Leuprorelin acetate depot in advanced prostatic cancer: a phase II multicentre trial.
The therapeutic efficacy and safety of various doses of leuprorelin acetate depot were determined in an open, multicentre study of patients with locally advanced or metastatic prostatic cancer (stages C, D1 or D2). Patients were randomly assigned to receive 3.75 mg (30 cases), 7.5 mg (eight cases), 15 mg (eight cases) and 30 mg (one patient) leuprorelin acetate depot administered subcutaneously once every 4 weeks. Of the 43 patients evaluable, two (5%) had complete remission, 23 (53%) partial remission and 13 (30%) patients stable disease. No significant differences were observed in response rates in relation to dose, disease stage or previous hormonal therapy. Disappearance or improvement in bone pain and urinary symptoms occurred in 63% and 79% of cases, respectively. Serum androgen concentrations decreased rapidly and persistently to castration levels, without significant differences for different doses. Treatment was well tolerated with a low incidence of mild side-effects - gynaecomastia (16%), nausea/vomiting (13%) and diarrhoea (2%). It is concluded that 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks is able to produce hormonal effects in all patients, an overall objective response comparable to that obtained using higher doses.


Excision of 8-oxoguanine from methylated CpG dinucleotides by human 8-oxoguanine DNA glycosylase.
CpG dinucleotides are targets for epigenetic methylation, many of them bearing 5-methylcytosine (mCyt) in the human genome. Guanine in this context can be easily oxidized to 8-oxoguanine (oxoGua), which is repaired by 8-oxoguanine-DNA glycosylase (OGG1). We have studied how methylation affects the efficiency of oxoGua excision from damaged CpG dinucleotides. Methylation of the adjacent cytosine moderately decreased the oxoGua excision rate while methylation opposite oxoGua lowered the rate of product release. Cytosine methylation abolished stimulation of OGG1 by repair endonuclease APEX1. The OGG1 S326C polymorphic variant associated with lung cancer showed poorer base excision and lost sensitivity to the opposite-base methylation. The overall repair in the system reconstituted from purified proteins decreased for CpG with mCyt in the damaged strand.


Study of ocular manifestations in tuberculosis and its association with HIV AIDS in a tertiary care hospital.
To assess and understand the prevalence and clinical presentation of ocular morbidity in patients suffering from tuberculosis and compare it with ocular involvement in patients coinfected with tuberculosis and HIV AIDS. This was a non-comparative, observational, cross sectional study done on 580 patients, who were diagnosed cases of tuberculosis, pulmonary or extrapulmonary, on or off treatment, visiting the Ophthalmology OPD, Tuberculosis OPD and ART Centre of the institute in the period from March 2015 to March 2018, screened for ocular morbidity. Out of 580, 408 patients had only tuberculosis and 172 had tuberculosis with HIV AIDS. 108 patients were found to have ocular involvement (18.6%) out of which 63 were males and 45 were females. The prevalence of ocular morbidity in patients with only tuberculosis was found to be 16.4% and in those having both tuberculosis and HIV AIDS was found to be 23.8%. Our study concludes that posterior uveitis, pan uveitis, periphlebitis and vitritis are the most common ocular manifestations in tuberculosis. In patients with both tuberculosis and HIV most common ocular findings included vitritis and herpes zoster ophthalmicus. Our study also concludes that lower CD4 counts (less than 200) in HIV AIDS patient is significantly associated with ocular involvement.


Effects of sodium and magnesium sulfate in drinking water on mallard ducklings.
One-day-old mallard (Anas platyrhynchos) ducklings were given drinking water for up to 28 days that contained concentrations of sodium and/or magnesium similar to those found in saline wetlands. Growth, tissue development, and biochemical characteristics of these ducklings were compared to those reared on fresh water. Much of the ingested salt was excreted by passage of voluminous fluid excreta. This effect occurred in birds given water with as little as 500 ppm Mg or 1,000 ppm Na. The supraorbital salt gland was active within 4 days in ducklings drinking water containing greater than or equal to 1,500 ppm of Na. Feather growth was decreased in ducklings drinking water with greater than or equal to 1,500 ppm of either Na or Mg. Ducklings drinking water with 3,000 ppm of either ion, or 1,500 ppm of each, grew more slowly than control birds. Ducklings drinking water with 3,000 ppm of either Na or Mg had reduced thymus size and bone breaking strength. Those drinking water with 3,000 ppm of Mg, or 3,100 ppm Na and 1,300 ppm Mg also had less trabecular bone and enlarged adrenals. Birds drinking the latter water had an elevated concentration of Na and calcium, and a decreased concentration of phosphorus and chloride in their serum, and elevated plasma protein levels. Ducklings reared on fresh or slightly saline water adapted very poorly to an abrupt change to more saline water (specific conductivity = 15,250 microns hos/cm) at 14 days of age. These birds stopped eating, became inactive and some died within 3 days; survivors had many tissue and biochemical abnormalities at 20 days of age. The level of salinity in these trials was similar to that in "brackish" or "moderately saline" wetlands and lower than that previously found to have effects on growth and feathering of ducklings. Many of the sublethal effects were subtle and non-specific manifestations of stress, and would be difficult to detect in wild ducklings on saline wetlands.


Importance of exercise stress testing in evaluation of unexplained cardiac arrest survivor.
In sudden cardiac arrest survivors without an immediately identifiable cause, additional extensive yet individualised testing is required. We describe 3 survivors of sudden cardiac arrest in whom exercise stress testing was not performed during the initial hospital admission. All 3 patients were incorrectly diagnosed with long QT syndrome based on temporary sudden cardiac arrest-related heart rate-corrected QT interval prolongation, and exercise stress testing was not performed during the initial work-up. When they were subjected to exercise stress testing during follow-up, a delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was made. As a result, these patients were initially managed inappropriately, and their family members were initially not screened for CPVT. In sudden cardiac arrest survivors without an immediately identifiable cause, omission of exercise stress testing or erroneous interpretation of the results can lead to a delayed or missed diagnosis of CPVT, which may have considerable implications for survivors and their family.


IL-26 modulates T cell function in autoimmune hepatitis.
Autoimmune hepatitis (AIH) is an aberrant autoimmune condition mediated by T cell abnormality, which may cause fulminant liver failure and persistent liver injury. This study aimed to disclose the histopathological and functional engagement of interleukin (IL)-26, a potent inflammation mediator, in AIH disease progression. We conducted immunohistochemical staining on liver biopsy samples to evaluate intrahepatic expression of IL-26. Cellular sources of hepatic IL-26 were detected by confocal microscopy. Flow cytometry was employed to determine the immunological alterations of CD4+ and CD8+ T cells following in vitro IL-26 treatment on primary peripheral blood mononuclear cells from healthy controls. Statistically significant increase in IL-26 level was observed in AIH (n = 48) liver samples in comparison with patients having chronic hepatitis B (n = 25), nonalcoholic fatty liver disease (n = 18), and healthy donors for living donor liver transplantation (n = 10). The number of intrahepatic IL-26+ cells was positively correlated with histological and serological severity. An immunofluorescence staining indicated that liver-infiltrating CD4+ T cells, CD8+ T cells, and CD68+ macrophages orchestrated IL-26 secretion in AIH. Both CD4+ and CD8+ T cells demonstrated effective activation, lytic, and proinflammatory functions upon IL-26 stimulation. We observed elevated IL-26 in AIH liver which promoted T cell activation and cytotoxic capacity, indicating a therapeutic potential of IL-26 intervention in AIH.


Gastric metastasis of breast cancer: A frequent mimicker of primary gastric cancer in breast cancer patients.
Gastric metastasis of breast cancer is a known mimicker of primary gastric cancer. This paper demonstrates that in patients with a history of breast cancer, gastric metastasis and primary gastric cancer are equally likely.


Predictors of mucositis in oropharyngeal and oral cavity cancer in patients treated with volumetric modulated radiation treatment: A dose-volume analysis.
The purpose of this study was to assess predictors of mucositis in oropharyngeal and oral cavity cancer after definitive or adjuvant volumetric modulated arc radiotherapy (VMAT) +/- chemotherapy. Fifty patients were evaluated. Statistical analysis was performed for the following parameters as potential predictors of mucositis ≥ G2: total oral mucosa and oral mucosa minus target high-low radiation dose regions (planning target volumes [PTVs]), mean dose (Dmean ), maximum dose (Dmax ), chemotherapy, weight loss, and dysphagia. Mucositis ≥ G2 was found to be statistically related to chemotherapy, weight loss, dysphagia ≥ G2, total oral mucosa Dmean ≥50 Gy and Dmax ≥65 Gy, V45 Gy >40%, V50 Gy >30%, and V55 Gy >20% of the oral mucosa minus target PTVs. A ratio between total oral mucosa and oral mucosa minus target PTVs >2.5 is related to G3 mucositis (p = .03). New parameters were found as predictors of moderate-severe mucositis. © 2015 Wiley Periodicals, Inc. Head Neck 38: E815-E819, 2016.


Human metapneumovirus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review.
Over the past decade, reported incidence of human metapneumovirus (hMPV) has increased owing to the use of molecular assays for diagnosis of respiratory viral infections in cancer patients. The seasonality of these infections, differences in sampling strategies across institutions, and small sample size of published studies make it difficult to appreciate the true incidence and impact of hMPV infections. In this systematic review, we summarized the published data on hMPV infections in hematopoietic cell transplant recipients and patients with hematologic malignancy, focusing on incidence, hMPV-associated lower respiratory tract infection (LRTI), mortality, prevention, and management with ribavirin and/or intravenous immunoglobulins. Although the incidence of hMPV infections and hMPV-associated LRTI in this patient population is similar to respiratory syncytial virus or parainfluenza virus and despite lack of directed antiviral therapy, the mortality rate remains low unless patients develop LRTI. In the absence of vaccine to prevent hMPV, infection control measures are recommended to reduce its burden in cancer patients.


Can ascospore ultrastructure differentiate between the genera Linocarpon and Neolinocarpon and species therein?
Ascospore appendages of two species of Linocarpon and three species of Neolinocarpon are illustrated using electron microscopy. The structure of these appendages can be used to distinguish between species. The ascospore appendages of species in both genera, however, were found to have similar structure. Thus, species of Linocarpon and Neolinocarpon could not be delineated at the generic level based on ascospore appendage structure.


Potassium currents activated in hippocampal neurons by serotonin are mediated by a change in intracellular calcium concentrations.
Intracellular activity was recorded from CA1 neurons in the slice preparation, by using K-acetate-, Bapta- or EGTA-filled micropipettes. The calcium chelator, Bapta, clamps [Ca]i more rapidly than EGTA and is less associated with pH changes. Neurons recorded with Bapta-filled micropipettes were much less sensitive to 5-HT and baclafen than those recorded with the standard K-acetate- or EGTA-filled micropipetes. These results suggest that [Ca]i is important for the generation of the 5-HT-dependent potassium current.


The tetraspanin network modulates MT1-MMP cell surface trafficking.
The membrane-type 1 matrix metalloproteinase (MT1-MMP) drives fundamental physiological and pathophysiological processes. Among other substrates, MT1-MMP cleaves components of the extracellular matrix and activates other matrix-cleaving proteases such as MMP-2. Trafficking is a highly effective means to modulate MT1-MMP cell surface expression, and hence regulate its function. Here, we describe the complex interaction of MT1-MMP with tetraspanins, their effects on MT1-MMP intracellular trafficking and proteolytic function. Tetraspanins are credited as membrane organizers that form a network within the membrane to regulate the trafficking of associated proteins. In short, we found MT1-MMP to interact with the tetraspanin-associated EWI-2 protein by a yeast two-hybrid screen. Immunoprecipitation analysis confirmed this interaction and further revealed that MT1-MMP also stably interacts with distinct tetraspanins (CD9, CD37, CD53, CD63, CD81, and CD82) and the tetraspanin-like MAL protein. By using different MT1-MMP truncation constructs and mutants, we observed that all tetraspanins and MAL associated with the hemopexin domain of MT1-MMP. Moreover, this interaction was independent of O-glycosylation of MT1-MMP and exclusively occurred in the endoplasmic reticulum. Here, the respective subcellular compartment was identified by fitting the MT1-MMP interaction pattern to a model for post-translational processing of MT1-MMP. In addition, tetraspanins differentially affected the cell surface localization of MT1-MMP, its capacity to activate pro-MMP-2, and the collagen invasion capacity. Interestingly, the degree of tetraspanin-MT1-MMP association did not correlate with its impact on MT1-MMP function. Tetraspanins thus distinctly affect MT1-MMP subcellular localization and function, and may constitute an effective mechanism to control MT1-MMP-dependent proteolysis at the cell surface.


RGS4 Regulates Proliferation And Apoptosis Of NSCLC Cells Via microRNA-16 And Brain-Derived Neurotrophic Factor.
Regulator of G-protein signaling (RGS) proteins are GTPase-activating proteins that target the α-subunit of heterotrimeric G proteins. Many studies have shown that RGS proteins contribute to tumorigenesis and metastasis. However, the mechanism in which RGS proteins, especially RGS4, affect the development of non-small cell lung cancer (NSCLC) remains unclear. The aim of this study was to characterize the role of RGS4 in NSCLC. RGS4 expression in NSCLC tissues was assessed using an immunohistochemistry tissue microarray. Additionally, RGS4 was knocked down using short-hairpin RNA to assess the regulatory function of RGS4 in the biological behaviors of human NSCLC cell lines. A xenograft lung cancer model in nude BALB/c mice was established to study whether RGS4 knockdown inhibits cancer cell proliferation in vivo. We observed an increase in RGS4 protein levels in NSCLC samples. RGS4 knockdown inhibited cell proliferation and induced apoptosis in H1299 and PC9 cell lines, but did not affect cell migration. Moreover, we found that RGS4 negatively regulated the expression of microRNA-16 (miR-16), a tumor suppressor. The inhibition of miR-16 resulted in upregulated RGS4 expression. We also found that RGS4 regulated the expression of brain-derived neurotrophic factor (BDNF) and activated the BDNF-tropomyosin receptor kinase B signaling pathway. This study revealed that RGS4 overexpression positively correlated with the development of NSCLC. TDownstream RGS4 targets (eg, miR-16 and BDNF) might be involved in the development of NSCLC and may serve as potential therapeutic targets for its treatment.


Poly (ADP-Ribose) and α-synuclein extracellular vesicles in patients with Parkinson disease: A possible biomarker of disease severity.
Despite multiple attempts, no surrogate biomarker of Parkinson disease (PD) has been definitively identified. Alternatively, identifying a non-invasive biomarker is crucial to understanding the natural history, severity, and progression of PD and to guide future therapeutic trials. Recent work highlighted alpha synuclein-containing extracellular vesicles and Poly (ADP-ribose) polymerase (PARP-1) activity as drivers of PD pathogenesis and putative PD biomarkers. This exploratory study evaluated the role of alpha-synuclein-positive extracellular vesicles and PARP-1 activity in the plasma of PD patients as non-invasive markers of the disease's severity and progression. We collected plasma of 57 PD patients (discovery cohort 20, replication cohort 37) and compared it with 20 unaffected individuals, 20 individuals with clinically diagnosed Alzheimer's disease, and 20 individuals with dementia with Lewy bodies. We analyzed alpha-synuclein-positive extracellular vesicles from platelet-free plasma by nanoscale flow cytometry and blood concentrations of poly ADP-ribose using sandwich ELISA kits. Median concentration of α-synuclein extracellular vesicles was significantly higher in PD patients compared to the other groups (Kruskal-Wallis, p < .0001). In the discovery cohort, patients with higher α-synuclein extracellular vesicles had a higher Unified Parkinson Disease Rating Scale score (UPDRS III median = 22 vs. 5, p = 0.045). Seven out of 20 patients (35%) showed detectable PAR levels, with positive patients showing significantly higher levels of α-synuclein extracellular vesicles. In the replication cohort, we did not observe a significant difference in the PAR-positive cases in relationship with UPDRS III. Non-invasive determination of α-synuclein-positive extracellular vesicles may provide a potential non-invasive marker of PD disease severity, and longitudinal studies are needed to evaluate the role of α-synuclein-positive extracellular vesicles as a marker of disease progression.


Construction of Z-scheme CdS/Ag/TiO2 NTs photocatalysts for photocatalytic dye degradation and hydrogen evolution.
The ternary CdS/Ag/TiO2 NTs photocatalysts with indirect Z-scheme heterojunctions were synthesized by the photoreduction deposition of Ag and successive ionic layer adsorption and reaction (SILAR) of CdS on TiO2 nanotube arrays (TiO2 NTs). The elemental composition, microstructure, photoresponse and photoelectrochemical property of the photocatalyst were systematically characterized. The results proved that compared with binary heterojunction, the light absorption range of the ternary CdS/Ag/TiO2 NTs photocatalyst was significantly extended, and the photoelectron transportation efficiency was improved. Under sunlight irradiation, the photocatalytic capacity was verified by investigating the photodegradation of MB and RhB dyes. The CdS/Ag/TiO2 NTs exhibited the optimal photocatalytic performance with the degradation efficiency of 82.24% for RhB and 100% for MB. The synthesized CdS/Ag/TiO2 NTs had high photocatalytic hydrogen evolution capacity and stability, and the hydrogen production reached 806.33 μmol·cm-2. Based on the results of electron spin resonance spectroscopy (ESR) and free radical trapping, the photocatalytic reaction mechanism was explained. The synthesis of ternary CdS/Ag/TiO2 NTs provides a practical reference and guidance for designing high-efficient photocatalysts with Z-scheme heterojunctions toward solar energy development for H2 generation, pollutant remediation and photoelectric conversion.


Mortality in Patients with Obesity and Acute Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation: The Multicenter ECMObesity Study.
Rationale: Patients with obesity are at increased risk for developing acute respiratory distress syndrome (ARDS). Some centers consider obesity a relative contraindication to receiving extracorporeal membrane oxygenation (ECMO) support, despite growing implementation of ECMO for ARDS in the general population. Objectives: To investigate the association between obesity and mortality in patients with ARDS receiving ECMO. Methods: In this large, international, multicenter, retrospective cohort study, we evaluated the association of obesity, defined as body mass index ⩾ 30 kg/m2, with ICU mortality in patients receiving ECMO for ARDS by performing adjusted multivariable logistic regression and propensity score matching. Measurements and Main Results: Of 790 patients with ARDS receiving ECMO in our study, 320 had obesity. Of those, 24.1% died in the ICU, compared with 35.3% of patients without obesity (P < 0.001). In adjusted models, obesity was associated with lower ICU mortality (odds ratio, 0.63 [95% confidence interval, 0.43-0.93]; P = 0.018). Examined as a continuous variable, higher body mass index was associated with decreased ICU mortality in multivariable regression (odds ratio, 0.97 [95% confidence interval, 0.95-1.00]; P = 0.023). In propensity score matching of 199 patients with obesity to 199 patients without, patients with obesity had a lower probability of ICU death than those without (22.6% vs. 35.2%; P = 0.007). Conclusions: Among patients receiving ECMO for ARDS, those with obesity had lower ICU mortality than patients without obesity in multivariable and propensity score matching analyses. Our findings support the notion that obesity should not be considered a general contraindication to ECMO.


Expression and stability of insulin-like growth factor-I (IGF-I) mRNA splicing variants in the GH3 rat pituitary cell line.
We have employed Northern blot analyses and solution hybridization/RNase protection assays to evaluate the presence and stability of IGF-I mRNA splicing variants in the GH3 rat pituitary cell line. All of the IGF-I mRNA size classes and IGF-I mRNAs with alternately-spliced 5'-untranslated regions and E-peptide coding regions seen in adult rat liver also were present in GH3 cells, although the proportions of the 5' splicing variants were significantly altered. In actinomycin D-treated cells, all IGF-I mRNA splicing variants were equally stable; thus, changes in the levels of some splicing variants were not due to differential mRNA stability. Additionally, all IGF-I mRNA size classes seen on Northern blots were equally stable; this data suggests that the large IGF-I mRNA species is not a precursor of the smaller species.


The management of anterior dislocation of the shoulder with proximal humerus fracture, bony Bankart lesion, and associated glenoid labrum avulsion: a report of 2 cases.
Proximal humerus fractures are common in the older population. These fractures can be associated with dislocation of the shoulder. Four-part fracture-dislocations and head-splitting 3-part fractures are generally indicated for shoulder hemiarthroplasty in the older population. When such surgery is warranted, inspection of the glenoid during the procedure is indicated, as loss of evaluation may lead to postoperative shoulder instability. There is value in alerting orthopedic surgeons to the possibility of anterior glenoid rim fracture in association with proximal shoulder fracture-dislocation. We focus on this issue and advise that the lesion can be visualized and confirmed at open reconstruction and does not need multiple radiographic views.


Activation studies of the β-carbonic anhydrases from Escherichia coli with amino acids and amines.
A β-carbonic anhydrase (CA, EC 188.8.131.52) from the widespread bacterium Escherichia coli (EcoCAβ), encoded by the CynT2 gene, has been investigated for its catalytic properties and enzymatic activation by a panel of amino acids and amines. EcoCAβ showed a significant catalytic activity for the hydration of CO2 to bicarbonate and a proton, with a kinetic constant kcat of 5.3 × 105 s- and a Michaelis-Menten constant KM of 12.9 mM. The most effective EcoCAβ activators were L- and D-DOPA, L-Tyr, 4-amino-Phe, serotonin and L-adrenaline, with KAs from 2.76 to 10.7 µM. L-His, 2-pyridyl-methylamine, L-Asn and L-Gln were relatively weak activators (KAs from 36.0 to 49.5 µM). D-His, L- and D-Phe, L- and D-Trp, D-Tyr, histamine, dopamine, 2-(aminoethyl)pyridine/piperazine/morpholine, L-Asp, L- and D-Glu have KAs from 11.3 to 23.7 µM. Endogenous CA activators may play a role in bacterial virulence and colonisation of the host.


Outcomes of acute care surgical cases performed at night.
Acute care surgeons operate during the day and night. Time of day or night may impact the outcome because of surgeon and team fatigue, operative delays, or other unmeasured factors. We performed matched retrospective cohort study of patients undergoing operative intervention at night by acute care surgeons over 16 months. Cases were matched on case complexity, age, and sex to daytime cases. Other confounders including comorbidities, presenting characteristics, complications, and mortality were abstracted. Outcomes differences between day and night cases were compared. Night cases (115) were matched 1:1 to daytime cases. Groups had similar degrees of comorbidity. Those operated at night had trends toward more hypotension and sepsis. After controlling for confounders using conditional logistic regression, surgical care at night was a potent predictor of mortality (odds ratio 30.02; 95% CI 2.33 to 387.40; P = .009) but had little impact on morbidity (odds ratio 1.34; 95% CI .77 to 2.36; P = .303). Emergency operations performed at night by acute care surgeons may have dissimilar outcomes compared with day cases.


Circularly polarized luminescence of pinene-modified tetradentate platinum(II) enantiomers containing fused 5/6/6 metallocycles.
In this study, a couple of tetradentate Pt(II) enantiomers ((-)-1 and (+)-1) and a couple of tetradentate Pt(IV) enantiomers ((-)-2 and (+)-2) containing fused 5/6/6 metallocycles have been synthesized by controlling reaction conditions. Two valence forms could transform into each other through mild chemical oxidants and reductants. Single-crystal X-ray diffraction confirms the structures of (-)-1 and (-)-2. The coordination sphere of the Pt(II) cation in (-)-1 displays a distorted square-planar geometry and a platinum centroid helix chirality. In contrast, the structure of (-)-2 reveals a distorted octahedral geometry. The solution and the solid of (-)-1 are highly luminescent. Complex (-)-1 shows a prominent aggregation-induced emission enhancement (AIEE) behavior in DMSO/water solution with emission quantum yield (Φ em) up to 73.2%. Furthermore, highly phosphorescent Pt(II) enantiomers exhibit significant circularly polarized luminescence (CPL) with a dissymmetry factor (g lum) of order 10-3 in CH2Cl2 solutions at room temperature. Symmetrically appreciable CPL signals are observed for the enantiomers (-)-1 and (+)-1.


Caveolae-dependent internalization and homologous desensitization of VIP/PACAP receptor, VPAC₂, in gastrointestinal smooth muscle.
The main membrane proteins of caveolae (caveolin-1, -2 and -3) oligomerize within lipid rich domains to form regular invaginations of smooth muscle plasma membrane and participate in receptor internalization and desensitization independent of clathrin-coated vesicle endocytosis. We have previously shown that Gs-coupled VIP/PACAP receptors, VPAC2, predominantly expressed in smooth muscle cells of the gut, are exclusively phosphorylated by GRK2 leading to receptor internalization and desensitization. Herein, we characterized the role of caveolin-1 in VPAC2 receptor internalization and desensitization in gastric smooth muscle using three approaches: (i) methyl β-cyclodextrin (MβCD) to deplete cholesterol and disrupt caveolae in dispersed muscle cells, (ii) caveolin-1 siRNA to suppress caveolin-1 expression in cultured muscle cells, and (iii) caveolin-1 knockout mice (caveolin-1(-/-)). Pretreatment of gastric muscle cells with VIP stimulated tyrosine phosphorylation of caveolin-1, and induced VPAC2 receptor internalization (measured as decrease in (125)I-VIP binding after pretreatment) and desensitization (measured as decrease in VIP-induced cAMP formation after pretreatment). Caveolin-1 phosphorylation, and VPAC2 receptor internalization and desensitization were blocked by disruption of caveolae with MβCD, suppression of caveolin-1 with caveolin-1 siRNA or inhibition of Src kinase activity by PP2. Pretreatment with VIP significantly inhibited adenylyl cyclase activity and muscle relaxation in response to subsequent addition of VIP in freshly dispersed muscle cells and in muscle strips isolated from wild type and caveolin-1(-/-) mice; however, the inhibition was significantly attenuated in caveolin-1(-/-) mice. These results suggest that caveolin-1 plays an important role in VPAC2 receptor internalization and desensitization.


Social resource patterns and health outcomes among Canadian LGBTQ2+ adults: A latent class analysis.
Decades of research have shown a strong association between wellbeing, health, and social resources. LGBTQ2+ communities are among those who historically have been excluded from accessing quality social resources. However, little is known about how access to different types of resources influences mental health and wellbeing. Data were drawn from an online sample of 3890 LGBTQ2+ people aged 18 years and older in Quebec, Canada. We identified key social resource patterns (from family of origin, friends, partner, neighbourhood, and LGBTQ2+ community) and investigated differences in socio-demographic and health outcomes across classes. A five-class solution best fitted the data, highlighting distinctive patterns in access to five key social resources: moderate friend support access (42.14%), overall high support access (23.51%), high friend support access (18.06%), only close ties support access (10.90%) and overall low support access (5.39%). Marginalized groups (trans and non-binary people, racialized or disabled people, immigrants) were less likely to access diverse, high-quality social resources. Accessing diverse social resources, particularly close ties (e.g., family of origin), was associated with better health outcomes. In the absence of close ties, having at least one other social resource was associated with better health outcomes compared to having limited access to all resources. We found a major imbalance in social resource access among LGBTQ2+ people. Creating safe spaces for LGBTQ2+ people and ensuring access to high-quality social resources is important in sustaining their health and wellbeing.


Variations in S-100 protein expression in naevocellular naevi may be related to metabolic activity.
Significant amounts of S-100 protein were demonstrated in naevus cells by an immunoperoxidase technique. Distribution of S-100 protein was similar in the various types of naevi tested. In most lesions, the superficial A-type naevus cells stained most heavily, while staining was weaker in the deeper B- and C-type naevus cells. The intensity of staining was not, however, homogeneous in the cells of the various layers of the naevus. S-100 protein was especially abundant in giant naevus cells which occurred in the vicinity of sub-epidermal A-type naevocytes. Cells from neurocutaneous melanosis contained extremely large amounts of S-100 protein. Normal melanocytes in the epidermis over dermal naevi contained variable amounts of S-100 protein, but mainly showed weak staining. However, in the basal epidermis of traumatized naevi there were many unusually large and partly dendritic melanocytes. In this part of the epidermis, S-100 protein-positive cells lay close together, and many stained strongly. In earlier work, large amounts of metabolic enzymes were found at the same sites in traumatized naevi and giant cells. These results suggest that a high degree of expression of S-100 protein is due to metabolic activity shown, for example, by giant naevus cells and basal melanocytes of the regenerating epidermis over traumatized naevi.


Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia.
A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3α,7α,12α-trihydroxy-5β-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAXα expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.


Liquid platelet-rich fibrin in root surface biomodification during gingival recession treatment: Randomized, controlled, split-mouth, clinical trial.
Free gingival graft (FGG) has been successfully used in the treatment of gingival recessions, as it is the most predictable technique for increasing the attached gingiva. This study aimed to evaluate the effect of liquid platelet-rich fibrin (PRF) with FGG on root surface coverage as root surface biomodification. The research sample consisted of 32 surgical sites in 16 patients, they had 2 bilateral recessions in the incisor area of the same dental arch, the sample was divided into 2 groups randomly, and liquid PRF was applied in the first group with the FGG (experimental group), and in the second group the FGG was applied alone (control group). Gingival recession depth (RD) and width of attached gingiva (WAG) were measured before starting, after 1, 3, and 6 months. The percentage of root coverage (RC) was calculated after 6 months. Healing Index (HI) was recorded after 1 week, 2 weeks, and 1 month. Both groups showed a reduction in gingival RD during all follow-up periods but the difference between both groups was not statistically significant (p > 0.05) at 1 and 3 months, whereas there were significant differences at 6 months (p = 0.001). RC was better in the liquid PRF group than in the control group, but this difference was not statistically significant (p > 0.05). The postoperative 7th and 14th days HI scores of the liquid PRF group were significantly better than the control group (p = 0.000 and p = 0.004, respectively), whereas there were no significant differences in HI scores between both groups at first month (p > 0.05). According to the results, the addition of liquid PRF to the root surface with FGG showed further development in terms of decreasing RD, increasing WAG, and accelerated wound-healing.


Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch.
Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like "triple negative" cancers lack steroid receptors but are cytokeratin (CK) 5-positive and require chemotherapy. Here we show that more than half of primary ER(+)PR(+) breast cancers contain an ER(-)PR(-)CK5(+) "luminobasal" subpopulation exceeding 1% of cells. Starting from ER(+)PR(+) luminal cell lines, we generated lines with varying luminal to luminobasal cell ratios and studied their molecular and biological properties. In luminal disease, luminobasal cells expand in response to antiestrogen or estrogen withdrawal therapies. The phenotype and gene signature of the hormone-resistant cells matches that of clinical triple negative basal-like and claudin-low disease. Luminobasal cell expansion in response to hormone therapies is regulated by Notch1 signaling and can be blocked by γ-secretase inhibitors. Our data establish a previously unrecognized plasticity of ER(+)PR(+) luminal breast cancers that, without genetic manipulation, mobilizes outgrowth of hormone-resistant basal-like disease in response to treatment. This undesirable outcome can be prevented by combining endocrine therapies with Notch inhibition.


Does the Impact of Intensive Lifestyle Intervention on Cardiovascular Disease Risk Vary According to Frailty as Measured via Deficit Accumulation?
Individuals are often counseled to use behavioral weight loss strategies to reduce risk for cardiovascular disease (CVD). We examined whether any benefits for CVD risk from weight loss intervention extend uniformly to individuals across a range of underlying health states. The time until first occurrence of a composite of fatal and nonfatal myocardial infarction and stroke, hospitalized angina, or CVD death was analyzed from 8 to 11 years of follow-up of 4,859 adults who were overweight or obese, aged 45-76 years with Type 2 diabetes. Individuals had been randomly assigned to either an intensive lifestyle intervention (ILI) or diabetes support and education (DSE). Participants were grouped by intervention assignment and a frailty index (FI) based on deficit accumulation, ordered from fewer (first tertile) to more (third tertile) deficits. Baseline FI scores were unrelated to intervention-induced weight losses and increased physical activity. The relative effectiveness of ILI on CVD incidence was inversely related to baseline FI in a graded fashion (p = .01), with relative benefit (hazard ratio = 0.73 [95% CI 0.55,0.98]) for individuals in the first FI tertile to no benefit (hazard ratio = 1.15 [0.94,1.42]) among those in the third FI tertile. This graded relationship was not seen for individuals ordered by age tertile (p = .52), and was stronger among participants aged 45-59 years (three-way interaction p = .04). In overweight/obese adults with diabetes, multidomain lifestyle interventions may be most effective in reducing CVD if administered before individuals have accrued many age-related health deficits. However, these exploratory analyses require confirmation by other studies. NCT00017953.


The relaxation response: reducing stress and improving cognition in healthy aging adults.
Aging adults are vulnerable to the effects of a negative emotional state. The relaxation response (RR) is a mind-body intervention that counteracts the harmful effects of stress. Previous studies with relaxation techniques have shown the non-pharmacological benefit of reducing stress and improving the memory of healthy older adults. Our pilot study evaluated whether a RR training program would decrease anxiety levels, improve attention, declarative memory performance and/or decrease salivary cortisol levels in healthy older adults. Fifteen adults participated and were randomly assigned to a RR training or control groups. Mean age was 71.3 years and mean education level was 17.9 years. Reaction time on a simple attention/psychomotor task was significantly improved (p<0.0025) with RR training, whereas there was no significant improvement on complex tasks of attention, verbal, or visual declarative memory tests. Self-reported state anxiety levels showed a marginally significant reduction (p<0.066). All subjects' salivary cortisol levels were within low-normal range and did not significantly change. Our 5-week program in highly educated, mobile, healthy, aging adults significantly improved performance on a simple attention task.


Polyamine biosynthesis inhibitors combined with systemic hyperthermia in cancer therapy.
A Phase I clinical trial has been initiated at the University of Arizona Cancer Center which combines escalating oral doses of the polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO), with systemic hyperthermia (approximately 41.5 degrees C) in the treatment of metastatic melanoma. The rationale for the combination of hyperthermia and polyamine biosynthesis inhibitors in the treatment of human cancers includes studies which show that depletion of endogenous polyamines, as a result of treatment with DFMO, sensitizes both rodent and human tumor cells to the cytotoxic effects of hyperthermia. Heat shock induces the first enzyme in polyamine catabolism, spermidine/spermine N1-acetyltransferase (N1-SAT). The consequently acetylated forms of spermidine and spermine are then constitutively oxidized by the enzyme polyamine oxidase (PAO). Both CHO and human A549 lung cancer cells exhibit heat-inducible polyamine acetylation, display potent heat sensitization after polyamine depletion, and ultimately reveal prolonged expression of thermotolerance. Conversely, HeLa cells do not demonstrate heat-inducible polyamine catabolism, are not sensitized to heat with DFMO, and display more rapid kinetics of thermotolerance decay. These laboratory studies suggest that enhancement of the cytotoxic action of hyperthermia by DFMO occurs as a consequence of the inhibition of polyamine catabolism, a heat-inducible process that affords some form of protection to cells undergoing heat stress. Human melanoma cultures demonstrate heat-inducible polyamine catabolism and are sensitized to hyperthermic cytotoxicity by DFMO. To date, 24 systemic hyperthermia treatments have been delivered to nine patients with metastatic melanoma in conjunction with oral DFMO under this Phase I clinical trial.


Characterizing Disease Manifestations and Treatment Patterns Among Adults with Systemic Sclerosis: A Retrospective Analysis of a US Healthcare Claims Population.
Real-world use of immunomodulating therapy (IMT) in patients with systemic sclerosis (SSc) was investigated for the first time in a descriptive, retrospective cohort analysis of claims made in a healthcare insurance database to characterize treatment patterns and their alignment with SSc disease manifestations. Treatment patterns and disease manifestations, symptoms, complications, and comorbidities were assessed in patients with SSc enrolled in a US healthcare claims database who received treatment between January 2006 and December 2013 and for whom data were available 6 months before and 12 months after SSc diagnosis. Among 7812 eligible patients, 6852 received treatments of interest for SSc and 2404 (30.8%) received IMT during the first year after SSc diagnosis. In the first year after diagnosis, the most common claims were for antibiotics (61.7%), opioids (50.6%), glucocorticoids (46.5%), and proton pump inhibitors (35.4%); the most common organs involved with complications among patients with SSc were lung (30.5%), heart (17.4%), and gastrointestinal tract (22.4%); the most common signs or symptoms were musculoskeletal (16.1%) and fatigue (10.5%); 1035 patients (15.1%) had infections and 14 (0.2%) had malignancies. Among patients who received IMT, 43.8% received at least hydroxychloroquine and 21.1% received at least methotrexate; 460 patients switched to a second IMT, 23.0% to at least methotrexate and 22.8% to at least mycophenolate mofetil. The most common comorbidities reported with first IMT were in lung (11.8%), overlap syndrome (8.4%), heart (5.3%), and gastrointestinal (6.8%) categories. One-third of patients with SSc in the healthcare claims population received IMTs during the first year after diagnosis. However, patients who received IMTs had disease manifestations similar to those of the overall SSc healthcare claims population.


Laparoscopic relief of reduction en-masse in an inguinal hernia: A case report.
Reduction en-masse is an extremely rare condition that usually develops in prolonged hernias. Spontaneous or iatrogenic reduction of this type of hernia may lead to disastrous consequences such as obstruction, gangrene, or peritonitis. According to the reports so far, surgical management is the only choice for this condition. In this paper, we report a 48-year-old man who presented with vague abdominal pain and a history of inguinal hernia for years and had reduced his hernia five days earlier. Computed tomography (CT) and ultrasonography confirmed the diagnosis, and the patient was taken to the operating room to relieve the bowel loop utilizing laparoscopy. Laparoscopic relief could be an effective tool in diagnosis and surgery of reduction en-masse. Transabdominal preperitoneal repair is the best choice due to its capability to explore the intraabdominal organs and its low risk of recurrence.


The retrospective analysis of posterior short-segment pedicle instrumentation without fusion for thoracolumbar burst fracture with neurological deficit.
This study aims to investigate the efficacy of posterior short-segment pedicle instrumentation without fusion in curing thoracolumbar burst fracture. All of the 53 patients were treated with short-segment pedicle instrumentation and laminectomy without fusion, and the restoration of retropulsed bone fragments was conducted by a novel custom-designed repositor (RRBF). The mean operation time and blood loss during surgery were analyzed; the radiological index and neurological status were compared before and after the operation. The mean operation time was 93 min (range: 62-110 min) and the mean intraoperative blood loss was 452 mL in all cases. The average canal encroachment was 50.04% and 10.92% prior to the surgery and at last followup, respectively (P < 0.01). The preoperative kyphotic angle was 17.2 degree (± 6.87 degrees), whereas it decreased to 8.42 degree (± 4.99 degrees) at last followup (P < 0.01). Besides, the mean vertebral body height increased from 40.15% (± 9.40%) before surgery to 72.34% (± 12.32%) at last followup (P < 0.01). 45 patients showed 1-2 grades improvement in Frankel's scale at last followup. This technique allows for satisfactory canal clearance and restoration of vertebral body height and kyphotic angle, and it may promote the recovery of neurological function. However, further research is still necessary to confirm the efficacy of this treatment.


Pharmaceutical use and costs in patients with coronary artery disease, using Australian observational data.
We aimed to estimate the annual pharmaceutical costs for patients with stable coronary artery disease, using Australian administrative data, comparing patients who had undergone interventional treatment with those had not. We also aimed to compare the duration of dual antiplatelet therapy (DAPT) prescription in the real-world, with recommended guidelines. An observational study using administrative data. We used data from the QSkin study, a population-based prospective study assessing skin cancer risk. Participants were invited from the Queensland population, not based on perceived skin cancer risk, and had consented to future use of their data for approved research projects. We calculated 12-month costs of pharmaceutical therapy for coronary artery disease for patients in each of three clinically relevant groups: medical therapy only, following coronary stent implantation and following coronary artery bypass graft surgery. We measured the duration of DAPT following stent implantation and total duration of DAPT, where it was prescribed, in the medical therapy only group. Estimated mean annual pharmaceutical costs were highest in the stent group at AUD$1920, compared with AUD$1481 in the medical therapy group, and AUD$881 in the coronary artery bypass group. There were similar rates of prescriptions of symptom relief drugs following stent insertion, compared with the medical therapy only group. The median duration of DAPT in the stent group was 16, and 31 months in the medical therapy group. Our results suggest that despite the common expectation that the burden of medical therapy is reduced following coronary stent insertion for stable coronary artery disease, this does not occur in practice. Many patients also appear to continue DAPT longer than guidelines recommend, which may put them at unnecessarily elevated risk of bleeding events.


Candida africana sp. nov., a new human pathogen or a variant of Candida albicans?
Atypical Candida strains were isolated from patients in Madagascar, Angola and Germany. These isolates were slow growing and were unable to produce chlamydospores. They had atypical carbohydrate assimilation profiles. All strains were unable to assimilate the amino sugars N-acteylglucosamine and glucosamine as well as the disaccharide trehalose and the organic acid DL-lactate. They were germ-tube-positive in serum, but only some of these organisms produced pseudohyphae after a long incubation. As shown by Fourier transform infrared spectroscopy the atypical Candida isolates clustered as a monophyletic group different from C. albicans and C. dubliniensis. All strains belonged to C. albicans serotype B. Considering all data presented here, this group of Candida strains differs from any other known member of the genus Candida. Therefore, it is suggested to represent a new species within the genus Candida for which the name Candida africana is proposed.


Evaluation of Salivary Biochemistry in Dogs with and without Plaque, Calculus, and Gingivitis: Preliminary Results.
This study evaluated whether salivary alpha-amylase, lysozyme, lactate dehydrogenase (LDH), calcium, and phosphorus can be used as markers of periodontal disease in dogs. Plaque, calculus, and gingivitis indexes were used to allocate 79 dogs in three groups: none (Group 1), moderate (Group 2), and severe (Group 3) periodontal disease. A blood sample and a saliva sample were collected from each dog to quantify biochemical parameters. LDH and phosphorus showed the highest values in Group 3 (LDH: Group 1, 2559.85 ± 676.95; vs. Group 2: 1636.76 ± 597.36 vs. Group 3: 4099.18 ± 545.45 U.I./l, p = 0.016; phosphorus: Group 1, 3.02 ± 0.76 vs. Group 2: 5.34 ± 0.67 vs. Group 3: 5.85± 0.61 mg/dl, p = 0.049) whereas calcium, amylase, and lysozyme did not differ among groups. A ROC curve analysis permitted the establishment of a salivary phosphorus cut-off value of 4.04 mg/dl, above which periodontal disease could be predicted (70% sensitivity (95% CI: 50.6-85.3%) and 72.41% specificity (95% CI: 52.8-87.3%)). Only salivary calcium was higher in males; no other salivary parameters appeared affected by gender or age. Although further results on a larger population are needed, this study shows that salivary LDH and phosphorus increase in dogs affected by plaque, supragingival calculus, and gingivitis, and this suggests their potential use as markers of periodontal disease in canine species.


Synthesis of a 4,8-dialkoxy-benzo[1,2-b:4,5-b']difuran unit and its application in photovoltaic polymer.
A new building block of benzo[1,2-b:4,5-b']difuran (BDF) was firstly designed and synthesized. The newly designed unit was applied for constructing a new photovoltaic low band gap polymer, PBDFDTBT, which exhibited promising power conversion efficiency of 5.0%.


["The future must look to the past"* : Prof. Dr. Abraham Aaron Buschke (1868-1943) and Wilhelm Ludwig Löwenstein (1895-1959)].
Like many other areas of medicine, dermatology with its comparatively high proportion of Jewish physicians was also not spared from the National Socialist appointment policy with dismissals, laws on "appreciation of the people", research influenced by National Socialist policies, and persecution of Jewish physicians. Prof. Abraham Aaron Buschke and Dr. Wilhelm Ludwig Lowenstein, who were the first to describe the Buschke-Lowenstein tumor, also suffered this destiny. In March 1933, Professor Buschke was dismissed from the position of directing physician at the Virchow Hospital in Berlin and in 1934 his teaching license was revoked. Despite affidavits of his "loyalty to the regime", Dr. Lowenstein fared the same treatment.


DNA and ribonucleotide binding characteristics of two forms of the androgen receptor from rat prostates.
Androgen receptors (sedimentation value approximately 4S and Stokes radius 2.8 nm) present in the cytoplasmic fraction obtained from prostates of castrated rats bind to DNA-Sepharose and double stranded DNA. A receptor fragment (sedimentation value approximately 3S and Stokes radius 2.3 nm) obtained from rat prostates in the course of a purification procedure showed greatly diminished binding affinity for both DNA-Sepharose and soluble DNA. In contrast, both the 4S cytosol receptor and the 3S receptor form interacted with equal affinity with prostate RNA or poly(UG). These observations provide evidence that for DNA binding a different or additional part of the receptor molecule is required than for RNA and polyribonucleotide binding.


A one-year observational study of all hospitalized and fatal acute poisonings in Oslo: epidemiology, intention and follow-up.
Up to date information on poisoning trends is important. This study reports the epidemiology of all hospitalized acute poisonings in Oslo, including mortality, follow-up referrals, and whether the introduction of over-the-counter sales of paracetamol outside pharmacies had an impact on the frequency of poisonings. All acute poisonings of adults (≥16 years) treated at the five hospitals in Oslo from April 2008 to April 2009 were included consecutively in an observational cross-sectional multicentre study. A standardized form was completed by the treating physician, which covered the study aims. All deaths by poisoning in and outside hospitals were registered at the Institute of Forensic Medicine. There were 1065 hospital admissions of 912 individuals; 460 (50%) were male, and the median age was 36 years. The annual incidence was 2.0 per 1000. The most frequent toxic agents were ethanol (18%), benzodiazepines (15%), paracetamol (11%), and opioids (11%). Physicians classified 46% as possible or definite suicide attempts, 37% as accidental overdoses with substances of abuse (AOSA), and 16% as other accidents. Twenty-four per cent were discharged without any follow-up and the no follow-up odds were highest for AOSA. There were 117 deaths (eight in hospital), of which 75% were males, and the median age was 41 years. Thus, the annual mortality rate was 25 per 100 000 and the in-hospital mortality was 0.8%. Opioids were the most frequent cause of death. The incidence of hospitalized acute poisonings in Oslo was similar to that in 2003 and there was an equal sex distribution. Compared with a study performed in Oslo in 2003, there has been an increase in poisonings with a suicidal intention. The in-hospital mortality was low and nine out of ten deaths occurred outside hospitals. Opioids were the leading cause of death, so preventive measures should be encouraged among substance abusers. The number of poisonings caused by paracetamol remained unchanged after the introduction of over-the-counter sales outside pharmacies and there were no deaths, so over-the-counter sales may be considered safe.


A Clinical Prediction Model to Determine Probability of Response to Certolizumab Pegol for Crohn's Disease.
Certolizumab pegol (CZP) is effective for moderately to severely active Crohn's disease (CD). Higher plasma concentrations are associated with better outcomes and increased drug clearance is the driver of subtherapeutic CZP concentrations. We aimed to develop a prediction model incorporating predicted CZP clearance and patient variables to allow estimation of the probability for remission prior to initiating therapy. A population pharmacokinetic model estimated baseline CZP clearance in patients with CD from nine phase II and III trials. Multivariable prediction models were developed and validated using the PRECiSE 1 and PRECiSE 2 datasets to identify candidate predictors for a composite remission outcome (Crohn's Disease Activity Index ≤ 150 and fecal calprotectin concentration ≤ 250 μg/g) at Weeks 6 or 26. An online clinical decision support tool (CDST) was developed. Baseline predicted CZP clearance ≥ 0.5 L/day was associated with subtherapeutic Week 6 CZP plasma concentrations. Baseline weight (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.02-1.07), calculated CZP clearance (OR 0.92; 95% CI 0.87-0.96), hematocrit (OR 2.55; 95% CI 1.43-4.54), and fecal calprotectin (OR 0.66; 95% CI 0.54-0.80) were associated with Week 6 remission (p ≤ 0.0015 for all predictors). Baseline weight (OR 1.04; 95% CI 1.02-1.07), calculated CZP clearance (OR 0.93; 95% CI 0.88-0.97), and Patient-Reported Outcome-2 (PRO2) (OR 0.93; 95% CI 0.87-0.99) were associated with Week 26 remission (p ≤ 0.033 for all predictors). Patients who are predicted to have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Patient-level probabilities for a composite remission outcome can be predicted for patients with CD by entering commonly available patient- and disease-related factors into an online CDST ( https://premedibd.com ) incorporating predicted CZP clearance.


IRS1-independent defects define major nodes of insulin resistance.
Insulin resistance is a common disorder caused by a wide variety of physiological insults, some of which include poor diet, inflammation, anti-inflammatory steroids, hyperinsulinemia, and dyslipidemia. The common link between these diverse insults and insulin resistance is widely considered to involve impaired insulin signaling, particularly at the level of the insulin receptor substrate (IRS). To test this model, we utilized a heterologous system involving the platelet-derived growth factor (PDGF) pathway that recapitulates many aspects of insulin action independently of IRS. We comprehensively analyzed six models of insulin resistance in three experimental systems and consistently observed defects in both insulin and PDGF action despite a range of insult-specific defects within the IRS-Akt nexus. These findings indicate that while insulin resistance is associated with multiple deficiencies, the most deleterious defects and the origin of insulin resistance occur independently of IRS.


Waldeyer ring microbiome in relation to chemoradiation-induced oral mucositis in patients with nasopharyngeal carcinoma.
Waldeyer lymphatic ring surrounds the nasopharynx and oropharynx, and no study to date has correlated its microbiome with the severity of oral mucositis (OM) in patients with nasopharyngeal carcinoma (NPC) receiving chemoradiotherapy. We performed 16S rRNA sequencing to characterize bacterial microbiome in tumor-affected nasopharynx and the surrounding normal oropharynx. We plotted the abundance and diversity of bacterial taxa and their phylogenetic distance and networks to visualize and compare the differences in pretreatment overall bacterial communities between the nasopharynx and oropharynx in patients with NPC with varying degrees of chemoradiotherapy-induced OM and quality of life. We found microbial signatures in nasopharynx around NPC were not only dissimilar to those in the surrounding oropharynx but were almost unique to each patient. The genetic distance metrics further showed that different tumor microbiota distributions in the nasopharynx among patients with NPC were well-correlated with OM severity and quality of life during chemoradiotherapy. At Waldeyer ring, the tumor-associated microbiome risk profiles of the respiratory region of nasopharynx, but not commensal microbiota of the alimentary region of oropharynx, could be noninvasive biomarkers for OM susceptibility and might include drug targets for the prevention of chemoradiation-induced OM in patients with Waldeyer ring-derived NPC.


Drain Contamination after Distal Pancreatectomy: Incidence, Risk Factors, and Association with Postoperative Pancreatic Fistula.
Distal pancreatectomy (DP) remains associated with significant morbidity, but little data is available about the clinical significance of drain contamination. We explored the incidence, risk factors, and association with surgical outcomes of positive drainage culture (PDC) after DP. In addition, the predictive capacity of early PDC for postoperative pancreatic fistula (POPF) was evaluated. We retrospectively analyzed our prospectively collected database of patients who underwent DP between January 2005 and December 2015. Surveillance drainage cultures for microorganisms were conducted until drain removal or positive culture. The relationships between clinical variables and PDC were examined. Of 480 consecutive cases who underwent DP, 176 (36.7%) had PDC. One hundred twelve patients (23.3%) developed POPF according to the 2016 ISGPS definition, with the 90-day mortality rate of 0.2%. Staphylococcus spp. was the most frequent isolate. Thirty-eight (21.6%) patients had PDC within 3 days after surgery, and 129 (73.3%) within the first 7 days of operation. Body mass index (BMI) ≥ 25 kg/m2 and massive intraoperative blood loss were independent predictors for PDC. PDC had a negative impact on surgical outcomes, including POPF. Early PDC was identified as a newly independent risk factor for POPF. Compared with other microorganisms, those contaminated with Staphylococcus and Klebsiella had higher incidences of POPF. PDC occurs commonly after DP and plays a critical role in the development of surgical morbidities including POPF. Extreme caution is warranted in patients involving contamination with specific types of microorganisms.


Pre-eclampsia and gestational age differently alter binding of endothelin-1 to placental and trophoblast membrane preparations.
The aim of the study was to compare the binding of endothelin-1 (ET-1) to membranes from placental tissue and trophoblast cells in normal and pre-eclamptic pregnancies. Plasma membranes from placental tissue and trophoblastic cells were prepared from 15 control and 18 pre-eclamptic pregnancies at either preterm (weeks 31-36) or term (weeks 37-40). ET-1 binding to tissue membranes was measured by a radioreceptor assay. In addition, binding of 56 nmol/l [125I]ET-1 to plasma membranes of trophoblastic cells was determined. In pre-eclampsia, placental membranes bound less (P < 0.01) ET-1 owing to fewer (P < 0.01) receptors at preterm than in the corresponding preterm controls. In contrast, binding of [125I]ET-1 to plasma membranes of trophoblast cells was higher (P < 0.01) in pre-eclampsia at both gestational stages than in the controls. Incubation of trophoblast cells with hydralazine reduced binding by 70%. We conclude that pre-eclampsia is associated with changes in the binding of ET-1 to its placental receptors. Moreover, the data suggest that pre-eclampsia affects non-trophoblast cells in the opposite manner to the trophoblast.


Ambient air pollution, genetic risk and telomere length in UK biobank.
Telomere length (TL) is a biomarker of genomic aging. The evidence on the association between TL and air pollution was inconsistent. Besides, the modification effect of genetic susceptibility on the air pollution-TL association remains unknown. We aimed to evaluate the association of ambient air pollution with TL and further assess the modification effect of genetic susceptibility. 433,535 participants with complete data of TL and air pollutants in UK Biobank were included. Annual average exposure of NO2, NOx, PM10 and PM2.5 was estimated by applying land use regression models. Genetic risk score (GRS) was constructed using reported telomere-related SNPs. Leukocyte TL was measured by quantitative polymerase chain reaction (qPCR). Multivariable linear regression models were employed to conduct associational analyses. Categorical exposure models and RCS models both indicated U-shaped (for NO2 and NOx) and L-shaped (for PM10 and PM2.5) correlations between air pollution and TL. In comparison to the lowest quartile, the 2nd and 3rd quartile of NO2 (q2: -1.3% [-2.1%, -0.4%]; q3: -1.2% [-2.0%, -0.3%], NOx (q2: -1.3% [-2.1%, -0.5%]; q3: -1.4% [-2.2%, -0.5%]), PM2.5 (q2: -0.8% [-1.7%, 0.0%]; q3: -1.3% [-2.2%, -0.5%]), and the third quartile of PM10 (q3: -1.1% [-1.9%, -0.2%]) were inversely associated with TL. The highest quartile of NO2 was positively correlated with TL (q4: 1.0% [0.0%, 2.0%]), whereas the negative correlation between the highest quartile of other pollutants and TL was also attenuated and no longer significant. In the genetic analyses, synergistic interactions were observed between the 4th quartile of three air pollutants (NO2, NOx, and PM2.5) and genetic risk. Our study for the first time revealed a non-linear trend for the association between air pollution and telomere length. The genetic analyses suggested synergistic interactions between air pollution and genetic risk on the air pollution-TL association. These findings may shed new light on air pollution's health effects, offer suggestions for identifying at-risk individuals, and provide hints regarding further investigation into gene-environment interactions.


The specificity of base-pair substitution induced by the mutL and mutS mutators in E. coli.
The Escherichia coli mutator alleles, mutL and mutS, produced transversion as well as transition base-pair substitutions with the trpA reversion system. Transversions, however, were generally mutator-induced at a lower level than transitions and the specific type of transversion and its nucleotide position appeared to strongly affect its level of enhancement. These results are interpreted to mean that mutL- and mutS-dependent mismatch correction is generally more effective at correcting transition mispairings than transversion mispairings. Correction of transversion mispairings is probably dependent upon site of occurrence and type of mismatch.


Decoding the encoding of functional brain networks: An fMRI classification comparison of non-negative matrix factorization (NMF), independent component analysis (ICA), and sparse coding algorithms.
Brain networks in fMRI are typically identified using spatial independent component analysis (ICA), yet other mathematical constraints provide alternate biologically-plausible frameworks for generating brain networks. Non-negative matrix factorization (NMF) would suppress negative BOLD signal by enforcing positivity. Spatial sparse coding algorithms (L1 Regularized Learning and K-SVD) would impose local specialization and a discouragement of multitasking, where the total observed activity in a single voxel originates from a restricted number of possible brain networks. The assumptions of independence, positivity, and sparsity to encode task-related brain networks are compared; the resulting brain networks within scan for different constraints are used as basis functions to encode observed functional activity. These encodings are then decoded using machine learning, by using the time series weights to predict within scan whether a subject is viewing a video, listening to an audio cue, or at rest, in 304 fMRI scans from 51 subjects. The sparse coding algorithm of L1 Regularized Learning outperformed 4 variations of ICA (p<0.001) for predicting the task being performed within each scan using artifact-cleaned components. The NMF algorithms, which suppressed negative BOLD signal, had the poorest accuracy compared to the ICA and sparse coding algorithms. Holding constant the effect of the extraction algorithm, encodings using sparser spatial networks (containing more zero-valued voxels) had higher classification accuracy (p<0.001). Lower classification accuracy occurred when the extracted spatial maps contained more CSF regions (p<0.001). The success of sparse coding algorithms suggests that algorithms which enforce sparsity, discourage multitasking, and promote local specialization may capture better the underlying source processes than those which allow inexhaustible local processes such as ICA. Negative BOLD signal may capture task-related activations.


[Isolation of three species of Nocardia in a patient receiving long-term corticosteroid therapy].
Nocardia are saprophyte bacteria of the environment responsible for systemic infections in immunodepressed patients, due essentially to long-term corticosteroids. A patient having received corticosteroids for sarcoidoses for a year was hospitalised because of disseminated granulomatosis (neurological, respiratory, abdominal and cutaneous). Culture of various bacteriological samples isolated three species of Nocardia: N. otitidiscaviarum in uretheral pus and pus from the right gland, N. nova and N. asteroides in respiratory samples (protected distal sampling and broncho-alveolar washing). Other than the mixed Nocardia infections described habitually, infections with two different species of Nocardia have recently been reported. Our case report is the first to have isolated three concomitant species of Nocardia.


Attitudes to the right- and left: frontal ERP asymmetries associated with stimulus valence and processing goals.
We used dense-array event-related potentials (ERP) to examine the time course and neural bases of evaluative processing. Participants made good vs. bad (evaluative) and abstract vs. concrete (nonevaluative) judgments of socially relevant concepts (e.g., "murder," "welfare"), and then rated all concepts for goodness and badness. Results revealed a late positive potential (LPP) beginning at about 475 ms post-stimulus and maximal over anterior sites. The LPP was lateralized (higher amplitude and shorter latency) on the right for concepts later rated bad, and on the left for concepts later rated good. Moreover, the degree of lateralization for the amplitude but not the latency was larger when participants were making evaluative judgments than when they were making nonevaluative judgments. These data are consistent with a model in which discrete regions of prefrontal cortex (PFC) are specialized for the evaluative processing of positive and negative stimuli.


Expression of sialyl-Tn antigen is correlated with survival time of patients with gastric carcinomas.
Expression of sialyl-Tn antigen (STN) was examined by an immunohistochemical method in 85 primary gastric carcinomas. The STN expression occurred in 53 (62.4%) cancers, and the positive staining was correlated with degree of gastric wall and lymph vessel invasion, lymph node metastasis, and stage of tumour. Five-year survival rates of patients with STN-positive cancers (47.2%) were significantly lower than those with STN-negative cancers (84.4%) (P < 0.01), and patients with STN-positive cancers at stage III and stage IV had a worse prognosis. In the cancers with serosal invasion, patients with STN-positive cancer disclosed a significantly poorer prognosis than those with STN-negative cancers (P < 0.01). Therefore, it is suggested that a careful follow-up study and intensive postoperative therapy are needed for patients with advanced gastric cancers with positive STN expression.


How to measure hazards/risks following exposures to nanoscale or pigment-grade titanium dioxide particles.
Due to its multifunctional applications, titanium dioxide particles have widespread use in commerce. The particle-types function as sources of pigment color, in food products, anti-bacterial components, ultraviolet radiation scavengers, catalysts, as well as in cosmetics. Because of its inherent properties in a diverse number of products, exposures may occur via any of the major point-of-entry routes, i.e., inhalation, oral or dermal. Although the majority of TiO2 applications are known to exist in the pigment-grade form, nanoscale forms of TiO2 are also common components in several products. This brief review is designed to identify relevant toxicology and risk-related issues which inform health effects assessments on the various forms of titanium dioxide particles. While there has been an abundance of hazard data generated on titanium dioxide particulates, many of the published reports have limited informational value for assessing health effects due, in large part, to shortcomings in experimental design issues, such as: (1) inadequate material characterization of test samples; (2) questionable relevance of experimental systems employed to simulate human exposures; (3) applications of generally high doses, exclusive focus on acute toxicity endpoints, and a lack of reference benchmark control materials, to afford interpretation of measured results; and/or (4) failure to recognize fundamental differences between hazard and risk concepts. Accordingly, a number of important toxicology issues are identified and integrated herein to provide a more comprehensive assessment of the health risks of different forms of pigment-grade and nanoscale titanium dioxide particles. It is important to note that particle-types of different TiO2 compositions may have variable toxicity potencies, depending upon crystal structure, particle size, particle surface characteristics and surface coatings. In order to develop a more robust health risk evaluation of TiO2 particle exposures, this review focuses on the following issues: (1) Introduction to TiO2 particle chemistry/functionality and importance of robust material characterization of test samples; (2) Implementation of meaningful hazard studies for gauging EHS safety issues – pulmonary bioassay data and development of the Nano Risk Framework for developmental nano TiO2 compounds; (3) Epidemiological study findings on titanium dioxide workers – the most heavily-exposed populations; (4) Methodologies for setting occupational exposure limits including benchmarking or bridging comparisons; and (5) The importance of particle overload data in the lungs of rats as it relates to gauging the relevance of health effects for humans. A comprehensive evaluation of the existing animal and human health data is a necessary prerequisite for facilitating accurate assessments of human health risks to TiO2 exposures.


Ketogenic diets and thermal pain: dissociation of hypoalgesia, elevated ketones, and lowered glucose in rats.
Ketogenic diets (KDs) are high-fat, low-carbohydrate formulations effective in treating medically refractory epilepsy, and recently we demonstrated lowered sensitivity to thermal pain in rats fed a KD for 3 to 4 weeks. Regarding anticonvulsant and hypoalgesic mechanisms, theories are divided as to direct effects of increased ketones and/or decreased glucose, metabolic hallmarks of these diets. To address this point, we characterized the time course of KD-induced thermal hypoalgesia, ketosis, and lowered glucose in young male rats fed ad libitum on normal chow or KDs. A strict 6.6:1 (fat:[carbohydrates + protein], by weight) KD increased blood ketones and reduced blood glucose by 2 days of feeding, but thermal hypoalgesia did not appear until 10 days. Thus, ketosis and decreased glucose are not sufficient for hypoalgesia. After feeding a 6.6:1 KD for 19 days, decreased thermal pain sensitivity and changes in blood chemistry reversed 1 day after return to normal chow. Effects were consistent between 2 different diet formulations: a more moderate and clinically relevant KD formula (3.0:1) produced hypoalgesia and similar changes in blood chemistry as the 6.6:1 diet, thus increasing translational potential. Furthermore, feeding the 3.0:1 diet throughout an extended protocol (10-11 weeks) revealed that significant hypoalgesia and increased ketones persisted whereas low glucose did not, demonstrating that KD-induced hypoalgesia does not depend on reduced glucose. In separate experiments we determined that effects on thermal pain responses were not secondary to motor or cognitive changes. Together, these findings dissociate diet-related changes in nociception from direct actions of elevated ketones or decreased glucose, and suggest mechanisms with a slower onset in this paradigm. Overall, our data indicate that metabolic approaches can relieve pain. Chronic pain is a common and debilitating condition. We show that a KD, a high-fat, very low carbohydrate diet well known for treating epilepsy, lowers sensitivity to thermal pain in rats. This reduced pain is not temporally correlated with hallmark diet-induced changes in blood glucose and ketones.


Recent-onset dilated cardiomyopathy associated with Borrelia burgdorferi infection.
Several recent small studies have suggested a causal link between Lyme disease and dilated cardiomyopathy (DCM) by demonstrating the presence of the Borrelia burgdorferi (Bb) genome in the myocardium of patients with recent-onset DCM. The aim of this study was to further investigate the effect of targeted antibiotic treatment of Bb-related recent-onset DCM in a larger cohort of patients. We performed endomyocardial biopsy (EMB) in 110 individuals (53 ± 11 years, 34 women) with recent-onset unexplained DCM, and detected the Bb genome in 22 (20 %) subjects. Bb-positive patients were subsequently treated with intravenous ceftriaxone for 21 days in addition to conventional heart failure medication. At the 1-year follow-up, a significant improvement in left ventricular (LV) ejection fraction (26 ± 6 vs. 44 ± 12 %; p < 0.01) and a decrease in LV end-diastolic (69 ± 7 vs. 63 ± 11 mm; p < 0.01) and end-systolic (61 ± 9 vs. 52 ± 4 mm; p < 0.01) diameters were documented. Moreover, a significant improvement in heart failure symptoms (NYHA class 3.4 ± 0.6 vs. 1.5 ± 0.7; p < 0.01) was also observed. Targeted antibiotic treatment of Bb-related recent-onset DCM in addition to conventional heart failure therapy is associated with favorable cardiac remodeling and improvement of heart failure symptoms.


Role of manganese dioxide in the recovery of oxide-sulphide zinc ore.
In this article, the role of MnO2 in the recovery of oxide-sulphide zinc ore discussed. Through adopting various modern analysis techniques (such as X-ray diffraction pattern, X-ray photoelectron spectroscopy, scanning electron microscope, energy dispersive X-ray analysis, and fourier transform infrared spectroscopy), the function and mechanism of MnO2 during the phase transformation process is found out. Thermodynamic mechanisms involved in the phase transformation process with or without addition of manganese dioxide investigated by exploiting the Equilib module of FactSage. What's more, XRD patterns, XPS spectra and SEM-EDAX analyses of zinc calcines verify well the calculations of FactSage. Results reveal that the addition of MnO2 will produce an aggregation of ZnMn2O4, a valuable energy material, while roasting on its own, results in generating undesirable Zn2SiO4, the oxidation degree being relatively low. Moreover, XRD pattern of zinc calcine and FT-IR spectrum of yellow product collected in the calcination process prove that the sulphur-fixing value of the additive MnO2, which can promote transforming to the elemental sulphur. The volatile S can be collected through a simple guiding device. In this process, the emission of SO2 effectively avoids, thus MnO2 deems as a potential additive in the recovery of oxide-sulphide zinc ore.


Skill Session on Writing Patient Assessments for Pediatric Clerkship Students.
Formulating written patient assessments requires the student to synthesize subjective and objective information and use clinical reasoning to reach a diagnosis. Medical students lack this skill, and clinical experience is not enough to acquire it. This session provides a structured process for learning how to formulate a patient assessment. Third-year medical students participated in a large-group interactive skill session at the beginning of their pediatrics clerkship. Instructors following a scripted model walked students through practice examples to ultimately formulate a complete written patient assessment. The session covered data synthesis, use of appropriate medical terminology, and differential diagnosis development. Students used an audience response system to practice these skills. Over 1 academic year, 250 medical students participated in six sessions, with an average of 40-50 attendees per session. Over 90% of students completed pre- and postsession written patient assessments. These assessments were evaluated using portions of the Pediatric History and Physical Exam Evaluation grading rubric. The session had a positive effect on patient assessment formulation skills, with a significant increase in scores after the session. The session improved students' skill in generating more complete written patient assessments. Almost all students found the session valuable regardless of prior clinical experience. Nearly 50% of students felt inadequately prepared to formulate a written patient assessment prior to the session, revealing a skills gap for learners and a curricular teaching gap. This skill session provided a structured method and active learning format for teaching this essential clinical skill.


Epidemiology and risk factors for thrombosis in children and newborns: systematic evaluation and meta-analysis.
Thrombosis is a serious condition in children and neonates. However, the risk factors for thrombosis have not been conclusively determined. This study aimed to identify the risk factors for thrombosis in children and neonates in Intensive Care Unit (ICU) through a meta-analysis to better guide clinical treatment. A systematic search of electronic databases (PubMed, Embase, Cochrane Library, WOS, CNKI, Wanfang, VIP) was conducted to retrieve studies from creation on 23 May 2022. Data on the year of publication, study design, country of origin, number of patients/controls, ethnicity, and type of thrombus were extracted. The publication bias and heterogeneity between studies were assessed, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed or random effects models. A total of 18 studies met the inclusion criteria. The incidence of thrombosis in children was 2% per year (95% CI 1%-2%, P < 0.01). Infection and sepsis (OR = 1.95, P < 0.01), CVC (OR = 3.66, [95%CL 1.78-7.51], P < 0.01), mechanical ventilation (OR = 2.1, [95%CL1.47-3.01], P < 0.01), surgery (OR = 2.25, [95%CL1.2-4.22], P < 0.01), respiratory distress (OR = 1.39, [95%CL0.42-4.63], P < 0.01), ethnicities (OR = 0.88, [95%CL 0.79-0.98], P = 0.78), gestational age (OR = 1.5, [95%CL1.34-1.68], P = 0.65)were identified as risk factors for thrombosis. This meta-analysis suggests that CVC, Surgery, mechanical ventilation, Infection/sepsis, gestational age, Respiratory distress, and different ethnicities are risk factors for thrombosis in children and neonates in ICU. These findings may help clinicians to identify high-risk patients and develop appropriate prevention strategies. PROSPERO (CRD 42022333449).


Cyclosporin A inhibits T cell receptor-induced interleukin-2 synthesis of human T lymphocytes by selectively preventing a transmembrane signal transduction pathway leading to sustained activation of a protein kinase C isoenzyme, protein kinase C-beta.
Stimulation of human peripheral blood lymphocytes via T cell receptor/CD3 complex resulted in a bimodal activation of protein kinase(s) C (PKC). Within 10 min of stimulation PKC-alpha was translocated to, and thus activated in, the plasma membranes of human lymphocytes, followed by a fast dissociation of this isotype from the plasma membrane. This short term activation and translocation PKC-alpha proved to be cyclosporin A (CsA) insensitive. After 90 min of stimulation PKC-beta was translocated to and remained bound to the plasma membranes for up to 4 h. Preincubation of human lymphocytes with 200 ng/ml CsA specifically and completely abolished the sustained activation of PKC-beta. Neither the phorbol ester-induced direct activation of PKC nor the specific activity of the plasma membrane-bound enzyme was influenced by CsA, suggesting that a signal transduction pathway leading to sustained activation of PKC-beta was influenced by the immunosuppressive agent. In fact, CsA inhibited, in a concentration-dependent manner, the activation of lysophosphatid acyltransferase-catalyzed elevated incorporation of cis-polyunsaturated fatty acids into plasma membrane phospholipids. While interleukin-2 (IL-2) synthesis and cellular proliferation were completely inhibited by 200 ng/ml CsA in BMA 030- or BMA 031-stimulated cells, expression of high-affinity IL-2 receptors was not influenced by the immunosuppressive drug. These results suggest that synthesis and expression of high-affinity IL-2 receptors might be regulated by a signal-transducing pathway involving activation and translocation of PKC-alpha. Lysophosphatid acyltransferase-catalyzed incorporation of cis-polyunsaturated fatty acids might represent another mechanism of signal transduction implicated in the activation and translocation of PKC-beta, which is specifically inhibited by CsA. Neutralization of PKC-beta by introducing anti-PKC-beta antibodies prevented IL-2 synthesis and proliferation in stimulated human lymphocytes. The results suggest a possible link between activation of PKC-beta and regulation of IL-2 synthesis in activated human lymphocytes. Thus, inhibition of the activation and translocation of PKC-beta by CsA may result in inhibition of IL-2 gene expression in human lymphocytes.


Landscape history improves detection of marginal habitats on semi-natural grasslands.
Semi-natural grassland habitats have markedly declined from their historical coverage, thus causing substantial losses for agricultural biodiversity and establishing a consequent need to spot the remaining habitat patches. These patches are generally remnants of once larger habitat areas, formed by uninterrupted and low-intensity management for centuries, but then later being isolated and fragmented into smaller pieces. In the light of this development, past landscape phases have a crucial role for the present existence of semi-natural grasslands. The importance of historical factors has been indicated in many studies but evaluation of their added value, or actual site-specific effects compared to observations of only the present landscape characteristics, is not generally provided. As data related to the past is often difficult to obtain, tedious to process and challenging to interpret, assessment of its advantages and related effects - or consequences of potential exclusion - would be needed. In this study, we used maximum entropy approach to model the distribution of Fumewort (Corydalis solida) which in the study area is a good indicator of valuable semi-natural habitats. We constructed three different models - one based on only the contemporary environment with expected indicators of habitat stability, one solely on the historical landscape phases and long-term dynamics, and one combining variables from the past and the present. Predictions of the three models were validated and compared with each other, followed by an analysis indicating the similarity of model results with known Fumewort occurrences. Our results indicate that present landscapes may provide workable surrogates to delineate larger core habitats, but utilization of historical data markedly improves the detection of small outlying patches. These conclusions emphasize the importance of previous landscape phases particularly in detecting marginal semi-natural grassland habitats, existing in contemporarily suboptimal conditions and being prone to disappear if no further actions are taken.


Are marine planktonic invertebrates food limited? The case of Mysis mixta (Crustacea, Mysidacea) in the Baltic Sea.
Linear regression analysis of field data from a coastal area of the Baltic Sea indicated that growth of the zooplanktivorous Mysis mixta was food limited. No statistically significant effects of temperature on growth were detected.


The characterization of static and dynamic brain functional networks in suicide attempters with major depressive disorder and its relation to psychological pain.
Psychological pain is a robust predictor of suicide attempts in patients with major depressive disorder (MDD). However, whether suicide and psychological pain share a common neural basis remains unclear. Patients with MDD (n = 64) and healthy controls (HC) (n = 35) were recruited and patients were allocated to two groups: those with a history of suicide attempts (MDD-SA) (n = 25) and those without such a history (MDD-NSA) (n = 39). All participants completed the measurements and underwent functional magnetic resonance imaging to investigate the resting-state static and dynamic brain functional networks in default mode (DMN), central executive (CEN), salience (SN), and basal ganglia (BGN) networks. The MDD-SA group scored higher in pain avoidance than the MDD-NSA and HC groups. Functional connectivity within the dorsal DMN in the MDD-SA group was greater than that in the MDD-NSA and HC groups, and was significantly correlated with pain avoidance and suicide attempts. Dynamic functional connectivity analysis revealed that the proportion of State I in the fraction windows in the MDD-SA group was higher than those in the MDD-NSA and HC groups. Therefore, the increased functional connectivity within the dorsal DMN and segregation of networks may represent potential biological markers for suicide attempts related to psychological pain processing.


Expression of a tyrosine phosphorylated, DNA binding Stat3beta dimer in bacteria.
The signal transducer and activator of transcription (STAT) proteins deliver signals from the cell membrane to the nucleus. An N-terminally truncated fragment of murine Stat3beta, Stat3betatc (127-722), was produced in bacteria. STAT proteins must be specifically phosphorylated at a single tyrosine residue for dimerization and DNA binding. Therefore, Stat3betatc was coexpressed with the catalytic domain of the Elk receptor tyrosine kinase. Stat3betatc was quantitatively phosphorylated by this kinase domain. Gel filtration chromatography revealed a Stat3betatc dimer. Y705 was identified as the major phosphorylated residue of Stat3betatc. This corresponds to the tyrosine residue which is phosphorylated by the Janus kinase in vivo. The phosphorylated Stat3betatc specifically bound to DNA binding sites. The described protocol allows the production of large amounts of activated protein for biochemical and pharmaceutical studies.


Knee joint biomechanics of patients with unilateral total knee arthroplasty during stationary cycling.
Stationary cycling is typically recommended following total knee arthroplasty (TKA) operations. However, knee joint biomechanics during cycling remains mostly unknown for TKA patients. Biomechanical differences between the replaced and non-replaced limb may inform applications of cycling in TKA rehabilitation. The purpose of this study was to examine the knee joint biomechanics of TKA patients during stationary cycling. Fifteen TKA participants cycled at 80 revolutions per minute and workrates of 80 W and 100 W while kinematics (240 Hz) and pedal reaction forces using a pair of instrumented pedals (1200 Hz) were collected. A 2x2 (limb × workrate) repeated measures ANOVA was run with an alpha of 0.05. Peak knee extension moment (KEM, p = 0.034) and vertical pedal reaction force (p = 0.038) were significantly reduced in the replaced limbs compared to non-replaced limbs by 21.3% and 5.3%, respectively. Peak KEM did not change for TKA patients with the increased workrate (p = 0.750). However, both peak hip extension moment (p = 0.009) and ankle plantarflexion moment (p = 0.017) increased due to increased workrate. Patients following TKA showed similar decreases in peak KEM and vertical pedal reaction force in their replaced compared to non-replaced limbs, as previously seen in gait. Patients of TKA may rely on their hip and ankle extensors to increases in workrate. Increasing intensity by 20 W did not exacerbate any inter-limb differences for peak KEM and vertical PRF.


Quercetin inhibits Toxoplasma gondii tachyzoite proliferation and acts synergically with azithromycin.
Quercetin (QUE) is a natural polyphenol known to have numerous pharmacological properties against infectious and non-infectious diseases. Azithromycin (AZ) is an antibiotic that belongs to the azalide class of antimicrobials and an antiparasitic that is known to be effective in combination with clindamycin against pyrimethamine/sulfadiazine-resistant Toxoplasma gondii tachyzoites in clinical settings. Both compounds are known to target protein synthesis and have anti-inflammatory properties. However, little is known about QUE and AZ synergistic interaction against T. gondii growth. Here, we report for the first time the effects of the combination of QUE and AZ on T. gondii growth. The 50% inhibitory concentration (IC50) for QUE at 72 h of interaction was determined to be 0.50 µM, whereas AZ gave an IC50 value of 0.66 µM at 72 h of interaction with parasites. Combination testing of QUE and AZ in a ratio of 2:1 (QUE:AZ) showed an IC50 value of 0.081 µM. Interestingly, a fractional inhibitory index value of 0.28 was observed, indicating a strong synergy. QUE was also found to upregulate the generation of reactive oxygen species and cause dysfunction of the mitochondria membrane of both intracellular and extracellular T. gondii tachyzoites. Overall, the results indicate that QUE is a novel lead capable of synergizing with AZ for inhibiting T. gondii growth and may merit future investigation in vivo for possible combination drug development.


Mast cell growth, differentiation, and death.
Mast cells (MC) begin development in the bone marrow. Following initial lineage commitment, the cells move into the vasculature as a committed progenitor (MCp) that is poorly phenotypically defined, but appears to be an agranular cell lacking the high-affinity IgE receptor characteristic of the mature tissue-localized MC. Full maturation occurs after the cells move into the various tissues. In the mouse, MCp localizing in the connective tissues appear to differentiate into mature MC, whereas those localizing in the lung and mucosal compartment of the small intestine remain largely as committed MCp. Movement of the MCp into the small intestine is controlled by the alpha 4 beta 7 integrin, whereas the factors controlling movement into other tissues remain to be defined. Following an inflammatory stimulus, Th2-derived cytokines drive the maturation process of these MCps, leading to the mature mucosal MC hyperplasia associated with events such as an intestinal helminth infection and possibly human allergy such as asthma and rhinitis. The expanded MC number disappears as the stimulus resolves. Various routes are used in the resolution of the MC hyperplasia including apoptosis, shedding along with the villous epithelium, and recirculation back to the spleen for elimination. Unlike the reactive MC that appears in association with inflammation, the connective tissue-localized MC is a long-lived radiation-resistant cell, which appears to depend principally on the presence of stem cell factor (SCF) for its persistence.


[Nephroscopy with carbon dioxide in combination with laparoscopy in the treatment of urinary stones].
Laparoscopy in combination with nephroscopy is rarely used for the treatment of complex urinary stones or anatomical abnormalities with difficult access stones. During the nephroscopy, in an opened renal pelvis, large amounts of fluid leaks and collects in the peritoneal cavity and can be a drawback. In these cases, the nephroscopy with use of carbon dioxide (CO2) can be an alternative. We present our experience in with this technique. We performed surgeries using the 3-port transperitoneal technique. Five patients with urolithiasis were included. Three patients had concomitant ureteropelvic junction stenosis, one with stones in ectopic kidney, and the third had a large stone impacted in the proximal ureter. Patients were treated by pyelolithotomy or ureterolithotomy combined with flexible nephroscopy using CO2 and dismembered pyeloplasty was performed in appropriate cases. A flexible cystoscope was passed through a port and guided laparascopically through the opening in the renal pelvis. The gas cannula was connected to the irrigation channel of the endoscope to insufflate CO2 and calculi were extracted with a nitinol basket. Median age was 45 years (24-58). Mean operative time of nephroscopy was 22.4 minutes (range 15-48). Mean intra-operative blood loss was inestimable. There were no complications or conversion. Residual lithiasis requiring ureteroscopy was present in one patient. Flexible nephroscopy using CO2 in combination with laparoscopy is a feasible and effective technique for the treatment of urinary stones in selected cases to avoid accumulation of fluid in the peritoneal cavity.


Diurnal variations of cloud and relative humidity profiles across the tropics.
Even though the diurnal cycle of solar forcing on the climate system is well defined, the diurnal evolutions of water vapor and clouds induced by the solar forcing are not yet established across the tropics. Here we combine recent satellite observations of clouds profiles and relative humidity profiles to document the diurnal variations of the water vapor and clouds vertical distributions over all the tropics in June-July-August. While the daily mean water vapor and cloud profiles are different between land and ocean, their diurnal variations with respect to their daily means exhibit similar features. Relative humidity profiles and optically thin cloud fraction profiles vary together which maximize during night-time in the entire troposphere and a minimize in day-time. The fraction of optically opaque clouds peak in the free troposphere in the early afternoon, transforms into a high altitude positive anomaly of optically thin clouds from nightfall to sunrise. In addition, land regions exhibit a daily low thin cloud positive anomaly, while oceanic regions exposed to subsidence air motions exhibit positive anomalies of opaque clouds in the lower atmosphere during the second half of the night, which grow until sunrise.