the basis for therapeutic strategies. Further studies of the pathogenesis of SARS may reveal new insight into the mechanisms of DAD.

The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P(2) leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.

[structure: see text] Studies on the glycosidation reactions of conformationally constrained glycosyl imidates 8a and 8b were performed to evaluate the possible involvement of "conformationally inverted" oxonium ion intermediates in glycosidation reactions with 2-deoxy-2-iodo-glucopyranosyl donors. The mechanistic implications of this study are discussed, and intermediates 23 and 24 are invoked to rationalize the observed beta-selectivities.

[reaction: see text] The formation of saccharide-derived carbamates and alkyl 2, 4-dialkylallophanates from alcohols and p-nitrophenyl carbamates is described. Optimization of allophanate formation has led to the synthesis of branched glycoforms with inter-saccharide allophanate linkages that are rigidified by intramolecular hydrogen bonds.

[formula: see text] The one-pot cyclooligomerization of a saccharide-derived p-nitrophenyl carbamate monomer was developed to generate a series of novel carbamate-containing cyclodextrin analogues. The "transcarbamoylation" occurs by initial base-induced activation to the isocyanate, followed by polycondensation/cyclization of the isocyanato alcohol. In the presence of NaH, only cyclized oligomers were observed, suggesting the importance of Na+ in promoting the efficiency of the cyclization process. The facile deprotection of the oligomers was achieved.

Aggressive fibromatosis is a locally infiltrative fibroblastic tumour that arises from fascial planes of soft tissue but does not metastasize. It is known to invade muscle, subcutaneous tissue and neurovascular structures. However, bone involvement is very rare and there has been few reports of bone involvement. We present a case of a young man with aggressive fibromatosis of the right lower leg with fibula involvement.

An unusual case of recurrent nasopharyngeal carcinoma occurring within the stroma of benign nasal polyps is described. The patient was primarily treated with radiotherapy at first diagnosis. Two years later, he was diagnosed to have benign nasal polyps and had endoscopic sinus surgery. The recurrence was only diagnosed from histological examination of the polyps. The necessity for preoperative histological examination of any nasal polyp in patients with a past history of nasopharyngeal carcinoma and the importance of histological examination of all nasal polyps removed at surgery are emphasized.

Small joint arthritis is an uncommon manifestation of tuberculosis. We report a case of tuberculosis presenting as arthritis of the midtarsal joints with concomitant spinal involvement. This case illustrates the difficulties in diagnosing tuberculous arthritis as it has an insidious onset, paucity of constitutional symptoms, unremarkable early physical findings and frequent absence of associated pulmonary involvement. A high index of suspicion in high-risk individuals with chronic monoarthritis, is required to avoid delayed diagnosis.

Extramammary Paget's disease (FMPD) is a rare skin disease with a tendency to recur even in the face of adequate excision. It was first suggested by Weiner in 1937 to be a carcinoma of the apocrine sweat gland with intraepithelial excision. Thus, most cases of EMPD occur in the perianal, perigenital and axilla regions where sweat glands abound, with scrotal EMPD being the commonest. EMPD can occur in both benign or malignant form and is often confused with chronic dermatitis. Diagnosis can only be confirmed by an excision biopsy. The long-term survival in patients without an underlying carcinoma is good. However, EMPD associated with an underlying adnexal carcinoma tends to be more aggressive and the prognosis is poor in such cases. EMPD is also associated with other malignancies such as prostatic, rectal, cervical, breast, bladder and skin carcinomas. Incidences of up to 40% have been reported. Thus, patients with EMPD should be thoroughly screened for associated primary growths. The treatment of EMPD is essentially by surgical excision with clear margins. The options available for a clear margin include intraoperative frozen section,Moh's surgery and paraffin section with delayed re-excision. In this report, we present three cases of EMPD with markedly different outcomes and a review of the literature.

Over a period of two and a half years, 36 biopsies performed for clustered microcalcifications not associated with a mass revealed 30 benign and 6 malignant lesions. Of the 30 benign cases, 4 showed histological features which are thought to be associated with an increased risk of developing carcinoma. As similarities can exist in the mammographic appearances between benign and malignant microcalcifications, clusters of microcalcifications showing overlapping features or increasing in number over time require histopathologic study as there is no radiologic means at present of predicting which cluster will be malignant. We observe that our Chinese female population has a tendency towards dense breast parenchyma often associated with microcalcifications, both scattered and clustered. The presence of these clustered microcalcifications prompts biopsy even though the yield for malignancy is anticipated to be low.

Chondroblastoma represents approximately one per cent of all primary bone tumours. It is even rarer in the temporal bone and so far only 34 cases have been reported. We report here two cases with chondroblastoma of the temporal bone. The first case was discovered as a small lesion of the attic and root of zygoma. It was removed via mastoidectomy and reconstruction of the bony defect achieved normal external ear canal anatomy and hearing post-operatively. The second case presented as an advanced tumour involving the infratemporal fossa and parapharyngeal space. It was treated surgically via the infratemporal fossa approach. As clear surgical margins were not obtained, post-operative radiotherapy was also given to minimize the chance of recurrence.

Four hundred and forty four thyroid glands were obtained from coronial autopsies from 1983 to 1984. These were fixed and serially sectioned. Forty five glands (10%) were found to contain carcinomas. Forty one of these were papillary carcinomas, 2 were follicular carcinomas and 2 were undifferentiated carcinomas. No medullary carcinomas were found.

We describe a 41 yr old leprosy patient treated for 10 yrs with clofazimine who underwent laparotomy for severe abdominal pain. At surgery, the only significant findings were that the coeliac lymph nodes were enlarged and stained purplish black as were the omentum and the intraperitoneal fat. No other cause of abdominal pain was identified. On histological examination, reddish-purple crystals were identified at frozen section but not in the paraffin sections.