[The Saint Petersburg Society of Pathologists is 100 years old].
The paper describes the history of the Saint Petersburg Society of pathologists since it was founded in 1909. It shows what great role is played by outstanding Russian medical scientists who have established their own schools of pathomorphologists and are respected in our and foreign countries. The activities of the society's members in research developments in cardiovascular and infectious diseases, cancer morphology, etc., as well as their practical participation in the work of the health care facilities of the city and its region are characterized. This work is characterized by the permanent conformance to the world standards of human pathology as a basic science of the present day, by steadily maintaining the established traditions of the Saint Petersburg school. The authors follow the evolution of a pathologist and his/her becoming to a clinical pathologist as the problems facing pathomorphology are extended and its methodic and methodological capacities are improved.


Computed tomographic image comparison between mediastinal and lung windows provides possible prognostic information in patients with small peripheral lung adenocarcinoma.
The purpose of this study was to determine whether the ratio of the area of the mediastinal computed tomographic image to that of the lung computed tomographic image can be a prognostic factor of small peripheral lung adenocarcinoma. We studied the computed tomographic images of 143 patients with primary peripheral lung adenocarcinoma of 30 mm or less in maximum diameter. Two groups were categorized according to the tumor's ratio of the area of the mediastinal computed tomographic image to that of the lung computed tomographic image (tumor's area in the mediastinal computed tomographic image/tumor's area in lung computed tomographic image x 100%), both faint density-type (<50%) and solid-type images (>/=50%). Clinical factors and prognoses of the 2 groups were analyzed. There were 58 patients with the solid-type tumor image and 85 patients with the faint density-type tumor image. The number of patients with tumor size of less than 20 mm in the faint density-type tumor group (n = 30) was significantly higher than that in the solid-type tumor group (n = 8, P =.008). The 5-year survival of patients with faint density-type tumors was 74.1%, whereas that in patients with solid-type tumors was 54.2% (P =.013). Furthermore, the survival curve of patients with the solid-type computed tomographic image combined with ground-glass opacity was similar to that of patients with the faint density-type image. Multivariate analysis revealed the prognostic influence of the ratio of the area of the mediastinal computed tomographic image to that of the lung computed tomographic image on survival (P =.029, relative risk = 0.48) and showed to be of second highest influence after the N factor. It is suggested that the ratio of the area of the mediastinal computed tomographic image to that of the lung computed tomographic image can be a prognostic factor in patients with small peripheral lung adenocarcinoma.


Reduced cerebral oxygen saturation measured by absolute cerebral oximetry during thoracic surgery correlates with postoperative complications.
Regional cerebral oxygen saturation (S(ct)O(2)) has recently been shown to decrease significantly during thoracic surgery. The present study investigates whether these desaturations are related to postoperative complications. Fifty patients undergoing thoracic surgery with a single-lung ventilation (SLV) of >45 min duration were enrolled. Regional cerebral oxygen saturation was measured using absolute oximetry; standard clinical variables, and SOFA and Clavien scores were recorded. Correlation between minimum S(ct)O(2) during SLV and postoperative complication scores was analysed using Pearson's correlation test, chi(2) test, and logistic regression. Forty-seven patients underwent lobectomy, two patients a pneumonectomy and 1 patient a chest wall resection. Eighty-two per cent of the patients had a decrease in S(ct)O(2) of >15% from baseline value, and 10% of the patients had a minimal absolute S(ct)O(2) value between 45% and 55%. The minimal absolute S(ct)O(2) values during SLV correlated with the Clavien score (R(2)=0.098, P=0.0201) and the non-respiratory SOFA score (R(2)=0.090, P=0.0287). By defining a threshold of S(ct)O(2)=65%, the odds ratio of having a non-respiratory organ failure was 2.37 (95% CI 1.18-4.39, P=0.043) and a complication according to the Clavien score (Clavien score >0) was 3.19 (95% CI 1.60-6.34, P=0.0272). Thoracic surgery with SLV seemed to be associated with a significant decrease in S(ct)O(2), and minimal S(ct)O(2) values correlated positively with postoperative complications.


Sensitivity assessment of workflows detecting rare circulating cell-free DNA targets: A study design proposal.
The field of liquid biopsy has seen extensive growth in recent decades, making it one of the most promising areas in molecular diagnostics. Circulating cell-free DNA (ccfDNA) especially is used as an analyte in a growing number of diagnostic assays. These assays require specified preanalytical workflows delivering ccfDNA in qualities and quantities that facilitate correct and reliable results. As each step and component used in the preanalytical process has the potential to influence the assay sensitivity and other performance characteristics, it is key to find an unbiased experimental setup to test these factors in diagnostic or research laboratories. We defined one such setup by using blood from healthy subjects and commercially available products for blood collection, spike-in material, ccfDNA isolation, and qPCR assays. As the primary read-out, we calculated the probit model-based LOD95 (limit of detection of the 95th percentile) from the qPCR assay results. In a proof of principle study we tested two different but widely used blood ccfDNA profile stabilization technologies in blood collection tubes, the Cell-Free DNA BCT and the PAXgene Blood ccfDNA Tube. We tested assays for three different EGFR gene mutations and one BRAF gene mutation. The study design revealed differences in performance between the two tested technologies for all four mutations. In conclusion, we successfully established a blueprint for a test procedure capable of verifying and validating a liquid biopsy workflow from blood collection to the analytical result.


Fatal rhabdomyolysis caused by lipid-lowering therapy.
Treatment of hypercholesterolemia has been shown to reduce mortality in patients with coronary artery disease. Patients with severe lipid abnormalities may require high-dose statin therapy, at times used in combination with additional agents. We report a case of fatal rhabdomyolysis caused by the combination of simvastatin and gemfibrozil. Clinicians should be aware of risk factors for rhabdomyolysis, which include underlying renal insufficiency, high-dose statin therapy, and combination therapy with a fibrate.


Secretory breast carcinoma in a 12-year-old girl: A case report.
Secretory breast carcinoma (SBC) is a rare tumor that was originally described in children and adolescent women, with a characteristic morphology and controversy regarding the choice of treatment. This unusual breast cancer subtype generally has a favorable prognosis, although several cases have been described in adults with increased tumor aggressiveness and a risk of metastases. Surgery is considered the most appropriate treatment for this pathology. The present study describes the case of a 12-year-old female who presented with a painless lump in the left breast, and subsequently underwent a biopsy of the sentinel lymph node and a partial resection of the left breast (breast-conserving therapy). Periodic follow-up examinations after completion of the surgical and chemotherapeutic treatment have shown no evidence of either local regression or distant metastases and, one year later, the patient remains free of the disease. This study suggests that local excision with sentinel lymph node mapping may be a suitable therapeutic approach for children with SBC.


Novel O6-methylguanine-DNA methyltransferase SNPs: a frequency comparison of patients with familial melanoma and healthy individuals in Sweden.
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is involved in the cellular defense against alkylating agents. Genetic alterations in the MGMT gene may impair the protein's ability to remove alkyl groups from the O6-position of guanine, thereby raising the mutation rate and increasing the risk of cancer. We assessed polymorphisms in the promoter region and the 5 exons of the MGMT gene by PCR/SSCP and nucleotide sequence analysis of DNA extracted from blood samples. The population studied consisted of 89 melanoma patients, each belonging to a different family with a hereditary predisposition for melanoma, and 76 healthy individuals (blood donors). A total of 11 single nucleotide polymorphisms (SNPs) were detected, five in the promoter region, one in exon 1, two in exon 3 and three in exon 5. Six of the alterations were novel polymorphisms, of which five were located in the promoter region and one in exon 5. When the distribution of specific SNPs in cases and controls with only one variant was calculated; C575A was present only in melanoma patients (p=0.072). Moreover, while 20% of the healthy individuals had no SNPs this was the case in only 12.4% of the melanoma patients. However, no statistically significant differences were seen between cases and controls for any of the 11 SNPs.


Evidence for a recent increase in forest growth.
Forests and their soils contain the majority of the earth's terrestrial carbon stocks. Changes in patterns of tree growth can have a huge impact on atmospheric cycles, biogeochemical cycles, climate change, and biodiversity. Recent studies have shown increases in biomass across many forest types. This increase has been attributed to climate change. However, without knowing the disturbance history of a forest, growth could also be caused by normal recovery from unknown disturbances. Using a unique dataset of tree biomass collected over the past 22 years from 55 temperate forest plots with known land-use histories and stand ages ranging from 5 to 250 years, we found that recent biomass accumulation greatly exceeded the expected growth caused by natural recovery. We have also collected over 100 years of local weather measurements and 17 years of on-site atmospheric CO(2) measurements that show consistent increases in line with globally observed climate-change patterns. Combined, these observations show that changes in temperature and CO(2) that have been observed worldwide can fundamentally alter the rate of critical natural processes, which is predicted by biogeochemical models. Identifying this rate change is important to research on the current state of carbon stocks and the fluxes that influence how carbon moves between storage and the atmosphere. These results signal a pressing need to better understand the changes in growth rates in forest systems, which influence current and future states of the atmosphere and biosphere.


Chemically modified carbon paste electrode for iodide determination on the basis of cetyltrimethylammonium iodide ion-pair.
A new carbon paste electrode (CPE) for the determination of iodide ion based on a cetyltrimethylammonium iodide (CTMAI) ion pair as an electroactive material is described. The electrode shows a linear response for iodide ion over the concentration range of 4 x 10(-5) M to 1 x 10(-1) M with a lower detection limit of 4 x 10(-5) M at 25 degrees C. The electrode has a Nemstian slope of -55.0 +/- 0.4 mV/decade and a fast potential response of 45 s, which is almost constant over a pH range of 5.0 - 9.0. Selectivity coefficient data of the CTMAI-CPE for some common ions show negligible interference, and the electrode has high selectivity towards the iodide ion. An average recovery of 101.83% with a relative standard deviation of 1.53% has been achieved for the determination of iodide in Flaxedil (gallamine triethiodide) ampoules, a muscle relaxant drug. The electrode has been examined for the determination of iodide in saline water; the results were found to compare favorably with those obtained using Metrohm iodide ISE. The electrode has been utilized as an end-point indicator electrode for the determination of Hg(II) and phenylmercury(I) in their aqueous solutions using potentiometric titration with a potassium iodide standard solution.


Recent thymic emigrants in lymphoma patients with and without human immunodeficiency virus infection candidates for autologous peripheral stem cell transplantation.
Signal joint T cell receptor excision circles (sjTRECs) have been reported as a clinical marker to measure the potential for recovery of the immune system after immunosuppressive treatments. The aim of this study was to investigate the thymic regenerative potential in 55 human immunodeficiency virus (HIV)-1 infected (HIV(+)) and non-infected (HIV(-)) lymphoma patients, candidates for autologous stem cell transplantation (ASCT). Moreover, the possible associations between sjTRECs and other immunological and clinical parameters were examined. SjTRECs levels in peripheral blood mononuclear cells (PBMCs) were quantified by real-time polymerase chain reaction and T lymphocyte subsets were analysed by flow cytometry. Our data showed that sjTRECs were reduced in lymphoma patients compared to healthy controls, although a weak significant association between low sjTRECs levels and increasing age was maintained [odds ratio (OR) = 4.00; 95% confidence interval (CI) 1.09-17.17]. We found that different chemotherapeutic treatments seem to induce similar effects on the thymic reservoir, independently from their intensity (type and number of cycles of previous chemotherapy). Results from multivariate models including adjustment for patients' sex, type of lymphoma and type of chemotherapy showed that thymic output was independent from HIV infection (OR, 0.95; 95% CI 0.20-4.48). SjTRECs levels correlated with naive T cell subsets in overall lymphoma patients and after stratification by HIV infection (r > 0.37). HIV replication should be maximally suppressed to properly evaluate thymic output by sjTREC markers. Our results suggested that de novo T cell generation is maintained partially in pretreated recurrent lymphoma patients, candidates for ASCT, and could contribute to restore the immune function after transplantation.


Quantitation of blood flow after Le Fort I osteotomy.
Le Fort I maxillary osteotomies were performed on ten macaque monkeys. The particle distribution method (nondiffusible radioactive microspheres) was used to quantitate local blood flow before and after surgery. Significant reduction in blood flow to the osteotomized maxillary segment was noted in those animals (group S) where the descending palatine vessels were transected. Those animals in which the vascular pedicle was intact (group I) showed decreased blood flow to the attached gingiva and alveolar bone, but palatal tissue blood flow was unchanged or increased. The results reinforce the precept of the importance of maintaining an adequate nutrient pedicle when performing orthognathic surgical procedures.


Advanced Photonic Thin Films for Solar Irradiation Tuneability Oriented to Greenhouse Applications.
The world population is growing by 1 billion people every 10 years. There will come a time when there will be more people to feed but less land to grow food. Greenhouses can be the solution to this problem because they provide the highest production yield per m2 and also use less water, provide food safety, and offer high quality. Photosynthetic active radiation (PAR) favors vegetable growth with a specific blue and red light ratio. Thus, increasing the amount of red light improves chlorophyll absorption and photosynthetic efficiency. In this article, we present a hybrid system that combines luminescent materials and photonic crystals for better management of the light reaching the greenhouse. The luminescent dyes considered herein are combined ensuring a Förster resonance energy transfer (FRET) nonradiative mechanism to enhance the absorption range. The designed photonic crystal maximizes reflections in the Near-Infrared (NIR) range, and therefore, thermal losses are minimized. Thus, by converting harmful or ineffective radiation for plant growth to the PAR region, we aim to demonstrate growth-condition enhancement for the different vegetables that have been used as a model.


Adaptive LINE-P: An Adaptive Linear Energy Prediction Model for Wireless Sensor Network Nodes.
In the context of wireless sensor networks, energy prediction models are increasingly useful tools that can facilitate the power management of the wireless sensor network (WSN) nodes. However, most of the existing models suffer from the so-called fixed weighting parameter, which limits their applicability when it comes to, e.g., solar energy harvesters with varying characteristics. Thus, in this article we propose the Adaptive LINE-P (all cases) model that calculates adaptive weighting parameters based on the stored energy profiles. Furthermore, we also present a profile compression method to reduce the memory requirements. To determine the performance of our proposed model, we have used real data for the solar and wind energy profiles. The simulation results show that our model achieves 90-94% accuracy and that the compressed method reduces memory overheads by 50% as compared to state-of-the-art models.


E2F1 induces pituitary tumor transforming gene (PTTG1) expression in human pituitary tumors.
Rb/E2F is dysregulated in murine and human pituitary tumors. Pituitary tumor transforming gene (PTTG1), a securin protein, is required for pituitary tumorigenesis, and PTTG1 deletion attenuates pituitary tumor development in Rb(+/-) mice. E2F1 and PTTG1 were concordantly overexpressed in 29 of 46 Rb(+/-) murine pituitary tissues and also in 45 of 80 human pituitary tumors (P < 0.05). E2F1 specifically bound the hPTTG1 promoter as assessed by chromatin immunoprecipitation and biotin-streptavidin pull-down assay, indicating that hPTTG1 may act as a direct E2F1 target. Transfection of E2F1 and its partner DP1 dose-dependently activated hPTTG1 transcription up to 3-fold in p53-devoid H1299 cells but not in p53-replete HCT116 cells. E2F1 overexpression enhanced endogenous hPTTG1 mRNA and protein levels up to 3-fold in H1299 cells. The presence of endogenous p53/p21 constrained the induction, whereas knocking down either p53 or p21 in HCT116 cells restored E2F1-induced hPTTG1 transactivation and expression. Moreover, suppressing Rb by small interfering RNA concordantly elevated E2F1 and hPTTG1 protein levels. In contrast, transfection of E2F1 small interfering RNA lowered hPTTG1 levels 24 h later in HCT116 than in H1299 cells, indicating that p53 delays E2F1 action on hPTTG1. These results elucidate a mechanism for abundant tumor hPTTG1 expression, whereby Rb inactivation releases E2F1 to induce hPTTG1. This signaling pathway may underlie the requirement of PTTG1 for pituitary tumorigenesis.


Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model.
Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I(+). Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.


Triple synchronous tumour of female genital tract: cervical squamous cell carcinoma, right ovarian dermoid cyst and left ovarian benign Brenner tumour.
Synchronous tumours of two different histological type are not uncommon in the female genital tract. But triple synchronous tumours of three or more different histological types is extremely rare. We describe a case of a 48-year-old female patient who presented with cervical growth and bilateral ovarian masses. Pathological evaluation of the surgical specimen revealed synchronous cervical squamous cell carcinoma, right ovarian dermoid cyst and left ovarian benign Brenner tumour. The patient was treated as per the carcinoma cervix protocol and is disease free at 1-year follow-up. To our knowledge this is the first report of such an occurrence. This occurrence cannot be related to any known hereditary syndromes, hence may be considered a chance association. Although rare, awareness of such an occurrence is important for the surgeon, radiologist and the surgical pathologist for proper diagnosis and management.


Video-Rate Identification of High-Capacity Low-Cost Tags in the Terahertz Domain.
In this article, we report on video-rate identification of very low-cost tags in the terahertz (THz) domain. Contrary to barcodes, Radio Frequency Identification (RFID) tags, or even chipless RFID tags, operate in the Ultra-Wide Band (UWB). These THz labels are not based on a planar surface pattern but are instead embedded, thus hidden, in the volume of the product to identify. The tag is entirely made of dielectric materials and is based on a 1D photonic bandgap structure, made of a quasi-periodic stack of two different polyethylene-based materials presenting different refractive indices. The thickness of each layer is of the order of the THz wavelength, leading to an overall tag thickness in the millimetre range. More particularly, we show in this article that the binary information coded within these tags can be rapidly and reliably identified using a commercial terahertz Time Domain Spectroscopy (THz-TDS) system as a reader. More precisely, a bit error rate smaller than 1% is experimentally reached for a reading duration as short as a few tens of milliseconds on an 8 bits (~40 bits/cm2) THID tag. The performance limits of such a tag structure are explored in terms of both dielectric material properties (losses) and angular acceptance. Finally, realistic coding capacities of about 60 bits (~300 bits/cm2) can be envisaged with such tags.


Using a collaborative decision-making approach to identify, prioritise and respond to issues influencing Good Pharmacy Practice across countries of the Western Pacific Region.
The Western Pacific Pharmaceutical Forum aims to foster Good Pharmacy Practice (GPP) in the Western Pacific Region (WPR). Our objective in this work was to develop and implement a process that equitably and constructively engaged pharmacy associations from the diverse cultures, languages and models of pharmacy practice in the WPR to identify common issues influencing the implementation of GPP. The World Café concept was incorporated into a modified Tuckman's model for group development to conduct a workshop of leaders from the major pharmacy associations of the WPR. Facilitated discussion groups and collaborative decision-making were used to gather opinions and achieve agreement between the regional leaders. Participants reported the method to be open, systematic and enabled full contribution. Two major issues were identified in relation to each of the four key pharmacist roles associated with GPP. The regional pharmacy leaders agreed the common priority issue for implementing GPP as: 'National competency standards should be established to enable the formulation of professional development framework that lead to enhanced pharmacy practice and patient care' and developed a strategy and work plan to address this issue. Identification of GPP issues and the common major priority occurred with shared knowledge of the current state of practice across the WPR. The adopted methodology overcame cultural and practice differences to ensure full and equal participation of all delegates. The approach ensured ownership by all participants of the strategy and work plan developed to address competency and professional development in the WPR.


Severe acute hypertension among inpatients admitted from the emergency department.
Hospitalists often treat patients with severe acute hypertension (AH) presenting to the hospital. Little is known about the epidemiology of this syndrome. To examine the prevalence of severe AH in patients admitted through the emergency department (ED) and its associated outcomes. A cohort study using retrospectively collected vital signs and other clinical data. A total of 1,290,804 adults admitted between 2005 and 2007. One hundred fourteen acute-care hospitals. Severe AH was defined as at least 1 systolic blood pressure (SBP) >180 mmHg. We used multivariable regression to estimate AH-attributable in-hospital mortality, need for mechanical ventilation (MV), and length of stay (LOS). Severe AH occurred in 178,131 (13.8%) patients. Disease categories with the highest prevalence were nervous (29.0%), circulatory (16.0%), endocrine (14.7%), and kidney/urinary (13.5%). The overall in-hospital mortality was 3.6%. The relationship between severe AH strata and mortality was graded for nervous system diseases; mortality rates for each 10 mmHg increase in SBP from 180 to >220 mmHg were 6.5%, 8.1%, 9.9%, 12.0%, and 19.7%, respectively (P < 0.0001). The relationship between severe AH strata and need for MV was graded in the most pronounced way in respiratory and circulatory conditions (P < 0.0001). The relationship between severe AH strata and LOS was graded in most disease categories (P < 0.0001). Severe AH appears common and its prevalence varies by underlying clinical condition. Severe AH is associated with excess in-hospital mortality for patients with nervous system diseases and, for most disease categories, prolongs hospitalization.


An innovative multi-component variate that reveals hierarchy and evolution of structural damage in a solid: application to acrylic bone cement.
A major limitation of solid mechanics is the inability to take into account the influence of hierarchy and evolution of the inherent microscopic structure on evaluating the performance of materials. Irreversible damage and fracture in solids, studied commonly as cracks, flaws, and conventional material properties, are by no means descriptive of the subsequent responses of the microstructures to the applied load. In this work, we addressed this limitation through the use of a novel multi-component variate. The essence of this variate is that it allows the presentation of the random damage in the amplitude spectrum, probability space, and probabilistic entropy. Its uniqueness is that it reveals the evolution and hierarchy of random damage in multi- and trans-scales, and, in addition, it includes the correlations among the various damage features. To better understand the evolution and hierarchy of random damage, we conducted a series of experiments designed to test three variants of a poly (methyl methacrylate) (PMMA) bone cement, distinguished by the methods used to sterilize the cement powder. While analysis of results from conventional tension tests and scanning electron microscopy failed to pinpoint differences among these cement variants, our multi-component variate allowed quantification of the multi- and trans-scale random damage events that occurred in the loading process. We tested the statistical significance of damage states to differentiate the responses at the various loading stages and compared the damage states among the groups. We also interpreted the hierarchical and evolutional damage in terms of the probabilistic entropy (s), the applied stress (σ), and the trajectory of damage state. We found that the cement powder sterilization method has a strong influence on the evolution of damage states in the cured cement specimens when subjected to stress in controlled mechanical tests. We have shown that in PMMA bone cements, our damage state variate has the unique ability to quantify and discern the history and evolution of microstructural damage.


Encouraging results with inolimomab (anti-IL-2 receptor) as treatment for refractory acute graft-versus-host disease.
Inolimomab [corrected] an anti-interleukin-2 receptor (anti-IL-2R) monoclonal antibody, may be useful in the treatment of steroid-refractory acute graft-versus-host disease (aGVHD) by inhibiting 1 of its putative immunopathogenic pathways. We retrospectively analyzed 40 consecutive patients who received inolimomab [corrected] as salvage treatment for steroid refractory aGVHD at a single institution between June 1999 and December 2004. Inolimomab [corrected] was given intravenously at a dose of 11 mg/d for 3 consecutive days, followed by 5.5 mg/d for 7 consecutive days and then 5.5 mg every other day for 5 doses. No infusion-related side effects were noted. Twenty-three patients (58%) responded, including 15 (38%) complete and 8 (20%) partial responses. Median overall survival was 294 days (58-996 days) for responders versus 14 days for nonresponders (P < .001), with a 1 year probability of 59% vs 0% for overall survival (P < .0001). Patients without gastrointestinal (GI) involvement showed a higher response rate (100% versus 50% for those without versus with GI involvement, P = .03) In addition, patients who showed some response by day 15 had a higher overall survival (73 +/- 12% vs 24 +/- 12%, respectively, P = .02). The results of this study suggest that inolimomab [corrected] may be an effective salvage therapy for patients with steroid-refractory aGVHD, particularly for those without GI disease, and supports further studies with this agent in prospective controlled trials.


Role of innervation, excitability, and myogenic factors in the expression of the muscular chloride channel ClC-1. A study on normal and myotonic muscle.
The muscular chloride channel (ClC-1) is essential for a normal excitability of mature mammalian muscle fibers; inactivation of the corresponding gene by mutations leads to hyperexcitability of muscle, the hallmark of the disease myotonia. In the mouse, there is very little ClC-1 mRNA in myotubes, and its concentration increases steeply during postnatal development, suggesting a role of the motor nerve in ClC-1 expression. We investigated the response of the expression of the corresponding gene Clc-1 to different patterns of muscle activity as controlled by sarcolemmal excitability and by innervation. In rat and mouse, the level of ClC-1 mRNA was higher in fast (extensor digitorum longus) than in slow (soleus) muscle. Myotonia in the ADR mouse is caused by an insertional mutation leading to the adr allele of the Clc-1 gene and to grossly abnormal ClC-1 mRNAs. Nevertheless, in +/adr heterozygous, phenotypically wild type (WT) animals, the expression levels of both alleles correspond to the gene dosage. However, in the myotonic ADR mouse in which both Clc-1 genes are defective, ClC-1 mRNA levels in slow muscle were nearly as high as in WT fast muscle. In WT muscle, denervation within 2 days caused a drastic reduction of the ClC-1 mRNA level and at the same time an increase of myogenin and MyoD mRNAs. Neither effect of denervation was observed in myotonic mice (homozygous for the alleles adr or adrK), suggesting that spontaneous electrical activity of the hyperexcitable sarcolemma may substitute for nerve activity. Furthermore, potential MyoD/myogenin-binding sequence motifs were identified in the 5' regulatory region of the Clc-1 gene. These findings suggest that the activity-dependent regulation of the muscular chloride channel 1 gene is mediated by myogenic factors.


Evolutionary changes in dopaminergic modulation of courtship behavior in Cnemidophorus whiptail lizards.
Preoptic dopamine release is integral to the display of copulatory behaviors in male mammals and birds. However, while the anatomical distributions of the dopamine synthesizing enzyme tyrosine hydroxylase are similar among vertebrates, evolutionary changes in the functional role of dopamine are poorly understood. In this study, we tested whether a dopamine D1 receptor agonist would facilitate the display of courtship and copulatory behaviors in two related Cnemidophorine lizards (Cnemidophorus inornatus and Cnemidophorus uniparens). Cnemidophorus lizards offer a unique system to study evolutionary changes in functionality because ancestral (e.g., C. inornatus) and descendant (e.g., C. uniparens) species can be studied in parallel. Cnemidophorus uniparens is an all-female, parthenogenetic species and is the triploid descendant of the sexual and diploid species C. inornatus. Here we report that in castrated male C. inornatus and ovariectomized C. uniparens a dopamine D1 agonist increased the proportion of individuals mounting and decreased the latency to mount. Moreover, there was a species difference in sensitivity to the agonist: Mounting was elicited at a lower dose in C. uniparens than in C. inornatus. One possible explanation for this heightened sensitivity in the triploid parthenogen is that, by virtue of the increased ploidy, the parthenogen has elevated levels of D1 receptor in limbic brain areas modulating courtship behavior.


Multigene Phylogeny Reveals Haploanthostomella elaeidis gen. et sp. nov. and Familial Replacement of Endocalyx (Xylariales, Sordariomycetes, Ascomycota).
During our investigation of palm fungi in Thailand, two interesting taxa from Elaeis guineensis and Metroxylon sagu (Arecaceae) were collected. Based on phylogenetic analyses of a combined dataset of ITS, LSU, rpb2, and tub2 nucleotide sequences as well as unique morphological characteristics, we introduce the new genus Haploanthostomella within Xylariales, and a new species Endocalyx metroxyli. Additionally, in our study, the genus Endocalyx is transferred to the family Cainiaceae based on its brown conidia and molecular phylogenetic evidence.


Monitoring and evaluation of alcoholic fermentation processes using a chemocapacitor sensor array.
The alcoholic fermentation of Savatiano must variety was initiated under laboratory conditions and monitored daily with a gas sensor array without any pre-treatment steps. The sensor array consisted of eight interdigitated chemocapacitors (IDCs) coated with specific polymers. Two batches of fermented must were tested and also subjected daily to standard chemical analysis. The chemical composition of the two fermenting musts differed from day one of laboratory monitoring (due to different storage conditions of the musts) and due to a deliberate increase of the acetic acid content of one of the musts, during the course of the process, in an effort to spoil the fermenting medium. Sensor array responses to the headspace of the fermenting medium were compared with those obtained either for pure or contaminated samples with controlled concentrations of standard ethanol solutions of impurities. Results of data processing with Principal Component Analysis (PCA), demonstrate that this sensing system could discriminate between a normal and a potential spoiled grape must fermentation process, so this gas sensing system could be potentially applied during wine production as an auxiliary qualitative control instrument.


A mediation model linking body weight, cognition, and sleep-disordered breathing.
Academic success involves the ability to use cognitive skills in a school environment. Poor academic performance has been linked to disrupted sleep associated with sleep-disordered breathing (SDB). In parallel, poor sleep is associated with increased risk for obesity, and weight management problems have been linked to executive dysfunction, suggesting that interactions may be operational between SDB and obesity to adversely affect neurocognitive outcomes. To test whether mediator relationships exist between body weight, SDB, and cognition. Structural equation modeling was conducted on data from 351 children in a community-based cohort assessed with the core subtests of the Differential Abilities Scales after an overnight polysomnogram. Body mass index, apnea-hypopnea index, and cognitive abilities were modeled as latent constructs. In a sample of predominantly white children 6 to 10 years of age, SDB amplified the adverse cognitive and weight outcomes by 0.55- to 0.46-fold, respectively. Weight amplified the risk by 0.39- to 0.40-fold for SDB and cognitive outcomes, respectively. Poor ability to perform complex mental processing functions increased the risk of adverse weight and SDB outcomes by 2.9- and 7.9-fold, respectively. Cognitive functioning in children is adversely affected by frequent health-related problems, such as obesity and SDB. Furthermore, poorer integrative mental processing may place a child at a bigger risk for adverse health outcomes.


The interaction with DNA of wild-type and mutant fushi tarazu homeodomains.
The in vitro DNA binding properties of wild-type and mutant fushi tarazu homeodomains (ftz HD) have been analysed. The DNA binding properties of the ftz HD are very similar to those of the Antp HD. In interference experiments with mutant ftz HDs, close approaches between specific portions of the ftz HD peptide and specific regions of the binding site DNA were mapped. A methylation interference, G7 on the beta strand of BS2, is absent from the interference pattern with a mutant ftz HD [ftz (R43A) HD] in which the Arg43 at the second position of helix III (the recognition helix) is replaced by an Ala. This indicated that Arg43 of the ftz HD is in close proximity to the N7 of G7 of the beta strand of BS2 in the major groove. The methylation and ethylation interference patterns with the ftz (NTD) HD, in which the first six amino acids of the homeodomain were deleted, were extensively altered relative to the ftz HD patterns. Methylation of A11 and G12 of the alpha strand and ethylation of the phosphate of nucleotide A12 of the alpha strand no longer interfere with binding. This indicated that the first six amino acids of the homeodomain of ftz interact with A11 of the alpha strand in the minor groove, the phosphate of the nucleotide A13 on the alpha strand and G12 of the alpha strand in the adjacent major groove of BS2. In a binding study using a change of specificity mutation [ftz (Q50K) HD], in which the Gln50 at the ninth position of the third helix is exchanged for a Lys (as in the bicoid HD), and variant binding sites, we concluded that position 50 of the ftz HD and the ftz (Q50K) HD peptides interacts with base pairs at positions 6 and 7 of BS2. These three points of contact allowed us to propose a crude orientation of the ftz HD within the protein-DNA complex. We find that the ftz HD and the Antp HD peptides contact DNA in a similar way.


Proteomics in prostate cancer research.
The incidence of early prostate cancer (PCa) among middle-aged men has increased rapidly. For many of these men, curatively intended treatment does more harm than good. Established prognostic factors are tumor stage and grade. As a result of earlier detection a majority of patients now have nonpalpable tumors (T1c) of intermediate grade (Gleason score 6). Prostate specific antigen in serum in such cases is generally at a low level and not a reliable predictor of prognosis. Altogether there is an urgent need for adjunctive prognostic indicators. In the search for relevant tumor markers for improved patient selection an exploration of the proteome (the human proteins) could be fruitful. This paper critically reviews the use of 2-dimensional gel electrophoresis (2-DE) for proteome research. Additional steps such as image analysis and mass spectrometry are described. Techniques based on non-2-DE platforms: surface-enhanced laser desorption/ionization (SELDI), isotope coded affinity tags (ICAT) and array-based technologies are also summarized. Although labor-intensive and time-consuming, 2-DE is presently the most powerful method for analysis of cellular protein phenotype and may potentially reveal gene regulations that cannot be detected on a genetic level.


Intense Pulsed-light Therapy Significantly Improves Keratosis Pilaris: A Randomized, Double-blind, Sham Irradiation-controlled Trial.
Background: Keratosis pilaris (KP) is a common benign follicular disorder for which various topical and laser treatments have been used, with limited efficacy. Objective: We evaluated the efficacy of intense pulsed light (IPL) therapy for the reduction of skin roughness, erythema, and hyperpigmentation in Thai subjects with KP. Material and Methods: Twenty-four Thai patients with untreated KP on the upper outer arms were enrolled in a randomized, double-blind study. Only one arm of each subject was included and divided into upper and lower parts (25 cm2 per each part). One part was randomized to be treated with IPL using 645 to 950-nm cutoff filter and fluences of 15 to 18 J/cm2, while the other part was treated with sham irradiation. Subjects received four consecutive treatments at four-week intervals. Antera3D was used to measure skin roughness, erythema, and hyperpigmentation at baseline and four weeks after the last treatment. Moreover, clinical outcomes were also evaluated by subject Global Improvement Scores (GIS) and subject satisfaction grading scores. Results: Twenty-three subjects completed the study. There was statistically significant reduction of skin roughness, measured by Antera3D, compared to control group (p<0.001). However, the reduction of skin erythema was not significantly different between two groups (p=0.660). Skin hyperpigmentation significantly increased in the control group compared with intervention group (p=0.01). There were statistically significant improvements in skin roughness, erythema, hyperpigmentation, and overall appearance, graded by subject Global Improvement Scores (p<0.001). Subject satisfaction scores were significantly better in treatment parts (p<0.001). No adverse events, including burning, bulla, erosion, postinflammatory hyper/hypopigmentation, and scar formation developed in any subjects throughout study period. Conclusion: IPL has demonstrated the ability to significantly and safely reduce skin roughness in subjects with KP compared to control after four sessions.


Spatiotemporal complexity of chaos in a phase-conjugate feedback laser system.
An 852 nm semiconductor laser is experimentally subjected to phase-conjugate time-delayed feedback achieved through four-wave mixing in a photorefractive ($ {{\rm BaTiO}_{3}} $BaTiO3) crystal. Permutation entropy (PE) is used to uncover distinctive temporal signatures corresponding to the sub-harmonics of the round-trip time and the relaxation oscillations. Complex spatiotemporal outputs with high PE mostly upwards of $ \sim 0.85 $∼0.85 and chaos bandwidth (BW) up to $ \sim 31\;{\rm GHz} $∼31GHz are observed over feedback strengths up to 7%. The low-feedback region counterintuitively exhibits spatiotemporal reorganization, and the variation in the chaos BW is restricted within a small range of 1.66 GHz, marking the transition between the dynamics driven by the relaxation oscillations and the external cavity round-trip time. The immunity of the chaos BW and the complexity against such spatiotemporal reorganization show promise as an excellent candidate for secure communication applications.


Prenatal Substance Exposure: Associations with Neurodevelopment in Middle Childhood.
Single-substance exposure effects on neurodevelopmental outcomes, such as problem behavior and intelligence quotient (IQ), have been studied in children for decades. However, the long-term consequences of polysubstance exposure are poorly understood. Longitudinal neurodevelopmental data were gathered from cohorts across the United States through the Environmental Influences on Child Health Outcomes Program. Data on prenatal exposure to opioids, nicotine, marijuana, and alcohol were collected from children ages 6 to 11 years (N = 256). Problem behavior was assessed using the Child Behavior Checklist (school-age version), and verbal IQ (VIQ) and performance IQ (PIQ) were assessed using the Weschler Intelligence Scale for Children, Fifth Edition. We first identified latent profiles in the overall sample, then evaluated differences in profile membership for children with and without prenatal substance exposure. Latent profile analysis identified two mutually exclusive categories: average VIQ and PIQ, with typical problem behavior, and below-average VIQ with average PIQ and clinically significant problem behavior. Children with prenatal nicotine and polysubstance exposures were more likely to be classified in the below-average VIQ, elevated problem behavior profile compared with children without prenatal nicotine exposure. The presence of clinically significant behavior problems in children with average PIQ, but below-average VIQ, could represent a unique endophenotype related to prenatal nicotine exposure in the context of other prenatal substance exposures. · The neurodevelopmental consequences of prenatal polysubstance exposure are poorly understood.. · Children with prenatal polysubstance exposure exhibited reduced IQ and elevated problem behavior.. · We found significant behavior problems in children with average PIQ and below-average VIQ.. · This may represent a unique endophenotype related to prenatal nicotine exposure..


Epigenetic programming: the challenge to species hybridization.
In many organisms, the genomes of individual species are isolated by a range of reproductive barriers that act before or after fertilization. Successful mating between species results in the presence of different genomes within a cell (hybridization), which can lead to incompatibility in cellular events due to adverse genetic interactions. In addition to such genetic interactions, recent studies have shown that the epigenetic control of the genome, silencing of transposons, control of non-additive gene expression and genomic imprinting might also contribute to reproductive barriers in plant and animal species. These genetic and epigenetic mechanisms play a significant role in the prevention of gene flow between species. In this review, we focus on aspects of epigenetic control related to hybrid incompatibility during species hybridization, and also consider key mechanism(s) in the interaction between different genomes.


Impact of community care services on the health of older adults: evidence from China.
The rapid growth in the population of older adults has put tremendous pressure on medical and social services in countries including China. Community care services are a feasible solution for promoting healthy aging in developing countries. This study investigated the association between community care services and the health of older adults in China. Using nationally representative survey data from China, consisting of four waves conducted in 2005, 2008, 2011, and 2014, a balanced panel dataset was constructed using a sample of 4,700 older adults (33.1% aged 80 years or older, 51.0% residing in rural areas, and 48.8% women). We employed linear regression models with time-fixed effects and instrumental variable approaches to estimate the effect of community care services on the health of older adults, as well as the differences in these effects across subgroups. The results showed that community care services lead to a significant improvement in both the objective and subjective health and wellbeing of older adults. Among the various service offerings, spiritual recreation services led to a significant increase in both objective and subjective health scores, while medical care services significantly improved wellbeing. This suggests a varied effect of subdivided service types. Further evidence suggests that spiritual recreation services have a significant health-enhancing effect on multiple groups of older adults, and the effect of medical care services is more effective for those living in rural areas, women, and those who are older than 80 years (all p < 0.05). Few studies have examined the impact of community care services on the health of older adults in developing countries. The findings present important implications for improving the health status of older adults and provide suggestions for establishing a socialized aged care system in China.


Synthesis and Biological Evaluation of Steviol Derivatives with Improved Cytotoxic Activity and Selectivity.
Steviol is an ent-kaurene diterpenoid with interesting pharmacological activity. Several steviol derivatives with an exo-methylene cyclopentanone unit were discovered as potent antitumor agents. However, their poor selectivity for tumor cells relative to normal cells reduces their prospects as potential anticancer drugs. In this study, based on previous work, 32 steviol derivatives, including 28 new analogues, were synthesized. Their cytotoxicity against tumor cells and normal cells was evaluated. Several new derivatives, such as 7a, 7h, and 8f, with improved cytotoxic selectivity and antiproliferative activity were obtained, and the structure-activity relationship correlations were investigated. The new compound 8f displayed potent antiproliferative activity against Huh7 cells (IC50 = 2.6 μM) and very weak cytotoxicity against the corresponding normal cells HHL5 (IC50 = 97.0 μM). Further investigation showed that 8f arrested the cell cycle at the G0/G1 phase and caused reactive oxygen species overproduction, decreased mitochondrial membrane potential, and induced apoptosis of Huh7 cells through inhibition of the PI3K/Akt/mTOR and NF-κB pathway as well as upregulation of Bax/Bcl-2 ratio. The present study suggested that 8f is a promising lead compound for new cancer therapies, and the results presented herein may encourage the further modification of steviol for additional derivatives with enhanced efficacy and selectivity.


Rediscovery and redescription of a deep-sea shrimp Lebbeus longidactylus (Kobjakova, 1936) (Crustacea: Decapoda: Caridea: Thoridae) based on material from the Nemuro Strait, southwestern Sea of Okhotsk.
A poorly known thorid shrimp, Lebbeus longidactylus (Kobjakova, 1936), is redescribed on the basis of material collected from the Nemuro Strait, southwestern part of the Sea of Okhotsk, at depths of 600-800 m. The newly collected samples represent the second finding of this rarely collected species since the type description. The species belongs to the informal species group characterized by the possession of epipods on maxilliped 3 to pereopod 2, and appears close to L. scrippsi Wicksten & Méndez, 1982, known from the eastern Pacific, in that the slender dactyli of pereopods 3-5 each terminate in a simple, non-biunguiculate tip and by having accessory spiniform setae restricted to the proximal half of the flexor margin. The elongate rostrum with more numerous dorsal spines, more numerous dorsolateral spiniform setae on the telson, and a single spine on the dorsodistal margin of article 1 of the antennular peduncle readily differentiate L. longidactylus from L. scrippsi.


Adapting RISE: meeting the needs of healthcare workers during the COVID-19 pandemic.
The COVID-19 pandemic has placed extraordinary stresses on healthcare workers. Combined with disruptions to daily life outside of work, health care professionals experience a high prevalence of anxiety, depression, acute stress reaction, burnout, and PTSD. Top leaders at Johns Hopkins Medicine appreciated the mission-critical importance of maintaining the well-being and resilience of its essential workers. In March 2020 they asked the Johns Hopkins RISE (Resilience in Stressful Events) peer support program to help organize support for all staff. RISE made several adjustments, including adding virtual encounters to the usual in-person support, training additional peer responders, and rounding proactively on active units. Communication was broadened to reach less visible and lower wage workers. RISE collaborated actively with hospital epidemiology and infection control and began reporting regularly at incident command centre briefings. RISE also began to coordinate efforts with the other helping programs within the institution including the Office of Well-being, Employee Assistance, Spiritual Care, and Psychiatry. The number of calls and staff supported rose sharply. RISE supported over 4226 workers in the first 9 months of the pandemic. The adoption of RISE programs was accelerated at affiliated hospitals, as well as at other hospitals across the country in partnership with the Maryland Patient Safety Center. Experience with large scale disasters predicted correctly that worker distress would increase and persist beyond the initial wave of the pandemic. With subsequent surges of COVID-19, exhaustion and moral distress became nearly universal among workers. It is urgent for institutions to provide mechanisms to help their workers cope with the ongoing crisis and other crises that will inevitably occur in the future.


Vygotsky, sign language, and the education of deaf pupils.
This article considers the impact of Vygotsky on the education of deaf children in Russia and is a translation/adaptation of an article currently being published in Defektologiia. While Vygotsky perceived sign language as limited in some aspects nevertheless, he always considered that it had a role in education of deaf pupils. He believed that sign language should not be 'treated like an the enemy' and said that 'bilingualism of def people is an objective reality'. However, sign language was banned from Russian schools following a conference decision in 1938. The changing political climate in Russia has lead to the reevaluation of many aspects of life, including approaches to education, and to a reassessment of Vygotsky's ideas and an appreciation of their continuing relevance. Among other things, this has resulted in a reevaluation of the role of sign language for deaf pupils and an emerging interest in sign bilingualism.


Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria.
To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes. This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders. Unadjusted mean HbA(1c) decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA(1c) decreased significantly by 0.038% per year (95% CI 0.032-0.043%), average odds ratio (OR) per year for HbA(1c) >7.5% (>9.0%) was 0.969 (95% CI 0.961-0.977) (0.948, 95% CI 0.941-0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA(1c) >9%; P = 0.005) but not with average HbA(1c) (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918-0.979; RR 0.917, 95% CI 0.885-0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time. This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.


Study on the Action Mechanism of the Yifei Jianpi Tongfu Formula in Treatment of Colorectal Cancer Lung Metastasis Based on Network Analysis, Molecular Docking, and Experimental Validation.
The lung is the second most common site of colorectal cancer (CRC) metastasis. This study aims to investigate the therapeutic effects and potential action mechanisms of Yifei Jianpi Tongfu formula (YJTF) in CRC lung metastasis in a comprehensive and systematic way by network analysis, molecular docking, and experimental verification. The main ingredients in YJTF were screened from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID), and the disease-related targets from the Online Mendelian Inheritance in Man (OMIM) and GeneCards and the compound-related targets from SwissTargetPrediction were collected. Then, Metascape was used for pathway annotation and enrichment analysis, and meanwhile, a protein-protein interaction (PPI) network was constructed. Molecular docking was carried out to investigate interactions between the active compounds and the potential targets. The in vivo effect of YJTF on CRC lung metastasis was observed in a tail vein injection mouse model. A total of 243 active compounds and 81 disease-related targets of YJTF were selected for analysis. The results of multiple network analysis showed that the core targets of YJTF were enriched onto various cancer-related pathways, especially focal adhesion and adherens junction. The results of molecular docking demonstrated that all core compounds (quercetin, kaempferol, luteolin, apigenin, and isorhamnetin) were capable of binding with AKT1, EGFR, SRC, ESR1, and PTGS2. Experimental validation in vivo demonstrated that YJTF combined with oxaliplatin could significantly reduce the number of lung metastases and improve the quality of life in mice. Further research suggested that YJTF inhibited CRC lung metastasis probably by modulating epithelial-to-mesenchymal transition (EMT). According to the analysis, YJTF can be considered as an effective adjuvant therapy for CRC lung metastasis.


Epidemiology of Leptospirosis: The First Literature Review of the Neglected Disease in the Middle East.
Leptospirosis is a major zoonotic disease that has emerged worldwide, and numerous studies performed in affected countries have provided epidemiological knowledge of the disease. However, currently, there is inadequate knowledge of leptospirosis in the Middle East. Therefore, we grouped publications from various Middle Eastern countries to acquire a general knowledge of the epidemiological situation of leptospirosis and provide an initial description of the leptospiral relative risk and circulating serogroups. We conducted a detailed literature search of existing studies describing Leptospira prevalence and seroprevalence in Middle Eastern countries. The search was performed using online PubMed and ScienceDirect databases. One hundred and one articles were included in this review. Some countries, including Iran, Turkey, and Egypt, reported more publications compared to others, such as Lebanon, Kuwait, and Saudi Arabia. Frequently, the seroprevalence of leptospirosis varied considerably between and within countries. The prevalence of leptospirosis was comparable in most Middle Eastern countries; however, it varied between some countries. The methods of detection also varied among studies, with the microscopic agglutination test used most commonly. Some hosts were more recurrent compared with others. This review summarizes the epidemiological situation of Leptospira infection in the Middle East, reporting predominant serogroups-Sejroe, Grippotyphosa, Icterohaemorrhagiae, Autumnalis, and Pomona-that were identified in the most commonly tested hosts. Our findings emphasize the need to develop a deeper understanding of the epidemiology of Leptospira spp. and prioritize the disease as a public health problem in this region. To achieve this goal, increased awareness is critical, and more publications related to the topic and following a standardized approach are needed.


Biochemical changes of saliva in tobacco chewers tobacco smokers, alcohol consumers, leukoplakia and oral cancer patients.
Normal salivary function is considered to be critical for the maintenance of healthy oral mucosa. Oral fluids provide an easily available non-invasive for the diagnosis of a wide range of diseases and clinical situations. The present study evaluated the variations in the biochemical constituents of saliva of leukoplakia and oral cancer patients when compared with that of the control group. 90 individuals were grouped into 6 categories with 15 individuals in each group. The groups included individuals without tobacco or alcohol habits, tobacco smokers, tobacco chewers, alcohol consumers, leukoplakia and oral cancer patients. There was significant alteration in the salivary biochemical composition of leukoplakia and oral cancer patients which could be attributed to the impairment of salivary gland function caused by tobacco and alcohol usage or by the disease process itself.


The misapplication of the term spinal cord injury without radiographic abnormality (SCIWORA) in adults.
Spinal cord injury without radiographic abnormality (SCIWORA) is generally considered a disease of children; however, it is commonly used when referring to adults who have spinal cord injury without computed tomography evidence of trauma (SCIWOCTET). The purpose of this study was to describe characteristics of patients with both adult and pediatric cervical SCIWOCTET admitted to hospitals in our region. A retrospective review of all patients admitted to our two ACS-verified trauma centers with cervical spinal cord injury from January 2005 to December 2009 was performed. All patients with vertebral or ligamentous injury identified on computed tomographic (CT) scan of the cervical spine were excluded. Data gathered on the remaining patients included demographics, injury mechanism, Injury Severity Score, neurologic level and severity of spinal cord injury, magnetic resonance imaging results, and mortality rates. During the 5-year period of this study, 11,644 adult patients and 3,458 pediatric trauma patients were admitted. Of these, 313 patients were thought to have cervical spinal cord injury based on International Classification of Diseases, Ninth Revision (ICD-9) codes, 279 (89.1%) were excluded due to injury noted on CT cervical spine, and 9 were excluded as they were found to not truly have cervical spinal cord injury after review of the medical record. The remaining 25 patients were identified as having cervical SCIWOCTET. Twenty-three patients (92%) were male. The patient ages ranged from 10 to 83 years with a median age of 56 years. The mean Injury Severity Score was 22.6. Sixty-eight percent had a mechanism of fall. Degenerative changes were found on the CT scan of the cervical spine in 96% of all patients and in all 24 adult patients. There was only one pediatric patient with SCIWORA, a 10-year-old boy who had a normal CT scan of the cervical spine but had a persistent neurologic deficit. SCIWOCTET is mainly a disease of adults, and its subset SCIWORA, a disease of children, is much less common. Adults with this disease have CT scans showing canal stenosis and significant degenerative changes in the cervical spine; thus, it is not accurate to state that they have SCIWORA. The characteristics of this patient population are important as SCIWOCTET is the concern when clearing the cervical spines of trauma patients with a CT scan of the cervical spine negative for injury. Epidemiologic study, level III.


[Common fungal infections of the foot].
Among the dermatological diseases affecting the foot, fungal infections are frequent in a daily practice. Treatments now available allow us to control most of them. However, multiple different clinical manifestations and the variety of fungal agents may lead to inappropriate diagnosis and treatments. The paper will consider cutaneous and nail manifestations of common fungal foot infections, their differential diagnosis and their local and systemic treatments.


Cervical myelography with iohexol and metrizamide. A randomized double blind clinical study.
A randomized double-blind study with iohexol and metrizamide in cervical myelography was performed in 100 patients. The concentration of the contrast medium was 240 mg I/ml. The image quality was equal with both contrast media. Forty-two per cent of the patients receiving iohexol had side effects (headache 22%, nausea 6%, vomiting 2% and mental reactions 6%), in contrast to 80 per cent of the patients receiving metrizamide (headache 56%, nausea 34%, vomiting 24% and mental reactions 26%). The majority of side effects appeared within 6 hours after injection of contrast medium. Two patients had a late onset of symptoms - one in each group. Once appearing, the side effects tended to be equally severe.


Australasian survey of split skin graft donor site dressings.
There is an ever increasing array of products available for wound dressings. The aim of the present study was to establish which dressings should be used as standard controls for future studies; what factors are regarded as most important in assessing a dressing; what the level of satisfaction is with the available products; what the strengths and weaknesses of the commonly used dressings are; and what dressings would be preferred if cost were no issue. A postal survey was sent to every plastic and reconstructive surgeon registered in Australasia (n = 217). A total of 53% responded. The most commonly used dressing type overall is the calcium alginates, despite the fact that they were not the highest performing dressings. This is also the most commonly used in Australia. In contrast scarlet red is still used most commonly in New Zealand. The level of satisfaction with the most commonly used dressing varied very little. The factor regarded most important was patient comfort level. A profile of the commonly used dressing was constructed. Calcium alginates and or scarlet red should be used as the control for new product comparisons. Most of the respondents were satisfied with their preferred dressing and were not interested in trying alternative dressings.


Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for rapid identification of Beta-hemolytic streptococci.
This study was undertaken to evaluate matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for the rapid identification of beta-hemolytic streptococci. We compared Bruker Biotyper 2.0 with Vitek2 coupled to the agglutination test. MALDI-TOF MS analysis of 386 beta-hemolytic streptococcal isolates yielded high-confidence identification to the species level for all 386 isolates. The Vitek2 gave high-confidence identification to the species level for 88% of Streptococcus agalactiae isolates (n = 269/306), 92% of Streptococcus pyogenes isolates (n = 48/52), and 39% of isolates of Streptococcus dysgalactiae serogroups C and G (n = 11/28).


Accuracy of routine flow-cytometric bitmap selection for three leukocyte populations.
A double-blind study was performed with peripheral blood of 41 human subjects to check the accuracy of determination of lymphocyte, monocyte, and granulocyte windows with which every flow cytometric analysis of leukocyte markers starts. White blood cell suspensions were prepared according to the whole blood method and analyzed on an EPICS-C flow cytometer using the two-parameter 90 degrees light scatter vs. forward angle light scatter (granularity vs. cell size) data distribution. Windows (bitmaps) for lymphocytes, monocytes, and granulocytes were drawn and numbers of cells determined in each. The proportions of lymphocytes, monocytes, and granulocytes were calculated in relation to total cell number, counted and in relation to the sum of cells in three bitmaps, and then compared with proportions determined by microscopic whole blood cell (WBC) differential and a WBC differential determined in an automated hematology analyzer. Average proportions of lymphocytes obtained by the flow cytometer were significantly lower than those obtained by either microscopic or automated differential, suggesting that some of the relevant cells were not included in the bitmaps. Granulocyte proportion related to total cell number was lower and that related to bitmap cell number higher than that obtained by microscopic and automatic differentials, suggesting that nongranulocytic cells were included in the granulocyte bitmaps. Proportions of lymphocytes and granulocytes obtained by the flow cytometer correlated well with those obtained by both microscopic and automatic differential. In contrast, the proportions of monocytes showed a poor correlation, which is probably due to their low number and delicate position in the distribution, and which makes them difficult to delineate.


Interaction between thiopental and fentanyl in mice is different between hypnotic and lethal doses.
Much is known about the interaction of intravenous anesthetics and opioids at the therapeutic level, but less is known regarding their combined lethal effect, leaving some uncertainty regarding the window of safety for their clinical use. We set out to document the type of interaction between thiopental and fentanyl for both the hypnotic effect (loss of righting reflex) and lethal effect in mice. Hypnotic and lethal dose-response curves were constructed for thiopenthal alone and in combination with fentanyl (0.8 microg/kg, each based on five to seven subgroups of six to ten ICR mice. The dose of fentanyl was that needed to double the lag time to tail flick following a noxious stimulus (the equivalent of human analgesia). While fentanyl did not change the median effective hypnotic dose of thiopental (8.9 mg/kg [95% confidence interval {CI} 8.0-9.9 mg/kg] alone versus 7.8 mg/kg [95% CI 6.7-8.7 mg/kg] in combination), it significantly reduced its median lethal dose from 71.8 mg/kg (95% CI 68.3-74.8 mg/kg) to 64.5 mg/kg (95% CI 63.7-65.2 mg/kg). Most remarkably, it increased the slope of the curve from 0.17 (95% CI 0.10-0.36) to 0.61 (95% CI 0.24-1.10), virtually eliminating the difference between the non-lethal and lethal ranges. We conclude that the type of interaction between thiopental and fentanyl is stronger for the lethal effect than for the hypnotic effect. This may become relevant to clinical situations in humans when higher doses of thiopental are used.


[Study of adventitial inflammation and inflammatory factors in pathogenesis of allograft arteriosclerosis in rats].
To study the roles of serum inflammatory factors IL-6 and TNF-alpha and allograft adventitial inflammation in the pathogenesis of allograft arteriosclerosis in rats. Thirty-six allogeneic allograft rats and 16 syngeneic allograft rats were randomly divided into 4 groups (9 rats in each experimental group and 4 in each control group): A, harvested at Week 1 post-operation; B, harvested at Week 2 post-operation; C, harvested at Week 3 post-operation; D, harvested at Week 4 post-operation. Blood samples were collected before transplantation and after harvest. The method of ELISA was used for testing serum inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor-alpha(TNF-alpha), HE staining for pathologic changes of aortic allograft and immunohistochemical method for expression of alpha-actin, cyclin dependent kinase-1 (CDK(1)) and proliferating cell nuclear antigen (PCNA). Compare the inflammatory factors and other observations between groups and preoperative. At Week 1 post-operation, a large amount of inflammatory cell infiltration in adventitia was observed; at Week 2 post-operation, slight collagen fibers hyperplasia with inflammatory infiltration; at Week 4 post-operation, obvious adventitia thickening with a large number of smooth muscle cells, collagen fibers and inflammatory cells, smooth muscle cells migration from adventitia to intima. Expressions of alpha-actin, CDK(1) and PCNA kept increasing with time in adventitia (P < 0.05). There was a significant increase in serum TNF-alpha level in Groups A, B, C and D, as compared with pre-operative basal level (P < 0.01). There was no difference between controls and pre-operative basal level. IL-6 level slightly declined in the middle stage, but finally increased in experimental group B (P < 0.05) while it significantly increased in Groups A, C, D (P < 0.01). In the control groups A, B, C, it was higher than pre-operative level (P < 0.05). In experimental groups A, C, D, it had a significant increase as compared with controls (P < 0.01). In abdominal aortic allograft models, obvious angiosclerosis was found in adventitia and intima in accordance with the severity of adventitial inflammation. Thus the inflammatory factors and inflammatory cell infiltration in adventitia are both involved in the pathogenesis of early allograft arteriosclerosis.


Waste to white light: a sustainable method for converting biohazardous waste to broadband white LEDs.
The Covid-19 pandemic has generated a lot of non-degradable biohazardous plastic waste across the globe in the form of disposable surgical and N95 masks, gloves, face shields, syringes, bottles and plastic storage containers. In the present work we address this problem by recycling plastic waste to single system white light emitting carbon dots (CDs) using a pyrolytic method. The synthesized CDs have been embedded into a transparent polymer to form a carbon dot phosphor. This CD phosphor has a broad emission bandwidth of 205 nm and is stable against photo degradation for about a year. A white LED with CRI ∼70 and CIE co-ordinates of (0.25, 0.32) using the fabricated CD phosphor is reported. Further our phosphor is scalable and is environmentally sustainable, and will find wide application in next generation artificial lighting systems.


Hydroxamates: relationships between structure and plasma stability.
Hydroxamates are valuable tools for chemical biology as well as interesting leads for medicinal chemistry. Although many hydroxamates display nanomolar activities against metalloproteases, only three hydroxamates have reached the market, among which is the HDAC inhibitor vorinostat. Failures in development are generally attributed to lack of selectivity, toxicity, or poor stability. To help medicinal chemists with respect to plasma stability, we have performed the first and preliminary study on structure-plasma stability for hydroxamates. We define some structural rules to predict or improve the plasma stability in the preclinical stage.


Anaphylaxis: An Uncommon Cause of Rhabdomyolysis-Related Acute Kidney Injury.
Anaphylaxis is an acute, severe, and potentially lethal form of an allergic reaction. It can lead to a sepsis-like syndrome and multisystem involvement with complications. It can cause distributive shock with preferential blood supply to vital organs, at the expense of blood supply to skeletal muscle. Skeletal muscle ischemia leads to the fast depletion of myocyte energy source and a cascade of inflammatory reactions leading to myocyte injury and death. Myocyte lysis or rhabdomyolysis releases the cellular contents into circulation. Rhabdomyolysis is not an oft-discussed complication of anaphylaxis. We describe a 21-year-old male with no known comorbidity who presented with anaphylactic shock after consuming one tablet paracetamol + ibuprofen and was found to have rhabdomyolysis-related acute kidney injury.


Genetic diversity of HLA system in two populations from San Luis Potosí, Mexico: San Luis Potosí City and rural San Luis Potosí.
We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 117 Mexicans from the state of San Luis Potosí living in the city of San Luis Potosí (N = 30) and rural communities (N = 87), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state include 13 Native American, six European, two African and two Asian haplotypes. Admixture estimates revealed that the main genetic components are Native American (52.72 ± 0.66% by ML; 48.29% of Native American haplotypes) and European (34.62 ± 4.28% by ML; 32.48% of European haplotypes), and a relatively high African genetic component (12.66 ± 4.61% by ML; 10.26% of African haplotypes).


TashHN, a Theileria annulata encoded protein transported to the host nucleus displays an association with attenuation of parasite differentiation.
The intracellular apicomplexan parasite, Theileria annulata, manipulates its bovine host cell by over-riding the cells natural apoptotic response and inducing proliferation of the infected leukocyte. We have recently identified a T. annulata encoded family of polypeptides (TashATs) with characteristics that indicate that they are involved in control of host cell gene expression. Here we present data on another member of this family, TashHN, showing that it is located to the parasite and host cell nucleus. Immunoblot analysis demonstrated that, unlike TashAT2 and 3, TashHN displays three forms, the largest of which is enriched in the host nuclear fraction and appears to be phosphorylated. Northern and 5 prime race analyses identified multiple TashHN RNA species in infected cells that have retained the ability to differentiate. These transcripts showed subtly different kinetics, but all decreased during differentiation to the merozite, and two showed reduced levels prior to down-regulation of the other TashATs. In addition, analyses of multiple cell lines that have become severely attenuated in their potential to differentiate, indicated a substantial increase in TashHN expression, with host nuclear reactivity particularly enhanced.


Inflammatory bowel disease: a systematic review on the value of diagnostic testing in primary care.
The clinical presentation of inflammatory bowel disease in primary care represents a diagnostic challenge as its symptoms are heterogeneous and common. To assist the primary care physician, we have summarized the available evidence on diagnostic tests in patients with abdominal symptoms. We searched PubMed and Embase and screened references. Studies were selected if the design was a primary diagnostic study. Patients were adults attending with nonacute abdominal symptoms. Tests included clinical assessment, blood or faecal tests or abdominal ultrasonography. Quality assessment using a modified version of the QUADAS tool and data extraction was performed by two reviewers independently. Diagnostic two-by-two tables and pooled estimates of sensitivity and specificity are given. We refrained from pooling when there was considerable clinical or statistical heterogeneity. A total of 24 studies were included. While the diagnostic performance of the individual symptoms was highly variable (range sensitivity 0.0-0.96, specificity 0.09-1.0), the performance of symptom-based classification systems was both more consistent and better (sensitivity 0.65-1.0, specificity 0.17-0.82). Among faecal and blood tests, calprotectin was studied most frequently and showed the best results (sensitivity 0.61-1.0, specificity 0.71-1.0). Statistical pooling for ultrasonography resulted in a sensitivity of 0.73 (0.65-0.80) and a specificity of 0.95 (0.91-0.97). Although calprotectin and ultrasonography showed consistent and promising findings, none of the studies was performed in primary care. To assist primary care physicians in diagnostic decision making, we urgently need high quality studies performed in primary care.


[Preventing papillomavirus infectious and herpes zoster: new vaccines].
Two new vaccines have been recently licensed : a quadrivalent vaccine against Human papillomavirus infections (HPV) 6, 11, 16 and 18, recommended to children from 9 years old and to young adults under the age of 26 years, and a vaccine against herpes zoster for adults from 60 years old onwards. A bivalent vaccine against HPV 16 and 18 will be shortly available. HPV vaccines are composed of the L1 structural proteins of 2 or 4 HPV genotypes, produced by genetic engineering and self-assembled. These inert vaccines are devoid of genetic materials and mimic the viral particle (virus-like particle, VLP). They allow, as suggested by the 4.5 to 5 years follow-up, to prevent HPV infections and the onset of pre-cancerous lesions associated with genotypes contained within the vaccine. They represent a major overhang in the vaccinology field, and, as anti-hepatitis B vaccine, will probably be effective in cancer prevention. Their use must be associated with the continued detection of cervix cancer by smears and also with the prevention of other sexually transmitted diseases. The herpes zoster vaccine is a living attenuated vaccine produced from the OKA/Merck strain already used in the vaccine against varicella. Its safety is good among persons 50 years old and over and its efficiency on lowering herpes zoster incidence, on the burden of illness and on post-herpetic neuralgia has been demonstrated in persons over 60 years old.


Effects of pH and carbonate concentration on dissolution rates of the lead corrosion product PbO(2).
Lead(IV) oxide is a corrosion product that can develop on lead pipes and affect lead concentrations in drinking water. Continuously stirred flow-though reactors were used to quantify the dissolution rates of plattnerite (beta-PbO(2)) at different pH values and dissolved inorganic carbon (DIC) concentrations. Organic pH buffers were not used, because several were found to be reductants for PbO(2) that accelerated its dissolution. Most plattnerite dissolution rates were on the order of 10(-10) mol/min-m(2). The rate of dissolution increased with decreasing pH and with increasing DIC. The effect of DIC is consistent with a reductive dissolution mechanism that involves the reduction of Pb(IV) to Pb(II) at the plattnerite surface followed by the formation of soluble Pb(II)-carbonate complexes that accelerate Pb(II) release from the surface. Under the experimental conditions, dissolved lead concentrations were controlled by the dissolution rate of plattnerite and not by its equilibrium solubility. A dissolution rate model was developed and can be used to predict dissolution rates of plattnerite as a function of pH and DIC.


Cefodizime administration in healthy subjects: studies of natural killer cells, urinary hormones and electrolytes.
Two studies are here discussed: the first one on changes of the natural killer cell activity of PBM cells exposed in vitro to CDZ and the second one on urinary electrolytes, cortisol, aldosterone and DHEA-S circadian rhythms, evaluated in healthy subjects who received a single dose (2 g i.v.) of cefodizime (CDZ). The effect of CDZ in health includes a reduction of the circadian amplitude of natural killer cell activity. With the methods used, no difference was found between placebo and CDZ, as far as circadian rhythms of urinary electrolytes, cortisol, aldosterone and DHEA-S are concerned.


Deep dyslexia is right-hemisphere reading.
Two views exist concerning the proper interpretation of the form of acquired dyslexia known as deep dyslexia: (a) that it represents reading by a multiply damaged left hemisphere reading system; (b) that it represents reading which relies extensively on right-hemisphere orthographic and semantic processing. Price, Howard, Patterson, Warburton, Friston, and Frackowiak (1998) have recently reported a brain-imaging study whose results, they claim, "preclude an explanation of deep dyslexia in terms of purely right-hemisphere word processing." Their claim conflicts with the conclusions of previous published work, which strongly supports the RH hypothesis, work which they do not mention. Furthermore, I argue that their own results also favor the RH hypothesis (even though they claim otherwise); indeed, their results permit the formulation of a much more detailed version of the RH hypothesis than has hitherto been possible. Hence I conclude that the right-hemisphere interpretation of deep dyslexic reading remains the preferred explanation of deep dyslexia.


Capturing a Pentacyclic Fragment-Based Library Derived from Perophoramidine: Their Design, Synthesis and Evaluation as Anticancer Compounds by DNA Double-Strand Breaks (DSB) and PARP-1 Inhibition.
Herein we have reported the discovery of a pentacyclic building block comprised of fused indole-quinoline and piperidinone from the natural product perophoramidine as a formidable anticancer agent. The compounds were synthesized in six steps where the key steps involved a blue LED mediated intramolecular cyclopropanation of the indole intermediates and concomitant reduction of the associated aryl nitro moiety to nitroso in the molecule. Cytotoxicity screening of the compounds against an array of cancer cells that is, MCF7, HCT116 and A549 demonstrated 0.6 to 9 μM IC50 s by few of the compounds. γH2AX immunofluorescence assay of the two most potent molecules from the phenotypic screening with anti-γ-H2AX Alexa Fluor 488 antibody revealed extensive DNA damage of the A549 cells which indicated probable PARP inhibition (similar to Perophoramidine). Through molecular docking and molecular dynamic (MD) simulation studies the binding efficiency of our compounds with poly(ADP-ribose)polymerase 1 (PARP 1) enzyme was determined. Chemiluminescent PARP Assay with Histone-coated strips indicated that the most active compounds from the phenotypic screening induced PARP-1 inhibition with IC50 s of 1.3→1.5 μM.


Reversible hyperkalemia during antihypertensive therapy in a hypertensive diabetic patient with latent hypoaldosteronism and mild renal failure.
A 66-year-old hypertensive diabetic patient with latent hypoaldosteronism and mild renal failure was treated by adding enalapril, an angiotensin converting enzyme inhibitor, to the furosemide and nifedipine regimen because of an insufficient antihypertensive response for 1 month. Seven days after enalapril addition, the blood pressure was significantly reduced, but frank hyperkalemia occurred with a marked rise in BUN and a slight increase in serum creatinine. Plasma renin activity (PRA) and plasma aldosterone (PA) values remained low before and during enalapril therapy. Transient treatment with sodium polystyrene sulfate after enalapril withdrawal improved the hyperkalemia and renal function, but PRA and PA levels were low. PA and its precursor steroids also responded poorly to graded angiotensin II infusion and rapid ACTH injection. Latent hypoaldosteronism probably predisposed this patient to frank hyperkalemia with progressive dehydration and slightly reduced renal function during antihypertensive therapy.


Analysis of reproductive toxicity and classification of glufosinate-ammonium.
CONCLUSION REGARDING CLASSIFICATION OF GLUFOSINATE-AMMONIUM: Science Partners' Evaluation Group (Evaluation Group) has conducted an independent analysis of the herbicide glufosinate-ammonium (GA) relative to its potential to cause reproductive toxicity in humans. Further, the Evaluation Group has evaluated the implementation of Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC) and Council Directive 91/414/EEC, with respect to classification of chemicals posing potential reproductive hazards. After consideration of all information available to us relevant to the potential of glufosinate-ammonium (GA) to cause reproductive toxicity, the Science Partners Evaluation Group concludes that no classification of GA is justified. The following form the basis of this conclusion. There are no human data to suggest that GA causes reproductive toxicity in women or in their conceptus. The issue concerning possible reproductive hazard to humans is raised solely on the basis of positive animal test results that show GA to cause preimplantation or implantation losses in rats. SPECIFICALLY: a. Daily treatment with GA had no detectable effect on the earliest stages of the reproductive sequence including gametogenesis, ovulation, mating and conception; b. Treatment with GA interfered with rat gestation before and at the stage when the conceptus implants into the uterus. This effect occurred at doses of 360 ppm in the feed (corresponding to daily doses of 27.8 mg/kg bw) and above; and c. After implantation, no further effect of GA on prenatal and post-natal development was recognized. Previous concerns that GA might be toxic to embryonic stages after implantation were not supported by the data. Abortions and stillbirth seen were associated with, and regarded as secondary to, maternal toxicity. There was no evidence suggesting the induction of malformations in the offspring. The mechanism underlying this adverse effect in experimental laboratory animals is identified-inhibition of glutamine synthetase. Glutamine is essential to the viability of the embryo. The embryo is dependent on a maternal source of the amino acid. For embryo lethality to occur, a significant reduction of maternal glutamine is required. Such reduction in maternal glutamine depends on a significant inhibition of glutamine synthetase by GA. This can only occur when the mother is exposed to very high levels of GA. SPECIFICALLY: a. The reproductive toxicity of GA is confined to very short, early stages of reproduction, during which the conceptus is dependent on maternal glutamine; and b. In order for the effect to occur, significant reduction in maternal blood glutamine level is required, which in turn depends on a significant inhibition of glutamine synthetase, induced by high levels of GA in the maternal system. There is no evidence for accumulation of GA in the mammalian organism beyond a factor of two and no evidence for its metabolic toxification. To raise a concern in humans, women would have to be exposed to GA during the very limited time frame of preimplantation or implantation and the exposure would have to be to the exceedingly high levels necessary to alter the maternal metabolism and, correspondingly, result in glutamine levels in maternal tissue and blood plasma being drastically reduced. There is no basis to suggest that such exposures would occur under conditions of normal handling and use. SPECIFICALLY: a. Under conditions of normal handling and use, operators would never be exposed to GA levels that could potentially inhibit glutamine synthetase to the extent that this inhibition could impair preimplantation or implantation. b. All acceptable exposure measurements and predictive calculations confirm this conclusion, and in fact demonstrate that reasonably foreseeable exposure of workers would be to levels significantly below the AOEL. c. The evidence is also clear that there is no reproductive toxicity hazard to workers upon reentry tosprayed fields, bystanders, consumers or toddlers. The safety margin compared to the NOAEL in animal studies is sufficiently large to assure protection of the health of workers using GA as well as bystanders, consumers, and toddlers. Pursuant to Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC), to justify a classification of category 2 there must be sufficient evidence to produce a strong presumption that human exposure to the substance may result in impaired fertility in humans. It is the conclusion of the Science Partners Evaluation Group that there is no reasonable evidence to suggest a strong presumption of impairment. To the contrary, there is clear evidence demonstrating a strong presumption that exposure to GA would not cause the adverse effect demonstrated in rats. Pursuant to Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC), to justify a classification of category 3, there must be sufficient evidence to provide a strong suspicion of impaired fertility in humans. There is no basis to conclude that the animal data demonstrating impaired preimplantation or implantation has any relevance to humans in that the effect found in rats only occurs at levels which would never be experienced by workers under conditions of normal handling and use or by bystanders, consumers, or toddlers.


Systematic review, meta-analysis, and meta-regression: Successful second-line treatment for Helicobacter pylori.
Multiple Helicobacter pylori second-line schedules have been described as potentially useful. It remains unclear, however, which are the best combinations, and which features of second-line treatments are related to better cure rates. The aim of this study was to determine that second-line treatments achieved excellent (>90%) cure rates by performing a systematic review and when possible a meta-analysis. A meta-regression was planned to determine the characteristics of treatments achieving excellent cure rates. A systematic review for studies evaluating second-line Helicobacter pylori treatment was carried out in multiple databases. A formal meta-analysis was performed when an adequate number of comparative studies was found, using RevMan5.3. A meta-regression for evaluating factors predicting cure rates >90% was performed using Stata Statistical Software. The systematic review identified 115 eligible studies, including 203 evaluable treatment arms. The results were extremely heterogeneous, with 61 treatment arms (30%) achieving optimal (>90%) cure rates. The meta-analysis favored quadruple therapies over triple (83.2% vs 76.1%, OR: 0.59:0.38-0.93; P = .02) and 14-day quadruple treatments over 7-day treatments (91.2% vs 81.5%, OR; 95% CI: 0.42:0.24-0.73; P = .002), although the differences were significant only in the per-protocol analysis. The meta-regression did not find any particular characteristics of the studies to be associated with excellent cure rates. Second-line Helicobacter pylori treatments achieving>90% cure rates are extremely heterogeneous. Quadruple therapy and 14-day treatments seem better than triple therapies and 7-day ones. No single characteristic of the treatments was related to excellent cure rates. Future approaches suitable for infectious diseases-thus considering antibiotic resistances-are needed to design rescue treatments that consistently achieve excellent cure rates.


Bilateral renal aspergillosis with a fungal cast masquerading as renal malignancy.
Invasive isolated renal aspergilloma in an immunocompetent host is rare, and few cases have been reported in the literature. It is a unique entity encountered by a urologist that can lead to catastrophic complications like end-stage renal disease. Infective pathology may closely resemble renal mass, and timely, appropriate investigations are obligatory for early intervention. This case report highlights the importance of strong consideration of renal fungal infections in the differential diagnosis of a renal mass with atypical radiological findings in an immunocompetent host. Meticulous decision-making and appropriate management help to prevent disastrous sequelae.


Rapid and reproducible Agrobacterium-mediated transformation of sorghum.
A rapid and reproducible Agrobacterium-mediated transformation protocol for sorghum has been developed. The protocol uses the nptII selectable marker gene with either of the aminoglycosides geneticin or paromomycin. A screen of various A. tumefaciens strains revealed that a novel C58 nopaline chromosomal background carrying the chrysanthopine disarmed Ti plasmid pTiKPSF(2), designated NTL(4)/Chry5, was most efficient for gene transfer to sorghum immature embryos. A NTL(4)/Chry5 transconjugant harboring the pPTN290 binary plasmid, which carries nptII and GUSPlus expression cassettes, was used in a series of stable transformation experiments with Tx430 and C2-97 sorghum genotypes and approximately 80% of these transformation experiments resulted in the recovery of at least one transgenic event. The transformation frequencies among the successful experiments ranged from 0.3 to 4.5%, with the average transformation frequency being approximately 1% for both genotypes. Over 97% of the transgenic events were successfully established in the greenhouse and were fully fertile. Co-expression of GUSPlus occurred in 89% of the transgenic T(0) events. Seed set for the primary transgenic plants ranged from 145 to 1400 seed/plant. Analysis of T(1) progeny demonstrated transmission of the transgenes in a simple Mendelian fashion in the majority of events.


The histone acetyltransferase CLOCK is an essential component of the herpes simplex virus 1 transcriptome that includes TFIID, ICP4, ICP27, and ICP22.
Studies published elsewhere have shown that the herpes simplex virus regulatory protein ICP0 interacts with BMAL1, a partner and regulator of circadian histone acetyltransferase CLOCK, that both proteins localize at ND10 bodies and are stabilized by viral proteins, that enzymatically active CLOCK partially complements ΔICP0 mutants, and that silencing of CLOCK suppresses the expression of viral genes. Here we report that CLOCK is a component of the transcriptional complex that includes TFIID, ICP4, ICP27, and ICP22. The results suggest that the CLOCK histone acetyltransferase is a component of the viral transcriptional machinery throughout the replicative cycle of the virus and that ICP27 and ICP22 initiate their involvement in viral gene expression as components of viral transcriptome.


May the Fittest Protein Evolve: Favoring the Plant-Specific Origin and Expansion of NAC Transcription Factors.
Plant-specific NAC transcription factors (TFs) evolve during the transition from aquatic to terrestrial plant life and are amplified to become one of the biggest TF families. This is because they regulate genes involved in water conductance and cell support. They also control flower and fruit formation. The review presented here focuses on various properties, regulatory intricacies, and developmental roles of NAC family members. Processes controlled by NACs depend majorly on their transcriptional properties. NACs can function as both activators and/or repressors. Additionally, their homo/hetero dimerization abilities can also affect DNA binding and activation properties. The active protein levels are dependent on the regulatory cascades. Because NACs regulate both development and stress responses in plants, in-depth knowledge about them has the potential to help guide future crop improvement studies.