Adult acute lymphoblastic leukemia: concepts and strategies.
Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment strategies are pursued. Although ALL is a success story in pediatric oncology, results in adults lag behind those in children. An expansion of new drugs, more reliable immunologic and molecular techniques for the assessment of minimal residual disease, and efforts at more precise risk stratification are generating new aspects of adult ALL therapy. For this review, the authors summarized pertinent and recent literature on ALL biology and therapy, and they discuss current strategies and potential implications of novel approaches to the management of adult ALL. Cancer 2010. (c) 2010 American Cancer Society.


Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants.
The liver is the main organ of drug metabolism, but the expression and induction by xenobiotics of drug-metabolizing enzymes is also often observed in extrahepatic tissues. Recently, we reported that lipophilic cytochrome P450 inducers, beta-naphthoflavone (BNF), phenobarbital, and dexamethasone, induced CYP1, CYP2B, and CYP3A enzymes, respectively, in rat epididymal white adipose tissue (WAT) at both mRNA and protein levels. To further confirm the xenobiotic-induced expression of drug-metabolizing enzymes in adipose tissue, we studied the induction of CYP1A1 and other detoxifying enzymes by aryl hydrocarbon receptor (AhR) agonists and antioxidants. BNF increased CYP1A1 mRNA levels in several visceral WATs (epididymal, perirenal, and mesenteric) to a greater degree than in subcutaneous WAT in rats. Using C57BL/6 and DBA/2 mice with different responsiveness to aryl hydrocarbons and detecting cytoplasmic levels of AhR proteins, we have demonstrated that AhR mediates this CYP1A1 induction by BNF in WAT. Moreover, the NF-E2-related factor 2 (Nrf2)/antioxidant responsive element pathway is also functional in WAT, since BNF, which is known to activate both AhR and Nrf2, and antioxidants including tert-butylhydroquinone, 1-chloro-2,4-dinitrobenzene, and menadione induced the expression of Nrf2-target genes (NAD-(P)H:quinone oxidoreductase, glutathione S-transferase A subunits, and heme oxygenase-1) in rats and mice. These results suggest that both AhR and Nrf2 pathways are active in WAT and that lipophilic compounds accumulated in WAT can activate these transcription factors to increase detoxification capability in the tissue.


Prevention and treatment of thrombosis associated with central venous catheters in cancer patients.
Central venous catheters (CVC) play an essential role in the management of cancer patients. Venous thrombosis is a common complication of CVC. The incidence of CVC-associated venous thromboembolism (CVC-VTE) is 1.7 per 1000 catheter days. Risk factors for CVC-VTE include the patient's underlying cancer, a history of previous thrombotic events and the location and type of CVC. Anticoagulant prophylaxis is not effective for CVC-VTE. Anticoagulation alone is the preferred initial treatment for CVC-VTE. CVC removal may be considered in refractory cases or when anticoagulation is contraindicated. Thrombolytic therapy is reserved for patients with limb-threatening thrombosis or thrombosis unresponsive to conventional treatment. Anticoagulation should be continued for at least 3 months or as long as the CVC is present.


Pediatric genitourinary tumors.
Each year advances are made in the clinical evaluation and treatment of genitourinary tumors in children. Understanding of cellular, molecular, and genetic processes in tumorigenesis is evolving rapidly. In addition, information is accumulating about the long-term outcome and complications associated with treatment modalities. This article reviews the 2001 literature on pediatric Wilms tumor, other renal tumors, rhabdomyosarcoma of the pelvis, paratesticular rhabdomyosarcoma, and testicular tumors. The emphasis in molecular biology is to identify molecular or genetic markers that predict outcome. The National Wilms' Tumor Study Group reported on the complications of surgery and the decreased complication rate when these procedures are performed by pediatric surgical specialists. Long-term complications of treatment are also discussed, including short stature and leukemia. The Intergroup Rhabdomyosarcoma Study Group reported on the results of treatment for nonmetastatic disease and the goals of the upcoming Study V, reduction of chemotherapy and radiotherapy. They also presented data from Study IV and discussed the findings on improved prognosis.


Matriptase-2 inhibits HECV motility and tubule formation in vitro and tumour angiogenesis in vivo.
The type II transmembrane serine proteases (TTSP) are cell surface proteolytic enzymes that mediate a diverse range of cellular functions, including tumour invasion and metastasis. Matriptase-2 is a member of the TTSP family and has been shown to have a key role in cancer progression. The role of matriptase-2 in angiogenesis and angiogenesis-related cancer progression is currently poorly understood. This study aims to elucidate the role of matriptase-2 in tumour angiogenesis. Matriptase-2 was over-expressed in human vascular endothelial cells, HECV, using a mammalian expression plasmid. The altered cells were used in a number of in vitro and in vivo assays designed to investigate the involvement of matriptase-2 in angiogenesis. Over-expression had no significant effect on the growth and adhesion of HECV cells. However, there was a significant reduction in the motility of the cells and their ability to form tubules in an artificial basement membrane (p < 0.01 for both). HECV(mat2 exp) cells inoculated into CD-1 athymic mice along with either PC-3 prostate cancer cells or MDA-MB-231 breast cancer cells showed a dramatic decrease in tumour development and growth in the prostate tumours (p < 0.01) and a lesser, non-significant, decrease in the breast tumours (p = 0.08). Over-expression of matriptase-2 also decreased urokinase type plasminogen activator total protein levels in HECV and prostate cells. The study concludes that matriptase-2 has the ability to suppress the angiogenic nature of HECV cells in vitro and in vivo. It also suggests that matriptase-2 could have a potential role in prostate and breast tumour suppression through its anti-angiogenic properties.


Macro- and micro-vascular complications and their determinants among people with type 2 diabetes in Bangladesh.
To identify the prevalence of micro- and macro-vascular complications and their associated factors for type 2 diabetes mellitus in Bangladesh. This retrospective and cross-sectional study was conducted in six diabetes hospitals, covered urban and rural population. From April to September in 2017, a total of 1253 type 2 diabetes patients aged ≥18 years were recruited. Participants answered a pre-tested electronic questionnaire, and their medical records were reviewed for documented diabetes complications. Mean age was 55.1 (±12.6) years. Among macrovascular complications, the prevalence of coronary artery disease was found to be 30.5%, 10.1% for stroke and 12.0% for diabetic foot. Among microvascular complications, nephropathy was prevalent among 34.2%, retinopathy among 25.1% and neuropathy among 5.8% of patients. Risk factors found to be associated with one or more of the complications were female gender, higher age, lower education level, an urban area of residence, higher household income, smoking, physical inactivity, hypertension, poor glycaemic control, poor adherence to treatment, longer duration of diabetes, and insulin use. Diabetes complications are highly prevalent among type 2 diabetes population in Bangladesh. Prevention strategies should focus on increasing physical activity, weight loss, smoking cessation, and more strict control of hypertension and glycaemic level.


Identifying common genes and networks in multi-organ fibrosis.
Fibroproliferative diseases of organs are poorly understood and generally lack effective anti-fibrotic treatments. Our goal was to identify the key regulatory factors in pathologic fibrosis, common between organ-based fibrotic disease. We analyzed 9 microarray datasets publicly available in the GEO datasets from lung, heart, liver and kidney fibrotic disease tissue (489 microarrays total, disease and control). We identified a set of 90 genes differentially expressed in at least five microarray datasets. We used IPA and DAVID analysis to identify gene networks and their molecular functions. A mutual information based network work activity analysis showed that a connective tissue disorders network was the most active for all types of fibrosis included in this analysis. Our analysis indicates that despite different disease manifestation, organ fibrosis share a specific set of genes suggesting the potential for a common origin.


Mental health nurse prescribing: a difficult pill to swallow?
This paper develops an interpretation of the impact of mental health nurse prescribing in the UK. A constructivist-grounded theory methodology was applied to 13 semi-structured interviews with mental health clinicians and service users. The same interpretivist methodology was applied to the literature. Thirty-two practising UK mental health nurse prescribers gave structured feedback on the coherence of the emergent theory. It was found that the theory describes the process of becoming competent in mental health nurse prescribing. This process highlights possible deficits in non-prescribing mental health nurses. It is recommended that if this is corroborated then structured education in medicines management be introduced into pre- and postregistration mental health nursing in UK. The findings of this research offer a framework. That is, the categories emerging within this research translate easily into learning outcomes which can underpin delivery of a consistent medicine management strategy across all levels of nurse education.


Functional Exercise Capacity in Children With Electrical Burns.
Electrical burns are a severe form of thermal injury extending deep into tissue. Here, we investigated the effect of electrical burns on metabolic rate, body composition, and aerobic capacity. We prospectively studied a cohort of 24 severely burned children. Twelve patients had a combination of electrical and flame burns and 12 matched controls had only flame burns. Endpoints were cardiopulmonary fitness (maximal oxygen consumption [VO2]), muscle strength (peak torque per body weight), body mass index, lean body mass index, and days of myoglobinemia (≥500 mg/dl). Demographics of both the groups were comparable. The electrical burn group had more days of myoglobinemia during acute hospitalization than the flame burn group (3.6 ± 1.8 days vs 0.3 ± 0.5 days, P < .0001). Maximal VO2 was significantly lower in the electrical burn group than in the flame burn group at intensive care unit discharge (27 ± 6 ml/kg/min vs 34 ± 5 ml/kg/min, P < .0014). Electrical burns are associated with myoglobinemia and decreased cardiopulmonary fitness.


POEMS syndrome - a unique presentation of a rare paraneoplastic syndrome.
POEMS (peripheral neuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome is a rare multisystem paraneoplastic disorder. A 40-year-old male with a history of peripheral neuropathy and erectile dysfunction presented with a pathological fracture of the neck of the femur, found to be a solitary plasmacytoma. Additional unusual features included splenomegaly, hyperprolactinaemia and skin changes. The patient had a total hip replacement at a specialist orthopaedic hospital and is due to undergo radiotherapy to the femoral lesion and autologous stem cell transplantation.


Modulating Children's Manual Preference Through Spontaneous Nondominant Hand Use.
We evaluated the effect of repeated use of the nonpreferred hand on young children's manual preference by positioning toys in the left hemifield in egocentric coordinates to induce right-handed 4-5-year-olds to use their left hands spontaneously. We induced motor activities in the laterally biased workspace by presenting tasks in a ludic context over different days, similar to their daily kindergarten experience. Preceding and following these lateralized experiences, the children were tested on a task requiring reaching, grasping, and inserting cards into a slot. In the 1-day retention assessment, we found that repeated use of the nonpreferred left hand in the previous phase led to increased use of the left hand to perform the probing task. Following 14 days of rest, the children with induced left-hand experiences used exclusively their left hands to manipulate the leftmost card positions. We propose that repeated use of the nonpreferred left hand leads to increased confidence to plan left-handed movements for subsequent tasks.


Molecular determinants of dofetilide block of HERG K+ channels.
The human ether-a-go-go-related gene (HERG) encodes a K+ channel with biophysical properties nearly identical to the rapid component of the cardiac delayed rectifier K+ current (IKr). HERG/IKr channels are a prime target for the pharmacological management of arrhythmias and are selectively blocked by class III antiarrhythmic methanesulfonanilide drugs, such as dofetilide, E4031, and MK-499, at submicromolar concentrations. By contrast, the closely related bovine ether-a-go-go channel (BEAG) is 100-fold less sensitive to dofetilide. To identify the molecular determinants for dofetilide block, we first engineered chimeras between HERG and BEAG and then used site-directed mutagenesis to localize single amino acid residues responsible for block. Using constructs heterologously expressed in Xenopus oocytes, we found that transplantation of the S5-S6 linker from BEAG into HERG removed high-affinity block by dofetilide. A point mutation in the S5-S6 linker region, HERG S620T, abolished high-affinity block and interfered with C-type inactivation. Thus, our results indicate that important determinants of dofetilide binding are localized to the pore region of HERG. Since the loss of high-affinity drug binding was always correlated with a loss of C-type inactivation, it is possible that the changes observed in drug binding are due to indirect allosteric modifications in the structure of the channel protein and not to the direct interaction of dofetilide with the respective mutated site chains. However, the chimeric approach was not able to identify domains outside the S5-S6 linker region of the HERG channel as putative candidates involved in drug binding. Moreover, the reverse mutation BEAG T432S increased the affinity of BEAG K+ channels for dofetilide, whereas C-type inactivation could not be recovered. Thus, the serine in position HERG 620 may participate directly in dofetilide binding; however, an intact C-type inactivation process seems to be crucial for high-affinity drug binding.


Financial burden of raising CSHCN: association with state policy choices.
We examined the association between state Medicaid and State Children's Health Insurance Program (SCHIP) income eligibility and the financial burden reported by low-income families raising children with special health care needs (CSHCN). Data on low-income CSHCN and their families were from the National Survey of Children With Special Health Care Needs (N = 17039), with a representative sample from each state. State Medicaid and SCHIP income-eligibility thresholds were from publicly available sources. The 3 outcomes included whether families had any out-of-pocket health care expenditures during the previous 12 months for their CSHCN, amount of expenditure, and expenditures as a percentage of family income. We used multilevel logistic regression to model the association between Medicaid and SCHIP characteristics and families' financial burden, controlling state median income and child- and family-level characteristics. Overall, 61% of low-income families reported expenditures of >$0. Among these families, 30% had expenses between $250 and $500, and 34% had expenses of more than $500. Twenty-seven percent of the families reporting any expenses had expenditures that exceeded 3% of their total household income. The percentage of low-income families with out-of-pocket expenses that exceeded 3% of their income varied considerably according to state and ranged from 5.6% to 25.8%. Families living in states with higher Medicaid and SCHIP income-eligibility guidelines were less likely to have high absolute burden and high relative burden. Beyond child and family characteristics, there is considerable state-level variability in low-income families' out-of-pocket expenditures for their CSHCN. A portion of this variability is associated with states' Medicaid and SCHIP income-eligibility thresholds. Families living in states with more generous programs report less absolute and relative financial burden than families living in states with less generous benefits.


Synchrony and motor mimicking in chimpanzee observational learning.
Cumulative tool-based culture underwrote our species' evolutionary success, and tool-based nut-cracking is one of the strongest candidates for cultural transmission in our closest relatives, chimpanzees. However the social learning processes that may explain both the similarities and differences between the species remain unclear. A previous study of nut-cracking by initially naïve chimpanzees suggested that a learning chimpanzee holding no hammer nevertheless replicated hammering actions it witnessed. This observation has potentially important implications for the nature of the social learning processes and underlying motor coding involved. In the present study, model and observer actions were quantified frame-by-frame and analysed with stringent statistical methods, demonstrating synchrony between the observer's and model's movements, cross-correlation of these movements above chance level and a unidirectional transmission process from model to observer. These results provide the first quantitative evidence for motor mimicking underlain by motor coding in apes, with implications for mirror neuron function.


An epidemic of type B viral hepatitis: its course and outcome.
Between June and August, 1977 there was a small epidemic of type B viral hepatitis in a market town in South-East England during which 4 people developed acute hepatitis. Their close friends and contacts were all negative for hepatitis B surface antigen (HBsAg) at this time. One year later, in July 1978, 3 of the original 4 patients were available for follow-up. All were HBsAg negative but hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc) positive. Two had disturbed liver function tests and chronic persistent hepatitis on liver biopsy. Also at this time 2 of the original contacts were found to show evidence, from the serum markers, of previous infection by the type B virus. Both had abnormal liver function tests and showed chronic persistent or chronic active hepatitis on liver biopsy. A further subject was identified who had had an overt hepatitis 1 year previously and who also showed evidence of continuing liver disease. The origin of the epidemic and its spread through the group were identified. The varying modes of transmission, and the variation in clinical picture and sequelae are discussed. The importance of anti-HBc as a marker of hepatitis B virus infection is emphasised.


Predicted shortfall in open aneurysm experience for vascular surgery trainees.
Since the introduction of endovascular aneurysm repair (EVAR), the volume of open aneurysm repair (OAR) has steadily declined since 2000. The introduction of next-generation devices and branched and fenestrated endograft technology continues to increase the anatomic applicability of EVAR, further decreasing the need for OAR. This study models the decline in OAR and uses historical trends to forecast future decline in volume and its potential effect on vascular surgery training. An S-curve modified logistic function was used to model the effect of introducing a new technology (EVAR) on the standard management of abdominal aortic aneurysm (AAA) with OAR starting in the year 2000, when an International Classification of Diseases, Ninth Revision, code was first introduced for EVAR. Patients who underwent EVAR and OAR for AAA were determined using the Nationwide Inpatient Sample from 1998 to 2011. Weighted samples and data from the United States Census Bureau were used to extrapolate these numbers to estimate population statistics. The number of cases completed at teaching hospitals was calculated using the Nationwide Inpatient Sample, and Accreditation Council for Graduate Medical Education case logs were used to forecast the number of cases completed by vascular surgery trainees. The highest number of OAR cases in this study was 42,872 in 2000 compared with just 10,039 in 2011. This was mirrored by a rise in EVAR from 2358 cases in 2000 (5.2%) to 35,028 in 2011 (76.5% by volume). Of the OAR volume in 2011, 6055 cases (60.3%) were completed at teaching institutions. An S-curve model with a correlation coefficient of R2 = 0.982 predicted 3809 open AAA cases at teaching hospitals by 2015, 2162 by 2020, and 1231 by 2025. When compared with the 2011 Accreditation Council for Graduate Medical Education National Resident Report, vascular surgery residents had 44.4% utilization with regard to OAR (2690 cases covered of 6055 total). When combined with the increase in vascular surgery trainees and lower number of open repairs, vascular fellows will complete about 10 OAR cases in 2015 and five OAR cases in 2020. The decreasing number of OAR cases will limit exposure for vascular trainees, who may be ill equipped to treat patients who require open repair beyond 2015. Additional methods for providing OAR training should be explored.


Using cognitive interviewing to bridge the intent-interpretation gap for nutrition coverage survey questions in India.
Designing survey questions that clearly and precisely communicate the question's intent and elicit responses based on the intended interpretation is critical but often undervalued. We used cognitive interviewing to qualitatively assess respondents' interpretation of and responses to questions pertaining to maternal and child nutrition intervention coverage. We conducted interviews to cognitively test 25 survey questions with mothers (N = 21) with children less than 1 year in Madhya Pradesh, India. Each question was followed by probes to capture information on four cognitive stages-comprehension, retrieval, judgement, and response. Data were analysed for common and unique patterns across the survey questions. We identified four types of cognitive challenges: (1) retention of multiple concepts in long questions: difficulty in comprehending and retaining questions with three or more key concepts; (2) temporal confusion: difficulty in conceptualizing recall periods such as "in the last 6 months" as compared to life stages such as pregnancy; (3) interpretation of concepts: mismatch of information being asked, meaning of certain terms and intervention scope; and (4) understanding of technical terms: difficulty in understanding commonly used technical words such as "breastfeeding" and "antenatal care" and requiring use of simple alternative language. Findings from this study will be useful for stakeholders involved in survey design and implementation, especially those conducting large-scale household surveys to measure coverage of essential nutrition interventions.


Inhibitory activity of Podospermum canum and its active components on collagenase, elastase and hyaluronidase enzymes.
Present study is aimed to investigate in vitro inhibitory effects of the extract prepared from the aerial parts of Podospermum canum (syn: Scorzonera cana var. jacquiniana) (Asteraceae) on hyaluronidase, collagenase, and elastase enzymes using a bioassay-guided fractionation. Inhibitory effects of the extract, sub-extracts, fractions obtained by column chromatography, and isolated compounds on collagenase, elastase, and hyaluronidase were performed by using in vitro enzyme inhibitory assays based on spectrophotometric evaluation. The methanolic extract obtained from P. canum exhibited strong inhibitory activities on elastase and collagenase while the insignificant activity was observed on hyaluronidase. Through bioactivity-guided fractionation, the ethyl acetate and remaining water sub-extracts obtained from the methanolic extract displayed significant inhibitory activities on collagenase and elastase, while petroleum ether and chloroform extracts did not show any inhibitory activity. Eleven known compounds: arbutin, 6́-O-caffeoylarbutin, cichoriin, 3,5-dicaffeoylquinic acid methyl ester, apigenin 7-O-β-glucoside, luteolin 7-O-β-glucoside, apigenin 7-O-β-rutinoside, isoorientin, orientin, vitexin, procatechuic acid, and new compound 4-hydroxy-benzoic acid 4-(6-O-α-rhamnopyranosyl-β-glucopyranosyl) benzyl ester have been obtained from ethyl acetate sub-extract. Results of the present study have revealed that apigenin 7-O-β-glucoside, luteolin 7-O-β-glucoside, apigenin 7-O-β-rutinoside, and isoorientin showed potent enzyme inhibitory activities. However, methanolic extract of P. canum displayed a greater inhibitory activity than fractions and isolated compounds both on collagenase and elastase.


Polymeric nanoparticle-encapsulated hedgehog pathway inhibitor HPI-1 (NanoHHI) inhibits systemic metastases in an orthotopic model of human hepatocellular carcinoma.
To illustrate the prognostic significance of hedgehog (Hh) signaling in patients with hepatocellular carcinoma (HCC) and to evaluate the efficacy of a novel nanoparticle-encapsulated inhibitor of the Hh transcription factor, Gli1 (NanoHHI) using in vitro and in vivo models of human HCCs. Patched1 (Ptch1) expression was detected in tumor tissue microarrays of 396 patients with HCC who underwent curative surgical resection during February 2000 to December 2002. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. The effects of NanoHHI alone and in combination with sorafenib were investigated on HCC cell lines. Primary HCC tumor growth and metastasis were examined in vivo using subcutaneous and orthotopic HCC xenografts in nude mice. Elevated expression of Ptch1 in HCC tissues was significantly related to disease recurrence, as well as a shorter time to recurrence in patients with HCC. In vitro, NanoHHI significantly inhibited the proliferation and invasion of HCC cell lines. NanoHHI potently suppressed in vivo tumor growth of HCC xenografts in both subcutaneous and orthotopic milieus, and in contrast to sorafenib, resulted in significant attenuation of systemic metastases in the orthotopic setting. Furthermore, NanoHHI significantly decreased the population of CD133-expressing HCC cells, which have been implicated in tumor initiation and metastases. Downstream Hh signaling has prognostic significance in patients with HCC as it predicts early recurrence. Gli inhibition through NanoHHI has profound tumor growth inhibition and antimetastatic effects in HCC models, which may provide a new strategy in the treatment of patients with HCC and prevention post-operative recurrence.


Adherence patterns and DNA probe types of Escherichia coli isolated from diarrheal patients in China.
One hundred and seventy-two strains of Escherichia coli isolated from diarrheal patients in Beijing, P.R. China, were analyzed for plasmid DNA profile, HEp-2 cell adherence ability and reactivity to 10 previously described DNA probes. They had not been recognized as pathogenic E. coli in China. Of the 110 strains tested, 76 (69%) contained one or multiple large plasmids. Of the 71 strains with the large plasmids 64 could adhere to HEp-2 cells. Of the 172 strains, 102 (59.3%) were hybridized with at least one of the 10 probes. Of those, seven strains hybridized with enteroaggregative E. coli (EAggEC) probe. Their serotypes were O128 (two strains), O6 (one strain), and O111 (one strain). Three strains were untypable. Six and three strains were hybridized with enteropathogenic E. coli (EPEC) attaching and effacing genes (eae) or EPEC adherence factor (EAF) probe, respectively. Two non-O157: H7 strains hybridized with enterohemorrhagic E. coli (EHEC) probe. Seventy-two strains (41.9%) hybridized with shiga-like toxin 2 or 1 (SLT2 or SLT1) probes. Among the SLT1 or SLT2 probe-positive strains, 54 hybridized with invasive (INV) plasmid probe developed for identification of enteroinvasive E. coli (EIEC) and Shigella species. The INV and SLT probe-positive strains might represent a new variety of verotoxin-producing E. coli (VTEC).


A top-r feature selection algorithm for microarray gene expression data.
Most of the conventional feature selection algorithms have a drawback whereby a weakly ranked gene that could perform well in terms of classification accuracy with an appropriate subset of genes will be left out of the selection. Considering this shortcoming, we propose a feature selection algorithm in gene expression data analysis of sample classifications. The proposed algorithm first divides genes into subsets, the sizes of which are relatively small (roughly of size h), then selects informative smaller subsets of genes (of size r < h) from a subset and merges the chosen genes with another gene subset (of size r) to update the gene subset. We repeat this process until all subsets are merged into one informative subset. We illustrate the effectiveness of the proposed algorithm by analyzing three distinct gene expression data sets. Our method shows promising classification accuracy for all the test data sets. We also show the relevance of the selected genes in terms of their biological functions.


Chirality manifestation in elastic coupling between the layers of double-walled carbon nanotubes.
The search for new relatively easy physicochemical methods for the structural identification of carbon nanotubes represents a key challenge. Here, analyzing the experimental data on double-walled carbon nanotubes (DWCNTs) obtained by us and taken from the literature, we have expressed the magnitude of elastic coupling between two tubular walls forming a DWCNT as a simple function dependent not only on DWCNT diameters but also on the difference between the chirality angles of the constituent nanotubes. To get this quite unexpected result, which allows us to relate more precisely the structural parameters of a DWCNT with frequencies of its radial breathing-like modes (RBLM), we have developed a new model for the RBLM dynamics that takes into account a possible deposition of water molecules from ambient air onto the DWCNT surface. The model constructed allows us to predict the higher prevalence of DWCNTs comprising two walls with identical handedness. The application of the results obtained for the identification of DWCNTs is also considered.


Psychometric Validation of the Indonesian Version of Children's Revised Impact of Event Scale 13.
A psychometric evaluation of the Children's Revised Impact of Event Scale 13 (CRIES-13), which measures the posttraumatic stress disorder (PTSD) symptoms in children and adolescents caused by the coronavirus disease 2019 (COVID-19) pandemic, was conducted. We aimed to cross-culturally adapt and test the psychometric qualities of the CRIES-13 that was applied to Indonesian adolescents exposed to COVID-19 risk across gender groups. A cross-sectional study was conducted at a junior high school in Yogyakarta, Indonesia, in May 2022; 346 Indonesian adolescents aged 12 to 18 years completed the Indonesian version of the CRIES-13. The factorial validity results supported the scale's three-factor structure (intrusion, avoidance, and arousal), which satisfied all parameter index requirements and exhibited a favorable level of internal consistency reliability. Excellent results were obtained across genders for the four-level measurement of invariance (i.e., configural, metric, scalar, and full invariance), and they met the recommended criteria. Our Cronbach's alphas and composite reliability ratings were high (>0.7), indicating a strong correlation and reliability of the items for measuring each construct. We strongly support the use of the Indonesian CRIES-13, which was demonstrated to be valid and reliable for an adolescent population.


Functional definition of outer membrane proteins involved in preprotein import into mitochondria.
The role of plant mitochondrial outer membrane proteins in the process of preprotein import was investigated, as some of the principal components characterized in yeast have been shown to be absent or evolutionarily distinct in plants. Three outer membrane proteins of Arabidopsis thaliana mitochondria were studied: TOM20 (translocase of the outer mitochondrial membrane), METAXIN, and mtOM64 (outer mitochondrial membrane protein of 64 kD). A single functional Arabidopsis TOM20 gene is sufficient to produce a normal multisubunit translocase of the outer membrane complex. Simultaneous inactivation of two of the three TOM20 genes changed the rate of import for some precursor proteins, revealing limited isoform subfunctionalization. Inactivation of all three TOM20 genes resulted in severely reduced rates of import for some but not all precursor proteins. The outer membrane protein METAXIN was characterized to play a role in the import of mitochondrial precursor proteins and likely plays a role in the assembly of beta-barrel proteins into the outer membrane. An outer mitochondrial membrane protein of 64 kD (mtOM64) with high sequence similarity to a chloroplast import receptor was shown to interact with a variety of precursor proteins. All three proteins have domains exposed to the cytosol and interacted with a variety of precursor proteins, as determined by pull-down and yeast two-hybrid interaction assays. Furthermore, inactivation of one resulted in protein abundance changes in the others, suggesting functional redundancy. Thus, it is proposed that all three components directly interact with precursor proteins to participate in early stages of mitochondrial protein import.


Assessment of gelatinase and tumor necrosis factor-α level in the vitreous and serum of patients with Eales disease: role of inflammation-mediated angiogenesis in the pathogenesis of Eales disease.
Eales disease (ED) is an idiopathic, inflammatory, venoocclusive disorder of peripheral retina resulting in retinal angiogenesis and vitreous hemorrhage. The objective of the present study is to investigate the expression and activation of gelatinase associated with the retinal neovascularization in ED and the relation between the levels of gelatinase and the cytokine tumor necrosis factor-α, known to upregulate matrix metalloproteinase (MMP) expression on various cells. Vitreous and serum samples from 19 patients with ED who underwent retinal surgery were estimated for levels of MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, and tumor necrosis factor-α by enzyme-linked immunosorbent assay method. Matrix metalloproteinase-2 and MMP-9 activities in serum and vitreous samples were evaluated by gelatin zymography method. Vitreous samples from 16 patients with macular hole undergoing vitrectomy were used as controls. Among the 2 gelatinase examined in vitreous and serum samples, only level and activity of MMP-9 were significantly higher in serum (P = 0.0001) and vitreous (P = 0.0002) samples of patients with ED than those of control subjects. Simultaneously, a positive correlation was found between intraocular tumor necrosis factor-α and MMP-9 concentration (Spearman correlation coefficient, r = 0.7040, P = 0.0023) in patients with ED. Increase in MMP-9 activity and its concentration in serum and vitreous of patients with ED compared with that of control subjects and correlation between intraocular levels of MMP-9 and tumor necrosis factor-α in patients with ED seem to provide a plausible explanation for inflammation-mediated angiogenesis during the development of this condition.


SUMO Losing Balance: SUMO Proteases Disrupt SUMO Homeostasis to Facilitate Cancer Development and Progression.
Small ubiquitin-like modifiers (SUMO) conjugation to cellular proteins is a reversible posttranslational modification that mediates the protein's function, subcellular localization, and/or expression. The SUMO proteases (SENP) deconjugate modified proteins and thus are critical for maintaining the level of SUMOylated and un-SUMOylated substrates required for normal physiology. Altered expression of SENPs is observed in several carcinomas. This review focuses on how the change in SENP levels disturbs SUMO homeostasis and contributes to cancer development and progression. We reported that one member of the SENP family, SENP1 can transform normal prostate epithelia to a dysplasic state and directly modulate several oncogenic pathways in prostate cells, including AR, c-Jun, and Cyclin D1. Assessment of tissue from human prostate cancer patients indicates elevated mRNA levels of SENP1 and the SUMO2/3 deconjugating enzyme, SENP3. The induction of SENP3 in cancer cells initiates the angiogenic pathway; specifically SENP3 regulates the transcriptional activity of hypoxia-inducible factor 1α (HIF1α) via deSUMOylation of the co-regulatory protein p300. Unlike prostate cancer, enhanced SUMOylation is favored with onset of breast cancer and correlated with the reduced SENP6 mRNA levels found in several breast cancer tissue arrays. Preventing enhanced SUMO conjugation of cellular substrates in breast cancer cells reduces tumorigenesis. Hence, distortion of SUMO equilibrium contributes to both the initiation and progression of cancer, specifically in prostate and breast cancers. The deSUMOylation machinery may be key to restoring balance to the SUMO system and hence serve as ideal targets for therapeutic agents.


Identification of a novel complex between human kallikrein 2 and protease inhibitor-6 in prostate cancer tissue.
Human kallikrein (hK) 2 is an arginine-selective serine protease expressed predominantly in the prostate that has an 80% sequence identity with prostate-specific antigen. Expression of hK2 is elevated in the tumor epithelium compared to benign prostate tissue. We have purified, sequenced, and identified a novel hK2 complex in prostate tissue consisting of hK2 and a serine protease inhibitor known as protease inhibitor-6 (PI-6). This 64-kDa SDS-PAGE stable complex is elevated in the tumor and is approximately 10% of total hK2. No comparable complex of prostate-specific antigen was detected. PI-6, also known as cytoplasmic antiprotease, has been characterized as an intracellular inhibitor of trypsin and chymotrypsin-like proteases, which has high homology to plasminogen activator inhibitor 1 and 2. The physiological role of PI-6 in the prostate and its relationship to hK2 and prostate cancer are under investigation.


[Secondary infection with methacillin resistant Staphylococcus aureus in Dutch hospitals (July 1997-June 1996].
To study the spread of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals, especially secondary MRSA infections in relation to the origin of the MRSA strain and the measures taken regarding contact isolation. Secondary data analysis. As part of the national MRSA surveillance of the National Institute of Public Health and the Environment, data were collected using questionnaires. The analysis covered the period July 1994-June 1996 and was performed for index cases of secondary infections versus sporadic cases. Possible risk factors were determined. In the study period 30 index cases of (clusters of) secondary infections and 191 sporadic cases were found. The size of the clusters was limited. Strict contact isolation as described in the guidelines of the Dutch Working Group on Infection Prevention prevented secondary infections in most cases. Patients for whom no relation could be found between the MRSA infection and a stay abroad were found to have caused more secondary infections, even when the data were corrected for contact isolation measures.


Preparation of a gap junction fraction from uteri of pregnant rats: the 28-kD polypeptides of uterus, liver, and heart gap junctions are homologous.
A procedure for the preparation of a gap junction fraction from the uteri of pregnant rats is described. The uterine gap junctions, when examined by electron microscopy of thin sections and in negatively stained preparations, were similar to gap junctions isolated from heart and liver. Major proteins of similar apparent molecular weight (Mr 28,000) were found in gap junction fractions isolated from the uterus, heart, and liver, and were shown to have highly homologous structures by two-dimensional mapping of their tryptic peptides. An Mr 10,000 polypeptide, previously deduced to be a proteolytic product of the Mr 28,000 polypeptide of rat liver (Nicholson, B. J., L. J. Takemoto, M. W. Hunkapiller, L. E. Hood, and J.-P. Revel, 1983, Cell, 32:967-978), was also studied and shown by chymotryptic mapping to be homologous in the uterine, heart, and liver gap junction fractions. An antibody raised in rabbits to a synthetic peptide corresponding to an amino-terminal sequence of the liver gap junction protein recognized Mr 28,000 proteins in the three tissues studied, showing that the proteins shared common antigenic determinants. These results indicate that gap junctions are biochemically conserved plasma membrane specializations. The view that gap junctions are tissue-specific plasma membrane organelles based on previous comparisons of Mr 26,000-30,000 polypeptides is not sustained by the present results.


Human rabies--Michigan, 2009.
On November 9, 2009, a Michigan hospital informed CDC of suspected rabies in a man aged 55 years. The patient reportedly had awakened with a bat on his arm 9 months earlier but had not sought medical evaluation. He went to a local emergency department (ED) on October 30 and soon after was hospitalized; he died 12 days later. On November 14, CDC confirmed infection with a rabies virus variant that commonly infects the silver-haired bat (Lasionycteris noctivagans). This report summarizes the patient's clinical course and the associated public health investigation. The report highlights the importance of public awareness of rabies, particularly among persons who might be at risk for wildlife exposures. Persons who experience contact with a bat and cannot confidently rule out a bite or scratch should seek prompt medical attention.


Impedance modulation and feedback corrections in tracking targets of variable size and frequency.
Humans are able to adjust the accuracy of their movements to the demands posed by the task at hand. The variability in task execution caused by the inherent noisiness of the neuromuscular system can be tuned to task demands by both feedforward (e.g., impedance modulation) and feedback mechanisms. In this experiment, we studied both mechanisms, using mechanical perturbations to estimate stiffness and damping as indices of impedance modulation and submovement scaling as an index of feedback driven corrections. Eight subjects tracked three differently sized targets (0.0135, 0.0270, and 0.0405 rad) moving at three different frequencies (0.20, 0.25, and 0.33 Hz). Movement variability decreased with both decreasing target size and movement frequency, whereas stiffness and damping increased with decreasing target size, independent of movement frequency. These results are consistent with the theory that mechanical impedance acts as a filter of noisy neuromuscular signals but challenge stochastic theories of motor control that do not account for impedance modulation and only partially for feedback control. Submovements during unperturbed cycles were quantified in terms of their gain, i.e., the slope between their duration and amplitude in the speed profile. Submovement gain decreased with decreasing movement frequency and increasing target size. The results were interpreted to imply that submovement gain is related to observed tracking errors and that those tracking errors are expressed in units of target size. We conclude that impedance and submovement gain modulation contribute additively to tracking accuracy.


Phylogenetic analysis of the Caliciviruses.
A phylogenetic portrait of the genus Calicivirus in the family Caliciviridae was developed based upon published sequences and newly characterized calicivirus (CV) strains, including additional Sapporo-like HuCV strains in pediatric diarrhea stool specimens from South Africa, the United Kingdom, and the United States. Distance and parsimony methods were applied to nucleotide and amino acid sequences of human and animal calicivirus 3D RNA-dependent RNA polymerase (approximately 470nt) and capsid hypervariable regions (approximately 1,200nt) to generate phylogenetic trees. Pairwise amino acid identity in the 3D region among the Sapporo-like strains ranged from 61% to 100%. Human and animal caliciviruses (HuCVs and AnCVs) separated into five genogroups: small round-structured viruses (SRSV), Sapporo-like, and hepatitis E virus (HEV)-like HuCVs and rabbit-, and vesicular exanthema of swine virus (VESV)-like AnCVs, each with a distinct genome organization. Each genogroup, including the Sapporo-like HuCVs, subdivided further into subgenogroups. The capsid region trees had higher levels of confidence than the 3D region trees and limited conclusions about genogroups could be drawn from the 3D region analyses. This analysis suggested that CVs include five potential virus subfamilies.


Clinical characteristics of severe fever with thrombocytopenia syndrome (SFTS) sepsis and non-SFTS sepsis.
Severe fever with thrombocytopenia syndrome (SFTS) is a new infectious disease caused by bunyavirus, and the critically cases conform to the definition of sepsis. In order to compare the differences between SFTS sepsis and non-SFTS sepsis, a retrospective analysis was performed. Thirty-seven SFTS sepsis and 96 non-SFTS sepsis patients were enrolled. The clinical characteristics, laboratory results were compared between the two groups and independent prognostic risk of mortality were investigated respectively. Compared with non-SFTS sepsis, SFTS cases had lower white blood cell, neutrophil and platelet counts, prolonged activated partial thromboplastin time and decreased fibrinogen, slightly elevated inflammatory indicators. Interleukin-6 (IL-6), and acute physiology and chronic health evaluation Ⅱ (APACHE II) score were independent prognostic risk factors in non-SFTS sepsis. The mortality risk of STFS sepsis was related to the viral clearance. There was no difference in viral load between SFTS survivors and non-survivors on admission. However, the differences were significant on 5th, 7th, 10th, and 14th day, and all SFTS non-survivors died within 14 days. Viral clearance rate on 7th day was an independent risk factor for mortality in SFTS sepsis. The mortality risk of STFS sepsis was related to the viral clearance rate.


Therapeutic roles of heme oxygenase-1 in metabolic diseases: curcumin and resveratrol analogues as possible inducers of heme oxygenase-1.
Metabolic diseases, such as insulin resistance, type II diabetes, and obesity, are associated with a low-grade chronic inflammation (inflammatory stress), oxidative stress, and endoplasmic reticulum (ER) stress. Because the integration of these stresses is critical to the pathogenesis of metabolic diseases, agents and cellular molecules that can modulate these stress responses are emerging as potential targets for intervention and treatment of metabolic diseases. It has been recognized that heme oxygenase-1 (HO-1) plays an important role in cellular protection. Because HO-1 can reduce inflammatory stress, oxidative stress, and ER stress, in part by exerting antioxidant, anti-inflammatory, and antiapoptotic effects, HO-1 has been suggested to play important roles in pathogenesis of metabolic diseases. In the present review, we will explore our current understanding of the protective mechanisms of HO-1 in metabolic diseases and present some emerging therapeutic options for HO-1 expression in treating metabolic diseases, together with the therapeutic potential of curcumin and resveratrol analogues that have their ability to induce HO-1 expression.


Under the volcano, or pheochromocytoma revisited.
Pheochromocytoma is a well-defined clinical entity often remembered in clinical practice, but seldom encountered. Rather often, however, these patients are initially referred to a cardiologist and then a correct diagnosis is important because this disease is curable and may otherwise be lethal. Somehow clinical signs and symptoms are embedded in a sort of subconscious memory but specific knowledge is rather limited as far as, for example, the pathophysiological background is concerned. Perhaps this has something to do with the fact that already in 1922 a syndrome of paroxysmal hypertension associated with an adrenal medullary tumour was reported and that its nature and clinicopathological manifestations were described as early as the 1950s. Nevertheless it is not amiss to shed some new light upon old and established views not only for the better of our patients but as a catalyst for the motivation in search of coherence as well. The patient presented here pairs a very unusual case with unusual features. The pathophysiology is revealed with the closely monitored sequence of events. At a time where the medical professional leans heavily on test results and sophisticated technology it is refreshing to see how basic diagnostic tools pay off in clarifying and understanding as well.


Intimate partner violence and increased lifetime risk of sexually transmitted infection among women in Ukraine.
Population-based, cross-sectional data from 3587 ever-married Ukrainian women aged 17-44 are used to examine the association between physical violence perpetrated by a sexual partner (defined as kicking, hitting, slapping, pushing, or attacking with a weapon) and sexual health knowledge, sexual behavior, and the likelihood of reporting a sexually transmitted infection (STI). Such violence, both past and recent, is found to be associated with increased lifetime risk of acquiring an STI. Women who have been abused by a sexual partner, whether in the past 12 months or less recently, are significantly less likely to use condoms currently, and are significantly more likely to report having had multiple sexual partners in the past year. Findings from the study indicate that physical violence perpetrated by a sexual partner is associated with risky sexual behaviors and increased risk of sexually transmitted infection in Ukraine, and may constitute a barrier to prevention of HIV/STI transmission.


Mechanism investigation of ketone hydrogenation catalyzed by ruthenium bifunctional catalysts: insights from a DFT study.
In this paper, the mechanism of ketone hydrogenation catalyzed by five Ru bifunctional catalysts with different structural frameworks was studied in detail using density functional theory (DFT). This mechanism contains hydrogen transfer, dehydrogenation of alcohol, and dihydrogen activation fundamental reactions. The involvement of alcohol is also discussed and found with different activities in hydrogen transfer, dehydrogenation and dihydrogen activation steps in five systems. Our calculated results indicate that the weak Ru-H bond, stronger basicity of hydride and stronger X-H acidity will decrease the barrier of the HT step, and that the polar micro-environment of dihydrogen coordinating with Ru catalysts and short hydrogen transfer distance would be able to facilitate the heterolytic splitting of dihydrogen in the dihydrogen activation step.


3-Chlorotyrosine in sputum of COPD patients: relationship with airway inflammation.
The airways of patients with chronic obstructive pulmonary disease (COPD) are associated with increased numbers of inflammatory cells, in particular neutrophils and macrophages. Contained within the primary granules of neutrophils is the heme enzyme called myeloperoxidase (MPO) that has been used as a biomarker of neutrophilic inflammation in COPD and other inflammatory diseases. MPO is the only enzyme in the body that produces hypochlorous acid (HOCl), which effectively chlorinates tyrosine residues in proteins. The presence of 3-chlorotyrosine (3Cl-Tyr) in sputum of COPD patients has yet to be established. Spontaneously produced sputum was collected from 14 stable COPD patients, and ultra-centrifuged to prepare sol phase samples for analysis. Sputum 3Cl-Tyr levels were measured using Mass Spectrometry (LC-MSMS). Sputum MPO activity was measured using a standard chromogenic substrate assay. The Spearman rank correlation was used to analyse the data. We report for the first time the measurement of 3Cl-Tyr in sputum from stable COPD patients. The sputum levels of 3Cl-Tyr correlated well with sputum MPO activity (r = 0.88; p < 0.0001). The presence of 3Cl-Tyr in the sputum of stable COPD patients suggests an active process related to MPO that may play a role in the pathophysiology of this disease.


Comparison of Ca2+ -dependent phosphorylation in viable dispersed brain cells with calmodulin-dependent protein kinase activity in cell-free preparations of rat brain.
Using two depolarizing agents, veratrine and high concentrations of extracellular KCl, we studied depolarization-stimulated phosphorylations in 32P-labelled dispersed brain tissue in order to identify phosphoprotein substrates for Ca2+ - and calmodulin-dependent protein kinase activity at the cellular level, for comparison with findings in cell-free preparations. In intact brain cells, the only prominent depolarization-stimulated phosphorylation was a 77 kDa protein separated on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. This phosphorylation was dependent on external Ca2+, since chelation of Ca2+ in media with 6 mM-EGTA or the presence of verapamil (a Ca2+ -channel blocker) in the incubation media inhibited depolarization-stimulated phosphorylation of the 77 kDa protein. Phosphorylation of the 77 kDa protein also appeared to be dependent on calmodulin, because depolarization-stimulated phosphorylation was significantly decreased (P less than 0.05) when 100 microM-trifluoperazine was present in the incubation media. Polymyxin B, an inhibitor of Ca2+- and phospholipid-dependent phosphorylation, and 12-O-tetradecanoylphorbol 13-acetate, the phorbol ester enhancing Ca2+- and phospholipid-dependent phosphorylation, had no effect on the phosphorylation of the 77 kDa protein. The 77 kDa phosphoprotein was identified as a protein previously named synapsin I [Ueda, Maeno & Greengard (1973) J. Biol. Chem 248, 8295-8305] on the basis of similar migration of native and proteolytic fragments of the 77 kDa protein with those of authentic synapsin I on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. Whereas several studies with cell-free preparations showed that 57 kDa and 54 kDa endogenous phosphoproteins were the most prominent species phosphorylated in a Ca2+ and calmodulin-dependent manner, these results indicate that synapsin is the most prominent Ca2+-and calmodulin-dependent phosphorylation in intact cells. The phosphorylations of 54 kDa and 57 kDa proteins may not be as important in vivo, but instead occur as a result of the disruption of cellular integrity inherent in preparation of cell-free subfractions of brain tissue.


An evaluation of the pharmacodynamics and pharmacokinetics of nicardipine combined with enalapril in essential hypertension.
Recent observations suggest that calcium antagonists may enhance the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors. Twelve essential hypertensives who had blood pressures greater than 160/90 after a minimum of 6 weeks of monotherapy with the ACE inhibitor enalapril 20 mg daily received additional treatment with nicardipine 30 mg t.i.d. and placebo, each for 2 weeks, in a double-blind crossover study. The combination of nicardipine with enalapril was well tolerated. The addition of the first dose of nicardipine was associated with significant reductions (p less than 0.05) in blood pressure during the first 4 h: from a baseline of 165/99 to 128/80 (supine) at 2 h after nicardipine as compared with 167/101-146/90 following placebo. Two weeks of combined treatment with nicardipine and enalapril significantly reduced the predosing blood pressure, 12 h after the last dose of nicardipine (158/96 as compared with 172/106 with placebo), and there were further significant reductions in blood pressure during the subsequent dosage interval. The profile of plasma ACE inhibition and the pharmacokinetics of enalaprilat were unaffected by the addition of nicardipine. These results suggest that nicardipine and enalapril are an effective and well-tolerated antihypertensive combination.


A new molecular mechanism underlying the EGCG-mediated autophagic modulation of AFP in HepG2 cells.
Epigallocatechingallate (EGCG) is a major bioactive component of green tea and is associated with health benefits against multiple diseases including cancer. As an indicator of hepatocellular carcinoma (HCC), high levels of α-fetal protein (AFP) are related to malignant differentiation and poor prognosis of cancer cells. In this study, EGCG can effectively reduce AFP secretion and simultaneously induce AFP aggregation in human HCC HepG2 cells. EGCG-stimulated autophagy induces the degradation of AFP aggregates in HepG2 cells. Furthermore, we thoroughly studied the underlying molecular mechanisms behind EGCG-stimulated autophagy by using large-scale all-atom molecular dynamics simulations, which revealed a novel molecular mechanism. EGCG directly interacts with LC3-I protein, readily exposing the pivotal Gly-120 site of the latter to other important binding partners such as 1,2-distearoyl-sn-glycero-3-phosphoethanolamine and promoting the synthesis of LC3-II, a characteristic autophagosomal marker. Our results suggest that EGCG is critical in regulating AFP secretion and in modulating autophagic activities of HepG2 cells, providing a molecular basis for potentially preventing and treating HCC.


Reconstruction of blood propagation in three-dimensional rotational X-ray angiography (3D-RA).
This paper presents a framework of non-interactive algorithms for the mapping of blood flow information to vessels in 3D-RA images. With the presented method, mapping of flow information to 3D-RA images is done automatically without user interaction. So far, radiologists had to perform this task by extensive image comparisons and did not obtain visualizations of the results. In our approach, flow information is reconstructed by forward projection of vessel pieces in a 3D-RA image to a two-dimensional projection series capturing the propagation of a short additional contrast agent bolus. For accurate 2D-3D image registration, an efficient patient motion compensation technique is introduced. As an exemplary flow-related quantity, bolus arrival times are reconstructed for the vessel pieces by matching of intensity-time curves. A plausibility check framework was developed which handles projection ambiguities and corrects for noisy flow reconstruction results. It is based on a linear programming approach to model the feeding structure of the vessel. The flow reconstruction method was applied to 12 cases of cerebral stenoses, AVMs and aneurysms, and it proved to be feasible in the clinical environment. The propagation of the injected contrast agent was reconstructed and visualized in three-dimensional images. The flow reconstruction method was able to visualize different types of useful information. In cases of stenosis of the middle cerebral artery (MCA), flow reconstruction can reveal impeded blood flow depending on the severeness of the stenosis. With cases of AVMs, flow reconstruction can clarify the feeding structure. The presented methods handle the problems imposed by clinical demands such as non-interactive algorithms, patient motion compensation, short reconstruction times, and technical requirements such as correction of noisy bolus arrival times and handling of overlapping vessel pieces. Problems occurred mainly in the reconstruction and segmentation of 3D-RA images in cases of complex AVMs. The concentration of injected contrast agent was often not sufficient to provide highly contrasted vessels in 3D-RA images. Another segmentation-related problem is known as 'kissing vessels' [19]. Kissing vessel artifacts introduce artificial vessel junctions and thereby distort the feeding structure of the vessel. This may finally cause implausible flow reconstruction results and inverse flow directions in vessel segments. We are currently planning to validate our reconstruction results using particle imaging velocimetry (PIV). PIV experiments with phantoms, for which the true flow parameters are known, will allow for the assessment of the accuracy of our contrast agent based method. In the context of computational fluid dynamics techniques, the potential of the presented flow reconstruction method is high. Flow reconstruction results based on the presented method could be used both as boundary conditions for simulations and as a reference for the validation of simulation results. Computational fluid dynamics provide useful information such as arterial wall shear stress and complex flow patterns in aneurysms.


Heart-rate variability indices as predictors of the response to vagus nerve stimulation in patients with drug-resistant epilepsy.
To assess heart-rate variability (HRV) measures of interictal electrocardiography (ECG) for drug-resistant epilepsy and to relate the findings to the outcome of vagus nerve stimulation (VNS) treatment. Time-domain, frequency-domain, and nonlinear analyses were used to analyze preoperative HRV measures in 32 patients with drug-resistant epilepsy who had received VNS implants at the same hospital and 32 healthy age- and sex-matched control subjects. HRV measurements based on ambulatory 24 h ECG recordings were analyzed to identify seizure reduction 1 year after VNS treatment. Responders were defined as having at least 50% seizure reduction 1 year after treatment. Patients with drug-resistant epilepsy had significantly lower time domain (SDNN, RMSSD, pNN50), frequency domain (VLF, LF, HF, TP), and nonlinear (SD1, SD2) HRV measurements than matched healthy controls. None of the analyzed HRV measures of the responders differed significantly from their controls, whereas those of the nonresponders had significantly lower RMSSD, pNN50, HF, and SD1 than the responders. The preoperative HRV indices demonstrate that nonresponders have more pronounced impairment of their cardiac autonomic function than the responders. Presurgical HRV measurements representing parasympathetic cardiac control or vagal tone were significantly associated with the responsiveness to VNS. Thus the measurements show promise for predicting the reduction of seizure frequency after VNS treatment.


A survey of epidermolysis bullosa care in the United States and Canada.
Epidermolysis bullosa (EB) is a group of rare, inherited, blistering diseases that typically present in infancy. EB is not curable, and treatment is entirely supportive. There is a paucity of standardized recommendations to guide management. To assess the current state of EB care, an original online survey was conducted targeting attending physicians experienced with the care of EB. Members of the Society for Pediatric Dermatology residing in the United States and Canada served as the source pool. Parameters assessed included clinic visits, availability of subspecialists, and performance of surveillance studies. Fifty-six completed surveys were analyzed. Most providers saw between 1 and 10 individuals with EB per year in a general dermatology clinic. For each EB type there was considerable variation in the frequency of clinic visits, availability and use of specialists, and use of laboratory and imaging studies. Some agreement was observed in the frequency of follow-up for infants with more severe EB types, as well as for the components of a history, physical, and routine laboratory studies. These findings describe variations in the current state of EB care that pediatric dermatologists provide. The development and acceptance of evidence-based guidelines and outcome measures may lead to greater uniformity in EB care.


F-actin regulates the polarized secretion of pollen tube attractants in Arabidopsis synergid cells.
Pollen tube attraction is a key event of sexual reproduction in flowering plants. In the ovule, two synergid cells neighboring the egg cell control pollen tube arrival via the active secretion of attractant peptides such as AtLURE1 and XIUQIU from the filiform apparatus (FA) facing toward the micropyle. Distinctive cell polarity together with longitudinal F-actin and microtubules are hallmarks of the synergid cell in various species, though the functions of these cellular structures are unclear. In this study, we used genetic and pharmacological approaches to indicate the roles of cytoskeletal components in FA formation and pollen tube guidance in Arabidopsis thaliana. Genetic inhibition of microtubule formation reduced invaginations of the plasma membrane but did not abolish micropylar AtLURE1.2 accumulation. By contrast, the expression of a dominant-negative form of ACTIN8 induced disorganization of the FA and loss of polar AtLURE1.2 distribution toward the FA. Interestingly, after pollen tube reception, F-actin became unclear for a few hours in the persistent synergid cell, which may be involved in pausing and resuming pollen tube attraction during early polytubey block. Our data suggest that F-actin plays a central role in maintaining cell polarity and in mediating male-female communication in the synergid cell.


The Design of the RAND Health Insurance Experiment: A Retrospective.
This article, prepared as part of a special issue on multiarmed experiments, describes the design of the RAND Health Insurance Experiment, paying particular attention to the choice of arms. It also describes how the results of the Experiment were used in a simulation model and, looking back, how the design might have differed, and how the results apply today, 4 decades after the Experiment was conducted.


Linguistic generalization on the basis of function and constraints on the basis of statistical preemption.
How do people learn to use language in creative but constrained ways? Experiment 1 investigates linguistic creativity by exposing adult participants to two novel word order constructions that differ in terms of their semantics: One construction exclusively describes actions that have a strong effect; the other construction describes actions with a weaker but otherwise similar effect. One group of participants witnessed novel verbs only appearing in one construction or the other, while another group witnessed a minority of verbs alternating between constructions. Subsequent production and judgment results demonstrate that participants in both conditions extended and accepted verbs in whichever construction best described the intended message. Unlike related previous work, this finding is not naturally attributable to prior knowledge of the likely division of labor between verbs and constructions or to a difference in cue validity. In order to investigate how speakers learn to constrain generalizations, Experiment 2 includes one verb (out of 6) that was witnessed in a single construction to describe both strong and weak effects, essentially statistically preempting the use of the other construction. In this case, participants were much more lexically conservative with this verb and other verbs, while they nonetheless displayed an appreciation of the distinct semantics of the constructions with new novel verbs. Results indicate that the need to better express an intended message encourages generalization, while statistical preemption constrains generalization by providing evidence that verbs are restricted in their distribution.


FcgammaRIIa polymorphism in Japanese patients with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an immune complex-mediated disease and organ damage is caused by the deposition of immune complex. Receptors which recognize the Fc portion of immunoglobulin G (FcgammaR) play a key role in the phagocytosis of immune complexes. As the gene encoding for FcgammaR of class IIa (FcgammaRIIa) has two allelic forms, H131 and R131, which differ in their affinity to IgG2, this polymorphism might have implications in handling immune complex. We studied the distribution of the FcgammaRIIa polymorphism in 90 Japanese patients with SLE. We also examined the association between FcgammaRIIa polymorphism and the disease activity of SLE and the histopathological findings of lupus nephritis. FcgammaRIIa polymorphism was determined by PCR and dot blot analysis. The allelic frequency of H131 in patients with SLE was significantly lower (H131/R131 = 0.44/0.56) than that of normal controls (H131/R131 = 0.62/0.38; P < 0.05). No significant association was observed between FcgammaRIIa polymorphism and the clinical parameters for the activity of SLE. There was no association between FcgammaRIIa polymorphism and the histological findings in lupus nephritis. The difference in the distribution of FcgammaRIIa alleles between patients with SLE and normal subjects indicates that this polymorphism is a candidate of susceptibility gene for SLE in Japanese.


Clinical haematology and biochemistry profiles of cattle naturally infected with Theileria orientalis Ikeda type in New Zealand.
To present the haematology and biochemistry profiles for cattle in New Zealand naturally infected with Theileria orientalis Ikeda type and investigate if the results differed between adult dairy cattle and calves aged <6 months. Haematology and biochemistry results were obtained from blood samples from cattle which tested positive for T. orientalis Ikeda type by PCR, that were submitted to veterinary laboratories in New Zealand between October 2012 and November 2014. Data sets for haematology and biochemistry results were prepared for adult dairy cattle (n=62 and 28, respectively) and calves aged <6 months (n=62 and 28, respectively), which were matched on the basis of individual haematocrit (HCT). Results were compared between age groups when categorised by HCT. Selected variables were plotted against individual HCT, and locally weighted scatterplot smoothing (Loess) curves were fitted to the data for adult dairy cattle and calves <6 months old. When categorised by HCT, the proportion of samples with HCT <0.15 L/L (severe anaemia) was greater for adult dairy cattle than for beef or dairy calves, for both haematology (p<0.002) and biochemistry (p<0.001) submissions. There were differences (p<0.05) between adult dairy cattle and calves aged <6 months in the relationships between HCT and red blood cell counts, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentrations, lymphocyte and eosinophil counts, and activities of glutamate dehydrogenase and aspartate aminotransferase. In both age groups anisocytosis was frequently recorded. The proportion of blood smears showing mild and moderate macrocytosis was greater in adults than calves (p=0.01), and mild and moderate poikilocytosis was greater in calves than adults (p=0.005). The haematology and biochemistry changes observed in cattle infected with T. orientalis Ikeda type were consistent with extravascular haemolytic anaemia. Adult dairy cattle were more likely to be severely anaemic than calves. There were differences in haematology and biochemistry profiles between adult dairy cattle and calves, but most of these differences likely had a physiological rather than pathological basis. Overall, the haematological changes in calves aged <6 months appeared less severe than in adult dairy cattle.


One-Year Clinical Success of Embrace Hydrophilic and Helioseal-F Hydrophobic Sealants in Permanent First Molars: A Clinical Trial.
This study sought to compare the one-year clinical success of a hydrophilic and a hydrophobic fissure sealant in permanent first molars. This split-mouth clinical trial was conducted on 23 six to nine year olds who had four fully erupted sound first molars. Helioseal-F and Embrace sealants were randomly applied on the first molars, and follow-ups were scheduled at three, six and 12 months to examine the teeth according to USPHS criteria (retention, marginal adaptation, color match, surface smoothness and caries recurrence). The Wilcoxon signed rank test, the Friedman test and the Mann Whitney test were applied for statistical analyses (P<0.05). No significant differences were noted between Embrace and Helioseal-F in retention, smoothness of surface, marginal adaptation, color match or caries at three, six or 12 months (all P>0.05). In addition, the retention of sealants between the maxilla and mandible was not significantly different (P>0.05). Friedman test revealed no significant difference in any of the five parameters at different time points in any sealant group (P>0.05). Embrace hydrophilic and Helioseal-F hydrophobic sealants have the same one-year clinical success rate.


Ultradian oscillations in Notch signaling regulate dynamic biological events.
Notch signaling regulates many dynamic processes; accordingly, expression of genes in this pathway is also dynamic. In mouse embryos, one dynamic process regulated by Notch is somite segmentation, which occurs with a 2-h periodicity. This periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic expression of the Notch effector gene Hes7. Loss of Hes7 expression and sustained expression of Hes7 result in identical and severe somite defects, suggesting that Hes7 oscillation is required for proper somite segmentation. Mathematical models of this oscillator have been used to generate and test hypothesis, helping to uncover the role of negative feedback in regulating the oscillator. Oscillations of another Notch effector gene, Hes1, plays an important role in maintenance of neural stem cells. Hes1 expression oscillates with a period of about 2-3h in neural stem cells, whereas sustained Hes1 expression inhibits proliferation and differentiation of these cells, suggesting that Hes1 oscillations are important for their proper activities. Hes1 inhibits its own expression as well as the expression of the proneural gene Neurogenin2 and the Notch ligand Delta1, driving oscillations of these two genes. Delta1 oscillations in turn maintain neural stem cells by mutual activation of Notch signaling, which re-activates Hes1 to close the cycle. Hes1 expression also oscillates in embryonic stem (ES) cells. Cells expressing low and high levels of Hes1 tend to differentiate into neural and mesodermal cells, respectively. Furthermore, Hes1-null ES cells display early and uniform neural differentiation, indicating that Hes1 oscillations act to promote multipotency by generating heterogeneity in both the differentiation timing and the fate choice. Taken together, these results suggest that Notch signaling can drive short-period oscillatory expression of Hes7 and Hes1 (ultradian oscillation) and that ultradian oscillations are important for many biological events.


Synthesis, X-ray structure and in vitro cytotoxicity studies of Cu(I/II) complexes of thiosemicarbazone: special emphasis on their interactions with DNA.
4-(p-X-phenyl)thiosemicarbazone of napthaldehyde {where X = Cl (HL¹) and X = Br (HL²)}, thiosemicarbazone of quinoline-2-carbaldehyde (HL³) and 4-(p-fluorophenyl)thiosemicarbazone of salicylaldehyde (H₂L⁴) and their copper(I) {[Cu(HL¹)(PPh₃)₂Br]·CH₃CN (1) and [Cu(HL²)(PPh₃)₂Cl]·DMSO (2)} and copper(II) {[(Cu₂L³₂Cl)₂(μ-Cl)₂]·2H₂O (3) and [Cu(L⁴)(Py)] (4)} complexes are reported herein. The synthesized ligands and their copper complexes were successfully characterized by elemental analysis, cyclic voltammetry, NMR, ESI-MS, IR and UV-Vis spectroscopy. Molecular structures of all the Cu(I) and Cu(II) complexes have been determined by X-ray crystallography. All the complexes (1-4) were tested for their ability to exhibit DNA-binding and -cleavage activity. The complexes effectively interact with CT-DNA possibly by groove binding mode, with binding constants ranging from 10⁴ to 10⁵ M⁻¹. Among the complexes, 3 shows the highest chemical (60%) as well as photo-induced (80%) DNA cleavage activity against pUC19 DNA. Finally, the in vitro antiproliferative activity of all the complexes was assayed against the HeLa cell line. Some of the complexes have proved to be as active as the clinical referred drugs, and the greater potency of 3 may be correlated with its aqueous solubility and the presence of the quinonoidal group in the thiosemicarbazone ligand coordinated to the metal.


Comparative in-vitro activity of new quinolones against clinical isolates and resistant mutants.
The in-vitro activity of five new fluoroquinolones, WIN 57273, sparfloxacin, fleroxacin, temafloxacin and ciprofloxacin was determined against 543 recent clinical isolates and eight quinolone resistant strains derived by mutation and their five parent strains. WIN 57273 was the most active compound against Gram-positive bacteria, sparfloxacin had a broad spectrum which was similar to that of ciprofloxacin. Ciprofloxacin showed the greatest activity against Gram-negative bacteria. Temafloxacin showing some activity against Gram-positive organisms and Acinetobacter spp. Fleroxacin was the least active compound studied. Compared to wild type parent strains, the mutated strains produced the following results. In Enterobacter cloacae OmpF deficiency increased the MICs of all quinolones by 8-32-fold. In Pseudomonas aeruginosa OmpF deficiency had a limited effect, Omp D2 deficiency combined with an increased lipopolysaccharide content produced greater resistance, i.e. 4-16-fold; mutations in gyrase were associated with variously increased MICs, depending on the strain and compound tested.


Recurrence of COVID-19 Documented with RT-PCR.
We present a case of coronavirus disease 2019 (COVİD-19) re-infection where the time interval between two COVİD-positive episodes is the longest in the literature. A 40-year male patient was admitted to the Emergency Department with complaints of sore throat, cough and diarrhea; and was re-diagnosed as COVİD-19 positive after a virus-free period. He did not have a chronic disease in his anamnesis and used no medication. After COVİD-19 infection and a long recovery period, he became COVİD-19 positive again. In this case, the time to second COVİD-19 infection was 94 days from the first positive PCR test and 86 days from the complete resolution of symptoms. This is one of the longest COVID-19-free period between two episodes of infection in the literature. Key Words: COVID-19, Recurrence, Re-infection, Recovery.


Longitudinal change in CDC42 in psoriasis: correlation with disease activity and treatment response.
Objective: To investigate longitudinal CDC42 change and its correlation with disease activity and treatment response in patients with psoriasis. Methods: This prospective study detected serum CDC42 at months (M) 0, M1, M3 and M6 in 150 patients with psoriasis with current initiation of topical therapy/phototherapy/systemic therapy. Results: CDC42 was positively related to systemic biologic treatment history (p = 0.025) but negatively associated with psoriatic area (p = 0.010) and Psoriasis Area Severity Index (PASI; p < 0.001). CDC42 continuously elevated from M0 to M6 (p < 0.001). CDC42 at M1/M3/M6 was enhanced in patients with current systemic biologic therapy and PASI 75 or 90 response at M6 versus those without (all p < 0.050). Conclusion: Increased serum CDC42 level reflects reduced disease severity and better treatment response in patients with psoriasis.


Anaerobic bacteria from the large intestine of mice.
Anaerobic bacteria from the colon of laboratory mice were enumerated and isolated using strict anaerobic techniques. Direct microscopic counts revealed 4.4 X 10(10) organisms in each gram (wet weight) of colon contents. Actual cultural counts averaged 3.2 X 10(10) organisms, which was 73% of the direct microscopic count. The tentatively identified genera were Bacteroides, Eubacterium, Fusobacterium, Lactobacillus, Peptostreptococcus, and Propionibacterium. Strains of Fusobacterium, Lactobacillus, Peptostreptococcus, and Propionibacterium were biochemically homogeneous. Strains of Bacteroides and Eubacterium, on the other hand, were biochemically heterogeneous and were subdivided into several distinct groups. The data indicate that many of the isolates are different from previously described species of the respective genera and may belong to new species.


API ionic liquids: probing the effect of counterion structure on physical form and lipid solubility.
Lipid based formulations (LBFs) are extensively utilised as an enabling technology in drug delivery. The use of ionic liquids (ILs) or lipophilic salts (LS) in drug delivery has also garnered considerable interest due to unique solubility properties. Conversion of active pharmaceutical ingredients (API) to ILs by pairing with an appropriately lipophilic counterion has been shown to decrease melting point of the salt complex and improve solubility in LBFs. However, the relationship between the structure of the counterion, the physicochemical properties of the resulting salts and solubility in LBFs has not been systematically explored. This study investigates the relationship between alkyl sulfate counterion structure and melting temperature (T m or T g) in addition to LBF solubility, utilizing cinnarizine and lumefantrine as model weakly basic APIs. Three series of structurally diverse alkyl sulfate counterions were chosen to probe this relationship. Pairing cinnarizine and lumefantrine with a majority of these alkyl sulfate counterions resulted in a reduction in melting temperature and enhanced solubility in model medium chain and long chain LBFs. The chain length of the alkyl sulfate plays a crucial role in performance, and consistently branched alkyl sulfate counterions perform better than straight chain alkyl sulfate counterions, as predicted. Most interestingly, trends in counterion performance were found to be consistent across two APIs with disparate chemical structures. The findings from this study will facilitate the design of counterions which enhance solubility of ionisable drugs and unlock the potential to develop compounds previously restrained by poor solubility.


Serum and urinary biochemical markers for knee and hip-osteoarthritis: a systematic review applying the consensus BIPED criteria.
Molecules that are released into biological fluids during matrix metabolism of articular cartilage, subchondral bone, and synovial tissue could serve as biochemical markers of the process of osteoarthritis (OA). Unfortunately, actual breakthroughs in the biochemical OA marker field are limited so far. By reviewing the status of commercially available biochemical OA markers according to the "Burden of disease, Investigative, Prognostic, Efficacy of intervention, and Diagnostic" ("BIPED") classification, future use of this "BIPED" classification is encouraged and more efficient biochemical OA marker research stimulated. Three electronic databases [PubMed, Scopus, EMBASE (1997-May 2009)] were searched for publications on blood and urinary biochemical markers in human primary knee and hip-OA. Stepwise selection of original English publications describing human studies on blood or urinary biochemical markers in primary knee or hip-OA was performed. Selected articles were fully read to determine whether biochemical markers were investigated on performance within any of the "BIPED" categories. Eighty-four relevant publications were identified. Data from relevant publications were tabulated according to the "BIPED" classification. Individual analyses within a publication were summarized in general "BIPED" scores. An uneven distribution of scores on biochemical marker performance and heterogeneity among the publications complicated direct comparison of individual biochemical markers. Comparison of categories of biochemical markers was therefore performed instead. In general, biochemical markers of cartilage degradation were investigated most extensively and performed well in comparison with other categories of biochemical markers. Biochemical markers of bone metabolism performed less adequately. Biochemical markers of synovial tissue metabolism were not investigated extensively, but performed quite well. Specific biochemical markers and categories of biochemical markers as well as their nature, origin and metabolism, need further investigation. International standardization of future investigations should be pursued to obtain more high-quality, homogenous data on the full spectrum of biochemical OA markers.


Association of Depression and Post-Traumatic Stress with Polyvictimization and Emotional Transgender and Gender Diverse Community Connection Among Black and Latinx Transgender Women.
Purpose: This study examines the relationship between polyvictimization, emotional transgender and gender diverse community connection (eTCC), and symptoms of depression and post-traumatic stress disorder (PTSD) among Black and Latinx transgender women in Baltimore, MD, and Washington, DC. Methods: A purposive sample (N = 197) completed surveys containing a 15-item Polyvictimization Inventory (encompassing sexual violence, physical violence, and threats of violence) and screeners for lifetime symptoms of PTSD and past 2-week symptoms of depression. Data were analyzed using linear regression modeling. Results: Most participants (91.4%) experienced at least one form of violence and 86.8% experienced multiple forms. The model including polyvictimization, age, and city explained 8% of the variance in depressive symptoms [F(2, 193) = 6.58, p < 0.001] and 15% of the variance in PTSD symptoms [F(2, 193) = 12.78, p < 0.001]. In separate models, polyvictimization was positively associated with symptoms of depression [b(SEb) = 0.08 (0.03), p < 0.01], and PTSD [b(SEb) = 0.13 (0.02), p < 0.001], controlling for age and city. eTCC was not significantly associated with polyvictimization or symptoms of PTSD and depression, and did not moderate the relationship between polyvictimization and symptoms. Conclusion: These findings highlight a high prevalence of violence experienced by participants and support the association between polyvictimization and poor mental health-consistent with the existing literature. Service providers who work with Black and Latinx transgender women should assess for polyvictimization as part of their routine mental health risk assessments to develop person-centered mental health interventions. Further inquiry is needed to identify factors that modify the relationship between polyvictimization and mental health, providing information to guide the development and timing of effective interventions.


Warning signals evolve to disengage Batesian mimics.
Prey that are unprofitable to attack are typically conspicuous in appearance. Conventional theory assumes that these warning signals have evolved in response to predator receiver biases. However, such biases might be a symptom rather than a cause of warning signals. We therefore examine an alternative theory: that conspicuousness evolves in unprofitable prey to avoid confusion with profitable prey. One might wonder why unprofitable prey do not find a cryptic means to be distinct from profitable prey, reducing both their risk of confusion with profitable prey and their rate of detection by predators. Here we present the first coevolutionary model to allow for Batesian mimicry and signals with different levels of detectability. We find that unprofitable prey do indeed evolve ways of distinguishing themselves using cryptic signals, particularly when appearance traits can evolve in multiple dimensions. However, conspicuous warning signals readily evolve in unprofitable prey when there are more ways to look different from the background than to match it. Moreover, the more unprofitable the prey species, the higher its evolved conspicuousness. Our results provide strong support for the argument that unprofitable species evolve conspicuous signals to avoid confusion with profitable prey and indicate that peak shift in conspicuousness-linked traits is a major factor in its establishment.


Beneficial and detrimental effects of intensive glycaemic control, with emphasis on type 2 diabetes mellitus.
Diabetes mellitus is a major health problem in the world. Several clinical trials have shown that some of the major complications of diabetes mellitus can be partially prevented or delayed by intensive glycaemic control. However, there are benefits and risks in aiming for near normal blood glucose levels. Intensive glycaemic control delays the onset and progression of retinopathy, nephropathy and neuropathy. Epidemiological and observational studies have shown that cardiovascular events may be correlated with the severity and duration of diabetes mellitus, but major randomised trials have only shown weak and nonsignificant benefits of intensive glycaemic management in decreasing event rates. A modest improvement in lipid profile results from blood glucose control although, in the majority of cases, not enough to reach current targets. Detrimental effects of intensive glycaemic control include bodyweight gain and hypoglycaemia. Controversial issues in the management of patients with diabetes mellitus include the unproven increase in cardiovascular morbidity from sulphonylureas and hyperinsulinaemia, and the still unknown long term effects of newer oral antihyperglycaemic agents alone or in combination with traditional therapies (such as sulphonylureas and metformin). It is important to individualise management in setting glycaemic goals. Control of cardiovascular risk factors through blood pressure and lipid control and treatment with aspirin (acetylsalicylic acid) and ACE inhibitors have consistently shown benefits in the prevention of both macro- and microvascular complications in patients with diabetes mellitus; these measures deserve priority.


Differential modulation of zinc-stimulated p21(Cip/WAF1) and cyclin D1 induction by inhibition of PI3 kinase in HT-29 colorectal cancer cells.
Activation of the extra cellular signal regulated kinase (ERK) pathway is involved in both proliferation and growth arrest of cells depending on intensity and duration of stimuli. In this study, we have elucidated differential regulation of the zinc-stimulated p21(CiP/WAF1) and cyclin D1 activation by inhibition of phosphoinositide 3-kinase (PI3K). In HT-29 colorectal cancer cells, the ERK activities were increased by zinc, which was accompanied by the induction of p21(Cip/WAF1) and cyclin D1. However, in the HT-29 cells pre-treated with PI3K inhibitor, LY294002, zinc induced further the p21(CiP/WAF) induction whereas abrogated cyclin D1 induction. In addition, the induction of p21(Cip/WAF1) expression completely inhibited the incorporation of bromodeoxyuridine (BrdU) into the nucleus, indicating that p21(CiP/WAF1) is an important indicator for ERK-dependent growth arrest. These studies suggest presence of an inter-related regulatory mechanism of cell proliferation by ERK and PI3K pathways.


ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.
The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation. The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs, whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks. Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.


Multiresolution imaging in elastography.
The range of strains that can be imaged by any practical elastographic imaging system is inherently limited, and a performance measure is valuable to evaluate these systems from the signal and noise properties of their output images. Such a measure was previously formulated for systems employing cross-correlation based time-delay estimators through the strain filter. While the strain filter predicts the signal-to-noise ratio (SNR(e)) for each tissue strain in the elastogram and provides valuable insights into the nature of image noise, it understated the effects of image resolution (axial resolution, as determined by the cross-correlation window length) on the noise. In this work, the strain filter is modified to study the strain noise at multiple resolutions. The effects of finite window length on signal decorrelation and on the variance of the strain estimator are investigated. Long-duration windows are preferred for improved sensitivity, dynamic range, and SNR(e). However, in this limit the elastogram is degraded due to poor resolution. The results indicate that for nonzero strain, a window length exists at which the variance of strain estimator attains its minima, and consequently the elastographic sensitivity, dynamic range and SNR(e) are strongly affected by the selected window length. Simulation results corroborate the theoretical results, illustrating the presence of a window length where the strain estimation variance is minimized for a given strain value. Multiresolution elastography, where the strain estimate with the highest SNR(e) obtained by processing the pre- and post-compression waveforms at different window lengths is used to generate a composite elastogram and is proposed to improve elastograms. All the objective elastogram parameters (namely: SNR(e), dynamic range, sensitivity and the average elastographic resolution-defined as the cross-correlation window length) are improved with multiresolution elastography when compared to the traditional method of utilizing a single window length to generate the elastogram. Experimental results using a phantom with a hard inclusion illustrates the improvement in elastogram obtained using multiresolution analysis.


Five-Year Experience with Fifth-to-Seventh Nerve Transfer for Smile.
Masseteric- or deep temporal-to-facial nerve transfer (five-to-seven nerve transfer) is increasingly used in facial reanimation; however, the indications and clinical variables affecting outcomes for five-to-seven nerve transfer have not been defined. The authors describe their early experience with five-to-seven nerve transfer, reporting function and patient-reported outcomes, to identify potential parameters that are predictive of outcome. The authors conducted a retrospective chart review of all patients who underwent five-to-seven nerve transfer for smile reanimation from 2012 to 2017. Age, sex, cause of facial paralysis, onset and duration of paralysis, history of adjuvant chemotherapy and/or radiation therapy, donor nerve used, adjunctive procedures, and final excursion were recorded. Standard photographs and videos, and data regarding clinical facial nerve function and patient-reported quality of life, were obtained preoperatively and postoperatively. Sixty patients were identified. Forty-seven had flaccid facial paralysis and 13 had postparalysis facial palsy. Among flaccid facial paralysis patients, masseteric nerve transfer was successful in 30 patients (88 percent) and deep temporal nerve transfer was successful in three cases (60 percent). Among postparalysis facial palsy patients, five-to-seven nerve transfer was successful in two patients (20 percent). Average quality-of-life scores improved significantly from preoperatively (46) to postoperatively (59) among flaccid facial paralysis patients with successful five-to-seven nerve transfer. Five-to-seven nerve transfer is a viable option in facial reanimation. Shorter denervation times and preoperative flaccidity are favorable predictors of outcome. Five-to-seven nerve transfer as an adjunct to primary repair appears highly effective for enhancing smile function. Five-to-seven nerve transfer results are not reliable in patients with postparalysis facial palsy. Therapeutic, IV.


Oleuropein prevents the progression of steatohepatitis to hepatic fibrosis induced by a high-fat diet in mice.
Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and inflammatory cell infiltration, which has been linked to peripheral insulin resistance and increased levels of triglycerides in the liver. The purposes of this study were to establish a mouse model of NASH by feeding mice a 60% high-fat diet (HFD) and to demonstrate the anti-fibrotic effects of oleuropein, which has been shown to have anti-oxidant and anti-inflammatory properties, in this HFD-induced mouse model of NASH. C57BL/6 mice were divided into three groups: a regular diet group (Chow), a HFD group and an oleuropein-supplemented HFD group (OSD), which was fed a 0.05% OSD for 6 months. The effects of oleuropein in this model were evaluated using biochemical, histological and molecular markers. The expression levels of alpha-smooth muscle actin (α-SMA)and collagen type I in the HFD and OSD groups were evaluated using real-time PCR and western blotting. The body weight, biochemical marker levels, nonalcoholic fatty liver disease activity score, homeostasis model of assessment-insulin resistance (HOMA-IR) and leptin levels observed in the HFD group at 9 and 12 months were higher than those observed in the Chow group. The HOMA-IR and leptin levels in the OSD group were decreased compared with the HFD group. In addition, α-SMA and collagen type I expression were decreased by oleuropein treatment. We established a NASH model induced by HFD and demonstrated that this model exhibits the histopathological features of NASH progressing to fibrosis. Our results suggest that oleuropein may be pharmacologically useful in preventing the progression of steatohepatitis and fibrosis and may be a promising agent for the treatment of NASH in humans.