Dominant negative mutation of the TGF-beta receptor blocks hypoxia-induced pulmonary vascular remodeling.
The present study utilized a novel transgenic mouse model that expresses an inducible dominant negative mutation of the transforming growth factor (TGF)-beta type II receptor (DnTGFbetaRII mouse) to test the hypothesis that TGF-beta signaling plays an important role in the pathogenesis of chronic hypoxia-induced increases in pulmonary arterial pressure and vascular and alveolar remodeling. Nine- to 10-wk-old male DnTGFbetaRII and control nontransgenic (NTG) mice were exposed to normobaric hypoxia (10% O2) or air for 6 wk. Expression of DnTGFbetaRII was induced by drinking 25 mM ZnSO4 water beginning 1 wk before hypoxic exposure. Hypoxia-induced increases in right ventricular pressure, right ventricular mass, pulmonary arterial remodeling, and muscularization were greatly attenuated in DnTGFbetaRII mice compared with NTG controls. Furthermore, the stimulatory effects of hypoxic exposure on pulmonary arterial and alveolar collagen content, appearance of alpha-smooth muscle actin-positive cells in alveolar parenchyma, and expression of extracellular matrix molecule (including collagen I and III, periostin, and osteopontin) mRNA in whole lung were abrogated in DnTGFbetaRII mice compared with NTG controls. Hypoxic exposure had no effect on systemic arterial pressure or heart rate in either strain. These data support the hypothesis that endogenous TGF-beta plays an important role in pulmonary vascular adaptation to chronic hypoxia and that disruption of TGF-beta signaling attenuates hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial hypertrophy and muscularization, alveolar remodeling, and expression of extracellular matrix mRNA in whole lung.


Prediction of outcome by neurohumoral activation, the six-minute walk test and the Minnesota Living with Heart Failure Questionnaire in an outpatient cohort with congestive heart failure.
To compare the precursor of atrial and brain natriuretic peptide (N-ANP, N-BNP), brain natriuretic peptide (BNP), big endothelin-1, the 6-min walk test and the Minnesota Living with Heart Failure Questionnaire (LHFQ) with regard to short-term outcome in an ambulatory heart failure population. Ninety-six individuals (left ventricular ejection fraction of 26+/-10%) were included in the study. Within 1 day blood samples of N-ANP, N-BNP, BNP and big endothelin-1 were obtained, and the 6-min walk test and LHFQ were measured. The predictive power of these variables - including renin-angiotensin system antagonist therapy - in respect of 1-year event-free survival were calculated with a Cox regression analysis. All investigated variables had the power to predict outcome in a univariate analysis. Multivariate analysis revealed that N-ANP (chi-square=58 P<0.0001), BNP (chi-square=8 P<0.01), the LHFQ (chi-square=6 P<0.02) and the renin-angiotensin system antagonist (chi-square=4 P<0.05), are independent predictors. We conclude that, in an open clinical cohort of patients with large differences in the progression of the disease, N-ANP, BNP and LHFQ are the most reliable predictors of worsening heart failure in the short term. However, the dosage of the ACE inhibitor influenced short-term survival in this population.


The comparative pathology of equine cutaneous phycomycosis.
Pythiosis (204 cases, 77%), basidiobolomycosis (48 cases, 18%), and conidiobolomycosis (14 cases, 5%) were diagnosed morphologically from 266 horses with phycomycosis. All lesions were cutaneous ulcerative granulomas and three horses with pythiosis had metastatic lesions in regional lymph nodes. Lesions of pythiosis contained characteristic yellow, coral-like coagula and had a fibrotic surface containing sinus tract openings. Basidiobolomycosis was characterized by infrequent small yellow coagula and a yellow line of fungal invasion beneath an edematous surface. Lesions of conidiobolomycosis had numerous small coagula and a nasal location. There were minor differences in inflammatory cell populations within the granulomatous lesions. Most differences were associated with coagula size and fungal morphology. Coagula were composed of collagen, fibrin, cellular debris, degranulated and whole eosinophils and hyphae. Histochemistry revealed no major differences among the three diseases. Pythium sp hyphae were 2.6 to 6.4 micrometers in diameter, had thick walls, and occasionally were septate. Basidiobolus haptosporus hyphae were 5.1 to 20.5 micrometers in diameter, had thin walls, and commonly were septate. Conidiobolus coronatus hyphae were 5.1 to 12.8 micrometers in diameter, had thin walls, and commonly were septate. A perihyphal eosinophilic cuff ( Splendore - Hoeppli phenomenon) with a radius of up to 20 micrometers was associated with the latter two fungi. Ultrastructurally, Pythium sp was composed of a thick, single density cell wall while B. haptosporus and C. coronatus had thin, double-layered cell walls.


Metastases of transverse colon cancer to bilateral ovaries (Krukenberg tumor) and the left breast: A case report.
Breast cancer has the highest rate of incidence among all types of cancer in women. Only ~0.43% of breast malignancies occur as a result of metastatic lesions from extramammary tumors. The present study reports an extremely rare case of transverse colon cancer metastasizing to the bilateral ovaries and the left breast. The patient was a 47-year old female, who had a lump in the left breast without axillary lymphadenopathy. Specimens obtained by core needle biopsy were submitted for hematoxylin and eosin examination, and results revealed that the lump was a poorly differentiated adenocarcinoma. Since the patient had elevated levels of the carcinoembryonic antigen and a medical history of a Krukenberg tumor metastasized from colon cancer, immunohistochemical examinations were applied. Results identified that caudal-related homeobox protein 2 and cytokeratin 20 were positively stained, whilst cytokeratin 7 was negatively stained. Therefore, this patient was diagnosed as having colon cancer that had metastasized to the bilateral ovaries and the left breast. As the life expectancy of patients with cancer is increasing, types of metastases that used to be seen as rare are increasingly becoming more common. For clinicians, diagnosis should be cautious, and differential diagnosis should always be kept in mind.


Constitutive heterochromatin during mouse oogenesis: the pattern of histone H3 modifications and localization of HP1alpha and HP1beta proteins.
Centromeres are the fragments of DNA that are responsible for proper chromosome segregation. They consist of centromeric chromatin surrounded by blocks of pericentric heterochromatin, playing an important role in centromere function. In somatic cells, the pericentric domains have a specific pattern of epigenetic modifications of core histones and contain specific pericentric proteins. These features are probably more important for the centromere function than the sequence of the centromeric DNA itself. In somatic cells, the HP1alpha and HP1beta proteins are indispensable for constitutive heterochromatin formation and maintenance. We have analyzed the localization of these proteins in the primordial, growing, fully-grown, and maturing mouse oocytes. Additionally, we have analyzed post-translational modifications of histone H3, which can influence HP1alpha and HP1beta association with the heterochromatin. We showed that the regions of constitutive heterochromatin have a distinct pattern of histone H3 acetylation and di-, and trimethylation of its lysine 9. We demonstrated that HP1beta protein was present in pericentric chromatin domains in primordial oocytes, growing (transcriptionally active) oocytes, and in fully-grown oocytes, and was released to the cytoplasm after germinal vesicle breakdown. In contrast, the HP1alpha was never detected in primordial oocytes, was first detected in pericentric heterochromatin in growing oocytes, dissociated from pericentric heterochromatin in fully-grown oocytes, and it was never detected in maturing oocytes. The presence of HP1alpha and HP1beta proteins on the heterochromatin of transcriptionally active oocytes and their absence in transcriptionally silent oocytes suggest that they are necessary for the repression of RNA synthesis in heterochromatin domains of transcribing oocytes.


In vitro cell-mediated immune responses of human immunodeficiency virus-infected and -uninfected individuals to whole cytomegalovirus antigens and their subunits.
The aim of this study was to optimize the ability to detect cytomegalovirus (CMV)-specfic cell-mediated immunity (CMI) in human immunodeficiency virus (HIV)-infected individuals by comparing different assays (the lymphocyte proliferation assay [LPA] and assays for gamma interferon [IFN-gamma] and interleukin-2 [IL-2] production) and CMV antigenic preparations. Thresholds discriminating positive from negative CMI results were developed with specimens from 36 CMV-seropositive and 21 CMV-seronegative healthy individuals. The analysis showed that the CMI elicited by any of the four CMV whole lysates tested in this study tended to be more robust and sensitive than the responses to the subunit antigens gB and pp65. LPA and inducible IFN-gamma but not IL-2 were highly sensitive measures of CMV-specific CMI in HIV-infected and -uninfected individuals. The ability to detect CMV-specific LPA or IFN-gamma responses in HIV-infected individuals significantly increased with higher CD4 cell numbers. Nevertheless, the proportion of HIV-infected subjects with CD4 counts of >or=500 cells/mul who had a detectable CMV-specific CMI remained significantly lower than that of healthy adults. The ability to detect CMV-specific CMI in HIV-infected individuals decreased with higher levels of HIV replication, with discriminative thresholds of 10(3) to 10(4) HIV RNA copies/ml of plasma, for LPA or inducible IFN-gamma production elicited by different antigens. The LPA responses obtained with CMV whole lysate and phytohemagglutinin were significantly correlated in HIV-infected subjects but not uninfected controls, indicating a novel characteristic of the CMI defect caused by HIV. The intrasubject variabilities of the CMV-specific CMI were similar in HIV-infected and -uninfected individuals. These data show that LPA and the inducible IFN-gamma production elicited by CMV whole lysates may be used to assess modifications of the immune competency of HIV-infected individuals.


Qualitative case studies of five cochlear implant recipients' experience with music.
Cochlear implantation has revolutionized the management of those who suffer from severe-to-profound hearing loss because many patients now achieve excellent speech understanding with objective testing. Nevertheless, speech understanding in noisy conditions and music appreciation remain significant challenges to cochlear implant (CI) users. Music appreciation is an extremely complex experience that is difficult to quantify through a conventional outcome study. This paper aims at documenting the experience of five CI patients with regard to music appreciation using qualitative techniques. This information was obtained through a semi-structured interview process. The interviews were then transcribed and analysed using a constant comparative method of qualitative description. The results together with medical case records were used to identify emerging themes. The common themes that evolved were: musical background, the experience of receiving the implant, current experience with music, attention, musical prediction ability, internal hearing, hedonic vs. critical listening, determination, and timbre perception. By documenting their experiences in this manner, novel insights into the patient perspective are provided that are unique to the literature. These descriptions will aid clinicians and researchers who work in the area of cochlear implantation to better understand the needs of their patients.


Surgical margin in hepatic resection for colorectal metastasis: a critical and improvable determinant of outcome.
To update the analysis of technical and biologic factors related to hepatic resection for colorectal metastasis in a large single-institution series to identify important prognostic indicators and patterns of failure. Surgical therapy for colorectal carcinoma metastatic to the liver is the only potentially curable treatment. Careful patient selection of those with resectable liver-only metastatic disease is crucial to the success of surgical therapy. Two hundred forty-four consecutive patients undergoing curative hepatic resection for metastatic colorectal carcinoma were analyzed retrospectively. Variables examined included sex, stage of primary lesion, size of liver lesion(s), number of lesions, disease-free interval, ploidy, differentiation, preoperative carcinoembryonic antigen level, and operative factors such as resection margin, use of cryotherapy, intraoperative ultrasound, and blood loss. Surgical margin, number of lesions, and carcinoembryonic antigen (CEA) levels significantly control prognosis. Patients with only one or two liver lesions, a 1-cm surgical margin, and low CEA levels have a 5-year disease-free survival rate of more than 30%. Disease-free interval, original stage, bilobar involvement, size of metastasis, differentiation, and ploidy were not significant predictors of recurrence. The pattern of failure correlates with surgical margin. Routine use of intraoperative ultrasound resulted in an increased incidence of negative surgical margin during the period examined. Surgical resection or cryotherapy of hepatic metastasis from colorectal cancer is safe and curable in appropriately selected patients. Biologic factors, such as number of lesions and carcinoembryonic antigen levels, determine potential curability, and surgical margin governs the patterns of failure and outcome in potentially curable patients. Optimization of selection criteria and surgical resection margins will improve outcome.


Evaluation of shallow foundation bearing capacity in the case of a two-layered soil and spatial variability in soil strength parameters.
In this study, a probabilistic approach for evaluating the bearing capacity of surface footings is discussed. The evaluation is based on a kinematic approach. The considered substrate consists of two different layers of soil: a top layer formed of medium or dense sand followed by a layer of soft clay. The sand layer is assumed to be homogenous, whereas the undrained shear strength of the soft clay layer is assumed to be spatially variable, described by a lognormal random field. The random field is discretized according to Vanmarcke's spatial averaging along dissipation regions in the considered failure mechanism. The mechanism utilizes plane strain conditions; however, due to consideration of the soil spatial variability in three dimensions, the impact of the length of the foundation on the random bearing capacity evaluation is considered in this study. As a result of the discretization procedure, a set of correlated random variables is obtained (each associated with an individual dissipation region in the failure mechanism). A series of numerical analyses are performed for two thicknesses of the first layer and a set of anisotropic correlation structures for the spatial variability of the undrained shear strength. The proposed method is computationally efficient and allows consideration of three-dimensional spatial variability in soil strength properties. The results are discussed and compared with those obtained by other methods.


[Developmental adrenal tuberculosis. Value of x-ray computed tomography].
Two cases of Addison's disease secondary to active adrenal tuberculosis are reported. Computed tomography showed hypertrophy of the adrenal gland, which was bilateral in one case and unilateral in the other. Repeat computed tomography scans during antituberculous chemotherapy demonstrated a progressive change of the adrenals toward atrophy and calcification, while the adrenal function remained impaired. The authors recall that adrenal tuberculosis may be unilateral first, then bilateral, and that the gland is initially hypertrophic before hormonal deficiency appears; later on, adrenal atrophy and calcification develop. Computed tomography seems to be useful in the aetiological diagnosis of Addison's disease. Moreover, it helps in determining whether or not antituberculous therapy is indicated, which is not always easy to decide in the absence of "active" focus. The finding, with or without positive tuberculin skin tests, of an adrenal hypertrophy unexplainable by any other pathology (e.g. metastasis, histoplasmosis) should call for antituberculous treatment, especially since it sometimes results in recovery of adrenal function.


Creation of bismuth-tungsten oxide nanoclusters using lacunary polyoxometalates.
Three types of heterometallic bismuth-tungsten oxide nanoclusters were successfully synthesized by the reactions of lacunary silicotungstates (trivacant [A-α-SiW9O34]10- and divacant [γ-SiW10O36]8-) and Bi3+ in organic solvents. Lone pairs on Bi3+ acted as structure-directing groups in these nanoclusters.


Saprophytic growth of inoculated Frankia sp. in soil microcosms.
The potential of two Frankia strains to grow saprophytically was studied in nonsterile soil microcosms with ground leaf litter of Alnus glutinosa as the sole carbon and nitrogen sources. Strains Ag45/Mut15 and ArI3, which represent two taxonomic subgroups within the Alnus host infection group were inoculated alone, or together to investigate potential competition. Their growth was analyzed by in situ and dot-blot hybridization. A significant increase in cell numbers and filament length was observed during the first 6 weeks after inoculation for strain Ag45/Mut15, both alone and in mixed culture with strain ArI3, followed by a decrease until the end of the study after 12 weeks. The number of filaments remained unchanged. In contrast, the cell numbers and filament length of strain ArI3 were reduced significantly during the first 2 weeks and were undetectable for the remainder of the study. These results were comparable with those obtained in sterile mineral medium amended with leaf litter of A. glutinosa, although reductions in cell numbers and filament length were less pronounced than in soil microcosms. In concomitant control studies without leaf litter amendments for both experimental setups, filaments of both strains could only be detected immediately after inoculation. These results were matched in all experimental setups by concomitant shifts in the rRNA content of both strains, i.e., an immediate decline in the rRNA content for strain ArI3 after inoculation, and an increase in the rRNA content, followed by a late decline during incubation for strain Ag45/Mut15. These results demonstrated that Frankia strain Ag45/Mut15 could grow saprophytically in soil with complex carbon and nitrogen sources such as leaf litter, while the growth of strain ArI3 was not supported.


Complex reconstruction of the clavicle with a prefabricated medial femur condyle chimeric flap including a superficial circumflex iliac artery perforator flap: A case report.
The medial femur condyle (MFC) cortico-periosteal flap is a popular flap for bone reconstruction. The use of a chimeric version of this flap with a skin island has been described, but anatomical arterial variation can occur that prevent its harvest. Furthermore, the donor area of the skin paddle has been debated as poor because of the scarring in a visible area and because of the difficulty in obtaining pliable thin skin. We present a fabricated chimeric MFC cortico-periosteal flap joined with a superficial inferior epigastric perforator (SCIP) flap to reconstruct and augment a sclerotic and insufficient small clavicula with the skin paddle acting as a monitor and as a substitute for the overlying skin. A 52-year-old female patient had a history of multiple refractures of the right hypoplastic clavicle with a diameter of 7 mm, resulting in a sclerotic bone with a fibrotic scar. The reconstruction was done in one surgical session using a cortico-periosteal flap from the left medial condyle and a thin SCIP flap from the left groin. The area of the clavicle to be reconstructed was 3 cm, and the direct overlying skin (approximately 6 × 3 cm) was severely scarred and painful. The MFC flap was 5 × 4 cm, while the SCIP flap was 7 × 3.5 cm. The SCIP flap artery was anastomosed on the table end-to-side to the descending genicular (DG) artery of the MFC, and the vein was anastomosed end-to-end to a comitans vein of the DG artery. The flap fully survived after an initial congestion. At 12 months, we observed a satisfactory reconstruction of the clavicle with an enhanced diameter of 12 mm. The patient recovered full function of the shoulder with no pain. Using a fabricated chimeric flap composed of a medial femoral condyle and a superficial circumflex artery perforator flap may be an additional option for tailored reconstruction of complex osteo-cutaneous defect of clavicle.


The maternal gene skn-1 encodes a protein that is distributed unequally in early C. elegans embryos.
The autonomous or cell-intrinsic developmental properties of early embryonic blastomeres in nematodes are thought to result from the action of maternally provided determinants. After the first cleavage of the C. elegans embryo, only the posterior blastomere, P1, has a cell-intrinsic ability to produce pharyngeal cells. The product of the maternal gene skn-1 is required for P1 to produce pharyngeal cells. We show here that the Skn-1 protein is nuclear localized and that P1 appears to accumulate markedly higher levels of Skn-1 protein than its sister, the AB blastomere. We have examined the distribution of Skn-1 protein in embryos from mothers with maternal-effect mutations in the genes mex-1, par-1, and pie-1. These results suggest that mex-1(+) and par-1(+) activities are required for the unequal distribution of the Skn-1 protein and that pie-1(+) activity may function to regulate the activity of Skn-1 protein in the descendants of the posterior blastomere P1.


Social challenges faced by queer Latino college men: Navigating negative responses to coming out in a double minority sample of emerging adults.
In this paper, we qualitatively examine the social challenges experienced by queer, Latino college men in the coming out process. Using an intersectional perspective informed by the double jeopardy hypothesis, intersectional invisibility, and Latino/a cultural norms, we asked 22 queer Latino college men to describe the major challenges they experienced with their sexual identities. To examine the subjective experiences of participants' multiple minority identities, we conducted semistructured interviews. Our sample consisted of 22 college student men who identified as Latino, queer, and cisgender. Participant ages ranged from 18 to 29 (M = 21.50, SD = 3.70). For race/ethnicity, all participants identified with the broad category Latino. For sexual orientation, 18 participants self-identified as gay or homosexual, 3 identified as "other," and 1 identified as bisexual. Sixty-eight percent of participants (15/22) described encountering negative social responses to their sexual identity disclosure, including Loss of Relationships, Aggression, Pathologizing, and Self-Serving Responses. Additionally, 55% spontaneously reinterpreted or Cognitively Reframed their negative experiences (12/22), including the subthemes of It's never happened to me, Minimizing, and Victim Blame. We relate each subtheme to potentially influential social and cultural norms among queer, Latino college men, such as collectivistic values and familismo. Suggestions for research and practice with individuals at this identity intersection are described. (PsycINFO Database Record


Epilepsy in children: the evidence for new antiepileptic drugs.
Childhood epilepsy remains a challenge to treat. Despite the availability of antiepileptic drugs (AEDs), >25% of children with childhood epilepsy continue to have seizures. Conventional AEDs have been the mainstay of therapy for many years but are often poorly tolerated and have a tendency to interact with other drugs. Current American Academy of Neurology guidelines support the use of four of the newer AEDs (gabapentin, lamotrigine, topiramate, and oxcarbazepine) as adjunctive treatment of refractory partial seizures in children, based on class I evidence. This paper includes a summary of the results from a recent randomized, double-blind, placebo-controlled study, which shows that levetiracetam is also effective and well tolerated in this pediatric population, and provides evidence supporting its use in refractory partial seizures in children.


Jordanian nurses' barriers to screening for intimate partner violence.
Screening rates for intimate partner violence (IPV) among nurses are still very low. The study purpose is to evaluate IPV screening and barriers by Jordanian nurses. A cross-sectional design was used with a stratified random sample (N = 125) of Jordanian nurses. Findings included a significantly lower IPV screening rate among Jordanian nurses compared with those in the United States, no difference in screening between IPV victims compared with non-victimized nurses, and that the IPV screening barriers related to a lack of system support were the most clinically important barriers. Nurses can work in partnership with health care providers and managers to increase screening and overcome barriers.


Dermatosis papular acantolítica de la vulva con buena respuesta a tacrólimus tópico.
Papular acantholytic dermatosis of the vulva is a rare, chronic disorder and is an entity that remains to be fully understood. It shares clinical and histopathological overlap with Darier disease and Hailey-Hailey disease. We describe a 30-year-old woman with papular acantholytic dermatosis of the vulva. The lesions consisted of whitish papules and erosions on the labia majora. Histologically, there was hyperkeratosis and focal parakeratosis with acantholytic and dyskeratotic cells. She did not respond completely to topical steroids but clinical improvement occurred after the use of topical tacrolimus.


Roles of salt‑inducible kinases in cancer (Review).
Salt inducible kinases (SIKs) with three subtypes SIK1, SIK2 and SIK3, belong to the AMP‑activated protein kinase family. They are expressed ubiquitously in humans. Under normal circumstances, SIK1 regulates adrenocortical function in response to high salt or adrenocorticotropic hormone stimulation, SIK2 is involved in cell metabolism, controlling insulin signaling and gluconeogenesis and SIK3 coordinates with the mTOR complex, promoting cancer. The dysregulation of SIKs has been widely detected in various types of cancers. Based on most of the existing studies, SIK1 is mostly considered a tumor inhibitor, SIK2 and SIK3 are usually associated with tumor promotion. However, the functions of SIKs have shown contradictory in certain tumors, suggesting that SIKs cannot be simply classified as oncogenes or tumor suppressor genes. The present review provided a comprehensive summary of the roles of SIKs in the initiation and progression of different cancers, aiming to elucidate their clinical value and discuss potential strategies for targeting SIKs in cancer therapy.


Adult listeriosis--a review of 18 cases.
Eighteen cases of adult listeriosis (nine with meningitis, one brain abscess and eight bacteraemia) were diagnosed in the Chaim Sheba Medical Center in the years 1964-1982. The infection seemed to be opportunistic in all. Eleven patients had malignant disease, two had cirrhosis of the liver, one had ulcerative colitis, one had bronchial asthma with chronic obstructive pulmonary disease, one had pemphigus, one had diabetes mellitus and one had a renal transplantation. Twelve patients (66%) received radiation therapy and/or cytotoxic and steroid medication. Diabetes mellitus as an additional underlying disease was strikingly frequent and was found in eight out of 18 patients (44%), in one as the only underlying disease. In the meningitis group cerebrospinal fluid (CSF) cultures were positive in five patients, and negative in four who had, however, positive blood cultures. The cells in the CSF were predominantly lymphocytes in five and polymorphs in four. It may be concluded that diabetes mellitus is an important underlying disease in listeriosis. The results also reinforce the fact that lymphocytosis in the CSF does not exclude bacterial meningitis.


Interventional cardiac catheterisation in congenital heart disease.
As a result of recent technological advances, more types of congenital heart disease are amenable to treatment in the cardiac catheter laboratory than ever before.1 Improved imaging techniques allow for better selection of patients, and the development of a wide range of devices specifically for use in children means that many patients can avoid surgery altogether, while those with complex congenital heart disease may require fewer or less complex surgical procedures.2 This allows for a quicker recovery and a shorter hospital stay, and gives many patients an improved quality of life in the short to medium term. However, the long term outcome for many of the newer forms of intervention is still unknown.


[Clinical characteristics and risk factors of deaths in patients with Wiskott-Aldrich syndrome].
Objective: To explore the clinical characteristics and risk factors of pediatric patients with Wiskott-Aldrich syndrome (WAS). Methods: This was a case-control study. Clinical data of 165 cases of pediatric patients with WAS, who visited the Department of Rheumatology, Children's Hospital of Chongqing Medical University between January 2007 and August 2020 were retrospectively analyzed and divided into death group and survival group (control group) according to the prognosis in the follow-up. Two independent samples t-test, Welch approximate t-test, Mann-Whitney U test, Pearson χ² test, Yates corrected χ² test, or Fisher exact probability test were used for comparison between groups. Risk factors were analyzed by multivariate Logistic regression analysis. Results: A total of 165 patients with Wiskott-Aldrich syndrome were enrolled in this study, including 40 cases in the death group and 125 cases in the survival group. The WAS score was (4.1±0.8) score in the death group and (3.1±1.2) score in the survival group. The age was 19 (9, 28) months in the death group and 60 (36,86) in the survival group. The episode rates of recurrent infection and (or) severe infection, intracranial hemorrhage and eczema in the death group were significantly higher than those in the survival group (95.0% (38/40) vs.32.0% (40/125),25.0% (10/40) vs. 2.4% (3/125), 90.0% (36/40) vs. 72.0% (90/125), χ²=48.253, 18.325, 5.440, all P<0.05). Infection (22 cases, 55.0%) and intracerebral hemorrhage (15 cases, 37.5%) were the main causes of death, 3 cases (7.5%) died of severe graft-versus-host disease after transplantation. The Logistic regression model indicated that repeated infection and (or) severe infection and non-use of intravenous immunoglobulin (IVIG) replacement therapy were risk factors for death in Chinese WAS patients (OR values were 8.999 and 2.860, 95% CI were (2.041-39.667) and (1.375-5.950), respectively, all P<0.05). Conclusions: Recurrent and (or) severe infection is the main risk factor of death for WAS patietns. Regular IVIG treatment can improve the survival rate of patients with WAS.


[Vital capacity rapid inhalation induction (VCRII) technique with sevoflurane for a rheumatoid patient with difficult airway].
Successful airway management in an adult female patient with limited cervical extension and a subluxation of bilateral jaw joints caused by rheumatoid arthritis was reported. We planned to reduce the intensity of pain in her right hand through neurolysis of the ulnar nerve in her right elbow joint. Right axillary nerve blockade with 1% lidocaine 10 ml and 0.25% bupivacaine 10 ml, was employed unsuccessfully to achieve adequate anesthetic effect. Anesthesia was administered using a vital capacity rapid inhalation induction (VCRII) technique with 5% sevoflurane in the oxygen. When the patient lost consciousness, a size 3 laryngeal mask airway (LMA) was inserted under spontaneous breathing on the first trial. There was very little hemodynamic change during the insertion of the LMA. Anesthesia was maintained with sevoflurane 1.5-2.0% in oxygen under spontaneous breathing. Emergence from anesthesia was rapid and no signs of upper airway obstruction were observed after the removal of the LMA. The use of the LMA with VCRII technique and anesthetic maintenance using sevoflurane, are likely to be an optional technique of airway management in patients with problematic airway.


Structure-Property Relationships for Nickel Aluminate Catalysts in Polyethylene Hydrogenolysis with Low Methane Selectivity.
Earth-abundant metals have recently been demonstrated as cheap catalyst alternatives to scarce noble metals for polyethylene hydrogenolysis. However, high methane selectivities hinder industrial feasibility. Herein, we demonstrate that low-temperature ex-situ reduction (350 °C) of coprecipitated nickel aluminate catalysts yields a methane selectivity of <5% at moderate polymer deconstruction (25-45%). A reduction temperature up to 550 °C increases the methane selectivity nearly sevenfold. Catalyst characterization (XRD, XAS, 27Al MAS NMR, H2 TPR, XPS, and CO-IR) elucidates the complex process of Ni nanoparticle formation, and air-free XPS directly after reaction reveals tetrahedrally coordinated Ni2+ cations promote methane production. Metallic and the specific cationic Ni appear responsible for hydrogenolysis of internal and terminal C-C scissions, respectively. A structure-methane selectivity relationship is discovered to guide the design of Ni-based catalysts with low methane generation. It paves the way for discovering other structure-property relations in plastics hydrogenolysis. These catalysts are also effective for polypropylene hydrogenolysis.


Relations of microbiome characteristics to edaphic properties of tropical soils from Trinidad.
Understanding how community structure of Bacteria, Archaea, and Fungi varies as a function of edaphic characteristics is key to elucidating associations between soil ecosystem function and the microbiome that sustains it. In this study, non-managed tropical soils were examined that represented a range of edaphic characteristics, and a comprehensive soil microbiome analysis was done by Illumina sequencing of amplicon libraries that targeted Bacteria (universal prokaryotic 16S rRNA gene primers), Archaea (primers selective for archaeal 16S rRNA genes), or Fungi (internal transcribed spacer region). Microbiome diversity decreased in the order: Bacteria > Archaea > Fungi. Bacterial community composition had a strong relationship to edaphic factors while that of Archaea and Fungi was comparatively weak. Bacterial communities were 70-80% alike, while communities of Fungi and Archaea had 40-50% similarity. While each of the three component communities differed in species turnover patterns, soils having relatively similar bacterial communities also housed similar archaeal communities. In contrast, the composition of fungal communities had no correlation to bacterial or archaeal communities. Bacterial and archaeal diversity had significant (negative) correlations to pH, whereas fungal diversity was not correlated to pH. Edaphic characteristics that best explained variation between soils in bacterial community structure were: total carbon, sodium, magnesium, and zinc. For fungi, the best variables were: sodium, magnesium, phosphorus, boron, and C/N. Archaeal communities had two sets of edaphic factors of equal strength, one contained sulfur, sodium, and ammonium-N and the other was composed of clay, potassium, ammonium-N, and nitrate-N. Collectively, the data indicate that Bacteria, Archaea, and Fungi did not closely parallel one another in community structure development, and thus microbiomes in each soil acquired unique identities. This divergence could in part reflect the finding that unknown factor(s) were stronger than edaphic characteristics in shaping fungal and archaeal communities.


Flavonoids and other chemical constituents of fossil miocene zelkova (ulmaceae).
Organic solvent extractions of Zelkova oregoniana, a Miocene angiosperm compression fossil, indicate the chemical preservation of kaempferol, dihydrokaempferol, an n-alkane chain length range of 10 to 32 carbons, hydroxy acids, steranes, triterpenoids, and methyl pheophorbide a. This appears to be the oldest occurrence of flavonoids in fossil sediments reported.


Smart region definition: a new way to improve the predictive ability and interpretability of three-dimensional quantitative structure-activity relationships.
This report describes a new methodology aimed at grouping 3D-QSAR interaction energy descriptors into regions of neighbor variables bearing the same chemical and statistical information. These regions represent the structural variability of the series better than individual descriptor variables and can advantageously replace them in the chemometric analysis. The algorithm used to generate such regions is described, together with their application for improving the quality of GOLPE variable selection. The method is illustrated on a series of 47 glucose analogues, inhibitors of glycogen phosphorylase b, and is shown to improve both the predictive ability and the interpretability of the 3D-QSAR models obtained, comparing favorably with other methods previously described.


Considering the vascular hypothesis for the pathogenesis of small intestinal atresia: a case control study of genetic factors.
Small intestinal atresia (SIA) is a rare congenital occlusion of the small intestine. SIA development, particularly in the jejunum and ileum, has been associated with in utero disruption of vascular supply. However, the number of studies of the vascular hypothesis is limited. This study considers the vascular hypothesis by exploring risks associated with 32 SNPs of genes involved in vascular processes of homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. A total of 206 SIA cases were ascertained by the California Birth Defects Monitoring Program, and 573 infants with no major congenital anomalies by their first birthday were selected as controls. Genomic DNA was genotyped for 32 SNPs involving the following genes: MTHFR, F2, F5, F7, SERPINE1, FGB, ITGA2, ITGB3, SELE, ICAM1, MMP3, TNF, LTA, NOS3, AGTR1, AGT, NPPA, ADD1, SCNN1A, GNB3, and ADRB2. Risks were estimated as odds ratios, adjusted for maternal age and race, with 95% confidence intervals. Cases were considered collectively and by subgroups based on atresia location (duodenal/jejunum/ileum). Three SNPs had reduced risk: SERPINE1 11053 T/G, MMP3 (-1171) A6/A5, and ADRB2 gln27glu. Two had increased risk: ITGA2 873 G/A and NPPA 2238 T/C. No intestinal subphenotypes showed a unique pattern of SNP associations. The association of two SNPs with increased risk lends some, albeit limited, support to vascular impairment as a possible mechanism leading to SIA. These results also identify genes meriting further exploration in SIA studies. Hence, this study makes an important contribution by exploring the long-held but not well-investigated vascular hypothesis.


Reconstitution of the fatty acid hydroxylase activity of cytochrome P450BM-3 utilizing its functional domains.
Cytochrome P450BM-3, a catalytically self-sufficient fatty acid monooxygenase from Bacillus megaterium, is a multidomain protein containing heme, FAD, and FMN. Previous attempts to reconstitute the fatty acid monooxygenase activity of intact P450BM-3 utilizing equimolar concentrations of the separate heme (BMP) and reductase (BMR) domains, have been unsuccessful because two-electron reduced FMN, which rapidly accumulates, is incapable of electron transfer to the heme iron. The present study of the reconstitution of the monooxygenase activity of P450BM-3 utilized combinations of the different functional domains of P450BM-3. For this purpose, the FAD/NADPH- and FMN-binding domains of P450BM-3 as well as the combination of the heme- and FMN-binding domains (BMP/FMN) have been expressed and purified. The reconstitution systems, consisting of either BMP/FMN and FAD domains or BMP, FMN, and FAD domains, were still less effective than the holoenzyme, P450BM-3, but were much more effective than a system consisting of BMP and BMR. The maximal rate of oxidation of palmitic acid by the newly developed reconstitution systems is still only approximately 5% of the activity of the holoenzyme. The reconstitution systems produced omega-1, omega-2, and omega-3 monohydroxy palmitic acid, but not the secondary products of palmitic acid hydroxylation observed with the holoenzyme. The physical cause of the inability to reconstitute fully the maximal activity of the holoenzyme as well as the lack of secondary product formation is not presently understood.


Cubosomes: Versatile Nanosized Formulation for Efficient Delivery of Therapeutics.
Cubosomes are bicontinuous cubic phase nanoparticles with a size range from 10-500 nm. They offer various advantages with some limitations at the production level, e.g., cubosomes have the feature to encapsulate a large amount of the drug due to its large internal area owing to cuboidal shape but limited in large scale production due to its high viscosity which is associated with the problem in homogenization. This nanoparticulate formulation is compatible for administration by various routes like oral, transdermal, topical, buccal, etc. The drug release mechanism from cubosomes was reported to be dependent on the partition coefficient and diffusion process. Compared with liposomes, cubosomes show many differences in various aspects like shape, size, ingredients, and mode of action. The main ingredients for the preparation of cubosomes include lipids, stabilizers, aqueous phase and therapeutic agents. Several methods have been reported for cubosomes, including the top-down method, the bottom-up method and the adopted coarse method. For the optimization of cubosomes, the key factors to be considered, which will affect the cubosomes characteristics include the concentration of lipid, temperature and pH. At present, many research groups are exploring the potential of cubosomes as biosensors and nanocarriers. Based on the latest reports and research, this review illuminates the structure of the cubosomes, mechanism of the drug release, different methods of preparation with factors affecting the cubosomes, application of cubosomes in different sectors, differences from the liposomes, and their advantages.


Polynomial Monogamy Relations for Entanglement Negativity.
The notion of nonclassical correlations is a powerful contrivance for explaining phenomena exhibited in quantum systems. It is well known, however, that quantum systems are not free to explore arbitrary correlations-the church of the smaller Hilbert space only accepts monogamous congregants. We demonstrate how to characterize the limits of what is quantum mechanically possible with a computable measure, entanglement negativity. We show that negativity only saturates the standard linear monogamy inequality in trivial cases implied by its monotonicity under local operations and classical communication, and derive a necessary and sufficient inequality which, for the first time, is a nonlinear higher degree polynomial. For very large quantum systems, we prove that the negativity can be distributed at least linearly for the tightest constraint and conjecture that it is at most linear.


Changing constituents of genitourinary cancer in recent 50 years in Beijing.
To assess the changes in constituents of genitourinary cancer inpatients in Beijing following the growing economy of China. Urological inpatients treated from January 1951 to December 2000 at the Institute of Urology, Peking University were studied retrospectively. In the period of about 50 years 28 474 urological inpatients were reviewed. Cancer patients in 1951-1965 and 1966-2000 comprised 19.5% and 28.2%, respectively [corrected]. Since the 1970s the incidence rates of renal cancer and prostate cancer increased dramatically from 10.4% to 28.7% and from 3.3% to 13.4%, respectively. The introduction of new diagnostic instruments, the expansion of the aged population and a high fat diet are considered to be responsible for the change of constituents of genitourinary cancer inpatients.


[MEDICAL AND SANITATION PROVISION FOR THE REFUGEES IN THE IRKUTSK PROVINCE IN 1914-1916].
On the basis of the archival documents, the article studies and provides information on the creation of medical and sanitary bodies, public organizations to provide the refugees of the Irkutsk province with medical care in 1914-1916, to carry out comprehensive anti-epidemic measures to combat the emerging epidemics of diseases characteristic of wartime. The study shows the role of medical and sanitary bodies, committees, commissions to ensure the epidemiological well-being of the refugees. The dynamics of an increase in the number of beds, the number of hospitals, the opening of infectious barracks, an increase in financial allocations for the provision of medical assistance to refugees were noted.


Dissemination of clonal complex 2 Acinetobacter baumannii strains co-producing carbapenemases and 16S rRNA methylase ArmA in Vietnam.
Acinetobacter baumannii strains co-producing carbapenemase and 16S rRNA methylase are highly resistant to carbapenems and aminoglycosides. Ninety-three isolates of multidrug-resistant A. baumannii were obtained from an intensive care unit in a hospital in Vietnam. Antimicrobial susceptibility tests and whole genome sequencing were performed. Multilocus sequence typing and the presence of drug resistant genes were determined and a maximum-likelihood phylogenetic tree was constructed by SNP alignment of whole genome sequencing data. The majority of isolates belonged to clonal complex 2 (ST2, ST570 and ST571), and carried carbapenemase encoding genes bla OXA-23 and bla OXA-66. Two isolates encoded carbapenemase genes bla NDM-1 and bla OXA-58 and the 16S rRNA methylase encoding gene armA and did not belong to clonal complex 2 (ST16). A. baumannii isolates producing 16S rRNA methylase ArmA and belonging to clonal complex 2 are widespread, and isolates co-producing NDM-1 and ArmA are emerging, in medical settings in Vietnam.


Pressure-Regulated Single-Entity Electrochemistry Inside Carbon Nanopipettes.
Conductive nanopipettes have been widely used as a multifunctional platform for emerging sensing applications in small spaces, although the electrochemical processes involved are not well controlled and fully quantified. Herein, we use an external pressure to precisely control the solution volume and regulate the electrochemical signals in carbon nanopipettes. In addition to polarizing the redox concentration profile, the pressure is found to generate a convective flow to control the transport processes of redox molecules and nanoparticles as well, and their quantitative correlation is established by a numerical simulation. The elucidated pressure-regulated electrochemistry in conductive nanopipettes would reveal the fundamental charge transport processes at the nanoscale and promote better usage of conductive nanopipettes for delivery and sensing applications in single-cell analysis.


Serum Exosomal Long Noncoding RNA Growth Arrest-Specific 5 Predicts 3-Month Mortality in Acute-on-Chronic Hepatitis B Liver Failure.
Acute-on-chronic hepatitis B liver failure (ACHBLF) is a clinical syndrome with an extremely high mortality. In this study, we aim to evaluate the potential role of serum exosomal long noncoding RNA (lncRNA) growth arrest-specific 5 (GAS5) in ACHBLF and its predictive value for 3-month mortality. From December 2017 to June 2022, we enrolled 110 patients with ACHBLF and 42 healthy controls (HCs). Exosomes were isolated from the serum of the participants. Serum exosomal lncRNA GAS5 was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The functional role of lncRNA GAS5 on hepatocyte phenotypes was investigated through loss-of-function and gain-of-function assays. Exosomal labeling and cell uptake assay were used to determine the exosomes-mediated transmission of lncRNA GAS5 in hepatocytes in vitro. The serum exosomal lncRNA GAS5 was identified to be an independent predictor for 3-month mortality of ACHBLF. It yielded an area under the receiver operating characteristic curve (AUC) of 0.88, which was significantly higher than MELD score (AUC 0.73; P < 0.01). Further study found that lncRNA GAS5 could inhibit hepatocytes proliferation and increase hepatocytes apoptosis. Exosomes-mediated lncRNA GAS5 transfer promoted hepatocytes injury. The knocked down of lncRNA GAS5 weakened H2O2-induced hepatocytes injury. We revealed that serum exosomal lncRNA GAS5 might promote hepatocytes injury and showed high predictive value for 3-month mortality in ACHBLF.


BREEDING SYSTEM AND GENETIC VARIANCE IN THE MONOGAMOUS, SEMI-SOCIAL SHREW, CROCIDURA RUSSULA.
The population-genetic consequences of monogamy and male philopatry (a rare breeding system in mammals) were investigated using microsatellite markers in the semisocial and anthropophilic shrew Crocidura russula. A hierarchical sampling design over a 16-km geographical transect revealed a large genetic diversity (h = 0.813) with significant differentiation among subpopulations (FST = 5-6%), which suggests an exchange of 4.4 migrants per generation. Demic effective-size estimates were very high, due both to this limited gene inflow and to the inner structure of subpopulations. These were made of 13-20 smaller units (breeding groups), comprising an estimate of four breeding pairs each. Members of the same breeding groups displayed significant coancestries (FLS = 9-10%), which was essentially due to strong male kinship: syntopic males were on average related at the half-sib level. Female dispersal among breeding groups was not complete (~39%), and insufficient to prevent inbreeding. From our results, the breeding strategy of C. russula seems less efficient than classical mammalian systems (polygyny and male dispersal) in disentangling coancestry from inbreeding, but more so in retaining genetic variance.


Excitatory effects of synchronized intestinal electrical stimulation on small intestinal motility in dogs.
The aim of this study was to investigate effects of synchronized intestinal electrical stimulation (SIES) on small intestinal motility in dogs. Seventeen dogs were equipped with a duodenal cannula for the measurement of small bowel motility using manometry; an additional cannula was equipped in six of the dogs with 1.5 m distal to the first one for the measurement of small intestinal transit. Two pairs of bipolar electrodes were implanted on the small intestinal serosa with an interval of 5 cm; glucagon was used to induce postprandial intestinal hypomotility. Eleven dogs were used for the assessment of the small intestinal contractions in both fasting and fed states. The other six dogs were used for the measurement of small intestinal transit. We found that 1) SIES induced small intestinal contractions during phase I of the migrating motor complex (MMC) (contractile index or CI: 5.2 +/- 0.6 vs. 10.3 +/- 0.7, P = 0.003); 2) in the fed state, SIES significantly improved glucagon-induced small intestinal postprandial hypomotility (CI: 3.4 +/- 0.5 vs. 6.0 +/- 0.3, P = 0.03); 3) SIES significantly accelerated small intestinal transit delayed by glucagon (70.4 +/- 3.1 vs. 44.5 +/- 3.1 min, P < 0.01); 4) there was a negative correlation between the CI and transit time (r = -0.427, P = 0.048); and 5) the excitatory effect of SIES was blocked by atropine. SIES may have a therapeutic potential for treating patients with small intestinal disorders.


Bevirimat: a novel maturation inhibitor for the treatment of HIV-1 infection.
Existing antiretroviral treatments for HIV type-1 (HIV-1) disease are limited by problems of resistance and drug-drug interactions. Bevirimat is a novel HIV-1 maturation inhibitor with a mechanism of action that is distinct from other antiretroviral agents. Specific inhibition of the final rate-limiting step in Gag processing by bevirimat prevents release of mature capsid protein from its precursor (CA-SP1), resulting in the production of immature, non-infectious virus particles. Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients, with peak plasma concentrations attained approximately 1-3 h after dosing. Plasma concentrations decrease in a log-linear manner with a mean plasma elimination halflife of 58-80 h, supporting once-daily dosing. Animal studies suggest that elimination of bevirimat is primarily by hepatic glucuronidation and hepatobiliary excretion. There is minimal renal elimination, with < 1% of the administered dose appearing in the urine. In responsive patients, bevirimat has demonstrated a robust dosedependent reduction in viral load (> 1.5 log10 copies/ml). Short-term administration (< or = 14 days) of bevirimat is well tolerated, even when used in combination with other antiretroviral agents. Further studies to evaluate the long-term efficacy and tolerability of bevirimat are currently underway.


The beliefs and practices of traditional birth attendants in the Manxili area of KwaZulu, South Africa: a qualitative study.
The World Health Organization recommends that people be within an hour of the nearest health care facility. In the Manxili region of KwaZulu, South Africa, difficult terrain and tribal fighting make this nearly impossible for pregnant women. Therefore, traditional birth attendants provide much of the midwifery services in this area. They have no medical training, and their beliefs and practices are not well understood. This study, therefore, gathered data on the beliefs and practices of seven attendants, using a case study analysis. Beneficial as well as harmful customs were identified and suggestions made for education of the attendants.


Pandemics, Polycentricity and Public Perceptions: Lessons from the Djokovic Saga.
Since the early 1960s the analytical lens of polycentricity has provided an opportunity to understand complex systems and how they intersect in a variety of environments. With a contemporary origin in governance, regulation and political science scholarship, polycentricity analysis has focused on overlap and conflict in systems and the potential for reduction in effectiveness of service provision. This paper reviews contemporary thinking on polycentricity, including in the context of the COVID-19 pandemic. It instances the unfortunate events leading to the failed application for judicial review in the Full Court of the Federal Court of Australia by the tennis player, Novak Djokovic (Djokovic v Minister for Immigration, Citizenship, Migrant Services and Multicultural Affairs [2022] FCAFC 3) as an example of the efforts that need to be made in the midst of a public health crisis in the interests of community trust in government to ensure that there is co-ordination and consistency of messaging and decision-making.


Effects of stress on psychophysiological parameters of electricity distribution network controllers in Ukraine.
The purpose was to reveal the effects of stress on the parameters of cognitive performance and cardiovascular system activities in controllers working 12-hour shifts. Sixteen controllers were studied, and altogether 384 subject observations were acquired. A 5-point scale was used to estimate the perceived level of stress experienced by the controllers. Increased heart rate and heart activity-related haemodynamic parameters were found with an increase in perceived stress. Decreases found in heart rate, circulatory minute volume, and Kerdo's vegetative index over the shift became less pronounced with increased stress. Better attention was found under the average level of stress that was found on the first day shift. An effect of stress on short-term memory was not revealed. As a whole, the most pronounced changes were found during the first day shift and less pronounced changes appeared during the first night shift. Effects of stress were not found in changes of the studied parameters during the second consecutive day or night shift. Thus, increased stress causes the activation of some psychophysiological functions (attention and cardiac activity) that are indispensable for high work efficiency under increased production demands. However, the necessary activation could not be maintained during the second consecutive 12-hour shifts, probably because of accumulated fatigue, and also night work. On the other hand, too high stress may lead to the excessive activation of cardiac activity and deterioration of attention.


Anterior cerebral artery dissection presenting subarachnoid hemorrhage and cerebral infarction.
A 35-year-old man presented with simultaneous occurrence of subarachnoid hemorrhage (SAH) and cerebral infarction (CI) caused by anterior cerebral artery (ACA) dissection. He complained of sudden onset of left frontal headache and his symptoms progressed to consciousness disturbance and right hemiparesis. Computed tomography and magnetic resonance imaging demonstrated SAH localized in the left interhemispheric fissure and CI in the territory of the left ACA. Right carotid angiography demonstrated a long double lumen sign at the left A2 to A4 segment of the left ACA, leading to a diagnosis of the combined type of CI and SAH caused by ACA dissection. Although many surgeons have previously tried to perform endovascular treatment, we selected only medication in this case, and his neurological findings gradually improved. Only 9 cases including the present case presented with simultaneous occurrence of SAH and CI caused by ACA dissection. Many of these patients showed stenosis with dilatation of ACA on carotid angiography. The prognoses of these patients were good. However, many SAH patients with dissecting aneurysm had poor prognoses. To improve the strategy for managing ACA dissection, we need to accumulate a greater number of such cases in the future. We also recommend that angiography should be performed in the patients with ACA dissection.


Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts.
Bone and immune system are functionally interconnected. Immune and bone cells derive from same progenitors in the bone marrow, they share a common microenvironment and are being influenced by similar mediators. The evidence on increased bone resorption associated with inappropriate activation of T cells such as during inflammation, is well established. However, the molecular mechanisms beyond this clinical observation have begun to be intensively studied with the advancement of osteoimmunology. Now days, we have firm evidence on the influence of numerous proinflammatory cytokines on bone cells, with the majority of data focused on osteoclasts, the bone resorbing cells. It has been shown that some proinflammatory cytokines could possess osteoclastogenic and/or anti-osteoclastogenic properties and can target osteoclasts directly or via receptor activator of nuclear factor kappaB (RANK)/RANK ligand(RANKL)/osteoprotegerin (OPG) system. Several studies have reported opposing data regarding (anti)osteoclastogenic properties of these cytokines. Therefore, the first part of this review is summarizing current evidence on the influence of pro-inflammatory cytokines on osteoclasts and thus on bone resorption. In the second part, the evidence on the role of pro-inflammatory cytokines in osteoporosis and osteoarthritis is reviewed to show that unravelling the mechanisms beyond such complex bone diseases, is almost impossible without considering skeletal and immune systems as an indivisible integrated system.


Optimization of Escherichia coli growth by controlled addition of glucose.
During aerobic growth of Escherichia coli (recombinant K-12 and strain B) on protein hydrolysate (L-broth) and a carbon source (glucose), acetic acid is produced via glucose metabolism until the late log phase. At this point, the culture pH starts to increase and the growth rate decreases. In cultures without further glucose supplementation, these changes are associated with the accumulation of ammonia, the utilization of acetic acid, the depletion of amino acids, and the complete depletion of glucose. We hypothesize that, after depletion of the glucose, the bacteria catabolize amino acids for energy and carbon and give off the nitrogen as ammonia. Also contributing to the overall increase in pH is the depletion of the acetic acid produced earlier as it is metabolized upon exhaustion of glucose. However, there is a lag time of about 1 hour after the initial pH increase before the sustained accumulation of ammonia begins. This lag indicates that an unidentified factor, in addition to the increase in ammonia, contributes to the increase in pH. Advantage was taken of the turnaround from acid production to base production as reflected in the culture pH to implement the addition of glucose. In growth experiments during which the pH was controlled in the basic direction by glucose addition, the observed decrease in growth rate was significantly postponed and the pH change in the basic direction was reversed as a result of acid production by the cells from the newly added glucose. Furthermore, coll densities of twice that obtained without glucose feeding were demonstrated. Based on the media cost per unit cell density, the data indicate a 31% cost savings.


The effect of temperature change on the working and setting time of two luting cements.
The effect of temperature change on the working and setting time of a glass ionomer luting cement and a resin luting cement was measured using the oscillating rheometer. The time taken for each cement to set was calculated from the chart recordings. It was observed that as the temperature increased, the working and setting time of both materials decreased. However, the reduction was much more marked for the dual curing resin cement.


Angiotensin II generation at the cell surface of activated neutrophils: novel cathepsin G-mediated catalytic activity that is resistant to inhibition.
Human neutrophils express inducible, catalytically active cathepsin G on their cell surface. Herein, we report that membrane-bound cathepsin G on intact neutrophils has potent angiotensin II-generating activity. Membrane-bound cathepsin G on activated neutrophils 1) converts both human angiotensin I and angiotensinogen to angiotensin II; 2) expresses angiotensin II-generating activity equivalent to 8.6 +/- 2.3 (+/-SD) x 10(-18) mol of free cathepsin G (5.2 +/- 1.4 x 10(6) molecules)/cell; and 3) has similar high affinity for angiotensin I compared with free cathepsin G (Km = 5.9 x 10(-4) and 4.6 x 10(-4) M; k(cat) = 4.0 and 2.0/s, respectively). In marked contrast to soluble cathepsin G, membrane-bound enzyme was substantially resistant to inhibition by plasma proteinase inhibitors and converted angiotensin I to angiotensin II even in undiluted plasma. There was a striking inverse relationship between inhibitor size and its effectiveness against membrane-bound cathepsin G activity. Alpha1-antichymotrypsin was a markedly ineffective inhibitor of membrane-bound enzyme (IC50 = 2.18 microM and 1.38 nM when tested against 1 nM membrane-bound and free cathepsin G, respectively). These data indicate that membrane-bound cathepsin G expressed on neutrophils is an inducible and mobile angiotensin II-generating system that may exert potent local vasoactive and chemoattractant properties at sites of inflammation.


Transcranial direct current stimulation suggests not improving postural control during adapted tandem position in people with Parkinson's disease: A pilot study.
Balance impairments in people with Parkinson's disease (PD) demonstrated mainly in challenging postural tasks, such as increased body oscillation may be attributed to the deficits in the brain structures functionality involved in postural control (e.g., motor cortex, midbrain, and brainstem). Although promising results, the effect of transcranial direct current stimulation (tDCS) on postural control in people with PD is unclear, especially in objective measures such as the center of pressure (CoP) parameters. Thus, we analyzed the effects of a single session of tDCS on the CoP parameters during the adapted tandem position in people with PD. Nineteen people with PD participated in this crossover, randomized, and double-blind study. Anodal tDCS was applied over the primary motor cortex in two conditions of stimulation (2 mA/active and sham) on two different days for 20 min immediately before the postural control evaluation. Participants remained standing in an adapted tandem position for the postural control assessment for 30 s (three trials). CoP parameters were acquired by a force plate. No significant differences were demonstrated between stimulation conditions (p-value range = 0.15-0.89). Our results suggested that a single session of tDCS with 2 mA does not improve the postural control of people with PD during adapted tandem.


Antibacterial capacity of differentiated murine embryonic stem cells during defined in vitro inflammatory conditions.
Embryonic stem (ES) cells are a powerful model for the development of cells responsible for the cellular immune response. Therefore, we analyzed the defense and phagocytic capacity of embryoid bodies (EBs) derived from ES cells using in the vitro inflammatory conditions caused by Escherichia coli. Further, we used this phagocytic activity to purify activated immune cells. Our data show that spontaneously differentiated 18-day-old EBs of the cell line CGR8 contained immune cells, which were positive for CD45, CD68, CD11b, F4/80, and CD19. Exposure of these EBs to E. coli with defined infection doses of bacterial colony-forming units (CFUs) led to a significant time-dependent reduction of CFUs, indicating the immune responses exerted by EBs. This was paralleled by an upregulation of inflammatory cytokines, that is, IL-1β and TNF-α. Western blot analysis of infected EBs indicated an upregulation of CD14 and cytochrome b-245 heavy chain (NOX2). Silencing of NOX2 significantly reduced the antibacterial capacity of EBs, which was partially explained by reduction of F4/80-positive cells. To identify, isolate, and further cultivate phagocytic active cells from differentiated EBs, a cocultivation assay of differentiated ES cells with green fluorescent protein (GFP)-labeled E. coli was established. Colocalization of GFP-labeled E. coli with cells positive for CD45, CD68, and F4/80 revealed time-dependent phagocytotic uptake, which was underlined by colocalization with the LysoTracker-Red(®) dye as well as preincubation with cytochalasin D. In conclusion, a primitive immune response with efficient phagocytosis was responsible for the antibacterial capacity of differentiated EBs.


Comparison of the broncoalveolar lavage fluid proteomics between foals and adult horses.
Neonates have different cellular composition in their bronchoalveolar lavage fluid (BALF) when compared to foals and adult horses; however, little is known about the non-cellular components of BALF. The objective of this study was to determine the proteomic composition of BALF in neonatal horses and to compare it to that of foals and adult horses. Bronchoalveolar lavage fluid samples of seven neonates (< 1 week age), four 5 to 7-week-old foals, and six adult horses were collected. Quantitative proteomics of the fluid was performed using tandem mass tag labeling followed by high resolution liquid chromatography tandem mass spectrometry and protein relative abundances were compared between groups using exact text. A total of 704 proteins were identified with gene ontology terms and were classified. Of these, 332 proteins were related to the immune system in neonates, foals, and adult horses. The most frequent molecular functions identified were binding and catalytic activity and the most common biological processes were cellular process, metabolic process, and biological regulation. There was a significant difference in the proteome of neonates when compared to foals and to adult horses. Neonates had less relative expression (FDR < 0.01) of many immune-related proteins, including immunoglobulins, proteins involved in the complement cascade, ferritin, BPI fold-containing family B member 1, and macrophage receptor MARCO. This is the first report of equine neonate BALF proteomics and reveals differential abundance of proteins when compared to BALF from adult horses. The lower relative abundance of immune-related proteins in neonates could contribute to their susceptibility to pulmonary infections.


Distribution of H type 1 and H type 2 antigenic determinants in human sera and saliva.
A radioimmunoassay specific for the H type 1 antigenic determinant demonstrated that the H type 1 antigen is under the strict control of the Se gene in both serum and saliva. Similar amounts of H type 1 antigenic determinants were found in saliva from Se/-, le/le donors and in saliva from Se/-, Le/- donors. However, sera from Se/-, le/le donors were about 100 times more efficient in inhibiting the H type 1 assay than were sera from Se/-, Le/- donors. A radioimmunoassay, based on the binding of Ulex europaeus with the H type 2 antigenic determinant, showed that all the H type 2 antigen in saliva is under the control of the Se gene, while only one-third of the H type 2 antigen present in serum is under the control of this gene. The remaining two-thirds of H type 2 antigen in sera is independent of the ABH secretor status of the donor. The amount of H type 2 antigen in both serum and saliva is independent of the Le gene. These results are compatible with the existence of two alpha (1 leads to 2) fucosyl-transferases but suggest that the enzyme of epithelial origin, coded by the Se gene, should be able to transform both type 1 and type 2 natural substrates, while the enzyme of mesodermic origin, coded by the H gene, would work preferentially on the natural type 2 substrates.


Eye color as a predictor of outcomes in behavior therapy.
Eye color research has centered primarily on the dimension of self-paced vs. reactive performance. Self-paced activities are those in which the individual may initiate the activity when he/she chooses while the stimulus situation remains relatively constant. Reactive activities must be initiated at the precise time dictated by a rapidly changing stimulus situation. The present study examined the relationship between outcomes of behaviorally oriented treatment for children (N = 366) and eye color. The findings were consistent with theoretical expectations: Dark-eyed children and teenagers responded better to reactive treatment programs than their light-eyed counterparts, while the reverse was true for self-paced treatment programs. Implications for research and practice were discussed.


[Neurological complications in renal transplant recipients].
Renal transplantation is method of choice for treatment of patients with end-stage renal disease without contraindications for immunosuppressive therapy. Neurological complications occur frequently in renal transplant recipients. They may be the consequence of immunosuppressive treatment, but more often evolve as the consequence of previous disturbances which developed during the state of uraemia and treatment with dialysis. The most pronounced neurotoxic effect has calcineurin inhibitors tacrolimus and cyclosporine. The spectrum of neurological disturbances caused by calcineurin inhibitors range from very mild symptoms as paraesthesiae, tremor, headache or flushing, to severe changes that may cause lethal outcome. Peripheral neuropathies in renal transplant recipients may occur in the form of mononeuropathy or polyneuropathy. Cerebrovascular diseases are consequence of changes on blood vessels caused by uraemia, dialysis and side effects of immunosuppressive drugs. They cause death in 8% of renal transplant recipients. Central nervous system (CNS) infections usually occur during the first posttransplant year. Unclear symptomatology frequently postpones the diagnosis. Diagnostic evaluation should include magnetic resonance imaging for localization of the process, as well as lumbal puncture in cases without contraindications for the procedure, in order to determine the causative agent. Regarding the ominous prognosis of CNS infections in the immunocompromised host, only timely diagnosis may improve survival. The most common causative agents are Cryptococcus neoformans, Listeria monocytogenes and Aspergillus funigatus. Viral infections also occur, and are commonly caused by herpes virideae, varicella-zoster virus and papova virus. CNS infections clinically present as meningitis, progressive dementia or focal neurological defect. The most common primary brain tumors are B-cell lymphomas, but glioblastoma, hemangioblastoma, leiomyosarcoma or glioma may also occur. In cases of neurological posttransplant complications, optimal treatment should be guided by neurologist, nephrologist and infectologist, in some cases also by neurosurgeons.


Square and rhombic lattices of magnetic skyrmions in a centrosymmetric binary compound.
Magnetic skyrmions are topologically stable swirling spin textures with particle-like character, and have been intensively studied as a candidate of high-density information bit. While magnetic skyrmions were originally discovered in noncentrosymmetric systems with Dzyaloshinskii-Moriya interaction, recently a nanometric skyrmion lattice has also been reported for centrosymmetric rare-earth compounds, such as Gd2PdSi3 and GdRu2Si2. For the latter systems, a distinct skyrmion formation mechanism mediated by itinerant electrons has been proposed, and the search of a simpler model system allowing for a better understanding of their intricate magnetic phase diagram is highly demanded. Here, we report the discovery of square and rhombic lattices of nanometric skyrmions in a centrosymmetric binary compound EuAl4, by performing small-angle neutron and resonant elastic X-ray scattering experiments. Unlike previously reported centrosymmetric skyrmion-hosting materials, EuAl4 shows multiple-step reorientation of the fundamental magnetic modulation vector as a function of magnetic field, probably reflecting a delicate balance of associated itinerant-electron-mediated interactions. The present results demonstrate that a variety of distinctive skyrmion orders can be derived even in a simple centrosymmetric binary compound, which highlights rare-earth intermetallic systems as a promising platform to realize/control the competition of multiple topological magnetic phases in a single material.


Network Optimization of Functional Connectivity Within Default Mode Network Regions to Detect Cognitive Decline.
The rapid aging of the world's population is causing an increase in the prevalence of cognitive decline and degenerative brain disease in the elderly. Current diagnoses of amnestic and nonamnestic mild cognitive impairment, which may represent early stage Alzheimer's disease or related degenerative conditions, are based on clinical grounds. The recent emergence of advanced network analyses of functional magnetic resonance imaging (fMRI) data taken at cognitive rest has provided insight that declining functional connectivity of the default mode network (DMN) may be correlated with neurological disorders, and particularly prodromal Alzheimer's disease. The goal of this paper is to develop a network analysis technique using fMRI data to characterize transition stages from healthy brain aging to cognitive decline. Previous studies primarily focused on inter-nodal connectivity of the DMN and often assume functional homogeneity within each DMN region. In this paper, we develop a technique that focuses on identifying critical intra-nodal DMN connectivity by incorporating sparsity into connectivity modeling of the k -cardinality tree (KCT) problem. Most biological networks are efficient and formed by sparse connections, and the KCT can potentially reveal sparse connectivity patterns that are biologically informative. The KCT problem is NP-hard, and existing solution approaches are mostly heuristic. Mathematical formulations of the KCT problem in the literature are not compact and do not provide good solution bounds. This paper presents new KCT formulations and a fast heuristic approach to efficiently solve the KCT models for large DMN regions. The results in this paper demonstrate that traditional fMRI group analysis on DMN regions cannot detect any statistically significant connectivity differences between normal aging and cognitively impaired subjects in DMN regions, and the proposed KCT approaches are more sensitive than the state-of-the-art regional homogeneity approach in detecting significant differences in both left and right medial temporal regions of the DMN.


The control of firing pattern in nigral dopamine neurons: burst firing.
In addition to firing in a single spiking mode, dopamine (DA) cells have been observed to fire in a bursting pattern with consecutive spikes in a burst displaying progressively decreasing amplitude and increasing duration. In vivo intracellular recording demonstrated the bursts to typically ride on a depolarizing wave (5 to 15 mV amplitude). Although the burst-firing frequency of DA cells showed little correlation with the base line firing rate, increases in firing rate were usually associated with an increase in burst firing. Increases in burst firing could also be elicited by intracellular calcium injection and could be prevented by intracellular injection of EGTA, suggesting a calcium involvement in bursting. Blockade of potassium conductances with extracellular iontophoresis of barium or intracellular injection of tetraethylammonium bromide could also trigger an increased degree of burst firing in DA cells. These data suggest that the increased calcium influx accompanying an increased firing rate triggers burst firing, possibly by inactivating a potassium conductance. A switch from a single spiking mode to a burst-firing mode may be important in modulating striatal DA release, as shown for burst firing in other preparations.


PIKfyve inhibitor cytotoxicity requires AKT suppression and excessive cytoplasmic vacuolation.
PIKfyve phosphoinositide kinase produces PtdIns(3,5)P2 and PtdIns5P and governs a myriad of cellular processes including cytoskeleton rearrangements and cell proliferation. The latter entails rigorous investigation since the cytotoxicity of PIKfyve inhibition is a potential therapeutic modality for cancer. Here we report the effects of two PIKfyve-specific inhibitors on the attachment/spreading and viability of mouse embryonic fibroblasts (MEFs) and C2C12 myoblasts. Importantly, 18-h treatment of adherent cells with YM201636 (800 nM) and apilimod (20 nM) in serum-containing culture media did not affect cell viability despite the presence of multiple cytoplasmic vacuoles, a hallmark of PIKfyve inhibition. Strikingly, at the same dose and duration the inhibitors caused excessive cytoplasmic vacuolation, initial suppression of cell attachment/spreading and subsequent marked detachment/death in serum-deprived cells. The remaining adherent cells under serum-deprived conditions had smaller surface area, lacked vinculin/actin-positive focal adhesions and displayed vacuoles occupying the entire cytoplasm. Serum or growth factors protected against PIKfyve inhibitor cytotoxicity. This protection required Akt activation evidenced by the abrogated beneficial effect of serum upon treatment with the clinically-relevant Akt inhibitor MK-2206. Moreover, Akt inhibition triggered cell detachment/death even in serum-fed adherent MEFs treated with apilimod. Intriguingly, BafilomycinA1 (H+-vacuolar ATPase inhibitor), which prevents the cytoplasmic vacuolation under PIKfyve perturbations, rescued all defects in attaching/spreading as well as in adherent cells under serum-starved or serum-fed conditions, respectively. Together, the results indicate that the cytotoxicity of PIKfyve inhibitors in MEFs and C2C12 myoblasts requires Akt suppression and excessive cytoplasmic vacuolation.


Disparate developmental patterns of immune responses to bacterial and viral infections in fish.
During early stages of development vertebrates rely on an immature immune system to fight pathogens, but in non mammalian species few studies have taken an in-depth analysis of the transition from reliance on innate immune mechanisms to the appearance of adaptive immunity. Using rainbow trout as a model we characterized responses to two natural pathogens of this species, the Gram negative bacterium Aeromonas salmonicida and the virus VHSV, using microarray analysis at four early life history stages; eyed egg, post hatch, first feeding and three weeks post first feeding when adaptive immunity starts to be effective. All stages responded to both infections, but the complexity of the response increased with developmental stage. The response to virus showed a clear interferon response only from first feeding. In contrast, bacterial infection induced a marked response from early stages, with modulation of inflammatory, antimicrobial peptide and complement genes across all developmental stages. Whilst the viral and bacterial responses were distinct, there were modulated genes in common, mainly of general inflammatory molecules. This work provides a first platform to explore the development of fish immunity to infection, and to compare the age-dependent changes (from embryo to adults) across vertebrates.


Transplantation of displaced and dilacerated anterior teeth.
The therapy of dilacerated permanent anterior teeth usually involves surgically removing the tooth. Subsequently, orthodontic methods for closing the space or keeping it open are preferred until the patient reaches an age when definitive implantological or prosthetic treatments may be used. Anterior tooth transplantation should be considered as an alternative to surgically extracting the tooth. This study describes a period of investigation covering 3 years during which neither replacement resorption nor inflammatory resorption was diagnosed in the five transplanted teeth. The clinical tooth mobility was similar to that of the adjacent teeth. In spite of the vertical loss of bone shown radiographically no pathologically enlarged pockets or recessions have been found. It is not yet possible to make any comments on the prognosis for the long term.


Pharmacokinetic drug evaluation of avibactam + ceftazidime for the treatment of hospital-acquired pneumonia.
Ceftazidime-avibactam (CAZ-AVI) is a combination of a third-generation cephalosporin and a non-β-lactam, β-lactamase inhibitor, recently approved for urinary tract infections and complicated abdominal infections. Moreover, it represents a treatment option for patients with hospital acquired pneumonia (HAP), especially when caused by multidrug-resistant (MDR) bacteria. Areas covered: The review focuses on the pharmacokinetics (PK) of CAZ-AVI in HAP and on preclinical and clinical studies evaluating PK/pharmacodynamics (PD) in this field. Expert opinion: In vitro and in vivo data about PK/PD of CAZ-AVI confirm that penetration of CAZ-AVI in the epithelial lining fluid (ELF) represents approximately 30% of the plasma concentrations. Clinical studies documented that CAZ-AVI 2000 mg/500 mg every 8 h is the optimal dose regimen to achieve the PK/PD target attainment in patients with HAP. Thus, CAZ-AVI could represent an option both to treat HAP caused by Gram-negative bacilli (GNB) displaying resistance to most of the antibiotics and to reduce the use of carbapenems, limiting the onset of resistance profiles among GNB. Additional information about specific patients populations, such as critically-ill subjects or pediatric patients, are needed for a more individualized use of CAZ-AVI.


[Protection of patient rights in system of compulsory medical insurance].
The features of patients' strategies realizing their legal interests in compulsory medical insurance was studied. The survey included 568 respondents and 3 in-focus interviews was organized. The research data revealed people's lower awareness of their health care rights. Typology of behavior models related to rights protection had been developed on the basis of such criteria as readiness to protect one's own legal interests in compulsory medical insurance and expected outcomes of one's activities. The patterns of passive pessimistic, active pessimistic and active optimistic patients' strategies had been highlighted.


[Varicella zoster infections and neurologic complications].
We describe three patients who suffered from neurological complications to varicella-zoster virus infections. One had polyradiculoneuritis, another myelitis, and a third suffered from focal encephalitis. These patients were all treated with acyclovir, and showed good recovery within a few days. The diagnosis must be based on clinical characteristics, together with virological and immunological tests. The indications for antiviral treatment are discussed.


Causes of enlarged sternal bursas (breast blisters).
Bursas were taken weekly as normal turkeys developed from 3 to 22 weeks of age, and no specific bacterial or viral infection was found. Bacterial cultures were also made of condemned bursas taken at processing. Of 144 collected, 91% were sterile; the others had staphylococci, streptococci, or coliform organisms. Experiments with turkeys measured the effect of strain, body conformation, completeness of breast-feather cover, protection of the keel with sheepskins, age when put on range, and type of range on the incidence of enlarged sternal bursas. The strain difference of 25.4% breast blisters against 11.5% was highly significant (99% confidence). In one experiment the effect of feather cover was significant at the 95% level of confidence (61.7% breast blisters with no feather cover, versus 40% with complete feather cover). The effect of protecting the breast with sheepskin was significant at the 95% level of confidence in reducing incidence of breast blisters. There was no significant difference in the incidence of breast blisters in relation to body conformation, age, or type of range.


Renal vascular adjustments to partial renal venous obstruction in dog kidney.
Blood flow studies were conducted in neurolept anesthetized dogs to characterize the involvement of renal nerves in ipsilateral renal vasoconstriction seen during acute elevation of renal venous pressure above 30 mm Hg. Renal blood flow was measured electromagnetically. The vasoconstrictor response was almost abolished by acute surgical denervation of the kidney, since renal vascular conductance remained unchanged during renal venous pressure elevation from 30-60 mm Hg. However, following additional alpha-adrenoceptor blockade or chronic renal denervation, renal vascular conductance increased progressively during renal venous pressure elevation to 60 mm Hg. The effect of acute decapsulation of kidney was studied in another group of dogs. Decapsulation induced a vasoconstriction. The decrease in renal vascular conductance observed during renal venous pressure elevation was unaffected by acute surgical denervation of decapsulated kidney, but was almost abolished following additional alpha-adrenoceptor blockade or chronic denervation. In decapsulated chronically denervated kidney, the increase in renal vascular conductance during renal venous pressure elevation to 60 mm Hg was still present but considerably attenuated as compared with the chronically denervated kidney with intact capsule. The renin-angiotensin system did not participate in acute vascular adjustments to renal venous stasis in intact kidney or in decapsulated acutely surgically denervated kidney. The data favor the view that neurogenic and myogenic mechanisms significantly influence the vasoconstrictor response to renal venous pressure elevation in dog kidney. The neurogenic contribution to the vasoconstrictor response comprises intrarenal and extrarenal vasoconstrictor mechanisms evoked reflexively by renal venous pressure elevation, and the myogenic contribution to the vasoconstrictor response comprises opposing vasodilator mechanisms due to increase in renal interstitial tissue pressure during renal venous pressure elevation.


Recurrence patterns identify aggressive form of human papillomavirus-dependent vulvar cancer.
Vulvar cancer is rare and, as a result, is understudied. Treatment is predominantly surgery, irrespective of the type of vulvar cancer, and is associated with physical, emotional and sexual complications. A cluster of human papillomavirus (HPV)-dependent vulvar cancer patients was identified in Arnhem Land Northern Territory (NT), Australia, in which young Indigenous women were diagnosed at 70 times the national incidence rate. To assess whether women from the Arnhem Land cluster differ from women with vulvar squamous cell carcinoma (VSCC) and vulvar intraepithelial neoplasia (VIN) resident elsewhere in the NT in recurrence after treatment, disease progression and mortality. A retrospective cohort study of NT-resident women diagnosed with VIN or invasive vulvar cancer (VSCC) between 1 January 1993 and 30 June 2015 was undertaken. Time to recurrence was assessed using cumulative incidence plots and Fine and Gray competing risk regression models. Mean cumulative count was used to estimate the burden of recurrent events. Indigenous women from Arnhem Land experienced more recurrences after treatment than non-Indigenous women, the cancers recurred faster, and Indigenous women have worse survival at five years. In characterising the epidemiological features of this cluster, we have identified a particularly aggressive form of vulvar cancer. This provides a unique opportunity for elucidating the aetiopathological pathways driving vulvar cancer development that may ultimately lead to preventive and therapeutic targets for this neglected malignancy. Further, these findings have important implications for clinical practice and HPV vaccination policy in the affected population.


Pyrrolizine/indolizine-bearing (un)substituted isoindole moiety: design, synthesis, antiproliferative and MDR reversal activities, and in silico studies.
Two new series of pyrrolizine/indolizine derivative-bearing (un)substituted isoindole moiety were designed and synthesized. The anticancer potential of the new compounds was evaluated against hepatocellular carcinoma (HepG-2), colorectal carcinoma, colon cancer (HCT-116), and breast cancer (MCF-7) cell lines. Compounds 6d and 6o were the most potent derivatives with IC50 values ranging from 6.02 to 13.87 μM against HePG-2, HCT-116, and MCF-7 cell lines. Moreover, methyl analog of the fluoro-substituted indolizine derivative 6m revealed significant antiproliferative activity against HePG-2, HCT-116, and MCF-7 cancer cell lines with IC50 values of 11.97, 28.37, and 19.87 μM, respectively. The most active anticancer analogs, 6d, 6m, and 6o, were inspected for their putative mechanism of action by estimating their epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK 2) inhibitory activities. Thus, compound 6o displayed the most inhibitory activity against EGFR and CDK 2 with IC50 values of 62 and 118 nM, respectively. Additionally, the quantitative real-time PCR analysis for the P-glycoprotein effect of compounds 6d, 6m, and 6o was performed, in which compound 6o illustrated significant down-regulation of P-gp against the HepG-2 cell line by 0.2732 fold. Mechanistic studies for the most active compounds involving the reversal doxorubicin (DOX) effect of compounds 6d, 6m, and 6o were performed, which illustrated cytotoxic activity with IC50 22.27, 3.88, and 8.79 μM, respectively. Moreover, the apoptotic activity of the most active derivative 6o on HCT-116 cancer cells showed accumulation in the G1 and S phases of the cell cycle.


Coronary bypass versus percutaneous intervention: sex matters. The impact of gender on long-term outcomes of coronary revascularization.
Women have a higher mortality than men following coronary artery bypass grafting (CABG). The influence of patient sex on outcomes of percutaneous coronary interventions (PCI) is controversial. Since patient selection for randomized clinical trials may not reflect clinical practice, we investigated the impact of sex on outcomes of CABG versus PCI in a comprehensive registry of coronary revascularization (CR). All patients undergoing CR in a network of eight community hospitals were enrolled. Follow-up was obtained after 5 years (median, 79.7 months). ST-elevation myocardial infarction (MI) patients were excluded. Propensity-score matching accounted for differences between groups. There were 2162 men (673 CABG, 1489 PCI) and 991 women (294 CABG, 697 PCI). Survival free from major adverse cardiac events (MACE)-all cause mortality, nonfatal MI, re-intervention at 5 years for PCI versus CABG was 77.1 +/- 1.1 vs. 83.1 +/- 1.5, hazard ratio (HR) 0.588 (95% confidence interval [CI]: 0.491-0.704; P < 0.001) for men, but 75.0 +/- 1.6 vs. 74.5 ± 2.5, HR 0.869 (95% CI: 0.687-1.100; P = 0.24) for women. After matching, MACE-free survival for men remained significantly different, 69.5 +/- 2.2 vs. 79.5 +/- 2.0, HR 0.548 (95% CI: 0.424-0.682; P < 0.001) but not for women, 68.1 +/- 3.4 vs. 69.4 +/- 3.4, HR 0.752 (95% CI: 0.540-1.049; P = 0.093). In a 'real world' unselected cohort of CR patients, men enjoy improved survival and reduced MACE with CABG versus PCI. Outcomes for women are worse than for men and are equivalent with either procedure, emphasizing importance of accounting for sex in assessing outcomes of comparative CR procedures.


A unified approach to photon and beta particle dosimetry.
The purpose of this investigation was to develop a unified and practical method for photon and beta particle dosimetry. This was achieved by developing a point-source function that is equally valid for photons and beta particles. This function contains four fitting parameters. These were computed on the basis of Berger's tables for a wide range of photon and beta particle energies. Explicit formulas were derived for the absorbed fraction within and outside of spheres containing a uniform distribution of activity. For photons, calculations of the absorbed fraction at the center of spheres were compared with the results of Monte Carlo calculations. The two methods yielded essentially identical results, validating the approach used in this study. The results of this study show that there are absorbed-dose gradients as a function of distance from the center of a sphere. These should be taken into account in absorbed-dose calculations. For beta particles, it is shown explicitly that for spheres with a radius of 0.08 cm, absorbed-dose rates from 131I and 90Y beta particles are equal. An important feature of this work is that calculations can be made on the macroscopic, cellular and subcellular levels. The approach employed and results obtained in this work should be particularly useful for tumor dosimetry in radionuclide therapy and applicable radiobiological investigations.


Machine learning application for the prediction of SARS-CoV-2 infection using blood tests and chest radiograph.
Triaging and prioritising patients for RT-PCR test had been essential in the management of COVID-19 in resource-scarce countries. In this study, we applied machine learning (ML) to the task of detection of SARS-CoV-2 infection using basic laboratory markers. We performed the statistical analysis and trained an ML model on a retrospective cohort of 5148 patients from 24 hospitals in Hong Kong to classify COVID-19 and other aetiology of pneumonia. We validated the model on three temporal validation sets from different waves of infection in Hong Kong. For predicting SARS-CoV-2 infection, the ML model achieved high AUCs and specificity but low sensitivity in all three validation sets (AUC: 89.9-95.8%; Sensitivity: 55.5-77.8%; Specificity: 91.5-98.3%). When used in adjunction with radiologist interpretations of chest radiographs, the sensitivity was over 90% while keeping moderate specificity. Our study showed that machine learning model based on readily available laboratory markers could achieve high accuracy in predicting SARS-CoV-2 infection.


Status of physical exercise and its association with obesity and hypertension in two urban assembly constituencies of East Delhi.
In a community based study using systematic random sampling in two urban Assembly constituencies in East Delhi, 420 subjects above the age of 30 years were interviewed to find out their status regarding physical exercise. People doing regular exercise were found to be only 44.8%. The commonest reason associated for not doing/irregular physical exercise was nonavailability of time (63.3%), followed by no need felt by the respondents to exercise (23.3%). The prevalence of obesity in the group doing regular exercise was much lower than the group that was not doing regular exercise and the results were statistically significant. Though a similar association was found with hypertension also, the results were not statistically significant.