A trans-acting factor that binds to a GT-motif in a phytochrome gene promoter.
The regulatory photoreceptor, phytochrome, controls the expression of numerous genes, including its own phyA genes, which are transcriptionally repressed in response to light. Functional analysis of a rice phyA gene promoter, by means of microprojectile-mediated gene transfer, indicates that a GT motif, GCGGTAATT, closely related to elements in the promoters of a number of other light-regulated genes, is critical for expression. Partial complementary DNA clones have been obtained for a rice nuclear protein, designated GT-2, that binds in a highly sequence-specific fashion to this motif. Mutational analysis shows that the paired G's are most crucial to binding. GT-2 has domains related to certain other transcription factors. Northern blot analysis shows that GT-2 messenger RNA levels decline in white light although red and far red light pulses are ineffective.


Molecular biology of circulatory shock. Part II. Expression of four groups of hepatic genes is enhanced after resuscitation from cardiogenic shock.
Despite an initially successful resuscitation from circulatory shock, multiple organ failure (MOF) develops in some patients. The marked biochemical alterations associated with shock and MOF include clinically important changes in gene expression, such as altered rates of albumin and procoagulant synthesis. To characterize the MOF-associated changes at the cellular level, sequential liver biopsies were obtained from a swine model of cardiogenic shock associated with MOF. Preshock and postresuscitation biopsies were used not only to create a complementary DNA (cDNA) library but also to screen, to confirm, and, in nine out of 12 cases, to specifically identify genes whose expression is enhanced at least fivefold after resuscitation. The twelve genes thus characterized can be separated according to function into distinct groups, including the acute-phase genes and the heat-shock genes. Expression of acute-phase genes is liver specific and is essential for systemic homeostasis; heat-shock gene expression is generic to all cells and important for intracellular homeostasis.


Herbicide-resistant weed management: focus on glyphosate.
This review focuses on proactive and reactive management of glyphosate-resistant (GR) weeds. Glyphosate resistance in weeds has evolved under recurrent glyphosate usage, with little or no diversity in weed management practices. The main herbicide strategy for proactively or reactively managing GR weeds is to supplement glyphosate with herbicides of alternative modes of action and with soil-residual activity. These herbicides can be applied in sequences or mixtures. Proactive or reactive GR weed management can be aided by crop cultivars with alternative single or stacked herbicide-resistance traits, which will become increasingly available to growers in the future. Many growers with GR weeds continue to use glyphosate because of its economical broad-spectrum weed control. Government farm policies, pesticide regulatory policies and industry actions should encourage growers to adopt a more proactive approach to GR weed management by providing the best information and training on management practices, information on the benefits of proactive management and voluntary incentives, as appropriate. Results from recent surveys in the United States indicate that such a change in grower attitudes may be occurring because of enhanced awareness of the benefits of proactive management and the relative cost of the reactive management of GR weeds.


The prognostic significance of the triple negative phenotype in endometrial cancer.
To determine if the triple negative phenotype (TNP) has prognostic significance in endometrial cancer with respect to various surgicopathologic outcomes and survival. A tissue microarray was constructed of 396 endometrial cancers from patients who underwent surgical staging at the Ohio State University Medical Center. Immunohistochemistry was used to test for estrogen receptor, progesterone receptor, and HER2 expression. Fluorescent in-situ hybridization (FISH) was also used to test for HER2 amplification. TNP negative patients served as controls. Pearson's chi-square was used to evaluate the association of the TNP with variables associated with a poor prognosis. Cox proportional hazards model was used to perform univariate and multivariate analyses. Progression free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier curves, and the log rank test was used to compare the groups. Twenty-seven percent of patients had the TNP. The TNP was associated with lymph node metastasis, myometrial invasion (>50%), high grade disease, non-endometrioid histology, and advanced staged disease (p<0.023 for lymph node metastasis and p<0.0001 for all others). The TNP was associated with a significantly worse survival, including a decreased PFS (p=0.009) and OS (p=0.01), but not in a fashion independent of other prognostic variables. The TNP is associated with advanced stage, high grade, and high risk histology, as well as poor survival. Continued investigation of the exploitation of this phenotype with targeted therapies is necessary.


Selective laparoscopic adhesiolysis in the management of acute and chronic recurrent adhesive bowel obstruction.
Laparoscopic adhesiolysis became popular in the last decade for the management of postoperative adhesive small bowel obstruction. This paper investigates the feasibility, effectiveness and safety of laparoscopy in this field; the details of a selective adhesiolysis were discussed as well. The patients who underwent laparoscopic management of acute or chronic recurrent adhesive bowel obstruction were included into the study. The patients were managed according to a specific algorithm. If the conservative management has failed, selective laparoscopic adhesiolysis to the transition zone of distended /collapsed bowel was performed. Patients, who were suffering from chronic recurrent obstruction attacks and those who tolerated oral intake, underwent preoperative enteroclysis studies and selective adhesiolysis was performed according to imaging findings. Computerized tomography was performed in all cases to exclude other diagnoses. Thirty-one patients (22 female, 9 male) underwent laparoscopic adhesiolysis from January 1998 to June 2007. The mean age was 48 (range: 20-80). Enteroclysis--guided laparoscopic adhesiolysis was performed in nineteen patients. Twelve patients underwent laparoscopic adhesiolysis for acute obstruction. Enteroclysis was able to demonstrate the pathological adhesion or band in all of the patents who underwent this imaging technique. Conversion and complication rates were 9.6%. The entire patients tolerated well oral intake postoperatively except one who had underwent enteroclysis-guided adhesiolysis; the patient presented with transient subileus on postoperative day 34 and responded well to conservative management. Mean hospital stay was 4.1 days (range: 2-7). The patients are free of symptoms on their follow-up. Laparoscopy is feasible, safe and effective in postoperative adhesive disease. Laparoscopic adhesiolysis should be performed as selective as possible in acute and chronic cases. Enteroclysis is a helpful imaging modality for performing selective laparoscopic adhesiolysis in chronic obstruction.


A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes.
Autoimmune-mediated destruction of pancreatic islet β cells results in type 1 diabetes (T1D). Serum islet autoantibodies usually develop in genetically susceptible individuals in early childhood before T1D onset, with multiple islet autoantibodies predicting diabetes development. However, most at-risk children remain islet-antibody negative, and no test currently identifies those likely to seroconvert. We sought a genomic signature predicting seroconversion risk by integrating longitudinal peripheral blood gene expression profiles collected in high-risk children included in the BABYDIET and DIPP cohorts, of whom 50 seroconverted. Subjects were followed for 10 years to determine time of seroconversion. Any cohort effect and the time of seroconversion were corrected to uncover genes differentially expressed (DE) in seroconverting children. Gene expression signatures associated with seroconversion were evident during the first year of life, with 67 DE genes identified in seroconverting children relative to those remaining antibody negative. These genes contribute to T cell-, DC-, and B cell-related immune responses. Near-birth expression of ADCY9, PTCH1, MEX3B, IL15RA, ZNF714, TENM1, and PLEKHA5, along with HLA risk score predicted seroconversion (AUC 0.85). The ubiquitin-proteasome pathway linked DE genes and T1D susceptibility genes. Therefore, a gene expression signature in infancy predicts risk of seroconversion. Ubiquitination may play a mechanistic role in diabetes progression.


Acquired dysfibrinogenemia secondary to mithramycin toxicity.
A 58-year-old black woman with IgD multiple myeloma developed a hemorrhagic diathesis within 48 hours after receiving mithramycin (20 micrograms/kg/day) for therapy of hypercalcemia. Her coagulation studies were characterized by prolonged prothrombin, partial thromboplastin, thrombin, and reptilase clotting times. Her plasma and partially purified fibrinogen were inhibitory to the clotting of normal plasma and fibrinogen. The patient's isolated fibrinogen showed a normal rate of fibrinopeptide release, but her fibrin monomer aggregation was markedly abnormal. These studies document the development of a dysfibrinogenemia secondary to mithramycin toxicity.


Associations between religiosity and sexual and contraceptive behaviors.
To determine associations between religiosity and female adolescents' sexual and contraceptive behaviors. We conducted a secondary analysis on data from a randomized controlled trial comparing interventions designed to prevent pregnancy and sexually transmitted diseases (STDs). Multivariable modeling assessed the association between a religiosity index consisting of items related to religious behaviors and impact of religious beliefs on decisions and sexual outcomes. 572 female adolescents aged 13 to 21, recruited via a hospital-based adolescent clinic and community-wide advertisements. Sexual experience, pregnancy, STDs, number of lifetime partners, frequency of sexual activity, previous contraceptive use, and planned contraceptive use. Mean participant age was 17.4 +/- 2.2 years and 68% had been sexually active. Most (74.1%) had a religious affiliation and over half (52.8%) reported that their religious beliefs impact their decision to have sex at least "somewhat." Multivariate analyses showed that, compared with those with low religiosity, those with high religiosity were less likely to have had sexual intercourse (OR = 0.23, 95% CI = 0.14, 0.39). Among sexually active participants, those with high religiosity were less likely to have been pregnant (OR = 0.46, 95% CI = 0.22, 0.97), to have had an STD (OR = 0.42, 95% CI = 0.22, 0.81), or to have had multiple (>or=4) lifetime partners (OR = 0.38, 95% CI = 0.21, 0.68) compared to those with low religiosity. Levels of religiosity were not significantly associated with frequency of intercourse, contraception use at last intercourse, or planned contraceptive use. In this cohort, religiosity appeared to be a protective factor rather than a risk factor with regard to sexual behavior and was not associated with contraception use.


Relation between QRS duration and atrial synchronicity in patients with systolic heart failure.
The association of QRS duration (QRSd) with ventricular dyssynchrony is well-known in systolic heart failure (HF). However, there are no data regarding the relationship between QRSd and atrial dyssynchrony in patients with HF. We aimed to investigate the association of QRSd with intra-atrial and inter-atrial dyssynchrony in patients with systolic HF by using color tissue Doppler imaging (TDI). The study consisted of 70 systolic HF patients and 35 healthy controls. According to QRSd, HF patients were categorized into 2 subgroups as narrow QRS (n = 35) and wide QRS (n = 35) groups. Time intervals between the onset of P-wave and the onset of A-wave on color TDI from the right atrium (P-RA), inter-atrial septum (P-IAS) and left atrium (P-LA) were measured. Atrial dyssynchrony was defined as differences between P-RA and P-IAS (RA dyssynchrony), between P-LA and P-IAS (LA dyssynchrony) and between P-RA and P-LA (inter-atrial dyssynchrony). In patients with either HF groups, we observed significant impairment in intra-atrial and inter-atrial synchronicity compared with the controls (P < 0.001). Moreover, LA, RA and inter-atrial synchrony were found to be significantly impaired in the wide QRS group compared to narrow QRS group. There was also a positive and strong correlation between atrial and ventricular dyssynchrony parameters. In stepwise multivariate analysis, QRSd was found to be the independent predictor of intra-atrial and inter-atrial dyssynchrony in systolic HF. Among patients with systolic HF, prolonged QRSd is associated with impaired intra-atrial and inter-atrial synchrony. Atrial and ventricular dyssynchrony parameters were well-correlated with each other.


MR Imaging Characteristics of Primary T-Cell Lymphoma of the Cauda Equina: A Case Report and Literature Review.
Primary central nervous system lymphoma is a rare form of extranodal non-Hodgkin lymphoma, and primary T-cell lymphoma of the cauda equina is extremely rare. We describe a case involving a 56-year-old female who presented with low back pain and radiating leg pain for 4 months. MRI of the lumbar spine revealed an elongated, multinodular intradural lesion of approximately 10 cm from the L4 body to the S2 body level with iso-signal intensity on T1-weighted imaging, heterogeneous iso- and high-signal intensity on T2-weighted imaging, and a heterogeneous intense enhancement on gadolinium contrast-enhanced T1-weighted imaging. A peripheral T-cell lymphoma of the cauda equina was diagnosed on the basis of immunohistochemical and T-cell receptor gamma gene rearrangement analysis after intradural biopsy of the mass.


Robotic total pelvic exenteration.
Pelvic exenteration is now becoming widely acceptable as a curative procedure rather than a palliative one. Performing these surgeries by minimally invasive techniques helps to improve the quality of life and decrease the morbidity of these extensive procedures. To demonstrate the feasibility of performing a total pelvic exenteration robotically, and to study the morbidity associated with such extensive surgery. A 35-year-old female with advanced cervical cancer presented with a vesicovaginal fistula and a rectovaginal fistula. In view of these, we performed a total robotic pelvic exenteration with colo-anal anastomosis and uretero-sigmoidostomy. The patient refused an ileal-loop conduit for urinary tract diversion due to social reasons associated with a stoma. The total operative time was 240 min and the console time was 120 min. The estimated blood loss was 300 ml and the intensive care unit stay was 2 days. Post-operatively, the patient had good faecal and urinary continence and good quality of life.


The multifunctional dopamine D2/D3 receptor agonists also possess inhibitory activity against the full-length tau441 protein aggregation.
Neurodegeneration leads to variety of diseases which are linked to aberrant protein or peptide aggregation, as a one possible mechanism. Hence, small drug molecules targeting aggregation are of interest. Tau protein aggregation is one of the biomarkers of neurodegenerative diseases and is a viable drug target. Toward multifunctional inhibitors, we aim to incorporate structural elements in a potential drug in order to preserve dopamine agonist activity, which elevates disease symptoms associated with motor skills, and promote inhibitory activity against aggregation of the full-length tau (2N4R, tau441) protein. In our design, we introduced various moieties (catechol, non-catechol, biphenyl, piperazine, and thiazole) to determine which functional group leads to the greatest aggregation inhibition of tau. In vitro, tau aggregation was induced by heparin and monitored by using fluorescence aggregation assay, transmission electron microscopy and 4,4'-Dianilino-1,1'-binaphthyl-5,5'-disulfonic acid dipotassium salt (Bis-ANS) fluorescence spectroscopy. The catechol containing compounds, D-519 and D-520, prevented aggregation of tau. By contrast, non-catechol and thiazole containing compounds (D-264 and D-636) were poor inhibitors. The Bis-ANS studies revealed that the potent inhibitors bound solvent-exposed hydrophobic sites. Based on the density functional theory calculations on inhibitors tested, the compounds characterized with the high polarity and polarizability were more effective aggregation inhibitors. These findings could lead to the development of small multifunctional drug inhibitors for the treatment of tau-associated neurodegeneration.


Defining Quality of Rheumatolgic Care: Argentina.
Health care system in Argentina is highly fragmented and disconnected. Argentina's health system is divided into 3 major nonintegrated subsystems as follows: public subsystem, financed through taxes; the social security subsystem, financed through obligatory insurance schemes; and the private subsystem, financed through voluntary insurance. There are approximately 800 rheumatologists in Argentina, serving a population of approximately 40 million people, representing approximately 1.8 rheumatologists per 100.000 inhabitants; however, most of them are concentrated in large cities, and patients need to travel several hours to reach a specialist. Although the health care system in Argentina is highly fragmented and disconnected, health coverage is universal, accessible, and of good quality. Quality or value assessment of care and use of electronic medical records are not part of the system in Argentina, and there does not appear they would be in the near future.


Knowledge, attitudes, and practices of primary health care physicians regarding the pre-travel counselling of patients with type 2 diabetes in Riyadh, Saudi Arabia.
Travel has become an integral part of Saudi life. People with diabetes face many challenges while travelling that can have detrimental effects on glycaemic control. However, no previous studies have investigated pre-travel counselling in Saudi Arabia. This study aims to assess the knowledge, attitudes and practices of primary health care (PHC) physicians regarding pre-travel counselling for patients with type 2 diabetes. This cross-sectional study was conducted in PHC centres under the Ministry of Health in Riyadh, Saudi Arabia, during the period 2018-2019. A cluster multistage random sampling technique was used to recruit physicians. The data were collected through a self-administered questionnaire. Three hundred and eighty-five primary health care physicians were recruited. This study showed that more than half (57.9%) of PHC physicians had poor knowledge scores. Additionally, the following characteristics were significantly associated with poor knowledge: being younger in age, being male, being Saudi, being a general practitioner, and having limited (0-5 years) experience. A total of 183 (47.5%) subjects showed disagreement attitudes towards the importance of pre-travel counselling among patients with diabetes. Furthermore, these disagreement attitudes were significantly associated with being older and having more years of experience. The majority (62.6%) of the physicians had poor practice scores. Poor practices were detected among physicians who were younger, male, and Saudi and who had a general practitioner specialty and degree. It could be concluded that a gap was detected in the knowledge and practices of primary health care physicians regarding pre-travel counselling for people with type 2 diabetes. Therefore, it is necessary to create easily accessible travel medicine education programmes for Saudi PHC providers to improve the management of travellers with diabetes.


[Diagnostic value of the atropine test in the sick sinus syndrome].
Altogether 63 patients with clinical signs of the SNWS (the 1st group), 16 patients with coronary heart disease and the latent SNWS (the 2nd group), 26 patients with heart coronary disease without disorder of sinus node function (the 3rd conventionally control group) and 60 healthy persons (the 4th control group) were examined. Atropine was administered i. v. to them all at a a dose of 0.02 mg/kg of the body mass. The heart beat rate (HBR) was measured before atropine injection as well as its increment after atropine injection. The HBR after atropine injection in the patients of the 1st group was significantly higher than that in the 2nd-4th groups; in the patients of the 2nd group the HBR was significantly less than that in the 3rd-4th groups. In the 3rd group the HBR was significantly less than that in the 4th group. An increased percentage of the HBR in the patients with clinical signs of the SNWS and in the healthy persons did not differ significantly (46.6 +/- 3.7% and 51 +/- 2.4% P greater than 0.2). The sensitivity of the atropine test in the patients of the 1st group was 76.3%. The test specificity was 93.3%. Among the patients with coronary heart disease the atropine test specificity was much less (65.4%).


The role of the input on the development of the LC bias: a crosslinguistic comparison.
Previous studies have described the existence of a phonotactic bias called the Labial-Coronal (LC) bias, corresponding to a tendency to produce more words beginning with a labial consonant followed by a coronal consonant (i.e. "bat") than the opposite CL pattern (i.e. "tap"). This bias has initially been interpreted in terms of articulatory constraints of the human speech production system. However, more recently, it has been suggested that this presumably language-general LC bias in production might be accompanied by LC and CL biases in perception, acquired in infancy on the basis of the properties of the linguistic input. The present study investigates the origins of these perceptual biases, testing infants learning Japanese, a language that has been claimed to possess more CL than LC sequences, and comparing them with infants learning French, a language showing a clear LC bias in its lexicon. First, a corpus analysis of Japanese IDS and ADS revealed the existence of an overall LC bias, except for plosive sequences in ADS, which show a CL bias across counts. Second, speech preference experiments showed a perceptual preference for CL over LC plosive sequences (all recorded by a Japanese speaker) in 13- but not in 7- and 10-month-old Japanese-learning infants (Experiment 1), while revealing the emergence of an LC preference between 7 and 10 months in French-learning infants, using the exact same stimuli. These crosslinguistic behavioral differences, obtained with the same stimuli, thus reflect differences in processing in two populations of infants, which can be linked to differences in the properties of the lexicons of their respective native languages. These findings establish that the emergence of a CL/LC bias is related to exposure to a linguistic input.


Developmental switch in synaptic mechanisms of hippocampal metabotropic glutamate receptor-dependent long-term depression.
The presynaptic and postsynaptic properties of synapses change over the course of postnatal development. Therefore, synaptic plasticity mechanisms would be expected to adapt to these changes to facilitate alterations of synaptic strength throughout ontogeny. Here, we identified developmental changes in long-term depression (LTD) mediated by group 1 metabotropic glutamate receptors (mGluRs) and dendritic protein synthesis in hippocampal CA1 slices (mGluR-LTD). In slices prepared from adolescent rats [postnatal day 21 (P21) to P35], mGluR activation induces LTD and a long-term decrease in AMPA receptor (AMPAR) surface expression, both of which require protein synthesis. In neonatal animals (P8-P15), mGluR-LTD is independent of protein synthesis and is not associated with changes in the surface expression of AMPARs. Instead, mGluR-LTD at neonatal synapses results in large decreases in presynaptic function, measured by changes in paired-pulse facilitation and the rate of blockade by the use-dependent NMDA receptor blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate. Conversely, mGluR-LTD at mature synapses results in little or no change in presynaptic function, suggesting a postsynaptic mechanism of expression. The developmental switch in the synaptic mechanisms of LTD would differentially affect synapse dynamics and perhaps information processing over the course of postnatal development.


Immunohistochemical analysis of epidermal growth factor receptor (EGF-R) and c-erbB-2 and correlation with pathological prognostic variables in endometrial carcinomas.
In this study the immunohistochemical expressions of epidermal growth factor receptor (EGF-R) and erbB-2 in endometrial carcinomas at different stages of disease progression were evaluated and correlated with clinicopathological prognostic variables. Our results indicate that EGF-R and erbB-2 molecules are expressed in normal endometrium as well as in the majority of the carcinomas evaluated (83% and 92% respectively). The intensity of the immunostaining varied greatly (1+ to 3+) in the different tumors. Within these tumors we focused on those characterized by high levels of expression (i.e. overexpression). Expression and overexpression of EGF-R has been associated with poorly differentiated tumors and with a 3.3 times higher risk of a more rapid disease relapse. Overexpression of the erbB-2 oncoprotein was significatively correlated with depth of myometrial invasion (M0-M1 vs M2-M3 p=0.05), pathological stage (stage I vs II-IV p=0.02) and grade of tumor differentiation (G1 vs G2-G3 p=0.001). In particular, c-erbB-2 overexpression was able to discriminate between the different subsets of stage I carcinomas. None of the IA tumors overexpressed the oncoprotein, as compared to IB and IC (41% and 100% respectively, p=0.04). This finding highlights a role for erbB-2 protein as a prognostic parameter in stage I endometrial carcinoma patients.


Single-session percutaneous ethanol sclerotherapy in simple renal cysts in children: long-term follow-up.
Simple renal cysts are rare in children and managed conservatively unless symptomatic. To demonstrate the efficacy and long-term results of single-session ethanol sclerotherapy in symptomatic simple renal cysts in children. Three simple renal cysts in three children (age 1, 5 and 16 years) were included in the study. Indications for treatment were flank pain (n = 1), hypertension (n = 1), and increasing cyst size and urinary tract infection (n = 1). The mean follow-up period was 5.5 years (range 3-7 years). The procedures were performed with the guidance of US and fluoroscopy and under IV sedation. After the cystogram, 95% ethanol with a volume of 40% of the cyst volume (but not more than 100 ml) was used as the sclerosing agent. Two cysts disappeared completely, while the volume reduction was 99% for the third cyst at the end of the first year. CT demonstrated calcification of the cyst without an enhancing soft-tissue component in the third one 7 years after sclerotherapy. After the procedures, hypertension and pain resolved without any medication. There were no complications during the procedures or during follow-up. Cytological examination was unremarkable in all patients. Percutaneous treatment of symptomatic simple renal cysts in children with single-session ethanol sclerotherapy is a safe, effective and minimally invasive procedure. Calcification owing to sclerotherapy can be observed on follow-up.


[Emotional well-being and discomfort at work in call center].
The theme of well-being and discomfort at work has attracted increasing interest in recent years. The present study, according to Job Demands-Resources model (JD-R), inquires the effects of personal (optimism, internal locus of control) and organizational resources (job autonomy, supervisors and colleagues support) and general (work-to-family conflict, workload) and context specific demands (emotional dissonance) on emotional well-being and discomfort at work in call centre employees. This research was conducted through an online questionnaire, composed by measures present in scientific literature, filled out individually by call center agents (N = 507) of the same telecommunication firm. Data analysis (PASW 18) provides: descriptive statistics, correlations and multiple regressions. Personal and organizational resources improve emotional well-being at work, except for colleagues support. Optimism and supervisors support reduce emotional discomfort at work. Among organizational demands, work-family conflict and emotional dissonance increase emotional discomfort at work and, to a lesser extent, reduce the emotional well-being at work. The results, according to theoretical model, highlight the different role of demands and resources on emotional well-being and discomfort at work. The results suggest organizational politics and investments to promote emotional well-being at work, in particular training program to support emotional skills, training for supervisors, increasing job autonomy and support to work-family balance.


Vascular endothelial growth factor (VEGF) - part 2: in endocrinology and oncology.
Endocrine glands are well vascularised and the structure of their vessels facilitates the exchange of various substances, including hormones. These glands are a frequent experimental model in research on VEGF and angiogenesis. VEGF participates in the pathogenesis of diabetes. Diabetic nephropathy is in essence a microvascular disease that develops as a result of a confluence of haemodynamic and metabolic perturbations. Diabetic retinopathy is the commonest microvascular complication of diabetes mellitus and is the leading cause of blindness. In diabetic retinopathy, ischaemic states, and hence tissue hypoxia and angiogenesis, take place. The participation of angiogenesis and VEGF in the pathogenesis of neoplastic disease has been described in many papers. VEGF protein and mRNA have been found in cancers of the thyroid, bronchus, lungs, oesophagus, stomach, colon, liver, breast, ovary, uterus, kidney, and urinary bladder, and in malignant tumours of the brain and bone. There have been many reports of the connections between the degree of VEGF expression and tumour aggression and prognosis in patients. Richly vascularised are GEP NET. In neuroendocrine tumours, strong expression of VEGF, Flt-1 and KDR in relation to the unchanged surrounding tissues has been demonstrated. Depending on the disease entity or the degree of its severity, attempts to apply angiogenic and antiangiogenic therapy have being made. Antiangiogenic therapy (usually regarded as a form of cancer therapy) is based on: 1. inhibitory effects of proangiogenic ligands and their receptors; 2. stimulation or delivery of angiogenesis inhibitors; and 3. direct destruction of neoplastic tumour vasculature.


Azacitidine with or without lenalidomide in higher risk myelodysplastic syndrome & low blast acute myeloid leukemia.
Standard treatment for higher risk myelodysplastic syndromes, chronic myelomonocytic leukemia and low blast acute myeloid leukemia is azacitidine. In single arm studies, adding lenalidomide had been suggested to improve outcomes. The ALLG MDS4 phase II trial randomized such patients to standard azacitidine or combination azacitidine (75mg/m2/d days 1 to 5) with lenalidomide (10mg days 1-21 of 28-day cycle from cycle 3) to assess clinical benefit (alive without progressive disease) at 12 months. A total of 160 patients were enrolled; median age 70.7 years (range 42.5-87.2), 31.3% female with 14% chronic myelomonocytic leukemia, 12% acute myeloid leukemia and 74% myelodysplastic syndromes. Adverse events were similar in both arms. There was excellent delivery of protocol therapy (median azacitidine cycles 11 both arms) with few dose reductions, delays or early cessations. At median follow up 33.1 months (range 0.7-59.5), the rate of clinical benefit at 12 months was 65% azacitidine arm and 54% lenalidomide+azacitidine arm (P=0.2). There was no difference in clinical benefit between each arm according to WHO diagnostic subgroup or IPSS-R. Overall response rate was 57% in azacitidine arm and 69% in lenalidomide+azacitidine (P=0.14). There was no difference in progression- free or overall survival between the arms (each P>0.12). Although the combination of lenalidomide and azacitidine was tolerable, there was no improvement in clinical benefit, response rates or overall survival in higher risk myelodysplastic syndrome, chronic myelomonocytic leukemia or low blast acute myeloid leukemia patients compared to treatment with azacitidine alone. This trial was registered at www.anzc-tr.org.au as ACTRN12610000271000.


Q-TOF LC/MS identification and UHPLC-Online ABTS antioxidant activity guided mapping of barley polyphenols.
The polyphenol composition and antioxidant activity of seven Australian-grown barley varieties were characterized in this study. UHPLC with an online ABTS system was used to identify individual polyphenols while simultaneously measuring their antioxidant activity. The Q-TOF LC/MS system was utilized to identify the phenolic compounds that demonstrated substantial antioxidant activity. The variety, Hindmarsh, showed the highest total phenolic content and antioxidant activity. There was no significant difference observed amongst the other varieties in their total phenolic content, however, they did have significant variation in proanthocyanidin content and antioxidant activity (p < 0.05). Prodelphinidin B3 was the most abundant polyphenol with the highest antioxidant activity amongst all the barley varieties tested. Other polyphenols identified with antioxidant activity included procyanidin, glycosides of catechin and flavan-3-ols. Polyphenol characterization of Australian grown barley varieties demonstrated that they have significant antioxidant activity, hence, promoting the value of whole grain barley as a potential functional food ingredient.


The role of liver transplantation in the management of paediatric liver tumours.
In recent years, considerable progress has been made in the treatment of children with hepatoblastoma largely due to effective pre-operative chemotherapy. Total hepatectomy and liver transplantation has emerged as an effective treatment for the small proportion of children with unresectable hepatoblastoma limited to the liver. A 5-year survival of 70% can be achieved in such cases. In contrast, the results of liver transplantation in children with hepatocellular cancer remain poor because these tumours are usually advanced with evidence of major vascular invasion and/or extrahepatic spread at the time of presentation. An exception is those children in whom the hepatocellular carcinoma is detected during surveillance of chronic liver disease - they typically have smaller tumours and frequently have a good prognosis after liver transplantation. The role of liver transplantation in children with other primary hepatic malignancies remains uncertain because experience is very limited. Liver transplantation is rarely needed in the management of children with benign liver tumours but, if other treatments have failed, it can be a life-saving intervention.


Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Schistosomiasis and pulmonary arterial hypertension.
Schistosomiasis is caused by infection with the parasite Schistosoma, which is a flat-worm or fluke. The dominant species are Schistosoma mansoni, Schistosoma japonicum, and Schistosoma haematobium. Schistosomiasis is the third most common parasitic disease in the world after malaria and amoebiasis. It is endemic in more than 70 countries affecting about 200 million people worldwide, of whom 80% are in sub-Saharan Africa. There are pockets of infection in north-eastern Brazil, near the Yangtze River in China, and some pockets in south East Asia. In the East Mediterranean regions, the Schistosoma have been reported in Iraq and Egypt as well as in Sudan. The latter has the highest infection rate nowadays, particularly in the Al Jazeera area, due to the poor Schistosoma control program. In the Arabian peninsula, schistosomiasis has been reported in southwest part of Saudi Arabia, mainly in the Asir province and Jizan province, which lay in the southwest corner of Saudi Arabia and directly north of the border with Yemen. The efforts to control schistosomiasis have been very successful in Saudi Arabia due to the irrigation system control. However, the infection is prone in Yemen, where the schistosomiasis control is much less strict. Thus as a result, the problem still exists due to transmigration of the populations from both countries. As a cause of pulmonary arterial hypertension (PAH), schistosomiasis is still under diagnosed and undertreated. This article with give a highlight about the pathophysiology of the disease and both diagnostic and therapeutic strategies.


Prevalence and spectrum of PITX2c mutations associated with congenital heart disease.
Congenital heart disease (CHD) is the most common form of birth defect and is the leading noninfectious cause of infant death. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic defects underlying CHD in an overwhelming majority of patients remain unclear. In this study, the whole coding region and splice junction sites of the PITX2c gene, which encodes variant 3 of paired-like homeodomain transcription factor 2 crucial for normal cardiovascular morphogenesis, were sequenced in 382 unrelated patients with CHD, and 2 novel heterozygous mutations, p.W147X and p.N153D, were identified in 2 unrelated patients with CHD, respectively, including a 1-year-old male patient with double outlet right ventricle in combination with ventricular septal defect and a 4-year-old female patient with ventricular septal defect. The mutations were absent in 400 control chromosomes and were both predicted to be disease-causing by MutationTaster. Multiple alignments of PITX2c proteins across species displayed that the altered amino acids were completely conserved evolutionarily. Functional analysis revealed that the mutated PITX2c proteins were associated with a significantly reduced transactivational activity compared with their wild-type counterpart. These findings provide a novel insight into the molecular mechanisms implicated in CHD, suggesting potential implications for the antenatal prophylaxis and allele-specific treatment of CHD.


Experimental approaches for the estimation of uncertainty in analysis of trace inorganic contaminants in foodstuffs by ICP-MS.
Total Diet Studies to estimate dietary exposure to food contaminants need to evaluate laboratory measurements data variance. In this process it is critical that data from analytical methods are reliable to correctly scrutinize and compare values over time and between countries. In Europe it is widely recognized that the evaluation of measurement uncertainty is an important parameter when assessing the sources of analytical data variability. Two approaches are considered to estimate uncertainty in analytical measurement. Arsenic, Lead, Chromium and Cadmium, content in several food matrix determined by Inductively Coupled Mass Spectrometry (ICP-MS) microwave digestion assisted, are used as examples. The aim of the present research work is to compare both approaches accepted by Eurolab and GUM: Mathematical modeling to assess uncertainty components based on a classical model (bottom up) and an empirical method (top down), based on either experimental data obtained from a single laboratory validation data or inter-laboratory data from Proficiency Testing schemes. Relative expanded uncertainty calculated by both approaches agree when U (%) <20%. These values are concordant with RSDR reported in collaborative studies of EN 15763 (2009), which were assumed as target uncertainty. The top down approach described is simple and easy to use when compared with the mathematical modeling approach providing considerable benefits to those who assess data produced by several laboratories.


Sex differences in intensive care unit admissions in Australia and New Zealand.
Introduction: Fewer women than men are admitted to intensive care units (ICUs) worldwide. Objectives: To quantify the relative contribution of each major diagnostic category to the overall sex balance in ICU admissions in Australia and New Zealand, and to describe changes in the sex balance over time and with patient age. Methods: Retrospective cross-sectional study of Australian and New Zealand ICU admissions recorded in the Australian and New Zealand Intensive Care Society Adult Patient Database between 2005 and 2018. Multivariate logistic regression for the likelihood of female admission considered key explanatory variables: diagnostic category, patient age, admission year, geographic region, hospital type, and planned versus unplanned ICU admission. Results: Overall, 42.3% of 1 616 856 Australian and New Zealand ICU patients were women (99% CI, 42.2-42.4%). 247 988 more men than women were admitted to an ICU during the 14-year study period. There was a sex imbalance in most diagnostic categories: less than 48% women in 15 of 23 diagnostic categories, and greater than 52% women in four diagnostic categories (P < 0.001). Admissions following cardiovascular surgery accounted for over half of the total sex imbalance. The percentage of ICU patients who are women increased linearly from 40.8% in 2005 to 43.6% in 2018 (R2 = 93.1%; P < 0.001). Compared with admission in 2005, the adjusted odds ratio for female admission in 2018 was 1.03 (99% CI, 1.01-1.06). Conclusion: There is a significant sex imbalance in ICU admissions in Australia and New Zealand, widespread across the diagnostic categories. Cardiovascular admissions contribute most to the observed preponderance of men. The proportion of female ICU patients is steadily increasing.


Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin.
Inflammatory bowel disease (IBD) is a complex, multi-factorial disease thought to arise from an inappropriate immune response to commensal bacteria in a genetically susceptible person that results in chronic, cyclical, intestinal inflammation. Dietary and environmental factors are implicated in the initiation and perpetuation of IBD; however, a singular causative agent has not been identified. As of now, the role of environmental priming or triggers in IBD onset and pathogenesis are not well understood, but these factors appear to synergize with other disease susceptibility factors. In previous work, we determined that the polysaccharide dietary additive, maltodextrin (MDX), impairs cellular anti-bacterial responses and suppresses intestinal anti-microbial defense mechanisms. In this addendum, we review potential mechanisms for dietary deregulation of intestinal homeostasis, postulate how dietary and genetic risk factors may combine to result in disease pathogenesis, and discuss these ideas in the context of recent findings related to dietary interventions for IBD.


[Diagnostic image (308). A man with dyspnoea after a soccer accident].
During a soccer match, the foot of a goal keeper collided with the right thoracoabdominal area of a player, who afterwards suffered from dyspnoea caused by a ruptured liver.


Electrodeposition of hierarchical MnO2 spheres for enzyme immobilization and glucose biosensing.
Here we report the template-free growth of hierarchical MnO2 spheres on indium tin oxide by electrodeposition for the first time. The structural evolution and growth mechanism of MnO2 was carefully investigated. The hierarchical MnO2 showed mesoporous structure and good biocompatibility for the immobilization of glucose oxidase (GOx). The bioconjugate of a GOx/MnO2-modified electrode was successfully employed for the mediatorless biosensing of glucose.


Prerace aspirin to protect susceptible runners from cardiac arrest during marathons: is opportunity knocking?
While endurance exercise such as marathon training is cardioprotective, an increasing frequency of race-related cardiac arrests and sudden death has been observed in middle-aged men since the year 2000. An evidence-based strategy for prevention is considered based on identifying atherothrombosis as the underlying cause in this susceptible subgroup. Review of all articles on PubMed related to acute cardiac events during marathons. Male gender and the marathon compared with the half-marathon were identified as significant risk factors for race-related cardiac arrests, which events increased 2.3-fold in the latter half of a 10-year prospective registry beginning in the year 2000. There were 50 cardiac arrests in runners who were 86% male with a mean age of 42 years. The main cause of sudden death was atherosclerotic heart disease in those over the age of 40 including myocardial infarction in 12 of 13 (93%) cases over the age of 45 as assessed retrospectively. Inflammatory biomarkers predicting acute cardiac events and hypercoagulability with in vivo platelet activation were demonstrated in same-aged asymptomatic middle-aged men during marathons. Excess cardiac morbidity and mortality in middle-aged men during marathons is mediated by atherothrombosis which may render non-obstructive coronary atherosclerotic plaques vulnerable to rupture. Prerace low-dose aspirin usage is prudent to protect susceptible runners from a high, if transient, risk for cardiac arrest during races as evidence-based to prevent first myocardial infarctions in same-aged healthy men.


Tumor necrosis factor alpha drives cadherin 11 expression in rheumatoid inflammation.
Cadherin 11 expressed on fibroblast-like synoviocytes (FLS) plays a key role in normal synovial architecture. The purpose of this study was to examine the expression of cadherin 11 in human synovitis. Cadherin 11 expression in synovial biopsy samples from patients with various types of arthritis and in lung biopsy samples from patients with interstitial pneumonitis (IP) was examined by immunostaining. The regulation of cadherin 11 expression in human FLS was assessed by quantitative reverse transcription-polymerase chain reaction analysis and Western blotting. Therapeutic modulation of synovial cadherin 11 was assessed before and after effective antiinflammatory therapy. Abundant staining for cadherin 11 was seen in the intimal lining layer and the synovial sublining in inflamed tissues, with discrete staining in noninflammatory osteoarthritic (OA) tissues. The pattern and degree of immunostaining were similar in tissues from patients with rheumatoid arthritis (RA), nonpsoriatic spondylarthritis (SpA), psoriatic arthritis (PsA), and inflammatory OA. Clear staining for cadherin 11 was also observed in lung tissues from RA-associated IP and idiopathic IP patients, but was very limited in normal lung tissue. Cadherin 11 staining correlated strongly with the degree of inflammatory infiltration of the tissue, as well as with the C-reactive protein level and the erythrocyte sedimentation rate in RA patients. In vitro, cadherin 11 expression by FLS was consistently up-regulated by tumor necrosis factor alpha (TNFalpha) at the protein, but not the messenger RNA, level. Cadherin 11 staining in vivo was strongly down-regulated by prednisone treatment in RA patients and by TNFalpha blockade in SpA patients. Cadherin 11 expression is regulated by mediators of inflammation, such as TNFalpha. Since cadherin 11 plays an important role in cartilage destruction in experimental arthritis, down-modulation of cadherin 11 by potent antiinflammatory therapies in humans with arthritis may contribute to halting cartilage damage.


Product-limit survival functions with correlated survival times.
A simple variance estimator for product-limit survival functions is demonstrated for survival times with nested errors. Such data arise whenever survival times are observed within clusters of related observations. Greenwood's formula, which assumes independent observations, is not appropriate in this situation. A robust variance estimator is developed using Taylor series linearized values and the between-cluster variance estimator commonly used in multi-stage sample surveys. A simulation study shows that the between-cluster variance estimator is approximately unbiased and yields confidence intervals that maintain the nominal level for several patterns of correlated survival times. The simulation study also shows that Greenwood's formula underestimates the variance when the survival times are positively correlated within a cluster and yields confidence intervals that are too narrow. Extension to life table methods is also discussed.


Reexamining the arthritis-employment interface: perceptions of arthritis-work spillover among employed adults.
To examine employed individuals' perceptions of arthritis-work spillover (AWS), the reciprocal influence of arthritis on work and work on arthritis, and the demographic, illness, and work context factors associated with AWS. The study group comprised 492 employed individuals with osteoarthritis or inflammatory arthritis. Participants completed an interview-administered, structured questionnaire assessing AWS, demographic (e.g., age, sex), illness (e.g., disease type, pain, activity limitations), and work context (e.g., workplace control, hours of work) variables. Principal components analysis, reliability analysis, and multiple linear regression were used to analyze the data. A single factor solution emerged for AWS. The scale had an internal reliability of 0.88. Respondents were more likely to report that work interfered with caring for their arthritis than they were to report that their disease affected their work performance. Younger respondents, those with more fatigue and workplace activity limitations, and those working in trades and transportation reported more AWS. Individuals with more control over their work schedules reported less AWS. The results of this study extend research on arthritis by reexamining the interface between arthritis and employment. This study introduces a new measure of AWS that enhances the range of tools available to researchers and clinicians examining the impact of arthritis in individuals' lives.


South Africa's salt reduction strategy: Are we on track, and what lies ahead?
On 2 September 2016, 25 local and international participants from various sectors met in Cape Town to take stock of South Africa (SA)'s progress in salt reduction and develop a roadmap for action. SA is centre stage on salt reduction globally, being the first country to mandate salt reduction across a wide range of processed foods. Excessive salt intake contributed by processed foods and discretionary sources motivated SA to implement a public awareness campaign in parallel with legislation to reduce salt intake to the World Health Organization target of 5 g per day. Five priority areas were identified for continued action on salt reduction, including obtaining research funds for continued monitoring and compliance of salt reduction targets. Determining the contribution of foods eaten out of home to total salt intake and implementing strategies to address this sector were also highlighted as key actions. Lastly, implementing the next stage of the Salt Watch awareness campaign to change.


Error-based structure prediction in language comprehension: Evidence from verb bias effects in a visual-world structural priming paradigm for Mandarin Chinese.
Structural priming studies in production have demonstrated stronger priming effects for unexpected sentence structures (inverse preference effect). This is consistent with error-based implicit learning accounts that assume learning depends on prediction error. Such prediction error can be verb-specific, leading to strong priming when a verb that is for instance biased toward the prepositional object (PO) structure occurs with an unexpected double object (DO) structure. However, it is unclear whether this mechanism also holds for language comprehension, especially for languages like Mandarin Chinese, which arguably depends strongly on semantics to predict syntax in comprehension. Experiment 1 was a norming study (N = 367) that measured the biases (DO vs. PO) of 48 Mandarin Chinese dative verbs. Experiment 2 (N = 72) crossed verb bias (DO-bias or PO-bias) and structure (DO or PO) of prime sentences in a visual-world paradigm, to examine whether Mandarin comprehenders show an inverse preference effect. The priming effect is expressed as the proportion of looks to the predicted referent (i.e., the recipient after a DO-prime, the theme after a PO-prime), for two critical time windows during target sentence processing: the verb and the first syllable of the first postverbal noun (which was identical in theme and recipient). There was priming in both time windows, even though the verb differed between prime and target. Importantly, there was an inverse preference effect (i.e., stronger priming after a DO prime with a PO-biased verb than with a DO-biased verb) in the second time window. These results provide evidence for an error-based structure prediction system in comprehension. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


"Why do they become vulnerable when faced with the challenges of old age?" Elderly people who committed suicide, described by those who knew them.
Suicidal behavior among the elderly is a research field in which qualitative and quantitative methods can and should supplement each other. The objective of this qualitative study is to investigate whether the descriptions of elderly people who committed suicide, given by those who knew them, can provide common features that create recognizable patterns, and if so whether these patterns can help to shed light on the suicidal process. This is a psychological autopsy study based on qualitative interviews with 63 informants concerning 23 suicides committed by persons aged over 65 in Norway. The informants were relatives, their family doctors, and home-based care nurses. In general, the analysis of the interviews follows the systematic text condensation method. The descriptions have three main topics: life histories, personality traits and relationships. "Life histories" includes the sub-topics ability to survive and action-oriented achievers. They describe people who came through difficult circumstances when growing up and who were action-oriented in life in general and in crises. "Personality traits" includes the sub-topics obstinacy and controlling others. The informants saw the elderly people as strong-willed, obstinate and possessing a considerable ability to control themselves and those around them. "Relationships" includes the sub-topics I didn't know him and He showed no ability to meet us halfway, and describes the informants' experience of emotionally closed persons who kept a distance in their relationships. On the basis of the descriptions of the elderly people given in this study, we argue that these individuals will find difficulty in accepting and adapting to age-related loss of function since their self-esteem is so strongly associated with being productive and in control. Loss of control reveals their vulnerability - and this they cannot tolerate.


Prevalence of tuberculosis among mentally ill patients in conflict-stricken Afghanistan: A cross-sectional study.
Tuberculosis (TB) and mental illness share underlying factors such as poverty, malnutrition, and stress. This study's objective was to determine the prevalence of TB among mentally ill patients in Afghanistan. A cross-sectional study was conducted in five public and one private health facility. All patients in those centers were screened for TB, and the diagnosis of TB was made with GeneXpert or made clinically by a physician. Out of 8598 patients registered, 8324 (96.8%) were reached and 8073 (93.9%) were screened for TB, of whom 1703 (21.1%) were found to be presumptive TB patients. A total of 275 (16.7%) were diagnosed with all forms of TB, of whom 90.5% were women. Eighty-eight (32%) of them were bacteriologically confirmed and 187 (68%) were clinically diagnosed. The number needed to screen (NNS) was 29.3 and the number needed to test (NNT) was 6.1. The overall prevalence of TB among mentally ill patients was 3,567/100,000-20 times higher than the national incidence rate. TB was independently associated with married and widowed adults, young adults, females, and oral sleep drug users. TB among mentally ill patients is very high, and we recommend that TB care and prevention services be integrated into mental health centers.


Effect of methyl substitution on mutagenicity of 2-aminodipyrido.
The mutagenicities of 2-aminodipyrido [1,2-a:3',2'-d] imidazole (Glu-P-2, a mutagen obtained from pyrolysate of glutamic acid) and six methyl substituted derivatives of Glu-P-2 were tested with Salmonella typhimurium TA98 and TA100 with S-9 mix. Glu-P-1 (6-Me-Glu-P-2) was the strongest mutagen to TA98 and TA100. 3-Me-Glu-P-2 was weakest. The presence of a methyl group, and its position were shown to affect the mutagenicity significantly.


In vitro folding and functional analysis of an anti-insect selective scorpion depressant neurotoxin produced in Escherichia coli.
The selective toxicity of depressant scorpion neurotoxins to insects is useful in studying insect sodium channel gating and has an applied potential. In order to establish a genetic system enabling a structure-activity approach, the functional expression of such polypeptides is required. By engineering the cDNA encoding the depressant scorpion neurotoxin, LahIT2, behind the T7 promoter, large amounts of recombinant insoluble and nonactive toxin were obtained in Escherichia coli. Following denaturation and reduction, the recombinant protein, constructed with an additional N-terminal methionine residue, was subjected to renaturation. Optimal conditions for reconstitution of a functional toxin, having a dominant fold over many other possible isoforms, were established. The recombinant active toxin was purified by RP-HPLC and characterized. Toxicity (ED50) to insects, binding affinity (IC50) to an insect receptor site, and electrophysiological effect on an insect axonal preparation were found to be similar to those of the native toxin. Substitution of the C-terminal glycine by a Gly-Lys-Lys triplet did not abolish folding but affected toxicity (3.5-fold decrease) of LqhIT2. Apparently, this efficient bacterial expression system (500 micrograms HPLC-purified toxin/1 liter E. coli culture) provides the means for studying structure/ activity relationship and the molecular basis for the phylogenetic selectivity of scorpion depressant neurotoxins.


Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole.
Underlying cellular hypoxia, which may be difficult to detect, has been postulated to be a major cause of morbidity and mortality in sepsis. We employed the novel hypoxic marker [18F]fluoromisonidazole to determine whether cellular hypoxia was present in a peritonitis model of sepsis in the rat. A second group of septic and control rats had organ blood flow measurements determined by the radiolabeled microsphere technique to relate possible ischemia to decreased organ perfusion. No evidence of cellular hypoxia was detected in skeletal muscle, brain, liver, heart, or diaphragm in the septic rats. Ligation of the femoral artery caused a greater reduction in flow (55% decrease vs. 20% decrease, P less than 0.05) and an increased retention of [18F]fluoromisonidazole in skeletal muscle of the septic rats. We conclude that sepsis does not invariably result in systemic, i.e., multiorgan, cellular hypoxia and that underlying cellular hypoxia is not the major pathophysiological abnormality in sepsis. The greater reduction in muscle blood flow and the increased retention of [18F]fluoromisonidazole in the ischemic muscle of septic rats implies that they may be more vulnerable to hypoxia.


Effect of Caffeine on Colonic Manometry in Children.
Coffee and caffeinated products have been widely consumed for many centuries. Previous adult studies have suggested that both coffee and decaffeinated beverages induce colonic motility. However, no study has been conducted in pediatrics, and the role of caffeine alone in pediatric colonic motility needs to be explored. A prospective study of pediatric patients undergoing standard colonic motility testing that were able to consume caffeinated coffee, decaffeinated coffee, and caffeine tablet during colonic manometry. Patients who had a gastrocolonic reflex and high amplitude propagated contractions (HAPCs) in response to intraluminal administration of bisacodyl in the colon were included in the final analyses. Thirty-eight patients were recruited, 22 of which were excluded, 11 due to abnormal studies (no HAPC seen in response to intraluminal response to bisacodyl), and 11 due to inability to consume all study agents or complete the study. Sixteen patients met criteria for final analyses. Intracolonic bisacodyl produced a larger area under the curve (AUC) compared to all other agents. Caffeinated coffee resulted in a higher AUC, motility index (MI), and time to HAPC compared with decaffeinated coffee ( P < 0.05). There was no significant difference between caffeinated coffee and caffeine tablet, or caffeine tablet and decaffeinated coffee. Caffeine is indeed a colonic stimulant; however, other components of caffeinated and non-caffeinated beverages likely induce colonic response and require further evaluation for possible use as a colonic stimulant.


A Systematic Review to Define the Speech and Language Benefit of Early (<12 Months) Pediatric Cochlear Implantation.
This review aimed to evaluate the additional benefit of pediatric cochlear implantation before 12 months of age considering improved speech and language development and auditory performance. We conducted a search in PubMed, EMBASE and CINAHL databases and included studies comparing groups with different ages at implantation and assessing speech perception and speech production, receptive language and/or auditory performance. We included studies with a high directness of evidence (DoE). We retrieved 3,360 articles. Ten studies with a high DoE were included. Four articles with medium DoE were discussed in addition. Six studies compared infants implanted before 12 months with children implanted between 12 and 24 months. Follow-up ranged from 6 months to 9 years. Cochlear implantation before the age of 2 years is beneficial according to one speech perception score (phonetically balanced kindergarten combined with consonant-nucleus-consonant) but not on Glendonald auditory screening procedure scores. Implantation before 12 months resulted in better speech production (diagnostic evaluation of articulation and phonology and infant-toddler meaningful auditory integration scale), auditory performance (Categories of Auditory Performance-II score) and receptive language scores (2 out of 5; Preschool Language Scale combined with oral and written language skills and Peabody Picture Vocabulary Test). The current best evidence lacks level 1 evidence studies and consists mainly of cohort studies with a moderate to high risk of bias. Included studies showed consistent evidence that cochlear implantation should be performed early in life, but evidence is inconsistent on all speech and language outcome measures regarding the additional benefit of implantation before the age of 12 months. Long-term follow-up studies are necessary to provide insight on additional benefits of early pediatric cochlear implantation.


Effect of quantization error on the computed phase of phase-shifting measurements.
The effect of the quantization of fringe intensity on the phase error in phase-shifting measurements is formulated by a characteristic polynomial method. A numerical simulation is performed, and its result is in good agreement with the analytical one. Several factors influencing the quantization effects are investigated.


Potential role of glycosidase inhibitors in industrial biotechnological applications.
The nutrient content of food and animal feed may be improved through new knowledge about enzymatic changes in complex carbohydrates. Enzymatic hydrolysis of complex carbohydrates containing alpha or beta glycosidic bonds is very important in nutrition and in several technological processes. These enzymes are called glycosidases (Enzyme Class 3.2.1) and include amylases, pectinases and xylanases. They are present in many foods such as cereals, but their microbial analogues are often produced and added in many food processes, for instance to improve the shelf-life of bakery products, clear beer, produce glucose, fructose or dextrins, hydrolyse lactose, modify food pectins, or improve processes. However, many plant foods also contain endogenous inhibitors, which reduce the activity of glycosidases, in particular, proteins, peptides, complexing agents and phenolic compounds. The plant proteinaceous inhibitors of glycosidases are in focus in this review whose objective is to report the effect and implications of these inhibitors in industrial processes and applications. These studies will contribute to the optimisation of industrial processes by using modified enzymes not influenced by the natural inhibitors. They will also allow careful selection of raw material and reaction conditions, and future development of new genetic varieties low in inhibitors. These are all new and very promising concepts for the food and feed sector.


In-situ green synthesis of copper tannic acid framework in the presence of graphene quantum dots: Improved colloidal and antibacterial properties.
This work reports the preparation of a copper tannic acid MOF (CuTA) and graphene quantum dot (GQD) nanocomposite, GQD/CuTA, by a simple, environmentally friendly, and inexpensive method with exceptionally enhanced antibacterial properties. To end this, GQDs were first fabricated from citric acid using a neoteric, simple and straightforward hydrolysis approach and followed by they effectively anchor MOF nanoparticles (CuTA) by a green hydrothermal in situ synthesizing method. The constructed GQD/CuTA nanomaterials were characterized and validated using XRD, FT-IR, TEM, DLS, UV-vis, and PL techniques. Significant antibacterial activity against E. coli bacteria for both CuTA and GQD/CuTA (0 CFU/mL) and S. aureus bacteria for CuTA and GQD/CuTA (300 and 40 CFU/mL) was observed for the GQD/CuTA nanocomposite. The MTT assay showed good cytocompatibility for the GQD/CuTA nanocomposite against human dermal fibroblast cells (HFF-2). The result suggests that the synthesized GQD/CuTA nanocomposite with improved colloidal and antibacterial properties has the potential to be used as a safe photoluminescent nanoplatform with strong antimicrobial activity.


Evolution of neural precursor selection: functional divergence of proneural proteins.
How conserved pathways are differentially regulated to produce diverse outcomes is a fundamental question of developmental and evolutionary biology. The conserved process of neural precursor cell (NPC) selection by basic helix-loop-helix (bHLH) proneural transcription factors in the peripheral nervous system (PNS) by atonal related proteins (ARPs) presents an excellent model in which to address this issue. Proneural ARPs belong to two highly related groups: the ATONAL (ATO) group and the NEUROGENIN (NGN) group. We used a cross-species approach to demonstrate that the genetic and molecular mechanisms by which ATO proteins and NGN proteins select NPCs are different. Specifically, ATO group genes efficiently induce neurogenesis in Drosophila but very weakly in Xenopus, while the reverse is true for NGN group proteins. This divergence in proneural activity is encoded by three residues in the basic domain of ATO proteins. In NGN proteins, proneural capacity is encoded by the equivalent three residues in the basic domain and a novel motif in the second Helix (H2) domain. Differential interactions with different types of zinc (Zn)-finger proteins mediate the divergence of ATO and NGN activities: Senseless is required for ATO group activity, whereas MyT1 is required for NGN group function. These data suggest an evolutionary divergence in the mechanisms of NPC selection between protostomes and deuterostomes.


Language Fluency Deficits in Post-treatment Lyme Disease Syndrome.
Recent neurocognitive studies of patients with post-treatment Lyme disease syndrome (PTLDS) find consistent deficits in memory and processing speed. Language fluency deficits are observed as well but may be secondary to poor memory and slowing rather than an independent deficit. This study performed a secondary analysis of data presented previously, including individuals with PTLDS and comparison samples of healthy volunteers (HC) and patients with major depressive disorder (MDD), to determine if language fluency deficits could be accounted for by poor performance in these other neurocognitive domains. Basic verbal abilities, memory, and processing speed were all significantly associated with fluency performance. MDD patients' fluency deficits relative to HC were accounted for by these covariates. However, PTLDS patients' poorer fluency performance relative to both other groups was not. Language fluency appears to be an independent area of neurocognitive deficit within the constellation of PTLDS symptoms.


MK-801 is a potent nematocidal agent. Characterization of MK-801 binding sites in Caenorhabditis elegans.
MK-801, an N-methyl-D-aspartate antagonist in mammalian brain tissue, is a potent nematocidal agent. Specific MK-801 binding sites have been identified and characterized in a membrane fraction prepared from the free-living nematode Caenorhabditis elegans. The high-affinity MK-801 binding site has an apparent dissociation constant, Kd, of 225 nM. Unlike the MK-801 binding site in mammalian tissues, the C. elegans binding site is not effected by glutamate or glycine, and polyamines are potent inhibitors of specific MK-801 binding.


PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity.
Metabolic rewiring and defective immune responses are considered to be the main driving forces sustaining cell growth and oncogenesis in many cancers. The atypical enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), is produced by the liver in large amounts and plays a major role in lipid metabolism via the control of the low density lipoprotein receptor (LDLR) and other cell surface receptors. In this context, many clinical studies have clearly demonstrated the high efficacy of PCSK9 inhibitors in treating hyperlipidemia and cardiovascular diseases. Recent data implicated PCSK9 in the degradation of major histocompatibility complex I (MHC-I) receptors and the immune system as well as in other physiological activities. This review highlights the complex crosstalk between PCSK9, lipid metabolism and immunosuppression and underlines the latest advances in understanding the involvement of this convertase in other critical functions. We present a comprehensive assessment of the different strategies targeting PCSK9 and show how these approaches could be extended to future therapeutic options to treat cancers with a main focus on the liver.


Applying the Multiphase Optimization Strategy for the Development of Optimized Interventions in Palliative Care.
Recent systematic reviews and meta-analyses have reported positive benefit of multicomponent "bundled" palliative care interventions for patients and family caregivers while highlighting limitations in determining key elements and mechanisms of improvement. Traditional research approaches, such as the randomized controlled trial (RCT), typically treat interventions as "bundled" treatment packages, making it difficult to assess definitively which aspects of an intervention can be reduced or replaced or whether there are synergistic or antagonistic interactions between intervention components. Progressing toward palliative care interventions that are effective, efficient, and scalable will require new strategies and novel approaches. One such approach is the Multiphase Optimization Strategy (MOST), a framework informed by engineering principles, that uses a systematic process to empirically identify an intervention comprised of components that positively contribute to desired outcomes under real-life constraints. This article provides a brief overview and application of MOST and factorial trial design in palliative care research, including our insights from conducting a pilot factorial trial of an early palliative care intervention to enhance the decision support skills of advanced cancer family caregivers (Project CASCADE).


Retinoid antagonism of NF-IL6: insight into the mechanism of antiproliferative effects of retinoids in Kaposi's sarcoma.
All-trans-retinoic acid (RA) is active in the treatment of Kaposi's sarcoma (KS), and retinoids inhibit KS cell growth in vitro. To understand the mechanism of retinoid action in KS, we studied the expression of autocrine growth factors of KS cells after RA treatment. We demonstrate that RA and its synthetic analogs inhibit the proliferation of KS cells by inhibiting the mRNA and protein levels of interleukin-6 (IL-6), an autocrine growth factor for KS cells. We further demonstrate that nuclear retinoid receptors (RA receptors [RARs] and retinoid X receptors [RXRs]) inhibit IL-6 promoter action by antagonizing the enhancer action of NF-IL6, a basic domain leucine zipper transcription factor belonging to the family of CAAT enhancer binding proteins. Furthermore, RARs and RXRs do not bind in vitro to an NF-IL6 binding site. However, the secondary folded structure of the DNA binding domain of RAR and RXR is obligatory for inhibiting NF-IL6 activity. Thus, NF-IL6 is a potential therapeutic target for the treatment of KS. Finally, using receptor-selective synthetic retinoids, we demonstrate that NF-IL6 antagonism and transactivation are separable functions of RAR alpha, thus indicating that synthetic retinoids with properties of NF-IL6 antagonism but lacking transactivation capabilities can be synthesized. Such retinoids might increase therapeutic potential in KS.


Monoarthritis caused by Mycobacterium avium complex in a liver transplant recipient.
A 38-yr-old liver transplant recipient presented with a monoarthritis caused by Mycobacterium avium complex (MAC). Diagnosis was not obtained with repeated microscopy and culture of SF aspirate, and required synovial biopsy.


Radiation damage to triplex DNA induced by gamma-rays: a footprinting study and Monte Carlo simulation.
This study is aimed at comparing the radiosensitivity of a 21-mer DNA fragment in duplex and triplex form (Py x Pu duplex and Py x Pu:Py triplex) and to give insights into the fine structural features due to the different strandedness. The triplex sample was characterized by means of electrophoretic mobility, circular dichroism spectra and UV melting experiments. Triplex and duplex, labelled on the homopyrimidine or homopurine strand, were irradiated with 60Co gamma-rays. The samples were analysed by sequencing gel electrophoresis and the patterns of relative probabilities of frank strand breakage (FSB) and alkali-revealed breakage (ARB) at each nucleotide site were determined. Relative probabilities of OH* radical attack to duplex and triplex DNA built up with a molecular modelling software were calculated using a previously reported simulation procedure (Sy et al. 1997). The experimental data were compared with the results of the theoretical simulations of OH* radical attack to DNA. Globally, the duplex is more attacked than the triplex, mainly in the Pu strand. Sequence-dependent variations of FSB and FSB+ARB probabilities in both duplex and triplex were revealed. No significant differences between the patterns of damage in the triplex and in the duplex were observed. The presence of the third Py strand located in the major groove of the DNA duplex modifies the total yields of radiation-induced DNA damage, but not the sequence-dependent patterns of relative probability of damage at each nucleotide site.


On emergencies and emigration: how (not) to justify compulsory medical service.
I have argued that the best way to understand the supposed right to restrict emigration is with reference to the concept of an emergency; restrictions on emigration are permitted, if at all, only as responses to an emergency situation, and must be judged with reference to the ethics of responding to such an emergency. Eszter Kollar argues, against this, that the concept of 'emergency' fails to describe the actual situation in low/middle-income countries, in which shortages of medical personnel are long-standing problems; she also argues that there is no need to invoke the concept of an emergency, when we might simply discuss these restrictions with reference to the relative importance of the human goods and interests involved. I argue, against Kollar, that we have no reason to think that an emergency must involve novelty; if the moral stakes are significant enough, we have reason to think of a situation as an emergency, regardless of when that situation began. I argue, too, that we have reason to differentiate between restrictions of liberties undertaken as part of the process of specifying liberal freedoms and emergency restrictions of those liberties defended by liberalism itself. The latter, I suggest, ought to be recognised and defended as a distinct moral category, if only to recognise the continuing moral remainder when a liberal right is temporarily suspended under emergency circumstances. I conclude that a permission to restrict emigration is, if at all, only justifiable as an emergency response to unfavourable circumstances, and ought not to be analysed in the more conventional liberal terms Kollar deploys.


Optimising success of neonatal extubation: Respiratory support.
In this review, we examine lung physiology before, during and after neonatal extubation and propose a three-phase model for the extubation procedure. We perform meta-analyses to compare different modes of non-invasive respiratory support after neonatal extubation and based on the findings, the following clinical recommendations are made.


Gastrointestinal tolerance of chicory inulin products.
The use of inulin in foods as a fiber source has increased recently. Consumption of inulin products can cause gastrointestinal (GI) distress. Acceptable intakes of inulin need to be determined. To determine the GI tolerance of two inulin fibers, shorter chain length oligofructose and native inulin, at 5- and 10-g doses compared to a placebo. A randomized, double-blind, controlled, crossover design that included a phone screening and five visits for breakfast fiber challenges consisting of a bagel, cream cheese, and orange juice. Twenty-six healthy men and women ages 18 to 60 years participated in the study. Healthy subjects with no history of GI conditions consumed diets with typical amounts of fiber. GI tolerance was calculated as the sum of scores on seven GI tolerance domains via questionnaire administered at t=0, 2, 4, 24, and 48 hours following fiber challenge. A mixed effects linear model was used to compare the tolerance scores among the five fiber challenges. The two inulin fibers tended to increase GI symptoms mildly. Most frequently reported symptoms were flatulence followed by bloating. The 10-g dose of oligofructose substantially increased GI symptoms compared to control. Doses up to 10 g/day of native inulin and up to 5 g/day of oligofructose were well-tolerated in healthy, young adults.


Africa Guidelines for Hepatocellular Carcinoma Buildup Process.
Hepatocellular carcinoma (HCC), the fourth most common cancer in Africa, has a dismal overall survival of only 3 months like in sub-Saharan Africa. This is affected by the low gross domestic product and human development index, absence of coherent guidelines, and other factors. An open forum for HCC-experienced health care workers from Africa and the rest of the world was held in October 2021. Participants completed a survey to help assess the real-life access to screening, diagnoses, and treatment in the North and Southern Africa (NS), East and West Africa (EW), Central Africa (C), and the rest of the world. Of 461 participants from all relevant subspecialties, 372 were from Africa. Most African participants provided hepatitis B vaccination and treatment for hepatitis B and C. More than half of the participants use serum alpha-fetoprotein and ultrasound for surveillance. Only 20% reported using image-guided diagnostic liver biopsy. The Barcelona Clinic Liver Cancer is the most used staging system (52%). Liver transplant is available for only 28% of NS and 3% EW. C reported a significantly lower availability of resection. Availability of local therapy ranged from 94% in NS to 62% in C. Sorafenib is the most commonly used systemic therapy (66%). Only 12.9% reported access to other medications including immune checkpoint inhibitors. Besides 42% access to regorafenib in NS, second-line treatments were not provided. Similarities and differences in the care for patients with HCC in Africa are reported. This reconfirms the major gaps in access and availability especially in C and marginally less so in EW. This is a call for concerted multidisciplinary efforts to achieve and sustain a reduction in incidence and mortality from HCC in Africa.


Evaluation of pest vulnerability of 'Benning' soybean value added and insect resistant near isogenic lines.
Crop enhancement with value added traits may affect vulnerability to insects, and evaluating the susceptibility levels of the various value added traits in elite germplasm would aid in developing integrated pest management strategies. During 2007-2008, five 'Benning' soybean (Glycine max (L.) Merr) lines with different value added nutritional traits and four insect resistant quantitative trait loci (QTL) lines were evaluated in an effort to determine their pest vulnerability under artificial and natural insect pest populations. The lines showed variable susceptibility to lepidopterous insect pests classified as defoliators and stem feeders in replicated greenhouse and field tests. The study was carried out in Athens and Midville, GA. The green cloverworm (Hypena scabra (F.)) was the most common lepidopteran defoliator occurring in the fields. Other caterpillar pests found included the soybean looper (Pseudoplusia includens (Walker)), the bollworm (Helicoverpa zea (Boddie)), and the velvetbean caterpillar (Anticarsia gemmatalis (Hübner)). Data indicated that there was no significantly increased pest susceptibility among the value added cultivars with improved nutritional qualities, with the insect resistant quantitative trait loci lines Benning M and Benning MGH consistently being less susceptible to lepidopterous (Noctuidae) leaf injury.


[Sense and nonsense of examinations in hematogenous and exogenous intra-ocular infections].
Diagnosis of intraocular inflammations can be difficult, particularly if the patient is suffering from immunodeficiency. Among the endogenous inflammations this applies mainly to cases of hyaloretinitis caused by Candida or other fungi, often presenting as an acute hyalitis with sudden onset; the various ocular complications of AIDS, especially those due to toxoplasmosis (rare) and cytomegalovirus, and lyme disease, which can occasionally cause chronic panuveitis. Among the exogenous cases it applies to postoperative and posttraumatic endophthalmitis. In all these cases the diagnosis has to be established clinically if possible, since, as a consequence of the immunodeficiency, serology is hardly helpful, and only biopsy (of the vitreous) may provide additional information. Rapid diagnosis is very important because of the urgent need for therapy.


Patterns and predictors of cultural competence practice among Nigerian hospital-based healthcare professionals.
Being culturally competent would enhance the quality of care in multicultural healthcare settings like Nigeria, with over 200 million people, 500 languages, and 250 ethnic groups. This study investigated the levels of training and practice of cultural competence among clinical healthcare professionals in two purposively selected Nigerian tertiary hospitals. The research was a cross-sectional study. A multi-stage sampling technique was used to recruit participants who completed the adapted version of Cultural Competence Assessment Instrument (CCAI-UIC). Data were analysed using descriptive statistics, Pearson's correlation, ANOVA, and multivariate linear regression. The participants were mainly women (66.4%), aged 34.98 ± 10.18 years, with ≤ 5 years of practice (64.6%). Personal competence had a positive weak correlation with age (p < 0.001), practice years (p = 0.01), training (p = 0.001), practice (p < 0.001), and organisational competence (p < 0.001). There were significant professional differences in the level of training (p = 0.005), and differences in training (p = 0.005), and personal competence (p = 0.015) across levels of educational qualifications. Increasing practise years (p = 0.05), medical/dental profession relative to nursing (p = 0.029), higher personal (p = 0.013), and organisational (p < 0.001) cultural competences were significant predictors of the level of training. Male gender (p = 0.005), higher years in practice (p = 0.05), local language ability (p = 0.037), rehabilitation professionals relative to nursing (p = 0.05), high culturally competent practice (p < 0.001), higher training opportunities (p = 0.013), and higher organisational competence (p = 0.001) were significant predictors of higher personal competence. About a third of the participants had no formal training in cultural competence. Incorporating cultural competence in the Nigerian healthcare professionals' education curricula may enhance the quality of care in the multicultural setting.


Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease.
We describe the generation of mice that express a transgenic T cell receptor (TCR) (5B6) specific for the encephalitogenic myelin proteolipid protein (PLP) peptide 139-151, on the experimental autoimmune encephalomyelitis-resistant (EAE-resistant) B10.S background. Despite harboring a high frequency of self-reactive T cells, 5B6 transgenic mice on the B10.S background rarely develop spontaneous EAE, which is in striking contrast to 5B6 transgenic mice on the EAE-susceptible SJL background. The relative resistance to spontaneous EAE in transgenic B10.S mice is not due to deletion or anergy of T cells, but appears to be controlled by APCs. Analysis of APCs revealed a lower activation state and a lower T cell-activating capacity for APCs from B10.S mice than for those from EAE-susceptible SJL mice. When APCs in 5B6 transgenic B10.S mice were activated, for example, via TLR9 or TLR4, T cell tolerance was broken, resulting in EAE. Our findings demonstrate that activation of APCs via innate immune receptors can break self tolerance and trigger the development of autoimmunity even in a genetically resistant strain. These findings suggest that the development of autoimmune diseases such as multiple sclerosis is determined at least partly by the endogenous activation state of APCs.


Knowledge evaluation instruments for dementia caregiver education programs: A scoping review.
With the increase in our older adult population, there is a need for dementia training for informal and formal dementia caregivers. The objective of this scoping study is to assess dementia knowledge instruments utilized in educational programs and interventions intended for formal and informal dementia caregivers. Scoping review methodology was used to search PubMed, PsycInfo, CINAHL and Web of Science with tailored database search terms. The search yielded 8101 results, with 35 studies meeting inclusion. Studies were conducted in eight countries, had varying study designs (randomized controlled trials [RCTs] = 9, non-RCTs = 6, one-group study design = 20) and utilized previously published (19) and author developed (16) instruments. Furthermore, the studies were internationally diverse, conducted in the United States (n = 18), Australia (n = 7), UK (n = 3), China (n = 2), Canada (n = 2), Taiwan (n = 1), Brazil (n = 1) and multi-country (n = 1). Only two studies focused on minority populations. While author-developed instruments may be more relevant and timesaving, studies should strive to validate instruments or use previously published instruments to help standardize findings across studies and understand better the effects of educational programs on caregiver knowledge. Geriatr Gerontol Int 2020; 20: 397-413.


Smooth muscle-specific gene delivery in the vasculature based on restriction of DNA nuclear import.
The two currently employed approaches restricting gene delivery and/or expression to desired cell types in vivo rely on cell surface targeting or cell-specific promoters. We have developed a third approach based on cell-specific nuclear transport of the delivered plasmid DNA. We have previously shown that plasmid nuclear import in non-dividing cells is sequence-specific and have identified a set of cell-specific DNA nuclear targeting sequences that can be used to limit DNA nuclear import to desired cell types. Specifically we have identified elements of the smooth muscle gamma actin (SMGA) promoter that direct plasmid nuclear import selectively in smooth muscle cells (SMCs) in vitro (Vacik et al, 1999, Gene Therapy 6:1006-1014). In the present study, we demonstrate that the SMC-specific DNA nuclear targeting sequence from the SMGA promoter drives nuclear accumulation of plasmids and subsequent gene expression exclusively in the smooth muscle cell layer of the vessel wall in the intact vasculature of rats using electroporation mediated delivery. These results demonstrate that certain DNA nuclear targeting sequences can be used to restrict DNA nuclear import to specific cell types providing a new, novel means of cell targeting for gene therapy.


Conditional expression of hepatocyte nuclear factor-1beta, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic beta-cells.
Mutations in the gene encoding hepatocyte nuclear factor (HNF)1beta result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing beta-cell mass. The functional role of HNF1beta in normal beta-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1beta, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic beta-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1beta was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1beta also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent beta-cells are sensitive to increased expression of WT HNF1beta and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.


Tilted-component telescopes. Part I: theory.
A simple but unorthodox application of third-order aberration theory enables one to design a simple form of highly corrected off-axis telescope. Known as the tilted component telescope, with subclasses (a) Schiefspiegler, (b) Yolo, and (c) catadioptric herschelian (CHT), is it distinguished by axially symmetric components that frequently require only spherical curvature.


Identification of Pold2 as a novel interaction partner of protein inhibitor of activated STAT2.
Pold2 is a subunit of the DNA polymerase δ complex, encoding a protein involved in DNA replication and repair. In this study, using a yeast two-hybrid screening technique and the common cDNA fragment of the mouse PIAS2 as a bait, Pold2 was found to interact with PIAS2. A direct interaction between Pold2 and PIAS2 was confirmed by direct yeast two-hybrid. In vivo evidence of Pold2 association with PIAS2 was obtained by co-immunoprecipitation using HEK-293 cells. Subcellular localization studies demonstrated that Pold2 and PIAS2 were partially co-localized in mammalian cells. Collectively, our results suggest that Pold2 interacts under physiological conditions with PIAS2.


[Preparation of a block copolymer-based temperature-responsive affinity chromatography stationary phase for antibody separation and purification].
Antibodies play an essential role in cancer diagnosis and treatment because of the specificity for target biomolecules and reduction of side effects. However, antibodies separation and purification still face some challenges. Antibody elution from columns using a low-pH aqueous solution leads to aggregation or loss of activity of the antibody drugs. In this paper, a block copolymer-based temperature-responsive affinity chromatography (TRAC) stationary phase, SiO2-P[NIPAM-b-4VP]-MEP using the block temperature-responsive copolymer poly(N-isopropylacrylamide-b-4-vinylpyridine) (P[NIPAM-b-4VP]) as the space arms and 4-mercaptoethyl pyridine (MEP) as the ligand was prepared for antibody separation. The TRAC column was tested using bovine serum albumin (BSA) and γ-globulin as model proteins, and the effects of salt concentration in the mobile phase and temperature on their separation were studied in detail. At 40 ℃, the TRAC stationary phase only selectively retained γ-globulin due to the specific affinity interaction between antibodies and the ligand MEP. At 5 ℃, γ-globulin can be eluted from the column with a mass recovery of 92.7% using a Tris-HCl buffer (pH 8.0) solution containing 0.6 mol/L NaCl. The adsorption capacity of γ-globulin on this stationary phase was (71.5 ±2.1) mg/g (n=3), which was twice that of a traditional temperature-sensitive affinity chromatography stationary phase SiO2-PNIPAM-MEP. The stationary phase was also used to separate and purify immunoglobulin (IgG) in human serum in one step by altering the temperature and ion strength of the mobile phase, resulting in a purity of 97.4%±0.7%. Thus, this new technology has specific selectivity for antibodies, as well as mild and green elution conditions, ultimately resolving the problem of traditional affinity chromatography using acid elution, which can lead to the antibodies aggregation/inactivation. This technology has great application potential for the industrial production of antibody drugs.


Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms.
The macrolide antibiotic azithromycin (CP-62,993; 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A; also designated XZ-450 [Pliva Pharmaceuticals, Zagreb, Yugoslavia]) showed a significant improvement in potency against gram-negative organisms compared with erythromycin while retaining the classic erythromycin spectrum. It was up to four times more potent than erythromycin against Haemophilus influenzae and Neisseria gonorrhoeae and twofold more potent against Branhamella catarrhalis, Campylobacter species, and Legionella species. It had activity similar to that of erythromycin against Chlamydia spp. Azithromycin was significantly more potent versus many genera of the family Enterobacteriaceae; its MIC for 90% of strains of Escherichia, Salmonella, Shigella, and Yersinia was less than or equal to 4 micrograms/ml, compared with 16 to 128 micrograms/ml for erythromycin. Azithromycin inhibited the majority of gram-positive organisms at less than or equal to 1 micrograms/ml. It displayed cross-resistance to erythromycin-resistant Staphylococcus and Streptococcus isolates. It had moderate activity against Bacteroides fragilis and was comparable to erythromycin against other anaerobic species. Azithromycin also demonstrated improved bactericidal activity in comparison with erythromycin. The mechanism of action of azithromycin was similar to that of erythromycin since azithromycin competed effectively for [14C]erythromycin ribosomebinding sites.


Chemical grafting of Co9S8 onto C60 for hydrogen spillover and storage.
Metal modified C60 is considered to be a potential hydrogen storage medium due to its high theoretical capacity. Research interest is growing in various hybrid inorganic compounds-C60. While the design and synthesis of a novel hybrid inorganic compound-C60 is difficult to attain, it has been theorized that the atomic hydrogen could transfer from the inorganic compound to the adjacent C60 surfaces via spillover and surface diffusion. Here, as a proof of concept experiment, we graft Co9S8 onto C60via a facile high energy ball milling process. The Raman, XPS, XRD, TEM, HTEM and EELS measurements have been conducted to evaluate the composition and structure of the pizza-like hybrid material. In addition, the electrochemical measurements and calculated results demonstrate that the chemical "bridges" (C-S bonds) between these two materials enhance the binding strength and, hence, facilitate the hydriding reaction of C60 during the hydrogen storage process. As a result, an increased hydrogen storage capacity of 4.03 wt% is achieved, along with a favorable cycling stability of ∼80% after 50 cycles. Excluding the direct hydrogen storage contribution from Co9S8 in the hybrid paper, the hydrogen storage ability of C60 was enhanced by 5.9× through the hydriding reaction caused by the Co9S8 modifier. Based on these experimental measurements and theoretical calculations, the unique chemical structure reported here could potentially inspire other C60-based advanced hybrids.