Reduction of ferrylmyoglobin by theanine and green tea catechins. Importance of specific Acid catalysis.
Reduction of the hypervalent heme pigment ferrylmyoglobin by green tea catechins in aqueous solution of pH = 7.5 was investigated by stopped-flow spectroscopy. Reduction by the gallic acid esters epigallocatechin gallate (EGCG, k2 = 1460 L mol(-1) s(-1), 25.0 °C, 0.16 ionic strength) and epicatechin gallate (ECG, 1410 L mol(-1) s(-1)) was found faster than for epicatechin (EC, 300 L mol(-1) s(-1)) and epigallocatechin (EGC, 200 L mol(-1) s(-1)), even though the gallate ion (G, 330 L mol(-1) s(-1)) is similar in rate to EC. The rate for reduction by EC, EGC, ECG, EGCG, and G shows no correlation with their oxidation potentials or phenolic hydrogen-oxygen bond dissociation energy, but with the pKa of the most acidic phenol group. Theanine, with an acidity similar to that of EC, reduces ferrylmyoglobin with a similar rate (200 L mol(-1) s(-1)), in support of general acid catalysis with an initial proton transfer prior to electron transfer.


Localization of inhibin in human testes by immunoperoxidase technique.
Immunohistological studies on the localization of inhibin in human testes were carried out to investigate the cell types involved in inhibin synthesis/storage. The paraffin embedded testicular tissues were stained by an indirect immunoperoxidase technique. Specific antiserum to human testicular inhibin generated against the homogenous preparation of human testicular inhibin at our laboratory was used as the first antibody. Inhibin was found to be localized in Sertoli cells, spermatogonia, and primary spermatocytes. A weak positive reaction was also observed in spermatids. Interestingly, Leydig cells showed positive reaction indicating presence of inhibin in these cells too.


High-yield interferon induction by 10-carboxymethyl-9-acridanone in mice and hamsters.
10-Carboxymethyl-9-acridanone (CMA) was shown to be a very potent interferon inducer in young and old Swiss albino as well as congenitally asplenic mice. This compound (molecular weight, 275) induced titers of interferon in plasma comparable to those obtained with the best viral inducers, attaining > 400,000 U/ml in mice in 2 to 3 h. CMA concentrations were highest in mouse plasma 1 h after intraperitoneal or oral delivery. Induction was dose dependent over a wide range. Intraperitoneal, subcutaneous, or intramuscular injections of CMA gave comparable ranges of interferon titers. Oral delivery by gavage gave lower titers (65,000 U/ml), but higher than those reported with other low-molecular-weight interferon inducers in mice. CMA injected into week-old hamsters (which usually produce iterferon poorly) induced levels of interferon as high as 6,400 U per ml of plasma in a dose-dependent fashion, but kinetics of interferon induction was less rapid than in mice. The mouse and hamster interferons induced by CMA had physical characteristics similar to those of virus-induced interferons of the homologous species. The unusually high yields of interferon obtainable with this chemical inducer suggest its use for further experimental antiviral or antitumor therapy.


Subharmonic gap structure of normal-state conductance and thermoelectric effect in a graphene-based nano device.
Using the quantum transport of chiral Dirac fermions in graphene, we investigate the normal-state conductance and thermoelectric effect of a nano device under the ballistic superconductor-graphene-superconductor (SGS) model. Because of the Josephson effect and Andreev reflections, there exists an oscillatory behavior of the normal-state conductance flowing through the successive discrete energy levels on a finite-sized graphene contacted to the superconducting leads. The normal-state conductance displays a rich structure of subharmonic gaps controlled by means of a gate voltage on the discrete energy levels near the Fermi energy. Since the Fermi energy is an essential factor in determining the nature of conduction such as n or p type, we study the thermoelectric effect over the graphene-based nano device. It is shown that the thermoelectric effect can provide information on the location of the Fermi energy with respect to the energy levels of the finite-sized graphene.


Transthoracic delivery of large devices into the left ventricle through the right ventricle and interventricular septum: preclinical feasibility.
We aim to deliver large appliances into the left ventricle through the right ventricle and across the interventricular septum. This transthoracic access route exploits immediate recoil of the septum, and lower transmyocardial pressure gradient across the right versus left ventricular free wall. The route may enhance safety and allow subxiphoid rather than intercostal traversal. The entire procedure was performed under real-time CMR guidance. An "active" CMR needle crossed the chest, right ventricular free wall, and then the interventricular septum to deliver a guidewire then used to deliver an 18Fr introducer. Afterwards, the right ventricular free wall was closed with a nitinol occluder. Immediate closure and late healing of the unrepaired septum and free wall were assessed by oximetry, angiography, CMR, and necropsy up to four weeks afterwards. The procedure was successful in 9 of 11 pigs. One failed because of refractory ventricular fibrillation upon needle entry, and the other because of inadequate guidewire support. In all ten attempts, the right ventricular free wall was closed without hemopericardium. There was neither immediate nor late shunt on oximetry, X-ray angiography, or CMR. The interventricular septal tract fibrosed completely. Transventricular trajectories planned on human CT scans suggest comparable intracavitary working space and less acute entry angles than a conventional atrial transseptal approach. Large closed-chest access ports can be introduced across the right ventricular free wall and interventricular septum into the left ventricle. The septum recoils immediately and heals completely without repair. A nitinol occluder immediately seals the right ventricular wall. The entry angle is more favorable to introduce, for example, prosthetic mitral valves than a conventional atrial transseptal approach.


Altered glucose homeostasis in mice lacking the receptor protein tyrosine phosphatase sigma.
Several protein tyrosine phosphatases (PTPs) expressed in insulin sensitive-tissues are proposed to attenuate insulin action and could act as key regulators of the insulin receptor (IR) signaling pathway. Among these PTPs, RPTPsigma is expressed in relatively high levels in insulin-target tissues. We show that RPTPsigma-/- knockout mice have reduced plasma glucose and insulin concentrations in the fasted state compared with their wild-type siblings. The knockout animals were also more sensitive to exogenous insulin as assayed by insulin-tolerance tests. Despite increased whole-body insulin sensitivity, tyrosine phosphorylation of the IR was not increased in muscle of RPTPsigma-/- animals, as would be expected in insulin-sensitive animals. Instead, the levels of IR tyrosine phosphorylation and PI3-kinase activity were reduced in the muscle of knockout animals stimulated with insulin in vivo. However, insulin-stimulated Akt serine phosphorylation was essentially identical between both groups of mice. Accordingly, muscles isolated from RPTPsigma-/- mice did not have a significant increase in glucose uptake in response to insulin, suggesting that RPTPsigma did not play a direct role in this process. Taken together, our results suggest an indirect modulation of the IR signaling pathways by RPTPsigma. Since low dose injection of growth hormone (GH) normalized the response to exogenous insulin in RPTPsigma-/- mice, we propose that the insulin hypersensitivity observed in RPTPsigma-/- mice is secondary to their neuroendocrine dysplasia and GH/IGF-1 deficiency.


The potential long-term comparative effectiveness of larotrectinib vs standard of care for treatment of metastatic TRK fusion thyroid cancer, colorectal cancer, and soft tissue sarcoma.
BACKGROUND: Larotrectinib is approved for patients with metastatic TRK fusion cancers, including differentiated thyroid (DTC), colorectal cancer (CRC), and soft tissue sarcoma (STS). Given the basket clinical trial design of larotrectinib, direct comparisons against standard of care in each of the mentioned cancers have not been assessed. Also, owing to the limited duration of follow-up in clinical trials, long-term outcomes for treatments are generally not known or estimated. OBJECTIVE: To compare expected life-years (LYs) and quality-adjusted life-years (QALYs) for patients with metastatic DTC, CRC, and STS who are eligible to receive larotrectinib against patients with unknown NTRK gene fusion status receiving standard-of-care therapy. METHODS: We developed a partitioned survival model to estimate the long-term comparative effectiveness of larotrectinib and standard of care for 3 tumor types. Larotrectinib survival data, assessed by independent review committee, were derived from an updated July 2020 analysis of 19, 8, and 23 adult patients (aged ≥ 18 years) with metastatic TRK fusion DTC, CRC, and STS, respectively. The DTC survival data also included 2 patients aged less than 18 years for a total of 21 patients. Survival estimates for standard of care were derived from published clinical trials. Progressionfree and overall survival for all treatments were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Lognormal) fit to the available data. The final exponential form was selected based on goodness-of-fit and clinical plausibility. QALYs were estimated by adjusting the time spent in the preprogression and postprogression health states by utility weights derived from publicly available literature. RESULTS: Patients receiving larotrectinib experienced more LYs and QALYs compared with those receiving standard-of-care treatments across all 3 assessed cancer types. In DTC, patients receiving larotrectinib had 7.15-8.26 additional LYs (5.87-6.12 QALYs); in CRC, patients receiving larotrectinib had 1.26-1.27 additional LYs (1.00 QALYs); and in STS, patients receiving larotrectinib had 5.56 additional LYs (1.99 QALYs). CONCLUSIONS: Compared with standard of care in metastatic TRK wild-type cancers, larotrectinib is estimated to result in improved LY and QALY outcomes based on parametric extrapolations of intrial survival data. Because patient-level data were unavailable for adjusted analyses, a cross-trial comparison was performed. Given the limitations of this analytic approach and the small sample size for larotrectinib in trials, future studies should reassess the comparative effectiveness of larotrectinib vs standard of care as treated patients accrue and long-term survival data mature. DISCLOSURES: K. Suh, J. Carlson, and S. Sullivan report consulting fees from Bayer US LLC. F. Xia and T. Williamson are employees of Bayer US LLC. This study was funded by Bayer US LLC. The sponsor had no role in the design of the study and did not have any role in the execution, analyses, interpretation of the data, or decision to submit results.


First characterization of immunogenic conjugates of Vi negative Salmonella Typhi O-specific polysaccharides with rEPA protein for vaccine development.
Efficacious typhoid vaccines for young children will significantly reduce the disease burden in developing world. The Vi polysaccharide based conjugate vaccines (Vi-rEPA) against Salmonella Typhi Vi positive strains has shown high efficacy but may be ineffective against Vi negative S. Typhi. In this study, for the first time, we report the synthesis and evaluation of polysaccharide-protein conjugates of Vi negative S. Typhi as potential vaccine candidates. Four different conjugates were synthesized using recombinant exoprotein A of Pseudomonas aeruginosa (rEPA) and human serum albumin (HSA) as the carrier proteins, using either direct reductive amination or an intermediate linker molecule, adipic acid dihydrazide (ADH). Upon injection into mice, a significantly higher antibody titer was observed in mice administrated with conjugate-1 (OSP-HSA) (P=0.0001) and conjugate 2 (OSP-rEPA) (P≤0.0001) as compared to OSP alone. In contrast, the antibody titer elicited by conjugate 3 (OSPADH-HSA) and conjugate 4 (OSPADH-rEPA) were insignificant (P=0.1684 and P=0.3794, respectively). We conclude that reductive amination is the superior method to prepare the S. Typhi OSP glycoconjugate. Moreover, rEPA was a better carrier protein than HSA. Thus OSP-rEPA conjugate seems to be efficacious typhoid vaccines candidate, it may be evaluated further and recommended for the clinical trials.


Link between Alzheimer's disease and benzodiazepines suspected.
While the acute effects of benzodiazepines on memory and cognition are well documented, the possibility that they increase risk of dementia is still debated. This study matched 1,796 people with a diagnosis of Alzheimer's with 7,184 people over the age of 66 who did not have the condition. The researchers examined benzodiazepine use begun at least five years before the start of the study. Findings showed an association with increased risk of Alzheimer's disease.


Adsorption of DNA oligonucleotides by titanium dioxide nanoparticles.
Titanium dioxide (TiO2) or titania shows great promise in detoxification and drug delivery. To reach its full potential, it is important to interface TiO2 with biomolecules to harness their molecular recognition function. To this end, DNA attachment is an important topic. Previous work has mainly focused on long double-stranded DNA or single nucleotides. For biosensor development and targeted drug delivery, it is more important to use single-stranded oligonucleotides. Herein, the interaction between fluorescently labeled oligonucleotides and TiO2 nanoparticles is reported. The point of zero charge (PZC) of TiO2 is around 6 in water or acetate buffer; therefore, the particles are positively charged at lower pH. However, if in phosphate or citrate buffer, the particles are negatively charged, even at pH ∼2, suggesting strong adsorption of buffer anions. DNA adsorption takes place mainly via the phosphate backbone, although the bases might also have moderate contributions. Peptide nucleic acids (PNAs) with an amide backbone cannot be adsorbed. DNA adsorption is strongly affected by inorganic anions, where phosphate and citrate can strongly inhibit DNA adsorption. DNA adsorption is promoted by adding salt or lowering pH. DNA adsorption is accompanied with fluorescence quenching, and double-stranded DNA showed reduced quenching, allowing for the detection of DNA using TiO2 nanoparticles.


Dissociation of apoptosis and activation of IL-1beta-converting enzyme/Ced-3 proteases by ALG-2 and the truncated Alzheimer's gene ALG-3.
Recent attention has been focused on the members of the IL-1beta-converting enzyme (ICE)/Ced-3 family of cysteine protease as the key components of programmed cell death. However, the molecular events that lead to protease activation and link it to the final apoptotic processes remain poorly characterized. We have shown recently that ALG-2 is a Ca2+-binding protein required for apoptosis. ALG-2 depletion protects the mouse T cell hybridoma 3DO from programmed cell death induced by several stimuli, such as synthetic glucocorticoids, TCR, and Fas triggering. In this work, we show that in the ALG-2-depleted clones the ICE/Ced-3 proteases are normally activated upon TCR, Fas, and dexamethasone stimulation, as determined by cleavage of the endogenous substrate poly(ADP-ribose) polymerase and of a fluorogenic substrate. ALG-3, a truncated form of the familial Alzheimer's disease gene PS2, confers resistance to TCR- and Fas-induced apoptosis. Of interest, it also reduces protease activity and inhibits poly(ADP-ribose) polymerase cleavage upon Fas triggering. Our results suggest that, during apoptosis, ALG-2 functions downstream of, and that ALG-3 interferes with the sequential activation of members of the ICE family proteases.


Lack of association of CFD polymorphisms with advanced age-related macular degeneration.
Age-related macular degeneration (AMD) is the most common cause of irreversible central vision loss worldwide. Research has linked AMD susceptibility with dysregulation of the complement cascade. Typically, complement factor H (CFH), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3) are associated with AMD. In this paper, we investigated the association between complement factor D (CFD), another factor of the complement system, and advanced AMD in a Caucasian population. Six single nucleotide polymorphisms (SNPs), rs1683564, rs35186399, rs1683563, rs3826945, rs34337649, and rs1651896, across the region covering CFD, were chosen for this study. One hundred and seventy-eight patients with advanced AMD and 161 age-matched normal controls were genotyped. Potential positive signals were further tested in another independent 445 advanced AMD patients and 190 controls. χ2 tests were performed to compare the allele frequencies between case and control groups. None of the six SNPs of CFD was found to be significantly associated with advanced AMD in our study. Our findings suggest that CFD may not play a major role in the genetic susceptibility to AMD because no association was found between the six SNPs analyzed in the CFD region and advanced AMD.


Autoimmune gastritis: relationships with anemia and Helicobacter pylori status.
Autoimmune gastritis (AIG) is a gastric pathologic condition affecting the mucosa of the fundus and the body and eventually leading to hypo-achlorhydria. We report our clinical and pathological experience with AIG. Data from patients with a diagnosis of AIG seen in the period January 2002-December 2012 were retrieved. Only patients with complete sets of biopsies were analyzed. Data from 138 patients were available for analysis. Pernicious anemia was present in 25% of patients, iron deficiency anemia was found in 29.7% of patients, hypothyroidism in 23% of patients, type 1 diabetes in 7.9% of patients, and vitiligo in 2.8% of patients. Parietal cell antibodies were positive in 65% of patients, and no patient had serology positive for celiac disease. All gastric biopsies showed glandular atrophy associated with enterochromaffin-like (ECL)-cells hyperplasia, features limited to the mucosa of the fundus and body, and focal glandular intestinal metaplasia. Helicobacter pylori was negative in all cases. AIG was strongly associated with anemia; atrophy, intestinal metaplasia and ECL hyperplasia in the gastric fundus and body are hallmarks of this condition.


The Autophagy Receptor Adaptor p62 is Up-regulated by UVA Radiation in Melanocytes and in Melanoma Cells.
UVA (315-400 nm) is the most abundant form of UV radiation in sunlight and indoor tanning beds. However, much remains to be understood about the regulation of the UVA damage response in melanocytes and melanoma. Here, we show that UVA, but not the shorter waveband UVB (280-315 nm), up-regulates adaptor protein p62 in an Nrf2- and reactive oxygen species (ROS)-dependent manner, suggesting a UVA-specific effect on p62 regulation. UVA-induced p62 up-regulation was inhibited by a mitochondria-targeted antioxidant or Nrf2 knockdown. In addition, p62 knockdown inhibited UVA-induced ROS production and Nrf2 up-regulation. We also report here a novel regulatory feedback loop between p62 and PTEN in melanoma cells. PTEN overexpression reduced p62 protein levels, and p62 knockdown increased PTEN protein levels. As compared with normal human skin, p62 was up-regulated in human nevus, malignant melanoma and metastatic melanoma. Furthermore, p62 was up-regulated in melanoma cells relative to normal human epidermal melanocytes, independent of their BRAF or NRAS mutation status. Our results demonstrated that UVA up-regulates p62 and induces a p62-Nrf2 positive feedback loop to counteract oxidative stress. Additionally, p62 forms a feedback loop with PTEN in melanoma cells, suggesting p62 functions as an oncogene in UVA-associated melanoma development and progression.


[Influence of the type of arterial anastomosis on the development of endothelial hyperplasia].
This study was designed to evaluate intimal hyperplasia distal to the suture line in two types of vascular anastomosis: end to end and end to side. 49 aorto-iliac homografts have been performed on rabbits New-Zealand. The aortic anastomosis was side to end, iliac anastomosis were end to end on one side, end to side on the other one. Scanning electronic microscopical study and histological evaluation were carried out at various time of survival from 2 hours to 180 days. The scanning microscopy has evidenced the surface changes: early platelets adhesion and the healing process. Histological evaluation demonstrated that the intimal proliferation was prevailing at the level of the suture line in both anastomosis, and at the opposite to the mouth of the anastomosis in the end to side one. Intimal thickness was measured on arterial section immediately distal to the suture line. In the end to end anastomosis, hyperplasia was absent on the 5th post-operative days, it reached 120 mu +/- 33 on the 40th days, and decreased to 40 mu +/- 35 on the 150th post-operative day. In the end to side anastomosis evolution was the same: 0 mu on the 5th, 106 mu +/- 49 on the 40th day and 53 mu +/- 45 on the 150th post-operative day. In conclusion, this experimental study gives some support to the fact that the type of anastomosis, per se, end to side or end to end does not influence the development of intimal hyperplasia.


[Lumbar intervertebral disk herniation in adolescents].
The authors present 28 patients aged 15-19 years selected from 1600 cases treated surgically for intervertebral disc prolapse. In the light of these cases and a survey of the pertinent literature the authors consider that disc prolapse is not always a consequence of injury. Certain differences of the clinical picture could be observed in younger patients.


Pre-treatment radiographic features predict root resorption of treated impacted maxillary central incisors.
To determine independent predictors of root resorption for surgical-orthodontic treatment of impacted maxillary central incisors. The Department of Dentistry at Show Chwan Hospital, Changhua, Taiwan. Eighty patients with unilateral osseous-impacted maxillary central incisors receiving a surgical-orthodontic treatment. This is a retrospective observational study. Root resorption and its predictors were abstracted from patients' charts, pre-treatment cephalometric radiographs, and post-treatment periapical radiographs. Predictors included demographics, treatment duration, crown angle, crown height, crown depth, and root dilacerations. The patients' mean age was 9.2 ± 2.3 years (6.4-20.6 years), and 60% were females. Impacted maxillary central incisors had greater root resorption than naturally erupted contralateral incisors (Δ = -2.8 mm, p < 0.001). Independent predictors of root resorption for impacted maxillary central incisors were shown by linear regression analysis to be crown height (β = -0.2, p < 0.01), crown depth (β = -0.3, p = 0.001), treatment duration (β = 0.2, p < 0.01), and root dilacerations (β = 3.1, p = 0.001). Impacted maxillary central incisors had greater root resorption during surgical-orthodontic treatment than their naturally erupted contralateral incisors. Predictors of a greater root resorption were highly and deeply impacted incisors, longer treatment, and root dilacerations. These predictors may help to inform patient and family counseling before treatment.


[New antibiotics to deal with antibiotic resistance].
NEW ANTIBIOTICS TO DEAL WITH ANTIBIOTIC RESISTANCE. The current increase in antibiotic resistance exposes to the risk of therapeutic impasse. To deal with this public health problem, developing new antibiotics that are effective (directly or in combination with older drugs) against these multi-resistant bacteria seems important. Over the last 10 years, new drugs (beta-lactams, beta-lactamase inhibitors, cyclin and carbapenems) have been developed against Gram-negative bacteria. A new oxazolidinone, two glycopeptides and a quinolone have been developed against Gram-positive bacteria. Their use must absolutely be controlled to avoid resistance mechanisms emergence.


High resolution computed tomography and magnetic resonance imaging in the pre-operative assessment of cochlear implant patients.
Optimal imaging protocols for cochlear implantation have yet to be determined. Pre-operative computed tomography (CT) and magnetic resonance image (MRI) scans are used to assess cochlear anatomy and patency, to delineate surgical access, and to aid in choice of side for implantation. However, opinion still differs as to which modality provides more information in pre-operative assessment, or if, indeed, a combination of the two is superior. The first 88 patients on the Irish National Cochlear Implant Programme (NCIP) were retrospectively studied to determine the accuracy of pre-operative CT and MRI in predicting abnormalities at the time of surgery. Correlation with surgical findings was determined in three separate groups of patients (those who had CT only, those who had MRI only, and those who had both CT and MRI performed). Of the 24 patients that had both CT and MRI performed, both modalities had a 79 per cent correlation with surgical findings. CT and MRI reports concurred in 75 per cent of cases. Specificity and negative predictive value were high (86 per cent and 90 per cent, respectively). CT alone (47 cases) correlated with surgery in 39 cases (83 per cent); MRI alone (17 cases) correlated in 15 cases (88 per cent). The findings of this study suggest that CT and MRI are effective at predicting normal inner ear anatomy, and thus at predicting the patient and the cochlea most suitable for implantation. Both modalities are useful in determining the side of implantation, thus avoiding potential surgical difficulties in cases of unilateral abnormalities. There was no significant difference between the ability of MRI and CT to detect abnormalities at the time of surgery. In this series the combination of CT and MRI has not been shown to be superior to either modality used alone, although anecdotal evidence to the contrary was noted.


Description of a new and two known species of Cephaloboides Rahm, 1928 (Nematoda: Rhabditidae) from India, with discussion on the taxonomy of the genus.
A new species of Rhabditidae, collected from manure, is described and illustrated. Cephaloboides anisospiculus sp. n., an amphimictic species with a 1:1 sex ratio, is characterized by a small to medium-sized body (female: L = 0.5-0.7 mm, a = 13.6-20.0, b = 2.7-3.6, c = 15.4-22.7, c' = 1.0-1.8, V = 51.2-60.9), finely striated, punctated cuticle; slightly raised labial papillae; stoma with slightly anisomorphic metastegostom; presence of epiptygma; eggs measuring 37-42 x 20-24 µm; slightly protruded vulval lips with cuticular flaps; rectum 16-19 µm long; males with small, stout, slightly arcuate spicules with hood-like capitula and genital papillae in 1/2/(1+3)+2+P configuration; bursa leptoderan, greatly reduced and not enveloping the caudal spike. C. curvicaudatus (Schneider, 1866) Zullini, 1982 is also redescribed, with an emended diagnosis. The present population of C. curvicaudatus shows a few minor differences viz., relatively smaller 'b' value, presence of elongate capitula of spicules and strong copulatory muscle bands. Another species, C. parapapillosus (Schuurmans Stekhoven, 1951) comb. n. has been reinstated.


The insulin-like growth factor system in hematopoietic cells.
The insulin-like growth factor (IGF) system regulates proliferation and differentiation of hematopoietic cells. IGFs exert their effects through specific receptors on growing and differentiating blood cells as they emerge from their small pool of ancestral stem cells. The IGF system is complex as both stimulating and inhibiting effects occur by interaction of IGFs and IGF-binding proteins (IGFBPs). IGFs stimulate erythrocytes and lymphocytes but also promote leukemic hematopoietic cell proliferation. IGF-I appears to be correlated with hemoglobin levels in anemia and could also be of benefit for patients with bone marrow aplasia after transplantation. Hypersensitivity to IGF-I has been implicated as an underlying cause of polycythemia vera. Loss of imprinting of IGF-II is found in acute myeloid leukemia and myelodysplastic syndrome. Apoptosis of hematopoietic cells is significantly reduced by IGF-I involving an intriguing signal transduction pathway. IGFs could therefore, although not classical hematopoietic growth factors, be of benefit for patients with diverse hematopoietic disorders.


Temperature dependence of the violation of Purcell's theorem experienced by a folding molecular motor.
We investigate the violation of Purcell's scallop theorem experienced by a mono-molecular motor, successively folding and unfolding inside a soft matter environment due to an external stimulus. We find a breakdown of the Purcell theorem due to fluctuations, that permits the molecular motor's efficient motion. The diffusion of the motor, its efficiency and its elementary displacement strongly depend on the characteristic time of the folding, but only slightly on the temperature. The increase of the motor's efficiency when the folding characteristic time τ decreases agrees with the fluctuation theorem expectation as the entropy generated inside the medium increases. The constant efficiency with respect to temperature is more difficult to understand as it suggests a generated entropy independent of temperature. In contrast with these results, the diffusion of the medium induced by the motor's folding strongly depends on the temperature, but doesn't depend on the characteristic time of the folding. That result suggests that the medium's diffusion is not due to the motor's displacement. We find that cooperative motions known as dynamic heterogeneity depend significantly on both temperature and folding time, leading in some conditions to a decoupling between dynamic heterogeneity and the medium's diffusion. Eventually, we find that the cooperative motions induced by the folding are larger when the motor cannot move.


Hospital Outcomes in Patients Hospitalized for COVID-19 Pneumonia: The Effect of SARS-CoV-2 Vaccination and Vitamin D Status.
SARS-CoV-2 vaccination promises to improve outcomes for patients with COVID-19 pneumonia (most notably those with advanced age and at high risk for severe disease). Here, we examine serum 25-Hydroxyvitamin D (25(OH)D) status and outcomes in both old (>70 years) and young vaccinated (n = 80) and unvaccinated (n = 91) subjects, who were hospitalized due to COVID-19 pneumonia in a single center (Connolly Hospital Dublin). Outcomes included ICU admission and mortality. Serum 25(OH)D levels were categorized as D30 (<30 nmol/L), D40 (30-49.99 nmol/L) and D50 (≥50 nmol/L). In multivariate analyses, D30 was independently associated with ICU admission (OR: 6.87 (95% CI: 1.13-41.85) (p = 0.036)) and mortality (OR: 24.81 (95% CI: 1.57-392.1) (p = 0.023)) in unvaccinated patients, even after adjustment for major confounders including age, sex, obesity and pre-existing diabetes mellitus. While mortality was consistently higher in all categories of patients over 70 years of age, the highest observed mortality rate of 50%, seen in patients over 70 years with a low vitamin D state (D30), appeared to be almost completely corrected by either vaccination, or having a higher vitamin D state, i.e., mortality was 14% for vaccinated patients over 70 years with D30 and 16% for unvaccinated patients over 70 years with a 25(OH)D level greater than 30 nmol/L. We observe that high mortality from COVID-19 pneumonia occurs in older patients, especially those who are unvaccinated or have a low vitamin D state. Recent vaccination or having a high vitamin D status are both associated with reduced mortality, although these effects do not fully mitigate the mortality risk associated with advanced age.


Microorganisms Associated With Osteomyelitis of the Foot and Ankle.
Osteomyelitis of the foot and ankle is a challenge to treat and creates a significant demand on both the patient and the healthcare system. The purposes of this study were to determine the microorganisms associated with foot and ankle osteomyelitis, to evaluate the change in methicillin-resistant Staphylococcus aureus (MRSA) between 2005 and 2010, and to determine the relationship between these infecting organisms and patient comorbidities. The medical records for 302 patients diagnosed with osteomyelitis of the foot and ankle, 151 in 2005 and 151 in 2010, were randomly selected and evaluated. The authors reviewed the demographics, comorbidities, microorganism(s) confirmed with bone biopsy and culture, location, and use of antibiotics before bone biopsy. Gram-positive bacteria were the most prevalent, composing 81.9% of the isolates in 2005 and 59.6% in 2010. Methicillin-sensitive Staphylococcus aureus was the most common in both cohorts. Conversely, the incidence of MRSA statistically decreased from 28.3% to 10.6% from 2005 to 2010 (p < .0001). Gram-negative bacteria were found in 39.5% of the 2005 isolates and 31.8% of those from 2010. Pseudomonas sp. was the most common gram-negative bacteria. Patients with peripheral vascular disease had a significantly higher incidence of gram-negative bacteria (odds ratio 2.1, 95% confidence interval, 1.3 to 3.6, p = .003). The results of this study reveal that MSSA was the most common bacteria, incidence of MRSA decreased between the 2005 to 2010, and patients with peripheral vascular disease have a significantly higher incidence of gram-negative bacteria.


Stimulation-associated redistribution of H+-K+-ATPase activity in isolated gastric glands.
The objective of this work is to establish a procedure to study the stimulation-dependent membrane redistribution and properties of H+-K+-ATPase in an in vitro model system, rabbit isolated gastric glands. Stimulated (10(-4) M histamine plus 10(-5) M forskolin) and resting (10(-4) M metiamide) glands were homogenized and fractionated into PO (40 g, 5 min), P1 (400 g, 10 min), P2 (14,500 g, 10 min), P3 (48,200 g, 90 min), and supernatant, S3. Significant changes occurred in the distribution of our marker for H+-K+-ATPase (K+-p-nitrophenyl phosphatase) activity: a reduction in activity of P3 and a compensatory increment in P1. P3 showed valinomycin (Val)-dependent vesicular H+ uptake, while H+ uptake in P1 was Val independent. Direct measurements of ATPase revealed that H+-K+-ATPase activity of P3 was Val dependent and decreased by stimulation; H+-K+-ATPase activity of P1 was Val independent and increased by stimulation. Further density gradient purification of P1 showed that membranes lighter than 17% Ficoll contained higher specific H+-K+-ATPase activity, and the observed increase in H+-K+-ATPase associated with stimulation was more pronounced. Also, the lighter fractions from stimulated P1 had much latent H+-K+-ATPase activity that was unmasked by n-octylglucoside. The properties of membrane fractions from isolated glands were consistent with results obtained in vivo: high H+-K+-ATPase activity of P3 from resting glands corresponds to cytoplasmic tubulovesicles lacking KCl transport pathways; high activity of P1 from stimulated glands corresponds to apical plasma membrane vesicles containing KCl transport in addition to the H+-K+-ATPase, and full competency for the generation of HCl.


How child protective services investigators decide to substantiate mothers for failure-to-protect in sexual abuse cases.
The purpose of this study was to determine how Child Protective Services (CPS) investigators decide to substantiate mothers for failure-to-protect from sexual abuse. A case-comparison study was used to compare 31 mothers who were and 62 mothers who were not substantiated for failure-to-protect by CPS. The multivariate analysis showed that mothers who did not consistently believe the sexual abuse occurred and who did not consistently act protectively were more likely to be substantiated. In addition, if they knew about the abuse from more than one source were less supportive of the children; and had a substance abuse problem, a mental health problem or were being battered, then they were more likely to be substantiated. Investigators appear to apply criteria consistently to substantiate mothers. doi:10.1300/J070v15n04_04.


A web-based educational intervention module to improve knowledge and attitudes towards thalassaemia prevention in Malaysian young adults.
Thalassaemia is a public health burden in Malaysia and its prevention faces many challenges. In this study, we aimed to assess the effectiveness of a web-based educational module in improving knowledge and attitudes about thalassaemia prevention amongst Malaysian young adults. We designed an interactive web-based educational module in the Malay language wherein videos were combined with text and pictorial visual cues. Malaysians aged 18-40 years old who underwent the module had their knowledge and attitudes assessed at baseline, post-intervention and at 6-month follow-up using a selfadministered validated questionnaire. Sixty-five participants: 47 Malays (72.3%), 15 Chinese (23.1%), three Indians (4.6%) underwent the module. Questionnaires were completed at baseline (n=65), postintervention (n=65) and at 6-month follow-up (n=60). Out of a total knowledge score of 21, significant changes were recorded across three time-points- median scores were 12 at pre-intervention, 19 at post-intervention and 16 at 6-month follow-up (p<0.001). Post-hoc testing comparing preintervention and 6-month follow-up scores showed significant retention of knowledge (p<0.001). Compared to baseline, attitudes at 6-month follow-up showed an increased acceptance for "marriage avoidance between carriers" (pre-intervention 20%, 6-month follow-up 48.3%, p<0.001) and "prenatal diagnosis" (pre-intervention 73.8%, 6-month follow-up 86.2%, p=0.008). Acceptance for selective termination however, remained low without significant change (pre-intervention 6.2%, 6-month follow-up 16.7%, p=0.109). A web-based educational module appears effective in improving knowledge and attitudes towards thalassaemia prevention and its incorporation in thalassaemia prevention programs is potentially useful in Malaysia and countries with a high internet penetration rate.


The performance of Pipelle endometrial sampling in a dedicated postmenopausal bleeding clinic.
Endometrial sampling using the Pipelle device is widely used in the UK especially in the investigation of postmenopausal bleeding. This study was aimed at evaluating the clinical benefit and diagnostic accuracy of the procedure in the setting of a dedicated one-stop clinic for women with postmenopausal bleeding. The study also examined the factors that would affect the adequacy of endometrial samples in terms of their suitability for histopathalogical examination. Data from 97 consecutive patients attending the clinic were collected and analysed. All the patients had a transvaginal ultrasound scan and an endometrial Pipelle sample was attempted unless refused by the patient. The analysis revealed that the procedure avoided the need for hysteroscopy in 61.5% of cases with an endometrial thickness of > 4mm. No cases of endometrial cancer were missed after successful Pipelle sampling. The ability to obtain an adequate endometrial sample was primarily affected by the endometrial thickness. There is only a 27% probability of getting an adequate endometrial sample in the group of women with an endometrial thickness of < 5 mm. The study recommends this procedure for the group of women with an endometrial thickness of > 4 mm. However, when the endometrial thickness is < or = 4 mm, little can be gained from endometrial sampling as malignancy is rare and the chance of getting an adequate sample is small.


Lid-wiper epitheliopathy in contact lens users and patients with dry eye.
To evaluate lid-wiper epitheliopathy (LWE) in contact lens users and in patients with symptoms characteristic of dry eye but with normal dry-eye tests and to compare the results with those of controls. One hundred fifty-five patients were enrolled in the study and were divided into three groups. The first group included 69 contact lens users, the second group included 46 patients with dry eye, and the third group included 40 controls. The contact lens users were also divided as symptomatic and asymptomatic according to the Standard Patient Evaluation of Eye Dryness questionnaire and Ocular Surface Disease Index. The patients were examined for LWE with three different dyes (fluorescein, rose bengal, and lissamine green). The results were compared using chi-square and T tests. More LWEs were detected in the contact lens and dry-eye groups compared with controls. In the contact lens group, 67% of the symptomatic patients and 32% of the asymptomatic patients showed LWE. The difference was statistically significant (P = 0.001). No significant correlation was found between LWE and the dry-eye tests (fluorescein breakup time and Schirmer test). LWE should be investigated in symptomatic contact lens users and in patients with symptoms characteristic of dry eye but with normal dry-eye tests. Lid wiper may traumatize the corneal epithelium and increase the sensitivity of the cornea. This could be the main cause of the symptoms in patients without any significant dry-eye test findings.


Is endovascular repair of ruptured abdominal aortic aneurysms associated with improved in-hospital mortality compared with surgical repair?
A best evidence topic in vascular surgery was constructed according to a structured protocol. The question addressed was whether patients with ruptured abdominal aortic aneurysm (AAA) treated with endovascular aneurysm repair (EVAR) have improved in-hospital outcomes compared with conventional surgical repair. The reported search retrieved 1398 reports, of which 6 papers were thought to represent the best available evidence to answer the study question. Three randomized trials were identified. The first was a pilot trial conducted in a single centre in the UK, which recruited 32 patients and found similar 30-day mortality in the patient groups. The second trial, conducted in Netherlands, recruited 116 patients anatomically suitable for EVAR. This trial found no significant difference in the composite of death and severe complications within 30 days of intervention between patients subjected to EVAR and those undergoing open repair (42 vs 47%; absolute risk reduction 5.4%, 95% confidence interval: -13% to +23%). The IMPROVE trial, based on a pragmatic design, demonstrated similar 30-day mortality in the 613 patients randomized to endovascular strategy or open repair (35.4 vs 37.4%, P = 0.62). The average hospital costs within the first 30 days of randomization were similar between the randomized groups, with an incremental cost-saving for the endovascular strategy vs open repair of £1186. Meta-analysis of all three randomized trials in a Cochrane review found no difference in 30-day or in-hospital mortality between EVAR and open repair (odds ratio: 0.91, 95% confidence interval: 0.67-1.22; P = 0.52). In contrast, a systematic review and meta-analysis, mainly of observational, cohort studies, and another large, nationwide study demonstrated EVAR to be associated with improved in-hospital results compared with open repair, as expressed by mortality, severe complications, length of hospital stay and proportion of patients discharged home. Even though randomized trials demonstrate equivalent in-hospital mortality with EVAR and open repair, large-scale, nationwide, observational studies and meta-analyses have shown EVAR to confer improved in-hospital mortality and morbidity in patients with favourable aneurysm morphology stable enough to undergo imaging. Reconfiguration of acute aortic services and establishment of standardized institutional protocols might be advisable for improvements in the management of ruptured AAA.


Assessing the Novel Myval Balloon-Expandable Valve with the Evolut Valve: A Propensity-Matched Study.
The Myval balloon-expandable (BE) valve has shown encouraging early clinical data in terms of safety and efficacy. Comparative data with other well-established contemporary valves are nonetheless still scarce. This study aims to compare the performance of the Myval BE valve with the Evolut self-expanding (SE) valve. In this retrospective single-center study, 223 patients with symptomatic severe aortic stenosis (AS) were included and treated with the Myval BE valve (n = 120) or with the Evolut SE valve (n = 103). Then, 91 pairs were compared after matching. Clinical outcomes were evaluated at 30 days and 1 year. Echocardiographic follow-up was performed at 30 days. Procedural complications were rare in both groups. At the 30-day follow-up, no significant difference in cardiac death (Myval: 1% vs. Evolut: 2%, p = 0.56), stroke (2% vs. 4%, p = 0.41) and myocardial infarction (1% vs. 3%, p = 0.31) was observed. A permanent pacemaker implantation (PPI) was significantly less needed in the Myval group (4% vs. 15%, p = 0.01). At 1 year, cardiac death (2% vs. 4%, p = 0.41) and the stroke rate (7% vs. 5%, p = 0.76) were similar. Moderate-severe paravalvular leakage (PVL) was also comparable in both groups (1% vs. 4%, p = 0.17). Safety and efficacy outcomes were comparable between the two valves, except for a higher PPI rate for the Evolut SE valve. Up to 1-year follow-up, clinical outcomes showed acceptable rates of stroke and cardiac death with both valves. Valve hemodynamics were excellent with a low rate of moderate-severe PVL in both groups.


[Monitoring clinical stages of testicular tumors using markers].
The authors evaluate a group of patients with a germinal testicular tumour treated at the urological clinic in Hradec Králové in 1975-1987. The group of 212 patients comprised 60 with seminomas, 152 with non-seminomas. Of these 152 138 men were examined for HCG and 84 for AFP. According to different diagnoses and the clinical stage the authors analyze in detail the assessed values of HCG and AFP. Both markers were on average elevated by 30 to 40%, only in patients with teratocarcinoma stage B 3 AFP is elevated in 100% of the men. The findings are consistent with data in the literature.


Congestive heart failure: experimental model.
Surgically induced, combined volume and pressure overload has been used in rabbits to create a simplified and reproducible model of acute left ventricular (LV) failure. New Zealand white male rabbits (n = 24, mean weight 3.1 ± 0.2 kg) were randomly assigned to either the Control group (n = 10) or to the Heart Failure group (HF, n = 14). Animals in the Control group underwent "sham" procedures. Animals in the HF group underwent procedures to induce LV volume overload by inducing severe aortic valve regurgitation with aortic cusp disruption and pressure overload using an occlusive silver clip positioned around the pre-renal abdominal aorta. Following Procedure-1 (volume overload) echocardiography confirmed severe aortic regurgitation in all animals in the HF group, with increased mean pulse pressure difference from 18 ± 3 to 38 ± 3 mmHg (P < 0.0001). After Procedure-2 (pressure overload) all animals in the HF group showed clinical and echocardiographic signs of constriction of the abdominal aorta and echocardiography confirmed progressively declining LV function. At the end of the protocol there was a significant increase of the heart/body weight ratio in the HF group vs. Control group (4.6 ± 0.2 vs. 2.9 ± 0.1 g/kg, P < 0.05), and echocardiography showed in HF group significant increase of the LV end-diastolic diameter (2.15 ± 0.09 vs. 1.49 ± 0.03 cm, P < 0.001) and reduction of the LV shortening fraction (26.3 ± 3.8 vs. 41.3 ± 1.6%, P < 0.001). This experimental model: (a) consistently produces LV hypertrophy/dilatation and subsequent congestive heart failure, (b) provides new data on the time course of LV dilatation, hypertrophy and failure, (c) allows study of the progress and evolution of LV systolic and diastolic dysfunction in the presence of induced LV failure, (d) is suitable to study intervention or pharmacological administration to reduce the negative effects of acute LV failure.


Early rise in serum concentration of transferrin receptor induced by recombinant human erythropoietin in very-low-birth-weight infants.
The serum transferrin receptor (TfR) level reflects iron status and the rate of erythropoiesis. This study was undertaken to assess the role of serum TfR in the iron status and erythropoiesis in very-low-birth-weight infants under conditions in which erythropoiesis is stimulated by large doses of recombinant human erythropoietin (rHuEPO) and oral iron. The first 34 infants were followed from the 3rd to 11th wk of life or until discharged. They received iron at a rate of 3 mg/kg/d. The subsequent 21 infants were given rHuEPO (300 U/kg three times a week s.c.) and iron at a rate of 6 mg/kg/d from the 3rd or 4th wk of life for a mean of 3.4 wk. With this treatment, the need for transfusion was reduced from 1.4 +/- 0.4 to 0.1 +/- 0.1 transfusions per infant (p = 0.02). The serum TfR concentrations in the rHuEPO-treated infants increased gradually to values several-fold higher than those in the untreated infants. This increase was not related to intrauterine or postnatal growth, protein intake, or serum albumin concentration. Neither was an association observed between Hb and TfR concentration. In the treated infants, the serum ferritin concentration was lower at the 4th, 5th, and 7th wk of life than in the untreated infants. The very-low-birth-weight infants who were given large doses of rHuEPO and iron had a marked rise in serum TfR concentration and a small decline in serum ferritin concentration. These events have been related to iron deficiency.


Derivative chromosome 9 deletions in chronic myeloid leukemia: poor prognosis is not associated with loss of ABL-BCR expression, elevated BCR-ABL levels, or karyotypic instability.
Deletions of the derivative chromosome 9 have recently been reported in chronic myeloid leukemia. These deletions are large, occur at the time of the Philadelphia (Ph) translocation, span the translocation breakpoint, and represent a powerful prognostic indicator. However, the molecular mechanisms responsible for the poor prognosis associated with deletions are obscure, and several possible models are investigated here. First, we demonstrate that all derivative chromosome 9 deletions detected by fluorescence in situ hybridization were associated with an absence of ABL-BCR expression. However, loss of ABL-BCR expression also occurred without an overt deletion, suggesting the existence of other mechanisms by which ABL-BCR transcription can be abolished. Furthermore, analysis of survival in 160 patients demonstrated that loss of ABL-BCR expression, in contrast to deletion status, was not an indicator of poor prognosis. Second, we addressed the possibility that concomitant small deletions of the Ph chromosome modulate BCR-ABL transcription. Real-time reverse-transcription polymerase chain reaction was used to demonstrate that derivative chromosome 9 deletions were not accompanied by altered levels of BCR-ABL transcripts. Third, deletions may represent a consequence of genetic instability within the target cell at the time of the Ph translocation, with the poor prognosis reflecting a predisposition to subsequent additional genetic alterations. However, patients with deletions do not exhibit an increased frequency of secondary cytogenetic changes following disease progression. Taken together, these data support a model in which deletions of the derivative chromosome 9 result in rapid disease progression as a result of the loss of one or more genes within the deleted region.


Successful publication by medical students in New Zealand: the role of clinical versus academic supervisors.
Relatively little is known about factors that influence successful research publication by medical students. We aimed to examine the impact of having a clinical supervisor (compared with full-time academic supervisors) on publication rates of Bachelor of Medical Sciences (BMedSc(Hons)) theses at the University of Otago Medical School. A secondary analysis of an existing dataset was conducted. Publications from undergraduate medical theses were previously identified using standardised criteria. Degree grade was obtained using a publicly available local search database. Over a 10-year period (2002-2011), 36 (40.4%) out of 89 accepted theses resulted in 55 publications in peer-reviewed journals. There was a total of 137 supervisors (median 1 supervisor per student, range 1-3), 32.1% of whom were clinical supervisors (n=44). There were no statistically significant differences in the number of publications (P=0.10) or degree grades (P=0.49) between students who were supervised by clinical supervisors and those who were not. Clinical supervisors appear just as effective as full-time researchers in supervising medical students undertaking an intercalated degree in terms of degree grade and research output. Future research should focus on examining the association between clinical supervisors and publication rates from other curricular and extra-curricular research projects, and focus on reasons behind our observed association.


Differential sensitivity to adversity by income: Evidence from a study of Bereavement.
Adverse life events are often understood as having negative consequences for mental health via objective hardships, which are worse for persons with less income. But adversity can also affect mental health via more subjective mechanisms, and here, it is possible that persons with higher income will exhibit greater psychological sensitivity to negative events, for various reasons. Drawing on multiple sociological literatures, this article theorizes potential mechanisms of increasing sensitivity with income. The proposition of differential sensitivity is tested using the strategic case of spousal and parental bereavement among older US adults. The analyses find consistent evidence of increasing sensitivity of depressive symptoms with income. A series of robustness checks indicate that findings are not due to endogenous or antecedent selection. Further, exploratory analyses of mechanisms suggest that higher sensitivity among the affluent was driven by greater expectations and better relationship quality with the deceased. These findings problematize the conceptualization and assessment of human suffering in economically stratified societies.


[Blood coagulation shifts in patients with myocardial infarction treated with streptokinase].
Variation in major coagulation parameters was assessed in 87 patients with acute myocardial infarction, treated with streptokinase and/or heparin under angiographic control. Streptokinase treatment was associated with a drop in plasma fibrinogen, plasminogen and alpha 2-antiplasmin, and an increase in serum fibrin/fibrinogen degradation products. The magnitude of coagulation shifts was greater in case of intravenous streptokinase infusion (1,000,000 units over 60 min), as compared to intracoronary streptokinase administration in lower doses (120,000-180,000 units over 60-90 min). In all patients with regained coronary flow, fibrinogen, plasminogen and alpha 2-antiplasmin levels began to decline significantly earlier and/or became normal significantly later, as compared to patients with persisting coronary occlusion. The rates and severity of hemorrhagic complications were basically similar in intravenous and intracoronary routes of administration, in spite of different doses and magnitude of coagulation shifts.


Mitochondrial scenario: roles of mitochondrial dynamics in acute myocardial ischemia/reperfusion injury.
The main therapeutic strategy currently used for acute myocardial infarction (AMI) is to open occluded coronary arteries, a process defined as blood reperfusion. However, blood reperfusion will increase cardiac mortality, tissue damage and cardiac dysfunction in patients with AMI, which is mechanically defined as "ischemia/reperfusion (I/R) injury". It is currently believed that mitochondrial dynamics plays a key role in myocardial I/R, especially excessive mitochondrial fission, which is the main cause of cardiac dysfunction. Therefore, in the process of I/R injury, effective drug intervention and correct treatment strategies can be used to regulate mitochondrial dynamic balance to combat ischemia-reperfusion injury, which can play a huge role in improving the prognosis of patients. This review summarized the effects of mitochondrial fission and mitochondrial fusion balance on myocardial and mitochondrial functional changes during myocardial I/R injury. Finally, combined with the previous injury mechanisms, this review also briefly described some drug intervention that may be beneficial to clinical practice to improve the postoperative quality of life of patients with AMI.


Clinical effects of red-bellied black snake (Pseudechis porphyriacus) envenoming and correlation with venom concentrations: Australian Snakebite Project (ASP-11).
To describe the clinical features and laboratory findings in patients with definite red-bellied black snake (RBBS; Pseudechis porphyriacus) bites, including correlation with results of venom assays. Prospective cohort study of patients with definite RBBS bites, recruited to the Australian Snakebite Project from January 2002 to June 2010. Clinical and laboratory features of envenoming; peak venom concentrations and antivenom treatment. There were 81 definite RBBS bites; systemic envenoming occurred in 57 patients (70%) and local envenoming alone occurred in one patient. Systemic envenoming was characterised by local envenoming in 55 patients (96%), systemic symptoms in 54 patients (95%), anticoagulant coagulopathy with a raised activated partial thromboplastin time (aPTT) in 35 patients (61%) and myotoxicity in seven patients (12%). One patient required non-invasive ventilation for severe myotoxicity that resulted in muscle weakness. Three patients developed local ulceration. There were no deaths. Twenty-two envenomed patients (39%) received tiger snake or black snake antivenom, and administration within 6 hours of the bite was associated with normalisation of the aPTT. Eight patients (36%) had immediate hypersensitivity reactions to antivenom, including one case of anaphylaxis. The median peak venom concentration in 37 systemically envenomed patients with serum available was 19 ng/mL (interquartile range, 12-50 ng/mL; range, 3-360 ng/mL), which did not correlate with clinical severity. In 17 patients who received antivenom and had venom concentration measured, no venom was detected in serum after the first antivenom dose, including nine who were given one vial of tiger snake antivenom. RBBS envenoming caused local effects, systemic symptoms, anticoagulant coagulopathy and, uncommonly, myotoxicity. One vial of tiger snake or black snake antivenom appears to be sufficient to remove venom and neutralise reversible effects, but hypersensitivity reactions occurred in over a third of patients.


First report of Neophysopella vitis causing leaf rust on Parthenocissus semicordata in Guangdong Province, China.
In April 2022, leaf rust disease of Parthenocissus semicordata was discovered in the urban greenbelt in Guangzhou city, China (23.06°N, 113.16°E). The disease incidence was 70% and disease severity was 75%. Chlorotic spots and red-brown necrotic flecks were present on the upper surface of infected leaves, and orange uredinia were distributed on the lower surface (Fig. 1 a-c). Two representative disease plants were collected as voucher specimens and dried, then deposited in Mycological Herbarium of the Zhongkai University of Agriculture and Engineering (MHZU GR0413, MHZU GR0414). Microscopic examination of the pustules of the samples revealed the presence of uredial paraphyses and urediniospores (Fig.1 d-f). Uredial paraphyses were hyaline, incurved, length 20-25 μm and dorsal wall 4.5-8.5 μm thick. Urediniospores were subglobose to ovoid, 16-24.5 × 10.5-17 μm. The wall of the urediniospore was hyaline or pale yellow, echinulate, and 1.0-2.0 μm thick. Telial structures were not observed. The morphological characteristics of uredial paraphyses and urediniospores were consistent with Yoshitaka's description of Neophysopella vitis (Yoshitaka 2000). Ten uredinia were picked using a sterile tweezer and the FlaPure Plant DNA Extraction Kit (Genesand Biotech Co., Ltd) was used to extract genomic DNA. Primers ITS4-rust (5'-CAGATTACAAATTTGGGCT-3') /ITS 5u (5'-CAAGGTTTCTGTAGGTG-3') were used to amplify internal transcribed spacer (ITS) and Rust2inv (5'-GATGAAGAACACAGTGAAA-3') /LR6 (5'-CGCCAGTTCTGCTTACC-3') to amplify large subunit (LSU) rDNA regions (Zhao et al. 2021). The sequences were submitted to NCBI (ITS: OQ991182 OQ991183, LSU: OQ979612 OQ979613), and blastn analyses of ITS and LSU showed 99.81% and 99.84% identity with the sequences from N. vitis (ITS: OQ304336, LSU: OM420266), respectively, found in GenBank. ITS combined with LSU sequences from the current study and reference sequences from Zhao et al. (2021) were used to construct Maximum likelihood (ML) and Bayesian inference (BI) phylogenetic trees using CIPRES website. ML and BI phylogenetic trees showed that the sequences from the current study grouped with N. vitis, with bootstrap support and posterior probability of 98% and 1.0, respectively (Fig. 2). Morphological and molecular analyses confirmed that the rust fungus was N. vitis. In the pathogenicity test, urediniospores were picked from fresh diseased leaves with sterile tweezers, prepared into spore suspensions (1.0 × 106 urediniospores/ml), and sprayed on a one-week-old leaf from three healthy of potted plants of P. semicordata, while three other healthy leaves were sprayed with sterile water as control. Each treated leaf was wrapped in a plastic bag and incubated in the dark at 25℃ for 48 h after which plastic bags were removed and the plant were moved to a greenhouse at 25℃. At 15 days after inoculation, symptoms and the morphology of urediniospores were confirmed to be the same as those observed in the field collection and no symptoms or uredinia were observed in the control group (Fig.1 g, h). Yoshitaka first discovered leaf rust on P. semicordata caused by N. vitis in Nepal(Yoshitaka 2000). To our knowledge, this is the first report of N. vitis causing leaf rust on P. semicordata in China. P. semicordata is often used as an ornamental plant for exterior wall decoration in urban landscaping and court. The occurrence of this disease can lead to the decline of the P. semicordata leaves and the impairment of the plants aesthetically.


Advanced glycation end-product (AGE) induces apoptosis in human retinal ARPE-19 cells via promoting mitochondrial dysfunction and activating the Fas-FasL signaling.
Advanced glycation end-products (AGEs) are extremely accumulated in the retinal vascular and epithelial cells of diabetes mellitus (DM) patients, particularly with diabetic retinopathy (DR). To elucidate the pathogenesis of the AGE-induced toxicity to retinal epithelial cells, we investigated the role of Fas-Fas ligand (FasL) signaling and mitochondrial dysfunction in the AGE-induced apoptosis. Results demonstrated that the AGE-BSA- induced apoptosis of retinal ARPE-19 cells. And the AGE-BSA treatment caused mitochondrial dysfunction, via deregulating the B-cell lymphoma 2 (Bcl-2) signaling. Moreover, the Fas/FasL and its downstreamer Caspase 8 were promoted by the AGE-BSA treatment, and the exogenous α-Fas exacerbated the activation of Caspase 3/8. On the other side, the siRNA-mediated knockdown of Fas/FasL inhibited the AGE-BSA-induced apoptosis. Taken together, we confirmed the activation of Fas-FasL signaling and of mitochondrial dysfunction in the AGE-BSA-promoted apoptosis in retinal ARPE-19 cells, implying the important role of Fas-FasL signaling in the DR in DM.


Cation interdiffusion in squid giant axons.
Radiotracer techniques were used to study the influxes and effluxes of various univalent cations in internally perfused squid giant axons. Membrane currents and conductances were determined by the voltage-clamp technique under analogous internal and external conditions. Both sodium-containing and sodium-free internal and external media were studied. Membrane impedance was measured with an ac impedance bridge to determine the general magnitude and time course of the impedance loss which accompanied the excitation process in both varieties of external media. Maximum transmembrane currents were found to be of comparable magnitude to the charge transfer associated with the peak interdiffusion flux measured under the same conditions. The product of the membrane resistance and the interdiffusion flux remained constant over a wide range of resistance and flux values, both at rest and during activity, both in sodium-containing and sodium-free media. The implications of these findings for excitation theory are discussed.


Nature of Hard Tissues in Oral Pathological Lesions -Using Modified Gallego's Stain.
Histological stains are dyes that bind to various tissues. Special stains form an integral part of routine histopathology as an adjunct to Haematoxylin and Eosin (H&E), and give meaningful diagnostic information of the tissues available. By using routine histological procedure like H&E alone, it is difficult to differentiate the various hard tissues present in the oral pathological lesions. Modified Gallego's stain can be used as one of the differential stain for these hard tissues. To differentiate various hard tissues of teeth and to identify the presence of hard tissue components in different oral pathological lesions using Modified Gallego's stain under light microscope. A total sample of 20 cases, amongst which 10 were human extracted teeth and 10 oral pathological lesions were included. From 10 human extracted teeth, five ground sections and five decalcified sections were prepared. From pathological lesions, two slides of each lesion were prepared. All the sections were stained with Modified Gallego's stain and viewed under light microscopy. In properly stained slides, cementum stained red, dentin and bone stained green and enamel stained pink in colour. Modified Gallego's stain can be used as a differential stain for various hard tissues in oral pathological lesions and also for ground sections for which histochemical stains are very rare.


Enhancing human learning via spaced repetition optimization.
Spaced repetition is a technique for efficient memorization which uses repeated review of content following a schedule determined by a spaced repetition algorithm to improve long-term retention. However, current spaced repetition algorithms are simple rule-based heuristics with a few hard-coded parameters. Here, we introduce a flexible representation of spaced repetition using the framework of marked temporal point processes and then address the design of spaced repetition algorithms with provable guarantees as an optimal control problem for stochastic differential equations with jumps. For two well-known human memory models, we show that, if the learner aims to maximize recall probability of the content to be learned subject to a cost on the reviewing frequency, the optimal reviewing schedule is given by the recall probability itself. As a result, we can then develop a simple, scalable online spaced repetition algorithm, MEMORIZE, to determine the optimal reviewing times. We perform a large-scale natural experiment using data from Duolingo, a popular language-learning online platform, and show that learners who follow a reviewing schedule determined by our algorithm memorize more effectively than learners who follow alternative schedules determined by several heuristics.


Adenocarcinoma of the thymus, enteric type: report of 2 cases, and proposal for a novel subtype of thymic carcinoma.
We report 2 cases of primary thymic adenocarcinoma with enteric differentiation. One carcinoma occurred in a 41-year-old man as a 7-cm-diameter cystic tumor and the other one in a 39-year-old woman as a 6-cm-diameter solid mass. Both tumors were located in the anterior mediastinum. Clinical staging did not reveal any extrathymic tumor. Histologically, the tumors were classified as adenocarcinoma, not otherwise specified, and a mucinous (colloid) carcinoma, respectively. Immunohistochemically, both tumors were positive for cytokeratin 20 (CK20), CDX2, and carcinoembryonic antigen, reflecting enteric differentiation. A review of the literature on 43 other cases of primary thymic adenocarcinomas suggested 11 further cases with enteric differentiation, as assessed by CK20 and/or CDX2 expression. We propose that thymic adenocarcinoma with enteric differentiation represents a novel subtype of thymic carcinoma. It is mostly of mucinous morphology and frequently associated with thymic cysts. The clinical outcome is variable. Recognition of primary thymic adenocarcinoma with enteric differentiation is helpful for the differentiation from metastatic disease, mainly from the gastrointestinal tract.


Effect of thrombin, the thrombin receptor activation peptide, and other mitogens on vascular smooth muscle cell urokinase receptor mRNA levels.
Bovine vascular smooth muscle cells (SMC) express the urokinase-type plasminogen activator receptor (u-PAR) claimed to be important in cell invasion. Receptor numbers and affinity are regulated by thrombin and several other mitogens involved in SMC proliferation. We investigated the effects of these mitogens on u-PAR mRNA levels. On continuous thrombin stimulation the u-PAR message in SMC was 10 +/- 2.3-fold elevated reaching a maximum between 6 and 9 hours and declining to control values within 48 hours. Thrombin present for 30 minutes on the cell surface produced similar effects. Stimulation with the thrombin receptor activation peptide S-F-L-L-R-N representing the NH2-terminus of the tethered ligand also increased u-PAR mRNA levels with an identical time course. D-Phe-Pro-Arg-chloromethyl ketone (PPACK) active site blocked thrombin and the catalytically inactive thrombin mutant S205A did not affect u-PAR mRNA levels. Thrombin stimulation also resulted in a 2 +/- 0.2-fold transient increase in thrombin receptor mRNA preceding the rise in u-PAR message. Transforming growth factor beta 1 (TGF beta 1) and platelet-derived growth factor (PDGF) showed similar time courses for the elevation of u-PAR mRNA levels with a maximal 5.5 +/- 0.9 and 12 +/- 2.5-fold increase, respectively. Basic fibroblast growth factor (bFGF) and phorbol myristate acetate (PMA) showed a more prolonged effect increasing u-PAR mRNA levels 8 +/- 2.0-fold and 12.3 +/- 2.5-fold, respectively, within 6 hours but remaining 5 to 10-fold elevated at 48 hours. In order to decide if the u-PAR mRNA increase was due to message stabilization or a consequence of transcriptional activation we used the RNA polymerase II inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB) during the stimulation experiments. u-PAR mRNA levels on TGF beta 1 stimulation of SMC decayed after the addition of DRB indicating that enhancement of transcriptional activity was involved in the induction. In contrast, the time course of u-PAR mRNA elevation on thrombin, bFGF, and PMA stimulation was not significantly altered in the presence of DRB suggesting that in these latter cases u-PAR mRNA message accumulation was at least in part due to mRNA stabilization. Increased transcriptional activity, mRNA stabilization and expression of u-PAR protein on the SMC surface in response to growth factors may facilitate enhanced cell surface protease activity, cell migration, and development of atheromatous lesions.


New moment equations for chromatography using various stationary phases of different structural characteristics.
New moment equations were systematically developed for chromatography using various types of separation media having different structural characteristics, i.e., shape (spherical particle, cylindrical fiber, flat plate) and porous structure (full-porous, partially porous (pellicular), nonporous). First, a set of basic equations of the general rate model of chromatography representing the mass balance and the mass-transfer kinetics were analytically solved in the Laplace domain. Then, the moment equations in the real-time domain of the first absolute moment and the second central moment were derived from the analytical solution in the Laplace domain. The new moment equations were used for predicting the chromatographic behaviors of benzene in the hypothetical RPLC systems using the full-porous, partially porous (pellicular), and nonporous spherical particles as packing materials. The influence of the difference in their structure on the total performance of the three types of spherical particles as the separation media for the fast HPLC with a high efficiency was quantitatively evaluated from the viewpoints of the column efficiency, column back pressure, and sample retention strength. The framework of the new moment equations can provide not only the qualitative but also the quantitative information about the intrinsic characteristics of the chromatographic behaviors of various separation media having the different shapes and structures. This study is devoted to demonstrating the important advantage of the moment analysis strategy over the conventional plate theory and rate models of chromatography.


Increased resistance of hygroscopic condenser humidifiers when using a closed circuit suction system.
To examine a hygroscopic condenser after clinical use and to describe the interaction of a hygroscopic condenser and a closed circuit suction system used simultaneously. Prospective evaluation of hygroscopic condensers used clinically, and laboratory investigation of a hygroscopic condenser used with a closed circuit suction system. Tertiary referral centers. The hygroscopic condenser used during mechanical ventilation was removed and peak inflation pressure was measured by delivering a standard tidal volume and inspiratory flow across the isolated hygroscopic condenser while recording the peak inflation pressure. In the laboratory, four 10-mL aliquots of saline were instilled via closed circuit suction system into a test lung with fresh hygroscopic condensers (n = 15) inline. At baseline and after each instillation, the hygroscopic condenser was weighed and the peak inflation pressure was measured while in five condensers, peak expiratory flow rate was also measured. In these five devices, hygroscopic condenser resistance was measured with 100 L/min of constant gas flow while measuring the pressure drop across the hygroscopic condenser. In 11 hygroscopic condensers used for 27.5 +/- 11.9 hrs with no closed circuit suction system, the peak inflation pressure was 3.74 +/- 0.58 cm H2O. In the laboratory, instillation of saline via closed circuit suction system was associated with an increase in hygroscopic condenser weight. Peak inflation pressure increased in a quadratic fashion with the increase in hygroscopic condenser weight, while peak expiratory flow rate decreased in a linear fashion. After four saline instillations, hygroscopic condenser resistance increased from 5.66 +/- 0.31 to 13.9 +/- 2.42 cm H2O/L/sec. Clinical use of a hygroscopic condenser alone is not associated with a significant increase in peak inflation pressure. We caution the use of a hygroscopic condenser and a closed circuit suction system simultaneously, as an increase in hygroscopic condenser resistance may develop and may be poorly tolerated in patients with marginal ventilatory reserve.


Induction and inhibition of amphibian (Rana pipiens) oocyte maturation by protease inhibitor (TPCK).
We report for the first time that oocyte nuclear and cytoplasmic maturation are triggered in vitro in non-hormone-treated amphibian (Rana pipiens) ovarian follicles following transient exposure to synthetic chymotrypsin inhibitor N alpha-tosyl-L-phenylalanine-chloromethyl ketone (TPCK). The mechanism of action of TPCK in regulating oocyte maturation was investigated and compared to that induced by progesterone or pituitary hormone. Follicular oocytes failed to mature following continuous exposure to the same doses of TPCK in the presence or absence of progesterone. Continuous treatment of follicles with lower levels of TPCK occasionally induced GVBD in the absence of progesterone and augmented maturational effects of low levels of progesterone. TPCK induced maturation of intrafollicular oocytes without stimulating progesterone production and also induced maturation of naked oocytes. Stimulation of follicular progesterone synthesis following gonadotropin stimulation or addition of pregnenolone was inhibited by TPCK, indicating that TPCK affects metabolic processes in both the somatic and germinal components of the ovarian follicle. Oocyte maturation induced by either TPCK or progesterone was inhibited by cycloheximide, calcium-deficient medium, and forskolin. Results suggest that TPCK induces oocyte maturation independent of steroidogenesis via mechanisms similar to those triggered by progesterone involving protein synthesis, formation of cytoplasmic maturation-promoting factor (MPF), and changes in cAMP levels. Our data indicate that a chymotrypsin-like protease plays a role(s) in regulating the oocyte meiotic maturation process.


Radiolucent hair accessories causing depressed skull fracture following blunt cranial trauma.
Pediatric neurosurgeons frequently care for children with traumatic scalp and skull injury. Foreign objects are often observed on imaging and may influence the clinician's decision-making process. The authors report on 2 cases of poorly visualized hair beads that had become embedded into the skull during blunt trauma. In both cases, skull radiography and CT scanning demonstrated depressed, comminuted fractures with poorly demonstrated spherical radiolucencies in the overlying scalp. The nature of these objects was initially unclear, and they could have represented air that entered the scalp during trauma. In one case, scalp inspection demonstrated no evidence of the bead. In the other case, a second bead was observed at the site of scalp laceration. In both cases, the beads were surgically removed, the fractures were elevated, and the patients recovered uneventfully. Radiolucent fashion accessories, such as hair beads, may be difficult to appreciate on clinical examination and may masquerade as clinically insignificant air following cranial trauma. If they are not removed, these foreign bodies may pose the risk of an infection. Pediatric neurosurgeons should consider hair accessories in the differential diagnosis of foreign bodies that may produce skull fracture following blunt trauma.


Chlamydia pneumoniae inclusion membrane protein Cpn0585 interacts with multiple Rab GTPases.
Chlamydiae are intracellular bacteria that develop within a membrane-bound vacuole called an inclusion. To ensure that the inclusion is a safe niche for chlamydial replication, chlamydiae exploit a number of host cell processes, including membrane-trafficking pathways. Recently, several Rab GTPases were found to associate with the inclusions of various chlamydial species. Here we report that Cpn0585, a Chlamydia pneumoniae inclusion membrane protein (Inc), interacts with multiple Rab GTPases. The results from yeast two-hybrid experiments revealed that an amino-terminally truncated form of Cpn0585 (Cpn0585(102-651)) interacts with Rab1, Rab10, and Rab11 but not with Rab4 or Rab6. Cpn0585-Rab GTPase interactions are direct and GTP dependent as shown in glutathione S-transferase pull-down assays using native and recombinant Cpn0585. In C. pneumoniae-infected HEp-2 cells transfected with enhanced green fluorescent protein (EGFP)-tagged Rab GTPases, the colocalization with Cpn0585 at the inclusion membrane was partial for EGFP-Rab1 and EGFP-Rab10, but extensive for wild-type EGFP-Rab11A and the constitutively active GTPase-deficient EGFP-Rab11AQ70L. Moreover, Cpn0585 colocalized with EGFP-Rab11AQ70L as early as 2 h postinfection. Upon delivery into live C. pneumoniae-infected cells, Cpn0585(628-651)-specific antibodies bound to the inclusion membrane, demonstrating that the Rab GTPase-interacting domain of Cpn0585 faces the host cell cytosol. Finally, ectopic expression of Cpn0585(102-651) partially inhibited the development of C. pneumoniae inclusions in EGFP. but not in EGFP-Rab11AQ70L-expressing HEp-2 cells. Collectively, these data suggest that Cpn0585 is involved in the recruitment of Rab GTPases to the inclusion membrane and that interfering with this function may adversely impact the fitness of the C. pneumoniae inclusion for chlamydial replication.


Telephone psychotherapy in multiple sclerosis: A systematic review and meta-analysis.
The objective of the study was to review the evidence for the effectiveness of telephone psychotherapy on psychological outcomes in people with multiple sclerosis (MS). We conducted a systematic search of EMBASE, PsycINFO, PsycARTICLES, MEDLINE, CINAHL, Web of Science, and hand-searched relevant journals to identify randomized controlled trials (RCTs) that evaluated the effectiveness of telephone psychotherapy on psychological outcomes in people with MS (last search completed on October 1, 2015). The methodological quality of each included trial was assessed, based on a standardized list of methodological criteria. Where available, data were extracted and combined in a meta-analysis to compute effect size estimates. Eleven RCTs and 1,104 participants were identified. The meta-analysis found a moderate effect of the intervention on depression (SMD 0.47 [95% confidence interval 0.21-0.73]). The meta-analysis also found small to moderate short-term effects of the intervention on fatigue, quality of life, MS symptoms, physical activity, and medication adherence, compared with controls and other interventions. RCT designs were heterogeneous. All studies had at least 1 high or unclear risk of bias. Telephone psychotherapy provides small and moderate benefits in depression, fatigue, quality of life, MS symptoms, physical activity, and medication adherence in the short term. Few gains were sustained in the long term. Studies of better quality are needed. (PsycINFO Database Record


[Application of random amplification polymorphic DNA in the genotyping of Neisseria gonorrhoeae].
To set up random amplified polymorphic DNAs (RAPD) method in genotyping Neisseria gonorrhoeae on DNA level, and to explore its use to trace the source of infection. Four different pretreatments were used to extract the Neisseria gonorrhoeae genomic DNA with its advantages and disadvantages compared. Arbitrary sequence was then used to amplify the genomic DNA of Neisseria gonorrhoeae and RAPD fingerprint maps was applied to distinct the Neisseria gonorrhoeae strains. Finally, RAPD fingerprint of Neisseria gonorrhoeae strain between patient and his/her sexual partner was compared. Cetyltrimethylammonium bromide method was classical in extracting genomic DNA, and could get integrated genomic DNA and good fingerprint maps, since main segments were common to all the Neisseria gonorrhoeae but some were different among strains so that the fingerprint of different Neisseria gonorrhoeae were distinctive. However, fingerprint maps of Neisseria gonorrhoeae collected from sex partners were quite similar. Based on genomic levels, effective fingerprint maps could be identified and to classify the Neisseria gonorrhoeae into different genotypes. RAPD fingerprint maps could be used to trace the source of infection.


Treatment of obesity in adults. Council on Scientific Affairs.
Concern with weight control should begin sufficiently early in life to reduce the risk of developing obesity. The complex etiology of obesity is, in part, responsible for the difficulty physicians encounter in treating this condition. Prevention is the "treatment" of choice. Early identification of individuals genetically at risk can be helpful in targeting those most likely to gain excess weight. Numerous dietary regimens have been devised in an attempt to achieve progressive weight loss in obese individuals. Since the ultimate goal of a weight-reduction program is to lose weight and maintain the loss, a nutritionally balanced, low-energy diet that is applicable to the patient's life-style is most appropriate. Increasing energy expenditure through physical activity, in addition to decreasing energy intake, generally improves results in the management of obesity. Major changes in eating and exercise behaviors are necessary to ensure long-term weight control. Diet, exercise, and behavior modification are interdependent and mutually supportive. A comprehensive weight-reduction program that incorporates all three components is more likely to lead to long-term weight control.


The Influence of Oxytocin and Prolactin During a First Episode of Psychosis: The Implication of Sex Differences, Clinical Features, and Cognitive Performance.
Approximately 3% of the population suffers a first episode of psychosis (FEP), and a high percentage of these patients subsequently relapse. Because the clinical course following a FEP is hard to predict, it is of interest to identify cognitive and biological markers that will help improve the diagnosis, treatment, and outcome of such events and to define new therapeutic targets. Here we analyzed the plasma oxytocin and prolactin levels during an FEP, assessing their correlation with clinical and cognitive features. The oxytocin and prolactin in plasma was measured in 120 FEP patients and 106 healthy controls, all of whom were subjected to a clinical and neuropsychological assessment. Most patients were under antipsychotics. Statistical analyses aimed to identify factors associated with the FEP and to search for associations between the variables. This study is preliminary and exploratory because the P-values were not corrected for multiple comparisons. FEP patients had less oxytocin, more prolactin, and a poor premorbid IQ, and they performed worse in sustained attention. Male patients with higher prolactin levels experienced more severe psychotic symptoms and required higher doses of antipsychotics. Low oxytocin was associated with poor sustained attention in women, whereas low oxytocin and high prolactin in men correlated with better performance in sustained attention. Low oxytocin, high prolactin, and poor premorbid IQ and sustained attention are factors associated with an FEP, representing potential therapeutic targets in these patients. These biological factors and cognitive domains might play an important role during a FEP, which could help us to develop new strategies that improve the outcomes of this disorder and that should perhaps be gender specific.


Onset of audiogenic seizures in rodents after intake of near-toxic doses of rubidium chloride.
Rats and mice that were not genetically or otherwise predisposed toward audiogenic seizures were rendered susceptible to auditory stimuli by chronic treatment with large doses of rubidium chloride (RbCl). Animals given drinking water, 0.03 N with respect to RbCl, for four weeks responded with convulsive seizures when exposed to signals of 2 to 22 kHz and 74 dbA. The rate of development of audiosusceptibility was dose-related. Less rubidium was needed if the diet was deficient in potassium. No differences were found between tissue rubidium in treated rats which became audiosensitive and their counterparts which remained resistant to auditory stimuli.


Development of a high-sensitivity and short-duration fluorescence in situ hybridization method for viral mRNA detection in HEK 293T cells.
Coronavirus disease 2019 (COVID-19) is an extremely contagious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early disease recognition of COVID-19 is crucial not only for prompt diagnosis and treatment of the patients, but also for effective public health surveillance and response. The reverse transcription-polymerase chain reaction (RT-PCR) is the most common method for the detection of SARS-CoV-2 viral mRNA and is regarded as the gold standard test for COVID-19. However, this test and those for antibodies (IgM and IgG) and antigens have certain limitations (e.g., by yielding false-negative and false-positive results). We have developed an RNA fluorescence in situ hybridization (FISH) method for high-sensitivity detection of SARS-CoV-2 mRNAs in HEK 293T cell cultures as a model. After transfection of HEK 293T cells with plasmids, Spike (S)/envelope (E) proteins and their mRNAs were clearly detected inside the cells. In addition, hybridization time could be reduced to 2 hours for faster detection when probe concentration was increased. Our approach might thus significantly improve the sensitivity and specificity of SARS-CoV-2 detection and be widely applied for the high-sensitivity single-molecular detection of other RNA viruses (e.g., Middle East respiratory syndrome coronavirus (MERS-CoV), Hepatitis A virus, all influenza viruses, and human immunodeficiency virus (HIV)) in various types of samples including tissue, body fluid, blood, and water. RNA FISH can also be utilized for the detection of DNA viruses (e.g., Monkeypox virus, human papillomavirus (HPV), and cytomegalovirus (CMV)) by detection of their mRNAs inside cells or body fluid.


Outcomes of transjugular intrahepatic portosystemic shunt creation for flow-enabled dissolution of spleno-mesenterico-portal venous thrombosis.
To evaluate the outcomes of transjugular intrahepatic portosystemic shunt (TIPS) for flow-enabled clearance of portal (PVT), splenic (SVT) and/or superior mesenteric (MVT) vein thrombosis. In this single-center study, 12 patients underwent TIPS using Viatorr covered stent-grafts (W.L. Gore & Associates, Flagstaff, AZ, USA) from 2008-2014 for PVT as a primary (n=8) or secondary (n=4) indication. TIPS were not accompanied by pharmacomechanical clot disruption; rather, shunts served to increase portal blood flow to allow flow-mediated physiologic clot dissolution. Pre- and post-TIPS cross-sectional imaging were used to assess clot location, size, and clearance, defined by resolution (vessel patency with no clot), reduction (decrease in clot size), stability (no change in clot size), or extension (increase in clot size). The cohort included 5 men and 7 women (median age 63 years, range 45-73 years, median MELD score 15) with 30 non-occlusive and asymptomatic thrombi spanning main or intrahepatic PVT (n=15/30, 50%), SVT (n=6/30, 20%), and MVT (n=9/30, 30%). TIPS were generally created with 10mm covered stent-grafts; mean final portosystemic pressure gradient was 8mmHg. At mean 190 days post-TIPS, 58% (n=7/12) had clot resolution, 33% (n=4/12) had clot reduction, and 8% (n=1/12) had stable clot; there were no cases of clot extension. Resolution rate was 67% for PVT (10/15), SVT (4/6), and MVT (6/9). Two of 12 (17%) patients underwent successful liver transplant post-TIPS. TIPS prompts dissolution of or decrease in PVT, SVT, and MVT in cirrhotic patients. This may be a useful approach notwithstanding omission of pharmacomechanical methods.


Genetic susceptibility to cow's milk allergy in Chinese children.
Cow's milk allergy (CMA) is the most common food allergy in young children. Previous studies have reported that single-nucleotide polymorphisms (SNPs) are associated with CMA. The extent to which SNPs contribute to the occurrence of CMA is unknown. The purpose of this study was to investigate the independent relevance of genetic predisposition to CMA in Chinese children. 200 infants with CMA and 799 healthy controls aged 0-12 months were included. Five previously identified genetic variants (rs17616434, rs2069772, rs1800896, rs855791 and rs20541) were genotyped. Logistic regression was used to analyze the genetic associations or their interactions with a family history of allergy on CMA. Among the five SNPs, only IL10 rs1800896 was significantly associated with CMA (odds ratio (OR) 1.60, p=0.042). Each 1-risk allele increase in the genetic risk score (GRS) was suggestively associated with an 11% higher risk of CMA (1.11: 0.99-1.27, p=0.069) and a 45% increased risk of CMA in the GRS high-risk group compared to the GRS low-risk group (1.45: 1.02-2.06, p=0.037). Furthermore, parental allergy also increased the risk of CMA among children (1.87: 1.46-2.39, p<0.001). Importantly, parental allergy exacerbated the genetic effect on the risk of CMA. The rs1800896 variant in the IL-10 gene is associated with CMA in Chinese children. In addition, the GRS had an interaction with parental history of allergy, implying that genetic risk for CMA was exacerbated among those with parental history of allergy.


Aminofutalosine Synthase (MqnE): A New Catalytic Motif in Radical SAM Enzymology.
Aminofutalosine synthase (MqnE) is a radical SAM enzyme involved in the futalosine-dependent menaquinone biosynthetic pathway. Its ability to add the 5'-deoxyadenosyl radical to the substrate-rather than abstract a hydrogen atom-and to catalyze radical addition to a stable benzene ring gives it a unique place in the radical SAM superfamily and required the development of new strategies for trapping radical intermediates. This chapter describes the methodologies used for enzyme overexpression, purification, and in vitro reconstitution. We also describe the development of fast, radical triggered, carbon-halogen bond fragmentation reactions for the trapping of intermediates. We anticipate that these methods will be of general use in the study of other transient enzymatic radicals.


Patient-specific Finite Element Analysis of Fiber Post and Ferrule Design.
A ferrule on anterior endodontic-treated teeth has been evaluated using clinical trials, in vitro tests, and finite element analysis (FEA). The patient-specific FEA with a nonuniform ferrule and nonlinear contact biting load associated with clinical validation can be used to predict failure. A patient was selected with both maxillary central incisors with different ferrule designs who received endodontic treatment and restoration using a fiber post, composite core, and computer aided design and computer aided manufacturing lithium disilicate ceramic crowns. Strain gauges were attached to the buccal surfaces of both teeth to record ceramic strain during bite force recording for FEA validation. Cone-beam computed tomographic imaging was performed, and the Digital Imaging and Communication in Medicine files were exported to Mimics, 3-Matic (Materialise, Leuven, Belgium) and Patran (MSC Software, Santa Ana, CA) software to create a patient-specific FEA model. Bite load was applied using contact load applied by antagonist teeth (155 N). Mechanical properties were obtained from the literature. Modified von Mises equivalent stress was used for stress evaluation. Stresses on the dentin and fiber post on the left incisor, which had a nonuniform ferrule, were higher compared with the right incisor. The strain values recorded for the right central incisor (strain gauge =79.9 ± 3.8 μS and FEA = 69.5 μS) and the left central incisor (strain gauge = 83.5 ± 5.3 μS and FEA = 73.9 μS) validate the FEA analysis. FEA was validated with in vivo strain values measured at the buccal crown surfaces, supporting that the stress levels were realistic for investigation of the clinical performance of fiber posts. Maintaining a uniform ferrule was more favorable than a localized higher ferrule.


Managing Early Childhood Caries for Young Children in China.
The latest national survey found that 70% of 5-year-old children in China had dental caries. The prevalence of early childhood caries (ECC) may not only be attributed to poor oral hygiene and unhealthy diet, but also to limited access to and availability of dental care. The prevailing preventive measures adopted by industrialised countries for ECC management are neither practical nor affordable in China. Hence, an alternative approach to ECC management is necessary. Atraumatic restorative treatment (ART) has been advocated because the simple and short operative time renders ART affordable. However, the success rate of ART in restoring anterior primary teeth is unfavourable. Although there is no water fluoridation in China, topical fluorides may be used to manage ECC. Tooth brushing with fluoride toothpaste is effective for caries control, but not all toothpastes in China are fluoridated. Professionally applied fluorides such as sodium fluoride varnish can be a cost-effective treatment for managing the high prevalence of ECC in China. Silver diamine fluoride (SDF) at 38% is suggested to be effective in arresting ECC in China. It can be a simple, non-invasive and low-cost treatment. However, it stains caries black. Children and their parents must be well informed before SDF treatment.


Thermodynamic basis for the emergence of genomes during prebiotic evolution.
The RNA world hypothesis views modern organisms as descendants of RNA molecules. The earliest RNA molecules must have been random sequences, from which the first genomes that coded for polymerase ribozymes emerged. The quasispecies theory by Eigen predicts the existence of an error threshold limiting genomic stability during such transitions, but does not address the spontaneity of changes. Following a recent theoretical approach, we applied the quasispecies theory combined with kinetic/thermodynamic descriptions of RNA replication to analyze the collective behavior of RNA replicators based on known experimental kinetics data. We find that, with increasing fidelity (relative rate of base-extension for Watson-Crick versus mismatched base pairs), replications without enzymes, with ribozymes, and with protein-based polymerases are above, near, and below a critical point, respectively. The prebiotic evolution therefore must have crossed this critical region. Over large regions of the phase diagram, fitness increases with increasing fidelity, biasing random drifts in sequence space toward 'crystallization.' This region encloses the experimental nonenzymatic fidelity value, favoring evolutions toward polymerase sequences with ever higher fidelity, despite error rates above the error catastrophe threshold. Our work shows that experimentally characterized kinetics and thermodynamics of RNA replication allow us to determine the physicochemical conditions required for the spontaneous crystallization of biological information. Our findings also suggest that among many potential oligomers capable of templated replication, RNAs may have evolved to form prebiotic genomes due to the value of their nonenzymatic fidelity.