MRI multiparametric hemodynamic characterization of the normal brain.
Characterization of the brain's vascular system is of major clinical importance in the assessment of patients with cerebrovascular disease. The aim of this study was to characterize brain hemodynamics using multiparametric methods and to obtain reference values from the healthy brain. A multimodal magnetic resonance imaging (MRI) study was performed in twenty healthy subjects, including dynamic susceptibility contrast imaging and blood oxygen level dependence (BOLD) during hypercapnia and carbogen challenges. Brain tissues were defined using unsupervised cluster analysis based on these three methods, and several hemodynamic parameters were calculated for gray matter (GM), white matter (WM), blood vessels and dura (BVD); the three main vascular territories within the GM; and arteries and veins defined within the BVD cluster. The carbogen challenge produced a BOLD signal twice as high as the hypercapnia challenge, in all brain tissues. The three brain tissues differed significantly from each other in their hemodynamic characteristics, supporting the graded vascularity of the tissues, with BVD>GM>WM. Within the GM cluster, a significant delay of ∼1.2 s of the bolus arrival time was detected within the posterior cerebral artery territory relative to the middle and anterior cerebral artery territories. No differences were detected between right and left middle cerebral artery territories for all hemodynamic parameters. Within the BVD cluster, a significant delay of ∼1.9 s of the bolus arrival time was detected within the veins relative to the arteries. This parameter enabled to differentiate between the various blood vessels, including arteries, veins and choroid plexus. This study provides reference values for several hemodynamic parameters, obtained from healthy brains, and may be clinically important in the assessment of patients with various vascular pathologies.


Magnetic resonance findings in skeletal muscle tears.
Magnetic resonance (MR) images of skeletal muscle tears can clearly delineate the severity of muscle injury. Although MR imaging is seldom necessary in patients with acute muscle trauma, it can be helpful in deciding on clinical management. The two major MR findings in acute muscle tears are deformity of the muscle and the presence of abnormal signal reflecting hemorrhage and edema. In acute tears, methemoglobin within the extravascular blood causes high-signal areas on both T1- and T2-weighted images. With partial tears, the blood may dissect in a distinctive linear pattern along the muscle bundles and fibers. As healing begins, the muscle signal diminishes, first on the T1-weighted images and then on the T2-weighted images. When there is residual abnormal signal on images obtained more than several months after the injury, it is presumed to represent hemorrhage from recurrent tears. In patients with a questionable history of a remote injury, the clinical presentation may be that of persistent pain or a soft tissue mass. In these cases MR imaging may identify the cause of the pain and can exclude a neoplasm by proving that the mass is a hypertrophied or retracted muscle. Thus, MR imaging has a limited, but occasionally important role in selected patients with skeletal muscle tears.


Initiation of DNA replication requires actin dynamics and formin activity.
Nuclear actin regulates transcriptional programmes in a manner dependent on its levels and polymerisation state. This dynamics is determined by the balance of nucleocytoplasmic shuttling, formin- and redox-dependent filament polymerisation. Here, using Xenopus egg extracts and human somatic cells, we show that actin dynamics and formins are essential for DNA replication. In proliferating cells, formin inhibition abolishes nuclear transport and initiation of DNA replication, as well as general transcription. In replicating nuclei from transcriptionally silent Xenopus egg extracts, we identified numerous actin regulators, and disruption of actin dynamics abrogates nuclear transport, preventing NLS (nuclear localisation signal)-cargo release from RanGTP-importin complexes. Nuclear formin activity is further required to promote loading of cyclin-dependent kinase (CDK) and proliferating cell nuclear antigen (PCNA) onto chromatin, as well as initiation and elongation of DNA replication. Therefore, actin dynamics and formins control DNA replication by multiple direct and indirect mechanisms.


Personality disorders: community prevalence and socio-demographic correlates.
Multiple studies have reported community prevalence rates of personality disorders (PDs), but these studies differed in terms of diagnostic criteria, assessment instruments, communities sampled, and size, producing widely ranging estimates. We take a meta-analytic approach to characterizing PD community prevalence rates by comparing results from two reviews that pooled previous studies. Overall, particular PD rates are low in community samples, but the presence of any PD is relatively high, with approximately one person in seven experiencing personality psychopathology. High congruence of prevalence estimates, but low rank-order agreement of rates, was observed. We discuss how the presence of PD is associated with socio-demographic correlates such as gender, race/ethnicity, and age and highlight areas for further study.


Survey of cutaneous lesions in Indian newborns.
A total of 900 consecutive newborns delivered at the Nehru Hospital, Chandigarh, India, over a period of 7 months were examined for presence of skin lesions within 48 hours of birth. Commonly observed skin lesions were Epstein pearls (88.7%), mongolian spots (62.2%), milia (34.9%), sebaceous hyperplasia (31.8%), salmon patches (28.4%), and erythema toxicum neonatorum (20.6%). These figures are comparable with earlier reports. Impetigo neonatorum occurred in 11.3% of infants, and was frequent in our hot and humid climate from May to August. Traumatic skin lesions were most often present in babies who had forceps deliveries. Three hundred ten (34%) babies were available for follow-up up to six weeks. Additional skin lesions observed were omphalitis (16 babies), oral thrush (9) and postinflammatory hypomelanosis (8). Three infants had atopic dermatitis, two each had seborrheic dermatitis, diaper dermatitis, pityriasis versicolor, and nevus achromicus. One each had vitiligo, ichthyosis vulgaris, urticaria, and strawberry hemangioma. These observations highlight the importance of repeat examination for the appearance of skin lesions during the neonatal period.


Telehealth services in an outpatient nephrology clinic during the COVID-19 pandemic: a patient perspective.
In response to the COVID-19 pandemic, new policy waivers permitted reimbursement of telehealth services in urban settings. The aim of this study was to assess patient satisfaction with telehealth services during the COVID-19 pandemic in an outpatient urban nephrology practice. Patients who had virtual encounters were asked to complete an online survey regarding their experiences with telehealth services. Twenty-one percent of eligible patients completed the survey. Patients (83.6%) reported overall positive experiences with telehealth and want to see a hybrid healthcare model in the future (80.1%). Additionally, most patients found telehealth appointments convenient to make and telehealth encounters convenient to conduct. Ethnicity, age, gender, and insurance type did not have a statistically significant impact on satisfaction ratings. Technical issues were not encountered by 79.5% of patients and patients were willing to use the video feature. However, if they had technical issues, patient satisfaction ratings were negatively impacted. Telehealth services are beneficial to patients with regards to convenience, decreased transportation costs and time, increased accessibility to healthcare, and decreased overall opportunity costs. However, challenges still remain with the deployment of telehealth and will be dependent on patients' digital health literacy, access to broadband internet and devices, and legislation and/or regulations. Limitations of the study, including small sample size and surveying patients from a nephrology practice, may prevent it from being generalizable. Additional studies with a larger sample size and multiple specialties may be needed to generalize patients' satisfaction with telehealth services.


Causal Model of Survival After Pulmonary Metastasectomy of Colorectal Cancer: A Nationwide Prospective Registry.
Although numerous existing studies have analyzed the prognostic factors of patients who have had surgical intervention for lung metastases of colorectal carcinoma (CRC), many of the results obtained until now have been contradictory. As a consequence, there is no established consensus about which group of prognostic factors could have a greater value when considered together. This was a multicenter prospective cohort study that included all patients who underwent a first pulmonary metastasectomy of CRC, with radical intent, during a 2-year period (March 2008 to February 2010). The follow-up continued until March 2013, and an analysis of disease-specific survival (DSS), determined from the first pulmonary metastasectomy, was implemented. The selection of the best submodel was taken based on their coefficient of determination (R(2)) and how parsimonious they were depending on the number of variables included. The series, consisting of 522 patients, presented the following survival rates: median, 54.9 months; 3-year DSS, 69.4% (95% confidence interval [CI], 65% to 73.8%); and 5-year DSS, 46.1% (95% CI, 38.5% to 53.7%). The resulting survival model consisted of disease-free interval of 12 months or less (hazard ratio [HR], 1.76; 95% CI, 1.21 to 2.54; p = 0.003), carcinoembryonic antigen level exceeding 5 ng/mL (HR, 1.50; 95% CI, 1.04 to 2.17; p = 0.028), bilateral lung disease (HR, 1.81; 95% CI, 1.20 to 2.75; p = 0.005), and thoracic lymph node involvement (HR, 2.71; 95% CI, 1.44 to 5.12; p = 0.002). According to these results from the Spanish Group of Lung Metastases of Colo-Rectal Cancer, the combination of these four variables-disease-free interval, carcinoembryonic antigen level, laterality, and thoracic lymph node involvement-constitutes the first-choice survival causal model based on the clinical and pathologic factors most frequently referenced in literature.


Crucial transcription factors in endoderm and embryonic gut development are expressed in gut-like structures from mouse ES cells.
Mouse embryonic stem (ES) cells are pluripotent and retain the potential to form an organ similar to the gut showing spontaneous contractions in vitro. The morphological features of these structures and their formation, as assessed using the hanging drop method to produce embryoid bodies (EBs), seem to be similar to those in vivo. To determine whether the same molecular mechanisms are involved in the formation process, the expression pattern of transcription factors regulating endoderm and gut development in the mouse embryo was examined by in situ hybridization and compared with in vivo expression. Expression of gene products was also examined by immunohistochemistry, and expression colocalization was analyzed with double staining. The results showed that all factors examined, that is, Sox17, Id2, HNF3beta/Foxa2, and GATA4, were expressed in both EBs and gut-like structures. Moreover, their expression patterns were similar to those in the mouse embryo. EBs after the hanging drop period and before outgrowth already expressed all factors that were colocalized with each other in EB epithelial structures. These findings suggest that the origin of the gut-like structure is determined during the hanging drop period and that the gut-like structure is formed as the epithelial structure in EBs during the hanging drop period. They also indicate that the in vitro system using mouse ES cells mimics in vivo development and should prove useful in the study of molecular mechanisms for endoderm and gut development.


A new species of Deutonura (Collembola: Neanuridae: Neanurinae) from Algeria, with revised diagnosis of the genus and key to western Palaearctic species.
Deutonura adriani sp. nov. is described from the region of Tizi-Ouzou (Algeria). The species is morphologically similar to D. deficiens deficiens Deharveng, 1979 from southwestern France, differing by not having De3 chaetae integrated into the dorso-external tubercle on abdominal tergites I and II. The genus Deutonura is re-diagnosed and a key to its Western Palaearctic species is provided.


Genome-Wide Cell Type-Specific Mapping of In Vivo Chromatin Protein Binding Using an FLP-Inducible DamID System in Drosophila.
A thorough study of the genome-wide binding patterns of chromatin proteins is essential for understanding the regulatory mechanisms of genomic processes in eukaryotic nuclei, including DNA replication, transcription, and repair. The DNA adenine methyltransferase identification (DamID) method is a powerful tool to identify genomic binding sites of chromatin proteins. This method does not require fixation of cells and the use of specific antibodies, and has been used to generate genome-wide binding maps of more than a hundred different proteins in Drosophila tissue culture cells. Recent versions of inducible DamID allow performing cell type-specific profiling of chromatin proteins even in small samples of Drosophila tissues that contain heterogeneous cell types. Importantly, with these methods sorting of cells of interest or their nuclei is not necessary as genomic DNA isolated from the whole tissue can be used as an input. Here, I describe in detail an FLP-inducible DamID method, namely generation of suitable transgenic flies, activation of the Dam transgenes by the FLP recombinase, isolation of DNA from small amounts of dissected tissues, and subsequent identification of the DNA binding sites of the chromatin proteins.


Equilibrium and dynamic investigations of organic acids adsorption onto ion-exchange resins.
The aim of the study was to determine properties of selected ion-exchange resins for citric and lactic acids recovery, to define sorption isotherms for these acids at different temperatures (in the range of 20-60 degrees C) and to determine diffusion coefficients inside sorbent particles. A mathematical model of the ion-exchange process in the chromatographic column and its experimental verification is also presented. During investigations 18 types of ion-exchange resins were tested. It was found that weakly basic resins were more suitable for the recovery process than strongly basic ones. The best resin for the separation of citric acid was Amberlite IRA-67 and for lactic acid Amberlite IRA-92. As a result of transient-state sorption experiments diffusion coefficients of the citric acid inside the sorbent particle at different temperatures were obtained. It was found that D(p) increased with the temperature by two times in the range of 20-60 degrees C, and its value at 60 degrees C was 7.2 x 10(-10) m(2)/s. The proposed mathematical model was applied to identify bed operation parameters in the column for the needs of the simulated moving bed chromatography method.


Dithiothreitol separation of newborn rodent dermis and epidermis.
Incubation of newborn mouse skin in media containing 0.01 M dithiothreitol at 4 degrees C for 2 hr reduces dermal-epidermal cohesion, and the 2 layers may be separated readily. Unlike other methods of separation, this technique does not require heating, nonphysiologic pH or ionic strength, or addition of proteolytic enzymes. The split occurs beneath the basal lamina. The separated epidermal sheet retains the periodic acid Schiff-positive "basement membrane," and the basal cells can incorporate 3H-thymidine.


Pharmacokinetics of tazarotene cream 0.1% after a single dose and after repeat topical applications at clinical or exaggerated application rates in patients with acne vulgaris or photodamaged skin.
To evaluate the safety and pharmacokinetics of tazarotene cream 0.1% under standard (face only) or exaggerated (15% body surface area, including the face) application conditions after a single dose and after repeat topical applications once daily to patients with acne vulgaris or photodamaged skin. Two separate, randomised, single-centre, nonblinded, parallel-group pharmacokinetic studies were conducted. In one study, tazarotene cream 0.1% was applied either to the face of eight female patients with moderate acne or to 15% body surface area of ten female patients with severe acne. In the other study, tazarotene cream 0.1% was applied either to the face (six females, two males) or to 15% body surface area (8 females, 8 males) of patients with photodamaged skin. In both studies, tazarotene cream 0.1% was applied once daily (except on days 1 and 2) for 30 days. Blood was drawn for measurement of plasma concentrations of tazarotenic acid at defined time intervals after application of the cream. Plasma tazarotenic acid concentrations were determined by a validated gas chromatography-tandem mass spectrometry method with a lower limit of quantification of 0.005 microg/L. At exaggerated application rates in patients with acne vulgaris, the maximum average peak concentration (C(max)) and 24-hour area under the concentration-time curve (AUC) values of tazarotenic acid were (mean +/- SD) 1.20 +/- 0.41 microg/L (n = 10) and 17.0 +/- 6.1 microg. h/L (n = 10), respectively, and occurred on day 15. The single highest C(max) was 1.91 microg/L. At standard application rates in patients with acne vulgaris, the maximum average C(max) and AUC values of tazarotenic acid were 0.10 +/- 0.06 microg/L (n = 8) and 1.54 +/- 1.01 microg. h/L (n = 8), respectively, and occurred on day 15. At exaggerated application rates in patients with photodamaged skin, the maximum average C(max) and AUC values of tazarotenic acid were (mean +/- SD) 1.75 +/- 0.53 microg/L (n = 16) and 23.8 +/- 7.0 microg. h/L (n = 16), respectively, and occurred on day 22. The single highest C(max) was 3.43 microg/L on day 29. At standard application rates in patients with photodamaged skin, the maximum average C(max) and AUC values of tazarotenic acid were 0.236 +/- 0.255 microg/L (n = 8) and 2.44 +/- 1.38 microg. h/L (n = 8), respectively, and occurred on day 15. Gender had no influence on the systemic exposure of tazarotenic acid. The most common treatment-related adverse events were signs and symptoms of local irritation, of mild or moderate severity. The pharmacokinetics of tazarotene cream 0.1% in patients with acne vulgaris or photodamaged skin are similar. The maximum average plasma concentrations of tazarotenic acid after topical application of tazarotene cream 0.1% to the face were less than 0.25 microg/L. The maximum average plasma concentrations of tazarotenic acid following application to an exaggerated body surface area (15%) were less than 1.8 microg/L.


Electrically conductive crystalline polylactide nonwovens obtained by electrospinning and modification with multiwall carbon nanotubes.
Polylactide nonwovens were electrospun from solutions and then crystallized, one in α-form, and another, S-PLA, made of poly(l-lactide) and poly(d-lactide) 1:1 blend, in scPLA crystals with high melting temperature, close to 220 °C. To make the nonwovens electrically conductive, they were coated with multiwall carbon nanotubes (MWCNT) by padding and dip-coating with an aqueous dispersion of MWCNT. The electrical conductivity evidenced the formation of the electrically conductive MWCNT network on the fiber surfaces. Depending on the coating method, the surface resistivity (Rs) of S-PLA nonwoven of 1.0 kΩ/sq and 0.09 kΩ/sq was reached. To study the effect of surface roughness, before the modification the nonwovens were etched with sodium hydroxide, which additionally made them hydrophilic. The effect of etching depended on the coating method and led to an increase or decrease of Rs, in the case of padding or dip-coating, respectively. All MWCNT-modified nonwovens, unetched and etched, were hydrophobic with water contact angles of 138-144°. Scanning electron microscopy corroborated the presence of MWCNT on the fiber surfaces. Impedance spectroscopy confirmed the dominant role of the network of MWCNT direct contacts on the electrical properties of MWCNT-modified nonwovens in a broad frequency range.


Rituximab for rheumatoid arthritis-associated large granular lymphocytic leukemia, a retrospective case series.
To assess the efficacy and tolerance profile of rituximab in rheumatoid arthritis (RA)-associated large granular lymphocyte leukemia (LGLL). Multicenter retrospective case series. Inclusion criteria were RA defined by the ACR/EULAR 2010 criteria and LGLL defined by absolute LGL count ≥ 0.3 × 109/L with evidence of an expanded clonal LGL population (flow cytometry, TCR-γ polymerase chain reaction, or Stat3 mutation). Fourteen patients (10 women, mean age 55.2 ± 14.2 years) included; 13 were seropositive for anti-cyclic citrullinated peptides (n = 11) or rheumatoid factor (n = 10). LGLL diagnosis was made 9.5 [IQR: 3.25;15.5] years after RA diagnosis. Thirteen patients had T-LGLL. Rituximab was the first-line therapy for LGLL for 4 patients. Previous treatment lines included methotrexate (n = 7), cyclophosphamide (n = 2), cyclosporin A (n = 1), or granulocyte colony-stimulating factor (n = 4). Rituximab was used in monotherapy (n = 8) or associated to methotrexate (n = 3), granulocyte colony-stimulating factor (n = 2), or alkylating agents (n = 1). The number of rituximab cycles ranged from 1 to 11 (median 6), with high heterogeneity in dosing regimens. Median duration response after rituximab initiation was 35 [IQR: 23.5;41] months. The overall response rate was 100%: 8 patients experienced complete response (normalization of blood count and LGL ≤ 0.3 × 109/L) and 6 experienced partial responses (improvement in blood counts without complete normalization). The tolerance profile was good, with no infectious complications. rituximab appears as a valuable therapeutic option for RA-associated LGLL.


Amorphous calcium carbonate in the shells of adult Unionoida.
Shells of adult individuals from two different bivalve families, Hyriopsis cumingii and Diplodon chilensis patagonicus, were studied by Micro-Raman spectroscopy and Focussed Ion Beam-assisted TEM. The shells contain amorphous calcium carbonate in a zone at the interface between the periostracum and the prismatic layer. In this area, the initial prism structures protrude from the inner periostracum layer and it is demonstrated that these structures systematically consist of highly disordered and amorphous calcium carbonate. Within this zone, ordered and disordered areas are intermingled discounting the existence of a crystallization front and favouring models of domainal crystallization processes via so-called mesocrystals. These observations are the first documentation of the use of amorphous calcium carbonate as a precursor phase by adult mollusc species and lend further support to hypotheses postulating widespread use of amorphous phases as building material of skeletal tissue in biology.


Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner.
YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology.


Biochemical characterisation of four rhamnosidases from thermophilic bacteria of the genera Thermotoga, Caldicellulosiruptor and Thermoclostridium.
Carbohydrate active enzymes are classified in databases based on sequence and structural similarity. However, their function can vary considerably within a similarity-based enzyme family, which makes biochemical characterisation indispensable to unravel their physiological role and to arrive at a meaningful annotation of the corresponding genes. In this study, we biochemically characterised the four related enzymes Tm_Ram106B, Tn_Ram106B, Cb_Ram106B and Ts_Ram106B from the thermophilic bacteria Thermotoga maritima MSB8, Thermotoga neapolitana Z2706-MC24, Caldicellulosiruptor bescii DSM 6725 and Thermoclostridium stercorarium DSM 8532, respectively, as α-L-rhamnosidases. Cobalt, nickel, manganese and magnesium ions stimulated while EDTA and EGTA inhibited all four enzymes. The kinetic parameters such as Km, Vmax and kcat were about average compared to other rhamnosidases. The enzymes were inhibited by rhamnose, with half-maximal inhibitory concentrations (IC50) between 5 mM and 8 mM. The α-L-rhamnosidases removed the terminal rhamnose moiety from the rutinoside in naringin, a natural flavonone glycoside. The Thermotoga sp. enzymes displayed the highest optimum temperatures and thermostabilities of all rhamnosidases reported to date. The four thermophilic and divalent ion-dependent rhamnosidases are the first biochemically characterised orthologous enzymes recently assigned to glycoside hydrolase family 106.


The nucleotide sequences defining the signal peptides of the galactose-binding protein and the arabinose-binding protein.
The nucleotide sequences of the NH2-terminal regions of the mglB (galactose-binding protein) and the araF (arabinose-binding protein) genes have been determined. A "signal peptide" containing 23 amino acid residues immediately precedes the known sequence of the processed galactose-binding protein. The primary sequence of the signal peptide of the arabinose-binding protein has been redefined according to the established nucleotide sequence. The nucleotide sequences for the two signal peptides are preceded by apparent ribosome-binding sequences.


Production of phenols and biofuels by catalytic microwave pyrolysis of lignocellulosic biomass.
Catalytic microwave pyrolysis of biomass using activated carbon (AC) was investigated to determine the effects of pyrolytic conditions on the yields of phenol and phenolics. Bio-oils with high concentrations of phenol (38.9%) and phenolics (66.9%) were obtained. These levels were higher than those obtained by pyrolysis without AC addition and were closely related to the decomposition of lignin. A high concentration of esters (42.2% in the upgraded bio-oil) was obtained in the presence of Zn powder as catalyst and formic acid/ethanol as reaction medium. Most of the esters identified by GC-MS were long chain fatty acid esters. The high content of phenols and esters obtained in this study can be used as partial replacement of petroleum fuels after separation of oxygenates or as feedstock for organic syntheses in the chemical industry after purification.


Hypoxic regions exist in human prostate carcinoma.
The purpose of this study was to characterize, by use of the Eppendorf microelectrode, the extent of hypoxia (range/heterogeneity) in human prostate carcinomas. Custom-made Eppendorf pO2 microelectrodes were used to obtain PO2 measurements from the pathologically involved side of the prostate, as well as from a region of normal muscle for comparison. Each set of measurements comprised approximately 100 separate readings of pO2, for a total of 2145 individual measurements. Twelve patients were studied, 7 of whom underwent brachytherapy, 3 a radical prostatectomy, and 2 a cystoprostatectomy. The pO2 measurements were obtained in the operating room, using sterile technique, under spinal anesthesia for the brachytherapy group patients and under general anesthesia for the surgery group patients. The Eppendorf histograms were recorded and described by the median pO2, mean pO2, and percentage of measurements less than 5 mm Hg and less than 10 mm Hg. Because of differences in patient characteristics and the anesthesia employed, control measurements were obtained from nearby normal muscle as an internal control in all but 2 patients. This internal comparison showed that the oxygen measurements from the pathologically involved portion of the prostate were significantly lower than those from normal muscle. Similarly, higher pO2 readings were obtained from the pathologically normal prostates (in the patients with bladder cancer) than from the prostates of patients with prostate carcinoma. Increasing levels of hypoxia were observed with increasing clinical stage. Significant predictors of oxygenation include the type of tissue (pathologically involved prostate versus normal muscle or normal prostate), clinical stage, and type of anesthesia. This report, to our knowledge, represents the first study to obtain in vivo electrode measurements of oxygen levels in patients with prostate cancer and suggests that hypoxic regions exist in human prostate carcinoma. More patients will be accrued to this prospective study to correlate the oxygenation status of prostate carcinoma with known prognostic factors and treatment outcome.


Irreversible pan-ErbB tyrosine kinase inhibitor CI-1033 induces caspase-independent apoptosis in colorectal cancer DiFi cell line.
The epidermal growth factor receptor (EGFR) is overexpressed in the majority of colorectal carcinomas and represents a target for therapeutic interventions with signal transduction inhibitors. We investigated the ability of CI-1033 to induce apoptosis and inhibition of proliferation in the colorectal cancer cell lines DiFi and Caco-2, which both express high levels of EGFR. While in Caco-2 cells CI-1033 treatment at a concentration 0.1 microM for 72 hours demonstrated only antiproliferative (53.7 +/- 4.3%) but no pro-apoptotic effects, treatment of DiFi cells resulted in a reduced proliferation rate (31.4 +/- 3.1%) and in apoptosis (44.2 +/- 8.9%). In order to define proteins involved in the regulation of apoptosis, we aimed to determine differences in the proteome profile of both cell lines before and after treatment with CI-1033. Cellular proteins were analyzed by 2-D gel electrophoresis followed by computational image analysis and mass spectrometry. Our data show that DiFi cells differ from Caco-2 cells in nine significantly upregulated proteins, and their potential role in apoptosis is described. We demonstrate that induction of apoptosis was triggered via caspase-independent pathways. Overexpression of leukocyte elastase inhibitor (LEI) and translocation of cathepsin D to the cytosol accompanied by upregulation of other defined proteins resulted in Bax-independent AIF translocation from mitochondria into the nucleus and apoptosis. Definition of these proteins can pave the way for functional studies and contribute to a better understanding of the effects of CI-1033 and the pathways of caspase-independent cell death.


Efficacy and safety of 177Lu-EDTMP in bone metastatic pain palliation in breast cancer and hormone refractory prostate cancer: a phase II study.
(177)Lu-labeled ethylenediamine-N,N,N',N'-tetrakis methylene phosphonic acid ((177)Lu-EDTMP), was used to palliate metastatic bone pain as a new bone-seeking radiopharmaceutical. In this phase II study, we assessed the efficacy and safety of (177)Lu-EDTMP for bone pain palliation in patients with breast cancer and hormone refractory prostate cancer with bone metastases. Sixteen patients were enrolled in the trial and were subsequently divided into 2 groups, the low-dose group (1295 MBq) and the high dose group (2590 MBq) to determine differences in toxicities and response rates. Pain scores, Karnofsky indices, mobility scores, and requirement of analgesic administration were assessed at 0, 2, 4, 6, 8, and 12 weeks after injection of (177)Lu-EDTMP. Toxicity was assessed by analyzing hemoglobin, leukocyte, and platelet counts. An obvious reduction in the mean pain score was observed at 2 to 6 weeks after the administration of (177)Lu-EDTMP. The rate of complete responses in bone pain palliation was 55% in group 1 and 80% in group 2 at 6 weeks after treatment. Of the 5 patients who required additional analgesics, all were able to reduce or completely stop taking these medications by 4 weeks after therapy. Mean (SD) Karnofsky indices of 58.18 (9.82) (range, 50-70) and 56.00 (8.94) (range, 50-70) at baseline increased to 82.73 (9.05) (range, 60-90) at 6 weeks after (177)Lu-EDTMP treatment in group 1 and 85.00 (5.77) (range, 80-90) at 8 weeks after injection in group 2, respectively. Mobility scores decreased from 2.91 (1.04) (range, 1-4) and 2.80 (0.84) (range, 2-4) at baseline to 1.00 (0.67) (range, 0-2) and 0.50 (0.58) (range, 0-1) at 8 weeks after administration of (177)Lu-EDTMP in groups 1 and 2, respectively, primarily owing to improved mobility. In group 1, 1 patient experienced grade III toxicity in both hemoglobin and platelet counts. No grade IV toxicities were observed. In group 2, there were no grade III or IV toxicities found in hemoglobin, platelets, or leukocytes counts. Moreover, no clinically significant adverse effects were observed, and no significant differences in either efficacy or safety were detected between the 2 dose levels. This study indicated that (177)Lu-EDTMP was an effective and safe treatment for palliation of metastatic bone pain in patients with prostate or breast cancer. A dose of 1295 MBq (35 mCi) was sufficient for bone pain palliation therapy, and doses as high as 2590 MBq (70 mCi) were well tolerated.


Immune Signatures in Patients with Psoriasis Vulgaris of Blood-Heat Syndrome: A Systematic Review and Meta-Analysis.
Objective. To determine whether immunological serum markers IFN-γ, IL-4, IL-17, IL-23, IL-6, TNF-α, and IL-10 are elevated or decreased in patients compared with healthy controls. Methods. A complete search of the literature on this topic within the past 30 years was conducted across seven databases. Seventeen studies including 768 individuals were identified. Differences in serum marker levels between subjects and controls were pooled as MDs using the random-effects model. Results. The pooled MDs were higher in patients than in healthy controls for IFN-γ (MD 24.9, 95% CI 12.36-37.43), IL-17 (MD 28.92, 95% CI 17.44-40.40), IL-23 (MD 310.60, 95% CI 4.96-616.24), and TNF-α (MD 19.84, 95% CI 13.80-25.87). Pooled IL-4 (MD -13.5, 95% CI -17.74--9.26) and IL-10 (MD -10.33, 95% CI -12.03--8.63) levels were lower in patients. Conclusion. The pooled analyses suggest that levels of IFN-γ, IL-17, IL-23, and TNF-α are significantly elevated and that levels of IL-4 and IL-10 are significantly decreased in sera of patients with psoriasis vulgaris of blood-heat syndrome. Measuring progression of blood-heat syndrome of psoriasis vulgaris will require additional high-quality data, with a low risk of bias and adequate sample sizes, before and after antipsoriatic therapy.


The impact of the COVID-19 pandemic on nosocomial infections: a retrospective analysis in a tertiary maternal and child healthcare hospital.
The constant changes in the control strategies of the Corona Virus Disease 2019 (COVID-19) pandemic have greatly affected the prevention and control of nosocomial infections (NIs). This study assessed the impact of these control strategies on the surveillance of NIs in a regional maternity hospital during the COVID-19 pandemic. This retrospective study compared the observation indicators of nosocomial infections and their changing trends in the hospital before and during the COVID-19 pandemic. In total, 2,56,092 patients were admitted to the hospital during the study. During the COVID-19 pandemic, the main drug-resistant bacteria in hospitals were Escherichia coli, Streptococcus agalactiae, Staphylococcus aureus, Klebsiella pneumoniae, and Enterococcus faecalis. The detection rate of S. agalactiae increased annually, while that of E. faecalis remained the same. The detection rate of multidrug-resistant bacteria decreased during the pandemic (16.86 vs. 11.42%), especially that of CRKP (carbapenem-resistant Klebsiella pneumoniae 13.14 vs. 4.39, P < 0.001). The incidence of nosocomial infections in the pediatric surgery department decreased significantly (OR: 2.031, 95% CI: 1.405-2.934, P < 0.001). Regarding the source of infection, a significant reduction was observed in respiratory infections, followed by gastrointestinal infections. In the routine monitoring of the ICU, the incidence of central line-associated bloodstream infection (CLABSI) decreased significantly (9.4/1,000 catheter days vs. 2.2/1,000 catheter days, P < 0.001). The incidence of nosocomial infections was lower than that before the COVID-19 pandemic. The prevention and control measures for the COVID-19 pandemic have reduced the number of nosocomial infections, especially respiratory, gastrointestinal, and catheter-related infections.


Babao Dan alleviates gut immune and microbiota disorders while impacting the TLR4/MyD88/NF-кB pathway to attenuate 5-Fluorouracil-induced intestinal injury.
Adjuvant chemotherapy based on 5-fluorouracil (5-FU), such as FOLFOX, is suggested as a treatment for gastrointestinal cancer. Yet, intestinal damage continues to be a prevalent side effect for which there are no practical prevention measures. We investigated whether Babao Dan (BBD), a Traditional Chinese Medicine, protects against intestinal damage induced by 5-FU by controlling immune response and gut microbiota. 5-FU was injected intraperitoneally to establish the mice model, then 250 mg/kg BBD was gavaged for five days straight. 5-FU led to marked weight loss, diarrhea, fecal blood, and histopathologic intestinal damage. Administration of BBD reduced these symptoms, inhibited proinflammatory cytokine (IL-6, IL-1β, IFN-γ, TNF-α) secretion, and upregulated the ratio of CD3(+) T cells and the CD4(+)/CD8(+) ratio. According to 16S rRNA sequencing, BBD dramatically repaired the disruption of the gut microbiota caused in a time-dependent way, and increased the Firmicutes/Bacteroidetes (F/B) ratio. Transcriptomic results showed that the mechanism is mainly concentrated on the NF-κB pathway, and we found that BBD reduced the concentration of LPS in the fecal suspension and serum, and inhibited TLR4/MyD88/NF-κB pathway activation. Furthermore, at the genus level on the fifth day, BBD upregulated the abundance of unidentified_Corynebacteriaceae, Aerococcus, Blautia, Jeotgalicoccus, Odoribacter, Roseburia, Rikenella, Intestinimonas, unidentified_Lachnospiraceae, Enterorhabdus, Ruminiclostridium, and downregulated the abundance of Bacteroides, Parabacteroides, Parasutterella, Erysipelatoclostridium, which were highly correlated with intestinal injury or the TLR4/MyD88/NF-κB pathway. In conclusion, we established a network involving 5-FU, BBD, the immune response, gut microbiota, and key pathways to explain the pharmacology of oral BBD in preventing 5-FU-induced intestinal injury.


The inhibition of osteogenesis with human bone marrow mesenchymal stem cells by CdSe/ZnS quantum dot labels.
CdSe/ZnS quantum dots (QDs) have recently been used as cell tracers for long term imaging of live cells. A number of studies indicate that introduction of quantum dots to cells have no apparent deleterious effects on the morphology or growth of cells. In the present study, the human bone marrow mesenchymal stem cells (hBMSCs) were used as a model to examine the effects of QDs on the growth and osteogenic differentiation of the cells. The CdSe/ZnS QDs were delivered into hBMSCs by liposome-mediated transfection with high efficiency; analysis by transmission electron microscopy revealed that the internalized QDs could be located in the endosome-like vesicles. Uptake of QDs into hBMSCs did not affect the proliferation and cell cycle distribution of the cells. When induced to differentiate along the osteogenic lineage, the QD-containing-hBMSCs were shown to have mineral deposition on the extracellular matrix. However, the cells displayed lower alkaline phosphatase activity as compared to those without QDs. Analysis by reverse transcriptase polymerase chain reaction further demonstrated that the expression of two osteogenic markers, osteopontin and osteocalcin, was significantly inhibited. Together our results show that the presence of QDs in hBMSCs prevents the full response of the cells to induced osteogenic differentiation.


Mechanism of M2 type macrophage-derived extracellular vesicles regulating PD-L1 expression via the MISP/IQGAP1 axis in hepatocellular carcinoma immunotherapy resistance.
Hepatocellular carcinoma (HCC) is a prevailing cancer affecting human health. M2 macrophages are essential in mediating immune responses in tumors. This study investigated the action of M2 macrophages in immune escape of HCC. Mitotic spindle positioning (MISP), IQ motif containing GTPase activating protein 1 (IQGAP1) and programmed cell death-1 (PD-L1) levels in primary HCC/tumor-adjacent tissues were determined by Western blot, followed by correlation analysis. M2 macrophage and CD3+CD8+T cell percentages were estimated by flow cytometry. Hep3B and HepG2 cells were treated with M2 macrophage conditioned medium (M2-CM) and M2 macrophage-derived extracellular vesicles (M2-EVs) and/or co-cultured with CD8+T cells, followed by assessment of cell viability and apoptosis. TNF-α and INF-γ levels were measured by ELISA. MISP and IQGAP1 overexpression plasmids were transfected into HCC cells to explore their role in immune escape. The interactions among MISP, IQGAP1, STAT3, and PD-L1 were analyzed by co-immunoprecipitation. The mechanism of M2-EVs in HCC immune escape was verified in nude mice. MISP/IQGAP1/PD-L1 were upregulated in HCC tissues. MISP negatively-correlated with IQGAP1/PD-L1 and IQGAP1 positively-correlated with PD-L1. M2 macrophages were reduced but CD8+T cells were increased in HCC tissues with high MISP expression. M2-CM or M2-EVs inhibited the killing ability of CD8+T cells, increased HCC cell viability, impeded HCC cell apoptosis, induced CD8+T cell apoptosis, downregulated TNF-α and INF-γ, and upregulated PD-L1. M2-EVs facilitated HCC cell immune escape by potentiating IQGAP1 nuclear translocation and activating STAT3 phosphorylation through MISP downregulation. In vivo experiments further verified the action of M2-EVs through MISP. M2-EVs promote HCC cell immune escape by upregulating PD-L1 through the MISP/IQGAP1/STAT3 axis.


Peginterferon plus Ribavirin for chronic hepatitis C in opiate addicts on methadone/buprenorphine maintenance therapy.
In developed countries hepatitis C is prevalently transmitted by intravenous drug users (IDUs). The problems associated with management of HCV hepatitis in these patients have, in the past, discouraged treatment. To evaluate efficacy, safety and tolerability of a standard Peginterferon (Peg-IFN) alpha-2b or alpha-2a plus Ribavirin treatment in IDUs who were receiving methadone or buprenorphine. A multi-centre prospective observational study performed from September 2003 to September 2006 in Central Italy (Umbria and Marches regions). A shared care model of HCV management was used which integrated a multidimensional, multidisciplinary approach. Sixty-five subjects were evaluated and 52 satisfied inclusion criteria. Forty-five completed treatment (25 with Peg-IFN alpha-2b, 20 with Peg-IFN alpha-2a), a total of 37 showed a biochemical/virological response at the end of treatment (ITT 71.1%), 26 had a sustained virological response (ITT 50%; 38.4% of cases genotype 1-4, 61.6% genotype 3-2). The results indicate that patients on maintenance treatment with methadone/buprenorphine can be treated for HCV. The success rate was fairly good; tolerability and side effects were similar to those reported in non-IDU patients. Close cooperation with specialists in drug addiction and psychiatrists is however essential for success.


An audit of outcomes of a series of periampullary carcinomas.
Non-pancreatic periampullary carcinoma such as ampullary carcinoma (AmpCA), distal cholangiocellular carcinoma (CholCA) and duodenal carcinoma (DuoCA) have a better prognosis than pancreatic head adenocarcinoma (PanCA). This study describes the outcome and parameters, which predict survival of non-pancreatic periampullary carcinoma after resection. Data from 148 consecutive patients with non-pancreatic periampullary carcinomas were recorded prospectively between 1993 and 2005 and analyzed using univariate and multivariate models. One hundred thirty-three of 148 (90%) patients were resected for histologically proven non-pancreatic periampullary carcinomas. R0 resection was achieved for 92% of AmpCA, for 88% of CholCA and for all the DuoCA. The lowest recurrence rate was seen in DuoCA with 18%, followed by AmpCA with 21% and CholCA with 46%. The mean survival time was 60.9 months for AmpCA patients, 42.9 months for CholCA and 45.4 months for DuoCA patients. Five-year survival was 50.5%, 29.9% and 24.5% for AmpCA, CholCA and DuoCA, respectively. Multivariate analysis identified low bilirubin levels (<100 micromol/l), R0 resections and absence of surgical complications to be strong independent predictors of survival (p<0.05). In AmpCA low tumor stages are also an independent predictor of long-term survival (p<0.01). For T1/T2 AmpCA the 5-year survival rate was 61%, whereas none of the patients with a T3/T4 tumor survived 5 years. Only T1/T2 ampullary carcinomas have a good prognosis, whereas T3/T4 ampullary tumors show aggressiveness similar to that of pancreatic head adenocarcinomas. Absence of surgical complications determines long-term outcome. Therefore, the combination of a complication-free and radical resection is essential for long-term survival.


Nongenotoxicity of minoxidil in murine hair follicles as determined by the nuclear aberration assay.
A 1-cm2 area on the back of CD1 mice was prepared for topical application of minoxidil, N-methyl-N-nitrosourea (MNU), or cyclophosphamide (CY) by clipping or plucking hair from a patch of skin. Plucking stimulates hair follicle cell division while clipping does not. Minoxidil was topically administered for 8 consecutive days. CY or MNU was administered topically once on the eighth day postplucking. The incidence of nuclear aberrations and mitotic figures were measured in hair follicles while frequency of micronuclei and the ratio of RBC/PCE were measured in the bone marrow. Results with minoxidil showed no increase in either nuclear aberrations in the hair follicle or micronuclei in the bone marrow. These results suggest that topically applied minoxidil is not genotoxic. In contrast, a dose-dependent effect of MNU on the incidence of nuclear aberrations in the hair follicle was seen. CY induced a dose-dependent increase in the incidence of micronuclei in the bone marrow and in nuclear aberrations in the hair follicle after topical application. Minoxidil applied to clipped mice significantly increased the incidence of mitotic figures above that seen in both the clipped and plucked controls. This suggests that minoxidil is a mitogenic agent in the hair follicle. These findings are consistent with the success of topically applied minoxidil in the treatment of alopecia areata.


The unfolded protein response in Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and accumulation of amyloid-beta (Aβ) peptide, which are responsible for the progressive loss of memory. The mechanisms involved in neuron dysfunction in AD remain poorly understood. Recent evidence implicates the participation of adaptive responses to stress within the endoplasmic reticulum (ER) in the disease process, via a pathway known as the unfolded protein response (UPR). Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed.


Morphometric measurements and RNA content of axotomized feline cervical motoneurons.
Microspectrophotometric estimates of RNA content and morphometric measurements of cytoplasmic, nuclear and nucleolar areas were made on 30 to 60 motoneurons (somal areas greater than 1000 microns2) ipsilateral and contralateral to brachial plexotomy performed unilaterally on adult cats 2-90 days before sacrifice. Nerve cells of unoperated animals were also assayed. Somal and cytoplasmic areas of axotomized motoneurons were larger than those of the corresponding, contralateral motor nerve cells 4, 6 and 75 days postoperatively. Because of between animal variability, it could not be determined, however, whether this difference was due to an increase in the area of the axotomized motoneurons or to a decrease in the area of the contralateral nerve cells. Nucleolar sizes did not change. In contrast, nuclei of axotomized motoneurons showed a temporary but unequivocal areal decrease. The cytoplasmic RNA content of axotomized motoneurons fell 14-28 days postoperatively but rose thereafter, being increased slightly but significantly 75-90 days after operation. At no postoperative interval, however, did the nucleolar RNA content of the axotomized cells deviate unequivocally from the unoperated or zero day condition. The following points may be emphasized: 1. these results differ from similar measurements of axotomized motoneurons of rodents and lagomorphs; 2. the data do not provide certain evidence of change in either morphometric parameters or RNA content of motoneurons on the side contralateral to surgery, although the possibility of a decrease in the size of these uninjured neurons should be considered; 3. morphometric and RNA measurements on axotomized peripheral (extrinsic) neurons of spinal anterior horn of cat contrast with similar measurements on axotomized central (intrinsic) neurons of cat red nucleus.


Factors inhibiting assessment of students' professional behaviour in the tutorial group during problem-based learning.
We addressed the assessment of professional behaviour in tutorial groups by investigating students' perceptions of the frequency and impact of critical incidents that impede this assessment and 5 factors underlying these critical incidents. A questionnaire asking students to rate the frequency and impact of 40 critical incidents relating to effective assessment of professional behaviour on a 5-point Likert scale was developed and sent to all undergraduate medical students in Years 2-4 of a 6-year undergraduate curriculum. The response rate was 70% (n = 393). Important factors underlying critical incidents are: lack of effective interaction; lack of thoroughness; tutors' failure to confront students with unprofessional behaviour; lack of effort to find solutions, and lack of student motivation. Confirmatory factor analysis showed a good model fit. Because the relationship between frequency of occurrence and degree of impediment varies, the best information about the true impact of critical incidents and the underlying factors is provided by the product of frequency and degree of impediment. Frequency of occurrence remains stable and degree of impediment increases in Years 2-4. The results of this study can be used to design and improve faculty development programmes aimed at improving assessment of professional behaviour. Training programmes should motivate tutors by providing background information as to why and how sound assessment of professional behaviour is to be performed and encourage tutors to confront students with and discuss all aspects of professional behaviour, as well as provide appropriate feedback.


Depression of evoked potentials in brain slices by adenosine compounds.
1 A study has been made of the action of adenosine on surface slices of guinea-pig olfactory cortex in vitro. 2 With extracellular recordings from the pial surface and stimulation of the presynaptic input, the lateral olfactory tract (LOT) generated a monosynaptic negative wave representing dendritic excitatory potentials. This negative wave was depressed by bath application of 1 micron adenosine with increasing effect up to 1 mM. Adenosine 5'--triphosphate (ATP), adenosine 5'-monophosphate (AMP) and cyclic adenosine 3',5'-monophosphate (cyclic AMP) had similar depressant actions. Adenine and guanosine were very weak depressants. 3 Theophylline concentrations in the range 10 micron to 3 mM progressively antagonized the action of adenosine. 4 Dibuyryl cyclic AMP (100 micron) and agents which increase intracellular cyclic AMP were not depressants, suggesting that the action of adenosine was not cyclic AMP-mediated. 5 Intracellular recordings confirmed the depressant effect of adenosine on excitatory potentials generated by LOT stimulation and also showed that postsynatpic action potentials and the membrane of the soma were unaffected by adenosine. 6 Since presynaptic action potentials were also unaffected by adenosine, these experiments suggest that adenosine reduces excitatory transmission at LOT synapses and fortifies the idea that adenosine has a 'neurohumoral' action.


Improved endothelialization and reduced thrombosis by coating a synthetic vascular graft with fibronectin and stem cell homing factor SDF-1α.
Failure of synthetic small-diameter vascular grafts is determined mainly by the lack of endothelial cells, as these cells inhibit thrombosis and intimal hyperplasia. Coating of graft material with homing factors for circulating stem cells has the potential to improve endogenous endothelialization of these grafts and to reduce graft failure. Synthetic knitted polyester grafts (6mm diameter) were coated with FN and SDF-1α before surgical interposition in the carotid artery of sheep. Similar uncoated vascular grafts were implanted in the contralateral side as internal controls. To study the early attraction of stem cells, grafts were implanted in a first series of nine sheep and explanted after 1 or 3 days. In coated grafts, four times higher fractions of CD34(+) and three to four times higher fractions of CD117(+) cells adhering to the vessel walls were found than in control grafts (P<0.05). When such coated and non-coated grafts were implanted in 12 other sheep and explanted after 3 months, all coated grafts were patent, while one control graft was occluded. EcNOS staining revealed that FN-SDF-1α coating significantly increased coverage with endothelial cells from 27 ± 4% of the graft to 48 ± 4% compared with the controls (P=0.001). This was associated with a significant reduction of intimal hyperplasia (average thickness 1.03 ± 0.09 mm in controls vs. 0.69 ± 0.04 mm in coated grafts; P=0.009) and significantly less adhesion of thrombotic material in the middle part of the graft (P=0.029). FN-SDF-1α coating of synthetic small-caliber vascular grafts stimulated the attraction of stem cells and was associated with improved endothelialization and reduced intimal hyperplasia and thrombosis.


Human glutathione peroxidase activity in cases of high selenium exposures.
Four communities with water supplies having selenium concentrations of less than 3.1, 1.7, 189, and 496 micrograms/liter were selected for study. Samples of blood, urine, and tap water were obtained from participants in each community and analyzed for selenium content. Blood samples were also analyzed for glutathione peroxidase activity. Results showed an increase in selenium concentration in the urine as the water selenium increased. Selenium concentrations in blood did not reflect the increased selenium exposure. Glutathione peroxidase activity in whole blood decreased in highly exposed participants compared to those with low exposure. We conclude that glutathione peroxidase activity in cases of possible environmental toxic exposures will not show the increased activity seen in supplementation of selenium to deficient subjects.


Encapsulated Fe3O4 /Ag complexed cores in hollow gold nanoshells for enhanced theranostic magnetic resonance imaging and photothermal therapy.
Designed and fabrication of a novel magnetic hollow gold nanoshell complexes that incorporates iron oxide nanoparticles in the hollow interior. The combined effect of the smaller IONPs improved the overall magnetic properties of the design and MRI contrast capability. The overall complex could be synthesized in the range of 60-80 nm in diameter while still having a plasmonic peak in the near infrared region.


Gastrointestinal Disorders Associated with Common Variable Immune Deficiency (CVID) and Chronic Granulomatous Disease (CGD).
Common variable immune deficiency (CVID) and chronic granulomatous disease (CGD) are two of the well-characterized primary immune deficiencies with distinct pathologic defects. While CVID is predominantly a disorder of the adaptive immune system, in CGD, innate immunity is impaired. In both syndromes, the clinical manifestations include an increased susceptibility to infections and a number of non-infectious, inflammatory conditions including systemic autoimmunity, as well as organ-specific pathology. Among the organ-associated disorders, gastrointestinal (GI) manifestations are one of the most intractable. As such, non-infectious inflammatory disorders of the GI tract are clinically challenging as they have protean manifestations, often resembling inflammatory bowel disease (IBD) or celiac disease, are notoriously difficult to treat, and hence are associated with significant morbidity and mortality. Therefore, assessing the pathogenesis and defining appropriate therapeutic approaches for GI disease in patients with CVID and CGD is imperative.


The dynamics of kidney donation: viewpoints from the donor, the recipients, and the transplant team.
Living kidney transplantation has become increasingly widespread to reduce organ shortage. Very few studies have prospectively investigated the donor's long-term risks. Living donation is a complex medical decision in which different actors are involved. This therapeutic option needs educational programs for potential donors, recipients, and transplant professionals to make them aware of the possible risks and benefits. It is important to fully exploit living-donor kidney transplantation.


Template-controlled on-surface synthesis of a lanthanide supernaphthalocyanine and its open-chain polycyanine counterpart.
Phthalocyanines possess unique optical and electronic properties and thus are widely used in (opto)electronic devices, coatings, photodynamic therapy, etc. Extension of their π-electron systems could produce molecular materials with red-shifted absorption for a broader range of applications. However, access to expanded phthalocyanine analogues with more than four isoindoline units is challenging due to the limited synthetic possibilities. Here, we report the controlled on-surface synthesis of a gadolinium-supernaphthalocyanine macrocycle and its open-chain counterpart poly(benzodiiminoisoindoline) on a silver surface from a naphthalene dicarbonitrile precursor. Their formation is controlled by the on-surface high-dilution principle and steered by different metal templates, i.e., gadolinium atoms and the bare silver surface, which also act as oligomerization catalysts. By using scanning tunneling microscopy, photoemission spectroscopy, and density functional theory calculations, the chemical structures along with the mechanical and electronic properties of these phthalocyanine analogues with extended π-conjugation are investigated in detail.


A simple method to determine millimolar concentrations of sodium in nanoliter samples.
Measurement of sodium in the nanoliter samples obtained from in vitro studies of isolated, perfused nephron segments has traditionally been associated with time-consuming sample preparation and/or expensive instrumentation. A new instrument is described which can measure picomole quantities of sodium without the need for special processing. The instrument is based on the continuous flow devices developed by Vurek and a sodium-sensitive glass detector. The response to varying concentrations of NaCl was logarithmic as predicted from the Nernst equation. The response to 50 mM NaCl was 22.1 +/- 0.2 mV; 100 mM, 29.9 +/- 0.2 mV; 150 mM, 35.2 +/- 0.2 mV; and 200 mM, 39.3 +/- 0.6 mV (mean +/- SD). The slope of the standard curve was 27.8 mV/log unit change in sodium concentration. Potassium, calcium and ammonium, possible interfering ions, had no effect on the response to 100 mM NaCl. When the response to 100 mM NaCl was measured in buffered solutions of varying pH, it was 29.1 +/- 0.2 mV at pH 6.21, 28.9 +/- 0.4 mV at pH 7.04 and 28.7 +/- 0.4 mV at pH 8.54, indicating that pH did not alter the response to 100 mM NaCl. By treating the detector with NaOH and HCl, the response to 50, 100 and 150 mM improved to the point that the slope of the standard curve was 51.2 mV/log unit change in sodium concentration. The calculated resolution after treatment was 1.0 mM in the 50 to 100 mM range and 1.3 mM in the 100 to 150 mM range using a 10.9 nl pipet.(ABSTRACT TRUNCATED AT 250 WORDS)


Increasing age and carcinoma not otherwise specified: a 20-year population study of 40,118 lung cancer patients.
New treatment regimens require a differentiation between histological subsets of non-small cell lung cancer. We aimed to assess how the incidence and prognosis of carcinoma not otherwise specified (NOS) coincide with an aging patient population, disease stage, and diagnostic methods used. Complete national data on 40,118 cases (including 6,597 diagnosed with carcinoma NOS) from the Cancer Registry of Norway (1988-2007) are presented. The proportion of elderly patients (70 years and older) have increased to over half of all patients diagnosed, a trend also evident among carcinoma NOS patients. The proportion of carcinomas NOS reported to the cancer registry in this 20-year period has increased from 12% in 1988 to 19% in 2007. Crude 5-year relative survival in carcinoma NOS was lowest of all non-small cell lung cancer entities throughout the 20-year period; however, patients diagnosed with carcinoma NOS in the period 2003 to 2007 had about 24% lower risk of dying within 5 years after diagnosis compared with patients diagnosed between 1988 and 1992, adjusted for covariates. Most lung cancers are diagnosed by biopsy of the primary lesion; although the proportion is lower among carcinomas NOS than other histological entities. By the last 5-year period studied, carcinoma NOS was the histological entity most commonly diagnosed by cytology (38%). The proportion of carcinomas NOS has increased to 19% of all lung cancer cases. This histological entity is associated with older age and poor survival.


Erythrocyte enzyme polymorphisms in the Kamboh caste of Patiala, Punjab.
Data are presented on six erythrocyte enzyme polymorphisms (ADA, GLO I, EsD, AK, AP, GPI) in the Kamboh, a scheduled caste inhabiting the Patiala district of the Indian state of Punjab. With their high ADA2 (18.5%), Pa (42.5%) and GPI3 (5.3%) and a rather low GLO1 (18.8%) frequencies, the Kamboh differ from all other populations of Punjab.


Sustained use of an occupational sun safety program in a recreation industry: follow-up to a randomized trial on dissemination strategies.
The sustainability of evidence-based programs is needed to obtain long-term benefits. To assess sustainability of Go Sun Smart (GSS), an occupational skin cancer prevention program disseminated to the North American ski industry. Fifty-three of the 68 ski areas from the original dissemination trial participated in 2012 and 2013, 5 to 7 years after program distribution by enhanced or basic dissemination strategies. Sustained use was measured by: (1) on-site observation of sun protection communication and (2) an online survey with senior managers. In the sustainability assessment, sun safety communication had declined, and dissemination strategy did not affect continued use. Managers held weaker attitudes about skin cancer importance and program fit, but more managers provided free/reduced-cost sunscreen than in the dissemination trial. Manager turnover was a key factor in program discontinuance. Sustainability remains a challenge. Additional research is needed to determine the best strategies for sustainability.


Vaccination of chickens with a Salmonella enteritidis aroA live oral Salmonella vaccine.
A mouse-virulent strain of Salmonella enteritidis, Se795 (LD50 less than 10 organisms for mice), was non-virulent for 12-day-old chickens given 10(6) cfu intravenously; the organisms were cleared from liver and spleen by day 14 as measured by direct plating and by day 21 by enrichment. An Se795aroA mutant, CU58, was also cleared from liver and spleen by day 14 after intravenous inoculation of 10(7) cfu. Day-old chicks vaccinated orally with either one dose of 10(9) CU58 at 1 day of age, 10(7) at 1 and 14 days, or 10(5) at 1 and 7 days followed by 10(9) at 14 and 21 days of age, were challenged orally with a nalidixic acid resistant variant of the virulent phage type 4 S. enteritidis strain 109. All vaccinated groups showed a reduction in faecal shedding of the challenge. Chickens given four doses of CU58 showed a significant reduction of cfu in liver, spleen and faeces following intravenous challenge with virulent strain 109. Intramuscular vaccination with 10(9) cfu of Aro strain CU58 at 1 day of age gave no protection against oral challenge with virulent strain 109. Serum antibody production to LPS (ELISA) was minimal in all vaccinated birds. The results indicate that oral vaccination with Aro- S. enteritidis can confer protection to day old chicks against virulent S. enteritidis.


Repetitive transcranial magnetic stimulation (rTMS) fails to improve cognition in patients with parkinson's disease: a Meta-analysis of randomized controlled trials.
Cognitive decline is one of the greatest concerns for patients with Parkinson's disease (PD) and their care partners. Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological treatment option used to improve cognitive function in PD, but its efficacy is unclear. We performed a meta-analysis to determine whether rTMS improves cognition in PD patients. Eligibility criteria (PICOS) were as follows: (1) 'P': The patients participating were diagnosed with idiopathic PD; (2) 'I': Intervention using rTMS; (3) 'C': Sham stimulation as control; (4) 'O': The outcome of the study included cognitive evaluations; (5) 'S': The study adopted randomized controlled design. The standardized mean difference (SMD) of change of score was applied to measure efficacy, and we used Version 2 of the Cochrane tool to assess risk of bias. Twelve studies met the inclusion criteria. Compared with sham-controlled group, the pooled result showed a non-significant short-term effect of rTMS on global cognition (SMD: -0.15, 95% CI: -0.59 to 0.29, I2 = 36.7%), executive function (SMD: 0.03, 95% CI: -0.21 to 0.26, I2 = 0.0%), and attention and working memory (SMD: 0.05, 95% CI: -0.25 to 0.35, I2 = 0.0%). Long-term outcomes were either shown to be statistically nonsignificant. Based on a limited number of studies, rTMS fails to improve cognition in PD. We call for additional high-quality randomized controlled trials with adequate sample sizes to determine the efficacy of rTMS.


Similar thromboprophylaxis with rivaroxaban and low molecular weight heparin but fewer hemorrhagic complications with combined intra-articular and intravenous tranexamic acid in total knee arthroplasty.
To evaluate the efficacy of the combined intravenous and intra-articular administration of tranexamic acid (TXA) to control the collateral effects and complications of rivaroxaban (RIV) after total knee arthroplasty (TKA) and to compare thromboprophylaxis schemes with and without TXA, RIV and low molecular weight heparin (LMWH). We prospectively studied 158 TKA patients from 2014 to 2018. The patients were randomly assigned into three groups. Group A (46 patients) was administered intravenous and intra-articular TXA and RIV postoperatively; group B (58 patients) was administered TXA as in group A and LMWH postoperatively; and group C (54 patients) was administered saline as in group A and RIV postoperatively. We evaluated blood loss, transfusion requirements and hemorrhagic complications. Hct and Hb values significantly decreased in group C compared to groups A and B, without any difference between groups A and B. Suction drain blood volume output was significantly higher in group C compared to group A and B, without any difference between group A and B. Hemorrhagic complications were more common in group C. No patient experienced clinical findings of VTE. Combined intravenous and intra-articular administration of TXA is safe and effective in TKA, with fewer hemorrhagic complications compared to placebo. Thromboprophylaxis with RIV and LMWH is similar.


Effects of stretch receptors of bronchi or trachea on genioglossus muscle activity.
Activity of genioglossus muscle (GG) was recorded in anesthetized rabbits at control and under SO2 block of slowly adapting stretch receptors in thoracic airways (T) or in bronchi alone (B). At control peak activity occurred at 10% of inspiratory time, followed by a slight and a marked decrease. T and, particularly, B delayed onset and slowed rise of GG activity; then, this increased slightly under T and more under B, becoming greater than at control. During inspiratory efforts at end-expiratory volume GG activity at control was equal to that during open inspirations up to its peak, then progressively greater; during inspiratory efforts GG activity under T and B was equally smaller than at control. These findings indicate that bronchial input facilitates GG activity at end-expiratory volume and inhibits it at larger volumes: these effects are greater than those previously detected on diaphragm. Moreover, tracheal input inhibits onset and development of GG activity. Under all conditions end of inspiratory activity was simultaneous in GG and in diaphragm. Time to peak inspiratory flow correlated with time to early peak in GG activity.


Pharmacologic control of uterine contractility. In vitro human and in vivo monkey studies.
The exact cause and mechanism of the onset of labor are unknown but the theories are many. There is considerable evidence that prostaglandins are potent stimulants of uterine activity and may play a role in the onset of labor. Prostaglandin release may be the natural mediator of uterine contractions during labor. A group of anti-inflammatory compounds (aspirin-like compounds) that inhibit prostaglandin synthesis include indomethacin and fenoprofen. Inhibition of prostaglandin production is a reasonable approach to inhibiting premature labor. An excised muscle strip technique was used as a screening procedure for pharmacologic depression of human uterine activity in vitro, testing isoxsuprine, mesuprine, Alupent, ritodrine, indomethacin, and fenoprofen. The prostaglandin antagonists indomethacin and fenoprofen exhibited marked depressant activity. These drugs were further tested in an in vivo rhesus monkey preparation measuring uterine activity, maternal blood pressure, uterine blood flow, fetal heart rate, fetal blood pressure, and blood gases. Fenoprofen is effective in reducing uterine contractility without serious maternal or fetal side effects and shows promise as a clinically effective agent for pharmacologic control of premature labor.


A Comprehensive Approach to Managing Methamphetamine-Associated Cardiomyopathy.
Methamphetamines are illicit drugs of the amphetamine-type stimulant class that have been increasing in popularity, availability, and purity in recent decades. As a result, rates of methamphetamine-associated cardiomyopathy (MAC) are rising globally. MAC is associated with high rates of sudden cardiac arrest, late presentation, and poor outcomes. This review discusses the medical management of MAC, including anticipated challenges specific to methamphetamine users. Not only are patients with MAC more likely to present at a younger age and with multisystem disease than patients with cardiomyopathy of other etiologies, but there may also be significant behavioral, psychosocial, financial, and system-based challenges to providing the best medical care. An individualized treatment plan that emphasizes methamphetamine abstinence as the foundation of therapy, as well as introducing optimal heart failure therapy and providing multidisciplinary support is likely to result in optimal outcomes. Given the potential reversibility of MAC, institution of guideline-directed heart failure therapy and patient support for adherence to therapy and abstinence from methamphetamines should be energetically pursued.


Leaving no stone unturned in light of the COVID-19 faecal-oral hypothesis? A water, sanitation and hygiene (WASH) perspective targeting low-income countries.
The human coronavirus disease (COVID-19) is now a global pandemic. Social distancing, hand hygiene and the use of personal protective equipment dominate the current fight against COVID-19. In developing countries, the need for clean water provision, sanitation and hygiene has only received limited attention. The current perspective examines the latest evidence on the occurrence, persistence and faecal-oral transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent causing COVID-19. Evidence shows that SARS-CoV-2 proliferate in the human gastrointestinal system, and is shed via faeces. SARS-CoV-2 can survive and remain viable for up to 6 to 9 days on surfaces. Recent wastewater-based epidemiological studies from several countries also detected SARS-CoV-2 RNA in raw wastewaters. Shell disorder analysis shows that SARS-CoV-2 has a rigid outer shell conferring resilience, and a low shell disorder conferring moderate potential for faecal-oral transmission. Taken together, these findings point to potential faecal-oral transmission of SARS-CoV-2, which may partly explain its rapid transmission. Three potential mechanisms may account for SARS-CoV-2 faecal-oral transmission: (1) untreated contaminated drinking water, (2) raw and poorly cooked marine and aquatic foods from contaminated sources, (3) raw wastewater-based vegetatble production systems (e.g., salads) and aquaculture, and (4) vector-mediated transmission from faecal sources to foods, particularly those from open markets and street vending. SARS-CoV-2 faecal-oral transmission could be particularly high in developing countries due to several risk factors, including; (1) poor drinking water, wastewater and sanitation infrastructure, (2) poor hygiene and food handling practices, (3) unhygienic and rudimentary funeral practices, including home burials close to drinking water sources, and (4) poor social security and health care systems with low capacity to cope with disease outbreaks. Hence, clean drinking water provision, proper sanitation, food safety and hygiene could be critical in the current fight against COVID-19. Future research directions on COVID-19 faecal-oral transmission are highlighted.


Detection of visual events along the apparent motion trace in patients with paranoid schizophrenia.
Dysfunctional prediction in sensory processing has been suggested as a possible causal mechanism in the development of delusions in patients with schizophrenia. Previous studies in healthy subjects have shown that while the perception of apparent motion can mask visual events along the illusory motion trace, such motion masking is reduced when events are spatio-temporally compatible with the illusion, and, therefore, predictable. Here we tested the hypothesis that this specific detection advantage for predictable target stimuli on the apparent motion trace is reduced in patients with paranoid schizophrenia. Our data show that, although target detection along the illusory motion trace is generally impaired, both patients and healthy control participants detect predictable targets more often than unpredictable targets. Patients had a stronger motion masking effect when compared to controls. However, patients showed the same advantage in the detection of predictable targets as healthy control subjects. Our findings reveal stronger motion masking but intact prediction of visual events along the apparent motion trace in patients with paranoid schizophrenia and suggest that the sensory prediction mechanism underlying apparent motion is not impaired in paranoid schizophrenia.


Iodine-based radiographic contrast medium may precipitate metformin-associated lactic acidosis in diabetic patients. A case report, literature review and practical approach.
Lactic acidosis in diabetic patients undergoing metformin therapy is a widely recognized, rare but usually serious adverse event, particularly in presence of comorbidities such as cardiorespiratory disease, sepsis and renal failure. As demonstrated by the case of an elderly woman presented, administration of radiographic iodine-based contrast agents may precipitate lactic acidosis through worsening of renal function. Awareness of this condition, identification of at-risk patients, adequate prevention following published guidelines, early diagnosis and treatment including hemodialysis are necessary to avoid a fatal outcome.


A novel function for the sperm adhesion protein IZUMO1 in cell-cell fusion.
Mammalian sperm-egg adhesion depends on the trans-interaction between the sperm-specific type I glycoprotein IZUMO1 and its oocyte-specific GPI-anchored receptor JUNO. However, the mechanisms and proteins (fusogens) that mediate the following step of gamete fusion remain unknown. Using live imaging and content mixing assays in a heterologous system and structure-guided mutagenesis, we unveil an unexpected function for IZUMO1 in cell-to-cell fusion. We show that IZUMO1 alone is sufficient to induce fusion, and that this ability is retained in a mutant unable to bind JUNO. On the other hand, a triple mutation in exposed aromatic residues prevents this fusogenic activity without impairing JUNO interaction. Our findings suggest a second function for IZUMO1 as a unilateral mouse gamete fusogen.


High-risk left main coronary stenting supported by percutaneous left ventricular assist device.
Percutaneous left ventricular assist devices could nowadays offer a valid support to percutaneous coronary interventions even in very high risk patients. This case illustrates a successful distal left main coronary artery V-stenting supported by the Tandem Heart in a patient with severe left ventricular dysfunction, severe aortic stenosis, and refractory myocardial ischemia.


Severe postoperative vasculitis of the central nervous system in a child with arteriovenous malformation: case report.
Cerebral vasculitis is very rare complication after craniotomy. We report a case and discuss the etiology, diagnosis, and treatment of this complication. A 12-year-old boy was admitted because of a consciousness disturbance due to a ruptured AVM. Computed tomography revealed a left parietal subcortical hematoma. No apparent nidus was detected on the angiography findings, but AVM was suspected. After resection of the hematoma, the patient did not recover consciousness, and his high fever continued. Despite postoperative induced hypothermia, progressive multiple cerebral infarctions occurred. Postoperative angiography showed multiple arterial narrowing, and a "string of beads" phenomenon was observed in the anterior and posterior circulation in addition to the residual AVM. After administering steroid therapy, he recovered consciousness, but had a severe disability. After angiography, which was performed 1 year after onset, an improvement of the vasculitis and the complete occlusion of AVM were observed. We should therefore include cerebral vasculitis in the differential diagnosis when encountering a case with an unusual progressive stroke because a timely diagnosis and aggressive treatment are of critical importance for a successful recovery in such patients.


A longitudinal evaluation of the impact of the COVID-19 pandemic on a cohort of patients treated with clozapine.
We previously demonstrated that three months into the COVID-19 pandemic, the impact on individuals with treatment-resistant psychotic disorders was modest. Here, we examined and compared the psychological and social impact of the COVID-19 pandemic on the same patient cohort 12 months after their initial study engagement. Semi-structured interviews were conducted with 54 individuals (85.7% response rate) between June 12 and July 29, 2021, 12 months after their initial interviews. Participants' subjective experience of the impact of the COVID-19 pandemic on anxiety symptoms, social and vocational functioning was measured utilising the same Likert scales at both time points. Anxiety symptoms were additionally measured using subjective (Beck Anxiety Inventory) and objective (Hamilton Anxiety Rating Scale (HARS)) psychometric instruments. Paired t-tests or Wilcoxon ranked tests compared parametric or non-parametric data over time. Free-text responses pertaining to participants' perspectives on the impact of COVID-19 were grouped into themes. A minor increase in anxiety symptoms was demonstrated utilising the HARS (1.9 points, z = 3.017, p = 0.003), with a minimal increase in depressive symptoms noted using Likert ratings (0.8 points, z = 2.119, p = 0.034). Five themes were identified with the most prevalent being (i) positivity regarding vaccination, (ii) social isolation from family members and (iii) looking forward to post-COVID-19 'normality'. However, negative views pertaining to the psychosocial impact of COVID-19 and vaccination were additionally reported. No significant overall clinical change in symptomatology or functioning over time was noted.The study demonstrated that positive views regarding vaccination and optimism for the future were evident for some participants.


Conditional survival in ovarian cancer: results from the SEER dataset 1988-2001.
Survival statistics for patients with ovarian cancer are typically reported in terms of survival from time of diagnosis. For patients who have survived a period of time since diagnosis, however, conditional survival (CS) is a more clinically relevant measure, as it accounts for the changes in risk over time. The purpose of this study was to estimate CS for ovarian cancer patients through analysis of large-scale cancer registry data. Ovarian cancer cases were extracted from the Surveillance, Epidemiology, and End Results (SEER 17) database from the National Cancer Institute (NCI) for patients diagnosed between 1988-2001. Five-year relative CS calculations were performed with stratification by age, race, stage, histology, and grade for patients who had already survived up to 5 years from diagnosis. The 5-year overall relative CS improved over time for up to 5 years after diagnosis for ovarian cancer patients. The largest gains in CS over time were seen for patients with advanced stage disease, poor grade, and serous and undifferentiated epithelioid histologies. For patients with stage IV disease, 5-year CS more than tripled over the first 5 years of surveillance (17%-56%). Among histological types, patients with undifferentiated epithelioid histology saw 5-year CS rise from 29% at diagnosis to 84% after 5 years. Prognosis improves over time for almost all groups of ovarian cancer patients. For ovarian cancer survivors, CS provides a more relevant measure of prognosis than conventional survival estimates that are made at the time of diagnosis.


Proposal for probing energy transfer pathway by single-molecule pump-dump experiment.
The structure of Fenna-Matthews-Olson (FMO) light-harvesting complex had long been recognized as containing seven bacteriochlorophyll (BChl) molecules. Recently, an additional BChl molecule was discovered in the crystal structure of the FMO complex, which may serve as a link between baseplate and the remaining seven molecules. Here, we investigate excitation energy transfer (EET) process by simulating single-molecule pump-dump experiment in the eight-molecules complex. We adopt the coherent modified Redfield theory and non-Markovian quantum jump method to simulate EET dynamics. This scheme provides a practical approach of detecting the realistic EET pathway in BChl complexes with currently available experimental technology. And it may assist optimizing design of artificial light-harvesting devices.


Effect of the enteroinsular axis on both the A- and B-cell response to arginine after oral glucose in man.
Studies were made on the effect of the enteroinsular axis on amino acid-induced insulin and glucagon secretion during hyperglycaemia in man. The responses of plasma immunoreactive insulin, C-peptide, and immunoreactive glucagon to arginine infusion were investigated in nine healthy subjects after induction of hyperglycaemia by an oral glucose load and by intravenous glucose infusion to produce similar glucose concentrations in the arterialised blood. The plasma immunoreactive insulin and C-peptide levels increased to higher levels after an oral glucose load than after an intravenous infusion of glucose. The incremental areas under the immunoreactive insulin and C-peptide curves during arginine infusion were significantly greater (p less than 0.01) after oral than after intravenous glucose administration. The plasma immunoreactive glucagon level was suppressed equally after oral and intravenous glucose loads. However, during subsequent arginine infusion, the plasma immunoreactive glucagon level rose more in the presence of hyperglycaemia induced by oral than intravenous glucose. The incremental area under the plasma immunoreactive glucagon curve during arginine infusion was 1.6-fold greater after glucose ingestion than after intravenous glucose infusion. These results suggest that the enteroinsular axis has a stimulatory effect on the responses of pancreatic A and B cells to arginine after oral glucose administration.


Analysis of Ground Water Fluoride Content and its Association with Prevalence of Fluorosis in Zarand/Kerman: (Using GIS).
The concentration of fluoride in water is usually higher in areas around the coal mines. Zarand region in the south-east of Iran is known for its coal mines. Some studies have shown the high prevalence of fluorosis and some studies reported high levels of fluoride in the region. This study aimed to use Geographic Information System (GIS) to assess the relationship between water fluoride content and the prevalence of fluorosis and its spatial distribution in Zarand region. This cross-sectional study aimed to recruit 550 people aged 7-40 years in Zarand. Dental examination for fluorosis was conducted based on the Dean's Index. The level of fluoride in the water was determined in samples of water taken from 35 areas. Information on fluorosis and fluoride content was mapped on GIS. Most participants lived in rural areas (87.25%) and had an educational status of high school level (66%). About 23% of the examined people had normal teeth, 10% had severe and 67% had mild to moderate fluorosis. Distribution of severe fluorosis was higher in areas with higher levels of fluoride in the water according to GIS map. GIS map clearly showed a positive relationship between the prevalence and severity of fluorosis with the level of fluoride in water in Zarand. The GIS analysis may be useful in the analysis of other oral conditions.


Viable contribution of Tibetan sacred mountains in southwestern China to forest conservation.
The Tibetan sacred mountains (TSMs) cover a large area and may represent a landscape-scale conservation opportunity. We compared the conservation value of forests in these mountains with the conservation value of government-established nature reserves and unmanaged open-access areas in Danba County, southwestern China. We used Landsat satellite images to map forest cover and to estimate forest loss in 1974-1989, 1989-1999, and 1999-2013. The TSMs (n = 41) and nature reserves (n = 4) accounted for 21.6% and 29.7% of the county's land area, respectively. Remaining land was open-access areas (i.e., areas without any restrictions on resource use) (56.2%) and farmlands (2.2%). Within the elevation range suitable for forests, forest cover did not differ significantly between nature reserves (58.8%) and open-access areas (58.4%), but was significantly higher in TSMs (65.5%) after controlling for environmental factors such as aspect, slope, and elevation. The TSMs of great cultural importance had higher forest cover, but patrols by monastery staff were not necessarily associated with increased forest cover. The annual deforestation rate in nonsacred areas almost tripled in 1989-1999 (111.4 ha/year) relative to 1974-1989 (40.4 ha/year), whereas the rate in TSMs decreased in the later period (19.7 ha/year vs. 17.2 ha/year). The reduced forest loss in TSMs in 1989-1999 was possibly due to the renaissance of TSM worship and strengthened management by the local Buddhist community since late 1980s. The annual deforestation rate in Danba decreased dramatically to 4.4 ha/year in 1999-2013, which coincided with the implementation of a national ban on logging in 1998. As the only form of protected area across the Tibetan region during much of its history, TSMs have positively contributed to conserving forest at a landscape scale. Conservation of TSM forests largely relied on the strength of local religious institutions. Integrating community-based conservation of TSMs within the government conservation network would benefit the conservation of the Tibetan region.


Attaining the optimal flange for intrascleral intraocular lens fixation.
We describe a technique for making an optimal flange in intraocular lenses (IOLs) used for flanged intrascleral IOL fixation. The flange shape varies in poly(methyl methacrylate) (PMMA) haptics of different IOLs of different manufacturers. We identified the distance between the forceps grip of the haptic and the end of the haptic during heating with a cauter as a critical factor for the optimal flange shape in 5 PMMA haptics but not in 2 polyvinylidene fluoride haptics.


One-year outcome of postoperative swallowing impairment in pediatric patients with posterior fossa brain tumor.
Impaired swallowing in children who underwent posterior fossa brain tumor (PFBT) resection disrupts development and quality of life, yet its downstream consequences remain unclear. This study explored the risk factors and functional prognosis of postoperative swallowing impairment in pediatric patients (<19 years old) with PFBT. Among 183 patients with PFBT who underwent surgical resection, 39 patients with postoperative swallowing difficulty were analyzed using the videofluoroscopic swallowing study (VFSS). The association between clinical features, swallowing characteristics, and swallowing impairment was explored during the early postoperative phase and 1-year following surgical resection. Duration of tube feeding was investigated using Kaplan-Meier analysis. Twenty-seven (14.8 %) patients needed tube feeding in the early postoperative phase and 11 (6.01 %) at 1-year after surgical resection. Mean duration of tube feeding was 240.2 days and differed by tumor pathologies (P = 0.001), delayed triggering of pharyngeal swallow (DTP) (P = 0.002) and pharyngeal wall coating (P = 0.033). Tumor pathology was associated significantly with the referral for swallowing evaluation (P < 0.001) and 1-year tube feeding (P = 0.019). Tube feeding at 1-year was significantly associated with the tumor's brainstem involvement (P = 0.039), and swallowing abnormalities at early phase including DTP (P = 0.030) and pharyngeal wall coating (P = 0.004). Our results suggest that tumor pathology, brainstem involvement, and specific swallowing abnormalities at early phase are important risk factors for sustained 1-year swallowing impairment following surgical resection. These results can be applied to determine the plan of evaluation, nutrition, and intervention in clinical practice.


Sex-Specific Stress-Related Behavioral Phenotypes and Central Amygdala Dysfunction in a Mouse Model of 16p11.2 Microdeletion.
Substantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders, including autism spectrum disorder (ASD). Carriers of this deletion show divergent symptoms besides the core features of autism spectrum disorder, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. We used mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) and their sex-matched wild-type littermates for the study and examined their anxiety-related behaviors, auditory perception, and central amygdala circuit function using behavioral, circuit tracing, and electrophysiological techniques. Mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) had sex-specific anxiety-related behavioral and neural circuit changes. Specifically, we found that female, but not male, 16p11.2 del/+ mice showed enhanced fear generalization-a hallmark of anxiety disorders-after auditory fear conditioning and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male, 16p11.2 del/+ mice. Together, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.


Comparison of secretion and subcellular localization of von Willebrand protein with that of thrombospondin and fibronectin in cultured human vascular endothelial cells.
Cultured human vascular endothelial cells synthesize von Willebrand protein, thrombospondin and fibronectin. These proteins are secreted in the culture medium and incorporated into the extracellular matrix. We have compared the subcellular localization and the secretion of these proteins in response to stimulants in cultured human umbilical vein endothelial cells. Density gradient centrifugation using colloidal silica showed that the storage and secretion organelle with von Willebrand protein did not contain thrombospondin or fibronectin. Indirect immunofluorescence microscopy indicated that thrombospondin and fibronectin are not located in the rod-shaped organelles containing von Willebrand protein. Thrombin, ionophore A23187 and phorbol myristate acetate did not affect secretion of thrombospondin and fibronectin, while von Willebrand protein secretion was stimulated upon incubation of cells with these agents for 30 min. Prolonged incubation of cultured endothelial cells after a 1-h treatment with phorbol myristate acetate resulted in an increased secretion of von Willebrand protein into the conditioned medium; in contrast, accumulation of thrombospondin and fibronectin in endothelial cell-conditioned medium was decreased. These findings indicate that, unlike in platelets, these major endothelial proteins are not located in the same subcellular compartments. Von Willebrand protein is distinguished from thrombospondin and fibronectin both by its unique subcellular localization and its secretion rate in response to stimuli.


Inter-specific hybridization underlies phenotypic variability in Daphnia populations.
In the glacial lakes of the Palaearctic three species of Cladocera commonly coexist: Daphnia hyalina, D. galeata, and D. cucullata. Frequently these populations contain not only animals which are morphologically typical for the species but also individuals of an intermediate phenotype. Electrophoretic investigations of allozyme-patterns in morphologically typical individuals reveal that each species is fixed for a different allele at the GOT locus. Morphologically intermediate animals are heterozygous for the alleles of the two species which they resemble. The allelic pattern at other loci is also consistent with the assumption that morphological intermediates are formed via interspecific hybridization. Very few backcrosses between galeata-hyalina hybrids and their parent species are found, and there is no indication of gene flow between D. cucullata and the other species.