Stretch-dependent (myogenic) tone in rabbit ear resistance arteries.
Rabbit ear resistance arteries are vessels with three to six layers of smooth muscle cells and an unstretched lumen diameter of 75-150 micron. Ring segments of these arteries, in response to mechanical stretch in vitro, developed a maintained tonic contraction. The stretch-dependent contraction achieved a plateau within 10-30 min. Smooth muscle relaxants, such as NaNO2 and papaverine, substitution of extracellular Ca2+ by subthreshold Ca2+ (25 microM), or exposure to the Ca2+ influx antagonist Mn2+ abolished the stretch-dependent tone. The extent of the tone was dependent on the level of the applied stretch and the extracellular Ca2+ concentration ( [Ca2+]o). The maximal tone developed at optimal stretch, and [Ca2+]o in the bath solution was 18.1 +/- 4.6% of the maximal contraction of the vessel to histamine. This level of tone is comparable to neurogenic tone developed in response to nerve stimulation within the physiological frequency range. The stretch-dependent tone is considered probably myogenic in origin, since it was present in arterial segments that had been chronically denervated by surgical sympathectomy, mechanically deprived of the endothelium, and multireceptor blocked (phenoxybenzamine, 10(-6) M). Our findings suggest first that the stretch-dependent tone is myogenic and may be similar to basal vascular tone arising from the stretch of arterial pressure and its changes in vivo. Second, the magnitude of myogenic tone is a function of the applied stretch and the [Ca2+]o. Finally, myogenic tone is important in the physiological regulation of arterial tone in the rabbit ear resistance arteries.


Adverse environments: investigating local variation in child growth.
Epigenetic and life history approaches to child growth are centered on the relationship between the organism and its environment. However, defining and operationalizing the concept of environment is challenging, in light of the multiple variables that influence growth. Moreover, the concept of adaptation as it applies to child growth is seldom considered in the developed country context. This paper presents a study of children living in three neighborhoods in the City of Hamilton, Ontario, Canada. Two of the communities are considered adverse environments on the basis of low socioeconomic status, and their inner city, industrial location. In contrast to children living in the higher socioeconomic status area, children in these adverse environments display negative growth indicators, i.e., somewhat constrained linear growth in one and risk for overweight and obesity in both. Although both these inner city neighborhoods constitute adverse environments, they differ in ways that have a significant impact on children's growth. We argue for a definition of "adverse environment" that is broadly based, incorporating a range of physical, social, and temporal factors that are highly localized and sensitive to community-level influences on growth and health. As well, we consider whether higher prevalence of overweight and obesity is adaptive in any way to these adverse environments and conclude that they are more likely to be deleterious than adaptive in either the long or short term.


Lineage-specific variations in the trigger loop modulate RNA proofreading by bacterial RNA polymerases.
RNA cleavage by bacterial RNA polymerase (RNAP) has been implicated in transcriptional proofreading and reactivation of arrested transcription elongation complexes but its molecular mechanism is less understood than the mechanism of nucleotide addition, despite both reactions taking place in the same active site. RNAP from the radioresistant bacterium Deinococcus radiodurans is characterized by highly efficient intrinsic RNA cleavage in comparison with Escherichia coli RNAP. We find that the enhanced RNA cleavage activity largely derives from amino acid substitutions in the trigger loop (TL), a mobile element of the active site involved in various RNAP activities. The differences in RNA cleavage between these RNAPs disappear when the TL is deleted, or in the presence of GreA cleavage factors, which replace the TL in the active site. We propose that the TL substitutions modulate the RNA cleavage activity by altering the TL folding and its contacts with substrate RNA and that the resulting differences in transcriptional proofreading may play a role in bacterial stress adaptation.


Endothelial dysfunction, platelet activation, thrombogenesis and fibrinolysis in patients with hypertensive crisis.
Hypertensive crisis is an extreme phenotype of hypertension and hypertension-related thrombotic complications. This is most evident in patients with hypertensive crisis having advanced retinopathy and thrombotic microangiopathy (TMA). We examined whether hypertensive crisis complicated by advanced retinopathy is associated with endothelial dysfunction, platelet activation, thrombin generation and decreased fibrinolytic activity. In addition, we tested the association between these procoagulant changes and the development of TMA and end-organ dysfunction. Several key mediators of coagulation were assessed in 40 patients with hypertensive crisis with and without retinopathy and compared with 20 age, sex and ethnicity-matched normotensive controls. In patients with hypertensive crisis, associations with markers of TMA and renal dysfunction were assessed by regression analysis. Soluble P-selectin levels were higher in patients with hypertensive crisis compared with controls regardless of the presence or absence of retinopathy (P<0.01). Levels of von Willebrand factor (VWF), VWF propeptide, prothrombin fragment 1+2 (F1+2) and plasmin-antiplasmin (PAP) complexes were significantly higher in hypertensive crisis with retinopathy compared with normotensive controls (P-values<0.01), whereas in patients without retinopathy only VWF propeptide was higher (P=0.04). VWF, VWF propeptide, soluble tissue factor, F1+2 and PAP were positively associated with markers of TMA and renal dysfunction (P≤0.05). Hypertensive crisis with retinopathy confers a prothrombotic state characterized by endothelial dysfunction, platelet activation and increased thrombin generation, whereas fibrinolytic activity is enhanced. The observed changes in prothrombotic and antithrombotic pathways may contribute to the increased risk of ischaemic and haemorrhagic complications in this extreme hypertension phenotype.


League tables, institutional success and professional ethics.
League tables are just one example of the growing importance of "institutional success" in the health service. What are the implications of attaching importance to institutional success, and what impact might this have on professional ethics? This paper considers these issues and argues that public policy processes which centre on institutional performance, and which co-opt professional loyalties to this end, shift the balance between person-centred and impersonal standpoints in health care (from the former and towards the latter). There is no attempt to make a global ethical appraisal of this putative shift but rather to raise a matter of concern for those committed to a person-centred conception of professional ethics.


Conjoint research of WGCNA, single-cell transcriptome and structural biology reveals the potential targets of IDD and roles by menaquinone regarding JAK3.
This study conducted integrated analysis of bulk RNA sequencing, single-cell RNA sequencing and Weighted Gene Co-expression Network Analysis (WGCNA), to comprehensively decode the most essential genes of intervertebral disc degeneration (IDD); then mainly focused on the JAK3 macromolecule to identify natural compounds to provide more candidate drug options in alleviating IDD. In the first part, we performed single-cell transcriptome analysis and WGCNA workflow to delineate the most pivotal genes of IDD. Then series of structural biology approaches and high-throughput virtual screening techniques were performed to discover potential compounds targeting JAK-STAT signaling pathway, such as Libdock, ADMET, precise molecular docking algorithm and in-vivo drug stability assessment. Totally 5 hub genes were determined in the development of IDD, namely VEGFA, MMP3, TNFSF11, and TIMP3, respectively. Then, 3 novel natural materials, ZINC000014952116, ZINC000003938642 and ZINC000072131515, were determined as potential compounds, with less toxicities and moderate ADME characteristics. In-vivo drug stability assessment suggested that these drugs could interact with JAK3, and their ligand-JAK3 complexes maintained the homeostasis in-vivo, which acted as regulatory role to JAK3 protein. Among them, ZINC000072131515, also known as Menaquinone, demonstrated significant protective roles to alleviate the progression of IDD in vitro, which proved the nutritional therapy in alleviating IDD. This study reported the essential genes in the development of IDD, and also the roles of Menaquinone to ameliorate IDD through inhibiting JAK3 protein. This study also provided more options and resources on JAK3 targeted screening, which may further expand the drug resources in the pharmaceutical market.


First application of a high-resolution silicon detector for proton beam Bragg peak detection in a 0.95 T magnetic field.
To report on experimental results of a high spatial resolution silicon-based detector exposed to therapeutic quality proton beams in a 0.95 T transverse magnetic field. These experimental results are important for the development of accurate and novel dosimetry methods in future potential real-time MRI-guided proton therapy systems. A permanent magnet device was utilized to generate a 0.95 T magnetic field over a 4 × 20 × 15 cm3 volume. Within this volume, a high-resolution silicon diode array detector was positioned inside a PMMA phantom of 4 × 15 × 12 cm3 . This detector contains two orthogonal strips containing 505 sensitive volumes spaced at 0.2 mm apart. Proton beams collimated to a circle of 10 mm diameter with nominal energies of 90 MeV, 110 MeV, and 125 MeV were incident on the detector from an edge-on orientation. This allows for a measurement of the Bragg peak at 0.2 mm spatial resolution in both the depth and lateral profile directions. The impact of the magnetic field on the proton beams, that is, a small deflection was also investigated. A Geant4 Monte Carlo simulation was performed of the experimental setup to aid in interpretation of the results. The nominal Bragg peak for each proton energy was successfully observed with a 0.2 mm spatial resolution in the 0.95 T transverse magnetic field in both a depth and lateral profiles. The proton beam deflection (at 0.95 T) was a consistent 2 ±0.5 mm at the center of the magnetic volume for each beam energy. However, a pristine Bragg peak was not observed for each energy. This was caused by the detector packaging having small air gaps between layers of the phantom material surrounding the diode array. These air gaps act to degrade the shape of the Bragg peak, and further to this, the nonwater equivalent silicon chip acts to separate the Bragg peak into multiple peaks depending on the proton path taken. Overall, a promising performance of the silicon detector array was observed, however, with a qualitative assessment rather than a robust quantitative dosimetric evaluation at this stage of development. For the first time, a high-resolution silicon-based radiation detector has been used to measure proton beam Bragg peak deflections in a phantom due to a strong magnetic field. Future efforts are required to optimize the detector packaging to strengthen the robustness of the dosimetric quantities obtained from the detector. Such high-resolution silicon diode arrays may be useful in future efforts in MRI-guided proton therapy research.


Electrochemical Properties of a Rhodium(III) Mono-Terpyridyl Complex and Use as a Catalyst for Light-Driven Hydrogen Evolution in Water.
Molecular hydrogen (H2) is considered one of the most promising fuels to decarbonize the industrial and transportation sectors, and its photocatalytic production from molecular catalysts is a research field that is still abounding. The search for new molecular catalysts for H2 production with simple and easily synthesized ligands is still ongoing, and the terpyridine ligand with its particular electronic and coordination properties, is a good candidate to design new catalysts meeting these requirements. Herein, we have isolated the new mono-terpyridyl rhodium complex, [RhIII(tpy)(CH3CN)Cl2](CF3SO3) (Rh-tpy), and shown that it can act as a catalyst for the light-induced proton reduction into H2 in water in the presence of the [Ru(bpy)3]Cl2 (Ru) photosensitizer and ascorbate as sacrificial electron donor. Under photocatalytic conditions, in acetate buffer at pH 4.5 with 0.1 M of ascorbate and 530 μM of Ru, the Rh-tpy catalyst produces H2 with turnover number versus catalyst (TONCat*) of 300 at a Rh concentration of 10 μM, and up to 1000 at a concentration of 1 μM. The photocatalytic performance of Ru/Rh-tpy/HA-/H2A has been also compared with that obtained with the bis-dimethyl-bipyridyl complex [RhIII(dmbpy)2Cl2]+ (Rh2) as a catalyst in the same experimental conditions. The investigation of the electrochemical properties of Rh-tpy in DMF solvent reveals that the two-electrons reduced state of the complex, the square-planar [RhI(tpy)Cl] (RhI-tpy), is quantitatively electrogenerated by bulk electrolysis. This complex is stable for hours under an inert atmosphere owing to the π-acceptor property of the terpyridine ligand that stabilizes the low oxidation states of the rhodium, making this catalyst less prone to degrade during photocatalysis. The π-acceptor property of terpyridine also confers to the Rh-tpy catalyst a moderately negative reduction potential (Epc(RhIII/RhI) = -0.83 V vs. SCE in DMF), making possible its reduction by the reduced state of Ru, [RuII(bpy)(bpy•-)]+ (Ru-) (E1/2(RuII/Ru-) = -1.50 V vs. SCE) generated by a reductive quenching of the Ru excited state (*Ru) by ascorbate during photocatalysis. A Stern-Volmer plot and transient absorption spectroscopy confirmed that the first step of the photocatalytic process is the reductive quenching of *Ru by ascorbate. The resulting reduced Ru species (Ru-) were then able to activate the RhIII-tpy H2-evolving catalyst by reduction generating RhI-tpy, which can react with a proton on a sub-nanosecond time scale to form a RhIII(H)-tpy hydride, the key intermediate for H2 evolution.


Absence of association between 2019-20 influenza vaccination and COVID-19: Results of the European I-MOVE-COVID-19 primary care project, March-August 2020.
Claims of influenza vaccination increasing COVID-19 risk are circulating. Within the I-MOVE-COVID-19 primary care multicentre study, we measured the association between 2019-20 influenza vaccination and COVID-19. We conducted a multicentre test-negative case-control study at primary care level, in study sites in five European countries, from March to August 2020. Patients presenting with acute respiratory infection were swabbed, with demographic, 2019-20 influenza vaccination and clinical information documented. Using logistic regression, we measured the adjusted odds ratio (aOR), adjusting for study site and age, sex, calendar time, presence of chronic conditions. The main analysis included patients swabbed ≤7 days after onset from the three countries with <15% of missing influenza vaccination. In secondary analyses, we included five countries, using multiple imputation with chained equations to account for missing data. We included 257 COVID-19 cases and 1631 controls in the main analysis (three countries). The overall aOR between influenza vaccination and COVID-19 was 0.93 (95% CI: 0.66-1.32). The aOR was 0.92 (95% CI: 0.58-1.46) and 0.92 (95% CI: 0.51-1.67) among those aged 20-59 and ≥60 years, respectively. In secondary analyses, we included 6457 cases and 69 272 controls. The imputed aOR was 0.87 (95% CI: 0.79-0.95) among all ages and any delay between swab and symptom onset. There was no evidence that COVID-19 cases were more likely to be vaccinated against influenza than controls. Influenza vaccination should be encouraged among target groups for vaccination. I-MOVE-COVID-19 will continue documenting influenza vaccination status in 2020-21, in order to learn about effects of recent influenza vaccination.


pH signaling in human fungal pathogens: a new target for antifungal strategies.
Fungi are exposed to broadly fluctuating environmental conditions, to which adaptation is crucial for their survival. An ability to respond to a wide pH range, in particular, allows them to cope with rapid changes in their extracellular settings. PacC/Rim signaling elicits the primary pH response in both model and pathogenic fungi and has been studied in multiple fungal species. In the predominant human pathogenic fungi, namely, Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, this pathway is required for many functions associated with pathogenesis and virulence. Aspects of this pathway are fungus specific and do not exist in mammalian cells. In this review, we highlight recent advances in our understanding of PacC/Rim-mediated functions and discuss the growing interest in this cascade and its factors as potential drug targets for antifungal strategies. We focus on both conserved and distinctive features in model and pathogenic fungi, highlighting the specificities of PacC/Rim signaling in C. albicans, A. fumigatus, and C. neoformans. We consider the role of this pathway in fungal virulence, including modulation of the host immune response. Finally, as now recognized for other signaling cascades, we highlight the role of pH in adaptation to antifungal drug pressure. By acting on the PacC/Rim pathway, it may therefore be possible (i) to ensure fungal specificity and to limit the side effects of drugs, (ii) to ensure broad-spectrum efficacy, (iii) to attenuate fungal virulence, (iv) to obtain additive or synergistic effects with existing antifungal drugs through tolerance inhibition, and (v) to slow the emergence of resistant mutants.


Hyderabad Ocular Morbidity in Elderly Study (HOMES) - Rationale, Study Design and Methodology.
Purpose: To describe the study design, interobserver variability of the questionnaires and clinical procedures of Hyderabad Ocular Morbidity in Elderly Study (HOMES) designed to, (a) to investigate the prevalence, causes and risk factors for visual impairment, and (b) to assess the impact of dispensing spectacles and cataract surgery on visual functions, fear of falls (FOF) and depression among the elderly in India.Methods: Individuals aged ≥60 years are considered elderly. The non-clinical protocol was administered by two trained investigators and included collection of personal, sociodemographic information, ocular and systemic history, Indian Visual Function Questionnaire (IND-VFQ33), Patient Health Questionnaire (PHQ9), Mini-Mental State Examination (MMSE) questionnaire, Hearing Handicap Inventory for the Elderly Screening (HHIE), Short Falls Efficacy Scale (SFES) questionnaire. The eye examination was conducted by a trained optometrist and vision technicians in clinics set-up in the homes and included visual acuity (VA) assessment for distance and near, anterior segment examination and fundus examination, and imaging. The reliability assessments were carried out among 138 participants.Result: The intraclass correlation (ICC) coefficients for MMSE, PHQ9, HHIE, SFES was 0.73 (95% CI: 0.62-0.81), 0.67 (95% CI: 0.54-0.77), 0.63 (95% CI: 0.48-0.74) and 0.70 (95% CI: 0.58-0.79) respectively. The ICC for INDVFQ domains ranged from 0.66 (95% CI: 0.55-0.74) for Psychosocial Impact to 0.88 (95% CI: 0.84-0.91) for activity limitation. The ICC for VA was 0.94 (95% CI: 0.92-0.96).Conclusion: All questionnaires demonstrated acceptable reliability and can be applied in the main study. HOMES is expected to provide data that will help plan strategies to contribute towards 'healthy aging' in India.


Does Zygomatic Complex Symmetry Differ Between Healthy Individuals and Surgically Treated Patients Using Intraoperative 3-Dimensional Cone Beam Computed Tomographic Imaging?
Reconstruction of symmetry after zygomaticomaxillary complex (ZMC) fractures is essential for esthetic appearance as well as function. Therefore, this study aimed to analyze whether bony facial symmetry in patients surgically treated for unilateral ZMC fractures via intraoperative imaging differs from that of healthy individuals. Retrospective and cross-sectional radiographic measurements of patients treated for unilateral ZMC fractures via intraoperative cone beam computed tomography (CBCT) were performed to evaluate the postoperative ZMC symmetry. The same number of healthy individuals without any history of midfacial trauma matched for age and gender served as the control group. Asymmetry of the ZMC was determined by measuring bilateral differences in the malar eminence position on CBCT. In addition, demographic statistics, etiology, and fracture type were analyzed. Analysis of 57 surgically treated patients and 57 healthy individuals with a mean age of 29 years was performed. No significant difference in the symmetry of the malar eminence position was observed between healthy individuals and patients treated for a unilateral ZMC fracture (P = .890). In one third of patients, corrections were needed after intraoperative CBCT control. The results of this study indicate that, on average, a ZMC asymmetry of 1.6 mm is observed in healthy individuals. Furthermore, the use of intraoperative CBCT for the treatment of dislocated ZMC fractures helps to achieve precise anatomic, symmetrical repositioning and is suggested to improve the quality of care.


A vaccinia virus renaissance: new vaccine and immunotherapeutic uses after smallpox eradication.
In 1796, Edward Jenner introduced the concept of vaccination with cowpox virus, an Orthopoxvirus within the family Poxviridae that elicits cross protective immunity against related orthopoxviruses, including smallpox virus (variola virus). Over time, vaccinia virus (VACV) replaced cowpox virus as the smallpox vaccine, and vaccination efforts eventually led to the successful global eradication of smallpox in 1979. VACV has many characteristics that make it an excellent vaccine and that were crucial for the successful eradication of smallpox, including (1) its exceptional thermal stability (a very important but uncommon characteristic in live vaccines), (2) its ability to elicit strong humoral and cell-mediated immune responses, (3) the fact that it is easy to propagate, and (4) that it is not oncogenic, given that VACV replication occurs exclusively within the host cell cytoplasm and there is no evidence that the viral genome integrates into the host genome. Since the eradication of smallpox, VACV has experienced a renaissance of interest as a viral vector for the development of recombinant vaccines, immunotherapies, and oncolytic therapies, as well as the development of next-generation smallpox vaccines. This revival is mainly due to the successful use and extensive characterization of VACV as a vaccine during the smallpox eradication campaign, along with the ability to genetically manipulate its large dsDNA genome while retaining infectivity and immunogenicity, its wide mammalian host range, and its natural tropism for tumor cells that allows its use as an oncolytic vector. This review provides an overview of new uses of VACV that are currently being explored for the development of vaccines, immunotherapeutics, and oncolytic virotherapies.


Jumbo biopsy is useful for the diagnosis of colonic prolapsing mucosal polyps with diverticulosis.
We report here a case of multiple prolapsing mucosal polyps with diverticulosis in the sigmoid colon. A 52-year-old man was admitted to our hospital because of bloody diarrhea. Colonoscopy and barium enema showed multiple diverticula, markedly thickened mucosal folds and polypoid lesions with mucus on the top of them in the sigmoid colon. Endoscopic ultrasonography showed thickening of the mucosal and submucosal layers. Several endoscopic biopsy specimens were taken from the polypoid lesions. Histological examination revealed only chronic inflammatory cell infiltration. In order to obtain a definite diagnosis, we performed endoscopic jumbo biopsy for the polypoid lesions after obtaining informed consent. Histological examination revealed marked lymphocyte infiltration, hemosiderin deposits and fibromuscular obliteration in the lamina propria, features similar to those of mucosal prolapsing syndrome. After anti-diarrhetic treatment, clinical findings were improved. Thus, jumbo biopsy is useful for diagnosis and treatment of prolapsing mucosal polyps.


Biosorption of neodymium on Chlorella vulgaris in aqueous solution obtained from hard disk drive magnets.
In recent years, biosorption is being considered as an environmental friendly technology for the recovery of rare earth metals (REE). This study investigates the optimal conditions for the biosorption of neodymium (Nd) from an aqueous solution derived from hard drive disk magnets using green microalgae (Chlorella vulgaris). The parameters considered include solution pH, temperature and biosorbent dosage. Best-fit equilibrium as well as kinetic biosorption models were also developed. At the optimal pH of 5, the maximum experimental Nd uptakes at 21, 35 and 50°C and an initial Nd concentration of 250 mg/L were 126.13, 157.40 and 77.10 mg/g, respectively. Analysis of the optimal equilibrium sorption data showed that the data fitted well (R2 = 0.98) to the Langmuir isotherm model, with maximum monolayer coverage capacity (qmax) of 188.68 mg/g, and Langmuir isotherm constant (KL) of 0.029 L/mg. The corresponding separation factor (RL) is 0.12 indicating that the equilibrium sorption was favorable. The sorption kinetics of Nd ion follows well a pseudo-second order model (R2>0.99), even at low initial concentrations. These results show that Chlorella vulgaris has greater biosorption affinity for Nd than activated carbon and other algae types such as: A. Gracilis, Sargassum sp. and A. Densus.


Enzymatic assays for creatinine: time for action.
Accurate serum creatinine measurements in glomerular filtration rate estimation (eGFR) using equations are critical to ongoing global public health efforts to improve the diagnosis and treatment of chronic kidney disease. There is now an ongoing activity to promote worldwide standardization of methods to determine creatinine together with the introduction of a revised eGFR equation appropriate for use with standardized creatinine methods. Standardization of calibration, i.e., implementation of calibration traceability to high-order reference measurement procedures and reference materials, does not, however, correct for analytical interferences of field methods (non-specificity bias). To account for the sensitivity of alkaline picrate-based methods to non-creatinine chromogens, some manufacturers have adjusted the calibration to minimize the pseudo-creatinine contribution of plasma proteins, producing results more closely aligned to the reference method (isotope dilution-mass spectrometry), but this strategy makes an assumption that the non-creatinine chromogen interference is a constant among samples, which is an oversimplification. Thus, analytical non-specificity for substances found in individual patient samples can affect the accuracy of eGFR computed from serum creatinine values for any alkaline picrate method, including the so-called "compensated" Jaffé methods. The use of assays that are more specific for serum creatinine determination, such as those based on enzymatic reactions, may provide more reliable eGFR values. Supporting the choice of more specific assays by clinical laboratories represents one of the main tasks of our profession in order to achieve the ultimate clinical goal, which is to routinely report an accurate eGFR in all the pertinent clinical situations.


An Update on Addison's Disease.
Addison's disease - the traditional term for primary adrenal insufficiency (PAI) - is defined as the clinical manifestation of chronic glucocorticoid- and/or mineralocorticoid deficiency due to failure of the adrenal cortex which may result in an adrenal crisis with potentially life-threatening consequences. Even though efficient and safe pharmaceutical preparations for the substitution of endogenous gluco- and mineralocorticoids are established in therapy, the mortality in patients with PAI is still increased and the health-related quality of life (HRQoL) is often reduced.PAI is a rare disease but recent data report an increasing prevalence. In addition to the common "classical" causes of PAI like autoimmune, infectious, neoplastic and genetic disorders, other iatrogenic conditions - mostly pharmacological side effects (e. g., adrenal haemorrhage associated with anticoagulants, drugs affecting glucocorticoid synthesis, action or metabolism and some of the novel anti-cancer checkpoint inhibitors) are contributing factors to this phenomenon.Due to the rarity of the disease and often non-specific symptoms at least in the early stages, PAI is frequently not considered resulting in a delayed diagnosis. Successful therapy is mainly based on adequate patient education as a cornerstone in the prevention and management of adrenal crisis. A focus of current research is in the development of pharmacokinetically optimized glucocorticoid preparations as well as regenerative therapies.


Combined resistance and endurance exercise training improves arterial stiffness, blood pressure, and muscle strength in postmenopausal women.
Menopause is associated with increased arterial stiffness and reduced muscle strength. Combined resistance (RE) and endurance (EE) exercise training can decrease brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, in young men. We tested the hypothesis that combined circuit RE and EE training would improve baPWV, blood pressure (BP), and muscle strength in postmenopausal women. Twenty-four postmenopausal women (age 47-68 y) were randomly assigned to a "no exercise" control (n = 12) or to combined exercise training (EX; n = 12) group. The EX group performed concurrent circuit RE training followed by EE training at 60% of the predicted maximal heart rate (HR) 3 days per week. Brachial systolic BP, diastolic BP, mean arterial pressure, baPWV, HR, and dynamic and isometric muscle strength were measured before and after the 12-week study. Mean ± SE baPWV (-0.8 ± 0.2 meters/s), systolic BP (-6.0 ± 1.9 mm Hg), diastolic BP (-4.8 ± 1.7 mm Hg), HR (-4.0 ± 1.0 beats/min), and mean arterial pressure (-5.1 ± 1.6 mm Hg) decreased (P < 0.05), whereas dynamic leg strength (5.1 ± 1.0 vs 0.6 ± 1.0 kg for the EX and control groups, respectively) and isometric handgrip strength (2.8 ± 0.7 vs -0.6 ± 1.2 kg) increased (P < 0.05) in the EX group but not in the control group. Our findings indicate that a 12-week moderate-intensity combined circuit RE and EE training improves arterial stiffness, hemodynamics, and muscle strength in previously sedentary postmenopausal women. This study provides evidence that combined training may have important health implications for the prevention of hypertension and frailty in postmenopausal women.


Life Enhancing Activities for Family Caregivers of people with dementia: protocol for a randomized controlled trial of a positive affect skills intervention.
Given the increasing number of family caregivers of persons with dementia (PWD) and the associated burden and detriments to both physical and mental health, interventions that aim to improve such outcomes are important. Studies are increasingly demonstrating the unique importance of positive emotions in coping with stress, independent from the impact of negative emotions. However, none have examined the benefits of interventions that target positive emotions for caregivers of individuals with a chronic and debilitating disease such as dementia. This paper presents the design and methods for a randomized controlled trial (RCT) of a positive affect skills intervention for family caregivers of PWD. The RCT is of a skills-based intervention that seeks to increase the frequency and intensity of positive affect in order to improve outcomes such as well-being, coping, and physical and mental health. The skills are delivered by trained facilitators via five one-to-one Internet video sessions with family caregivers of persons diagnosed with dementia (eg, Alzheimer's disease, vascular dementia, unspecified). The control group is an emotion reporting/waitlist control. Follow-up assessments are conducted post-intervention and at 1, 3, and 6 months post-completion of the intervention. This study promises to be an important and needed step toward improving the lives of caregivers of PWD.


Assessment of nutritional status in older diabetic outpatients and related factors in Hanoi, Vietnam.
Purpose: Nutritional status is an important element for the wellness among older diabetic outpatients. This study aimed to assess the nutritional status of the older diabetic outpatient by using the Mini-Nutrition Assessment Short Form (MNA-SF) tool, and describe the relationship among related factors in older diabetic outpatients in the National Geriatric Hospital, Hanoi, Vietnam. Patients and methods: A cross-sectional study was conducted from June to September 2015 in the National Geriatric Hospital. A total of 158 diabetic patients aged ≥60 years at the Outpatient Department were included in this study. Patients were interviewed face-to-face to evaluate their nutritional status by using the MNA-SF. Socio-demographic, diabetic treatment information, frailty, exhaustion, cognitive function, hand grip strength and 4 m walk test were collected. Multivariate regression was used to determine factors associated with nutritional status. Results: The mean age was 69.52 (SD=6.758) with 31% patients malnourished and at risk of malnutrition. A significant association was found between the nutritional status and exhaustion, cognitive impairment, and frailty. In multiple logistic regression, the study found that risk of malnutrition was associated with frailty (OR=8.45; 95%CI=1.91-37.39) and cognitive impairment (OR=2.21; 95%CI=1.01-4.84). Conclusion: The results suggest that frailty was significantly associated with risk of malnutrition in older diabetic outpatients. Thus, early screening by nutritional assessment, and other interventions might improve the nutritional status of older outpatients with diabetes to prevent this complication and its effects.


Leucocyte and lymphocyte count in cases of bird flu infection in Thailand.
Bird flu or avian flu is a new emerging Infectious disease. The H5N1 virus has not only affected the fowls but also the human beings. Severe disease with high mortality in humans in Vietnam and Thailand are reported. This mini-study was undertaken in order to document the Impact of bird flu infection on leucocyte and lymphocyte counts among patients of Thailand. This study was designed as a descriptive retrospective study. A literature review on the papers concerning human bird flu in Thailand was performed. According to this study, there are 6 cases covering 12 Thai patients with confirmed diagnosis of bird flu. However, the complete data were available on only 6 patients. The reported leucocyte count ranges from 1,200 cells/cmm to 5,680 cells/cmm and the lymphocyte count ranges from 454 cells/ cmm to 1,440 cells/cmm. The average leucocyte and lymphocyte counts equalled to 3,230.0 +/- 1,552.7 cells/cmm and 748.7 +/- 348.5 cells/cmm, respectively. According to this study, low lymphocyte count is common. This can support the previous observation for the lymphocyte suppression effect of H5N1 virus.


[State of the blood prekallikrein-kallikrein system in patients with glomerulonephritis as affected by pathogenetic therapy].
A study was made of the effect of the treatment with glucocorticoids (GC), cyclophosphamide and indocide on the prekallikrein-kallikrein system (PKKS) of the blood in 108 patients with glomerulonephritis. It was revealed that in patients with acute and chronic GN, the PKKS was activated before treatment. The PKKS activation was marked by a decrease in the content of prekallikrein and elevation of the alpha 2-macroglobulin content, particularly in patients with the nephrotic syndrome. The efficacy of GC therapy was more pronounced the higher the basic activation of the PKKS. The clinical effect of indocide and cyclophosphamide did not depend on the initial characteristics of the PKKS.


Efficacy of Intraoperative Hypertonic Glucose Solution Administration on Persistent Air Leak After Extended Pleurectomy/Decortication for Malignant Pleural Mesothelioma: A Retrospective Case-Control Study.
Persistent air leak is a common complication occurring from 6% to 23% of cases after extended pleurectomy/decortication for malignant pleural mesothelioma. Treatment options for this complication after major lung resection are well documented in literature; nevertheless, lines of evidence in extended pleurectomy/decortication for malignant pleural mesothelioma are absent. The aim of the study is to evaluate the efficacy of intraoperative administration of 50% hypertonic glucose solution in reducing duration of air leak following extended pleurectomy/decortication for malignant pleural mesothelioma. In this retrospective case-control study, we analyzed our electronic health record and selected those patients with a histological diagnosis of malignant pleural mesothelioma who underwent extended pleurectomy/decortication in the period 2013-2021. From 2018, we introduced a lavage with 500 ml of glucose solution at 50% concentration into the chest cavity at the end of the surgical procedure. Patients operated before 2018 were used as the control group. Postoperative glycemia was measured, and patients were followed after hospital discharge until the air leak resolved and the chest tube was removed. Statistical analysis was performed using R software. A total of 71 patients met our criteria. Treatment and control groups were similar for age, sex, smoking status, number of comorbidities, tumor histotype, and side of disease. Use of hypertonic glucose solution resulted in shorter chest tube maintenance after hospital discharge (p = 0.0028). A statistically significant difference (p = 0.02) was also found in postoperative glycemia between the treatment (103 g/dl ± 8.9) and control group (98.8 g/dl ± 8.6). Days of hospitalization and chest tube maintenance during hospitalization did not significantly differ between the groups. Intraoperative administration of 50% hypertonic glucose solution reduced the duration of air leak after hospital discharge. An increase in postoperative glycemia was found in the treatment group, but with no clinical effect. Hypertonic glucose solution is an effective and safe method to manage persistent air leak after extended pleurectomy/decortication for malignant pleural mesothelioma.


Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodelling.
In the post-infarcted heart, grafting of precursor cells may partially restore heart function but the improvement is modest and the mechanisms involved remain to be elucidated. Here, we explored this issue by transplanting C2C12 myoblasts, genetically engineered to express enhanced green fluorescent protein (eGFP) or eGFP and the cardiotropic hormone relaxin (RLX) through coronary venous route to swine with experimental chronic myocardial infarction. The rationale was to deliver constant, biologically effective levels of RLX at the site of cell engraftment. One month after engraftment, histological analysis showed that C2C12 myoblasts selectively settled in the ischaemic scar and were located around blood vessels showing an activated endothelium (ICAM-1-,VCAM-positive). C2C12 myoblasts did not trans-differentiate towards a cardiac phenotype, but did induce extracellular matrix remodelling by the secretion of matrix metalloproteases (MMP) and increase microvessel density through the expression of vascular endothelial growth factor (VEGF). Relaxin-producing C2C12 myoblasts displayed greater efficacy to engraft the post-ischaemic scar and to induce extracellular matrix re-modelling and angiogenesis as compared with the control cells. By echocardiography, C2C12-engrafted swine showed improved heart contractility compared with the ungrafted controls, especially those producing RLX. We suggest that the beneficial effects of myoblast grafting on cardiac function are primarily dependent on the paracrine effects of transplanted cells on extracellular matrix remodelling and vascularization. The combined treatment with myoblast transplantation and local RLX production may be helpful in preventing deleterious cardiac remodelling and may hold therapeutic possibility for post-infarcted patients.


The elephant in the family: Costs and benefits of elder siblings on younger offspring life-history trajectory in a matrilineal mammal.
Many mammals grow up with siblings, and interactions between them can influence offspring phenotype and fitness. Among these interactions, sibling competition between different-age offspring should lead to reproductive and survival costs on the younger sibling, while sibling cooperation should improve younger sibling's reproductive potential and survival. However, little is known about the consequences of sibling effects on younger offspring life-history trajectory, especially in long-lived mammals. We take advantage of a large, multigenerational demographic dataset from semi-captive Asian elephants to investigate how the presence and sex of elder siblings influence the sex, survival until 5 years old, body condition, reproductive success (i.e. age at first reproduction and lifetime reproductive success) and long-term survival of subsequent offspring. We find that elder siblings have heterogeneous effects on subsequent offspring life-history traits depending on their presence, their sex and the sex of the subsequent offspring (named focal calf). Overall, the presence of an elder sibling (either sex) strongly increased focal calf long-term survival (either sex) compared to sibling absence. However, elder sisters had higher impact on the focal sibling than elder brothers. Focal females born after a female display higher long-term survival, and decreased age at first reproduction when raised together with an elder sister rather than a brother. Focal males born after a female rather than a male showed lower survival but higher body weight when both were raised together. We did not detect any sibling effects on the sex of the focal calf sex, survival until 5 years old and lifetime reproductive success. Our results highlight the general complexity of sibling effects, but broadly that elder siblings can influence the life-history trajectory of subsequent offspring. We also stress the importance of considering all life stages when evaluating sibling effects on life trajectories.


Prostate-specific antigen testing in untreated and treated prostatic adenocarcinoma.
The isolation and purification of prostate-specific antigen (PSA) and the development of a radioimmunoassay for this antigen represent major advancements for the detection of adenocarcinoma of the prostate and the monitoring of response to therapy in patients with this disease. Both monoclonal and polyclonal assays for PSA are available. In attempts to correlate pathologic tumor stage and PSA levels, tumors of higher stage (pathologic stages C1, C2, D1, and D2) have been associated with elevated PSA levels. Increased PSA levels have also been found in patients with benign prostatic diseases (benign prostatic hypertrophy and prostatitis). PSA has been shown to be an excellent marker after radical prostatectomy and for monitoring of radiation therapy. Patients with a persistently elevated PSA level for more than 6 months postoperatively should be assessed for residual or recurrent local or systemic disease. Thus far, routine use of PSA testing as a mass screening modality for prostatic cancer has not been considered cost-effective.


Back-scattered electron imaging and elemental analysis of retrieved bone tissue following sinus augmentation with deproteinized bovine bone or biphasic calcium phosphate.
To compare resorption of a synthetic biphasic calcium phosphate (BCP) bone-graft substitute with deproteinized bovine bone (DBB) used for human maxillary sinus augmentation. Eleven patients underwent bilateral maxillary sinus floor augmentation with DBB in one side and a BCP (40%beta-tricalcium phosphate (beta-TCP) and 60% hydroxyapatite) in the contralateral side. Simultaneously, with the augmentation on each side a microimplant was placed vertically from the top of the alveolar crest penetrating the residual bone and the grafting material. Eight months after initial surgery the microimplants were retrieved with a surrounding bone core. The composition of residual graft material and surrounding bone was analysed by scanning electron microscopy and energy dispersive X-ray spectroscopy. Residual graft material of both types was present as 10-500 mum particles in direct contact with, or completely surrounded by, newly formed bone; smaller particles were also present in non-mineralized tissue. In the case of BCP the bone-graft substitute interface showed evidence of superficial disintegration of particles into individual grains. Median Ca/P ratios (at.%), determined from >200 discreet sites within residual graft particles and adjacent bone, were: DBB: 1.61 (confidence interval [CI] 1.59-1.64); BCP: 1.5 (CI 1.45-1.52); DBB-augmented bone: 1.62 (CI 1.59-1.66); BCP-augmented bone: 1.52 (CI 1.47-1.55); P=0.028 for DBB vs. BCP and DBB- vs. BCP-augmented bone. The reduction in Ca/P ratio for BCP over the healing period is consistent with the dissolution of beta-TCP and reprecipitation on the surface of calcium-deficient hydroxyapatite. The beta-TCP component of BCP may be gradually substituted by calcium-deficient hydroxyapatite over the healing period. This process and superficial degranulation of BCP particles may influence the progress of resorption and healing.


Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine.
The rapid-acting and long-lasting antidepressant effects of (R,S)-ketamine have recently gained much attention. Although (S)-ketamine has been studied as an active isomer, recent evidence suggests that (R)-ketamine exhibits longer-lasting antidepressant effects than (S)-ketamine in rodents. However, the antidepressant potential of (R)-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of (R)-ketamine with those of (S)-ketamine in animal models of depression, including a model that is refractory to current medications. Both (R)-ketamine and (S)-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, (R)-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of (S)-ketamine was no longer observed. Moreover, (R)-ketamine, but not (S)-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both (R)-ketamine and (S)-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (<4-8 hours). The present results confirmed the previous findings that (R)-ketamine exerted longer-lasting antidepressant effects than (S)-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that (R)-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants.


Lupus erythematosus panniculitis with partial genetic deficiency of C2 and C4 in a child.
A 7-year-old girl developed recurrent febrile nodules and subcutaneous plaques on her arm, shoulder, and face. Primary acquired toxoplasmosis was diagnosed at onset, because of associated lymphadenopathy and detection of specific IgM. Skin lesions were responsive to therapy with systemic steroids but progressed to atrophy and poikiloderma within a few months. Subsequently, chloroquine therapy has been instituted and no relapse has occurred. Histopathologic findings and direct immunofluorescence studies were diagnostic of lupus erythematosus panniculitis. Electron microscopy showed lamellar inclusions within mast cells. Results of laboratory investigations disclosed leukopenia and hypocomplementemia with low C2 serum levels. A family study of the complement system, including C4 and Bf phenotyping and HLA A, B, and DR haplotyping, revealed the carriage of both C2 and C4A null alleles in the propositus. This observation suggests an additional link between lupus erythematosus panniculitis and the remainder of the lupus erythematosus clinical spectrum.


Evaluation for activities of component of Cyclotron-Based Epithermal Neutron Source (C-BENS) and the surface of concrete wall in irradiation room.
The workers employed in BNCT must enter the irradiation room just after an irradiation under the condition of remaining activities. To reduce the radiation exposure for the workers, it is important to identify the origins of the activities. In this research, the activities induced on the concrete wall surface were evaluated using MCNP-5 and the measurement results of thermal neutron distribution. Furthermore, the radioisotopes produced in the moderator were identified with a High Purity Germanium detector. It was found that the activities of the wall were mainly caused by (46)Sc, (60)Co and (152)Eu, and that (24)Na and (56)Mn were mainly produced in the moderator.


Recovery of finger sensibility and somatosensory evoked potentials following digit-to-digit replantation in man.
Recovery of finger sensation and digital nerve function following digit-to-digit replantation was studied in 14 patients by clinical sensory evaluation and somatosensory evoked potentials (SEP) to digital nerve stimulation. The mean interval between injury and surgery was 8 +/- 3h; that between surgery and study was 25 +/- 7 months. Sensory examination revealed a mild hypersensitivity to cold. Pinprick, touch and hot sensations had nearly complete recovery, while vibration and two-point discrimination were impaired. In digital SEPs from the replanted side, the N9 component was present and normal in 8 patients (57%), whereas the N13 and N20 components had prolonged latency with normal central conduction time. Absence of the N9 component appeared to correlate with a more proximal level of injury and poor surgical outcome. The present data indicate that sensory recovery of the replanted digits was in general satisfactory but incomplete, and that over half of the patients had normal digital nerve conduction.


Collinearity-preserving functions between Desarguesian planes.
Using concepts from valuation theory, we obtain a characterization of all collinearity-preserving functions from one affine or projective Desarguesian plane into another. The case in which the planes are projective and the range contains a quadrangle has been treated previously in the literature. Our results permit one or both planes to be affine and include cases in which the range contains a triangle but no quadrangle. A key theorem is that, with the exception of certain embeddings defined on planes of order 2 and 3, every collinearity-preserving function from one affine Desarguesian plane into another can be extended to a collinearity-preserving function between enveloping projective planes.


Explicit error bounds for the α-quasi-periodic Helmholtz problem.
This paper considers a finite element approach to modeling electromagnetic waves in a periodic diffraction grating. In particular, an a priori error estimate associated with the α-quasi-periodic transformation is derived. This involves the solution of the associated Helmholtz problem being written as a product of e(iαx) and an unknown function called the α-quasi-periodic solution. To begin with, the well-posedness of the continuous problem is examined using a variational formulation. The problem is then discretized, and a rigorous a priori error estimate, which guarantees the uniqueness of this approximate solution, is derived. In previous studies, the continuity of the Dirichlet-to-Neumann map has simply been assumed and the dependency of the regularity constant on the system parameters, such as the wavenumber, has not been shown. To address this deficiency, in this paper an explicit dependence on the wavenumber and the degree of the polynomial basis in the a priori error estimate is obtained. Since the finite element method is well known for dealing with any geometries, comparison of numerical results obtained using the α-quasi-periodic transformation with a lattice sum technique is then presented.


Bird's-Eye View of COVID-19 Knowledge, Attitude and Practice Among Emergency Physicians in the Kingdom of Bahrain: A Cross-Sectional Study.
Coronavirus 2019 (COVID-19) has exemplified the crucial role played by emergency physicians on the frontlines, by triaging, quarantining and treating myriad patients in time. Despite this, there exists a dearth of literature comprehensively assessing the knowledge and awareness of these health-care workers on the disease in the Kingdom of Bahrain. This study was designed to evaluate the knowledge, attitude, and practice (KAP) of emergency physicians in the Kingdom of Bahrain towards COVID-19. This cross-sectional descriptive study included 142 emergency physicians from three major hospitals in Bahrain. A self-designed questionnaire divided into 4 parts, which consists of demographics, knowledge, attitude and practices towards COVID-19, was completed by the emergency physicians working in these hospitals. Analysis of variance (ANOVA), t-test, chi-square test, and multiple linear regression were employed to evaluate KAP scores. The mean COVID-19 knowledge and practice score was 26.29 for a maximum score of 32 suggesting an overall 82.15% correct rate on the knowledge and practice test. Multiple linear regression analysis highlighted age (p=0.038), genders (p=0.033), marital status (p=0.021), organization (p=0.032), having children (p=0.008), and continuing professional development (CPD) activity (p=0.0001) as significant predictors for knowledge and practice scores. The attitude towards the final success in controlling COVID-19 significantly differed across marital status (p=0.021), organization of participants (p=0.020) and position of participants (p=0.012), respectively. Adequate knowledge, positive attitude and sufficient safe practice towards COVID-19 were observed in majority of the participants. These findings can foster development of nuanced and salient health management strategies that augment KAP so that proper control and elimination of the disease can be achieved, while prioritizing patient health and satisfaction.


Cardiac troponins and renal disease.
Cardiovascular disease is the most common cause of death in patients with renal failure. Patients with renal failure are at greater risk of atypical presentations of myocardial ischaemia. Traditional markers of myocardial damage are often increased in renal failure in the absence of clinically suspect myocardial ischaemia. The cardiac troponins are specific markers of myocardial injury. Large-scale trials, excluding patients with renal disease, have shown the importance of the cardiac troponins in predicting adverse outcome and in guiding both therapy and intervention in acute coronary syndromes. Cardiac Troponin T and cardiac Troponin I are increased in patients with renal failure and this is likely to represent multifactorial pathology including cardiac dysfunction, left ventricular hypertrophy and cardiac microinfarctions. Increases in serum troponin from baseline, in patients with renal disease with acute coronary syndromes, may represent a poor prognosis. Small studies of patients with renal failure have suggested that elevation of the cardiac troponins is associated with an increased risk of cardiac death.


Resting and Functional Pupil Response Metrics Indicate Features of Reward Sensitivity and ASD in Children.
The current study examined the relationship between quantitative measures of reward and punishment sensitivity, features of autism spectrum disorder (ASD), and resting and functional pupil response metrics across a clinically heterogeneous sample. Scores on a parent-report measure of punishment and reward sensitivity were correlated with ASD features. We also assessed whether pupil measurements could be used as a physiologic correlate of reward sensitivity and predictor of ASD diagnosis. In a logistic regression model, pupil dilation metrics, sex, and IQ, correctly classified 86.3% of participants as having an ASD diagnosis versus not. This research highlights individual differences of reward sensitivity associated with ASD features. Results support the use of pupil metrics and other patient-level variables as predictors of ASD diagnostic status.


The collagenase of Entamoeba histolytica.
The present work was designed to investigate the capacity of trophozoites of Entamoeba histolytica to adhere to and digest human collagen types I and III in vitro. The time-course of binding of ameba to both human collagen types I and III was similar. However, the kinetics of detachment were different for each collagen type. Trophozoites of E. histolytica cultured on heat-reconstituted type I collagen gels produced a well-defined area of lysis. Quantitative studies using 14C-labeled collagen revealed that after 24 h of incubation, Entamoeba digested three and a half times more type I than type III collagen, thus suggesting the presence of a collagenase with higher specificity for type I collagen. This activity was optimum with trophozoites harvested after 42 h in culture (1.5 X 10(5) trophozoites/ml). The digestion of type I collagen was a function of the number of trophozoites, and was inhibited by EDTA, L-cysteine, and serum, but not by soybean trypsin inhibitor, phenylmethanesulfonyl fluoride, or N-ethylmaleimide (NEM). Electrophoretic analysis of the type I collagen fragments revealed three main classes of polypeptides of 75,000, 50,000, and 25,000 daltons. Subsequent proteolysis of these collagen fragments was probably carried out by other proteases derived from trophozoites. This activity was inhibited with 10 mM NEM. Collagenase activity appeared to be located at the plasma membrane and direct contact of the ameba with the substrate is required for collagen digestion. The results suggest that collagenase activity of E. histolytica may play an important role in tissue invasion.


Immune recruitment or suppression by glycan engineering of endogenous and therapeutic antibodies.
Human serum IgG contains multiple glycoforms which exhibit a range of binding properties to effector molecules such as cellular Fc receptors. Emerging knowledge of how the Fc glycans contribute to the antibody structure and effector functions has opened new avenues for the exploitation of defined antibody glycoforms in the treatment of diseases. Here, we review the structure and activity of antibody glycoforms and highlight developments in antibody glycoengineering by both the manipulation of the cellular glycosylation machinery and by chemoenzymatic synthesis. We discuss wide ranging applications of antibody glycoengineering in the treatment of cancer, autoimmunity and inflammation. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.


Molecular typing and epidemiological survey of prevalence of Clostridium perfringens types by multiplex PCR.
Clostridium perfringens has been classified into five toxigenic types (A through E) on the basis of its capability to produce major lethal toxins (alpha, beta, epsilon, and iota toxins). Seroneutralization with mice or guinea pigs has been used to type each toxin, but this conventional method has some disadvantages. Therefore, we used a molecular biological technique to type the bacterium in the present study. A multiplex PCR was developed for this purpose. This method has several advantages in comparison with seroneutralization with mice or guinea pigs. By this method, we also investigated the most prevalent type(s) of the organism in Korean calves, piglets, and chickens showing clinical symptoms such as diarrhea, enterotoxemia, and necrotic enteritis. Only type A was isolated from calves and chickens, while type C (2 of 14 isolates), in addition to type A, was isolated from piglets. These results suggested that seroneutralization could be replaced by our new method and that type A of C. perfringens is the most prevalent type in livestock in Korea.


Guanylate-Binding Protein 1: An Emerging Target in Inflammation and Cancer.
Guanylate-binding protein 1 (GBP1) is a large GTPase of the dynamin superfamily involved in the regulation of membrane, cytoskeleton, and cell cycle progression dynamics. In many cell types, such as endothelial cells and monocytes, GBP1 expression is strongly provoked by interferon γ (IFNγ) and acts to restrain cellular proliferation in inflammatory contexts. In immunity, GBP1 activity is crucial for the maturation of autophagosomes infected by intracellular pathogens and the cellular response to pathogen-associated molecular patterns. In chronic inflammation, GBP1 activity inhibits endothelial cell proliferation even as it protects from IFNγ-induced apoptosis. A similar inhibition of proliferation has also been found in some tumor models, such as colorectal or prostate carcinoma mouse models. However, this activity appears to be context-dependent, as in other cancers, such as oral squamous cell carcinoma and ovarian cancer, GBP1 activity appears to anchor a complex, taxane chemotherapy resistance profile where its expression levels correlate with worsened prognosis in patients. This discrepancy in GBP1 function may be resolved by GBP1's involvement in the induction of a cellular senescence phenotype, wherein anti-proliferative signals coincide with potent resistance to apoptosis and set the stage for dysregulated proliferative mechanisms present in growing cancers to hijack GBP1 as a pro- chemotherapy treatment resistance (TXR) and pro-survival factor even in the face of continued cytotoxic treatment. While the structure of GBP1 has been extensively characterized, its roles in inflammation, TXR, senescence, and other biological functions remain under-investigated, although initial findings suggest that GBP1 is a compelling target for therapeutic intervention in a variety of conditions ranging from chronic inflammatory disorders to cancer.


Quantifying Social Reinforcement Among Family Members on Adherence to Medications for Chronic Conditions: a US-Based Retrospective Cohort Study.
More than 50% of patients are non-adherent to medications, often without an easily identifiable reason to clinicians. No study has quantified the extent to which health behaviors like medication-taking are correlated within families using national or routinely collected data for a range of conditions. To examine how an individual's health behaviors are influenced by those of their family members, particularly in adherence to medications for chronic conditions. Retrospective cohort study. Using claims from a large nationwide insurer, we identified patients initiating medications for one of five chronic conditions with a family member who also recently filled one of these medications. The primary exposure was whether family members were fully adherent (defined as a proportion of days covered ≥ 80%) before the patient's date of initiation. The outcome of interest was whether patients were fully adherent in the 12 months after initiation. Baseline demographic and clinical characteristics were also measured before initiation. We used multivariable modified Poisson regression to examine the association between prior family adherence and subsequent patient adherence. Among 254,144 patients, rates of full adherence among patients whose family members were and were not fully adherent were 37.3% and 26.9%, respectively (adjusted relative risk [aRR] 1.29, 95%CI 1.28-1.31). The association was stronger when both used cardiometabolic medications (aRR 1.35, 95%CI 1.32-1.37). Similarly, patients were also 38% more likely to be adherent if they and their family members used a medication for the same condition (aRR 1.38, 95%CI 1.35-1.40). Adherence among family members appeared to be highly correlated, suggesting positive reinforcement by family or the sharing of unmeasured behaviors or characteristics associated with better adherence. Regardless, information about prior adherence among family members from routinely collected data could potentially inform adherence prediction or intervention efforts.


Extrahepatic recurrence rates in patients receiving adjuvant hepatic artery infusion and systemic chemotherapy after complete resection of colorectal liver metastases.
This study investigated the effect of the reduced dose of systemic chemotherapy (SYS) on recurrence patterns in patients receiving adjuvant hepatic artery infusion (HAI) chemotherapy after complete colorectal liver metastases (CRLM) resection. Patients undergoing complete CRLM resection between 2000 and 2007 were selected from a prospectively maintained database and categorized as receiving SYS or HAI + SYS. Those with pre and/or intraoperative extrahepatic disease, documented death, or recurrence within 30 days of CRLM resection were excluded. Competing risk, Fine and Gray's tests were used to compare SYS versus HAI + SYS for time-to-organ recurrence. Of 361 study patients, 153 (42.4%) received SYS and 208 (57.6%) received HAI + SYS. The median follow-up for survivors was 100 (range = 12-185) and 156 months (range = 18-217) for SYS and HAI + SYS, respectively. The 5-year cumulative incidence (CI) of any liver recurrence was greater for those receiving SYS (SYS = 41.9% vs. HAI + SYS = 28.6%, p = .005). The 5-year CI of developing any lung or extrahepatic recurrence for SYS patients was 36.2% and 47.9% compared with 44.5% (p = .242) and 51.7% (p = .551), respectively, in patients receiving HAI + SYS. Despite the reduced dose of SYS, adjuvant HAI + SYS after CRLM resection is not associated with a significantly increased risk of extrahepatic recurrence.


The origin and early evolution of tracheids in vascular plants: integration of palaeobotanical and neobotanical data.
Although there is clear evidence for the establishment of terrestrial plant life by the end of the Ordovician, the fossil record indicates that land plants remained extremely small and structurally simple until the Late Silurian. Among the events associated with this first major radiation of land plants is the evolution of tracheids, complex water-conducting cells defined by the presence of lignified secondary cell wall thickenings. Recent palaeobotanical analyses indicate that Early Devonian tracheids appear to possess secondary cell wall thickenings composed of two distinct layers: a degradation-prone layer adjacent to the primary cell wall and a degradation-resistant (possibly lignified) layer next to the cell lumen. In order to understand better the early evolution of tracheids, developmental and comparative studies of key basal (and potentially plesiomorphic) extant vascular plants have been initiated. Ultrastructural analysis and enzyme degradation studies of wall structure (to approximate diagenetic alterations of fossil tracheid structure) have been conducted on basal members of each of the two major clades of extant vascular plants: Huperzia (Lycophytina) and Equisetum (Euphyllophytina. This research demonstrates that secondary cell walls of extant basal vascular plants include a degradation-prone layer ('template layer') and a degradation-resistant layer ('resistant layer'). This pattern of secondary cell wall formation in the water-conducting cells of extant vascular plants matches the pattern of wall thickenings in the tracheids of early fossil vascular plants and provides a key evolutionary link between tracheids of living vascular plants and those of their earliest fossil ancestors. Further studies of tracheid development and structure among basal extant vascular plants will lead to a more precise reconstruction of the early evolution of water-conducting tissues in land plants, and will add to the current limited knowledge of spatial, temporal and cytochemical aspects of cell wall formation in tracheary elements of vascular plants.


Comparison of measured and calculated dose rates in water near I-125 and Ir-192 seeds.
Recent theoretical and experimental work indicates that currently accepted 125I dosimetry data may overestimate dose in water at 1 cm by 10%-24%. Among the most comprehensive measurements are those of the NCI-sponsored brachytherapy contract participants. Absolute dose rates in water calculated by the Monte Carlo method have been compared with the NCI dose measurements about 125I and 192Ir seeds embedded in solid-water phantoms. The photon transport code allows realistic geometric simulation of the complex internal seed structure, the National Institute of Standards and Technology air-kerma strength standardization geometry, and the dose measurement setup. When the appropriate measurement medium and geometry are assumed, agreement between theory and measurement is excellent, within 3% at 1 cm and averaging 3% at larger distances. However, the data do not support the water equivalence of solid water at 125I energies indicating that solid-water measurements underestimate 125I specific dose-rate constants in water by 4.3%. Because of its higher ratio of absorption to scatter, 125I dose distributions measured in solid water are less penetrating (by 35% at 10 cm) than those measured in liquid water. For model 6711, model 6702, and steel-clad 192Ir seeds, Monte Carlo calculations yielded specific dose-rate constants (assuming liquid water medium) of 0.877, 0.932, and 1.122 cGy cm2 h-1 per unit air-kerma strength, respectively. For 125I, currently accepted values are 18% and 11% larger for the two seed models.


AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
The pace of anticancer drug discovery and development has accelerated over recent years based upon a better understanding of tumour biology at the molecular level. Modern drug development has moved from empiricism to rational design and this was the theme of the inaugural meeting of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics held in Washington DC, November 16 - 19.1999. This was an excellent meeting where state of the art research in the areas of drug discovery, development and clinical evaluation of new cancer therapeutics was presented. A few of the highlights of this meeting are presented in this article but further details can he found in a supplement to Clinical Cancer Research (1999) 5:3729-3897, where all abstracts accepted for the meeting are published. This meeting is set to become the premier meeting for scientists and clinicians involved in all aspects of anticancer drug development (i.e., from bench to the bedside) and the next meeting will take place in Amsterdam on November 7-10, 2000.


Efficient extraction of bagasse hemicelluloses and characterization of solid remainder.
To reduce the degradation of cellulose and obtain high molecular weight of hemicellulose from the extracts, pH pre-corrected hot water pretreatment was developed by employing sodium hydroxide (3.9mol/L). The response surface model was established to optimize the extraction process. The species composition and purity of hemicellulose extract was analyzed by High Performance Liquid Chromatography (HPLC). The obtained solid remainder was analyzed by FTIR and SEM. The results showed that the component of xylose in hemicellulose extract was similar with commercial xylan. FTIR and SEM were shown to be able to evaluate solid remainder composition and surface characterization of the bagasse. The biggest balance between solid remainder and dissolved solid was obtained. Not only the yield of dissolved solid was improved, but the structure of solid remainder was also proved, which was beneficial to pulping and papermaking.


Pentoxifylline in Prevention of Amphotericin B-induced Nephrotoxicity and Electrolyte Abnormalities.
Amphotericin B is an antifungal agent used to treat serious fungal infections mainly in critically ill patients. Despite its adverse effects including renal toxicity and electrolyte imbalances, amphotericin B remains one of the best choices for antifungal treatment. Information from animal studies has provided a strong scientific basis for the use of pentoxifylline as lowering nephroprotective agent. The present study was designed to evaluate the efficacy of pentoxifylline in preventing renal toxicity and electrolytes imbalances induced by amphotericin B. This study was conducted as a randomized controlled trial on 44 patients admitted to Sayyedoshohada Hospital, Isfahan, Iran, from October 2016 to August 2018. Patients were assigned to one of the two groups: Pentoxifylline, 400 mg twice a day, or matching placebo, from the 1st day of amphotericin B therapy till minimum of 7 days. All patients' information including lab data (serum and urine levels of Mg, Na, and K, serum creatinine level, blood urea nitrogen [BUN] and urinary creatinine excretion) were gathered at the time of drug initiation and during the study period. The results were analyzed by SPSS v. 20 software and Repeated measures test was used to assess the differences between groups. This study did not show any significant differences between the two groups in terms of all the assessed variables, including serum and urinary levels of electrolytes, and creatinine, as well as the number of cases presented acute kidney injury during the study period. Despite the positive effects of pentoxifylline in preventing renal complications in previous studies, this study could not show a definitive result in salt wasting or renal damage induced by amphotericin B. So, Designing robust studies with more included samples would be valuable.


The ascaphins: a family of antimicrobial peptides from the skin secretions of the most primitive extant frog, Ascaphus truei.
The tailed frog Ascaphus truei occupies a unique position in phylogeny as the most primitive extant anuran and is regarded as the sister taxon to the clade of all other living frogs. Eight structurally related peptides, termed ascaphins 1-8, were isolated from norepinephrine-stimulated skin secretions of A. truei and were shown to possess differential growth inhibitory activity against Escherichia coli and Staphylococcus aureus. Ascaphins 2-7 may be represented by the consensus amino acid sequence GX2DX2KGAAKX3KTVAX2IANX.COOH whereas ascaphin-1 (GFRDVLKGAAKAFVKTVAGHIAN.NH2) and ascaphin-8 (GFKDLLKGAAKALVKTVLF.NH2) contain a C-terminally alpha-amidated residue. The ascaphins show no appreciable structural similarity with other families of antimicrobial peptides from frog skin but display limited sequence identity with the cationic, amphipathic alpha-helical peptides pandinin 1 and opistoporin 1, isolated from the venoms of African scorpions. Ascaphin-8 shows the highest potency against a range of pathogenic microorganisms but has the greatest haemolytic activity. The data indicate that the host defence strategy of using antimicrobial peptides in skin secretions arose early in the evolution of anurans.


The evolving role of estrogen therapy in prostate cancer.
Estrogens, including diethylstilbestrol (DES), were used as the primary medical treatment for metastatic prostate cancer for many years but have been superceded in the past two decades by luteinizing hormone-releasing hormone (LHRH) agonists, primarily because of the cardiovascular toxicity associated with oral estrogen therapy. Recently, a renewed interest in estrogen therapy for prostate cancer in the United States has developed as a result of 3 major issues. First, when measured by declines in prostate-specific antigen of > or = 50%, clinical trials have demonstrated activity of DES, DES-diphosphate, and the estrogenic herbal therapy PC-SPES in 21%-86% of patients treated in phase II trials of androgen-independent prostate cancer patients. Second, the recent description of estrogen receptor (ER)-b has led to a reevaluation of the role of estrogens in normal prostate development and cancer pathogenesis. In contrast to ER-a, ER-b is strongly expressed in normal prostate epithelium. Furthermore, loss of ER-b expression has been demonstrated in prostate cancers, suggesting a possible role for this pathway in the development of cancer. Finally, the issues of cost and safety of estrogens are being reassessed in the current environment of rising health care costs and improved cardiovascular care. In Europe, estrogen therapy is more accepted as a low-cost and effective alternative to LHRH agonists and antiandrogens. Toxicity of DES and other estrogens has also been attenuated by strategies that use lower doses and parenteral routes of administration, thereby avoiding hepatic first-pass metabolism and decreasing the risk of thromboembolism. Nonetheless, there remain many unanswered questions about the role of estrogen therapy in prostate cancer, including differences between specific drugs, optimal dose, timing, and patient selection. Further research is needed.


Limited performance of MALDI-TOF for identification of fish Aeromonas isolates at species level.
The aim of this study was to evaluate the usefulness of the MALDI-TOF MS to identify 151 isolates of Aeromonas obtained mostly from diseased fish. MALDI-TOF MS correctly identified all isolates to the genus level but important differences in the percentage of isolates correctly identified depending on the species were observed. Considering exclusively the first identification option, Aeromonas bestiarum, Aeromonas hydrophila, Aeromonas salmonicida, Aeromonas veronii and Aeromonas sobria were the best identified with results >95%. However, considering the first and second identification options, the only species that showed values >90% was A. hydrophila. Overall, when the database was supplemented with 14 new spectra, the number of accurate identifications increased (41% vs. 55%) and the number of inconclusive identifications decreased (45% vs. 29%), but great differences in the success of species-level identifications were found. Species-distinctive mass peaks were identified only for A. hydrophila and A. bestiarum (5003 and 7360 m/z in 95.5% and 94.1% of their isolates, respectively). This work demonstrates the utility of MALDI-TOF MS for Aeromonas identification to the genus level, but there is no consistency for the accurate identification of some of the most prevalent species implicated in fish disease.


Expression patterns and roles of periostin during kidney and ureter development.
Periostin is a secreted extracellular matrix protein that is differentially expressed in the developing kidney. We analyzed the temporal-spatial expression of periostin in the developing kidney and ureter as well as its roles in ureter branching morphogenesis, nephrogenesis and ureter development. RNA in situ hybridization and immunofluorescence histochemistry were used to investigate the expression of periostin, αv integrin and α-smooth muscle actin during mouse renal and ureteral development. Metanephric explants were cultured in the presence of recombinant periostin, and ureteral branch points/tips and the glomerular number were quantified. Explants were also cultured in the presence of exogenous bone morphogenetic protein 4 and the effect on periostin mRNA levels was determined by quantitative real-time polymerase chain reaction. Periostin expression was observed in the mesenchyme surrounding the kidney and ureter, renal stroma, metanephric mesenchyme, ureter epithelium and developing nephrons. At embryonic day 15.5 periostin and αv integrin, a common subunit of periostin receptors, were co-expressed in smooth muscle cells of the ureter, renal artery and intrarenal arteries. Bone morphogenetic protein 4 up-regulated periostin mRNA expression and exogenous periostin inhibited branching morphogenesis and glomerular number. Bone morphogenetic protein 4 which inhibits ureteral branching morphogenesis and promotes smooth muscle cell migration in the ureter up-regulated periostin mRNA expression in the developing kidney. Ureteral smooth muscle cells express periostin and αv integrin. Periostin inhibited ureteral branching morphogenesis and glomerular number. Together these results suggest that periostin and bone morphogenetic protein 4 may have a role in branching morphogenesis, nephrogenesis and possibly smooth muscle cell migration.


Effect of nitrate and acetylene on nirS, cnorB, and nosZ expression and denitrification activity in Pseudomonas mandelii.
Nitrate acts as an electron acceptor in the denitrification process. The effect of nitrate in the range of 0 to 1,000 mg/liter on Pseudomonas mandelii nirS, cnorB, and nosZ gene expression was studied, using quantitative reverse transcription-quantitative PCR. Denitrification activity was measured by using the acetylene blockage method and gas chromatography. The effect of acetylene on gene expression was assessed by comparing denitrification gene expression in P. mandelii culture grown in the presence or absence of acetylene. The higher the amount of NO(3)(-) present, the greater the induction and the longer the denitrification genes remained expressed. nirS gene expression reached a maximum at 2, 4, 4, and 6 h in cultures grown in the presence of 0, 10, 100, and 1,000 mg of KNO(3)/liter, respectively, while induction of nirS gene ranged from 12- to 225-fold compared to time zero. cnorB gene expression also followed a similar trend. nosZ gene expression did not respond to NO(3)(-) treatment under the conditions tested. Acetylene decreased nosZ gene expression but did not affect nirS or cnorB gene expression. These results showed that nirS and cnorB responded to nitrate concentrations; however, significant denitrification activity was only observed in culture with 1,000 mg of KNO(3)/liter, indicating that there was no relationship between gene expression and denitrification activity under the conditions tested.


Evaluation of quantitative real-time PCR for rapid assessments of the exposure of sentinel fish to Myxobolus cerebralis.
Pathogen-free rainbow trout (Oncorhynchus mykiss) aged 735 degree days were experimentally exposed to a low dose of infectious Myxobolus cerebralis (20 triactinomyxons fish(-1)). Three time periods were chosen for sampling that included 10 days (d), 67 d, and 5 months (mo) post exposure. Five diagnostic assays were used: (1) conventional single-round polymerase chain reaction (PCR), (2) nested PCR, (3) real-time TaqMan PCR, (4) pepsin-trypsin digest, and (5) histopathology. M. cerebralis was detected among individual rainbow trout by all of the PCR diagnostic tests employed at each of the three sampling time points. This result demonstrates that any of these three diagnostic approaches are capable of detecting the parasite from infected fish tissues under the conditions tested. Real-time PCR provided good biological evidence that parasite replication increases temporally as shown by quantification values that were significantly different (P<0.0001) at 10 d as compared to 67 d and 5 mo postexposure. Although sampling at 10 d by real-time PCR may be too early to accurately predict quantities of the parasite that will be present at 5 mo, it does forecast the proportions of fish that are likely to be infected at 67 d and 5 mo postparasite exposure. Real-time PCR could potentially be used as a quantitative diagnostic PCR tool to predict parasite load and outcome of M. cerebralis infection.


Erratum: Berryman et al (2018).
In the article by Berryman N, Mujika I, Arvisais D, Roubeix M, Binet C, Bosquet L. Strength training for middle- and long-distance performance: a meta-analysis. Int J Sports Physiol Perform. 2018;13(1):57-63. doi: 10.1123/ijspp.2017-0032 , there were errors in an author's name and with 2 author affiliations: (1) Iñigo Mujika was incorrectly spelled as Inigo Mujika, (2) Mujika's second affiliation (School of Kinesiology, Universidad Finis Terrae, Santiago, Chile) was absent, and (c) University of Poitiers was incorrectly spelled as University or Poitiers. The online version of this article has been corrected. We apologize for these errors.


Isolation and characterization of novel Chlamydomonas mutants that display phototaxis but not photophobic response.
The unicellular green alga Chlamydomonas displays two distinct kinds of behavioral response to light: phototaxis, in which cells swim toward or away from the light source under constant illumination; and photophobic responses (also called stop responses or photoshock responses), in which cells transiently convert their flagellar waveform and swim backward upon sudden increase in light intensity. It has been suggested that the two responses partly share a common signal transduction pathway, but exactly how the different responses are produced has not been established. In this study, to help understand the molecular and cellular mechanisms that bring about the photophobic response, we isolated novel mutants (ppr1, ppr2, ppr3, and ppr4) that do not show the photophobic response. Importantly, these mutants retain the ability to display phototaxis, with almost the same sensitivities as in the wild type cell. Demembranated and reactivated flagellar axonemes of the ppr mutants were found to convert the bending patterns depending on the Ca2+ concentration, indicating that the axonemal mechanism for waveform conversion required for the photophobic response was unaffected by the mutations. In addition, measurements of electric currents in cell suspensions showed that these mutants generate normal photoreceptor currents (PRC) upon photostimulation, suggesting that they retain the normal activity of photoreception and the ionic channels that produce PRCs. However, the all-or-none flagellar current (FC), a Ca2+ current generated by PRC-induced depolarization of flagellar membrane, was absent or seriously impaired in the mutants. These findings clearly indicate that the all-or-none FC is necessary for the photophobic response but not for phototaxis. The isolation of the four genetically independent ppr mutants suggests that the generation of the FC is based on multiple components that are not used in the mechanism for phototaxis, and implies that the Chlamydomonas flagellar membrane possesses a voltage-dependent Ca2+-channel specifically used for generation of photophobic responses.


[Study on anticonvulsive effect of rhizoma pinelliae].
Anticonvulsive effect of water-soluble extract of rhizoma Pinelliae was studied. The result showed that the extract of rhizoma Pinelliae could remarkably inhibit the convulsion induced by strychnine and obviously reduce mortality rate in mice. But the extract could be destroyed easily by heat.


The aetiology of the hyperventilation syndrome. A review of the literature.
The aetiology of the hyperventilation syndrome is reviewed with special emphasis on psychological aspects. Early reports linking overbreathing and the emotions can be found as far back as the 16th century. During the last 50 years research has been carried out into respiration in psychiatric disorders but as far as the hyperventilation syndrome is concerned there have been few psychiatric studies. Though many people believe that hyperventilation occurs as a response to anxiety, it has recently been suggested that it is due to a bad breathing habit. Whichever view should prove to be correct, most people would agree that the distressing symptoms produced by hyperventilation may themselves cause anxiety and exacerbate the hyperventilation, thus setting up a vicious circle. By the time the patient presents, this vicious circle has usually become established.


Kernel Smoothed Profile Likelihood Estimation in the Accelerated Failure Time Frailty Model for Clustered Survival Data.
Clustered survival data frequently arise in biomedical applications, where event times of interest are clustered into groups such as families. In this article we consider an accelerated failure time frailty model for clustered survival data and develop nonparametric maximum likelihood estimation for it via a kernel smoother aided EM algorithm. We show that the proposed estimator for the regression coefficients is consistent, asymptotically normal and semiparametric efficient when the kernel bandwidth is properly chosen. An EM-aided numerical differentiation method is derived for estimating its variance. Simulation studies evaluate the finite sample performance of the estimator, and it is applied to the Diabetic Retinopathy data set.


Case Report: Role of Anterior Segment Optical Coherence Tomography for Managing Failed Endothelial Keratoplasty Graft.
Some patients show poor visual outcomes following Descemet stripping automated endothelial keratoplasty. In such cases, secondary Descemet membrane endothelial keratoplasty can be performed to achieve complete visual recovery. Anterior segment optical coherence tomography (AS-OCT) is a valuable tool for the follow-up of posterior lamellar keratoplasty outcomes and complications. This study aims to report the clinical outcome of secondary Descemet membrane endothelial keratoplasty for managing poor visual results in a patient with graft failure after a previous Descemet stripping automated endothelial keratoplasty, highlighting the importance of AS-OCT in the follow-up of endothelial keratoplasty. A 38-year-old female with high myopia underwent Descemet stripping automated endothelial keratoplasty for bullous keratopathy following explantation of an angle-supported phakic intraocular lens. Two years after keratoplasty, the patient experienced poor visual acuity (counting fingers) and significant corneal edema was observed on clinical examination hindering visualization of the anterior chamber structures. AS-OCT (Casia 2) showed a failed and thickened graft adhering well to the recipient cornea in an anterior chamber without other comorbidities. Therefore, the graft was removed and replaced with a Descemet membrane endothelial keratoplasty graft without any complications. One year later, the clinical outcome was evaluated by comparing the preoperative and postoperative best-corrected visual acuity, biomicroscopy findings, endothelial cell density, and corneal central thickness. AS-OCT is an important tool when deciding on the surgical technique to be applied and for the postsurgical monitoring of endothelial corneal grafts. This case demonstrates the successful management of Descemet stripping automated endothelial keratoplasty graft failure with Descemet membrane endothelial keratoplasty graft, highlighting the importance of AS-OCT in detecting complications such as graft dislocation and primary graft failure. Additionally, corneal thickness measured using AS-OCT serves as a critical predictor of graft failure, as observed in this case.


Methods for identifying SNP interactions: a review on variations of Logic Regression, Random Forest and Bayesian logistic regression.
Due to advancements in computational ability, enhanced technology and a reduction in the price of genotyping, more data are being generated for understanding genetic associations with diseases and disorders. However, with the availability of large data sets comes the inherent challenges of new methods of statistical analysis and modeling. Considering a complex phenotype may be the effect of a combination of multiple loci, various statistical methods have been developed for identifying genetic epistasis effects. Among these methods, logic regression (LR) is an intriguing approach incorporating tree-like structures. Various methods have built on the original LR to improve different aspects of the model. In this study, we review four variations of LR, namely Logic Feature Selection, Monte Carlo Logic Regression, Genetic Programming for Association Studies, and Modified Logic Regression-Gene Expression Programming, and investigate the performance of each method using simulated and real genotype data. We contrast these with another tree-like approach, namely Random Forests, and a Bayesian logistic regression with stochastic search variable selection.


Experimental versus computational analysis of micromotions at the implant-bone interface.
In total hip arthroplasty, micromotions at the implant-bone interface influence the long-term survival of the prosthesis. These micromotions are often measured using sensors that are fixed to the implant and bone at points that are remote from the interface. Given that the implant-bone system is not rigid, errors may be introduced. It is not possible to assess the magnitude of these errors with the currently available experimental methods. However, this problem can be investigated using the finite element method (FEM). The hypothesis that the actual interface micromotions differ from those measured in the experimental manner was tested using a case-specific FE model, validated against deflection experiments. The FE model was used to simulate an 'experimental' method to measure micromotions. This 'experimental' method was performed by mimicking the distance between the measurement points; the implant point was selected at the interface while the bony point was at the outer surface of bone. No correlation was found between the micromotions computed at the interface and when using remote reference points. Moreover, the magnitudes of micromotions computed with the latter method were considerably greater. By reducing the distance between the reference points the error decreased, but the correlation stayed unchanged. Care needs to be taken when interpreting the results of micromotion measurement systems that use bony reference points at a distance from the actual interface.


Reverse genetics in ecological research.
By precisely manipulating the expression of individual genetic elements thought to be important for ecological performance, reverse genetics has the potential to revolutionize plant ecology. However, untested concerns about possible side-effects of the transformation technique, caused by Agrobacterium infection and tissue culture, on plant performance have stymied research by requiring onerous sample sizes. We compare 5 independently transformed Nicotiana attenuata lines harboring empty vector control (EVC) T-DNA lacking silencing information with isogenic wild types (WT), and measured a battery of ecologically relevant traits, known to be important in plant-herbivore interactions: phytohormones, secondary metabolites, growth and fitness parameters under stringent competitive conditions, and transcriptional regulation with microarrays. As a positive control, we included a line silenced in trypsin proteinase inhibitor gene (TPI) expression, a potent anti-herbivore defense known to exact fitness costs in its expression, in the analysis. The experiment was conducted twice, with 10 and 20 biological replicates per genotype. For all parameters, we detected no difference between any EVC and WT lines, but could readily detect a fitness benefit of silencing TPI production. A statistical power analyses revealed that the minimum sample sizes required for detecting significant fitness differences between EVC and WT was 2-3 orders of magnitude larger than the 10 replicates required to detect a fitness effect of TPI silencing. We conclude that possible side-effects of transformation are far too low to obfuscate the study of ecologically relevant phenotypes.


Decompressive hemicraniectomy in pediatric patients with malignant middle cerebral artery infarction: case series and review of the literature.
Malignant middle cerebral artery infarction (mMCAI) is a life-threatening condition in pediatric patients. Despite strong evidence showing decreased morbidity and mortality in adult mMCAI patients with decompressive hemicraniectomy (DCH), there is a paucity of data on the use of DCH in children with similar conditions. Here we report experience from our center and perform a systematic review of published literature on outcomes after use of DCH in pediatric mMCAI patients. By retrospective chart review, we identified 3 children with large ischemic stroke who underwent DCH for life-threatening cerebral edema. Information was obtained about patient characteristics on admission, radiological features of the stroke, surgical procedures, complications of the DCH and cranioplasty, and functional outcomes during follow-up visits. We also reviewed the current literature on DCH in pediatric stroke. DCH was performed in all 3 cases after development of pupillary dilatation. All 3 children survived and were ambulatory at the time of follow-up. Review of literature identified 12 other published case series describing 26 cases of DCH in pediatric patients with ischemic stroke. Descriptive statistical analysis of these cases is presented. Published reports suggest that a good outcome is possible even in the presence of signs of herniation, low preoperative Glasgow Coma Scale score, involvement of multiple vascular territories, or longer time to surgery in pediatric ischemic stroke patients. The current data suggest a role for DCH in the management of cerebral edema in pediatric patients with mMCAI. Factors that help in prognostication for adult stroke patients undergoing DCH do not appear to convey similar information about the pediatric population. This highlights the urgent need for collaboration across institutes to further investigate this potentially life-saving procedure in pediatric stroke.