The cerebellar-hypothalamic circuits: potential pathways underlying cerebellar involvement in somatic-visceral integration.
The cerebellum has been considered only as a classical subcortical center for motor control. However, accumulating experimental and clinical evidences have revealed that the cerebellum also plays an important role in cognition, for instance, in learning and memory, as well as in emotional behavior and in nonsomatic activities, such as visceral and immunological responses. Although it is not yet clear through which pathways such cerebellar nonsomatic functions are mediated, the direct bidirectional connections between the cerebellum and the hypothalamus, a high autonomic center, have recently been demonstrated in a series of neuroanatomical investigations on a variety of mammals and indicated to be potential pathways underlying the cerebellar autonomic modulation. The direct hypothalamocerebellar projections originate from the widespread hypothalamic nuclei/areas and terminate in both the cerebellar cortex as multilayered fibers and the cerebellar nuclei. Immunohistochemistry studies have offered fairly convincing evidence that some of these projecting fibers are histaminergic. It has been suggested that through their excitatory effects on cerebellar cortical and nuclear cells mediated by metabotropic histamine H(2) and/or H(1) receptors, the hypothalamocerebellar histaminergic fibers participate in cerebellar modulation of somatic motor as well as non-motor responses. On the other hand, the direct cerebellohypothalamic projections arise from all cerebellar nuclei (fastigial, anterior and posterior interpositus, and dentate nuclei) and reach almost all hypothalamic nuclei/areas. Neurophysiological and neuroimaging studies have demonstrated that these connections may be involved in feeding, cardiovascular, osmotic, respiratory, micturition, immune, emotion, and other nonsomatic regulation. These observations provide support for the hypothesis that the cerebellum is an essential modulator and coordinator for integrating motor, visceral and behavioral responses, and that such somatic-visceral integration through the cerebellar circuitry may be fulfilled by means of the cerebellar-hypothalamic circuits.


Functional status associated with postural dizziness, but not postural hypotension, in older adults: a community-based study.
Functional status, postural dizziness (PD), and postural hypotension (PH) were important issues in older adults. Only one study on the relationship for the three of them in female was without adjusting some important associated factors. This study was intended to investigate the association of PD and PH with functional status in older people of both genders. Based on a stratified randomized cluster sampling, 1361 subjects ≥ 65 years in the community were recruited from Tainan City, Taiwan, from 2000 to 2001. PH was defined as a decrease in systolic/diastolic blood pressure of ≥ 20/10 mm Hg after 1 or 2 min of standing. PD was defined by a positive response to dizziness-like symptoms after standing up from a supine position. Functional status included the activities of daily living (ADLs) and instrumental activities of daily living (IADLs). After adjusting other variables, ADL disability (OR: 1.84, 95% CI: 1.35-2.51) and IADL disability (OR: 1.62, 95% CI: 1.21-2.17) were associated with PD, but not PH. In male and female subgroups, ADL disability (male OR: 1.70, 95% CI: 1.08-2.67; female OR 1.96, 95% CI: 1.26-3.07) was associated with PD. In male, IADL disability was associated with PD (OR: 2.32, 95% CI: 1.36-3.95). Impaired functional status, shown using ADLs or IADLs, was positively associated with PD, but not PH in older adults ≥ 65 years. Clinically, it may be important to evaluate PD in older adults with ADL or IADL disability.


(2E)-1-(5-Bromo-thio-phen-2-yl)-3-(2,3,4-trimeth-oxy-phen-yl)prop-2-en-1-one.
In the title compound, C(16)H(15)BrO(4)S, the thio-phene ring is not coplanar with the benzene ring; the dihedral angle between the two planes is 11.08 (12)°. The crystal structure is characterized by C-H⋯O inter-actions. Weak intra-molecular C-H⋯O hydrogen bonds also occur.


Repurposing of Mycobacterium indicus pranii for the severe form of COVID-19 patients in India: A cohort study.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces the production of proinflammatory cytokines, which results in a cytokine storm, and immune-modulators like Mycobacterium indicus pranii (MIP) might ameliorate coronavirus disease of 2019 (COVID-19) related cytokine storm. Therefore, the present study evaluates whether MIP offers an advantage in the treatment of severe COVID-19 patients infected with SARS-CoV-2. A prospective MIP cohort study was conducted in chest disease hospitals in Srinagar, Jammu and Kashmir, India. In the present prospective, randomized clinical study, critically severe COVID-19 patients were divided into two groups, the MIP group (n = 105) and the best standard treatment (BST) group (n = 210). Procalcitonin, ferritin, high-sensitive C-reactive protein, D-dimer levels, and interleukin levels on 5th-day posttreatment were significantly reduced in the MIP group compared to the BST group. Compared to the BST group, 105 consecutive patients with severe COVID-19 in the MIP group reported early weaning off ventilation, resolution of chest architecture (computed tomography [CT] scan), a significant increase in SpO2 levels, and decreased mortality with a hazard ratio: 0.234 (95% confidence interval: 0.264-2.31) (p = 0.001). MIP restored SpO2 , immune/inflammatory response, normalized lung abnormalities (chest CT scan), and reduced mortality without any serious complications. However, there is a need for placebo-controlled double-blind and controlled clinical trials to confirm the efficacy.


Role of neonatal androgens in sexual differentiation of brain structure, scent marking, and gonadotropin secretion in gerbils.
Gerbils display a sexually dimorphic scent marking behavior that responds to testosterone (T) in adulthood and develops under the influence of testosterone perinatally. A complex of cell groups between the preoptic area and anterior hypothalamus of the gerbil brain is also sexually dimorphic and responsive to testosterone. One of these cell groups, the sexually dimorphic area pars compacta (SDApc), usually exists only in males. Even when given testosterone, adult female gerbils rarely have an SDApc. To determine if the SDApc develops under the influence of testosterone, male gerbils were castrated or given sham operations on the day they were born or 1 day later, or were not manipulated. Female gerbils were injected subcutaneously with 0, 50, or 100 micrograms testosterone propionate (TP) on the day after birth. When given ovarian transplants as adults, neonatally castrated males scent marked at low levels typical of females. Neonatally androgenized females given testosterone as adults scent marked at high levels typical of males. Neonatal castration did not affect the probability that the SDApc would develop, but neonatal androgenization did. Half the females given either dose of TP as neonates had SDApcs bilaterally. The sizes of the SDApcs present in females depended on the dose of testosterone given neonatally. The larger dose produced larger SDApcs. The 100-micrograms dose of TP also defeminized gonadotropin secretion, but the 50-micrograms dose did not. The castration of males neonatally prevented the defeminization normally caused by endogenous testosterone. Both groups of neonatally castrated males formed corpora lutea in their ovarian transplants, but control males did not.


Imaging of current density distributions with a Nb weak-link scanning nano-SQUID microscope.
Superconducting quantum interference devices (SQUIDs) are accepted as one of the highest magnetic field sensitive probes. There are increasing demands to image local magnetic fields to explore spin properties and current density distributions in a two-dimensional layer of semiconductors or superconductors. Nano-SQUIDs have recently attracting much interest for high spatial resolution measurements in nanometer-scale samples. Whereas weak-link Dayem Josephson junction nano-SQUIDs are suitable to miniaturization, hysteresis in current-voltage (I-V) characteristics that is often observed in Dayem Josephson junction is not desirable for a scanning microscope. Here we report on our development of a weak-link nano-SQUIDs scanning microscope with small hysteresis in I-V curve and on reconstructions of two-dimensional current density vector in two-dimensional electron gas from measured magnetic field.


Mobocertinib: First Approval.
Mobocertinib (EXKIVITY™) is a first-in-class EGFR tyrosine kinase inhibitor being developed for the treatment of EGFR exon 20 insertion (EGFRex20ins) -positive non-small cell lung cancer (NSCLC). Based on efficacy in patients whose disease had progressed on or after platinum-based therapy in a phase I/II trial, mobocertinib was recently granted accelerated approval in the USA in this indication. The drug is also being assessed for marketing approval in various other countries and territories including the EU and China. This article summarizes the milestones in the development of mobocertinib leading to this first approval in the USA for locally advanced or metastatic EGFRex20ins-positive NSCLC that has progressed on or after platinum-based chemotherapy.


A critical evaluation of three methods of studying cell proliferation in human cervical epithelium.
Three experiments describing applications of cell kinetic techniques to the human cervix are presented. The mitotic index is shown not to be associated with histologic differentiation, node metastasis, or survival rates in cervical squamous carcinoma, although inherent sources of inaccuracy may be a contributory factor. The second experiment, a new application of the metaphase arrest technique to cervical epithelium, allows an estimation of cell production rates in normal, dysplastic, wart-affected cervical epithelium, and in invasive carcinoma. Confidence limits are wide, rendering individual values imprecise in isolation. The third project describes a modification of in vitro labeling of cervical biopsy specimens using tritiated thymidine followed by autoradiography. Labeling indexes are produced for normal and pathological cervical epithelium. Although successful labeling was not achieved in every case, the labeling index for cervical intraepithelial neoplasia (CIN stage III) is significantly greater than for normal epithelium. The metaphase arrest technique appears to be the most applicable of the three to the study of the human cervix, yielding a useful parameter of cell proliferative activity. The labeling index gives an indication of activity that is useful for comparative studies, but that does not provide data regarding actual proliferative rates. More sophisticated experiments using radioactive materials are ethically inadmissable.


Leveraging physiological data from literature into a pharmacokinetic model to support informative clinical study design in pregnant women.
Physiological changes during pregnancy can effect pharmacokinetic (PK) parameters, which may lead to altered dose requirements. We aimed to leverage literature-based physiological changes during pregnancy into a PK model and compare its performance to a published reference model in pregnant women and to use the literature-based model to determine informative PK sampling times for a clinical study that aims to quantify the PK of enoxaparin throughout pregnancy. Changes in total body water (BW) and creatinine clearance (CRCL) during pregnancy were described using regression models. BW and CRCL were linked to a PK model of enoxaparin in non-pregnant women. Performance of the literature-based PK model was compared to a previously published empirical reference model. D-optimal sampling times were determined and evaluated for literature-based and reference models. The literature-based model adequately predicted anti-Xa plasma concentrations when compared to reference model predictions. An informative sampling design was successfully developed, with parameters expected with good precision (RSE < 36.4%). A literature-based model describing enoxaparin PK during pregnancy was developed and evaluated. The modelling framework could be used to support development of informative designs in pregnancy when prior models are unavailable.


Behavioral characterization of CD36 knockout mice with SHIRPA primary screen.
CD36 is a member of the class B scavenger receptor family of cell surface proteins, which plays a major role in fatty acid, glucose and lipid metabolism. Besides, CD36 functions as a microglial surface receptor for amyloid beta peptide. Regarding this, we suggest CD36 might also contribute to neuropsychiatric disease. The aim of this study was to achieve a behavioral phenotype of CD36 knockout (CD36(-/-)) mice. We characterized the behavior of CD36(-/-) mice and C57BL/6J mice by subjecting them to a series of tests, which include SHIRPA primary behavioral screen test, 1% sucrose preference test, elevated plus-maze test, open-field test and forced swimming test. The results showed that CD36(-/-) mice traversed more squares, emitted more defecation, exhibited higher tail elevation and had more aggressive behaviors than C57BL/6J mice. The CD36(-/-) mice spent more time and traveled longer distance in periphery zone in the open-field test. Meanwhile, the numbers that CD36(-/-) mice entered in the open arms of elevated plus-maze were reduced. These findings suggest that CD36(-/-) mice present an anxious phenotype and might be involved in neuropsychiatric disorders.


Atrial Fibrillation and Brugada Syndrome.
Since its first description in 1992, the Brugada syndrome (BrS) has attracted significant attention from the cardiology community because of its association with malignant ventricular arrhythmias and sudden cardiac death. Supraventricular tachyarrhythmias in BrS represent a unique and seemingly higher-risk clinical subgroup of patients with BrS. Atrial fibrillation represents the most common supraventricular arrhythmia in patients with BrS, with average ranges reported in the literature of 20% to 40%. This article summarizes the current literature regarding the patient with BrS with atrial fibrillation and discusses the management of these clinically challenging and potentially higher-risk individuals.


Immunohistochemical, electron microscopic, and morphometric studies of human prolactinomas after short-term bromocriptine treatment.
Two cases of human prolactinomas after short-term treatment with bromocriptine were studied by means of immunohistochemistry for prolactin, electron microscopy, and morphometry at the ultrastructural level. The results obtained showed an abundance of immunoreactive secretory granules in the tumor cells, a paucity in the electron microscopic images suggesting exocytosis of secretory granules, and no significant changes in the volume density of rough endoplasmic reticulum when compared with untreated (control) tumor cells. These findings strongly suggest that the effects of short-term bromocriptine treatment for lowering serum prolactin levels did not inhibit protein and secretory granule synthesis but rather caused a disturbance in the secretion of prolactin granules. The present morphometrical data suggest the possibility that a reduction in the number of cytoplasmic microtubules might be related to the disturbance of prolactin secretion.


Retracted: Optimization of Sustainable Land Use Management in Water Source Area Using Water Quality Dynamic Monitoring Model.
[This retracts the article DOI: 10.1155/2021/3881092.].


Bridging the gap between clinical failure and laboratory fracture strength tests using a fractographic approach.
The aim of this study was to analyze and to compare the fracture type and the stress at failure of clinically fractured zirconia-based all ceramic restorations with that of morphologically similar replicas tested in a laboratory setup. Replicas of the same shape and dimensions were made for 19 crowns and 17 fixed partial dentures, all made of veneered zirconia frameworks, which fractured during intra-oral service. The replicas were statically loaded by applying axial load in a universal testing machine. The principles of fractography were used to identify the location and the dimensions of the critical crack and to estimate the stress at failure. Failure was classified according to origin and type (P<0.05 was considered significant). Clinically fractured restorations failed due to either: delamination of the veneer ceramic (28.2+/-9MPa), defects at core veneer interface (27.7+/-6MPa), the generation of Hoop stresses (884.3+/-266MPa), radial cracking (831MPa), or fracture of the connector (971+/-343MPa). The replicas failed by mainly by cone cracking of the veneer ceramic (52.4+/-34.8MPa) or by fracture of the connector (1098.9+/-259MPa). The estimated stress at failure was significantly higher for the replicas compared to the clinically fractured restorations (F=6.8, P<0.01). Within limitations of this study, careful design of fracture strength test would lead to more clinically relevant data. The performance of zirconia veneered restorations could be further improved with careful design considerations.


Bone mineral density changes after bariatric surgery.
Although bariatric surgery is associated with multiple health benefits, decreased bone mass is a known complication of the procedure. Roux-en-Y gastric bypass (RYGB) is associated with significant bone loss and increased fracture risk. However, data on the effect of sleeve gastrectomy (SG) on bone mineral changes are sparse. The impact of vitamin D and calcium levels on bone mineral density (BMD) after SG is also unknown. A retrospective chart review was performed to include patients who underwent RYGB or SG from 2014 to 2016 at a single institution. Patients were included if bone densitometry was performed preoperatively and within 2 years postoperatively. Serum 25-hydroxy vitamin D and calcium levels were collected preoperatively and at time of bone densitometry scan. BMD and T-score changes at the femoral neck, femoral trochanter, total hip, and lumbar spine were compared between RYGB and SG patients. A total of 40 patients were included. 24 (60%) of patients underwent RYGB and 16 (40%) patients underwent SG. No statistically significant difference in baseline characteristics was noted between RYGB and SG patients. All measurements, except for serum 25-hydroxy vitamin D, were significantly decreased in RYGB patients, postoperatively. All measurements, except for BMD and T-score at the lumbar spine and serum 25-hydroxy vitamin D, were significantly decreased in SG patients, postoperatively. The extent of decrease in serum 25-hydroxyvitamin D was significantly associated with decreased BMD (p = 0.049) and T-score (p = 0.032) at the lumbar spine. The extent of decrease in serum calcium was significantly associated with decreased BMD (p = 0.046) at the femoral neck. All patients were found to have decreased BMD after RYGB and SG. Surgery type was not a significant risk factor in BMD change. Despite vitamin D and calcium supplementation in all patients, a decrease in vitamin D and calcium levels were associated with a decrease in BMD. Close follow-up and treatment of vitamin D and calcium levels are warranted in all bariatric patients.


Cancer: a challenge to clinicians and biomedical scientists.
The multidisciplinary study of cancer by clinical and scientific oncologists is discussed. This approach is proposed as the optimal method of improving our understanding of the disease. The future role of general hospitals and of University Medical Schools in creating the appropriate environment for such work is outlined.


Evaluation of Clinical Outcomes in Children with Intrahepatic Cholestasis Postpartial External Biliary Diversion: A Single-Center Experience.
Severe pruritus caused by progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (AGS) is refractory to medical treatment. Surgical interruption of the enterohepatic circulation is considered the mainstay of alleviating distressing symptoms and delaying cirrhosis. This study aims to evaluate the short-term effect of partial external biliary diversion (PEBD) on pruritus, liver disease progression, patient's growth, and quality of life. This prospective cohort study enrolled children with PFIC and AGS from July 2019 to July 2021, whose guardians consented to the PEBD procedure. A standard surgical approach was performed by a single surgeon. Outcomes were measured subjectively and objectively pre- and post-procedure using the pruritus 5-D itching score, Paediatric Quality of Life Inventory scale (PedsQL), growth parameters, bile acids level, and liver function tests. Patients' follow-up period ranged from 6 to 12 months. Seven patients had PEBD procedure; five with PFIC and two with AGS. A significant improvement was detected in the 5-D itching score (p-value < 0.001), PedsQL (p-value < 0.001), and bile acids level (p-value 0.013). The preexisting growth failure was ameliorated. The downward trend in the bilirubin level was not significant. No influential difference in the other liver function tests occurred. No intra-operative complications encountered. Only one case had a post-operative stoma prolapse which was managed surgically. PEBD procedure could be considered as an effective and safe treatment options for intractable pruritus in patients with PFIC or AGS, providing preserved synthetic liver functions.


Isolation and partial sequence of the cyanogen bromide peptides from calf thymus non-histone chromosomal protein HMG 1.
Peptides produced by cyanogen bromide cleavage of non-histone chromosomal protein HMG 1 have been isolated and characterized, and their partial sequences determined. The sequence data presented here account for over half of the sequence of the HMG 1 molecule and, together with previously published results, provide interesting information on the charge distribution within the molecule.


Concurrent allopurinol and 5-fluorouracil: 5-fluoro-2'-deoxyuridylate formation and thymidylate synthase inhibition in rat colon carcinoma and in regenerating rat liver.
The formation of FdUMP and the inhibition of TS were studied in a subcutaneously growing transplantable rat colon carcinoma and in regenerating rat liver following bolus administration of 5-FU, with or without HPP pretreatment. In tumor, peak levels of FdUMP at 30 min following bolus 5-FU, 100 mg/kg, averaged 4931 +/- 587 pmol/g. Pretreatment with HPP, 50 mg/kg, 24 h and 1 h before 5-FU, reduced the peak FdUMP level to 2085 +/- 387 pmol/g. The inhibition of TS by 5-FU treatment was greater than 95% by 30 min, and after 48 h residual enzyme inhibition averaged 40%. No effect on TS inhibition by 5-FU treatment could be observed as a result of HPP pretreatment. The levels of TStot increased linearly after 5-FU treatment and doubled within 48 h. In regenerating rat liver, neither FdUMP levels nor TS inhibition, studied at 1 h after bolus 5-FU, were affected by HPP pretreatment.


Three-dimensional quantitative T1 and T2 mapping of the carotid artery: Sequence design and in vivo feasibility.
A novel three-dimensional (3D) T1 and T2 mapping protocol for the carotid artery is presented. A 3D black-blood imaging sequence was adapted allowing carotid T1 and T2 mapping using multiple flip angles and echo time (TE) preparation times. B1 mapping was performed to correct for spatially varying deviations from the nominal flip angle. The protocol was optimized using simulations and phantom experiments. In vivo scans were performed on six healthy volunteers in two sessions, and in a patient with advanced atherosclerosis. Compensation for patient motion was achieved by 3D registration of the inter/intrasession scans. Subsequently, T1 and T2 maps were obtained by maximum likelihood estimation. Simulations and phantom experiments showed that the bias in T1 and T2 estimation was < 10% within the range of physiological values. In vivo T1 and T2 values for carotid vessel wall were 844 ± 96 and 39 ± 5 ms, with good repeatability across scans. Patient data revealed altered T1 and T2 values in regions of atherosclerotic plaque. The 3D T1 and T2 mapping of the carotid artery is feasible using variable flip angle and variable TE preparation acquisitions. We foresee application of this technique for plaque characterization and monitoring plaque progression in atherosclerotic patients.


Expression of matrix metalloproteinase-9 in histological grades of oral squamous cell carcinoma: An immunohistochemical study.
Oral squamous cell carcinoma (OSCC) is characterized by a high degree of local invasiveness and metastasis to cervical lymph nodes and distant sites. Degradation of extracellular matrix (ECM) requires the concerted action of several extracellular enzymes, the most prominent of which are matrix metalloproteinases (MMPs). Proteolytic degradation of ECM components by (MMP-9) facilitates carcinoma cell invasion, enhances angiogenesis and tumor progression. To assess and correlate the immunohistochemical expression of MMP-9 with clinicopathological parameters and histological grades of OSCC. Thirty histopathologically diagnosed cases of OSCC including 12 cases of well-differentiated squamous cell carcinoma, 12 cases of moderately differentiated squamous cell carcinoma and 6 cases of poorly differentiated squamous cell carcinoma were included in the study group. The samples were subjected to staining using monoclonal antibodies against MMP-9 and visualized using the polymer-HRP detection system. Expression of MMP-9 was assessed in tumor epithelium/parenchyma and connective tissue stroma separately, and the mean of both was considered as average MMP-9 expression. The parametric independent samples "t" test, one-way ANOVA test and Pearson's correlation test were used for the statistical analysis. Immunoexpression of MMP-9 increased with advancing stage and histological grade of OSCC with statistically significant results. MMP-9 plays an important role in invasion and metastasis and can serve as an independent prognostic marker.


Ultrasonic polar scans: numerical simulation on generally anisotropic media.
Ultrasonic polar scans are based on the recording of the reflected or transmitted amplitude of sound, impinging a fiber reinforced composite from every possible angle of incidence. The mechanical anisotropy of such materials makes the reflection coefficient direction dependent, whence an ultrasonic polar scan forms a fingerprint of the investigated material. Such scans have already proved to be very valuable in the characterization of composites. Simulations have been performed for single layered and multi-layered systems, for pulsed and harmonic waves. Fiber reinforced composites are mostly orthotropic. The current report presents simulations not only on orthotropic materials but on materials of any kind of anisotropy. These extended numerical simulations are not only valuable in the characterization of highly sophisticated composites, but may also be used to characterize thin slices of crystals and even layered crystals.


Entrapment and release kinetics of furosemide from pegylated nanocarriers.
This study was designed to test the hypothesis that furosemide (Fur) can be entrapped into surfactant free pegylated nanocarriers (NCs) for controlled drug release. To test this hypothesis, Fur-loaded NCs were prepared by emulsion solvent diffusion method. A 2(3) factorial design was used to optimize the effect of three formulation variables [amounts of Fur (X(1)), poly(lactic-co-glycolic acid) (X(2)) and poly-ε-caprolactone-polyethylene glycol (X(3))] on particle mean diameter (Y(1)), polydispersity index (PDI, Y(2)), and percent drug encapsulation efficiency (EE%, Y(3)). The NCs were characterized for morphology, thermal behavior, optical properties, crystallinity, and drug release kinetics using electron microscopy (EM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD), and high performance liquid chromatography, respectively. The optimum formula produced with 6 mg of Fur, 7 mg of PLGA, and 1mg of PCL-PEG corresponded to 183.26 nm, 0.26, and 88.29% as Y(1), Y(2) and Y(3) values, respectively. DSC thermograms, FTIR spectra and PXRD diffractograms indicated that Fur was encapsulated in its polymorphic crystalline form I within the NCs polymeric matrix. This was further confirmed by a comparative study between native Fur, Fur nanocrystal and Fur loaded NCs using scanning EM, PXRD and drug release kinetics. The release kinetics of the optimized formula fit the Higuchi model indicating that the drug was released by diffusion in 12h. These results indicate that pegylated Fur-loaded NCs could be successfully prepared with high EE% and sustained release profile intended for the inner ear drug delivery.


Opiate effects on plasma corticosteroids: relationship to dysphoria and self-administration.
Narcotic analgesics have been shown to raise plasma corticosteroids in the rat. This effect has been interpreted as a response of the rat to the dysphoric properties of the drug. This interpretation is based on the observation that drugs such as nalorphine or cyclazocine which cause dysphoria in man elevate plasma corticosteroids in the rat at relatively low doses. Drugs like morphine or pentazocine which induce little dysphoria in man elevate plasma corticosteroids in the rat only at much larger doses. The corticosteroid-elevating effect is mediated by an opiate receptor since naloxone antagonizes the effect of morphine or the analgesic. U-50,488. Those narcotic analgesics which increased corticosteroid levels at low doses were also found to be poorly self-administered by rats. In contrast, compounds like morphine, pentazocine and the analgesic. U-49,274A, which were self-administered at high rates, elevated corticosteroids only after large doses. The relationship between the dose of a drug which causes elevations in corticosteroid levels and whether or not the drug is self-administered further supports the premise that elevated corticosteroid levels induced by analgesics is due to their dysphoric properties.


QUASIMODO1 is expressed in vascular tissue of Arabidopsis thaliana inflorescence stems, and affects homogalacturonan and xylan biosynthesis.
An insertion in the promoter of the Arabidopsis thaliana QUA1 gene (qua1-1 allele) leads to a dwarf plant phenotype and a reduction in cell adhesion, particularly between epidermal cells in seedlings and young leaves. This coincides with a reduction in the level of homogalacturonan epitopes and the amount of GalA in isolated cell walls (Bouton et al., Plant Cell 14: 2577 2002). The present study was undertaken in order to investigate further the link between QUA1 and cell wall biosynthesis. We have used rapidly elongating inflorescence stems to compare cell wall biosynthesis in wild type and qua1-1 mutant tissue. Relative to the wild type, homogalacturonan alpha-1-4-D-galacturonosyltransferase activity was consistently reduced in qua1-1 stems (by about 23% in microsomal and 33% in detergent-solubilized membrane preparations). Activities of beta-1-4-D-xylan synthase, beta-1-4-D-galactan synthase and beta-glucan synthase II activities were also measured in microsomal membranes. Of these, only beta-1-4-D-xylan synthase was affected, and was reduced by about 40% in qua1-1 stems relative to wild type. The mutant phenotype was apparent in inflorescence stems, and was investigated in detail using microscopy and cell wall composition analyses. Using in situ PCR techniques, QUA1 mRNA was localized to discrete cells of the vascular tissue and subepidermal layers. In mutant stems, the organization of these tissues was disrupted and there was a modest reduction in homogalacturonan (JIM5) epitopes. This study demonstrates a specific role for QUA1 in the development of vascular tissue in rapidly elongating inflorescence stems and supports a role of QUA1 in pectin and hemicellulose cell wall synthesis through affects on alpha-1,4-D-galacturonosyltransferase and beta-1,4-D-xylan synthase activities.


Parkin represses 6-hydroxydopamine-induced apoptosis via stabilizing scaffold protein p62 in PC12 cells.
Parkin has been shown to exert protective effects against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in different models of Parkinson disease. In the present study we investigated the molecular mechanisms underlying the neuroprotective action of parkin in vitro. HEK293, HeLa and PC12 cells were transfected with parkin, parkin mutants, p62 or si-p62. Protein expression and ubiquitination were assessed using immunoblot analysis. Immunoprecipitation assay was performed to identify the interaction between parkin and scaffold protein p62. PC12 and SH-SY5Y cells were treated with 6-OHDA (200 μmol/L), and cell apoptosis was detected using PI and Hoechst staining. In HEK293 cells co-transfected with parkin and p62, parkin was co-immunoprecipitated with p62, and parkin overexpression increased p62 protein levels. In parkin-deficient HeLa cells, transfection with wild-type pakin, but not with ligase activity-deficient pakin mutants, significantly increased p62 levels, suggesting that parkin stabilized p62 through its E3 ligase activity. Transfection with parkin or p62 significantly repressed ERK1/2 phosphorylation in HeLa cells, but transfection with parkin did not repress ERK1/2 phosphorylation in p62-knockdown HeLa cells, suggesting that p62 was involved in parkin-induced inhibition on ERK1/2 phosphorylation. Overexpression of parkin or p62 significantly repressed 6-OHDA-induced ERK1/2 phosphorylation in PC12 cells, and parkin overexpression inhibited 6-OHDA-induced apoptosis in PC12 and SH-SY5Y cells. Parkin protects PC12 cells against 6-OHDA-induced apoptosis via ubiquitinating and stabilizing scaffold protein p62, and repressing ERK1/2 activation.


Immunity markers in patients with Helicobacter pylori infection: effect of eradication.
Helicobacter pylori is a microorganism able to stimulate a robust inflammatory and systemic immune response. The aim of our study was to evaluate autoimmune markers in dyspeptic patients positive for H. pylori infection compared to a control group of non-H. pylori-infected subjects. The kinetics of cryoglobulins and autoantibodies was evaluated after treatment of the infection. Dyspeptic patients with active H. pylori infection and age- and sex-matched healthy H. pylori-negative controls were studied. Markers of immunity were compared, in H. pylori-infected patients before, 6 months and 1 year after the end of therapy. Results were also compared between those with and without successful eradication therapy. Eighty-six individual were entered (43 H. pylori-infected). H. pylori-infected patients had higher levels of IgG and/or IgA and/or IgM (22/43 versus 2/43). Circulating immune complexes and cryoglobulins were detected in patients more often than controls (p < .05 for both). Autoantibodies were observed in 13 patients (30% versus 5% in controls) and antithyroid antibodies in 12 (p < .04 versus controls). Lower levels of C3 and/or C4 complement fractions were observed in infected patients with respect to controls (7/43 versus 1/43; p = .014). After 1 year of follow-up, the markers of autoimmunity dramatically improved in patients eradicated for H. pylori infection compared to those in whom therapy failed. No patient developed a clinical autoimmune disorder. Additional studies are necessary to ascertain the clinical significance of the modifications of autoimmune markers in patients with H. pylori infection.


Increased retinal toxicity of intravitreal tissue plasminogen activator in a central retinal vein occlusion model.
Intravitreal injection of tissue plasminogen activator (tPA) is used to treat several ocular conditions, although excessive doses of intravitreal tPA cause retinal toxicity. Toxicity may increase in the ischemic retina, such as in central retinal vein occlusion (CRVO), because tPA toxicity to neural tissues increases under ischemic conditions. We investigated tPA toxicity to the retina in a CRVO rat model. CRVO was induced in pigmented rats with rose Bengal-assisted laser photothrombosis. One hour after CRVO induction, 3 microl of tPA (0.075, 0.75, 3, or 7.5 microg) was injected intravitreally. Eyes that did not receive laser treatment, which served as non-CRVO controls, received tPA (0.75, 3, or 7.5 microg). The same amount of balanced salt solution (BSS) was injected as a nondrug control. Eyes were enucleated at 12 hours after injection, and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) staining was performed to evaluate retinal cell apoptosis. The number of TUNEL-positive cells increased in a dose-dependent manner in both non-CRVO and CRVO group and significantly (P = 0.002) increased when 0.75, 3, or 7.5 microg of tPA was injected into the CRVO eyes. When comparing the number of TUNEL-positive cells between the eyes with and without CRVO that received the same treatment, apoptosis significantly increased in CRVO eyes. Retinal toxicity associated with intravitreally injected tPA can increase in a dose-dependent manner and be exacerbated in CRVO eyes, suggesting that the dose of tPA should be reduced when tPA is used to treat eyes with CRVO.


Theophylline. A review of its potential steroid sparing effects in asthma.
Theophylline is generally considered to be a bronchodilatory drug. However, recent pharmacodynamic studies indicate that it has anti-inflammatory effects. It reduced eosinophil survival rates in vitro, and reduced eosinophil accumulation in bronchial tissue in patients with atopic asthma. Theophylline has also been shown to reduce T cell proliferation and accumulation. These changes were mirrored by improved pulmonary function in patients with asthma in studies that evaluated this parameter. Three randomised double-blind studies have evaluated the potential role of theophylline as an anti-inflammatory treatment in patients with asthma not controlled by low doses of inhaled corticosteroids. Patients were randomised to receive low dose theophylline (400 to 750 mg daily) plus low dose inhaled corticosteroids, or an increased dose of inhaled corticosteroids. Clinical pulmonary function improved to the same or a greater extent in patients who received low dose inhaled corticosteroids plus theophylline than in those treated with high dose inhaled corticosteroids plus placebo. Where reported, the dosages of theophylline used in these studies resulted in serum theophylline concentrations of approximately 9 to 10 mg/L. Approximate monthly costs were provided in one study: these were $60 (year and currency not specified) for theophylline plus budesonide 800 micrograms/day, compared with $100 for budesonide 1600 micrograms/day, and $155 for a regimen of budesonide 800 micrograms/day and salmeterol 100 micrograms/day. Low dose theophylline has been shown to reduce requirements for inhaled corticosteroid therapy in patients with asthma and may reduce overall treatment costs.


Amelanotic acral melanomas: clinicopathological, BRAF mutation, and KIT aberration analyses.
Amelanotic acral melanoma (AAM) is very rare and difficult to diagnose both clinically and pathologically. Complete-type AAM shows no black to brown pigmentation in the lesion, whereas incomplete-type AAM shows focal or subtle pigmentation. AAM has been the subject of few investigations. We analyzed the clinicopathological features, BRAF mutations, and KIT aberrations in 35 Korean AAM cases. We included 28 cases of complete-type and 7 cases of incomplete-type AAM. In all, 26 AAMs (45.7%) were located on the feet of patients, 21 of which (82.9%) showed ulceration. Sixteen cases developed in subungual areas. Nodular melanoma was the most common histopathological subtype (63.6%). The most frequent cell types affected were epithelioid and spindled. HMB-45 staining was strongly positive in 66.7% of AAMs; 4 (12.1%) were negative for HMB-45, and 3 of these were complete-type AAMs. Of 33 total patients, BRAF mutations were detected in 2 AAM cases, and KIT aberrations were present in 11 cases (33.3%). Four cases (12.1%), all of which were complete-type AAMs, had KIT mutations. KIT aberrations were weakly correlated with c-kit staining. Twenty patients were TNM stage I or II, and mean survival was 30.14 ± 4.54 months. The study is limited by the small number of patients. Physicians should be aware of rare and hard-to-diagnose AAMs. We expect that tyrosine kinase inhibitors would be effective for KIT-mutated patients with complete-type AAMs.


Copy number aberrations in combined hepatocellular carcinoma and cholangiocarcinoma.
Combined hepatocellular carcinoma and cholangiocarcinoma (CHC) is a rare liver cancer which shares unequivocal features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). A greater awareness of genetic relationship between HCC and CC components is limited. To help characterize this rare liver neoplasm, we described clinicopathologic features and evaluated copy number (CN) changes in this study. A total of 13 cases of CHC were collected. Four paired HCC and CC components from four cases were first subject to genome-wide analysis. Nine target genes were subsequently selected for further analysis using quantitative polymerase chain reaction. The paired HCC and CC components in each case had a concordant trend of CN gain or loss in these nine genes. However, the magnitude of concordant CN gain or loss was different. There were significant differences of CN copies between HCC and CC in each case. We demonstrate genetic divergence between HCC and CC components in CHC.


Effects of single or combination therapy of teriparatide and anti-RANKL monoclonal antibody on bone defect regeneration in mice.
The purpose of this study is to investigate the effects of a single or combination therapy of teriparatide (TPTD) and anti-RANKL Ab (anti-murine receptor activator of nuclear factor κB ligand monoclonal antibody) on the regeneration of both cancellous and cortical bone. Nine-week-old mice underwent bone defect surgery on the left femoral metaphysis (cancellous-bone healing model) and right femoral mid-diaphysis (cortical-bone healing model). After surgery, the mice were assigned to 1 of 4 groups to receive 1) saline (5 times a week; CNT group), 2) TPTD (40μg/kg 5 times a week; TPTD group), 3) anti-RANKL Ab (5mg/kg once; Ab group), or 4) a combination of TPTD and anti-RANKL Ab (COMB group). The following analyses were performed: Time-course microstructural analysis of healing in both cancellous and cortical bone in the bone defect, the volumetric bone mineral density of the tibia with micro-computed tomography, histological, histomorphometrical, and biomechanical analysis of regenerated bone. Regeneration of cancellous bone volume in the COMB group was the highest among the 4 groups, and this combined administration prompted medullary callus formation in the early phase of bone regeneration. On the other hand, regeneration of cortical bone volume in the COMB group was significantly higher than in the Ab group and was almost same as in the TPTD group. Histological analysis showed remaining woven bones, cartilage matrix, and immature lamellar bone in the COMB and Ab groups. However, biomechanical analysis showed that hardness and Young's modulus of regenerated cortical bone in the COMB group was not lower than in both the CNT and TPTD groups. Volumetric bone mineral density in the tibia was significantly increased in the COMB group compared with the other 3 groups. In the early phase of bone regeneration, the combination of TPTD and anti-RANKL Ab accelerates regeneration of cancellous bone in bone defects and increases cancellous bone mass in the tibia more effectively than either agent does individually, but these additive effects are not observed in the regeneration of cortical bone.


Predictors of generic substitution: The role of psychological, sociodemographic, and contextual factors.
Escalating pharmaceutical costs have become a global challenge for both governments and patients. Generic substitution is one way of decreasing these costs. The aim of this study was to investigate factors associated with patients' choice between generic drugs and innovator drugs. The survey was conducted in June 2013, 1000 people from across Poland were chosen as a representative population sample. The outcome (a preference for generics/a preference for innovator pharmaceuticals/no preference) was modeled by multinomial logistic regression, adjusted for several variables describing patients' sensitivity to selected generic features (price, brand, and country of origin), to third-party opinions about generics (information on generics in the mass media, opinions of health professionals (i.e. physicians, pharmacists), relatives/friends), as well as patients' personal experiences and income per household. The results supported the predictive capacity of most independent variables (except for patient sensitivity to the country of origin and to the information on generics in the mass media), denoting patients' preferences toward generic substitution. Patient sensitivity to recommendations by physicians, generic brand, and household income were the strongest predictors of the choice between generic and innovator pharmaceuticals (P < 0.001). The probability of choosing generics over innovator drugs was significantly higher among respondents with the lowest income levels, in those who were indifferent to generic brand or their physician's opinion, as well as in respondents who were sensitive to recommendations by pharmacists or attached a greater value to a past experience with generics (their own experience or that of relatives/friends). In consideration of the foregoing, awareness-raising campaigns may be recommended, supported by a variety of systemic solutions and tools to encourage generic substitution.


Causes of Failure of Canal Wall down Mastoidectomy.
To identify the causes of failure of the canal wall down mastoidectomy and evaluate the causes for discharging mastoid cavity and to address the causes of failure of previous surgery to minimize the Revision surgery. This was a prospective and retrospective observational study conducted at a tertiary care hospital from May 2019 to December 2021. Total 20 Patients (11 male & 9 female) with age group (0-60 years) who previously underwent canal wall down mastoidectomy and presented with complaints of persistent ear discharge were included. All patients underwent otoscopic, oto-endoscopic and microscopic examination. Out of 20 cases,13 cases had residual/recurrent cholesteatoma, 11 cases had narrow meatoplasty and 9 cases had high facial ridge.Other causes for failure are graft defect, incomplete removal of anterior and posterior buttress. Recurrent/residual cholesteatoma and Narrow meatoplasty are most common cause for failure of previous surgery. Persistent granulation at un-exenterated area was the most common cause for suppuration. Regular follow up and cleaning of the debris from cavity enhances the epithelialization and healing of the cavity.


Neutrophil-endothelial interactions mediate angiopoietin-2-associated pulmonary endothelial cell dysfunction in indirect acute lung injury in mice.
Unresolved inflammation in the lung is thought to elicit loss of endothelial cell (EC) barrier integrity and impaired lung function. We have shown, in a mouse model of shock/sepsis, that neutrophil interactions with resident pulmonary cells appear central to the pathogenesis of indirect acute lung injury (iALI). Normally, EC growth factors angiopoietin (Ang)-1 and Ang-2 maintain vascular homeostasis through tightly regulated interaction with the kinase receptor Tie2 expressed on ECs. Although Ang-1/Tie2 has been shown to promote vessel integrity, stimulating downstream prosurvival/antiinflammatory signaling, Ang-2, released from activated ECs, is reported to promote vessel destabilization. This mechanism of regulation, together with recent clinical findings that plasma Ang-2 levels are significantly elevated in patients who develop acute respiratory distress syndrome, has focused our investigation on the contribution of Ang-2 to the development of iALI. A murine model of hemorrhagic shock-induced priming for the development of iALI after subsequent septic challenge was used in this study. Our findings show that 1) Ang-2 is elevated in our experimental model for iALI, 2) direct EC/neutrophil interactions contribute significantly to EC Ang-2 release, and 3) suppression of Ang-2 significantly decreases inflammatory lung injury, neutrophil influx, and lung and plasma IL-6 and TNF-α. These findings support our hypothesis and suggest that Ang-2 plays a role in the loss of pulmonary EC barrier function in the development of iALI in mice resultant from the sequential insults of hemorrhagic shock and sepsis and that this is mediated by EC interaction with activated neutrophils.


Kynurenine pathway dynamics in patients with schizophrenia spectrum disorders across the disease trajectory.
The aim of this study was to evaluate how schizophrenia spectrum disorders (SSD) and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum levels of tryptophan (Trp) metabolites. A total of 112 adults (54 first-episode psychosis [FEP] patients and 58 control subjects [CSs]) participated in the study. The investigated changes in the metabolite levels appeared against a background of persistent increase in BMI and waist circumference among the patients. Regarding the kynurenine (KYN) pathway, the strongest changes were seen in AP-naïve FEP patients. Trp, KYN, kynurenic acid (KYNA), and anthranilic acid (ANT) levels were significantly reduced in blood samples from patients in the early stage of the disease. Furthermore, 3-OH-kynurenine (3-HK) and quinolinic acid (QUIN) levels were somewhat lower in these patients. Most of these changes in the KYN pathway became weaker with AP treatment. The levels of serotonin and its metabolite 5-HIAA tended to be higher at 5.1 years in patients showing the relation of elevated serotonin turnover to increased BMI and waist circumference. The similar trend was evident for the ratio between xanthurenic acid (XA) and KYNA with strong link to the elevated BMI. Altogether, the present study supports the role of Trp-metabolites in the development of obesity and metabolic syndrome in SSD patients.


Nitro and Other Electron Withdrawing Group Activated Ruthenium Catalysts for Olefin Metathesis Reactions.
Advanced applications of the Nobel Prize winning olefin metathesis reaction require user-friendly and highly universal catalysts. From many successful metathesis catalysts, which belong to the two distinct classes of Schrock and Grubbs-type catalysts, the subclass of chelating-benzylidene ruthenium complexes (so-called Hoveyda-Grubbs catalysts) additionally activated by electron-withdrawing groups (EWGs) provides a highly tunable platform. In the Review, the origin of the EWG-activation concept and selected applications of the resulting catalysts in target-oriented synthesis, medicinal chemistry, as well as in the preparation of fine-chemicals and in materials chemistry is discussed. Based on the examples, some suggestions for end-users regarding minimization of catalyst loading, selectivity control, and general optimization of the olefin metathesis reaction are provided.


Inhibition of collagen- and ADP-induced platelet aggregation by substance P in vivo: involvement of endothelium-derived relaxing factor.
We examined the effect of substance P, a potent stimulator of endothelium-derived relaxing factor (EDRF) release, on responses to collagen and adenosine 3',5'-diphosphate (ADP) in an in vivo model of platelet aggregation. Substance P inhibited platelet aggregation induced in vivo by both collagen and ADP. This anti-platelet effect was particularly pronounced against collagen-induced aggregation and was prevented by prior administration of haemoglobin (Hb), a known inhibitor of EDRF-mediated responses. Collagen-induced platelet aggregation in vitro was unaffected by a concentration of substance P equivalent to that achieved in plasma following in vivo administration. This study provides a clear demonstration of the anti-platelet activity of EDRF in vivo and an indication that its effectiveness may depend on the aggregating agent used.


Blepharitis is a chronic condition and full recovery is difficult to achieve. It requires good patient compliance and an individual treatment regime. There are many conditions which can cause blepharitis, and it is essential to find the cause to give the proper treatment. There is scarce evidence for the recommended guidelines. Blepharitis itself rarely causes vision loss, but in case of complications like keratitis it is more frequently observed. When patients do not respond to the treatment it is important to consider if it is caused by immunological diseases or carcinoma, as argued in this review.


The in-vitro effect of antineoplastic agents on proliferative activity and cytoskeletal components of plaque-derived smooth-muscle cells from human coronary arteries.
Restenosis after successful percutaneous transluminal coronary angioplasty remains the major clinical problem limiting the long-term efficacy of the treatment. Recent advances in the understanding of the biology of restenosis indicate that its cause is predominantly a multifactorial stimulation of smooth-muscle cell proliferation. The aim of this study was to investigate the in-vitro effect of antineoplastic agents on smooth-muscle cells isolated from human coronary plaque material. Atherosclerotic tissue from coronary arteries was extracted from 15 patients of both sexes by thrombendarterectomy. Cells were isolated using enzymatic disaggregation and identified to be smooth-muscle cells with fluorescent antibodies for smooth-muscle-specific alpha-actin. The antineoplastic agents cytarabine (500-0.005 micrograms/ml), doxorubicin (50-0.0005 micrograms/ml), and vincristine (10-0.0001 micrograms/ml) were added to the cultures. Six days after seeding, the cells were trypsinized and then counted. All three antineoplastic agents had a strong dose-dependent antiproliferative effect on cultured smooth-muscle cells. After the application of cytostatic agents, cells either became rounded or underwent complete lysis. Cytoskeletal elements, such as actin, microtubules, and vimentin, were largely altered. This investigation examined the potential role of antineoplastic therapy in the prevention of restenosis after coronary angioplasty. The development of new intravascular delivery systems, such as coated stents, may open the way for local antiproliferative strategies in interventional cardiology.


Expression analysis of neuroleukin, calmodulin, cortactin, and Rho7/Rnd2 in the intact and injured mouse brain.
Subtracted cDNA libraries from the mouse developing inferior colliculus were previously constructed between postnatal day (P) 6 and 10. In the P10-P6 subtracted library, neuroleukin, calmodulin I, cortactin, and Rho7 were identified. The goal of the present study was to analyze their distribution, at the mRNA and protein levels, in both the adult and the developing mouse brain. The four molecules showed a wide expression throughout the brain, with a neuronal-enriched localization in structures such as the cortex, the hippocampus, the cerebellum, and the inferior colliculus. The level of expression of their corresponding mRNAs increased during brain postnatal development. The expression of these molecules was also investigated 2 weeks after a mechanical lesion in the adult cerebral cortex. Neuroleukin and cortactin were found to be expressed by reactive astrocytes, while there were no changes in the expression of calmodulin and Rho7. The expression of neuroleukin, calmodulin, cortactin, and Rho7 is discussed in the context of their putative role in the maturation of the brain and in the axonal regeneration process.


Modeling ocean-induced rapid Earth rotation variations: an update.
We revisit the problem of modeling the ocean's contribution to rapid, non-tidal Earth rotation variations at periods of 2-120 days. Estimates of oceanic angular momentum (OAM, 2007-2011) are drawn from a suite of established circulation models and new numerical simulations, whose finest configuration is on a ∘ grid. We show that the OAM product by the Earth System Modeling Group at GeoForschungsZentrum Potsdam has spurious short period variance in its equatorial motion terms, rendering the series a poor choice for describing oceanic signals in polar motion on time scales of less than ∼ 2 weeks. Accounting for OAM in rotation budgets from other models typically reduces the variance of atmosphere-corrected geodetic excitation by ∼ 54% for deconvolved polar motion and by ∼ 60% for length-of-day. Use of OAM from the ∘ model does provide for an additional reduction in residual variance such that the combined oceanic-atmospheric effect explains as much as 84% of the polar motion excitation at periods < 120 days. Employing statistical analysis and bottom pressure changes from daily Gravity Recovery and Climate Experiment solutions, we highlight the tendency of ocean models run at a 1 ∘ grid spacing to misrepresent topographically constrained dynamics in some deep basins of the Southern Ocean, which has adverse effects on OAM estimates taken along the 90 ∘ meridian. Higher model resolution thus emerges as a sensible target for improving the oceanic component in broader efforts of Earth system modeling for geodetic purposes.


Serine-Threonine Kinase 38 regulates CDC25A stability and the DNA damage-induced G2/M checkpoint.
Cells respond to DNA damage by activating protein kinase-mediated signaling pathways that promote cell-cycle arrest, DNA repair, or apoptosis. A key regulator of cell-cycle arrest is the CDC25A (cell division cycle 25 homologue A) phosphatase. CDC25A normally plays a pivotal role in regulating the G1/S and G2/M transitions by dephosphorylating and activating cyclin/cyclin-dependent kinase (CDK) complexes; however, CDC25A is specifically degraded in response to DNA damage. Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation. Taken together, these results indicate that the STK38-mediated phosphorylation of CDC25A at Ser-76 and the subsequent degradation of CDC25A are required to promote DNA damage-induced G2/M checkpoint activation.


The inhibitory effect of metoclopramide on plasma cholinesterase activity.
The in vitro effect of metoclopramide on plasma cholinesterase (PCHE) activity was studied to investigate a mechanism for metoclopramide-induced prolongation of succinylcholine action. The mean PCHE of the control samples was 0.86 +/- 0.02 unit.ml-1. PCHE activity in the presence of metoclopramide, at concentrations of 0.05, 0.10, 0.50, 1.0, 2.5 and 5.0 micrograms.ml-1, was reduced to 0.78 +/- 0.02, 0.69 +/- 0.04, 0.50 +/- 0.03, 0.39 +/- 0.02, 0.24 +/- 0.01 and 0.15 +/- 0.01 unit.ml-1, respectively. Our data demonstrated that PCHE activity was significantly depressed by metoclopramide at all concentrations studied (p less than 0.001). Our data also show that the concentration of metoclopramide required to inhibit 50 per cent of PCHE activity (I50) was 0.8 micrograms.ml-1 (2.4 x 10(-6) M). We recommend caution when succinylcholine and or ester type local anaesthetics are administered to patients who are also receiving metoclopramide, especially in high doses.


Template activity for histones of poly(A)-minus RNA fraction from different developmental stages of Artemia salina embryos.
Template activity for histones of RNA fractions derived from Artemia salina embryos at different developmental stages were measured in a Krebs ascites cell-free system. Appreciable amounts of acid-soluble polypeptides comigrating with Hela cell histone markers on acrylamide gel electrophoresis were detected only when RNA fractions from nauplii were used. Tryptic peptide analysis by high voltage electrophoresis of the translational products had a pattern qualitatively similar to that of in vivo labeled histone markers from Hela.


Scalable production and immunogenicity of a cholera conjugate vaccine.
There is a need to develop cholera vaccines that are protective in young children under 5 years of age, which induce long-term immunity, and which can be incorporated into the Expanded Programme of Immunization (EPI) in cholera-endemic countries. The degree of protection afforded by currently available oral cholera vaccines (OCV) to young children is significantly lower than that induced by vaccination of older vaccine recipients. Immune responses that protect against cholera target the O-specific polysaccharide (OSP) of Vibrio cholerae, and young children have poor immunological responses to bacterial polysaccharides, which are T cell independent antigens. To overcome this, we have developed a cholera conjugate vaccine (CCV) containing the OSP of V. cholerae O1, the main cause of endemic and epidemic cholera. Here, we describe production of CCV through a scalable manufacturing process and preclinical evaluation of immunogenicity in the presence and absence of aluminum phosphate (alum) as an adjuvant. The vaccine displays V. cholerae O1 Inaba OSP in sun-burst display via single point attachment of core oligosaccharide to a recombinant tetanus toxoid heavy chain fragment (rTTHc). Two different pilot-scale production batches of non-GMP CCV were manufactured and characterized in terms of physico-chemical properties and immunogenicity. In preclinical testing, the vaccine induced OSP- and lipopolysaccharide (LPS)-specific IgG and IgM responses, vibriocidal responses, memory B cell responses, and protection in a V. cholerae O1 challenge model. The addition of alum to the administered vaccine increased OSP-specific immune responses. These results support evaluation of CCV in humans.


REMOVED: Association between the BDNF C270T polymorphism and negative symptoms of schizophrenia.
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The REMIT scale: A novel prediction scale for embolism in hyperacute stroke with large vessel occlusion.
Large vessel occlusion (LVO) in hyperacute ischemic stroke occurs mainly by one of two mechanisms, embolism or atherosclerosis. However, the mechanism is difficult to identify prior to treatment. We aimed to investigate the factors associated with embolic LVO in hyperacute ischemic stroke, and to develop a preoperative predictive scale for the event. This retrospective multicenter study was conducted with consecutive ischemic stroke patients with LVO who underwent thrombectomy, thrombolysis, or both. The embolic LVO was defined as an occlusion that underwent recanalization with no residual stenosis. Multivariate logistic regression analysis for embolic LVO was performed to identity the independent risk factors. With this approach, a novel prediction scale (Rating of Embolic Occlusion for Mechanical Thrombectomy [REMIT] scale) was developed. A total of 162 patients (104 men; median age 76 years; interquartile range 68-83) were included in this study. Embolic LVO was observed in 121 patients (75%). Multivariate logistic regression analysis showed that embolic LVO was independently associated with high brain natriuretic peptide (BNP), high National Institutes of Health Stroke Scale (NIHSS) on admission, and absence of non-culprit stenosis (NoCS). The REMIT scale comprises high BNP (>100 pg/dL), high NIHSS (>14) and absence of NoCS, with one point for each risk factor. The frequencies of embolic LVO for the REMIT scale scores were as follows: score 0, 25%; score 1, 60%; score 2, 87%; score 3, 97% (C-statistic 0.80, P < 0.001). The novel REMIT scale has predictive value for embolic LVO.


Intervention Adherence in REHAB-HF: Predictors and Relationship With Physical Function, Quality of Life, and Clinical Events.
Background The REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial showed that a novel, early, transitional, tailored, progressive, multidomain physical rehabilitation intervention improved physical function and quality of life in older, frail patients hospitalized for acute decompensated heart failure. This analysis examined the relationship between intervention adherence and outcomes. Methods and Results Adherence was defined as percent of sessions attended and percent of sessions attended adjusted for missed sessions for medical reasons. Baseline characteristics were examined to identify predictors of session attendance. Associations of session attendance with change in physical function (Short Physical Performance Battery [primary outcome], 6-minute walk distance, quality of life [Kansas City Cardiomyopathy Questionnaire], depression, and clinical events [landmarked postintervention]) were examined in multivariate analyses. Adherence was 67%±34%, and adherence adjusted for missed sessions for medical reasons was 78%±34%. Independent predictors of higher session attendance were the following: nonsmoking, absence of myocardial infarction history and depression, and higher baseline Short Physical Performance Battery. After adjustment for predictors, adherence was significantly associated with larger increases in Short Physical Performance Battery (parameter estimate: β=0.06[0.03-0.10], P=0.001), 6-minute walk distance (β=1.8[0.2-3.5], P=0.032), and Kansas City Cardiomyopathy Questionnaire score (β=0.62[0.26-0.98], P=0.001), and reduction in depression (β=-0.08[-0.12 to 0.04], P<0.001). Additionally, higher adherence was significantly associated with reduced 6-month all-cause rehospitalization (rate ratio: 0.97 [0.95-0.99], P=0.020), combined all-cause rehospitalization and death (0.97 [0.95-0.99], P=0.017), and all-cause rehospitalization days (0.96 [0.94-0.99], P=0.004) postintervention. Conclusions In older, frail patients with acute decompensated heart failure, higher adherence was significantly associated with improved patient-centered and clinical event outcomes. These data support the efficacy of the comprehensive adherence plan and the subsequent intervention-related benefits observed in REHAB-HF. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT02196038.


The role of graphene oxide interlayer on corrosion barrier and bioactive properties of electrophoretically deposited ZrO2-10 at. % SiO2 composite coating on 316 L stainless steel.
In order to overcome the poor adhesion of zirconia-silica coating electrophoretically deposited on 316 L stainless steel, graphene oxide (GO) was used as an interlayer. The effect of this interlayer on morphological, microstructural, corrosion performance and bioactivity behavior of ZrO2-10 at. % SiO2 coating was studied. The zirconia-silica coating with the GO interlayer revealed a higher barrier performance as a more compact and a greater adhesive layer to the substrate was created. Indeed, the GO interlayer led to an improvement in apatite formation on zirconia-silica coating surface probably due to create higher roughness. Briefly, the GO interlayer was effective on enhancement of electrochemical performance and biological property of zirconia-silica composite coating, making it a suitable candidate for biomaterials applications.


Challenges and opportunities for HIV prevention and care: insights from focus groups of HIV-infected African American men.
Given the inordinate burden of HIV illness borne by African American men, investigations of HIV prevention and care in this population are urgently needed. In this qualitative study, a sample of 20 HIV-infected African American men participated in two focus groups in which they exchanged experiences and ideas about living with HIV. They shared details about how they were personally impacted by HIV, and together they constructed a perspective on the larger societal context in which the HIV infection rate among African American men continues unabated. The men focused on growing complacency about HIV/AIDS in the United States, underfunding of supports and services, stigmas operative in African American communities, and differential care based on race, gender, and diagnosis. They saw opportunity in personal strategies that help individual men infected with HIV to take a more empowered stance to deal with the disease and improve their health but looked for changes undertaken by African Americans at the community level to make a real difference in the epidemic. Their vision included enhanced support for HIV prevention and care from influential community institutions like Black churches, more open dialogue about drugs and sexual behavior, and capacity-building for families whose members are HIV-infected or at risk for HIV.


Visualization of polyribosomes in the postsynaptic area of the squid giant synapse by electron spectroscopic imaging.
Giant axons from squids (Loligo vulgaris and Loligo pealii) were studied by conventional electron microscopy and by electron spectroscopic imaging: electrons with a characteristic energy loss due to interaction with phosphorus atoms were used to image phosphorus-rich elements such as ribosomes. Patches of granular material were seen in the proximal region of giant axons, especially in the postsynaptic area of the giant synapse, but not on the presynaptic side. They were rare or absent in the more distal part of the axon. With electron spectroscopic imaging the patches emitted strong phosphorus signals, indistinguishable from signals of ribosomes in neuronal perikarya, confirming their identification as RNA-rich elements. In the part of the axon near the perikarya in the giant fibre lobe, the patches consisted of sacs of rough endoplasmic reticulum. It is suggested that patches of rough endoplasmic reticulum are transported to the synaptic region where ribosomes detach from the cisterns and aggregate into polyribosomes.


Comparative sequence analysis of the icm/dot genes in Legionella.
The icm/dot genes in Legionella pneumophila are essential for the ability of the bacteria to survive within macrophages in lung infections such as Legionnaires' disease, or amoebae in nature. The 22 genes of the complex, thought to encode a transport apparatus for transfer of effector molecules into the host cell cytoplasm, are located in two chromosomal loci. We demonstrate that these genes are present in all the L. pneumophila strains examined herein, but display a wide range of sequence variation among the different strains, none of which are clearly associated with virulence potential. The strains fall within seven phylogenetic groups, but discrepancies among the gene trees indicate a complicated evolutionary history for the icm/dot loci, with perhaps two independent gene acquisition events and subsequent genomic rearrangements. Significant findings include a probable t-SNARE domain in IcmG that may indicate a direct role for this putative inner membrane protein in altering the host's membrane fusion machinery, a potential functional domain in the central hydrophobic portion of IcmK that may allow it to participate in forming the pore of the secretion complex, and strict conservation of the amino acid physicochemical characteristics in the IcmP region corresponding to the trbA domain that could play a role in molecular transfer.


Experiences of hospital allied health professionals in collaborative student research projects: a qualitative study.
Active engagement in research by healthcare organisations and clinicians is associated with improvements in healthcare performance. Barriers to research engagement by clinician allied health (AH) professionals include competing priorities from high clinical workloads, lack of research skills and confidence, and lack of supportive research relationships. Collaboration with universities on joint clinical research projects is well recognised as a means of building health service research capacity. Research projects undertaken by students as part of their qualifying degree represent one such opportunity. However, there are few reports evaluating these collaborations from the health service perspective. A qualitative study using semi-structured interviews and thematic analysis to explore the experiences of AH professionals in the co-supervision of students completing research placements as part of their professional degree course. Fourteen health service employees from six allied health disciplines described collaborations on research projects with 24 students from four different universities. Student placements and projects varied widely in length of placement, extent of collaboration, supervision structure and study design. Three overarching themes were identified in the AH professional co-supervision experience: 1) Professional growth; 2) Mismatch with expectations; and 3) Focus on the student. Project outcomes were categorised from the health system perspective. These were 1) Healthcare performance improvements, including local increases in staff clinical practice knowledge and wider contributions to the evidence base; 2) Research capacity gains within the health service, including research knowledge and skill development, collaborative linkages and opportunity for future research; and 3) Staff-centred outcomes including increased job satisfaction. This study demonstrates the potential for AH professional supervision of students on research placements to contribute to healthcare performance improvements and research capacity gains within health services, alongside providing personal benefits for the AH professionals involved. Early consultation with a health service-employed research specialist may support health professional and student learning, team collaboration and project coordination for these student projects.


Ultrasensitive detection of ovarian cancer marker using immunoliposomes and gold nanoelectrodes.
Mucin-16 (MUC16) is the established ovarian cancer marker used to follow the disease during or after treatment for epithelial ovarian cancer. The emerging science of cancer markers also demands for the new sensitive detection methods. In this work, we have developed an electrochemical immunosensor for antigen MUC16 using gold nanoelectrode ensemble (GNEE) and ferrocene carboxylic acid encapsulated liposomes tethered with monoclonal anti-Mucin-16 antibodies (αMUC16). GNEEs were fabricated by electroless deposition of the gold within the pores of polycarbonate track-etched membranes. Afterwards, αMUC16 were immobilized on preformed self-assembled monolayer of cysteamine on the GNEE via cross-linking with EDC-Sulfo-NHS. A sandwich immunoassay was performed on αMUC16 functionalized GNEE with MUC16 and immunoliposomes. The differential pulse voltammetry was employed to quantify the faradic redox response of ferrocene carboxylic acid released from immunoliposomes. The dose-response curve for MUC16 concentration was found between the range of 0.001-300 U mL(-1). The lowest detection limit was found to be 5×10(-4) U mL(-1) (S/N=3). We evaluated the performance of this developed immunosensor with commercial ELISA assay by comparing results obtained from spiked serum samples and real blood serum samples from volunteers.


Deep learning model with collage images for the segmentation of dedicated breast positron emission tomography images.
Dedicated breast positron emission tomography (dbPET) has high contrast and resolution optimized for detecting small breast cancers, leading to its noisy characteristics. This study evaluated the application of deep learning to the automatic segmentation of abnormal uptakes on dbPET to facilitate the assessment of lesions. To address data scarcity in model training, we used collage images composed of cropped abnormal uptakes and normal breasts for data augmentation. This retrospective study included 1598 examinations between April 2015 and August 2020. A U-Net-based model with an uptake shape classification head was trained using either the original or augmented dataset comprising collage images. The Dice score, which measures the pixel-wise agreement between a prediction and its ground truth, of the models was compared using the Wilcoxon signed-rank test. Moreover, the classification accuracies were evaluated. After applying the exclusion criteria, 662 breasts were included; among these, 217 breasts had abnormal uptakes (mean age: 58 ± 14 years). Abnormal uptakes on the cranio-caudal and mediolateral maximum intensity projection images of 217 breasts were annotated and labeled as focus, mass, or non-mass. The inclusion of collage images into the original dataset yielded a Dice score of 0.884 and classification accuracy of 91.5%. Improvement in the Dice score was observed across all subgroups, and the score of images without breast cancer improved significantly from 0.750 to 0.834 (effect size: 0.76, P = 0.02). Deep learning can be applied for the automatic segmentation of dbPET, and collage images can improve model performance.


Impact of Individual Comorbidities on Survival of Patients with Myelofibrosis.
The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.


Validation of a model of intensive training in digestive laparoscopic surgery.
Our objective was to assess a laparoscopic training model for general surgery residents. Twelve general surgery residents carried out a training program, consisting of a theoretical session (one hour) and a hands-on session on simulator (7 h) and on animal model (13 h). For the first and last repetitions of simulator tasks and the Nissen fundoplication technique, time and scores from the global rating scale objective structured assessment of technical skills (OSATS) were registered. Before and after the course, participants performed 4 tasks on the virtual reality simulator LAPMentor™: 1) hand-eye coordination, 2) hand-hand coordination, 3) transference of objects and 4) cholecystectomy task, registering time and movement metrics. Moreover, the residents completed a questionnaire related to the training components on a 5-point rating scale. The last repetition of the tasks and the Nissen fundoplication technique were performed faster and with a higher OSATS score. After the course, the participants performed all LAPMentor™ tasks faster, increasing the speed of movements in all tasks. Number of movements decreased in tasks 2, 3 and 4; as well as path length in tasks 2 and 4. Training components were positively rated by residents, being the suture task the aspect best rated (4.90 ± 0.32). This training model in digestive laparoscopic surgery has demonstrated to be valid for the improvement of basic and advanced skills of general surgery residents. Intracorporeal suturing and the animal model were the best rated training elements.


Validation of the Korean Version of the Bronchiectasis Health Questionnaire.
The Bronchiectasis Health Questionnaire (BHQ) is a simple and repeatable, self-reporting health status questionnaire for bronchiectasis. We have translated the original version of the BHQ into Korean using a standardized methodology. The purpose of this study was to assess the validity of the Korean version of the BHQ (K-BHQ) with Korean patients. Stable state patients with bronchiectasis from two academic hospitals were enrolled in this study. The validity was assessed by investigating the relationship between the K-BHQ scores and the Korean version of the Chronic Obstructive Pulmonary Disease Assessment Test (K-CAT) scores. We also investigated the relationship between the K-BHQ scores and other variables of the modified Medical Research Council's (mMRC) dyspnea scale, lung function, and exacerbations. A total of 126 patients with bronchiectasis were enrolled. The mean age was 64.3 (standard deviation [SD], 9.7). Women comprised 53.2% of the patients. The mean forced expiratory volume in one second (FEV1) was 60% of the predicted value (SD, 18.9%); the mean K-CAT score was 17.6 (SD, 9.1). The K-BHQ scores correlated strongly with the K-CAT scores (r=-0.656, p<0.001). There was significant correlation between the K-BHQ scores and the mMRC dyspnea scale (ρ=-0.409, p<0.001), FEV1 (r=0.406, p<0.001), and number of exacerbations requiring hospitalization (ρ=-0.303, p=0.001). The K-BHQ is valid for assessing the health-related quality of life or health status of Korean bronchiectasis patients.


Long-term efficacy and cost-effectiveness of polyethylene glycol 3350 plus electrolytes in chronic constipation: a retrospective study in a disabled population.
The efficacy and safety of treatments for constipation in severely intellectually disabled patients and their associated cost-effectiveness are an under-investigated area of clinical practice. Aiming to address this, the objectives of the study were to evaluate the efficacy and tolerability of polyethylene glycol 3350 plus electrolytes (Movicol; PEG+E) by comparing clinical data collected before and after its introduction to a stable population of residents of a mental health care, long-stay institution. The study also attempted an economic evaluation of the use of PEG+E in this setting. This was a retrospective study of 54/66 severely intellectually and physically disabled residents of a specialist unit at La Milétrie University Hospital, Poitiers, France, who suffered regularly from constipation. A total of 54 residents were treated with PEG+E (1-3 sachets a day) for 24 months. The number of stools, episodes of diarrhoea (defined as frequent stools, not necessarily watery), body weights and blood biochemistry were recorded. Data were compared with those recorded during the 21 months preceding the introduction of PEG+E for 16/54 residents who had been treated regularly with a range of other interventions for the relief of constipation. The monthly use and costs of laxatives, enemas and suppositories was obtained from hospital pharmacy records, and the total hospital costs before and after the introduction of PEG+E treatment was calculated. The mean (+/- standard deviation) number of stools per patient per month was significantly greater following the introduction of PEG+E (24.9 +/- 6.3) compared to before its use (12.4 +/- 3.4) (p < 0.001). The mean (+/- standard deviation) monthly number of episodes of diarrhoea per patient before and after the introduction of PEG+E was 0.1 +/- 0.1 and 6.3 +/- 2.9, respectively (p < 0.001). Treatment with PEG+E was not associated with adverse effects on body weight or blood biochemistry values. Introduction of PEG+E and its increasing use reduced the total hospital medical ward expenditure on laxatives from 3788 to 1767 Euros per month. PEG+E is effective in the clinical management of constipation in an institutional setting. Furthermore, long-term intensive therapy with PEG+E was not associated with adverse effects on body weight or blood biochemistry values. Although the time periods over which the economic data and the efficacy and safety data were collected did not directly correspond, this study indicates that use of PEG+E in the management of constipation in people with severe intellectual disability may be cost-effective, reducing hospital laxative costs.


Lactogenic hormones and extracellular matrix regulate expression of IGF-1 linked to MMTV-LTR in mammary epithelial cells.
The cell line MD-IGF-1, containing an ovine IGF-1 cDNA driven by the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) promoter, was used to study expression of IGF-1 linked to the MMTV-LTR in bovine mammary epithelial cells in response to various hormonal and substratum stimuli. Acute sensitivity of the MMTV-LTR promoter to glucocorticoids and sex steroids was ascertained by transient transfection of parental MAC-T cells with an MMTV-CAT construct. Specifically, CAT activity was induced by glucocorticoids, but not by 17 beta-estradiol or progesterone. Induction of MD-IGF-1 cells with dexamethasone (DEX) alone triggered a 29.5-fold increase in secretion of recombinant IGF-1 (348.9 vs 11.8 pg/micrograms DNA), and stimulated a 1.7-fold increase in total DNA within 72 h. Growth of MD-IGF-1 cells was enhanced by exogenous IGF-1, insulin, and TGF-alpha. In contrast, TGF-beta inhibited cell proliferation, while epidermal growth factor, estrogen, progesterone, and testosterone had no effect. Extracellular matrix from the Engelbreth-Holm-Swarm (EHS) tumor, in the presence of DEX, prolactin (PRL), and insulin stimulated a 29.4-fold increase in secretion of IGF-1 (591.9 pg/microgram DNA), compared with cells in absence of hormones (20.1 pg/micrograms DNA). EHS and DEX plus PRL triggered a 63.2-fold increase in IGF-1 secretion (689.1 pg/micrograms DNA), compared with MD-IGF-1 cells cultured on plastic (10.9 pg/micrograms DNA), in the absence of hormones. These data indicate that the MMTV-LTR is regulated by both lactogenic hormones and extracellular matrix in MD-IGF-1 cells and that the MMTV-LTR may be a useful regulatory element for targeting expression of foreign proteins in bovine mammary epithelial cells.


Chk2 is required for HSV-1 ICP0-mediated G2/M arrest and enhancement of virus growth.
ICP0 is a multi-functional herpes simplex virus type 1 (HSV-1) immediate-early (IE) gene product that contributes to efficient virus growth and reactivation from latency. Here we show that HSV-1-induced cell-cycle arrest at the G2/M border requires ICP0 and Chk2 kinase and that ICP0 expression by transfection or infection induces ATM-dependent phosphorylation of Chk2 and Cdc25C. Infection of cells with a replication-defective mutant virus deleted for all the regulatory IE genes except ICP0 (TOZ22R) induced G2/M arrest whereas a mutant virus deleted in addition for ICP0 (QOZ22R) failed to do so. Chk2-deficient cells and cells expressing a kinase-deficient Chk2 did not undergo cell-cycle arrest in response to TOZ22R infection. Chk2 deficiency diminished the growth of wild-type HSV-1, but not the growth of an ICP0-deleted recombinant virus. Together, these results are consistent with the interpretation that ICP0 activates a DNA damage response pathway to arrest cells in G2/M phase and promote virus growth.


[Study of the element secretory glands of a tubicolous polychaete (Pectinaria (= Lagis) koreni) with the help of electron microprobe and ion microanalyzer (author's transl)].
Two histophysical methods (electron microprobe and ion microanalyzer) were used on sections of Annelids in order to study the inorganic composition of cement secretory glands. Mg, Ca and P were demonstrated in large amounts in the secretions, associated with organic matter. Traces, or no, Fe, Al and Si were found. Possibilities of artifacts are discussed, and these results are compared with biochemical methods. A hypothesis is proposed in order to explain the differences observed between biochemical and present results, which suggest, for the hardening of cements a different chemical mechanism to that suggested by Vovelle in annelid Sabellaria alveolata.


Weekly time spent in the standing position is independently related to a better quality of life in postmenopausal women.
To analyze the relationship between standing, sitting and reclining behaviors and quality of life in postmenopausal women. Cross-sectional study composed of forty postmenopausal women (aged 59.58±5.32) who do not practice regular physical exercise. Body composition was measured using Dual-energy X-ray absorptiometry and quality of life by the Short Form 36 Health Survey (SF-36). Physical activity level was assessed using an accelerometer (Actigraph GTX3x) and is reported as minutes per week of moderate-to-vigorous physical activity (MVPA). Inclinometer analysis was also measured using this accelerometer model and reported as a weekly percentage of time spent standing, sitting and reclining. All analyses were performed using SPSS 17.0 software with the significance level set at 5%. The percentage of time in the standing position was lower among women with poor quality of life (p<0.05). Adjusted analysis (age, years since menopause, percentage of fat mass, MVPA and occupation status) was used to evaluate the relationship between quality of life and accelerometer inclinometer measures. The relationship between time standing and general health status (β=0.353; 95%CI=0.017; 0.377), social function (β=0.429; 95%CI=0.060; 0.396) and overall score (β=0.336; 95%CI=0.015; 0.442) were statistically significant. The relationship between the reclining position and both overall score (β=-0.320; 95%CI=-0.492; 0.006) and emotional aspects (β=-0.337; 95%CI=-0.191; 0.001) showed a tendency to present statistical significance. In summary, our results suggest that postmenopausal women who spend more time in the standing position have a better overall quality of life regardless of confounders.


Time-course analyses addressing the acquisition of DBA lectin reactivity in mouse lymphoid organs and uterus during the first week of pregnancy.
Terminal differentiation of uterine natural killer (uNK) cells is induced in humans and mice at the time of endometrial decidualization. In mice, commitment to this lineage is first recognized at gestation day (gd)5.5 when small, non-granulated lymphocytes in the mesometrial decidua basalis become histochemically reactive with the lectin Dolichlos biflorus agglutinin (DBA). Transplantation experiments in mice have shown that the self-renewing progenitors of uNK cells are present in peripheral rather than uterine tissues. While lymphoid tissues of virgin mice lack DBA lectin reactive putative uNK cell precursors or progenitors, peripheral organs have not been systematically examined in female mice during early pregnancy while the uNK cell population is becoming established. Here we report such a study in gd0.5-7.5 random bred mice. Only mesenteric lymph nodes showed a transient gain in DBA lectin reactive lymphocytes between gd0.5 and 4.5. These cells had cytoplasmic but almost no surface DBA lectin reactivity. This study indicates that the decidual environment is unique and locally promotes DBA lectin surface expression in terminally differentiating uNK cells.


Standardized post-catheter nursing intervention reduces incidence of catheter complications in the disabled elderly and improves their quality of life.
The aim of this study was to determine the effect of standardized post-catheter nursing intervention on awareness rate of clinical knowledge and behavior, treatment compliance, and incidence of catheter complications in the disabled elderly. A total of 84 elderly patients with indwelling catheters treated in our hospital from September 2019 to March 2020 were retrospectively analyzed. Based on different nursing methods, 39 cases treated by routine nursing intervention were included in the control group (CG), and 45 cases receiving standardized post catheter nursing intervention were assigned to the experimental group (EG). The two groups were compared in terms of the following items: awareness rate of knowledge and behavior, treatment compliance, incidence of catheter complications before and after nursing, hospitalization time, nursing satisfaction and quality of life (QOL). The EG exhibited significantly shorter hospitalization time and lower incidence of catheter complications than CG. The awareness rate of knowledge and behavior, treatment compliance and nursing satisfaction were significantly higher in the EG than in the CG. Furthermore, the QOL scores were not significantly different between CG and EG before nursing intervention, but were significantly higher in the EG than the CG after nursing intervention. Standardized post-catheter nursing intervention for the disabled elderly can better enhance the awareness rate of knowledge and behavior, improve treatment compliance and QOL of patients, and reduce the incidence of catheter complications.


The FP-LAPW/GAM-MPW1K approach: a reliable abinitio method for calculating the band gap of II-VI semiconductors monochalcogenides.
The bandgap of metal monochalcogenides (MMCs) is a key property that governs their physical and chemical properties. Accurate measurement of the bandgap is essential for a range of applications, including optoelectronics and photovoltaics. However, many theoretical approximations fail to accurately calculate the bandgap for MMCs, making it difficult to obtain precise values. This study investigated the suitability of the FP-LAPW/GAM-MPW1K scheme for determining the bandgap of MMCs. The investigation included lattice parameters, bandgap, band structure, and density of states, which were compared against both previous theoretical calculations and available experimental data. The findings of the study indicate that the FP-LAPW/GAM-MPW1K approach accurately calculates the bandgap value of MMCs by efficiently treating d-state electrons. The results are consistent with prior studies, confirming the method's reliability in determining the bandgap of these semiconductors. our study used the GAM-MPW1K functional and the full potential linearized augmented plane wave method (FP-LAPW) in the ELK code to calculate the lattice parameters, electronic band structure, and bandgap of ZnS, ZnSe, ZnTe, CdS, CdSe, and CdTe compounds in the wurtzite structure. The crystallographic data were obtained from the COD database and the inputs were prepared by CIF2CELL code. The results were visualized using Xmgrace and VESTA software.


Circulation of influenza C virus of C/Sao Paulo/378/82 lineage among pediatric acute respiratory cases, Shandong, China.
Influenza C virus (ICV) was identified in five pediatric acute respiratory cases in Shandong. Co-infection with other respiratory viruses was detected in four of these cases. Two ICV genomes were obtained and clustered in the S1-sublineage of C/Sao Paulo/378/82, indicating that genetically diverse ICV strains have been circulating in mainland China.


[Molecular genetic characteristics of the Wx-B1e allele from common wheat and applicability of the DNA markers for its identification].
Molecular genetic characterization of the Wx-B1e allele identified by the authors of the study in the common wheat cultivar Korotyshka was performed. The 804-bp Wx-B1e fragment was cloned and sequenced. Comparison of the sequence obtained with that for the wild-type allele of common wheat (Wx-B1a) demonstrated that Wx-B1e carried the 34-bp insertion, 8-bp deletion, and 23 nucleotide substitutions. BLAST analysis revealed the highest homology with the nucleotide sequences of Wx genes from Triticum spelta and Triticum durum. The amplification variants of four Wx-B1 molecular markers, applied worldwide for testing the collections for different Wx allelic variants, are demonstrated.


Comparative improvement of asthma symptoms and expiratory flows after corticosteroid treatment: a method to assess the effect of corticosteroids on large vs. small airways?
The magnitude of improvement of respiratory symptoms (RS) and expiratory flows (EF) following corticosteroid treatment may vary from one asthmatic patient to another. The distribution of ratio of improvement of the above parameters was assessed in 937 patients with asthma of variable severity who took part in three clinical trials comparing the effects of chlorofluorocarbon-propelled beclomethasone dipropionate (CFC-BDP) with similar (n:316) or half-doses (n:581) of extrafine hydrofluoroalkane-propelled (HFA-BDP) on asthma control. We calculated the ratio of improvement of shortness of breath, wheezing, sleep disturbance, cough, and chest tightness over the following physiological parameters: forced expiratory volume in 1s (FEV1), FEF(25/75%), morning peak expiratory flow, and FVC, from the baseline value to the last set of measures in the study, while on the study medication. We hypothesized that the ratio of RS/EF would have a normal distribution and would be higher with extrafine HFA-BDP compared with CFC-BDP, which has a larger particle size, when FEV1 is used, as it mostly assesses large airways. Ratios of improvement were normally distributed for both drugs and no significant shift in its distribution curve was found for HFA-BDP. The ratio of changes in FEF(25/75%)/FEV1 was similar in the two groups. In conclusion, the ratio of improvement of RS/EF is normally distributed over a narrow range, showing a generally good correlation between improvements in EF and symptoms in asthma; it was, however, similar for the two BDP molecules tested. This may suggest that this ratio is not useful for evaluating the effect of corticosteroids on small airways, or that extrafine HFA-BDP acts at the level of large- to moderate-caliber airways to produce most of its beneficial effect.