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The practice of defensive medicine is highly evident with the purpose of the legal self‐interest of physicians. It might be widely increased during the coronavirus disease 2019 (COVID‐19) pandemic to avoid lawsuits, especially in the absence of specific effective treatment. This study aimed to evaluate the practice of defensive medicine among the Egyptian physicians, and to identify the impact of the COVID‐19 pandemic on malpractice suits. An electronic survey link was sent to the sampled physicians working at Faculty of Medicine, Tanta University Hospitals. It included personal information, two questions measuring the physicians' perceptions about defensive medicine, Defensive Medicine Behavior Scale (DMBS) and eight questions evaluating physicians' concerns in terms of the COVID‐19 pandemic effects. The study enrolled 1074 physicians; 78.5% of them didn't possess sufficient knowledge about defensive medicine. About 73% of participants practiced defensive medicine more after the COVID‐19 pandemic, and 68.2% demonstrated increasing concerns about malpractice suits after the emergence of COVID‐19. DMBS was statistically significant high among surgical specialties physicians and those who spent less duration in the field of their expertise. There is a need to legislate a malpractice law to control the precedent increase of defensive medicine practice in Egypt. This will help to control the prevalence of defensive medicine practice, improve the quality of care, and reduce healthcare costs. [ABSTRACT FROM AUTHOR]

Although postinterview communication (PIC) guidelines exist, adherence is voluntary. There are no studies of PIC practices in critical care medicine (CCM) and pulmonary and critical care medicine (PCCM) fellowship recruitment. What is the frequency, format, goals, and content of PIC between CCM/PCCM applicants and program directors? What is the impact of PIC on applicant and program rank order lists (ROLs)? CCM/PCCM applicants and program directors were separately surveyed after the 2022-2023 National Resident Matching Program Specialty Match. Surveys included multiple-choice, Likert-scale, and two free text questions. Thematic content analysis of free text responses was performed. One-third of eligible participants responded (applicants: n = 373 [34%]; program directors: n = 86 [32%]). Applicant respondents applied to CCM (19%), PCCM (69%), or both (12%). Program directors represented CCM (17%), PCCM (57%), or both (26%) programs. Applicant (66%) and program director (49%) respondents reported initiating PIC. PIC did not impact ROL decision for most applicants (73%) or program directors (83%), though 21% of applicants and 17% of program directors moved programs or applicants up on their ROL in response to PIC. One-quarter (23%) of applicants strongly agreed or agreed that PIC was helpful in creating their ROL, 27% strongly disagreed or disagreed, and 29% were neutral. PIC challenges identified by both groups included time; lack of uniformity; peer pressure; misleading language; and uncertainty about motives, rules, and response protocols. PIC is common among CCM/PCCM applicants and program directors. About 50% of applicants and 20% of program directors share ranking intentions via PIC. Although PIC did not impact ROL for most applicants and program directors, a minority of applicants and program directors moved programs up on their ROL after receiving PIC from the other party. Applicants have mixed perspectives on PIC value. Applicants and program directors alike desire clear guidance on PIC to minimize ambiguous and misleading communication. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The Ninth Perioperative Mortality Review Committee (POMRC) report found the likelihood of death was over three times higher in Māori youth compared to non‐Māori (age: 15–18 years) in the 30‐days following major trauma. The aim of our study is to investigate variations in care provided to Māori youth presenting to Te Whatu Ora Counties Manukau (TWO‐CM) with major trauma, to inform policies and improve care. Methods: This was a retrospective, observational study of 15–18‐year‐olds admitted to Middlemore Hospital from January 2018 to December 2021 following major trauma (Injury Severity Score (ISS) >12 or with (ISS) <12 who died). Data were obtained from the New Zealand Trauma Registry (NZTR). Six key performance indicators were studied against hospital guidelines/international consensus: Deaths, Cause‐of‐death, trauma call, RedBlanket activations, time‐to‐computed tomography (CT), and time‐to‐operating theatre (OT). Results: Of 77 patients, five deaths occurred, four non‐Māori, and one Māori (P = 0.645). Five trauma calls were not activated (P = 0.642). There was no statistically significant difference for both median time to CT (P = 0.917) and time to CT for patients with GCS >13 (P = 0.778) between Māori and non‐Māori. Five patients did not meet guidelines for time‐to‐OT (three non‐Māori and two Māori) (P = 0.377). Conclusion: No statistically significant variations in care were present for Māori youth presenting with major trauma, these findings did not match the national trend. We conducted a retrospective observational study aimed to investigate variations in care provided to Māori youth presenting to Te Whatu Ora Counties Manukau (TWO‐CM) with major trauma, to inform policies and improve care. Six Key Performance Indicators were studied against hospital guidelines/international consensus: Deaths, Cause‐of‐death, trauma call, RedBlanket activations, time‐to‐computed tomography (CT), and time‐to operating theatre (OT). We found that there were no statistically significant variations in care present for Māori youth presenting with major trauma and our findings did not match national trends. [ABSTRACT FROM AUTHOR]

Background: Black fungus (mycoses) is an opportunistic invasive infection that predominantly occurred among immunosuppressed persons. It has been recently detected in COVID-19 patients. The pregnant diabetic woman is susceptible to such infections and needs recognition for protection. This study aimed to evaluate the effect of the nurse-led intervention on the knowledge and preventive practice of diabetic pregnant women regarding fungal mycosis during the COVID-19 pandemic. Method: This quasi-experimental study was conducted at maternal health care centers in Shebin El-Kom, Menoufia Governorate, Egypt. The study recruited 73 diabetic pregnant women through a systematic random sampling of pregnant women attending the maternity clinic during the period of the study. A structured interview questionnaire was used to measure their knowledge regarding Mucormycosis and COVID-19 manifestations. The preventive practices were assessed through an observational checklist of hygienic practice, insulin administration, and blood glucose monitoring for the prevention of Mucormycosis infection. Results: The study revealed a statistically significant increment in the participants' knowledge, preventive practice, personal hygiene, and diabetes self-care scores (9.56 ± 1.75 ,3.6 ± 1.18, 3.18 ± 1.29 post-intervention) comparable to (6.19 ± 1.66, 1.97 ± 1.35, 0.89 ± 1.38 pre-intervention) respectively. There was a significant improvement in the overall COVID-19 protective score against Mucormycosis (from 2.66 ± 1.74 to 4.53 ± 1.43). Conclusion: Nursing educational sessions had a positive effect on pregnant women's awareness and preventive behavior. Hence, it is recommended to integrate nurse-led intervention targeting the preventive practice against COVID-19-associated Mucormycosis infection (CAM) as routine services for diabetic pregnant women during antenatal care. [ABSTRACT FROM AUTHOR]

Intestinal barrier function, critical for maintaining optimal gut health, is achieved primarily through mucins and tight junction proteins (i.e., zonula occludens-1 and occludin). An aberrant expression of these proteins results in increased paracellular permeability, leading to nonalcoholic steatohepatitis. Furthermore, enhanced expression of the inflammasome's nucleotide-binding domain, leucine-rich repeat-containing protein 3 (cryopyrin), and Toll-like receptor 4 are also associated with nonalcoholic steatohepatitis. To understand the role of probiotic supplementation (Lactobacillus acidophilus, Bifidobacterium longum, and Streptococcus thermophilus) in rats on a high-fat, high-fructose diet with nonalcoholic steatohepatitis, the expression of occludin, cryopyrin, and Toll-like receptor 4 was evaluated. A comparison of the results between the control, nonalcoholic steatohepatitis group, and probiotic-treated nonalcoholic steatohepatitis groups showed (a) a lack of any significant difference in occluding expression (P = 0.724) and (b) a significant reduction in serum Toll-like receptor 4 (P = 0.012) and cryopyrin (P = 0.025) by probiotics. Furthermore, only one rat developed nonalcoholic steatohepatitis in the probiotic group, compared to six rats in the non-probiotic group. In conclusion, there were hepatoprotective effects of probiotic administration on high-fat, high-fructose diet-induced nonalcoholic steatohepatitis in Sprague-Dawley rats. [ABSTRACT FROM AUTHOR]

Background: In face of the COVID-19 pandemic, many countries including Egypt implemented stay indoor rules. These regulations slowed the propagation of the coronavirus, meanwhile they contributed to increase mental health issues, particularly the risk of experiencing intimate partner violence (IPV). That might lead to adverse health and social outcomes on the abused women and the children. This study aimed to examine the effect of the COVID-19 pandemic on the incidence of intimate partner violence against married women in Egypt. Methods: A cross-sectional study enrolled 2068 married women through an electronic survey link. An anonymous self-administered questionnaire was used. It included demographic data and assessed the frequency of exposure to various forms of spousal violence before and after the COVID-19 pandemic. Results: The mean age of respondents was 33.8 ± 6.3 years. The commonest types of violent behaviors that have been increased significantly after the COVID-19 pandemic were: twisting arms/pulling the hair (pre 32.8%, post 75%), leaving the house without informing or giving the wife money (pre 12.2%, post 30.3%), restricting interaction with her family members (pre 26.1, post 40.4%), treating her as a servant (pre 28.7%, post 36.7%) and insulting her in front of others (pre 22.9%, post 30.8%).The associated determinants for higher violence rate were; low women education, young age at marriage, low educational and job rank of husband, husband's tobacco use and reduced family income (p < 0.05). Conclusions: The overall prevalence of economic and some types of physical and emotionally abusive behaviors have been increased after the emergence of COVID-19 pandemic. Special intervention should be designed to address this issue in collaboration with public health organizations. [ABSTRACT FROM AUTHOR]

Poxvirus genomes consist of a linear duplex DNA that ends in short inverted and complementary hairpin structures. These elements also encode loops and mismatches that likely serve a role in genome packaging and perhaps replication. We constructed mutant vaccinia viruses (VACV) where the native hairpins were replaced by altered forms and tested effects on replication, assembly, and virulence. Our studies showed that structure, not sequence, likely determines function as one can replace an Orthopoxvirus (VACV) hairpin with one copied from a Leporipoxvirus with no effect on growth. Some loops can be deleted from VACV hairpins with little effect, but VACV bearing too few mismatches grew poorly and we couldn't recover viruses lacking all mismatches. Further studies were conducted using a mutant bearing only one of six mismatches found in wild-type hairpins (SΔ1Δ3–6). This virus grew to ~20-fold lower titers, but neither DNA synthesis nor telomere resolution was affected. However, the mutant exhibited a particle-to-PFU ratio 10-20-fold higher than wild-type viruses and p4b/4b core protein processing was compromised, indicating an assembly defect. Electron microscopy showed that SΔ1Δ3–6 mutant development was blocked at the immature virus (IV) stage, which phenocopies known effects of I1L mutants. Competitive DNA binding assays showed that recombinant I1 protein had less affinity for the SΔ1Δ3–6 hairpin than the wild-type hairpin. The SΔ1Δ3–6 mutant was also attenuated when administered to SCID-NCR mice by tail scarification. Mice inoculated with viruses bearing wild-type hairpins exhibited a median survival of 30–37 days, while mice infected with SΔ1Δ3–6 virus survived >70 days. Persistent infections favor genetic reversion and genome sequencing detected one example where a small duplication near the hairpin tip likely created a new loop. These observations show that mismatches serve a critical role in genome packaging and provide new insights into how VACV "flip and flop" telomeres are arranged. Author summary: Poxviruses employ linear double-stranded DNA genomes that end in incompletely base-paired hairpin termini. These mismatched ends are thought to serve some role in virus assembly, and perhaps replication, but have not been amenable to genetic analysis. In this study we used a synthetic virology approach to alter the sequence and structure of these elements. Our research shows that although the encoded structures are of critical importance for function, the sequences are not because one can swap the ends of viruses from different poxviruses without affecting growth. When one tries to progressively delete the mismatches that are found at these ends (the telomeres) of wild-type genomes, it creates an assembly defect which shows up as an increase in the number of virus particles per infectious unit and an accumulation of incompletely assembled viruses. Electron microscopy showed that the development of mutant viruses is blocked at a stage after DNA is packaged but before the particles fully mature. This investigation supports earlier studies that had identified the telomeres as being sites where virus proteins bind and promote packaging. Viruses bearing these mutant telomeres are also less virulent but can still serve as vaccines to protect mice from a lethal virus challenge. [ABSTRACT FROM AUTHOR]

Dihydroartemisinin (DHA) is an FDA-approved antimalarial drug that has been repurposed for cancer therapy because of its preferential antiproliferative effects on cancer versus normal cells. Mitochondria represent an attractive target for cancer therapy based on their regulatory role in proliferation and cell death. This study investigates whether DHA conjugated to innately fluorescent N-alkyl triphenylvinylpyridinium (TPVP) perturbs mitochondrial functions resulting in a differential toxicity of cancer versus normal cells. TPVP-DHA treatments resulted in a dose-dependent toxicity of human melanoma and pancreatic cancer cells, whereas normal human fibroblasts were resistant to this treatment. TPVP-DHA treatments resulted in a G 1 -delay of the cancer cell cycle, which was also associated with a significant inhibition of the mTOR-metabolic and ERK1/2-proliferative signaling pathways. TPVP-DHA treatments perturbed mitochondrial functions, which correlated with increases in mitochondrial fission. In summary, TPVP mediated mitochondrial targeting of DHA enhanced cancer cell toxicity by perturbing mitochondrial functions and morphology. [Display omitted] • Synthesis of a novel mitochondria-targeted dihydroartemisinin (TPVP-DHA) fluorophore. • Preferential toxicity of TPVP-DHA in human cancer compared to normal cells. • TPVP-DHA treatment induces a G 1 -delay in cancer cells. • TPVP-DHA treatments suppressed ERK1/2-proliferative and mTOR-metabolic signaling pathways. • A higher abundance of mitochondrial fission in TPVP-DHA treated cells. [ABSTRACT FROM AUTHOR]

Aim: Transarterial radioembolization (TARE) is, by all standards, a radiation therapy. As such, according to Euratom Directive 2013/59, it should be optimized by a thorough treatment plan based on the distinct evaluation of absorbed dose to the lesions and to the non-tumoural liver (two-compartment dosimetry). Since the dosimetric prediction with 99mTc albumin macro-aggregates (MAA) of non-tumoural liver is much more accurate than the same prediction on lesions, treatment planning should focus on non-tumoural liver rather than on lesion dosimetry. The aim of this study was to determine a safety limit through the analysis of pre-treatment dosimetry with 99mTc-MAA single photon emission computed tomography (SPECT/CT), in order to deliver the maximum tolerable absorbed dose to non-tumoural liver. Methods: Data from intermediate/advanced hepato-cellular carcinoma (HCC) patients treated with 90Y glass microspheres were collected in this single-arm retrospective study. Injection was always lobar, even in case of bilobar disease, to avoid treating the whole liver in a single session. A three-level definition of liver decompensation (LD) was introduced, considering toxicity only in cases of liver decompensation requiring medical action (LD type C, LDC). We report LDC rates, receiver operating characteristic (ROC) analysis between LDC and NO LDC absorbed dose distributions, normal tissue complication probability (NTCP) curves and uni- and multivariate analysis of risk factors associated with toxicity. Results: A 6-month timeline was defined as necessary to capture all treatment-related toxicity events. Previous transarterial chemoembolization (TACE), presence or extension of portal vein tumoural thrombosis (PVTT) and tumour pattern (nodular versus infiltrative) were not associated with tolerance to TARE. On the contrary, at the multivariate analysis, the absorbed dose averaged over the whole non-tumoural liver (including the non-injected lobe) was a prognostic indicator correlated with liver decompensation (odds ratio = 4.24). Basal bilirubin > 1.1 mg/dL was a second even more significant risk factor (odds ratio = 6.35). NTCP analysis stratified with this bilirubin cut-off determined a 15% liver decompensation risk at 50 Gy/90 Gy for bilirubin >/< 1.1 mg/dL. These results are valid for a 90Y glass microsphere administration 4 days after the reference time. Conclusion: Given the low predictive accuracy of 99mTc-MAA on lesion absorbed dose reported by several authors, an optimized TARE with 90Y glass microspheres with lobar injection 4 days after reference time should aim at an absorbed dose averaged over the whole non-tumoural liver of 50 Gy/90 Gy for basal bilirubin higher/lower than 1.1 mg/dL, respectively. [ABSTRACT FROM AUTHOR]

Mercury (Hg) and potentially toxic elements (PTEs) are components of household dust and are a risk for human health. The aim of this study was to determine the concentrations of Hg and PTEs in household dust in individual housing facilities in the town of Šid, Serbia and their correlation to the content of the elements found in the surrounding garden soil. Total of 64 samples of household dust were collected from 16 locations of individual housing facilities on 4 occasions. Samples of surrounding yard and garden soil were simultaneously collected. None of the 64 analysed soil samples exceeded the threshold limit (TL) prescribed by law for non-agricultural soil, which is 0.3 mg kg-1 DM. Content of Hg in household dust was much higher than in the surrounding soil and ranged from 0.005 to 1.566 mg kg-1 DM. The resulting values of PTEs (As, B, Co, Cr, Cu, Ni, Pb, and Zn) in household dust had a significantly higher range than in the soil. Contents of Hg, B, Cu, and Zn were much higher in household dust than in the soil. According to the results of correlations of the analysed elements in household dust and surrounding soil, and according to the analysed locations, direct effect of Hg and PTEs contents on the content of the same elements in household dust was not confirmed. [ABSTRACT FROM AUTHOR]

Epithelioid hemangioendothelioma (EHE) is an uncommon low-grade malignant vascular tumor that may arise in soft tissue/bone or visceral sites such as the liver and lung. As this tumor exhibits epithelioid morphology, it frequently causes diagnostic confusion with other epithelioid vascular neoplasms as well as carcinoma. While 90% of classic EHE are driven by a WWTR1-CAMTA1 fusion gene, a histologically distinctive subset of EHE has been recently shown to harbor a different fusion gene, YAP1-TFE3. This variant is likely underrecognized given its rarity and only recent description. Notably, EHE frequently involves the liver but only one case of hepatic YAP1-TFE3 rearranged EHE has been reported to date. We present the second case of YAP1-TFE3 rearranged EHE affecting a 65-year-old woman and presenting as multiple liver masses, with characterization of the fusion gene at the transcriptomic and genomic levels. There are several educational points noted from this case. YAP1-TFE3 rearranged EHE shows distinctly vasoformative foci, unlike classic EHE and mimicking angiosarcoma or epithelioid hemangioma. The tumors cells show a histiocytoid appearance with voluminous cytoplasm, similar to other TFE3-rearranged tumors. Finally, in the liver, this tumor may in part mimic focal nodular hyperplasia of the liver which is an underrecognized diagnostic pitfall. This report highlights the key diagnostic and genetic features of this newly recognized variant of hepatic EHE to aid pathologists in appropriately classifying these tumors. [ABSTRACT FROM AUTHOR]

The optimal conditions for the extraction of eight polybrominated diphenyl ethers (PBDEs) were determined using 32 factorial design of experiments (DOE). The independent variables were coded at three levels and their actual values were selected on the basis of the preliminary experimental results. DOE consisted of nine runs with three replicates at the central point. A second-order polynomial model was used for predicting the response. After the optimization of the duration of extraction, the ratio of solvents and purification and instrumental parameters, the optimized conditions were applied on the samples taken from the surface layer of soil from 24 potentially contaminated locations (landfills, ex marshalling yard, dump of secondary raw materials and automotive waste). The gas chromatographic analysis with electron capture detection (GC-ECD) was used for the determination of PBDEs. The recovery values of BDE congeners at five concentration levels ranged between 80% and 115%. The total PBDEs concentrations ranged from 4.4 to 729 μg kg-1 of absolutely dry soil. The suitability of the experiment was proved by comparing the experimental and predicted values of the variable parameters. [ABSTRACT FROM AUTHOR]

Functional bowel disorders (i.e., constipation and diarrhea) are characterized by abdominal pain, bloating, distention, and/or bowel habit abnormalities in the absence of obvious anatomic or physiologic abnormalities on routine diagnostic tests. These symptoms are attributable to gastrointestinal sensorimotor dysfunctions resulting from peripheral and/or central mechanisms. Available drugs target the underlying bowel disturbance (i.e., constipation, diarrhea, or both), supplemented when necessary by management of pain. Osmotic and stimulant laxatives, secretagogues, and serotonin 5-HT 4 receptor agonists are approved for treating constipation. Loperamide, anticholinergic agents, rifaximin, bile-acid binding agents, eluxadoline, and clonidine are used to treat diarrhea. Several exciting new compounds, some of which have been evaluated in humans, are currently under development. [ABSTRACT FROM AUTHOR]

Background: Muscle preservation or decrease in muscle degeneration and progressive atrophy are major challenges in patients with severe peripheral nerve injury (PNI). Considerable interest exists in the potential therapeutic value of laser phototherapy (photobiomodulation) for restoring denervated muscle atrophy and for enhancing regeneration of severely injured peripheral nerves. As previously published, the laser phototherapy has a protective and immediate effect in PNI. Laser phototherapy in the early stages of muscle atrophy may preserve the denervated muscle by maintaining creatinine kinase (CK) activity and the amount of acetylcholine receptor (AChR). Objective and Methods: In the present study, the effectiveness of triple treatment laser phototherapy, namely, applied simultaneously at three areas: injured area of the peripheral nerve, corresponding segments of the spinal cord, and corresponding denervated muscle (triple treatment), was evaluated for the treatment of incomplete PNI in rats with the ultimate goal of achieving improved limb function. Results: Forty-five days after the sciatic nerve insult, all rats regained normal walking (functional sciatic index values returned to baseline); however, the long laser irradiation (7 min) group presented the fastest recovery as opposed to short laser irradiation (3 min). A histological evaluation of the nerves revealed that long laser irradiation led to a higher amount of neuronal fibers that were larger than 4 μm (543 ± 76.8, p < 0.01) than short irradiation (283 ± 35.36). A histological evaluation of muscular atrophy showed that long laser irradiation evolved with significantly less muscle atrophy (8.06% ± 1.23%, p < 0.05) than short irradiation (24.44% ± 7.26%). Conclusions: The present study and our previous investigations showed that the laser phototherapy increases biochemical activity and improves morphological recovery in muscle and, thus, could have direct therapeutic applications on muscle, especially during progressive atrophy resulting from PNI. [ABSTRACT FROM AUTHOR]

Purpose Large relaxing retinectomies have become increasingly used in the repair of retinal detachment related to proliferative vitreoretinopathy (PVR). Retinectomies expose the retinal pigment epithelium (RPE) to the vitreous cavity; the direct effects of silicone oil on the RPE are only beginning to be understood. Design Retrospective case series. Participants Twelve patients noted to develop pigmented epiretinal deposits at regularly scheduled follow-up visits after repair of complex retinal detachments using silicone oil tamponade and retinectomy. Methods Epiretinal pigment deposits were characterized clinically by wide-field color photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography (SD OCT). At the time of silicone oil removal, the pigmented membranes were preserved in fixative and analyzed by light microscopy/immunostaining or electron microscopy for histologic characterization. Main Outcome Measures Not applicable. Results We describe the development of diffuse preretinal pigmentary deposits in 12 eyes after surgery for complicated PVR detachments using retinectomies with oil, with an average onset of 3.2 months postoperatively. These pigment clumps produced a striking leopard-spot pattern on fundus autofluorescence imaging. Histopathologic and ultrastructural analysis of these epiretinal proliferations peeled at the time of silicone oil removal revealed RPE cells with intracellular silicone oil droplets, singly dispersed membrane-bound melanin granules, glial tissue (1 case), and a fibrous stroma. Conclusions Although in vitro studies have suggested that RPE cells can phagocytose emulsified oil droplets, this report represents the first in vivo documentation by electron microscopy of this phenomenon in patients. These findings underscore that direct contact with silicone oil may affect the behavior of the RPE, which may be clinically relevant in patients who have undergone large relaxing retinectomies with silicone oil tamponade for PVR-related retinal detachments. [ABSTRACT FROM AUTHOR]

Functional gastrointestinal disorders (FGIDs) are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. The two most prevalent FGIDs, affecting up to 16-26% of worldwide population, are functional dyspepsia and irritable bowel syndrome. Their etiopathogenic mechanisms remain unclear, however, recent observations reveal low-grade mucosal inflammation and immune activation, in association with impaired epithelial barrier function and aberrant neuronal sensitivity. These findings come to challenge the traditional view of FGIDs as pure functional disorders, and relate the origin to a tangible organic substrate. The mucosal inflammatory infiltrate is dominated by mast cells, eosinophils and intraepithelial lymphocytes in the intestine of FGIDs. It is well established that mast cell activation can generate epithelial and neuro-muscular dysfunction and promote visceral hypersensitivity and altered motility patterns in FGIDs, postoperative ileus, food allergy and inflammatory bowel disease. This review will discuss the role of mucosal mast cells in the gastrointestinal tract with a specific focus on recent advances in disease mechanisms and clinical management in irritable bowel syndrome and functional dyspepsia. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) represents a leading cause of blindness in the elderly, and Stargardt’s macular dystrophy (SMD) is the most common form of juvenile-onset macular degeneration. Dry AMD and SMD share an underlying pathophysiology, namely dysfunction and ultimately loss of the retinal pigment epithelium (RPE), suggesting that RPE transplantation may offer a potential treatment strategy for both patient populations. Stem cells have emerged as a promising source of replacement RPE. During the past 15 years, extraordinary strides have been made in the identification, characterization, and differentiation of stem cells. Recently, this large body of basic science and preclinical research has been translated to patient care with the publication of results from Phase 1/2 trials demonstrating safety of transplantation of human embryonic stem cell (hESC)-derived RPE into patients with AMD and SMD. While significant challenges remain before dry AMD and SMD become treatable diseases, the goal has become more tangible. [ABSTRACT FROM PUBLISHER]

Purpose: The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on Tc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images. Methods: We performed retrospective dosimetry of the standard TheraSphere® treatment on 52 intermediate ( n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50 % and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on Tc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of Tc-MAA and Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICS™ by Philips). STRATOS™ absorbed dose calculation was validated for Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BED) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment. Results: MAA and Y biodistributions were not different (71 % of cases), different in 23 % and uncertain in 6 %. Response correlated with absorbed dose (Spearman's r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted ( p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50 %) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3-5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14 %, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD was ≈ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD ≈ 75 Gy. Conclusion: A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed. [ABSTRACT FROM AUTHOR]

Purpose To evaluate intrafraction variability and deformation of the lumpectomy cavity (LC), breast, and nearby organs. Methods and Materials Sixteen left-sided postlumpectomy and 1 bilateral breast cancer cases underwent free-breathing CT (FBCT) and 10-phase 4-dimensional CT (4DCT). Deformable image registration was used for deformation analysis and contour propagation of breast, heart, lungs, and LC between end-exhale and end-inhale 4DCT phases. Respiration-induced motion was calculated via centroid analysis. Two planning target volumes (PTVs) were compared: PTV FBCT from the FBCT volume with an isotropic 10 mm expansion (5 mm excursion and 5 mm setup error) and PTV 4DCT generated from the union of 4DCT contours with isotropic 5 mm margin for setup error. Volume and geometry were evaluated via percent difference and bounding box analysis, respectively. Deformation correlations between breast/cavity, breast/lung, and breast/heart were evaluated. Associations were tested between cavity deformation and proximity to chest wall and breast surface. Results Population-based 3-dimensional vector excursions were 2.5 ± 1.0 mm (range, 0.8-3.8 mm) for the cavity and 2.0 ± 0.8 mm (range, 0.7-3.0 mm) for the ipsilateral breast. Cavity excursion was predominantly in the anterior and superior directions (1.0 ± 0.8 mm and −1.8 ± 1.2 mm, respectively). Similarly, for all cases, LCs and ipsilateral breasts yielded median deformation values in the superior direction. For 14 of 17 patients, the LCs and breast interquartile ranges tended toward the anterior direction. The PTV FBCT was 51.5% ± 10.8% larger ( P <.01) than PTV 4DCT . Bounding box analysis revealed that PTV FBCT was 9.8 ± 1.2 (lateral), 9.0 ± 2.2 (anterior–posterior), and 3.9 ± 1.8 (superior–inferior) mm larger than PTV 4DCT . Significant associations between breast and cavity deformation were found for 6 of 9 axes. No dependency was found between cavity deformation and proximity to chest wall or breast surface. Conclusions Lumpectomy cavity and breast deformation and motion demonstrated large variability. A PTV 4DCT approach showed value in patient-specific margins, particularly if robust interfraction setup analysis can be performed. [ABSTRACT FROM AUTHOR]

Background Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being riskassociated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility. Methods 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r2>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test. Results The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication. Conclusions Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/ TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia. [ABSTRACT FROM AUTHOR]

Objective The complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune, neuronal and barrier integrity genes is associated with IBS. Design 384 single nucleotide polymorphisms (SNPs) covering 270 genes were genotyped in an exploratory cohort (935 IBS patients, 639 controls). 33 SNPs with Puncorrected<0.05 were validated in an independent set of 497 patients and 887 controls. Genotype distributions of single SNPs were assessed using an additive genetic model in IBS and clinical subtypes, IBS-C and IBS-D, both in individual and combined cohorts. Trait anxiety (N=614 patients, 533 controls), lifetime depression (N=654 patients, 533 controls) and mRNA expression in rectal biopsies (N=22 patients, 29 controls) were correlated with SNP genotypes. Results Two SNPs associated independently in the exploratory and validation cohort: rs17837965-CDC42 with IBS-C (ORexploratory=1.59 (1.05 to 1.76); ORvalidation=1.76 (1.03 to 3.01)) and rs2349775-NXPH1 with IBS-D (ORexploratory=1.28 (1.06 to 1.56); ORvalidation=1.42 (1.08 to 1.88)). When combining both cohorts, the association of rs2349775 withstood post hoc correction for multiple testing in the IBS-D subgroup. Additionally, three SNPs in immune-related genes (rs1464510-LPP, rs1881457-IL13, rs2104286-IL2RA), one SNP in a neuronal gene (rs2349775-NXPH1) and two SNPs in epithelial genes (rs245051-SLC26A2, rs17837965-CDC42) were weakly associated with total-IBS (Puncorrected<0.05). At the functional level, rs1881457 increased IL13 mRNA levels, whereas anxiety and depression scores did not correlate with rs2349775-NXPH1. Conclusions Rs2349775 (NXPH1) and rs17837965 (CDC42) were associated with IBS-D and IBS-C, respectively, in two independent cohorts. Further studies are warranted to validate our findings and to determine the mechanisms underlying IBS pathophysiology. [ABSTRACT FROM AUTHOR]

Abstract: Age-related macular degeneration (AMD) represents the leading cause of blindness in the elderly, yet no definitive therapy exists for early, dry disease. Several lines of evidence have implicated oxidative stress-induced damage to the retinal pigment epithelium (RPE) in the pathogenesis of AMD, suggesting that the aging RPE may exhibit increased susceptibility to cell damage induced by exogenous stressors. The transcription factor Nrf2 serves as the master regulator of a highly coordinated antioxidant response in virtually all cell types. We compared Nrf2 signaling in the RPE of young (2 months) and old (15 months) mice under unstressed and stressed (sodium iodate) conditions. The aging RPE expressed higher levels of the Nrf2 target genes NQO1, GCLM, and HO1 compared with the RPE of younger mice under unstressed conditions, suggesting an age-related increase in basal oxidative stress. Moreover, the RPE of older mice demonstrated impaired induction of the protective Nrf2 pathway following oxidative stress induced with sodium iodate. The RPE of old mice exposed to sodium iodate also exhibited higher levels of superoxide anion and malondialdehyde than young mice, suggesting inadequate protection against oxidative damage. Induction of Nrf2 signaling in response to sodium iodate was partially restored in the RPE of aging mice with genetic rescue, using conditional knockdown of the Nrf2 negative regulator Keap1 (Tam-Cre; Keap1loxP) compared to Keap1loxP mice. These data indicate that the aging RPE is vulnerable to oxidative damage due to impaired Nrf2 signaling, and that Nrf2 signaling is a promising target for novel pharmacologic or genetic therapeutic strategies. [Copyright &y& Elsevier]

OBJECTIVES:Abnormal pain perception or visceral hypersensitivity (VH) is considered to be an important mechanism underlying symptoms in a subgroup of irritable bowel syndrome (IBS) patients. Increased TRPV1 (transient receptor potential cation channel subfamily V member 1) expression in rectal biopsies of IBS patients suggests a potentially important role for this nociceptor in the pathophysiology of IBS. However, evidence underscoring the involvement of TRPV1 in visceral perception in IBS is lacking. The objective of this study was to evaluate the role of TRPV1 in VH to rectal distension and clinical symptoms in patients with IBS.METHODS:A total of 48 IBS patients and 25 healthy volunteers (HVs) were invited to undergo subsequent assessment of sensitivity to rectal distensions and rectal capsaicin applications. Visceral sensitivity was evaluated by rectal distension at 3, 9, and 21 mm Hg above minimal distension pressure (MDP). Capsaicin was applied to the rectal mucosa (0.01%, 0.1%, or solvent only in random order). Visceral sensations (urge to defecate, pain, burning, and warmth sensation) were scored on a 100-mm visual analog scale (VAS). TRPV1 expression in rectal biopsies was determined by immunohistochemistry and real-time PCR.RESULTS:A total of 23 IBS patients (48%) were hypersensitive to rectal distensions (VH-IBS). A concentration-dependent increase of urge and pain perception was present in HVs and IBS patients during capsaicin 0.01 and 0.1% applications. VH-IBS patients experienced a significantly increased perception of pain, but not urge, during capsaicin applications compared with normosensitive patients (ns-IBS) and HVs. Increased pain perception was significantly associated with anxiety and VH, symptoms scores of abdominal pain, loose stools, and stool frequency. Anxiety experienced during the experimental procedure was enhanced in VH-IBS patients but not in ns-IBS or HVs. However, rectal TRPV1 expression was similar in VH-IBS, ns-IBS, and HVs on both mRNA and protein expression levels. TRPV1 expression levels did not correlate with pain perception to capsaicin or clinical symptoms in IBS patients or the subgroups.CONCLUSIONS:IBS patients with VH to rectal distension reveal increased pain perception to rectal application of capsaicin, as well as an increased anxiety response. No evidence for TRPV1 upregulation could be demonstrated. As both VH and anxiety are independently associated with increased pain perception to rectal capsaicin application, our data suggest that both peripheral and central factors are involved, with increased receptor sensitivity as a speculative possibility. [ABSTRACT FROM AUTHOR]

Abstract: Several series evaluating external-beam partial breast irradiation (PBI) have linked negative cosmetic outcomes to large normal tissue treatment volumes. We compared patients treated with PBI whose treatment plans included only photons to those whose plans incorporated electrons. Twenty-seven patients were identified: median age 67 years, pT1 82%, pN0 56%, margin negative 100%. All received 38.5 Gy using 3–5 noncoplanar photon beams (6-15X). Electrons (9–20 MeV) were included in 59%. Median follow-up was 22 months. Ninety percent experienced good/excellent cosmetic outcomes. Two patients had fair cosmesis, and both were treated with a mixed photon/electron approach. Median conformity index for photon-only treatment plans was 1.7 (range, 0.9–2.0) and for photon/electron plans, 1.0 (0.3–1.4). Median percent ipsilateral breast volume receiving 100% and 50% of prescription dose was 19 and 50 for photon-only plans vs. 10 and 38 for photon/electron plans (p < 0.05). Median percent target volume receiving 100% and 95% of prescription dose was 93 and 98 for photon-only plans vs. 75 and 94 for photon/electron plans (p < 0.05). A mixed photon/electron, noncoplanar technique decreases the volume of treated normal breast tissue at the cost of slightly decreased tumor bed coverage. Further study is needed to determine whether this results in a more favorable therapeutic ratio than photon-only approaches. [Copyright &y& Elsevier]

Abstract: Background: In the United States, women with young children have dramatically increased their participation in the workforce, resulting in greater potential conflict between work and family roles. However, few studies have examined postpartum work–family conflict. This study examined associations between work–family conflict and women’s health after childbirth. Methods: Employed women, 18 years of age and older, were recruited while hospitalized for childbirth and followed for 18 months (n = 541; 66% response rate). Health outcomes were measured using the Short Form 12, version 2. Longitudinal fixed-effects models estimated the associations between work–family conflict (modeled as job and home spillover) and health. Results: Women who reported high levels of job spillover to home had mental health scores slightly, but significantly, worse than women who reported low levels of spillover (β = −1.26; SE = 0.47). Women with medium and high levels of home spillover to job also reported worse mental health (β = −0.81, SE = 0.30; and β = −1.52, SE = 0.78) relative to those with low spillover. Women who reported medium (versus low) levels of home spillover reported slightly improved physical health (β = 0.64, SE = 0.30). There was no significant association between job spillover and physical health. Conclusion: This study focused exclusively on employed postpartum women. Results illustrate that job and home spillover are associated with maternal mental and physical health. Findings also revealed that flexible work arrangements were associated with poorer postpartum mental health scores, which may reflect unintended consequences, such as increasing the amount of work brought home. [Copyright &y& Elsevier]

The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 heterozygosity normalized Pdx1 protein levels in Pdx1(+/-) mouse islets, thereby increasing expression of key Pdx1 transcriptional targets. Remarkably, Pcif1 heterozygosity improved glucose homeostasis and β cell function and normalized β cell mass in Pdx1(+/-) mice by modulating β cell survival. These findings indicate that in adult mouse β cells, Pcif1 limits Pdx1 protein accumulation and thus the expression of insulin and other gene targets important in the maintenance of β cell mass and function. They also provide evidence that targeting the turnover of a pancreatic transcription factor in vivo can improve glucose homeostasis. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2DM) results from pancreatic β cell failure in the setting of insulin resistance. Heterozygous mutations in the gene encoding the β cell transcription factor pancreatic duodenal homeobox 1 (Pdx1) are associated with both T2DM and maturity onset diabetes of the young (MODY4), and low levels of Pdx1 accompany β cell dysfunction in experimental models of glucotoxicity and diabetes. Here, we find that Pdx1 is required for compensatory 13 cell mass expansion in response to diet-induced insulin resistance through its roles in promoting β cell survival and compensatory hypertrophy. Pdx1-deficient β cells show evidence of endoplasmic reticulum (ER) stress both in the complex metabolic milieu of high-fat feeding as well as in the setting of acutely reduced Pdx1 expression in the Min6 mouse insulinoma cell line. Further, Pdx1 deficiency enhances β cell susceptibility to ER stress-associated apoptosis. The results of high throughput expression microarray and chromatin occupancy analyses reveal that Pdx1 regulates a broad array of genes involved in diverse functions of the ER, including proper disulfide bond formation, protein folding, and the unfolded protein response. These findings suggest that Pdx1 deficiency leads to a failure of β cell compensation for insulin resistance at least in part by impairing critical functions of the ER. [ABSTRACT FROM AUTHOR]

Activation of the 5-hydroxytryptamine receptor 2B (5-HT2B), a Gq/11 protein-coupled receptor, results in proliferation of various cell types. The 5-HT2B receptor is also expressed on the pacemaker cells of the gastrointestinal tract, the interstitial cells of Cajal (ICC), where activation triggers ICC proliferation. The goal of this study was to characterize the mitogenic signal transduction cascade activated by the 5-HT2B receptor. All of the experiments were performed on mouse small intestine primary cell cultures. Activation of the 5-HT2B receptor by its agonist BW723C86 induced proliferation of ICC. Inhibition of phosphatidylinositol 3-kinase by LY294002 decreased base-line proliferation but had no effect on 5-HT2B receptor-mediated proliferation. Proliferation of ICC through the 5-HT23 receptor was inhibited by the phospholipase C inhibitor U73122 and by the inositol 1,4,5trisphosphate receptor inhibitor Xestospongin C. Calphostin C, the α, β, γ, and μ protein kinase C (PKC) inhibitor Gö6976, and the α, β, β, γ, and μ PKC inhibitor Gö6983 inhibited 5-HT2B receptor-mediated proliferation, indicating the involvement of PKC α, β, or γ. Of all the PKC isoforms blocked by Gö6976, PKCγ and μ mRNAs were found by single-cell PCR to be expressed in ICC. 5-HT2B receptor activation in primary cell cultures obtained from PKC-/- mice did not result in a proliferative response, further indicating the requirement for PKCγ in the proliferative response to 5-HT2B receptor activation. The data demonstrate that the 5-HT2B receptor-induced proliferative response of ICC is through phospholipase C, [Ca2+]i, and PKC7, implicating this PKC isoform in the regulation of cellular proliferation. [ABSTRACT FROM AUTHOR]

Abstract: Bioluminescence resonance energy transfer (BRET) is a powerful tool for the study of protein–protein interactions and conformational changes within proteins. Two common implementations of BRET are BRET1 with Renilla luciferase (RLuc) and coelenterazine h (CLZ, λem ∼475nm) and BRET2 with the substrate coelenterazine 400a (CLZ400A substrate, λem =395nm) as the respective donors. For BRET1 the acceptor is yellow fluorescent protein (YFP) (λem ∼535nm), a mutant of green fluorescent protein (GFP), and for BRET2 it is GFP2 (λem ∼515nm). It is not clear from previous studies which of these systems has superior signal-to-background characteristics. Here we directly compared BRET1 and BRET2 by placing two different protease-specific cleavage sequences between the donor and acceptor domains. The intact proteins simulate protein–protein association. Proteolytic cleavage of the peptide linker simulates protein dissociation and can be detected as a change in the BRET ratios. Complete cleavage of its target sequence by thrombin changed the BRET2 ratio by a factor of 28.9±0.2 (relative standard deviation [RSD], n =3) and changed the BRET1 ratio by a factor of 3.05±0.07. Complete cleavage of a caspase-3 target sequence resulted in the BRET ratio changes by factors of 15.45±0.08 for BRET2 and 2.00±0.04 for BRET1. The BRET2 assay for thrombin was 2.9 times more sensitive compared with the BRET1 version. Calculated detection limits (blank signal+3σb, where σb =standard deviation [SD] of blank signal) were 53 pM (0.002U) thrombin with BRET1 and 15pM (0.0005U) thrombin with BRET2. The results presented here suggest that BRET2 is a more suitable system than BRET1 for studying protein–protein interactions and as a potential sensor for monitoring protease activity. [Copyright &y& Elsevier]

Purpose: Since 1970, women of childbearing age have increasingly participated in the workforce. However, literature on work–family conflict has not specifically addressed the health of postpartum women. This study examined the relationship between work–family conflict and mental and physical health of employed mothers 11 weeks after childbirth. Methods: Employed women, 18 years and older, were recruited while in the hospital for childbirth (N = 817; 71% response rate). Mental and physical health at 11 weeks postpartum was measured using SF-12 version 2. General linear models estimated the associations between the independent variables and health. A priori causal models and directed acyclic graphs guided selection of confounding variables. Results: Analyses revealed that high levels of work interference with family were associated with significantly lower mental health scores. Medium and high levels of family interference with work revealed a dose-response relationship resulting in significantly worse mental health scores. Coworker support was strongly and positively associated with better physical health. Conclusions: Work–family conflict was negatively associated with mental health but not significantly associated with physical health. Availability of social support may relieve the burden women can experience when balancing work roles and family obligations. [Copyright &y& Elsevier]

The article cites a study which examines self-reported medical conditions related to perfluorooctanesulfonyl fluoride (PFOS) in manufacturing employees in Decatur, Alabama. The study relies heavily on the crucial relevance of PFOS and other perfluorinated chemicals, and the discoveries in animals exposure to the PFOS material. The primary purpose of the study is to investigate whether some cancers, other conditions, and pregnancy outcomes are connected to occupational (PFOS) exposure. The researchers have presents a survey on both previous and presently working employees of a perflourooctanesulfonyl fluoride production firm to check various cancers and health conditions. They conclude that the health conditions, and birth weight of workers are not associated with PFOS exposure.

Keratin 19 is a member of the cytokeratin family that is critical for maintenance of cellular architecture and organization, especially of epithelia. The pancreas has three distinct cell types, ductal, acinar, and islet, each with different functions. Embryologically, the pancreatic and duodenal homeobox 1 (PDX1) homeodomain protein is critical for the initiation of all pancreatic lineages; however, the later differentiation of the endocrine pancreas is uniquely dependent upon high PDX1 expression, whereas PDX1 is down-regulated in the ductal and acinar cell lineages. We find that this down-regulation may be required for normal ductal expression of cytokeratin K19. The K19 promoter-reporter gene assay demonstrates that ectopic PDX1 inhibits K19 reporter gene activity in primary pancreatic ductal cells. This is reinforced by our findings that retrovirally mediated stable transduction of PDX1 in primary pancreatic ductal cells suppresses K19 expression, and short interfering RNA to PDX1 in Min6 insulinoma cells results in the induction of normally undetectable K19. Complementary functional and biochemical approaches led to the unexpected finding that a multimeric complex of PDX1 and two members of the TALE homeodomain factor family, MEIS1a and PBX1b, regulates K19 gene transcription through a specific cis-regulatory element (–341 to –325) upstream of the 1(19 transcription start site. These data suggest a unifying mechanism whereby PDX1, myeloid ecotropic viral insertion site (MEIS), and pre-B-cell leukemia transcription factor 1 (PBX) may regulate ductal and acinar lineage specification during pancreatic development. Specifically, concomitant PDX1 suppression and MEIS isoform expression result in proper ductal and acinar lineage specification. Furthermore, PDX1 may inhibit the ductal differentiation program in the pancreatic endocrine compartment, particularly beta cells. [ABSTRACT FROM AUTHOR]

A nas gene region from Rhodobacter capsulatus E1F1 containing the putative nasB gene for nitrite reductase was previously cloned. The recombinant His6-NasB protein overproduced in E. coli showed nitrite reductase activity in vitro with both reduced methyl viologen and NADH as electron donors. The apparent Km values for nitrite and NADH were 0.5 mM and 20 μM, respectively, at the pH and temperature optima (pH 9 and 30°C). The optical spectrum showed features that indicate the presence of FAD, iron-sulfur cluster and siroheme as prosthetic groups, and nitrite reductase activity was inhibited by sulfide and iron reagents. These results indicate that the phototrophic bacterium R. capsulatus E1F1 possesses an assimilatory NADH-nitrite reductase similar to that described in non-phototrophic organisms. [ABSTRACT FROM AUTHOR]

Abstract: Interstitial cells of Cajal (ICC) are the so-called pacemaker cells of the gut. WLacZ/Wv and Sl/Sld mice lack ICC surrounding the myenteric plexus (MP) in the jejunum. We compared the gene expression profile of wild type (WT) and WLacZ/Wv and Sl/Sld mice using suppression subtractive hybridization (SSH), generating a cDNA library of 1303 clones from which 48 unique sequences were differentially expressed with Southern blot. Among them, we identified heme oxygenase2, TROY, and phospholamban in ICC using immunohistochemistry. Using RT-qPCR, c-Kit and two new transcripts Dithp and prenylcysteine oxidase1 were significantly lower expressed in Sl/Sld and WLacZ/Wv versus WT. Prenylcysteine oxidase1 appeared cytotoxic for COS-7 cells and was highly expressed in liver while Dithp was mainly expressed in small intestine. The combination of SSH, Southern blot, RT-qPCR, and immunohistochemistry turned out to be a useful approach to identify rarely expressed genes and genes with small differences in expression. [Copyright &y& Elsevier]

The periplasmic nitrate reductase (Nap) is widespread in proteobacteria. NapA, the nitrate reductase catalytic subunit, contains a Mo-bisMGD cofactor and one [4Fe-4S] cluster. The nap gene clusters in many bacteria, including Rhodobacter sphaeroides DSM158, contain an napF gene, disruption of which drastically decreases both in vitro and in vivo nitrate reductase activities. In spite its importance in the Nap system, NapF has never been characterized biochemically, and its role remains unknown. The NapF protein has four polycysteine clusters that suggest that it is an iron-sulfur-containing protein. In the present study, a His6-tagged NapF protein was overproduced in Escherichia coli and purified anaerobically. The purified NapF protein was used to obtain polyclonal antibodies raised in rabbit, and cellular fractionation of R. sphaeroides followed by immunoprobing with anti-NapF antibodies revealed that the native NapF protein is located in the cytoplasm. This contrasts with the periplasmic location of the mature NapA. However, NapA could not be detected in an isogenic napF- strain of R. sphaeroides. The His6-tagged NapF protein displayed spectral properties indicative of Fe-S clusters, but these features were rapidly lost, suggesting cluster lability. However, reconstitution of the Fe-S centers into the apo-NapF protein was achieved in the presence of Azotobacter vinelandii cysteine desulfurase (NifS), and this allowed the recovery of nitrate reductase activity in NapA protein that had previously been treated with 2,2′-dipyridyl to remove the [4Fe-4S] cluster. This activity was not recovered in the absence of NapF. Taking into account the cytoplasmic localization of NapF, the presence of labile Fe-S clusters in the protein, the napF- strain phenotype, and the NapF-dependent reactivation of the 2,2′-dipyridyl-treated NapA, we propose a role for NapF in assembling the [4Fe-4S] center of the catalytic subunit NapA. [ABSTRACT FROM AUTHOR]

Each year an estimated 600 000 new leprosy cases are diagnosed worldwide. The spectrum of the disease varies widely from limited tuberculoid forms to extensive lepromatous forms. A measure of the risk to develop lepromatous forms of leprosy is provided by the extent of skin reactivity to lepromin (Mitsuda reaction). To address a postulated oligogenic control of leprosy pathogenesis, we investigated in the present study linkage of leprosy susceptibility, leprosy clinical subtypes, and extent of the Mitsuda reaction to six chromosomal regions carrying known or suspected leprosy susceptibility loci. The only significant result obtained was linkage of leprosy clinical subtype to the HLA/TNF region on human chromosome 6p21 (P[SUBcorrected] = 0.00126). In addition, we established that within the same family different HLA/TNF haplotypes segregate into patients with different leprosy subtypes directly demonstrating the importance of this genome region for the control of clinical leprosy presentation. [ABSTRACT FROM AUTHOR]

Flavonoids are well known as effective free radical scavengers exhibiting therefore an antioxidant behaviour. Another antioxidant mechanism however may result from the ability they have to chelate metal ions, rendering them inactive to participate in free radical generating reactions. Electrospray mass spectrometry has been used to study metal ion interactions with a set of flavonoids from different classes. Complexes with a range of stoichiometries, of metal: flavonoid, 1:1, 1:2, 2:2, 2:3 have been observed. The stoichiometry 1:2 is in general the preferred one. It is established for flavones and for the flavanone naringenin that the binding metal sites are preferentially at the 5-hydroxyl and 4-oxo groups. Redox reactions are also observed through the change of the oxidation state of the metal, jointly with the oxidation of the flavonoid by loss of hydrogen. Structures of the oxidized species of some flavonoids are proposed. [ABSTRACT FROM AUTHOR]

Reports on the development of a strategy for the construction of the typical core structure of the Stemona alkaloids. Control of the relative stereochemistry of the groups on the core 1-azabicyclo[5.3.0]decane ring system by a [3,3] sigmatropic rearrangement of an acylimmonium ion followed by selective reduction; Direction of efforts toward elaboration of the characteristic butyrlactone substituent.

Abstract Aims To establish whether a system of differential shared care between general practitioners and specialists is compatible with patients receiving the level of care they require. Methods We sought to trace 200 shared care patients whose care had been kept at the general practitioner level after initial referral and compared them with a group of patients who had been re-referred to the Royal Prince Alfred Hospital Diabetes Centre for specialist review. Results There were no significant differences in glycaemic, blood pressure and lipid levels of returned and non-returned patients at initial assessment. However, non-returned patients were less likely to have a history of macrovascular disease or risk factor (adjusted odds ratio (OR) 0.4; 95% confidence interval (CI) 0.2–0.6). Their referral letter was also more likely to emphasize their type and/or duration of diabetes (adjusted OR 4.6; 95% CI 2.5–8.4). Nearly half (47.1%) of the non-returned group changed their doctor in the years following their initial specialist review, increasing their likelihood of not being re-referred five-fold (adjusted OR 5.0; 95% CI 2.9–8.8). At initial assessment, non-returned patients were given less treatment recommendations (adjusted OR 0.5; 95% CI 0.3–0.7). Doctors registered with the Diabetes Shared Care Programme referred more patients than their non-shared care counterparts. However, a higher proportion of these doctors (52.5% vs. 21.3%; χ2 = 16.5, 1 d.f., P = 0.00005) were selective in whom they re-referred. Conclusion Differential shared care encourages appropriate referral to specialist services, without compromise to standards of care. Diabet. Med. 18, 554–557 (2001). [ABSTRACT FROM AUTHOR]

Objectives: To examine the immunization coverage rates of 12-36-month-old Australian-born children from an Arabic-speaking background in Central Sydney as determined by parental report and documentary evidence.Methodology: Eligible children were identified by examination of the records of five hospitals. Eligibility criteria were that the mother gave an Arabic speaking country of birth and a Central Sydney post code (as her place of residence) and the child was born between 1 May 1994 and 30 April 1996. Parents of all eligible children were invited to participate, either by a special appointment to answer a structured questionnaire, or by telephone survey. Of the 1157 eligible children identified from hospital birth records, only 641 could be contacted, of whom 584 (91.1%) agreed to participate. Full information on age appropriate immunization rates, as reported by parents and documented in records, could be assessed for 403 children.Results: Parents reported that 97.6% of children were fully immunized. When the child's immunization status could be verified from either the child's personal health record and/or the service provider, the rate of full, age-appropriate immunization was 94.3% (95% confidence intervals 92.0-96.6) compared to a parent-reported rate of 98.0%. General practitioners provided 76.2% of immunizations.Conclusion: While a substantial proportion of children identified from birth records could not be contacted, comparisons with census data and other analyses indicate that this sample is likely to be representative of the general population of 12-36-month-old Australian-born children from an Arabic-speaking background. This group appeared to be highly immunized. Further studies examining why the rates for this ethnic group are high in Central Sydney may determine strategies which will enhance immunization rates in other communities. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the prevalence of serological evidence of immunity to measles and rubella in preschool children in central and southern Sydney (NSW, Australia) and the prevalence of immunity in children with either documented or parentally reported immunization.Methods: Geographical cluster random sampling was used to select children aged between 18 and 60 months to participate in the present study. Standardized interviews obtained information on each child's reported (by parents) immunization status and documentary evidence of immunization was recorded from the Personal Health Record. Venous blood was collected, serum was separated and stored frozen until tested. Measles and rubella antibodies were measured using ELISA, with either immunofluorescence or haemagglutination inhibition being used to clarify equivocal results. The study was conducted from 1992 to 1994 in conjunction with surveys of blood lead concentrations, iron status and micronutrient status.Results: Parents of 726 of 953 children identified between 9 and 60 months of age agreed to participate in the lead, immunization, iron status and micronutrient studies. Sufficient blood for antibody testing was obtained from 580 children, aged 18 to 62 months at the time of collection. Parents reported that 94.7% (95% confidence interval (CI) 92.7-96.5%) of children had received a measles-mumps or measles-mumps-rubella (MMR) immunization. General practitioners administered 72.8% of these immunizations. The prevalence of serological evidence of immunity to measles and rubella was 88.8% (95% CI 86.2-91.4%) and 91.9% (95% CI 89.6-94.2%). respectively. There was documented evidence of measles and rubella immunization for 88.4% (95% CI 85.7-91.2%) and 86.4% (95% CI 83.4-89.3%) of children, respectively. Of children with documented measles immunization, 91.6% (95% CI 89.2-94.0%) had detectable measles antibody. Of children with documented rubella immunization 97.2% (95% CI 95.8-98.6%) had detectable rubella antibody.Conclusions: Measles and rubella immunization rates in central and southern Sydney are relatively high and most of these immunizations are provided by the private sector. Immunity to rubella in children with documented rubella immunization is at the level that would be expected from seroconversion studies. Immunity to measles in children with documented measles immunization is slightly lower than expected from seroconversion studies, highlighting the need for the second MMR immunization in preschool children, as well as making near universal immunization imperative if this disease is to be eradicated. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the prevalence of serological evidence of immunity to measles and rubella in preschool children in central and southern Sydney (NSW, Australia) and the prevalence of immunity in children with either documented or parentally reported immunization. Methods: Geographical cluster random sampling was used to select children aged between 18 and 60 months to participate in the present study. Standardized interviews obtained information on each child’s reported (by parents) immunization status and documentary evidence of immunization was recorded from the Personal Health Record. Venous blood was collected, serum was separated and stored frozen until tested. Measles and rubella antibodies were measured using ELISA, with either immunofluorescence or haemagglutination inhibition being used to clarify equivocal results. The study was conducted from 1992 to 1994 in conjunction with surveys of blood lead concentrations, iron status and micronutrient status. Results: Parents of 726 of 953 children identified between 9 and 60 months of age agreed to participate in the lead, immunization, iron status and micronutrient studies. Sufficient blood for antibody testing was obtained from 580 children, aged 18 to 62 months at the time of collection. Parents reported that 94.7% (95% confidence interval (CI) 92.7–96.5%) of children had received a measles–mumps or measles–mumps–rubella (MMR) immunization. General practitioners administered 72.8% of these immunizations. The prevalence of serological evidence of immunity to measles and rubella was 88.8% (95% CI 86.2–91.4%) and 91.9% (95% CI 89.6–94.2%), respectively. There was documented evidence of measles and rubella immunization for 88.4% (95% CI 85.7–91.2%) and 86.4% (95% CI 83.4–89.3%) of children, respectively. Of children with documented measles immunization, 91.6% (95% CI 89.2–94.0%) had detectable measles antibody. Of children with documented rubella immunization, 97.2% (95% CI 95.8–98.6%) had detectable rubella antibody. Conclusions: Measles and rubella immunization rates in central and southern Sydney are relatively high and most of these immunizations are provided by the private sector. Immunity to rubella in children with documented rubella immunization is at the level that would be expected from seroconversion studies. Immunity to measles in children with documented measles immunization is slightly lower than expected from seroconversion studies, highlighting the need for the second MMR immunization in preschool children, as well as making near universal immunization imperative if this disease is to be eradicated. [ABSTRACT FROM AUTHOR]

Assesses the quality of communications between hospitals and general practitioners in New South Wales. Evaluation of medical records; Discussions with stakeholders; Survey of GP to identify potential measures of quality.

Patient‐reported outcomes (PROs) are closely related to the delivery of high‐quality care and services. Patient‐reported outcome measures (PROMs) are the tools used to measure the PROs. Despite the challenges and barriers associated with using PROs and PROMs, measuring PROs is valuable for a patient's health status and advancing evidence‐based medicine. Real‐world implementation of PROMs may especially open possibilities for healthcare systems under reform, such as Saudi Arabia. This paper highlights the concepts of PROs and PROMs. Moreover, it distinguishes between PROs and other concepts such as patient experience, quality of life, and patient satisfaction. It also explores the available literature in Saudi Arabia and the world regarding PROs and their role in improving healthcare systems. Last, this paper advocates for utilizing the national and comprehensive tools of PROMS in different levels and disciplines. Key points: Patient‐reported outcomes provide an opportunity to engage patients in their care, enhance shared decision making, and improve care effectively and safely.Integrating patient‐reported outcome measures (PROMs) in patient care has been associated with improving patient safety and patient experience and helping achieve more patient‐centered care.Related literature demonstrated some limitations that might hinder the effective implementation of PROMs, related to the integrity of data and lack of methodological standardization of PROMs data.Patient‐reported outcomes are poorly addressed within the Saudi literature, and the utilization of PROs is also underdeveloped and needs further consideration.There is an excellent opportunity for researching and implementing PROMs in the healthcare setting in Saudi Arabia, which is currently undergoing a major transformation. [ABSTRACT FROM AUTHOR]

Ionizing radiation (IR) and oncolytic viruses are both used to treat cancer, and the effectiveness of both agents depends upon stimulating an immune response against the tumor. In this study we tested whether combining image guided ionizing radiation (IG-IR) with an oncolytic vaccinia virus (VACV) could yield a better therapeutic response than either treatment alone. ΔF4LΔJ2R VACV grew well on irradiated human and mouse breast cancer cells, and the virus can be combined with 4 or 8 Gy of IR to kill cells in an additive or weakly synergistic manner. To test efficacy in vivo we used immune competent mice bearing orthotopic TUBO mammary tumors. IG-IR worked well with 10 Gy producing 80% complete responses, but this was halved when the tumors were treated with VACV starting 2 days after IG-IR. VACV monotherapy was ineffective in this model. The antagonism was time dependent as waiting for 21 days after IG-IR eliminated the inhibitory effect but without yielding any further benefits over IR alone. In irradiated tumors, VACV replication was also lower, suggesting that irradiation created an environment that did not support infection as well in vivo as in vitro. A study of how four different treatment regimens affected the immune composition of the tumor microenvironment showed that treating irradiated tumors with VACV altered the immunological profiles in tumors exposed to IR or VACV alone. We detected more PD-1 and PD-L1 expression in tumors exposed to IR+VACV but adding an αPD-1 antibody to the protocol did not change the way VACV interferes with IG-IR therapy. VACV encodes many immunosuppressive gene products that may interfere with the ability of radiotherapy to induce an effective anti-tumor immune response through the release of danger-associated molecular patterns. These data suggest that infecting irradiated tumors with VACV, too soon after exposure, may interfere in the innate and linked adaptive immune responses that are triggered by radiotherapy to achieve a beneficial impact. [ABSTRACT FROM AUTHOR]

Background: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs. Methods: We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6-15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a² = additive genetics; c² = common or shared environment; e² = unique or nonshared environment). We also assessed correlations with RRB severity. Results: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a² = 0.56 to 0.87), except for ACC white matter volume (a² = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a² = 0.65 to 0.97), but the cortical thickness of the ACC (c² = 0.44, 95% CI 0.22 to 0.66) and OFC (c² = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated. Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors. Conclusion: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD. [ABSTRACT FROM AUTHOR]