Levetiracetam and N-Cadherin Antibody Alleviate Brain Pathology Without Reducing Early Epilepsy Development After Focal Non-convulsive Status Epilepticus in Rats.
Focal non-convulsive status epilepticus (fNCSE) is a neurological condition characterized by a prolonged seizure that may lead to the development of epilepsy. Emerging experimental evidence implicates neuronal death, microglial activation and alterations in the excitatory and inhibitory synaptic balance as key features in the pathophysiology following fNCSE. We have previously reported alterations in the excitatory adhesion molecule N-cadherin in rats with fNCSE originating from the hippocampus that subsequently also develop spontaneous seizures. In this study, fNCSE rats were treated intraperitoneally with the conventional anti-epileptic drug levetiracetam in combination with intraparenchymal infusion of N-cadherin antibodies (Ab) for 4 weeks post-fNCSE. The N-cadherin Ab was infused into the fornix and immunohistochemically N-cadherin Ab-stained neurons were detected within the dorsal hippocampal structures as well as in superjacent somatosensory cortex. Continuous levetiracetam treatment for 4 weeks post-fNCSE reduced microglia activation, including cell numbers and morphological changes, partly decreased neuronal cell loss, and excitatory post-synaptic scaffold protein PSD-95 expression in selective hippocampal structures. The additional treatment with N-cadherin Ab did not reverse neuronal loss, but moderately reduced microglial activation, and further reduced PSD-95 levels in the dentate hilus of the hippocampus. Despite the effects on brain pathology within the epileptic focus, neither monotherapy with systemic levetiracetam nor levetiracetam in combination with local N-cadherin Ab administration, reduced the amount of focal or focal evolving into bilateral convulsive seizures, seizure duration, or interictal epileptiform activity during 1 month of continuous electroenephalogram recordings within the hippocampus after fNCSE. Behavioral tests for spatial memory, anxiety, social interaction and anhedonia did not detect gross behavioral differences between fNCSE rats with or without treatment. The results reveal the refractory features of the present rodent model of temporal lobe epilepsy following fNCSE, which supports its clinical value for further therapeutic studies. We identify the persistent development of epilepsy following fNCSE, in spite of partly reduced brain pathology within the epileptic focus.


Imaging biomarkers of posttraumatic epileptogenesis.
Traumatic brain injury (TBI) affects 2.5 million people annually within the United States alone, with over 300 000 severe injuries resulting in emergency room visits and hospital admissions. Severe TBI can result in long-term disability. Posttraumatic epilepsy (PTE) is one of the most debilitating consequences of TBI, with an estimated incidence that ranges from 2% to 50% based on severity of injury. Conducting studies of PTE poses many challenges, because many subjects with TBI never develop epilepsy, and it can be more than 10 years after TBI before seizures begin. One of the unmet needs in the study of PTE is an accurate biomarker of epileptogenesis, or a panel of biomarkers, which could provide early insights into which TBI patients are most susceptible to PTE, providing an opportunity for prophylactic anticonvulsant therapy and enabling more efficient large-scale PTE studies. Several recent reviews have provided a comprehensive overview of this subject (Neurobiol Dis, 123, 2019, 3; Neurotherapeutics, 11, 2014, 231). In this review, we describe acute and chronic imaging methods that detect biomarkers for PTE and potential mechanisms of epileptogenesis. We also describe shortcomings in current acquisition methods, analysis, and interpretation that limit ongoing investigations that may be mitigated with advancements in imaging techniques and analysis.


[Maturing of ribosomal RNAs in rat thymus cells].
The peculiarities of maturing of ribosomal RNAs in rat thymus cells were studied. It was found that the rRNA precursors (45s, 41s and 32s) are weakly extractable from the thymocytes at 45 degrees and are predominantly accumulated in the RNA 650 fraction. It was also shown that part of newly synthesized molecules of 18s RNA are broken down in the course of processing. The data obtained confirm the previously made assumption that degradation of some rRNAs in the course of maturing represents a mechanism of maintenance of a constant number of ribosomes in the cell.


[High life expectancy in multiple myeloma].
The authors describe the main clinicolaboratory finding of 9 patients with multiple myeloma (MM) who survived 10 and more years. The number of the "long-lived" survivors among 256 patients with MM seen from 1966 to 1980 amounted to 3.5%. The main characteristics of the disease of the "long-lived" survivors were correlated to those of 247 MM patients who survived for less than 10 years. In principle, no differences were revealed between the compared groups in term of the size of the initial tumor mass, red blood, and the degree of osteolysis. It was established that the 10-year and higher survival was observed in relatively young people without signs of renal insufficiency, who responded well to the cytostatic treatment. In 8 out of the 9 survivors, a long-term remission was attained by combining sarcolysine and prednisolone. The median survival rate for the entire group amounted to 25 months, that for the "long-lived" survivors to 133 months. In the authors' opinion, an unusually high survival rate among MM patients cannot be only attributed to successful cytostatic therapy. Among the 247 MM patients, 60% responded to the treatment fairly well. However, only 3.5% of the patients survived over 10 years. The prognosis of MM is likely to be determined by some individual features of the tumor and by the patients' antitumor defence mechanisms.


Readmissions Among Sepsis Survivors: Risk Factors and Prevention.
Hospital readmissions are common and result in increased mortality and cost while reducing quality of life. Readmission rates have been subjected to increasing scrutiny in recent years as part of a larger effort to improve the quality and value of healthcare in the United States. Emerging evidence suggests that sepsis survivors are at high risk for hospital readmission and experience readmission rates comparable to survivors of congestive heart failure, acute myocardial infarction, pneumonia, and chronic obstructive pulmonary disease, diseases whose readmission rates determine reimbursement penalties from the federal government. In this article, we review the unique challenges that sepsis survivors face as well as the patient-level and hospital-level risk factors that are known to be associated with hospital readmission after sepsis survival. Additionally, we identify the causes and outcomes of readmissions in this population before concluding with a discussion of readmission prevention strategies and future directions.


Bioprinted Cancer Model of Neuroblastoma in a Renal Microenvironment as an Efficiently Applicable Drug Testing Platform.
Development of new anticancer drugs with currently available animal models is hampered by the fact that human cancer cells are embedded in an animal-derived environment. Neuroblastoma is the most common extracranial solid malignancy of childhood. Major obstacles include managing chemotherapy-resistant relapses and resistance to induction therapy, leading to early death in very-high-risk patients. Here, we present a three-dimensional (3D) model for neuroblastoma composed of IMR-32 cells with amplified genes of the myelocytomatosis viral related oncogene MYCN and the anaplastic lymphoma kinase (ALK) in a renal environment of exclusively human origin, made of human embryonic kidney 293 cells and primary human kidney fibroblasts. The model was produced with two pneumatic extrusion printheads using a commercially available bioprinter. Two drugs were exemplarily tested in this model: While the histone deacetylase inhibitor panobinostat selectively killed the cancer cells by apoptosis induction but did not affect renal cells in the therapeutically effective concentration range, the peptidyl nucleoside antibiotic blasticidin induced cell death in both cell types. Importantly, differences in sensitivity between two-dimensional (2D) and 3D cultures were cell-type specific, making the therapeutic window broader in the bioprinted model and demonstrating the value of studying anticancer drugs in human 3D models. Altogether, this cancer model allows testing cytotoxicity and tumor selectivity of new anticancer drugs, and the open scaffold design enables the free exchange of tumor and microenvironment by any cell type.


University of California/Davis Interdepartmental Conference on gram-negative septicemia.
Gram-negative septicemia remains one of the most serious forms of hospital-acquired infection. The most consistently virulent component of the gram-negative lipopolysaccharide (endotoxin) appears to be lipid A. Elucidation of the structure-function relationships of lipid A and the biochemical configurations required for endotoxicity makes possible the design of lipopolysaccharide antagonists and/or the production of poly- or monoclonal antibodies that may abrogate the biologic effects of endotoxin. The mechanisms of activity of lipopolysaccharide and the pathophysiologic events it triggers are now better understood than in the recent past. Lipid A triggers the release of mediators such as cachectin (tumor necrosis factor), thereby initiating a cascade of potentially lethal events. Although recent studies indicate no routine role for corticosteroids in gram-negative septic shock or acute respiratory distress syndrome, considerable progress has been made in the development of effective antibiotics. Recent studies of septicemia in neutropenic patients show survival rates significantly higher than those reported more than two decades ago.


Keeping Our Classification UP to Date.
In Australia, the National Centre for Classification in Health (NCCH) is ultimately responsible for updating ICD-10-AM disease codes and Australian Classification of Health Interventions (ACHI) procedure codes, and the accompanying Australian Coding Standards (ACS). New editions of these publications are released every two years. This article outlines the updating procedure and lists the sources of information upon which the NCCH draws when compiling data for new coding manuals.


Functional Role of Class III Myosins in Hair Cells.
Cytoskeletal motors produce force and motion using the energy from ATP hydrolysis and function in a variety of mechanical roles in cells including muscle contraction, cargo transport, and cell division. Actin-based myosin motors have been shown to play crucial roles in the development and function of the stereocilia of auditory and vestibular inner ear hair cells. Hair cells can contain hundreds of stereocilia, which rely on myosin motors to elongate, organize, and stabilize their structure. Mutations in many stereocilia-associated myosins have been shown to cause hearing loss in both humans and animal models suggesting that each myosin isoform has a specific function in these unique parallel actin bundle-based protrusions. Here we review what is known about the classes of myosins that function in the stereocilia, with a special focus on class III myosins that harbor point mutations associated with delayed onset hearing loss. Much has been learned about the role of the two class III myosin isoforms, MYO3A and MYO3B, in maintaining the precise stereocilia lengths required for normal hearing. We propose a model for how class III myosins play a key role in regulating stereocilia lengths and demonstrate how their motor and regulatory properties are particularly well suited for this function. We conclude that ongoing studies on class III myosins and other stereocilia-associated myosins are extremely important and may lead to novel therapeutic strategies for the treatment of hearing loss due to stereocilia degeneration.


Deriving High-Resolution Emission Inventory of Open Biomass Burning in China based on Satellite Observations.
Open biomass burning plays an important role in atmospheric pollution and in climate change. However, the current emission inventory of open biomass burning is generally of highly uncertainty because of missing small fire data and limited resolution because of the lack of localized vegetation data. In this study, the MODIS (MODerate Resolution Imaging Spectroradiometer) burned area product MCD64Al combined with the active fire product MCD14 ML, as well as a high-resolution land cover data set, were applied to develop a high-resolution emission inventory of open biomass burning in China in 2013. Total CO, CH4, NOx, NMVOC (nonmethane volatile organic compounds), SO2, NH3, PM2.5, PM10, OC (organic carbon), BC (black carbon), and CO2 emissions were estimated to be 1.03 × 104, 666, 536, 1.91 × 103, 87, 138, 1.45 × 103, 2.09 × 103, 741, 137, and 2.45 × 105 Gg, respectively. The provinces that contributed the most emissions included Heilongjiang, Henan, Shandong, and Jilin. The major source for all pollutants was cropland burning, whereas Xizang, Xinjiang, and Heilongjiang had greater emissions from natural vegetation. The temporal distribution of average provincial emissions showed that the peaks were in June and October. This study updated the emission information that may support future research and policy-making on air pollution control and GHG emission abatement.


Distinct roles of the Salmonella enterica serovar Typhimurium CyaY and YggX proteins in the biosynthesis and repair of iron-sulfur clusters.
Labile [4Fe-4S](2+) clusters found at the active sites of many dehydratases are susceptible to damage by univalent oxidants that convert the clusters to an inactive [3Fe-4S](1+) form. Bacteria repair damaged clusters in a process that does not require de novo protein synthesis or the Isc and Suf cluster assembly pathways. The current study investigates the participation of the bacterial frataxin ortholog CyaY and the YggX protein, which are proposed to play roles in iron trafficking and iron-sulfur cluster repair. Previous reports found that individual mutations in cyaY or yggX were not associated with phenotypic changes in Escherichia coli and Salmonella enterica serovar Typhimurium, suggesting that CyaY and YggX might have functionally redundant roles. However, we have found that individual mutations in cyaY or yggX confer enhanced susceptibility to hydrogen peroxide in Salmonella enterica serovar Typhimurium. In addition, inactivation of the stm3944 open reading frame, which is located immediately upstream of cyaY and which encodes a putative inner membrane protein, dramatically enhances the hydrogen peroxide sensitivity of a cyaY mutant. Overexpression of STM3944 reduces the elevated intracellular free iron levels observed in an S. Typhimurium fur mutant and also reduces the total cellular iron content under conditions of iron overload, suggesting that the stm3944-encoded protein may mediate iron efflux. Mutations in cyaY and yggX have different effects on the activities of the iron-sulfur cluster-containing aconitase, serine deaminase, and NADH dehydrogenase I enzymes of S. Typhimurium under basal conditions or following recovery from oxidative stress. In addition, cyaY and yggX mutations have additive effects on 6-phosphogluconate dehydratase-dependent growth during nitrosative stress, and a cyaY mutation reduces Salmonella virulence in mice. Collectively, these results indicate that CyaY and YggX play distinct supporting roles in iron-sulfur cluster biosynthesis and the repair of labile clusters damaged by univalent oxidants. Salmonella experiences oxidative and nitrosative stress within host phagocytes, and CyaY-dependent maintenance of labile iron-sulfur clusters appears to be important for Salmonella virulence.


Neurorehabilitation Method for Preventing the Collapse of Internal Model: Verification of Unconscious Motor Change Caused by Implicit Error Involved in Multimodal Sensory FBs(Feedbacks).
It remains challenging for patients with stroke to regain the proper gait they had before stroke onset. In this study, one of the significant reasons for the problem is assumed to be the collapse of patients' internal model. Therefore, this study aimed to propose a method for lower-limb rehabilitation in the acute phase to prevent the collapse of the internal model and simultaneously promote voluntariness.To verify the effect of the proposed method and determine the optimal FB conditions, a supine pseudo-walking system has been developed providing multimodal sensory FBs, including somatosensory FB (walking on the walking robot), load transfer FB (plantar vibration provided by the robot), and visual FB (walking scene shown in virtual reality).First, the implicit error range of each sensory FB that was unable to recognize was investigated according to Weber's law. Subsequently, 12 participants were asked to perform 12 steps of walking exercise in the system to evaluate the unconscious motor-changing effect due to different/multimodal FBs. Errors were presented at the 7th step in either three FBs in the ratio determined or their combinations (two or three types of FBs simultaneously changing).Second, to examine whether the effect can last and influence the motion after the training, a pre-post comparison test was performed with the training in the middle, wherein implicit errors were presented in the three kinds of FBs.The results show that presenting implicit error can cause motor change, and multiple types of FBs may have a better effect. The statistical data of 12 participants of the pre-post comparison test show that the average integrated electromyogram in the post-test appears significantly larger than that in the pre-test. The result indicates that the motor-changing effect of the proposed method has a subsequent influence on motion and shows the possibility of the future application of the proposed method to the rehabilitation field.


Asymmetric development of the nervous system.
The human nervous system consists of seemingly symmetric left and right halves. However, closer observation of the brain reveals anatomical and functional lateralization. Defects in brain asymmetry correlate with several neurological disorders, yet our understanding of the mechanisms used to establish lateralization in the human central nervous system is extremely limited. Here, we review left-right asymmetries within the nervous system of humans and several model organisms, including rodents, Zebrafish, chickens, Xenopus, Drosophila, and the nematode Caenorhabditis elegans. Comparing and contrasting mechanisms used to develop left-right asymmetry in the nervous system can provide insight into how the human brain is lateralized. Developmental Dynamics 247:124-137, 2018. © 2017 Wiley Periodicals, Inc.


Computer-assisted pediatric diagnosis.
A system for computer aid to diagnosis was tested on 90 children hospitalized with systemic illness and discharged with a final diagnosis. A medical secretary and a pediatrician were equally successful (78% vs 77%) in having the system list the main final diagnosis when each independently supplied a list of details extracted only from the pediatric intern's admission notes. Even when the final diagnosis was not considered by the pediatric house staff and attending physicians caring for the patient until after the day of admission, the system was accurate in listing the diagnosis (or in raising the correct line of diagnostic inquiry) in at least 85% of the patients.


The genetic architecture of a host shift: An adaptive walk protected an aphid and its endosymbiont from plant chemical defenses.
Host shifts can lead to ecological speciation and the emergence of new pests and pathogens. However, the mutational events that facilitate the exploitation of novel hosts are poorly understood. Here, we characterize an adaptive walk underpinning the host shift of the aphid Myzus persicae to tobacco, including evolution of mechanisms that overcame tobacco chemical defenses. A series of mutational events added as many as 1.5 million nucleotides to the genome of the tobacco-adapted subspecies, M. p. nicotianae, and yielded profound increases in expression of an enzyme that efficiently detoxifies nicotine, both in aphid gut tissue and in the bacteriocytes housing the obligate aphid symbiont Buchnera aphidicola. This dual evolutionary solution overcame the challenge of preserving fitness of a mutualistic symbiosis during adaptation to a toxic novel host. Our results reveal the intricate processes by which genetic novelty can arise and drive the evolution of key innovations required for ecological adaptation.


[A new method to reconstruct the spatial structure of human proximal femur and establishment of the finite element model].
In current study of femoral head necrosis and femoral neck fractures, more attentions has been paid to relationship between the femoral head trabecular bone within the spatial structure and its biomechanics. In this connection, PMMA (polymethyl methacrylate), special square iron, dental base acrylic resin liquid and powder were used to embed and fix human dry femur. Then, M618 Lie Axle Rectangle Desk Plane Grinding Machine was applied to grind the femur specimen, and then air blower clean, two-dimensional cross section image was obtained by using scanner. With Mimics software reconstruction, a three-dimensional model of spatial structure of trabecular bone was obtained, and the trabecular bone three-dimensional parameters were calculated. The authors obtained clear three-dimensional model of trabecular bone, reconstructed the real anatomic morphology of proximal femur. This is a good method to research into the interior structure of femur and to provide the foundation for the three-dimensional finite element analysis.


Towards a single-use, low-cost endoscope for gastroenterological diagnostics.
Early diagnosis and treatment of diseases in the gastrointestinal (GI) tract including colorectal cancers (CRC) via natural orifices have led to a significant increase in patient survival rates. Most screening procedures utilize image-guided techniques via a conventional endoscope. The cost of conventional endoscopes is substantial, ranging in the tens of thousands of USD or more. This presents significant burden for developing countries, which are disproportionally affected by gastroenterological diseases. Conventional endoscopes also require sterilization between use. This increases the chance of cross-infection between patients. To address these problems, this paper introduces a soft endoscope with a disposable insertion tube that can be articulated. This prototype device is hydraulically actuated, capable of a 10 mm bend radius and 180-degree bend angle. The camera system provides 110 degrees field-of-view. The component parts of this disposable endoscope costs less than 200 USD.Clinical relevance-Our low-cost, single-use endoscope eliminates the sterilization step required by conventional systems, thereby reducing the risks of infection and lowering the operating costs. There is also significant scope for our device to be used beyond the human GI track, such as screening for lung or bladder cancers. Given the compact footprint, the minimal cost of the disposable parts, the proposed platform can widen cancer screening programs with quantifiable economic benefit for many patients, particularly those in developing countries.


Medical problems of porters and trekkers in the Nepal Himalaya.
The purpose of this study was to assess the incidence of medical illness among members of trekking groups in the Nepal Himalaya. The design was a cohort study using interview and clinical examination by a single physician. The setting was the Manaslu area in the central Nepal Himalaya along a 22-day trekking route with elevations ranging from 487 m to 5100 m. Subjects were 155 members of commercial trekking groups: 102 Nepali porters, 31 Nepali trek staff, and 22 Western trekkers. We found that medical problems occurred in 45% of party members. The porter cohort contained the highest diversity and severity of illness. The relatively larger porter cohort experienced 77% of the medical problems recorded compared with 17% among Western trekkers and 6% among trek staff. The incidence of medical problems was not significantly different in the porter staff (52%) and Western trekkers (55%) and was significantly lower for the trek staff (13%). High-altitude pharyngitis/bronchitis was the most common illness in the party (12%) followed by acute mountain sickness (8%) and gastroenteritis (6%). Other conditions included anxiety (3%), cellulitis (3%), scabies (3%), snow blindness (3%), acute alcohol intoxication (2%), conjunctivitis (2%), fever (2%), lacerations (2%), and hemorrhoids (1%). Illness with infectious etiologies comprised 33% of the medical problems. The incidence of altitude illness was not significantly less in the Nepali porter staff than in the Western trekkers. Evacuation was required in 5% of party members, all from the porter group. This study should alert expedition medical providers and trip leaders of the need to be observant for and prepared to treat the frequent and diverse medical problems among the porter staff in their party, in addition to the Western members. Medical problems are common in remote mountainous areas, indicating that trip physicians should be experienced in primary care.


Synthetic Hounsfield units from spectral CT data.
Beam-hardening-free synthetic images with absolute CT numbers that radiologists are used to can be constructed from spectral CT data by forming 'dichromatic" images after basis decomposition. The CT numbers are accurate for all tissues and the method does not require additional reconstruction. This method prevents radiologists from having to relearn new rules-of-thumb regarding absolute CT numbers for various organs and conditions as conventional CT is replaced by spectral CT. Displaying the synthetic Hounsfield unit images side-by-side with images reconstructed for optimal detectability for a certain task can ease the transition from conventional to spectral CT.


Spiral CT with ionic and nonionic contrast material: evaluation of patient motion and scan quality.
To assess the effect of rapidly injected ionic or nonionic contrast material on patient motion and scan quality in spiral computed tomography (CT). One hundred nine patients were prospectively, randomly chosen to receive ionic or nonionic contrast material. An acrylic rod was attached to the anterior abdomen with tape, which allowed an objective measurement of motion. Abdominal spiral CT was performed after intravenous injection of contrast material at a rate of 0.9 g of iodine per second. Scans were evaluated subjectively and objectively for motion and subjectively for quality. Complete data were available in 98 patients (47 in the ionic and 51 in the nonionic group). The acrylic rod moved an average of 0.44 mm per section in the nonionic group and 0.71 mm per section in the ionic group. Both subjective and objective measurements showed a statistically significant difference in patient motion. Use of nonionic contrast material resulted in less patient motion. Scan quality was better with nonionic contrast material. Less patient motion occurs and scan quality improves when spiral CT is performed with nonionic contrast material.


Eop1 from a Rubus strain of Erwinia amylovora functions as a host-range limiting factor.
Strains of Erwinia amylovora, the bacterium causing the disease fire blight of rosaceous plants, are separated into two groups based on host range: Spiraeoideae and Rubus strains. Spiraeoideae strains have wide host ranges, infecting plants in many rosaceous genera, including apple and pear. In the field, Rubus strains infect the genus Rubus exclusively, which includes raspberry and blackberry. Based on comparisons of limited sequence data from a Rubus and a Spiraeoideae strain, the gene eop1 was identified as unusually divergent, and it was selected as a possible host specificity factor. To test this, eop1 genes from a Rubus strain and a Spiraeoideae strain were cloned and mutated. Expression of the Rubus-strain eop1 reduced the virulence of E. amylovora in immature pear fruit and in apple shoots. Sequencing the orfA-eop1 regions of several strains of E. amylovora confirmed that forms of eop1 are conserved among strains with similar host ranges. This work provides evidence that eop1 from a Rubus-specific strain can function as a determinant of host specificity in E. amylovora.


Mutant-Huntingtin Molecular Pathways Elucidate New Targets for Drug Repurposing.
The spectrum of neurodegenerative diseases known today is quite extensive. The complexities of their research and treatment lie not only in their diversity. Even many years of struggle and narrowly focused research on common pathologies such as Alzheimer's, Parkinson's, and other brain diseases have not brought cures for these illnesses. What can be said about orphan diseases? In particular, Huntington's disease (HD), despite affecting a smaller part of the human population, still attracts many researchers. This disorder is known to result from a mutation in the HTT gene, but having this information still does not simplify the task of drug development and studying the mechanisms of disease progression. Nonetheless, the data accumulated over the years and their analysis provide a good basis for further research. Here, we review studies devoted to understanding the mechanisms of HD. We analyze genes and molecular pathways involved in HD pathogenesis to describe the action of repurposed drugs and try to find new therapeutic targets.


Characterization of site-specific glycosylation of secreted proteins associated with multi-drug resistance of gastric cancer.
Multi-drug resistance (MDR) remains a great obstacle to effective chemotherapy for gastric cancer. A number of secreted glycoproteins have been reported to be involved in the development of MDR in gastric cancer. However, whether glycosylation of secreted glycoproteins changes during MDR of gastric cancer is unclear. Our present work manifested that N-glycosites and site-specific glycoforms of secreted proteins in drug-resistant cell lines were distinctly different from those in the parental cell line for the first time. Further characterization highlighted the significance of some aberrantly glycosylated secretory proteins in MDR, suggesting that manipulating the glycosylation of specific glycoproteins could be a potential target for overcoming multi-drug resistance in gastric cancer.


Comparative response of the developing canine myocardium to inotropic agents.
Developmental changes in cardiac muscle function were assessed in isolated dog ventricular muscle strips obtained from dogs of three age groups: 2 day, 4 wk, and adult. Active tension (AT) and maximum rate of contraction and relaxation (+dT/dt, -dT/dt) increased significantly with age. Total contraction time increased with age. Time to peak tension increased between 4 wk and adulthood, and relaxation time increased between 2 day and 4 wk (P less than 0.05). The degree of post-"extra stimulus" potentiation in response to a single premature extra stimulus (SPES) or to sustained paired stimulation (SPS) was similar in all age groups. However, a longer period of SPS was necessary to reach peak AT in young animals than in adults. AT, +dT/dt, -dT/dt, and (-dT/dt)/T increased significantly in all age groups in response to increasing concentrations of isoproterenol. However, while (+dT/dt)/T increased significantly in the 4-wk and adult groups, it remained unchanged from control in the 2-day group with increasing concentration of isoproterenol. The ED50 of isoproterenol was significantly greater in the 2-day and 4-wk groups than in the adult group. AT increased significantly in young muscles but not in adult muscles when additional calcium was added to the bath containing the highest concentration of isoproterenol. In adult muscles SPS produced the greatest AT but not in the 2-day group, which required increased calcium concentration as well as isoproterenol. Maturation of several membrane systems is implicated.


A subset of high Gleason grade prostate carcinomas contain a large burden of prostate cancer syndecan-1 positive stromal cells.
There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility. Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters. We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells. The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma of prostate carcinomas, adjacent normal tissue, but not in non-diseased prostate. A subset of poor prognosis high Gleason grade 5 tumors had a particularly high PCSP cell burden, suggesting an association between this unidentified cell type and tumor aggressiveness.


Transgenerational rescue of a genetic defect in long-term potentiation and memory formation by juvenile enrichment.
The idea that qualities acquired from experience can be transmitted to future offspring has long been considered incompatible with current understanding of genetics. However, the recent documentation of non-Mendelian transgenerational inheritance makes such a "Lamarckian"-like phenomenon more plausible. Here, we demonstrate that exposure of 15-d-old mice to 2 weeks of an enriched environment (EE), that includes exposure to novel objects, elevated social interactions and voluntary exercise, enhances long-term potentiation (LTP) not only in these enriched mice but also in their future offspring through early adolescence, even if the offspring never experience EE. In both generations, LTP induction is augmented by a newly appearing cAMP/p38 MAP kinase-dependent signaling cascade. Strikingly, defective LTP and contextual fear conditioning memory normally associated with ras-grf knock-out mice are both masked in the offspring of enriched mutant parents. The transgenerational transmission of this effect occurs from the enriched mother to her offspring during embryogenesis. If a similar phenomenon occurs in humans, the effectiveness of one's memory during adolescence, particularly in those with defective cell signaling mechanisms that control memory, can be influenced by environmental stimulation experienced by one's mother during her youth.


Top 100 #PCOS influencers: Understanding who, why and how online content for PCOS is influenced.
With the exponential increase in digital space of social media platforms, a new group called social media influencers are driving online content of polycystic ovary syndrome (PCOS) which eventually influences behaviour and decision-making process. The objective of this study was to identify the top 100 social media (Twitter) influencers and organizations from across the globe who are advocating for PCOS. We further explored the origin and journey of these social media influencers. We identified the top 100 PCOS influencers and organizations between July and August 2022 using three social network analysis tools- Cronycle, Symplur and SocioViz. These influencers were invited to a semi-structured interview to explore why they chose to become an influencer and the support they have to deliver their online content. Two independent authors coded the anonymised transcripts from these interviews and broad themes were identified by thematic inductive analysis. 95.0% of individual influencers and 80% of organisations are from high-income countries. Most influencers in our study agree that social media is an essential tool in the present day to raise awareness of PCOS. However, they reiterated social media also has significant disadvantages that require consideration and caution. Most influencers were driven by poor personal experience and worked voluntarily to reduce misinformation and improve the experiences of women diagnosed with PCOS in the future. Although there is an interest in working together, there is currently minimal collaborative work between influencers. There is a global inequity of #PCOS influencers online. Establishing standards and support based on evidence may help develop more influencers, especially in low- and middle-income countries, so we can counter misinformation and provide locally acceptable guidance.


A typology of non-adherence in pediatric renal transplant recipients.
We reviewed 112 pediatric renal transplant recipients to document the rate of medication non-adherence (NA) and to examine the relationships between NA, comorbid psychiatric illness, and the outcome variables of acute and chronic rejection and graft loss. A total of 32.5% of subjects had clinically significant NA with treatment based on review of serum immunosuppressant levels. NA was found to be significantly related to acute and chronic rejection, and graft loss (p < 0.001). NA was also related to the presence of comorbid psychiatric illness (p < 0.001). Logistic regression indicated that NA was a significant predictor for acute and chronic rejection, while psychiatric illness predicted graft loss. Adolescents had significantly higher rates of NA as well as shorter intervals between transplant date and onset of NA when compared with child patients (p < 0.001). Physician ratings of the primary reasons for NA suggested that lack of parental supervision and parent-child conflict were the major factors related to NA.


[The elastase-like activity of the blood serum in patients with acute pneumonia].
A total of 168 patients were examined presenting with different clinical and roentgenological forms of acute pneumonia, such as focal one with an acute course, focal protracted, croupous with an acute course, croupous protracted, abscessing ones. Blood serum elastinase-like activity was studied. The complicated forms of pneumonia were found to be accompanied by two-phase dynamics of elastinase-like activity, such that it soars by day 10-15 of the disease process and declines by day 20-15, unlike the prognostically favourable forms of the condition where the initial reduction of this parameter turns to its gradual normalization.


Synthesis and processing of bovine herpesvirus 1 glycoproteins.
Four unique glycoproteins or glycoprotein complexes were recognized by a panel of monoclonal antibodies to bovine herpesvirus 1 (BHV-1), i.e., GVP 6/11a/16 (130,000-molecular-weight glycoprotein [130K glycoprotein]/74K/55K), GVP 7 (108K), GVP 3/9 (180K/91K), and GVP 11b (71K). The absence of any antigenic or structural relationship between GVP 11a and GVP 11b, which were previously identified as one glycoprotein, GVP 11, demonstrated that these two GVP 11 species are unique glycoproteins. GVP 3 and GVP 9 showed complete sequence homology, as shown by the identity of their antigenic determinants and by partial peptide mapping. This observation, as well as the ratio of their apparent molecular weights, indicated that GVP 3 (180K) is a dimeric form of GVP 9 (91K). GVP 6 and GVP 11a, as well as GVP 6 and GVP 16, showed at least partial sequence homology, since they shared several antigenic determinants and peptides. In addition, GVP 6, GVP 11a, and GVP 16 were derived from one primary precursor. These results, as well as the ratio of their apparent molecular weights, indicated that the GVP 6/11a/16 complex consists of two forms: one in which GVP 6 (130K) is uncleaved and the other one in which GVP 6 is cleaved and composed of GVP 11a (74K) and GVP 16 (55K), linked by disulfide bridges. An antigenically distinct precursor to each of the four BHV-1 glycoproteins or glycoprotein complexes was identified by monoclonal antibodies. These precursors, pGVP 6 (117K), pGVP 11a (62K), pGVP 7 (100K), pGVP 9 (69K), and pGVP 11b (63K) were sensitive to endo-beta-N-acetylglucosaminidase H treatment, indicating that they represent the partially glycosylated high-mannose-type intermediate forms generated by cotranslational glycosylation of the primary, unglycosylated precursors to GVP 6/11a/16, GVP 7, GVP 3/9, and GVP 11b, which were identified as having apparent molecular weights of 105,000, 90,000, 61,000, and 58,000, respectively. A new nomenclature for the BHV-1 glycoproteins, based on roman numerals, is proposed.


Cytologic Features of Lipogranulomatous Reaction in an Axillary Sentinel Lymph Node.
Multinucleated giant cells (MGC) are a rare finding when evaluating axillary sentinel lymph nodes. Some are described as foreign body-type MGC accompanied by foamy macrophages. They have been rarely reported in nodes from patients in which a previous breast biopsy was performed. The tissue damage induced by biopsy results in secondary changes including fat necrosis and hemorrhage that can migrate to axillary nodes. In this report, we illustrate a lipogranulomatous reaction in cytologic samples obtained during a sentinel lymph node examination of a woman previously biopsied because of breast carcinoma. We have found no previous cytologic descriptions and consider it an interesting finding that should be known to avoid diagnostic misinterpretations. A 51-year-old woman underwent mastectomy of the right breast with a sentinel lymph node biopsy at our medical center. One month before, a control mammography revealed suspicious microcalcifications and a vacuum-assisted breast biopsy resulted in a diagnosis of high-grade intraductal carcinoma with comedonecrosis. Surgery with a sentinel lymph node biopsy was performed. The sentinel node was processed as an intraoperative consultation. Frozen sections and air-dried Diff-Quik stained samples were obtained. They showed abundant lymphocytes with MGC and tumoral cells. MGC showed ample cytoplasm with evident vacuoles of variable size. Occasional hemosiderin-laden macrophages were also present. The complete histologic analysis and immunohistochemical studies revealed no malignant cells. Histologic analysis showed, in subcapsular location, occasional MGC phagocyting lipid droplets. Hemosiderin-laden macrophages were a common finding. Lipogranulomas may appear at axillary sentinel lymph nodes because of fat necrosis induced by previous breast biopsy. The most important consideration is not confounding MGC with epithelial cell clusters. This can occur with not well-processed samples, especially if unmounted.


Jarisch-Herxheimer Reaction Among Patients with Leptospirosis: Incidence and Risk Factors.
AbstractA Jarisch-Herxheimer reaction (JHR) may be precipitated after initiation of chemotherapy in spirochetal diseases, including leptospirosis. However, a clear idea of the importance of JHR in this disease is lacking. The incidence of and risk factors for JHR were investigated retrospectively among 262 patients with confirmed leptospirosis who received amoxicillin treatment in New Caledonia and Futuna. The overall rate of JHR was 21% (12% in New Caledonia and 44% in Futuna). Two risk factors were independently associated with JHR occurrence: Leptospira interrogans serogroup Australis as the infecting strain (odds ratio [OR] = 2.60, confidence interval [CI] = 1.40-5.62) and delays < 3 days between the onset of symptoms and the initiation of antibiotherapy (OR = 2.14, CI = 1.11-4.38). Clinicians should be aware of JHR as a potential complication of leptospirosis. Strain-related factors associated with JHR occurrence and its impact on outcome remains to be explored.


Confinement-Induced Enhancement of Parallel Dielectric Permittivity: Super Permittivity Under Extreme Confinement.
Enhancement of parallel (x-y plane) dielectric permittivity of confined fluids has been shown previously. However, a theoretical model that explains this enhancement is lacking thus far. In this study, using statistical-mechanical theories and molecular dynamics simulations, we show an explicit relation between the parallel dielectric permittivity, density variations, and dipolar correlations for protic and aprotic fluids confined in slit-like channels. We analyze the importance of dipolar correlations on enhancement of parallel dielectric permittivity inside large channels and extreme confinements. In large channels, beyond the interfacial region, dipolar correlations exhibit bulk-like behavior. Under extreme confinement, the correlations become stronger to the extent that they give rise to a giant increase in the parallel dielectric permittivity. This sudden increase in dielectric permittivity can be a signature of a liquid transition into higher-ordered structures and has important consequences for understanding ion transport, molecular dissociation, and chemical reactions inside nanoconfined environments.


Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape.
A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and granulocyte colony stimulating factor (G-CSF), that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance in a tumor stromal organoid (TSO) model, as well as an altered tumor microenvironment (TME) with augmented protumor immune signaling in a syngeneic mouse breast cancer model. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence.


Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1.
Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could thereby represent a specific therapeutic approach. We previously described the inhibitory activity of the 2-indolinone derivative RPI-1 (formerly Cpdl) on the tyrosine kinase activity and transforming ability of the products of the RET/PTC1 oncogene exogenously expressed in murine cells. In the present study, we investigated the effects of RPI-1 in the human papillary thyroid carcinoma cell line TPC-1 spontaneously harboring the RET/PTC1 rearrangement. Treatment with RPI-1 inhibited cell proliferation and induced accumulation of cells at the G2 cell cycle phase. In treated cells, Ret/Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase C(gamma), thereby indicating abrogation of constitutive signaling mediated by the oncoprotein. Activation of JNK2 and AKT was abolished, thus supporting the drug inhibitory efficacy on downstream pathways. In addition, cell growth inhibition was associated with a reduction in telomerase activity by nearly 85%. These findings in a cellular context relevant to the pathological function of RET oncogenes support the role of Ret oncoproteins as useful targets for therapeutic intervention, and suggest RPI-1 as a promising candidate for preclinical development in the treatment of thyroid tumors expressing RET oncogenes.


Endoscope-assisted clipping of a superior hypophyseal artery aneurysm without removal of the anterior clinoid process. Case report.
A 47-year-old man presented with a superior hypophyseal artery aneurysm and an ipsilateral posterior communicating artery aneurysm. Both lesions were successfully clipped without removal of the anterior clinoid process or retraction of the optic nerve by using endoscopic guidance. The endoscope was introduced into the prechiasmatic cistern and provided a clear visual field around the aneurysm that could not be seen via the operating microscope. The endoscope was useful in the identification of the medially projecting lesion and the small perforating branches of the ophthalmic segment of the internal carotid artery. A fenestrated clip could be introduced around the neck of the aneurysm and placed in the best position under endoscopic guidance. Endoscopy-assisted clipping is potentially a very useful procedure for aneurysm surgery.


Prevalence of transcription promoters within archaeal operons and coding sequences.
Despite the knowledge of complex prokaryotic-transcription mechanisms, generalized rules, such as the simplified organization of genes into operons with well-defined promoters and terminators, have had a significant role in systems analysis of regulatory logic in both bacteria and archaea. Here, we have investigated the prevalence of alternate regulatory mechanisms through genome-wide characterization of transcript structures of approximately 64% of all genes, including putative non-coding RNAs in Halobacterium salinarum NRC-1. Our integrative analysis of transcriptome dynamics and protein-DNA interaction data sets showed widespread environment-dependent modulation of operon architectures, transcription initiation and termination inside coding sequences, and extensive overlap in 3' ends of transcripts for many convergently transcribed genes. A significant fraction of these alternate transcriptional events correlate to binding locations of 11 transcription factors and regulators (TFs) inside operons and annotated genes-events usually considered spurious or non-functional. Using experimental validation, we illustrate the prevalence of overlapping genomic signals in archaeal transcription, casting doubt on the general perception of rigid boundaries between coding sequences and regulatory elements.


Uniform mesoporous silica coated iron oxide nanoparticles as a highly efficient, nontoxic MRI T(2) contrast agent with tunable proton relaxivities.
Monodisperse mesoporous silica (mSiO(2) ) coated superparamagnetic iron oxide (Fe(3) O(4) @mSiO(2) ) nanoparticles (NPs) have been developed as a potential magnetic resonance imaging (MRI) T(2) contrast agent. To evaluate the effect of surface coating on MRI contrast efficiency, we examined the proton relaxivities of Fe(3) O(4) @mSiO(2) NPs with different coating thicknesses. It was found that the mSiO(2) coating has a significant impact on the efficiency of Fe(3) O(4) NPs for MRI contrast enhancement. The efficiency increases with the thickness of mSiO(2) coating and is much higher than that of the commercial contrast agents. Nuclear magnetic resonance (NMR) relaxometry of Fe(3) O(4) @mSiO(2) further revealed that mSiO(2) coating is partially permeable to water molecules and therefore induces the decrease of longitudinal relaxivity, r(1) . Biocompatibility evaluation of various sized (ca. 35-95 nm) Fe(3) O(4) @mSiO(2) NPs was tested on OC-k3 cells and the result showed that these particles have no negative impact on cell viability. The enhanced MRI efficiency of Fe(3) O(4) @mSiO(2) highlights these core-shell particles as highly efficient T(2) contrast agents with high biocompatibility.


Clinical impact of the analytical specificity of the hybrid capture 2 test: data from the New Technologies for Cervical Cancer (NTCC) study.
The Hybrid Capture 2 (HC2) test targets 13 human papillomavirus (HPV) types. Here, cross-reactivity with non-HC2-targeted HPV types is described. We aimed to define the proportion of HC2-positive women who had negative results with HC2-targeted HPV types and estimate its determinants and impact on women's health management. The New Technologies for Cervical Cancer (NTCC) trial was followed in two predetermined phases. Women in the experimental arm were tested for the presence of HPV DNA by HC2 following a sample collection in PreservCyt (first phase) or Digene specimen transport medium (STM) (second phase). HPV genotyping was performed on DNA samples from HC2-positive women by PCR with GP5(+)/GP6(+) primers and reverse line blot (RLB) hybridization. Untyped samples were submitted to direct sequencing or restriction fragment length polymorphism. Multivariate logistic regression analysis estimated the adjusted odds ratios (ORs) between the presence of HC2-targeted types and age, viral load, and type of transport medium. Out of 2,920 HC2-positive samples, 2,310 (79.1%) were positive on RLB for HC2-targeted types, 396 were positive (13.6%) for only non-HC2-targeted types (mostly represented by HPV-53, HPV-66, and HPV-70), and in 214 (7.33%) samples, no HPV types were detected. The probability of detecting HC2-targeted types increased with increasing viral load expressed as the relative light unit/positive-control specimen ratio (RLU/PC) (OR for unitary increase of log RLU/PC, 1.35; 95% confidence interval [CI], 1.30 to 1.42) and with STM versus PreservCyt (OR, 1.56; 95% CI, 1.25 to 1.84). If only the samples containing HC2-targeted types tested positive, the positive predictive value (PPV) would have increased from 7.0% (95% CI, 6.1% to 8.0%) to 8.4% (95% CI, 7.3 to 9.6), although 4.9% (95% CI, 2.4% to 8.8%) of cervical intraepithelial neoplasia grade 2(+) (CIN2(+)) cases would have been missed. In conclusion, STM use and an increased cutoff would reduce the HC2 analytical false-positive rate and increase the positive predictive value for high-grade CIN. The gain in clinical sensitivity by detecting non-HC2-targeted HPV types is limited.


Development of intestinal ion-transporting mechanisms during smoltification and seawater acclimation in Atlantic salmon Salmo salar.
This study investigated the expression of ion transporters involved in intestinal fluid absorption and presents evidence for developmental changes in abundance and tissue distribution of these transporters during smoltification and seawater (SW) acclimation of Atlantic salmon Salmo salar. Emphasis was placed on Na(+) , K(+) -ATPase (NKA) and Na(+) , K(+) , Cl(-) co-transporter (NKCC) isoforms, at both transcriptional and protein levels, together with transcription of chloride channel genes. The nka α1c was the dominant isoform at the transcript level in both proximal and distal intestines; also, it was the most abundant isoform expressed in the basolateral membrane of enterocytes in the proximal intestine. This isoform was also abundantly expressed in the distal intestine in the lower part of the mucosal folds. The protein expression of intestinal Nkaα1c increased during smoltification. Immunostaining was localized to the basal membrane of the enterocytes in freshwater (FW) fish, and re-distributed to a lateral position after SW entry. Two other Nka isoforms, α1a and α1b, were expressed in the intestine but were not regulated to the same extent during smoltification and subsequent SW transfer. Their localization in the intestinal wall indicates a house-keeping function in excitatory tissues. The absorptive form of the NKCC-like isoform (sub-apically located NKCC2 and/or Na(+) , Cl(-) co-transporter) increased during smoltification and further after SW transfer. The cellular distribution changed from a diffuse expression in the sub-apical regions during smoltification to clustering of the transporters closer to the apical membrane after entry to SW. Furthermore, transcript abundance indicates that the mechanisms necessary for exit of chloride ions across the basolateral membrane and into the lateral intercellular space are present in the form of one or more of three different chloride channels: cystic fibrosis transmembrane conductance regulator I and II and chloride channel 3.


Decision forest analysis of 61 single nucleotide polymorphisms in a case-control study of esophageal cancer; a novel method.
Systematic evaluation and study of single nucleotide polymorphisms (SNPs) made possible by high throughput genotyping technologies and bioinformatics promises to provide breakthroughs in the understanding of complex diseases. Understanding how the millions of SNPs in the human genome are involved in conferring susceptibility or resistance to disease, or in rendering a drug efficacious or toxic in the individual is a major goal of the relatively new fields of pharmacogenomics. Esophageal squamous cell carcinoma is a high-mortality cancer with complex etiology and progression involving both genetic and environmental factors. We examined the association between esophageal cancer risk and patterns of 61 SNPs in a case-control study for a population from Shanxi Province in North Central China that has among the highest rates of esophageal squamous cell carcinoma in the world. High-throughput Masscode mass spectrometry genotyping was done on genomic DNA from 574 individuals (394 cases and 180 age-frequency matched controls). SNPs were chosen from among genes involving DNA repair enzymes, and Phase I and Phase II enzymes. We developed a novel adaptation of the Decision Forest pattern recognition method named Decision Forest for SNPs (DF-SNPs). The method was designated to analyze the SNP data. The classifier in separating the cases from the controls developed with DF-SNPs gave concordance, sensitivity and specificity, of 94.7%, 99.0% and 85.1%, respectively; suggesting its usefulness for hypothesizing what SNPs or combinations of SNPs could be involved in susceptibility to esophageal cancer. Importantly, the DF-SNPs algorithm incorporated a randomization test for assessing the relevance (or importance) of individual SNPs, SNP types (Homozygous common, heterozygous and homozygous variant) and patterns of SNP types (SNP patterns) that differentiate cases from controls. For example, we found that the different genotypes of SNP GADD45B E1122 are all associated with cancer risk. The DF-SNPs method can be used to differentiate esophageal squamous cell carcinoma cases from controls based on individual SNPs, SNP types and SNP patterns. The method could be useful to identify potential biomarkers from the SNP data and complement existing methods for genotype analyses.


Fabrication of calcium phosphate microcapsules using emulsion droplets stabilized with branched copolymers as templates.
We report on a versatile and time-efficient method to fabricate calcium phosphate (CaP) microcapsules by utilizing oil-in-water emulsion droplets stabilized with synthetic branched copolymer (BCP) as templates. The BCP was designed to provide a suitable architecture and functionality to produce stable emulsion droplets, and to permit the mineralization of CaP at the surface of the oil droplet when incubated in a solution containing calcium and phosphate ions. The CaP shells of the microcapsules were established to be calcium deficient hydroxyapatite with incorporated chlorine and carbonate species. These capsule walls were made fluorescent by decoration with a fluorescein-bisphosphonate conjugate.


Possible assortment of a1 and a2 region gene segments in human MHC class I molecules.
Using pair-wise comparison of aligned nucleotide sequences of distinct and complete human MHC class I molecules, we have constructed triangular tables to study the similarities and differences of various a1 (exon 2) and a2 (exon 3) region sequences. There are two HLA-A (A*6901 and A*6601) and 13 HLA-B (B*4201, B*8101, B*4102, B*4801, B*4007, B*4001, B*4802, Dw53, B*4406, B*4402, B*3901, B*1514 and B*3702) sequences that have identical a1 sequences with other known MHC class I molecules, while their a2 sequences are the same as those of different ones. Of these 15, A*6901, B*4001 and B*4802 have previously been suggested as the results of recombination between A*6801 and A*0201, B*4101 and B*8101, and B*4801 and B*3501, respectively. However, many other sequences can also be used to generate them by recombination. Furthermore, their reciprocal products have never been identified. Thus, gene conversion has subsequently been suggested as an alternative. Another possible genetic mechanism for generating these nucleotide sequence similarities can be assortment, or that some gene segments can be duplicated or multiplicated to be used in different human MHC class I molecules. Interestingly, this genetic mechanism is probably absent for the generation of different mouse MHC class I molecules.


Diffuse aggressive lymphoma.
The aggressive non-Hodgkin's lymphomas can be cured in more than half of the cases. However, there has been great variation in the results reported from individual clinical Phase II trials. This variation in result can be attributed to unrecognized heterogeneity in this group of diseases. Recent clinical and molecular studies have enabled us to define more homogenous population in which new therapies can be studied. For patients with advanced stages of diffuse large B cell lymphoma, a new standard of therapy exists. For patients with localized aggressive non-Hodgkin's lymphomas, heterogeneity in patient selection prevents us from defining a new standard of care. Finally, in mantle cell lymphoma, new opportunities in drug discovery may permit advances in the treatment of this uniformly fatal malignancy. In Section I, Dr. Richard Fisher reviews the development of combination chemotherapy for patients with advanced stage diffuse large B cell lymphoma. Because of great heterogeneity in patients enrolled in Phase II studies, large randomized Phase III studies were required in the 1980s to define CHOP has the standard of care. This heterogeneity has now been defined carefully in the international prognostic factor index and more recently by gene array studies. It will now need to be incorporated prospectively into studies or retrospectively analyzed to understand clinical trial results. The addition of rituximab to CHOP has now been demonstrated to improve survival in two large Phase III studies in elderly patients. A recently presented study in younger patients suggests a similar benefit. Thus CHOP/rituximab has become the established standard of care for all patients with advanced stage diffuse large B cell lymphoma. Other concepts being evaluated to further improve on these results include: dose intensification; initial treatment with chemotherapy plus allogeneic stem cell transplantation; and infusional chemotherapy. Finally, the status of the treatment for relapsed patients will be defined. In Section II, Dr. Thomas Miller defines the treatment for limited stage aggressive non-Hodgkin's lymphoma. Randomized trials have demonstrated the critical importance of initial chemotherapy for treatment of these patients. The amount of chemotherapy given needs to be increased for patients with bulky tumors. In most circumstances radiotherapy after the completion of chemotherapy has been shown to be advantageous. A modification of the international prognostic factor index for patients with early stage disease is presented to permit comparisons among different populations. Recently reported early-stage studies need to be analyzed in terms of the heterogeneity of the patients involved to understand the reported results. The addition of monoclonal antibodies, as well as radioimmunotherapy, are being tested in an effort to improve on the results for the poor prognosis patients. In Section III, Dr. Owen O'Connor describes the pathology immunophenotype and natural history of mantle cell lymphoma. Conventional treatment strategies with combination chemotherapy achieved objective responses in approximately half of the patients but no significant impact on survival. The addition to rituximab to CHOP chemotherapy or other treatment strategies appears to improve the remission rate; however, no major changes in survival have also been reported. Excellent single institution results have been reported with HyperCVAD plus rituximab regimen, which is currently being tested in a national cooperative group trial. The most excitement in this field currently relates to the variety of new agents which appear to have significant activity in relapsed patients with mantle cell lymphoma. This includes the proteosome inhibitor, bortezomib, which is shown to have approximately a 50% response rate with some CRs and reasonable durability in early single institution Phase II studies. Larger national multi-center trials are ongoing. In addition, agents such as thalidomide, flavopiridol, and piroxantrone will be reviewed.


Modulating inflammatory cell responses to spinal cord injury: all in good time.
Spinal cord injury can have a range of debilitating effects, permanently impacting a patient's quality of life. Initially thought to be an immune privileged site, the spinal cord is able to mount a timely and well organized inflammatory response to injury. Intricate immune cell interactions are triggered, typically consisting of a staggered multiphasic immune cell response, which can become deregulated if left unchecked. Although several immunomodulatory compounds have yielded success in experimental rodent spinal cord injury models, their translation to human clinical studies needs further consideration. Because temporal differences between rodent and human inflammatory responses to spinal cord injury do exist, drug delivery timing will be a crucial component in recovery from spinal cord injury. Given too early, immunomodulatory therapies may impede beneficial inflammatory reactions to the injured spinal cord or even miss the opportunity to dampen delayed harmful autoimmune processes. Therefore, this review aims to summarize the temporal inflammatory response to spinal cord injury, as well as detailing specific immune cell functions. By clearly defining the chronological order of inflammatory events after trauma, immunomodulatory drug delivery timing can be better optimized. Further, we compare spinal cord injury-induced inflammatory responses in rodent and human studies, enabling clinicians to consider these differences when initiating clinical trials. Improved understanding of the cellular immune response after spinal cord injury would enhance the efficacy of immunomodulatory agents, enabling combined therapies to be considered.


Benzodiazepine Use and Misuse Among Adults in the United States.
Goals were to determine the prevalence of benzodiazepine use (as prescribed and misuse), characterize misuse, and examine variation by age. A cross-sectional analysis was conducted of 2015 and 2016 National Survey on Drug Use and Health data limited to adults ≥18 (N=86,186) and data from those respondents reporting benzodiazepine use (N=10,290). Measurements included past-year prescription benzodiazepine use and misuse ("any way a doctor did not direct"), substance use disorders, mental illness, and demographic characteristics. Misuse was compared between younger (18-49) and older (≥50) adults. A total of 30.6 million adults (12.6%) reported past-year benzodiazepine use-25.3 million (10.4%) as prescribed and 5.3 million (2.2%) misuse. Misuse accounted for 17.2% of overall use. Adults ages 50-64 had the highest prescribed use (12.9%). Those ages 18-25 had the highest misuse (5.2%), and those ages ≥65 had the lowest (.6%). Misuse and abuse of or dependence on prescription opioids or stimulants were strongly associated with benzodiazepine misuse. Benzodiazepine misuse without a prescription was the most common type of misuse, and a friend or relative was the most common source. Adults ages ≥50 were more likely than younger adults to use a benzodiazepine more often than prescribed and to use a benzodiazepine to help with sleep. Benzodiazepine use among U.S. adults was higher than previously reported, and misuse accounted for nearly 20% of use overall. Use by adults ages 50-64 now exceeds use by those ages ≥65. Patients also prescribed stimulants or opioids should be monitored for benzodiazepine misuse. Improved access to behavioral interventions for sleep or anxiety may reduce some misuse.


A stable transcription complex directs mouse ribosomal RNA synthesis by RNA polymerase I.
Ribosomal RNA is synthesized from template molecules that are activated by a stable association with essential transcription factors. This activated template assembles prior to the onset of transcription as a preinitiation complex and factors remain firmly attached during active elongation as well. Sequential addition of differently marked rRNA genes to an S-100 mouse cell extract shows that the DNA binding factors of the stable complex are present in limiting quantities. They associate rapidly with template molecules and the resultant transcription complex remains intact over prolonged periods of incubation in the presence of competitor DNA. The resistance of the stable complex to the usual inhibitory effect of high DNA concentration suggests that more than one DNA binding factor recognizes the rDNA promoter region and is needed to direct faithful transcription. Finally, although the stable complex is specific for the rRNA initiation region, added vector sequences can neutralize nonspecific DNA binding components that are also present in the cell extract. This lowers the requirement for rDNA template and demonstrates that each activated rRNA gene can direct at least 10 rounds of elongation and reinitiation.


United States Health Policies and Late-stage Breast and colorectal cancer diagnosis: Why such disparities by age?
Colorectal and breast cancers are the second most common causes of cancer deaths in the US. Population cancer screening rates are suboptimal and many cancers are diagnosed at an advanced stage, which results in increased morbidity and mortality. Younger populations are more likely to be diagnosed at a later stage, and this age disparity is not well understood. We examine the associations between late-stage breast cancer (BC) and colorectal cancer (CRC) diagnoses and multilevel factors, focusing on individual state regulations of insurance and health practitioners, and interactions between such policies and age. We expect state-level regulations are significant predictors of the rates of late-stage diagnosis among younger adults. We included adults of all ages, with BC or CRC diagnosed between 2004 -2009, obtained from a newly available cancer population database covering 98 % of all known new cancer cases. We included personal characteristics, linked with a set of county and state-level predictors based on residence. We applied multilevel models to robustly examine differences in risk of late-stage cancer diagnosis across age groups (defined as age 65+ or < 65), focusing specifically on the effects of state regulatory factors and their interactions with age. Late stage BC diagnoses range from 24 %-36 %, while CRC diagnoses range from 54 %-60 % of newly diagnosed BC or CRC cases across states. After controlling statistically for many confounding factors at three levels, age < 65 is the largest person-level predictor for CRC, while black race is the largest predictor for BC. State regulations of health markets exhibit significant interactions with age groups. The state regulatory climate is an important predictor of late-stage BC and CRC diagnoses, especially among people younger than Medicare eligible age (65). State regulations can enhance the climate of access for younger, less well-insured or uninsured persons who fall outside normative screening guidelines.


Short- and long- term effects of cigarette smoke exposure on glutathione homeostasis in human bronchial epithelial cells.
Cigarette smoke extract (CSE), a model for studying the effects of tobacco smoke in vivo and in vitro, induces cell oxidative stress and affects the antioxidative glutathione system. We evaluated the impact of CSE on airway epithelial cells and the possible cytoprotective effect of the mucolitic drug S-carboximethilcysteine lysine salt (S-CMC-Lys). Reduced glutathione (GSH) and reactive oxygen species (ROS) intracellular levels were evaluated by fluorimetry in human bronchial epithelial cells (16-HBE) and the expression and activity of enzymes of the GSH metabolic pathway were investigated by RT-PCR, Western blot and colorimetric assays. CSE significantly increased cell mortality in a time and dose dependent manner, via an apoptosis-independent pathway. Short-term (3 hours) CSE exposure induced an increase in ROS levels and a GSH intracellular concentration drop. In parallel, the expression of glutathione peroxidases 2 and 3, glutathione reductase and glutamate-cysteine-ligase was increased. S-CMC-Lys was effective in counteracting these effects. CSE affects ROS levels, GSH concentration and GSH enzymes pathway. These effects can be to some extent reversed by S-CMC-Lys, that could represent a therapeutic tool to counteract CSE induced oxidative cellular injuries.


runt homology domain transcription factors (Runx, Cbfa, and AML) mediate repression of the bone sialoprotein promoter: evidence for promoter context-dependent activity of Cbfa proteins.
Expression of the bone sialoprotein (BSP) gene, a marker of bone formation, is largely restricted to cells in mineralized tissues. Recent studies have shown that the Cbfa1 (also known as Runx2, AML-3, and PEBP2alphaA) transcription factor supports commitment and differentiation of progenitor cells to hypertrophic chondrocytes and osteoblasts. This study addresses the functional involvement of Cbfa sites in expression of the Gallus BSP gene. Gel mobility shift analyses with nuclear extracts from ROS 17/2.8 osteoblastic cells revealed that multiple Cbfa consensus sequences are functional Cbfa DNA binding sites. Responsiveness of the 1.2-kb Gallus BSP promoter to Cbfa factors Cbfa1, Cbfa2, and Cbfa3 was assayed in osseous and nonosseous cells. Each of the Cbfa factors mediated repression of the wild-type BSP promoter, in contrast to their well known activation of various hematopoietic and skeletal phenotypic genes. Suppression of BSP by Cbfa factors was not observed in BSP promoters in which Cbfa sites were deleted or mutated. Expression of the endogenous BSP gene in Gallus osteoblasts was similarly downregulated by forced expression of Cbfa factors. Our data indicate that Cbfa repression of the BSP promoter does not involve the transducin-like enhancer (TLE) proteins. Neither coexpression of TLE1 or TLE2 nor the absence of the TLE interaction motif of Cbfa1 (amino acids 501 to 513) influenced repressor activity. However, removal of the C terminus of Cbfa1 (amino acids 362 to 513) relieved suppression of the BSP promoter. Our results, together with the evolutionary conservation of the seven Cbfa sites in the Gallus and human BSP promoters, suggest that suppressor activity by Cbfa is of significant physiologic consequence and may contribute to spatiotemporal expression of BSP during bone development.


Summary of 2021 Clinical Guidelines for the Diagnosis and Treatment of HIV/AIDS in HIV-infected Koreans.
Since the establishment of the Committee for Clinical Guidelines for the Diagnosis and Treatment of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) by the Korean Society for AIDS in 2010, clinical guidelines have been prepared in 2011, 2013, 2015, and 2018. As new research findings on the epidemiology, diagnosis, and treatment of AIDS have been published in and outside of Korea along with the development and introduction of new antiretroviral medications, a need has arisen to revise the clinical guidelines by analyzing such new data. The clinical guidelines address the initial evaluation of patients diagnosed with HIV/AIDS, follow-up tests, appropriate timing of medication, appropriate antiretroviral medications, treatment strategies for patients who have concurrent infections with hepatitis B or C virus, recommendations for resistance testing, treatment for patients with HIV and tuberculosis coinfections, and treatment in pregnant women. Through these clinical guidelines, the Korean Society for AIDS and the Committee for Clinical Guidelines for the Diagnosis and Treatment of HIV/AIDS contributes to overcoming AIDS by delivering latest data and treatment strategies to healthcare professionals who treat AIDS in the clinic.


Resource constraints in petroleum production potential.
Geologic reasons indicate that the dominant position of the Middle East as a source of conventional petroleum will not be changed by new discoveries elsewhere. The share of world crude oil production coming from the Middle East could increase, within 10 to 20 years, to exceed 50 percent, under even modest increases in world consumption. Nonconventional resources of oil exist in large quantities, but because of their low production rates they can at best only mitigate extant trends. Increased production of natural gas outside the United States, however, offers an opportunity for geographically diversified energy supplies in the near future.


[The effect of aging on the peripheral functions in farmers and chain saw operators part 1. age-related changes in pain and vibratory sense thresholds (author's transl)].
Vibration hazards caused by using vibrating tools include such disorders as peripheral circulatory disturbances, peripheral nervous disturbances and abnormalities of the bones and joints. It is generally acknowledged that the effect of physiological aging on the nervous system gradually increases with age. In this paper, therefore to assess the effect of aging on the peripheral nervous function as evaluated by pain and vibratory sense thresholds of fingers, 135 farmers and 130 chain saw operators ranging in age from 30 to 69 years were examined. Moreover, 27 normal persons aged between 21 and 37 years served as the control for comparison. The results obtained were as follows: 1) In the control subjects, there was no age-related change in the pain threshold. However, the vibratory sense threshold at a frequency of 125 Hz or 250 Hz showed a tendency to increase with advancing age. 2) In both farmers and chain saw operators, thresholds in the pain and the vibratory sense at a frequency of 125 Hz or 250 Hz showed a tendency to increase with advancing age. 3) The pain thresholds in chain saw operators seemed to be slightly higher than those in farmers in all age groups, but the differences were not statistically significant. On the other hand, the vibratory sense thresholds at a frequency of 125 Hz or 250 Hz in chain saw operators were significantly higher by 5 dB than those in farmers in all age groups. From these results it is suggested that we have to use age-adjusted standard criteria in evaluating thresholds of the pain and the vibratory sense at a frequency of 125 Hz or 250 Hz.


Using Linear Equating to Map PROMIS(®) Global Health Items and the PROMIS-29 V2.0 Profile Measure to the Health Utilities Index Mark 3.
Preference-based health-related quality of life (HR-QOL) scores are useful as outcome measures in clinical studies, for monitoring the health of populations, and for estimating quality-adjusted life-years. This was a secondary analysis of data collected in an internet survey as part of the Patient-Reported Outcomes Measurement Information System (PROMIS(®)) project. To estimate Health Utilities Index Mark 3 (HUI-3) preference scores, we used the ten PROMIS(®) global health items, the PROMIS-29 V2.0 single pain intensity item and seven multi-item scales (physical functioning, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, sleep disturbance), and the PROMIS-29 V2.0 items. Linear regression analyses were used to identify significant predictors, followed by simple linear equating to avoid regression to the mean. The regression models explained 48 % (global health items), 61 % (PROMIS-29 V2.0 scales), and 64 % (PROMIS-29 V2.0 items) of the variance in the HUI-3 preference score. Linear equated scores were similar to observed scores, although differences tended to be larger for older study participants. HUI-3 preference scores can be estimated from the PROMIS(®) global health items or PROMIS-29 V2.0. The estimated HUI-3 scores from the PROMIS(®) health measures can be used for economic applications and as a measure of overall HR-QOL in research.


Development of transmucosal patch using nanofibers.
In the present work we have attempted to develop a novel transmucosal patch of diclofenac sodium using electrospun polycaprolactone (PCL) nanofibers. PCL nanofibers were prepared by electrospinning techniques using different polymer concentrations. Nanofibers formulations were characterized by SEM, FTIR, drug loading, and in-vitro release study using Franz diffusion cell. Studies revealed the nanofibers fabricated from 13% PCL were fracture-free, non-beaded, and ultrafine with 120 nm diameter. Release studies demonstrated the sustained release behavior of PCL nanofibers. Nanofibers can be exploited for transmucosal drug delivery of NSAID with improved therapeutic efficacy.


Nutritional intakes and associated factors among tuberculosis patients: a cross-sectional study in China.
The objectives of this study were to examine nutrient intakes of tuberculosis (TB) patients and to identify their associated factors. In this cross-sectional study, 300 adult TB patients were surveyed in two impoverished counties in China. Nutrient intakes were evaluated through two consecutive 24-h dietary recalls and compared with the Chinese Dietary Reference Intakes (DRIs) 2013. The potential socio-demographic and behavioral factors were analyzed using multivariate logistic model to identify strong influential factors. We found that mean daily energy intake was 1655.0 kcal (SD: 619.3 kcal) and 1360.3 kcal (SD: 552.1 kcal) for male and female patients, respectively. The mean daily energy intake was significantly lower than that has been recommended by DRI (i.e., 2250 and 1800 kcal for males and females, respectively), with 87.4% of the male patients and 59.9% of female patients failed to consume adequate energy. The protein intakes were 44.6 g (SD: 18.2 g) and 35.9 g (SD: 12.3 g) for male and female patients, respectively, which were lower than the recommended values by DRI (i.e., 65 and 55 g for males and females, respectively). Most male (90.8%) and female (58.4%) TB patients had insufficient daily protein intake. Further analyses suggested that mean daily intakes of many micronutrients, were insufficient, while for most of patients, intakes of vitamin E and sodium were sufficient. We identified that unemployment was a risk factor for low energy intake (p < 0.05) and out-home-eating was a protective factor for low protein intake (p < 0.01). In impoverished areas in China, intakes of macronutrients and most micronutrients in TB patients were inadequate compared with DRIs, especially for unemployed patients and patients eating at home. These findings suggested that public health actions are needed to promote education on TB patients about significance of nutritional support, and, further interventions in TB patients' nutritional intakes are also required.


Validity and reliability of grade scoring in the diagnosis of exercise-induced laryngeal obstruction.
The current gold-standard method for diagnosing exercise-induced laryngeal obstruction (EILO) is continuous laryngoscopy during exercise (CLE), with severity classified by a visual grade scoring system. We evaluated the precision of this approach, by evaluating test-retest reliability of CLE and both inter- and intra-rater variability. In this prospective case-control study, subjects completed four consecutive treadmill CLE tests under identical conditions. Laryngoscopic video recordings were anonymised and graded by three expert raters. 2 months following initial scoring, videos were re-randomised and rating repeated to assess intra-rater agreement. 20 subjects (16 cases and four controls) completed four CLE tests. The time to exhaustion increased by 30 s (95% CI 0.02-57.8, p<0.05) in the second CLE compared with the first test, but remained identical in the subsequent tests. Only one-third of subjects retained their initial diagnosis in the subsequent three tests. Inter-rater agreement on grade scores (weighted Cohen's ϰ) was 0.16-0.45, while intra-rater agreement ranged from 0.30 to 0.67. The CLE test is key in the diagnostic assessment of patients with EILO. However, the widely adopted visual grade scoring system does not appear to be a robust means for reliably classifying severity of EILO.


Metabolic cost as a unifying principle governing neuronal biophysics.
The brain contains an astonishing diversity of neurons, each expressing only one set of ion channels out of the billions of potential channel combinations. Simple organizing principles are required for us to make sense of this abundance of possibilities and wealth of related data. We suggest that energy minimization subject to functional constraints may be one such unifying principle. We compared the energy needed to produce action potentials singly and in trains for a wide range of channel densities and kinetic parameters and examined which combinations of parameters maximized spiking function while minimizing energetic cost. We confirmed these results for sodium channels using a dynamic current clamp in neocortical fast spiking interneurons. We find further evidence supporting this hypothesis in a wide range of other neurons from several species and conclude that the ion channels in these neurons minimize energy expenditure in their normal range of spiking.


Metabolic and Proteomic Responses to Salinity in Synthetic Nitrifying Communities of Nitrosomonas spp. and Nitrobacter spp.
Typically, nitrification is a two-stage microbial process and is key in wastewater treatment and nutrient recovery from waste streams. Changes in salinity represent a major stress factor that can trigger response mechanisms, impacting the activity and the physiology of bacteria. Despite its pivotal biotechnological role, little information is available on the specific response of nitrifying bacteria to varying levels of salinity. In this study, synthetic communities of ammonia-oxidizing bacteria (AOB Nitrosomonas europaea and/or Nitrosomonas ureae) and nitrite-oxidizing bacteria (NOB Nitrobacter winogradskyi and/or Nitrobacter vulgaris) were tested at 5, 10, and 30 mS cm-1 by adding sodium chloride to the mineral medium (0, 40, and 200 mM NaCl, respectively). Ammonia oxidation activity was less affected by salinity than nitrite oxidation. AOB, on their own or in combination with NOB, showed no significant difference in the ammonia oxidation rate among the three conditions. However, N. winogradskyi improved the absolute ammonia oxidation rate of both N. europaea and N. ureae. N. winogradskyi's nitrite oxidation rate decreased to 42% residual activity upon exposure to 30 mS cm-1, also showing a similar behavior when tested with Nitrosomonas spp. The nitrite oxidation rate of N. vulgaris, as a single species, was not affected when adding sodium chloride up to 30 mS cm-1, however, its activity was completely inhibited when combined with Nitrosomonas spp. in the presence of ammonium/ammonia. The proteomic analysis of a co-culture of N. europaea and N. winogradskyi revealed the production of osmolytes, regulation of cell permeability and an oxidative stress response in N. europaea and an oxidative stress response in N. winogradskyi, as a result of increasing the salt concentration from 5 to 30 mS cm-1. A specific metabolic response observed in N. europaea suggests the role of carbon metabolism in the production of reducing power, possibly to meet the energy demands of the stress response mechanisms, induced by high salinity. For the first time, metabolic modifications and response mechanisms caused by the exposure to salinity were described, serving as a tool toward controllability and predictability of nitrifying systems exposed to salt fluctuations.


Effects of octreotide acetate and amniotic membrane on wound healing in experimental glaucoma surgery.
Wound healing affects the success of glaucoma filtering surgery. Antimetabolites and antifibrotic agents are used in the modulation of surgical trauma. This study is performed to evaluate the effects of amniotic membrane and octreotide acetate on wound healing. Thirty pigmented rabbits were divided into three groups each including 10 animals. Trabeculectomy and topical postoperative prednisolone sodium phosphate four times daily for 7 days were applied to one eye of all the rabbits. After trabeculectomy, octreotide 10 microg three times daily applied topically to the octreotide group for 14 days and amniotic membrane transplantation was performed by suturing amniotic membrane between scleral flap and sclera to the amniotic membrane group. The operated eyes of the rabbits were enucleated on the 14th day of the operation and histopathological specimens were obtained from the bleb sites and they were evaluated by light microscope. Fibroblast and macrophage number per cm2 were counted and the average values were calculated. Compared with the control group, the fibroblasts and macrophages significantly decreased in the other two groups (p < 0.0001, p < 0.0001, respectively). The mean number of fibroblasts was lower than those of the control and amniotic membrane groups (p < 0.0001, p < 0.0001, respectively). Similarly the mean macrophage number was significantly lower in the octreotide group versus the control and amniotic membrane groups (p < 0.0001, p < 0.01, respectively). Octreotide administration and amniotic membrane transplantation might be alternative treatments in modulating the wound healing after trabeculectomy.


Study of Anatomical Relationship between Posterior Teeth and Maxillary Sinus Floor in a Subpopulation of the Brazilian Central Region Using Cone-Beam Computed Tomography - Part 2.
This study evaluated the anatomical relationship between posterior teeth root apices and maxillary sinus floor (MSF) on 202 cone beam computed tomography (CBCT) exams. The distance between the root apices and the MSF, as well as the MSF thickness of the cortical bone closest to root apices and furcation regions were measured. The vertical and horizontal relationships of the MSF with the molar roots were classified into categories adapted from the criteria proposed by Kwak et al. (14). The shortest distances between MSF and the root apices were observed in the mesiobuccal root of the second molar (0.36±1.17 mm) and the palatal root of the first molar (0.45±1.10 mm) and the widest in buccal roots of the first premolars (5.47±4.43 mm). Significant differences were observed between the distance of MSF to the root apices of single-rooted first and second premolars. The cortical thickness ranged from 0.65±0.41 mm over the mesiobuccal root of the second molar to 1.28±0.42 mm over the buccal root of the first premolar. The most observed vertical and horizontal relationships were type II and 2H, respectively. The maxillary molar roots showed greater proximity to the MSF. The thickness of the MSF cortical bone closest to the apices and furcation regions was found to be similar only for premolars.


Boosting Photocatalytic Performance of ZnO Nanowires via Building Heterojunction with g-C3N4.
The development of a stable and highly active photocatalyst has garnered significant attention in the field of wastewater treatment. In this study, a novel technique involving a facile stirring method was devised to fabricate an array of g-C3N4/ZnO nanowire (ZnO NW) composites. Through the introduction of g-C3N4 to augment the generation of electron-hole pairs upon exposure to light, the catalytic efficacy of these composites was found to surpass that of the pristine ZnO NWs when subjected to simulated sunlight. The photocatalytic performance of a 20 mg·L-1 methylene blue solution was found to be highest when the doping rate was 25 wt%, resulting in a degradation rate of 99.1% after 60 min. The remarkable enhancement in catalytic efficiency can be ascribed to the emergence of a captivating hetero-junction at the interface of g-C3N4 and ZnO NWs, characterized by a harmoniously aligned band structure. This alluring arrangement effectively curtailed charge carrier recombination, amplified light absorption, and augmented the distinct surface area, culminating in a notable boost to the photocatalytic prowess. These findings suggest that the strategic engineering of g-C3N4/ZnO NW heterostructures holds tremendous promise as a pioneering avenue for enhancing the efficacy of wastewater treatment methodologies.


Taming the Beast of Biology: Synthetic Biology and Biological Systems Engineering.
Despite the availability of a variety of ' -omics ' technologies to support the system-wide analysis of industrially relevant microorganisms, the manipulation of strains towards an economically relevant goal remains a challenge. Remarkably, our ability to catalogue the participants in and model ever more comprehensive aspects of a microorganism's physiology is now complemented by technologies that permanently expand the scope of engineering interventions that can be imagined. In fact, genome-wide editing and re-synthesis of microbial and even eukaryotic chromosomes have become widely applied methods. At the heart of this emerging system-wide engineering approach, often labelled ' Synthetic Biology ' , is the continuous improvement of large-scale DNA synthesis, which is put to two-fold use: (i) starting ever more ambitious efforts to re-write existing and coding novel molecular systems, and (ii) designing and constructing increasingly sophisticated library technologies, which has led to a renaissance of directed evolution in strain engineering. Here, we briefly review some of the critical concepts and technological stepping-stones of Synthetic Biology on its way to becoming a mature industrial technology.


Optimization approaches to volumetric modulated arc therapy planning.
Volumetric modulated arc therapy (VMAT) has found widespread clinical application in recent years. A large number of treatment planning studies have evaluated the potential for VMAT for different disease sites based on the currently available commercial implementations of VMAT planning. In contrast, literature on the underlying mathematical optimization methods used in treatment planning is scarce. VMAT planning represents a challenging large scale optimization problem. In contrast to fluence map optimization in intensity-modulated radiotherapy planning for static beams, VMAT planning represents a nonconvex optimization problem. In this paper, the authors review the state-of-the-art in VMAT planning from an algorithmic perspective. Different approaches to VMAT optimization, including arc sequencing methods, extensions of direct aperture optimization, and direct optimization of leaf trajectories are reviewed. Their advantages and limitations are outlined and recommendations for improvements are discussed.


Protective effect of inactivated hepatitis A vaccine against the outbreak of hepatitis A in an open rural community.
To evaluate the protective effect of inactivated hepatitis A vaccine (Healive) against hepatitis A outbreak in an emergency vaccination campaign. During an outbreak of hepatitis A in Honghe Town, Xiuzhou District, Jiaxing City, Zhejiang Province, two nonrandomized controlled trials were conducted in September 2006. The first trial was to vaccinate 108 anti-HAV negative individuals with close contacts of the patients from September with 1 dose of an inactivated hepatitis A vaccine, Healive. The control group comprised of 115 individuals with close contacts of the patients before September. The second trial was to vaccinate 3365 primary and secondary school students who volunteered to receive a dose of Healive and 2572 students who did not receive Healive serving as its controls. An epidemiological survey was conducted to evaluate the protective efficacy of the vaccine. A total of 136 hepatitis A cases were reported during an outbreak that started in June, peaked in August and September, and ended after December of 2006. After a massive vaccination of school children in September, the number of cases declined significantly. No hepatitis A was detected in the 108 vaccinated individuals with close contacts of patients, whereas 4 cases of hepatitis A were found in the controls. The infection rate of hepatitis A was not significantly different in the individuals with close contacts of patients whether or not they received the vaccine (P = 0.122). No hepatitis A was detected in the 3365 students who received the vaccine, four cases of hepatitis A were found in the controls. The infection rate of students with or without vaccination was significantly different in the students who received the vaccine (0/3365 vs 4/2572, P = 0.035). The protective efficacy of the vaccine was 100%. Inactivated hepatitis A vaccine demonstrates a good protective effect against an outbreak of hepatitis A.