Pulsed dual electrospray ionization for ion/ion reactions.
A pulsed dual electrospray ionization source has been developed to generate positive and negative ions for subsequent ion/ion reaction experiments. The two sprayers, typically a nano-electrospray emitter for analytes and an electrospray emitter for reagents, are positioned in a parallel fashion close to the sampling orifice of a triple quadrupole/linear ion trap tandem mass spectrometer (Sciex Q TRAP). The potentials applied to each sprayer are alternately pulsed so that ions of opposite polarity are generated separately in time. Ion/ion reactions take place after ions of each polarity are sequentially injected into a high-pressure linear ion trap, where axial trapping is effected by applying an auxiliary radio frequency voltage to the end lenses. The pulsed dual electrospray source allows optimization of each sprayer and can be readily coupled to any spray interface with no need for instrument modifications, provided the potentials required to transmit the ion polarity of interest can be alternated in synchrony with the emitter potentials. Ion/ion reaction examples such as charge reduction of multiply charged protein ions, charge inversion of peptides ions, and protein-protein complex formation are given to illustrate capabilities of the pulsed dual electrospray source in the study of gas-phase ion/ion chemistry.


Reproductive outcomes from ten years of elective oocyte cryopreservation.
To assess the relationship between the number of oocytes retrieved during elective oocyte cryopreservation (EOC) cycles with various clinical, biochemical, and radiological markers, including age, body mass index (BMI), baseline anti-Müllerian hormone (AMH), antral follicle count (AFC), Oestradiol level (E2) and total number of follicles ≥ 12 mm on the day of trigger. To also report the reproductive outcomes from women who underwent EOC. A retrospective cohort of 373 women embarking on EOC and autologous oocyte thaw cycles between 2008 and 2018 from a single London clinic in the United Kingdom. 483 stimulation cycles were undertaken amongst 373 women. The median (range) age at cryopreservation was 38 (26-47) years old. The median numbers of oocytes retrieved per cycle was 8 (0-37) and the median total oocytes cryopreserved per woman was 8 (0-45). BMI, E2 level and number of follicles ≥ 12 mm at trigger were all significant predictors of oocyte yield. Multivariate analysis confirmed there was no significant relationship between AFC or AMH, whilst on univariate analysis statistical significance was proven. Thirty six women returned to use their cryopreserved oocytes, of which there were 41 autologous oocyte thaw cycles undertaken. There were 12 successful livebirths achieved by 11 women. The overall livebirth rate was 26.8% per cycle. No livebirths were achieved in women who underwent EOC ≥ 40 years old, and 82% of all livebirths were achieved in women who had done so between 36 and 39 years old. Clinical, biochemical and radiological markers can predict oocyte yield in EOC cycles. Reproductive outcomes are more favourable when cryopreservation is performed before the age of 36, with lower success rates of livebirth observed in women aged 40 years and above.


Hepatitis C Pretreatment Profile and Gender Differences: Cognition and Disease Severity Effects.
The hepatitis C virus (HCV) is known to infect the brain, however, the findings based on associated neuropsychiatric syndrome are controversial and the association itself remains unclear. Gender research in HCV infection is limited, failing to integrate the role of gender differences in neurocognitive syndrome. The aim of this study was to characterize psychological and neurocognitive profiles in HCV-infected patients before treatment and to explore gender differences in those profiles, as well as the impact of disease severity. A total of 86 patients diagnosed with chronic hepatitis C were included. Depression and anxiety were assessed using Hamilton anxiety scale (HAM-A), Hamilton depression scale (HAM-D), Beck Depression Inventory (BDI). For cognition, a neuropsychological battery to measure attention, concentration and memory was used, and executive function components validated for the Portuguese population was also used before starting treatment. To identify the disease severity, platelet ratio index, and FibroScan® were used. A statistically significant gender effect was found on HAM-A (B = 0.64, CI: 0.17-1.11) and HAM-D (B = 0.62, CI: 0.14-1.09), with women scoring higher compared to men. Regarding neuropsychological scores, significant differences between gender were identified in executive functions measured by Trail Making Test (TMT B) (B = 0.48, CI: 0.02-0.97), TMT B-A (B = 0.26, CI: -39.2 to -3.7) and in digit span total (B = -0.52, CI: -1.0 to -0.04), with women performing worse than men. Controlling for years of substance dependence, TMT-B and TMT B-A showed significant gender differences. Regarding the presence or absence of substance dependence, only HAM-A and HAM-D remained significant. For categorical variables, Digit Span Total was also influenced by gender, with women being more likely to be impaired: odds ratio (OR) = 7.07, CI: 2.04-24.45), and a trend was observed for Digit Span Backward (OR = 3.57, CI: 1.31-9.75). No significant differences were found between disease severity and neurocognitive performance. Data suggest that gender has an influence on depression, anxiety and cognitive functions with women showing greater impairment compared with men. This effect seems to be influenced by substance dependence.


Human cystic echinococcosis in southwest Iran: a 15-year retrospective epidemiological study of hospitalized cases.
Cystic echinococcosis (CE) is considered as a neglected disease with significant mortality and morbidity in most of the developing countries. The current study aimed to retrospectively assess the demographic and epidemiologic features of human CE surgical cases in a 15-year period in Fars province, southwestern Iran. A 15-year (2004-2018) retrospective study was conducted to find out the epidemiological and clinical picture of CE in patients who undergone surgeries for CE in two main hospitals in Fars Province, southwestern Iran. Hospital records were reviewed, and data were retrieved from each CE patient's record. A total of 501 CE surgical cases were recorded during a 15-year period, corresponding to an average annual incidence of 33.4 and a surgical incidence rate of 0.74/100,000 population. Of these, 242 (48.6%) were male, and 256 (52.4%) were female. Patients' age ranged from 2 to 96 years, with a mean age of 34.92 (± 19.87) years. A significantly higher rate of CE cases was noted in subject's ≥ 50 years of age. The highest frequency of cases (62:12.5%) was recorded in the year 2017. The most commonly involved organs were liver (339 cases; 57.8%) and lung (279 cases; 47.6%). Concurrent involvement of two organs was seen in 58 (9.9%) cases of both lung and liver, 10 (1.6%) cases of lung and other locations (but not liver), and 23 (3.9%) cases of liver and other locations (but not lung). Reoperation was noted in 67 (13.4%) of the cases. The size of the lung hydatid cyst varied, ranging between 2 and 24 cm (mean = 7.33, SD = 3.737). The size of liver hydatid cysts ranged from 1 to 26 cm (mean 9.04, SD = 4.275). The findings of the current study demonstrated a nearly constant prevalence of CE during the last 15 years in southern Iran. Further studies are needed to find out the reasons behind the recurrence of the disease, which is substantial, in surgically-treated patients.


Inhibition effect of enteropeptidase on RANKL-RANK signalling by cleavage of RANK.
Enteropeptidase can cleave trypsinogen on the sequence of Asp-Asp-Asp-Asp-Lys and plays an important role in food digestion. The RANKL-RANK signalling pathway plays a pivotal role in bone remodelling. In this study, we reported that enteropeptidase can inhibit the RANKL-RANK signalling pathway through the cleavage of RANK. A surrogate peptide blocking assay indicated that enteropeptidase could specifically cleave RANK on the sequence NEEDK. Osteoclast differentiation assay and NF-κB activity assay confirmed that enteropeptidase could inhibit osteoclastogenesis in vitro through the cleavage of RANK. This is the first study to prove that the RANKL-RANK signalling pathway can be inhibited by cleavage of RANK instead of targeting RANKL.


Synthesis of 1,3-Bis-(boryl)alkanes through Boronic Ester Induced Consecutive Double 1,2-Migration.
A general and efficient approach for the preparation of 1,3-bis-(boryl)alkanes is introduced. It is shown that readily generated vinylboron ate complexes react with commercially available ICH2 Bpin to valuable 1,3-bis-(boryl)alkanes. The introduced transformation, which is experimentally easy to conduct, shows broad substrate scope and high functional-group tolerance. Mechanistic studies reveal that the reaction does not proceed via radical intermediates. Instead, an unprecedented boronic ester induced sequential bis-1,2-migration cascade is suggested.


Yacon (Smallanthus sonchifolius) flour soluble extract improve intestinal bacterial populations, brush border membrane functionality and morphology in vivo (Gallus gallus).
This study evaluates the effects of intra-amniotic administration of yacon (Smallanthus sonchifolius) flour soluble extracts (YFSE) on intestinal bacterial populations, brush border membrane (BBM) functionality and morphology, by using the Gallus gallus model. The YFSE increased (p < 0.05) relative abundance of Lactobacillus, Bifidobacterium, Clostridium and E. coli compared to 18MΩ H2O. The YFSE had systematic effect on BBM functionality, via the upregulation of zinc (zinc transporters - ZnT1, ZnT7 and ZIP9) and iron (ferroportin, Duodenal cytochrome (DcytB) transporters, sucrose isomaltase (SI), and down regulation of Interleukin 1 beta (IL1β), and hepcidin genes expression when compared to the inulin administered group. The YFSE administration increased glycogen concentrations in pectoral muscle compared to noninjected and 18 Ω H2O groups, however, did not change gene expression of enzymes related to glycolysis (phosphofructokinase) and gluconeogenesis (glucose-6 phosphatase). The YFSE increased the depth of crypts, crypt goblet cell diameter, number and type (acidic), and villi goblet cell diameter and type (acidic) when compared to all other groups. Thus, YFSE demonstrated prebiotic effects resulting in improving intestinal bacterial populations profile, BBM functionality, digestive and absorptive capabilities, intestinal morphology, glycogen status and immune system.


Probing interhemispheric dorsal premotor-primary motor cortex interactions with threshold hunting transcranial magnetic stimulation.
To characterise the effect of altering transcranial magnetic stimulation parameters on the magnitude of interhemispheric inhibition (IHI) from dorsal premotor (PMd) to primary motor cortex (M1). We used a fully automated adaptive threshold hunting paradigm to quantify PMd-M1 IHI across a range of conditioning stimulus (CS) intensities (90%, 110%, 130% of resting motor threshold, rMT) and interstimulus intervals (ISIs) (8, 10, 40 ms). M1-M1 IHI was examined with CS intensities of 110%, 120%, and 130% rMT and ISIs of 10 and 40 ms. Two test coil orientations (inducing posterior-anterior or anterior-posterior current) were used. PMd-M1 IHI was obtained consistently with posterior-anterior (but not anterior-posterior) test stimuli and increased with CS intensity. M1-M1 IHI was expressed across all conditions and increased with CS intensity when posterior-anterior but not anterior-posterior induced current was used. The expression of PMd-M1 IHI is contingent on test coil orientation (requiring posterior-anterior induced current) and increases as a function of CS intensity. The expression of M1-M1 IHI is not dependent on test coil orientation. We defined a range of parameters that elicit reliable PMd-M1 IHI. This (threshold hunting) methodology may provide a means to quantify premotor-motor pathology and reveal novel quantitative biomarkers.


UCN-01 and UCN-02, new selective inhibitors of protein kinase C. I. Screening, producing organism and fermentation.
In the course of continued screening program for new selective inhibitors of protein kinase C (PKC), fermentation broths from over 5,000 soil isolates were screened for their inhibitory activity of PKC. HPLC analysis of active cultures revealed that five different strains (N-71, N-115, N-126, N-128 and N-139) of Streptomyces isolated from various local soil samples were found to produce staurosporine and related compounds. Of these strains, N-126, a high producing strain, was found to produce new selective inhibitors of PKC, UCN-01 and its stereoisomer, UCN-02. The pH control of fermentation resulted in an increase of the production of UCN-01 and UCN-02.


Etiology and epidemiology of diarrheal diseases in the United States.
Accurate data on the frequency of acute diarrheal illness and the distribution of pathogens are not available for several reasons, including the facts that only a small fraction of cases come to the attention of physicians and that available diagnostic tests establish an etiology in only about half of these. In a survey of three groups of patients in a community (upper-middle class and lower class outpatients and hospitalized infants), a possible cause was found in fewer than 20 percent of outpatients, and rotavirus accounted for the majority. However, asymptomatic colonization with rotavirus is very common in early infancy, and demonstration of the antigen correlates with a causative role in diarrhea in only about one half of cases. Data on cases of shigellosis over a 15-year period in Dallas compared with the Centers for Disease Control national data demonstrate that epidemiologic patterns in any given community can differ substantially from the national data. Day-care centers are important sources of Giardia and Shigella infections in the community. The epidemiologic roles of newly reported causes of diarrhea (Campylobacter laridis, Blastocystis hominis, Cryptosporidium species, and Aeromonas hydrophila) are being explored. Generalizations about etiology and epidemiology of pathogens in diarrheal disease are invalid unless the population group is defined socioeconomically and geographically.


Photodeposition mediated synthesis of silver-doped indium oxide nanoparticles for improved photocatalytic and anticancer performance.
Indium oxide nanoparticles (In2O3 NPs) are being investigated for a number of applications including gas-sensing, environmental remediation, and biomedicine. We aimed to examine the effect of silver (Ag) doping on photocatalytic and anticancer activity of In2O3 NPs. The Ag-doped (2%, 4%, and 6%weight) In2O3 NPs were synthesized by the photodeposition method. Prepared samples were characterized via X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR), UV-Vis spectroscopy, and the photoluminescence (PL). XRD data showed that Ag-doping increases the crystallinity of In2O3 NPs. SEM and TEM images indicated that In2O3 NPs have spherical morphology with smooth surfaces, and Ag-doping increases the size without affecting the particle's shape. XPS spectra showed the oxidation state and the presence of Ag in In2O3 NPs. Band gap energy of In2O3 NPs decreases with increasing the concentration of Ag (3.41 eV to 3.12 eV). The peak intensity of PL spectra of In2O3 NPs also reduces with the increment of Ag ions suggesting the hindrance of the recombination rate of e-/h+. The photocatalytic activity was measured by the degradation of Rh B dye under UV irradiation. The degradation efficiency of Ag-doped (6%) In2O3 NPs was 92%. Biochemical data indicated that Ag-doping enhances the anticancer performance of In2O3 NPs against human lung cancer cells (A549). Moreover, Ag-doped In2O3 NPs displayed excellent biocompatibility in normal human lung fibroblasts (IMR90). Overall, this study demonstrated that Ag-doping enhances the photocatalytic activity and anticancer efficacy of In2O3 NPs. This study warrants further investigation on the environmental and biomedical applications of Ag-In2O3 NPs.


[Extensive left ventricular myocardial fat deposition detected by cardiac MRI].
Although it is well known from pathological studies that intramyocardial fat deposition frequently occurs after left ventricular myocardial infarction, a left ventricular fat deposition is rarely diagnosed in the clinical routine. We report the case of extensive fat deposition in the left ventricular myocardium which was detected by routine cardiac magnetic resonance imaging.


Investigation of sitting position of paralympic wheelchair basketball players.
The aim of this study was to examine the sitting position (posture) of wheelchair basketball (WB) players who cannot walk and can walk in daily life and to compare them with the able-bodied sedentary individuals. A total of 22 male individuals, including six WB players who could not walk in daily life, eight WB players who walked in daily life, and eight able-bodied sedentary individuals (control group) were included in the study. Posture analysis of individuals was evaluated using rastersterographic system DIERS formetric 4D device. Kruskal-Wallis test was used to compare the data obtained during posture analysis. The Mann-Whitney U-test was used to determine which group caused the difference in the data determined to be different. Statistical significance level was taken as P < 0.05. Trunk-length, sacrum-width, sagittal and coronal imbalance, trunk-torsion, pelvic-obliqueness, pelvic-torsion, pelvic-inclination and fleche-cervicale were found to be values similar in the three groups (P > 0.05). It was determined that the lumbar lordosis and thoracic kyphosis angles were different between the groups, and the lumbar lordosis and thoracic kyphosis angles of the WB players who could not walk in daily life were higher than those of the WB players who walked in daily life and the control group (P < 0.05). Based on the results of our study, we suggest evaluating the sitting postures of WB players and rehabilitating WB players, especially those who cannot walk in daily life, with posture corrective exercises aimed at reducing and normalizing thoracic kyphosis.


Motor unit number estimation as a complementary test to routine electromyography in the diagnosis of amyotrophic lateral sclerosis.
Electromyographic (EMG) abnormalities that reveal denervation and reinnervation caused by lower motor neuron degeneration do not reflect the number of motor units that determines muscle strength. Consequently, motor unit activity potential (MUAP) parameters do not reflect muscle dysfunction. The aim of the study was to compare the value of motor unit number estimation (MUNE) and MUAP parameters as indicators of clinical muscle dysfunction in patients with amyotrophic lateral sclerosis (ALS), and to analyze the role of MUNE as a supplement to the EMG criteria for the diagnosis of ALS. In 25 patients with ALS, MUNE by the multipoint incremental method in the abductor digiti minimi (ADM) and quantitative EMG in the first dorsal interosseous (FDI) were obtained. The Medical Research Council (MRC) scale was used to evaluate clinical muscle dysfunction. A strong correlation between the number of motor units evaluated by MUNE and ADM clinical function by the MRC scale was found (P<0.001). An increased value of surface-detected single motor action potential was associated with a decreased MRC score for ADM (P<0.1). No relation was found between MUAP parameters in FDI and MRC scores. Our data support the value of the MUNE method for the detection of motor unit loss in ALS, and it could be postulated that MUNE studies may be considered complementary tests for ALS in a future revision of ALS criteria.


Anaplastic large-cell lymphoma of null-cell type with multiple bone involvement.
A 21-year-old man who had anaplastic large cell lymphoma (ALCL) of the null-cell type with multiple bone involvement is reported. On admission, he had symptoms of incomplete paraplegia and urinary and rectal incontinence. Workup studies for staging revealed para-aortic lymph node swellings and multiple bone involvement including skull, ribs, left iliac bone, and thoracic/lumbar spine. Because paraplegia was rapidly progressive, a decompression operation was performed. The biopsy specimen obtained from the lumbar spine revealed sheetlike proliferation of anaplastic large cells. These cells were positive for CD30 (Ki-1), EMA, vimentin, and p80NPM/ALK, and negative for CD3, CD20 (L26), and CD45 (LCA). Epstein-Barr virus-encoded small RNAs were not detectable in these cells. Thus, the patient was diagnosed as having ALCL of the null-cell type. He was treated with several courses of combination chemotherapy, and finally with total body irradiation plus high-dose chemotherapy supported by peripheral blood stem cell transplantation. However, soon after the treatment, the lymphoma cells massively infiltrated his bone marrow. He died of lymphoma 8 months after admission.


First web space post-burn contracture types: contracture elimination methods.
First web space adduction contractures are a common consequence of hand burns. Many reconstructive techniques are used and investigation for more effective methods continues. Effective hand reconstruction usually considers anatomy as its foundation. Based on the experience of over 500 web space contracture elimination cases, three anatomical types of thumb adduction contractures were identified: edge, medial and total. Edge contractures (80% of all thumb adduction contractures) are caused by a fold in which only one sheet is scarred, either the palmar or dorsal surface. The contraction is caused by a trapeze-shaped length deficiency of the scar sheet, which has a surface surplus in width. Reconstruction consists of surface deficiency compensation with trapezoid flap prepared from the non-scarred side and skin-fat tissues of the web space. In most cases, the small scar-fat trapezoid flaps should be prepared from the non-scarred side to cover the donor wounds on both sides of the main flap. Medial contractures (10% of thumb adduction contractures) are caused by the fold, both sheets of which are scarred and have trapeze-shaped surface deficiency in length and surplus in width. Both fold sheets are converted into one or several pairs of trapezoid scar-fat flaps by radial incisions. The oppositely located flaps are transposed towards each other. As a result of the counter flaps transposition, the contracture is eliminated; the web space's shape and depth are restored by the use of flaps alone or in combination with skin grafting. The trapeze-flap plasty is very simple and effective with the length gain of up to 100-200%. Neither flap loss nor re-contracture occurs. Total contractures (about 10% of all) have no fold. Reconstruction consists of the creation of the central zone of the first web space depth with the rectangular subdermal pedicle flap; the wounds on both sides of the flap are skin grafted. The flap sustains normal web depth and prevents the contracture recurrence and skin graft shrinkage.


Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC.
The C797S mutation confers resistance to covalent EGFR inhibitors used in the treatment of lung tumors with the activating L858R mutation. Isoindolinones such as JBJ-4-125-02 bind in an allosteric pocket and are active against this mutation, with high selectivity over wild-type EGFR. The most potent examples we developed from that series have a potential chemical instability risk from the combination of the amide and phenol groups. We explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. The 5-F quinazolinone 34 demonstrated tumor regression in an H1975 efficacy model upon once daily oral dosing at 25 mg/kg.


Myoadenylate deaminase deficiency caused by alternative splicing due to a novel intronic mutation in the AMPD1 gene.
We have examined two Caucasian brothers with myoadenylate deaminase (AMPD) deficiency who presented with exercise intolerance and muscle cramps. Allele-specific PCR amplification assays demonstrated that the common Q12X (C34T) and P48L (C143T) mutations were not found within their AMPD1 genes. Further analysis revealed that both brothers were compound heterozygotes for a previously reported K287I (A860T) mutation in exon 7 and a novel deletion within intron 2 (IVS2-(4-7)delCTTT). The intronic deletion appears to affect the splicing machinery since characterization of AMPD1 mRNA from skeletal muscle of one brother identified multiple alternatively spliced transcripts resulting in multiple deletions in exon 3, the complete deletion of either exon 3 or exons 3 and 4, and the activation of a cryptic splice site that resulted in an insertion at the 5' end of exon 4. The predominant transcript contains a 51 base deletion at the 5' end of exon 3 that is predicted to produce a functional form of AMPD containing a 17-amino acid residue deletion within its N-terminal region. Analysis of 137 Caucasian normal control patients determined that the K287I mutation is relatively frequent (5.1% carrier frequency), whereas the IVS2-(4-7)delCTTT mutation is rare and not present in 274 chromosomes.


[Rhythmic bioelectrical activity of the cerebral cortex analyzed with allowance for the nonlinear voltage dependence of excitatory postsynaptic potentials induced by neocortical neurons].
A nonlinear voltage dependence between the membrane and excitatory postsynaptic potentials coming via corticocortical connections was derived based on literature data. The existence of a region of stability of oscillations with increasing mean value of nonspecific afferent input was shown. As the afferent input strongly increases, a high-frequency component of oscillations (40-60 Hz), appeas which may result in the instability of oscillations and initiation of abnormal brain activity.


A broadly protective human monoclonal antibody targeting the sialidase activity of influenza A and B virus neuraminidases.
Improved vaccines and antiviral agents that provide better, broader protection against seasonal and emerging influenza viruses are needed. The viral surface glycoprotein hemagglutinin (HA) is a primary target for the development of universal influenza vaccines and therapeutic antibodies. The other major surface antigen, neuraminidase (NA), has been less well studied as a potential target and fewer broadly reactive anti-NA antibodies have been identified. In this study, we isolate three human monoclonal antibodies that recognize NA from A/H1N1 subtypes, and find that one of them, clone DA03E17, binds to the NA of A/H3N2, A/H5N1, A/H7N9, B/Ancestral-lineage, B/Yamagata-lineage, and B/Victoria-lineage viruses. DA03E17 inhibits the neuraminidase activity by direct binding to the enzyme active site, and provides in vitro and in vivo protection against infection with several types of influenza virus. This clone could, therefore, be useful as a broadly protective therapeutic agent. Moreover, the neutralizing epitope of DA03E17 could be useful in the development of an NA-based universal influenza vaccine.


Efficacy, safety and prognostic factors of camrelizumab plus carboplatin and pemetrexed chemotherapy in advanced lung adenocarcinoma patients.
Camrelizumab is a recently developed PD-1 inhibitor in China applied in treating different cancers including lung cancer. This study is designed to evaluate the efficacy, safety and prognostic factors for camrelizumab plus carboplatin and pemetrexed (CP) chemotherapy in treating patients with advanced lung adenocarcinoma. Of 51 advanced lung adenocarcinoma patients with negative driver genes who received camrelizumab plus CP chemotherapy were recruited. These patients received four cycles of camrelizumab plus CP chemotherapy in a 21-day cycle. Then, camrelizumab, pemetrexed or camrelizumab plus pemetrexed was administered as maintenance therapy. The rates of complete response, partial response, stable disease and progressive disease were 2.0%, 56.8%, 19.6% and 5.9%, respectively; while treatment response of 15.7% of patients was missing or not evaluable. The objective response and disease control rates were 58.8% and 78.4%, respectively. With a median follow-up period of 14.9 months (the follow-up duration ranged from 3.9 months to 24.3 months), 41 (83.4%) cases of disease progression and 22 (43.1%) cases of death were recorded. The median progression-free survival (PFS) was 10.5 months (95% confidence interval (CI): 8.4-12.6 months) with a 1-year PFS rate of 36.3% and a 2-year PFS rate of 7.5%. In addition, the median overall survival (OS) was 18.7 months (95% CI: 16.4-21.0 months) with a 1-year OS rate of 79.1% and a 2-year OS rate of 30.4%. In consideration of safety, the most frequent adverse events were peripheral neuropathy (37.3%), neutropenia (37.3%), alopecia (35.3%), etc. and most of them were grade 1-2 and could be controlled. Camrelizumab plus CP chemotherapy achieves favourable efficacy and tolerable adverse events in advanced lung adenocarcinoma patients.


Treatment of experimental tumors with a combination of a pulsing magnetic field and an antitumor drug.
We investigated the effects of a combination treatment involving a pulsing magnetic field (PMF) and an antitumor drug, mitomycin C (MMC), on two experimental tumors (fibrosarcoma KMT-17 and hepatocellular carcinoma KDH-8) in WKA rats, paying attention to possible potentiation of the therapeutic effect of the antitumor drug. PMF was obtained using a system generating a pulsed current in a solenoid coil. On day 7 after tumor implantation into the right thighs of rats, the region of the tumor was exposed to PMF (frequency 200 Hz, mean magnetic flux density 40 gauss) for 1 h immediately after iv injection of MMC at a dose of 1 mg/kg. Survival rates at day 90 of KMT-17 implanted rats were 0% (0/10) in the non-treated group, 34% (4/12) in the MMC-treated group, 47% (6/13) in the PMF-treated group and 77% (10/13) in the MMC/PMF combination group. The increase of life span (ILS) of KDH-8-implanted rats in the combination therapy group was significantly prolonged (%ILS 17.6%) compared with that in the MMC-treated (%ILS 3.4%) and PMF-treated (%ILS 7.6%) groups. By using cultured cells of the above two lines of tumor, the therapeutic effects of MMC and PMF were also determined from the cell colony-forming efficiency in soft agar. The colony-forming efficiencies of both cell lines were significantly suppressed in the combination therapy group compared with those in the other single therapy groups. The present results indicate that PMF exhibited a potentiation of the antitumor effect of mitomycin C.


Tetrazolyl isoxazole amino acids as ionotropic glutamate receptor antagonists: synthesis, modelling and molecular pharmacology.
Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b, of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA receptor agonist, and (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring agonist, were synthesized. Compounds 1a and 1b were pharmacologically characterized in receptor binding assays, and electrophysiologically on homomeric AMPA receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these receptors. Both analogues proved to be antagonists at all AMPA receptor subtypes, showing potencies (Kb=38-161 microM) similar to that of the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) (Kb=43-76 microM). Furthermore, the AMOA analogue, 1a, blocked two kainic acid receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 (Kb=19 microM). Unlike the iGluR antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [(S)-ATPO], the corresponding tetrazolyl analogue, 1b, lacks kainic acid receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA receptor subunit GluR2 and a homology model of the kainic acid receptor subunit GluR5, we were able to rationalize the observed structure-activity relationships.


DNA index and cell cycle analysis of primary breast cancer and synchronous axillary lymph node metastases.
The DNA Index (DI) and the percentage of cells in S-phase (S-phase fraction, SPF) were measured by flow cytometry in 80 primary breast carcinomas and in 80 accompanying axillary lymph node metastases. The DI in primary tumors and metastases agreed in 61 cases (76%). Cases with diploid primary tumors revealed more constancy of the DI in comparison to the metastases than the cases with aneuploid primary tumors (91% and 70% respectively). The mean values of the SPF were in close agreement in the primary tumors and in the lymph node metastases (6.1% and 6.0% respectively). Differences between the SPF of the two groups could be detected only by the consideration of case-related data pairs. In 50 cases (62%), the percentage of SPF agreed approximately in primary tumors and in the correspondent metastases. The cases with diploid primary tumors revealed more agreement of the SPF in the primary site and the metastases than did cases with aneuploid primary tumors (78% and 56% respectively). In conclusion, diploid carcinomas and their metastases revealed more constancy of the DI and the percentage of SPF than aneuploid carcinomas. These findings agree well with a better prognosis of diploid mammary carcinomas, as reported in the literature. Comparisons between the DI and the SPF in primary tumors and the corresponding metastases could be a source of valuable information on the biological behaviour and the aggressiveness of mammary carcinomas.


'Morphology of immune lymphocytes in homograft lymph'.
Uropod-bearing lymphocytes (UBLs) resembling cytotoxic cells found in vitro were identified in lymph collected from rabbit hind-limbs bearing homografts. UBLs were found in lymph leaving the regional lymph node (efferent), both before and after rejection, but not in that draining the homograft (afferent) even though they were present in the graft tissue itself. UBLs may represent the sub-class of immune lymphocytes which induce necrosis of the grafted cells. Mitotic lymphocytes and cells resembling lymphocytes transformed by phytohaemagglutinin were also found in efferent homograft lymph.


Fumaryl diketopiperazine based effervescent microparticles to escape macrophage phagocytosis for enhanced treatment of pneumonia via pulmonary delivery.
The treatment of pulmonary infections with antibiotics administered via pulmonary delivery provides for higher local therapeutic efficacy rather than through systemic administration. Pneumonia is globally considered a major cause of death due to a lack of proper medication. The treatment of pneumonia with inhalable antibiotics (such as azithromycin (AZM)) can provide a maximum pulmonary therapeutic effect without significant systemic side effects. Compared to non-effervescent microparticles, effervescent microparticles can provide an active driving force to release loaded antibiotics for subsequent distribution deep into the lung by virtue of its smaller size. In this study, N-fumaroylated diketopiperazine (FDKP) was used as a carrier to prepare effervescent inhalable microparticles loaded with AZM (AZM@FDKP-E-MPs). This effervescent dry powder was characterized for both in vitro and in vivo deposition in the lung and the results obtained showed significant improvement in lung deposition and anti-bacterial efficiency, suggesting a strong potential application for pneumonia treatment.


Efferent neurons of the lateral-line system and the VIII cranial nerve in the brainstem of anurans. A comparative study using retrograde tracer methods.
The octavo-lateral efferent system of several anuran species was studied by means of retrograde transport of horseradish peroxidase. This system is organized similarly in all larval anurans and in all adult aglossids. All have two groups of efferent neurons in the nucleus reticularis medialis between the VIIIth and the IXth motor nucleus. The caudal group consists of efferent neurons that supply the posterior lateral-line nerve (NLLp) and a considerably smaller group of neurons supplying both the NLLp and the anterior lateral-line nerve (NLLa). The rostral group is composed of efferent neurons supplying the NLLa, neurons projecting to the inner ear and neurons supplying both the inner ear and the NLLa. Efferent neurons of the VIIIth cranial nerve exhibit a rostrocaudal cytoarchitectonic differentiation. Caudal perikarya, which are rounder in shape than those of the rostral part, have a dendritic projection to the superior olive. It is suggested that this differentiation reflects a functional differentiation of acoustic and vestibular efferent neurons. Labeled neurons were ipsilateral to the site of application of HRP. None were found in the vestibular nuclei or in the cerebellum. Efferent axons projecting to neuromasts of the NLLa leave the medulla with the VIIth nerve, axons projecting to neuromasts of the NLLp exit via the IXth nerve. Cell counts and the observation of axonal branching revealed that efferent units of both the lateral-line and the VIIIth-nerve system supply more than one receptor organ. In contrast to the lateral-line system, dendrites of efferent neurons of the VIIIth nerve project dorsally onto its nuclei, and afferents of the VIIIth nerve project onto efferent neurons. These structures most probably represent a feedback loop between the afferent and efferent systems of the VIIIth cranial nerve.


Pulse-modulated light source for psychometric and vision experiments.
Light-emitting diodes (LED) of various colours were used to produce accurately controllable light sources. Variable light intensity was obtained by applying 800-ns current pulses to the LEDs at frequencies 1-1000 kHz using a single potentiometer. These current pulses were generated from an oscillator which was voltage-controlled from a potentiometer and an antilogarithmic amplifier. Its output was gated to produce an optional flicker of 1-100 Hz. The light intensity was indicated by a frequency meter connected to the oscillator. The reading of this was found to linearly indicate light intensity.


Silver Nanoparticles Against Salmonella enterica Serotype Typhimurium: Role of Inner Membrane Dysfunction.
The evolution of antibiotics-resistant bacteria is considered a major concern. To explore promising antibacterial materials and clarify their unknown mechanisms, the mode of action of silver nanoparticles (AgNPs) against Salmonella enterica serotype typhimurium was investigated. We investigated the effect of AgNPs on the bacterial membrane. The N-phenyl-1-naphthylamine assay showed that the permeability of the outer membrane was not changed by treatment with AgNPs. The O-nitrophenyl-β-D-galactopyranoside assay showed that the inner membrane permeability increased as AgNPs concentration increased. Our results showed that AgNPs affected the inner membrane without outer membrane damage. Generally, antibiotic-induced reactive oxygen species (ROS) and changes in the Ca2+ gradient are known to contribute to bacterial cell death. Likewise, we detected that AgNPs induced the accumulation of ROS and intracellular Ca2+ depending on its concentration, using 2',7'-dichlorodihydrofluorescein and Fura-2AM, respectively. At higher concentrations, no relationship between oxidative stress and bactericidal effects of AgNPs was confirmed through a cell viability assay and intracellular Ca2+ assay with antioxidant N-acetylcysteine. In this study, the inner membrane disruption followed by membrane dysfunction played a key role in the antibacterial activity of AgNPs against S. typhimurium. Contrary to the expected results, ROS do not influence growth inhibition of AgNPs.


Complete genome sequence of Streptococcus thermophilus MN-BM-A01, a strain with high exopolysaccharides production.
Streptococcus thermophilus MN-BM-A01 (ST MN-BM-A01) (CGMCC No. 11383) was a strain isolated from Yogurt Block in Gansu, China. The yogurt fermented with this strain has good flavor, acidity, and viscosity. Moreover, ST MN-BM-A01 could produce a high level of EPS which can confer the yogurt with improved rheological properties. We reported the complete genome sequence of ST MN-BM-A01 that contains 1,876,516bp encoding 1704 coding sequences (CDSs), 67 tRNA genes and 6 rRNA operons. The genomic sequence indicated that this strain included a 35.3-kb gene cluster involved in EPS biosynthesis.


Alleviation of experimental acute renal failure in rats by reduction of renal mass.
An acute renal failure (ARF) has been produced by glycerol injection on rats unilaterally nephrectomized 48 h before. Rats with reduced renal mass showed polyuria and significantly lower azotemia than controls with ARF. This data might be explained by increased glomerular plasma flow in the remnant kidney previous to ARF induction.


[The criteria of choice of the surgical treatment method in the injured persons with intrapleural post-traumatic hemorrhage in the closed thoracic trauma].
The role of clinic-instrumental methods of investigation for establishment of criteria in the choice in the injured persons surgical treatment with intrapleural posttraumatic hemorrhage as a consequence of the closed thoracic trauma was studied up.


Neurobiological substrates of chronic low back pain (CLBP): a brain [99mTc]Tc-ECD SPECT study.
Recent neuroimaging studies have demonstrated pathological mechanisms related to cerebral neuroplasticity in chronic low back pain (CLBP). Few studies have compared cerebral changes between patients with and without pain in the absence of an experimentally induced stimulus. We investigated the neurobiological substrates associated with chronic low back pain using [99mTc]Tc-ECD brain SPECT and correlated rCBF findings with the numeric rating scale (NRS) of pain and douleur neuropathique en 4 questions (DN4). Ten healthy control volunteers and fourteen patients with neuropathic CLBP due to lumbar disc herniation underwent cerebral SPECT scans. A quantitative comparison of rCBF findings between patients and controls was made using the Statistical Parametric Mapping (SPM), revealing clusters of voxels with a significant increase or decrease in rCBF. The intensity of CLBP was assessed by NRS and by DN4. The results demonstrated an rCBF increase in clusters A (occipital and posterior cingulate cortex) and B (right frontal) and a decrease in cluster C (superior parietal lobe and middle cingulate cortex). NRS scores were inversely and moderately correlated with the intensity of rCBF increase in cluster B, but not to rCBF changes in clusters A and C. DN4 scores did not correlate with rCBF changes in all three clusters. This study will be important for future therapeutic studies that aim to validate the association of rCBF findings with the pharmacokinetic and pharmacodynamic profiles of therapeutic challenges in pain.


Lead nephrotoxicity and associated disorders: biochemical mechanisms.
Lead may exert toxic effects on several organ systems, but those in the kidney are the most insidious. Acute lead nephropathy is characterized by proximal tubular dysfunction with the development of a Fanconi-type syndrome, alterations in mitochondrial structure and the development of cytosolic and nuclear inclusion bodies. Intracellular lead is associated with specific high affinity proteins and can also bind to metallothionein. Chronic lead nephropathy is irreversible and is typically accompanied by interstitial fibrosis, both hyperplasia and atrophy of the tubules, glomerulonephritis and, ultimately, renal failure. In addition, lead produces renal neoplasms in experimental animals. Chronic lead exposure is also implicated in the development of saturnine gout and hypertension. The metal interacts with renal membranes and enzymes and disrupts energy production, calcium metabolism, glucose homeostasis, ion transport processes and the renin-angiotensin system. This review summarizes the biochemical effects of lead on the kidney to understand the mechanisms of lead-induced nephropathy and other associated disorders.


Methodologic issues in follow-up studies of cancer incidence among occupational groups in the United States.
Incidence studies of occupational factors and cancer in the United States are problematic because the use of population-based registries to identify cases requires development of historical data on subjects' residences and often severely restricts the time period of follow up. This article describes procedures for addressing these challenges. We used data from studies of cancer incidence and mortality among microelectronics industry employees to assess various methods for developing residential histories and the relative informativeness of the two studies. We developed residential histories for 98% of 99,229 mortality study subjects. Analyses making alternative assumptions about residential histories yielded standardized incidence ratios varying by at most 6%. Use of postemployment residential histories increased person-years by up to 62% and increased the observed number of cancers by up to 28%. The proportion of mortality study person-years included in the cancer incidence study ranged from 40% to 77% among work activity subcohorts. The number of observed cancer cases in the incidence study was 60% higher than the number of observed cancer deaths in the mortality study. Assumptions about residential history had little impact on validity. Use of information sources with national coverage to develop residential histories increased the incidence study's precision. Despite geographic and temporal restrictions, incidence studies provide more data than mortality studies on cancers with good survival. However, the potential for selection bias in incidence studies may vary considerably among subcohorts, indicating the need for cautious interpretation of such research.


Rapid resolution liquid chromatography (RRLC) analysis and studies on the stability of Shuang-Huang-Lian preparations.
Shuang-Huang-Lian (SHL) is a traditional Chinese formula which comprises of three medicinal herbs: Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae, and is commonly used to treat acute upper respiratory tract infection, acute bronchitis and light pneumonia. A simple, reliable and reproducible rapid resolution liquid chromatography (RRLC) method was developed for the quality control of SHL preparations, which baseline separates the major bioactive compounds within 6min. The method uses a C18-HST column (2.5μm, 100mm×3.0mm) kept at 40°C. The mobile phases consist of 0.1% phosphoric acid aqueous solution and acetonitrile. Flow rate is 1.0ml/min and UV detection is performed at 327nm from 0 to 4min and 229nm from 4 to 7min. This method was further validated according to the ICH guidelines. Eight batches of commercial SHL preparations obtained from different pharmaceutical manufacturers as well as individual herbs were examined and their chromatographic profiles were compared. The stability test revealed that chlorogenic acid is stable only at acidic pH, and hence it is necessary to further evaluate and optimize the preparatory procedures and storage conditions for commercial SHL preparations.


ACOG Committee Opinion. Follow-up of abnormal screening mammography, number 272, May 2002.
Screening mammography facilitates the early diagnosis of breast carcinoma in women. Timely follow-up can optimize the diagnosis and treatment of women with abnormal screening test results. When test results reveal that additional studies are needed, no barriers should prohibit testing during the screening mammography visit.


Time shift in ventilation-induced density fluctuation of arterial blood.
In an artificially ventilated dog, the varying tracheal pressure causes a density fluctuation in the blood sampled from the aorta. We cross-correlated the tracheal pressure with the density to determine the time shift or delay of the latter from the former waveform for a ventilation frequency in the range of 6-30 CPM. The delay time was found to be 29% of the mean transit time (MTT) of the pulmonary vasculature and independent of the ventilation frequency. A comparison of this percentage with the reported arterial-to-capillary-to-venous fractional volumes of the lung suggested that the delay time may be the MTT time for blood flowing through the venous network of the lung and the cross-correlation may serve as an in vivo means to partition the MTT of the pulmonary vasculature at its capillaries. These results and an analysis on the deformation of the viscoelastic, pulmonary capillaries indicated that the tracheal pressure, acting primarily through the viscous part of the viscoelasticity, deforms the capillaries to produce the density fluctuation in blood outflowing from the lung.


Enhanced activity of the left precuneus as a predictor of visuospatial dysfunction correlates with disease activity in rheumatoid arthritis.
To identify the potential diagnostic biomarkers of rheumatoid arthritis (RA) and assess the relation between visuospatial dysfunction and disease activity in RA patients using mental rotation task (MRT)-based functional magnetic resonance imaging (fMRI). A total of 27 RA patients (11 in remission, 16 in active) and 27 well-matched controls were enrolled. The visuospatial function of the subjects was measured by MRT. Brain activity data were collected using blood oxygen level dependent fMRI technique under MRT. Disease activity score 28 (DAS28) was used to evaluate the disease severity of RA patients. An analysis of the correlations between abnormal visuospatial-related brain regions, MRT performance, and DAS28 was conducted. RA patients performed worse on MRT than controls. Compared to the control group, RA patients showed enhanced activation in the left precuneus, left superior frontal gyrus and right cingulate gyrus during the rotation task, with left hemisphere dominance. RA patients in active showed enhanced activation in the left precuneus, left middle frontal gyrus and right cingulate gyrus compared to the patients in remission. The left precuneus activation was negatively correlated with MRT accuracy (r = -0.621, p = 0.01) and positively correlated with DAS28 (r = 0.710, p = 0.002), and MRT accuracy was negatively correlated with DAS28 in RA patients (r = -0.702, p = 0.002). Enhanced activation of the left precuneus in RA patients affects visuospatial function and is closely related to disease activity. These changes may provide a valuable diagnostic neuroimaging biomarker of RA.


Closure of Fistula-in-Ano Using a Radial-Emitting Laser Probe: Initial Experience in Lagos, Nigeria.
Fistula-in-ano treatment has remained quite challenging with high failure rates and a potential for damage to the anal sphincteric complex leading to flatal or faecal incontinence. The treatment of fistula-in-ano using the fistula laser closure (FiLaC) as a minimally invasive, sphincter-saving procedure for complex disease has recently been documented. This review aimed to report the outcome of using it at the Lagos University Teaching Hospital. The procedures were performed with a radially emitting laser fibre from Biolitec AG-CeramOptec (Bonn, Germany). The duration of symptoms, type of fistula, duration of the procedures, and postoperative complications were evaluated. Eleven male patients had laser fistula-in-ano closure. The age range was 33-51 years, with a median age of 39 years and an interquartile range (IQR) of 37-47 years. Five patients were noted to have high fistula/e, whereas six had low fistula/e, seven had a single tract each, and three had three tracts each. The duration of surgery ranged, approximately from 3 to 60 min, with a median of 19 min and IQR of 9-33 min. Postoperative pain was mild in all patients and were all discharged as day case. There was no postoperative wound infection, anal incontinence, anal stenosis, and subcutaneous abscess. However, there was a recurrence in two patients. FiLaC has been demonstrated to be a reliable and safe sphincter-saving procedure for treating fistula-in-ano even for complex and high fistulae that is feasible in our subregion.


Incorporation of Flaxseed Flour as a Dietary Source for ALA Increases Bone Density and Strength in Post-Partum Female Rats.
In women, bone mass undergoes changes during pregnancy and the postpartum period, which has a risk for subsequent development of osteoporosis. Thus, the present study aims to evaluate the effects of flaxseed flour in femur quality during post-weaning of dam rats. After weaning, the rats were divided into control (C, n = 7) and experimental (F, n = 7) groups treated with a diet containing 25 g of flaxseed flour in the lactating period and 15 g in the maintenance period. After 51 days post-partum, serum hormone, fatty acids composition, bone compartments, computed tomography, and biomechanical analyses were determined. Food intake, length, body mass, hormone analysis, and total bone compartments showed similar results. For biomechanical and computed tomography analysis and fatty acids composition, the F group showed higher maximum force (+12%, p < 0.05), breaking strength (+25%, p < 0.05), rigidity (+17%, p < 0.0001), and femoral head radiodensity (+15%, p < 0.05) and presented lower total polyunsaturated fatty acids (-17%, p < 0.0001) and arachidonic acid (-44%, p < 0.0001) and higher ALA (+695%, p < 0.0001) and EPA (+160%, p < 0.05). Fatty acids composition of flaxseed flour, as well as its protein profile and calcium content, were able to improve the bone quality, which may be associated with lower serum levels of arachidonic acid and higher EPA, showing an anti-inflammatory profile and increased deposition of organic matrix during the post-weaning period, and may result in prevention of future osteoporosis.


Nanog suppression enhanced the chemosensitivity of human non-small-cell lung cancer cells to Cisplatin and inhibited cell migration.
Lung cancer is the leading cause of cancer-associated death in the world. As one of the leading transcription factors in controlling stemness features, Nanog was shown to promote cancer progression, metastasis, and drug resistance. Considering that, this research was conducted to evaluate the effect of Nanog suppression using specific siRNA on the chemosensitivity of lung cancer cells to Cisplatin through inhibition of cell proliferation, migration, and stemness as well as apoptosis induction. Then, A549 lung cancer cells were transfected with Nanog siRNA and treated with Cisplatin individually or combined. Subsequently, to investigate cell proliferation and apoptosis induction, MTT assay and Annexin V/PI staining were performed, respectively. Also, colony formation assay was carried out to evaluate cell stemness features, and migration ability of A549 cells was followed using a wound-healing assay. Gene expression was quantified via qRT-PCR. The obtained results illustrated that siRNA-mediated Nanog suppression remarkably increased the chemosensitivity of A549 cells to Cisplatin through apoptosis induction. Consistently, Nanog suppression combined with Cisplatin led to upregulation of Caspase-3 apoptotic gene and Bax/Bcl-2 ratio. Besides, Nanog knockdown, individually or combined with Cisplatin, prevented colony formation ability of A549 cells by downregulating Sox2 and CD44 genes. It was also indicated that the combination therapy remarkably downregulated MMP9 expression and subsequently suppressed A549 cell migration. A significant reduction was also observed in c-Myc and PD-L1 gene expression levels. In conclusion, the findings of the current study demonstrated that silencing Nanog combined with Cisplatin could be a potent treatment approach for lung cancer patients.


Development and evaluation of an observational Back-Exposure Sampling Tool (Back-EST) for work-related back injury risk factors.
We developed and evaluated an observational Back-Exposure Sampling Tool. A literature review suggested 53 exposure variables; these were reduced to 20 following field trials. Kappas for agreement beyond chance between six observers assessing exposures in 72 photos ranged from 0.21 to 1.0, with the highest values for posture type, trunk angle, manual materials handling, hands on item, and load weight. Intraclass correlations for agreement between pairs observing 17 workers once per minute for a full-shift were >0.74 for most postural, trunk angle, and manual materials handling variables. In validity testing, the proportions of shifts in flexion/extension and lateral bending observed for 169 full-shifts were compared to inclinometer measurements. Pearson correlations were 0.42 for 45-60 degrees flexion and 0.9 for >60 degrees flexion, but only 0.11-0.19 for lateral bending and trunk flexion less than 45 degrees . When lower flexion angles were collapsed to include trunk extension, correlations increased to >0.5.


Evaluating Costs Associated With Genetic Counseling Among Commercially Insured US Patients With Cancer From 2013 to 2019.
This cohort study describes the prevalence of out-of-pocket costs for cancer-related genetic counseling services in the US.


Epidemiologic trends in renal cell carcinoma in the cytokine and post-cytokine eras: a registry analysis of 28,252 patients.
Advances in the targeted treatment of renal cell cancer (RCC) have shown improvements in survival in clinical trials and have largely replaced cytokine therapies as the standard of care. However it is unclear if these advances have translated to the general RCC population. We present a retrospective study of a large clinical cancer registry that demonstrates statistically significant improvements in survival in cancer patients, but the causes of this improvement are difficult to determine because of many confounders. Before 2004, advanced renal cell cancer (RCC) therapy consisted primarily of cytokines such as interferon and/or interleukin-2. Subsequently, randomized trials of targeted therapies have shown a survival benefit, leading to the approval of several new agents since 2004. Whether the survival benefit seen in highly selected patients accrued to these trials has already translated to the general RCC patient population is unclear. To explore this, a large RCC patient registry was evaluated for changes in outcome between the cytokine (1998-2003) and post-cytokine (2004-2007) eras. Data from the California Cancer Registry (CCR), a population-based cancer surveillance system, was used to retrospectively analyze 28,252 patients with RCC diagnosed between 1998 and 2007. Inter-era differences in clinical variables-including year of diagnosis, histologic characteristics, age, sex, race, stage, nephrectomy status, overall survival (OS), and cause-specific survival (CSS)-were assessed. Univariate and multivariate Cox models were used. Crude 3-year OS (68.2% vs. 74.6%; 2P < .001) and CSS (78.1% vs. 82.3%; 2P < .001) were significantly higher in the post-cytokine era. In multivariate analysis, the 3 strongest predictors for improved survival were localized disease (hazard ratio [HR], 18.1; 95% confidence interval [CI], 16.6-19.6), nephrectomy (HR, 2.87; 95% CI, 2.68-3.08), and clear cell histologic type (HR, 1.33; 95% CI, 1.22-1.44). In this analysis of a large RCC registry, there was an apparent increase in crude OS and CSS in the post-cytokine era compared with the cytokine era. Insufficient follow-up time in the post-cytokine era and a higher proportion of localized disease in that era confound the possibility of benefit derived from targeted therapies. Longer follow-up for patients treated in the post-cytokine era is necessary for a more robust comparison of long-term OS.


A comparison of techniques for measuring intelligibility of dysarthric speech.
Eight techniques for quantifying intelligibility of dysarthric speech were compared. Eight dysarthric speakers who represented a wide range of severity were recorded producing single words and sentences. Thirty-two college students performed the following intelligibility quantification tasks: percentage estimates, rating scale estimates, work and sentence transcriptions, word and sentence completions, and word and sentence multiple-choice tasks. Intelligibility scores for transcriptions were compared to estimates and to other objective tasks with the following results: (1) all measurement techniques, except word completion, rank ordered speakers similarly to transcriptions, (2) mean estimates of intelligibility closely parallel transcription scores, but dispersion of listener estimates was large, and (3) objective tasks form a hierarchy with speakers receiving lowest scores on transcriptions, intermediate scores on completions, and highest scores on multiple-choice tasks. Mean scores for words and sentences were similar. Implications of results for clinical management of dysarthria are discussed.


Dynamics and orientation of glycolipid headgroups by 2H-NMR: gentiobiose.
Deuterium nuclear magnetic resonance has been used to investigate the dynamics and determine the orientation of the headgroup of the glycolipid 1,2-di-O-tetradecyl-3-O-(6-O-beta-D-glucopyranosyl-beta-D-glucopyranosyl )-sn- glycerol (beta-DTDGL), in aqueous multilamellar dispersions. In addition, its anomeric analog, having an alpha glucose-glycerol linkage, was prepared and examined. The lipids were labelled with deuterium at specific positions in the disaccharide moiety. Analysis of the deuterium quadrupolar splittings for the first glucose ring (glycerol-linked) gave segmental order parameters of 0.43 and 0.35 for the beta and alpha isomers, respectively. Both isomers had similar orientations of the sugar ring relative to the bilayer surface, as determined for lipid in the liquid-crystalline phase. 2H-NMR results for the lipid labelled at C-6' are consistent with a single conformation about the C-5'-C-6' bond of the first glucose residue, with a dihedral angle (O-5'-C-5'-C-6'-O-6') of -17 degrees. The results obtained for the second sugar ring suggest that two conformers may be present, which are in slow exchange on the 2H-NMR timescale. Measurements of longitudinal relaxation times, T1z, gave similar values for both sugar moieties in the headgroup, suggesting that the disaccharide does not exhibit the flexibility expected about the 1----6 linkage. Since T1z for 2H in these compounds decreases with increasing temperature and increases with magnetic field strength, the motion(s) dominating relaxation is in the long-correlation-time regime [omega 0 tau c)2 greater than 1). Thus, the gentiobiosyl headgroup undergoes the slowest motion of the glycolipid headgroups studied to date.


Single utility port approach in robot-assisted sleeve segmentectomy for bronchial carcinoid tumor.
Bronchial carcinoid tumors are low-grade malignant and lung-sparing surgery is preferred for the removal of these tumors. We describe a surgical technique of robot-assisted sleeve segmentectomy via single utility port approach with three robotic arms. This operation was performed in an aged patient with decreased pulmonary function, whose carcinoid tumor was located at the origin of the right superior segmental bronchus. A 1.5-cm incision was performed in the eighth intercostal space of the midaxillary line and another 4-cm incision was made in the fifth intercostal space of the anterior axillary line. Postoperative recovery of the patient was smooth without postoperative complications.


Effectiveness of educational interventions on hypertensive patients' self-management behaviours: an umbrella review protocol.
Although different educational interventions have been widely used to manage and treat hypertension, alone or in combination with other interventions, there is a significant variation in their claimed effectiveness. The objective of this umbrella review is to determine the effectiveness of educational interventions, alone or in combination with other interventions, for improving blood pressure control and self-management practices among hypertensive patients. The review question is: Do educational interventions, alone or in combination with other interventions, improve self-management practices among patients with hypertension? We will conduct a review of systematic reviews involving studies that implemented educational interventions, alone or in combination with other interventions, designed to change self-care practices among hypertensive patients who are 18 years and above, regardless of their sex and ethnicity. Following the guidelines set forth in the Preferred Reporting Items for Systematic Review and Meta-Analysis statement, a comprehensive literature search will be conducted from September to December 2023 on six electronic databases: MEDLINE, Embase, PsycINFO, CINAHL, Web of Science Core Collection and Google Scholar. Search terms will be developed using database-specific indexed terms and text words derived from the review aim. We will present the effects of the educational interventions, alone or in combination with other interventions, on hypertension self-management practices. We will report the outcome data with 95% CIs for each study. Relative risk, mean differences or ORs will be used, depending on the measuring indices in each study. Ethical approval is not required as this study will use aggregated data from previously published systematic reviews. However, we have registered the protocol in PROSPERO. We confirm that all methods will be performed following the guidelines of the Declaration of Helsinki. The findings from this study will be disseminated through presentations at academic conferences and publication in peer-reviewed international journals. CRD42022375581.


Phenotype/genotype correlation in a case series of Stargardt's patients identifies novel mutations in the ABCA4 gene.
To investigate phenotypic variability in terms of best-corrected visual acuity (BCVA) in patients with Stargardt disease (STGD) and confirmed ABCA4 mutations. Entire coding region analysis of the ABCA4 gene by direct sequencing of seven patients with clinical findings of STGD seen in the Retina Clinics of Southampton Eye Unit between 2002 and 2011.Phenotypic variables recorded were BCVA, fluorescein angiographic appearance, electrophysiology, and visual fields. All patients had heterozygous amino acid-changing variants (missense mutations) in the ABCA4 gene. A splice sequence change was found in a 30-year-old patient with severly affected vision. Two novel sequence changes were identified: a missense mutation in a mildly affected 44-year-old patient and a frameshift mutation in a severly affected 34-year-old patient. The identified ABCA4 mutations were compatible with the resulting phenotypes in terms of BCVA. Higher BCVAs were recorded in patients with missense mutations. Sequence changes, predicted to have more deleterious effect on protein function, resulted in a more severe phenotype. This case series of STGD patients demonstrates novel genotype/phenotype correlations, which may be useful to counselling of patients. This information may prove useful in selection of candidates for clinical trials in ABCA4 disease.


Anxiety, depression and sleepiness in OSA patients treated with barbed reposition pharyngoplasty: a prospective study.
To evaluate the efficacy of barbed reposition pharyngoplasty (BRP) on sleepiness, anxiety, and depression o adult patients with obstructive sleep apnea (OSA). We performed a prospective multicentric study to assess functional outcomes in 20 OSA patients treated with BRP and compare the results with an observational group of 20 subjects. All recruited subjects performed at baseline and 6-months postoperative follow-up Polysomnography (PSG), daytime sleepiness scoring using the Epworth Sleepiness Scale (ESS), and anxiety and depression evaluation via the Beck Anxiety Inventory (BAI) and the Beck Depression Inventory-II (BDI-II) questionnaires. At follow-up the BRP demonstrated greater improvements in AHI (8.92 ± 2.29 vs. 30.66 ± 2.56; p < 0.001) and ODI (7.65 ± 2.39 vs. 24.55 ± 3.20; p < 0.001) than control at intergroup analysis. Surgical group reported significant data in daytime sleepiness (5.15 ± 1.19 vs. 13.15 ± 1.35; p < 0.001), anxiety (12.65 ± 3.11 vs. 24.2 ± 2.37; p < 0.001), and depression domains (5.85 ± 1.19 vs. 17.55 ± 3.24; p < 0.001). AHI, ODI, and advanced age have been shown to multiple regression as independent predictors of treatment response for mood domains (p < 0.001; p = 0.02; p = 0.041, respectively). Patients with OSA may benefit from palate surgery, reducing not only the apnea and hypopnea index, daytime sleepiness but also associated mood comorbidities. However, further studies are needed to confirm our preliminary results to validate the evidence to date reported.


Effect of nutritional support in children with spastic quadriplegia.
Malnutrition is a common problem in patients with cerebral palsy. We evaluated the effect of nutritional support on clinical findings in children with spastic quadriplegia. Feeding history, numbers of lower respiratory tract infections, and gastrointestinal and neurologic findings were evaluated via questionnaire. Weight, height, head circumference, midarm circumference, and triceps skinfold thickness were measured. Height for age, weight for age, weight for height, body mass index, and weight and height z-scores were calculated. Clinical findings and anthropometric parameters were re-evaluated after nutritional support for 6 months. Forty-five patients were enrolled. No difference was evident between the first and the last height z-scores of 31 patients who completed the follow-up. Weight, height, weight z-scores, weight for age, weight for height, body mass index, midarm circumference, and triceps skinfold thickness exhibited improvement. Moreover, a significant decrease in number of infections was evident. Frequency of seizures and Gross Motor Function Classification System status did not change. Constipation decreased significantly. Nutritional therapy revealed improvements in some anthropometric findings and a decrease in number of infections. Although there was no difference regarding motor development or seizure frequency, further studies with a longer follow-up are required.


Molecular alterations in prostate cancer as diagnostic, prognostic, and therapeutic targets.
Prostatic adenocarcinoma is extremely common in Western nations, representing the second leading cause of cancer death in American men. The recent application of increasingly sophisticated molecular approaches to the study of prostate cancer in this "postgenomic" era has resulted in a rapid increase in the identification of somatic genome alterations and germline heritable risk factors in this disease. These findings are leading to a new understanding of the pathogenesis of prostate cancer and to the generation of new targets for diagnosis, prognosis, and prediction of therapeutic response. Although we are still in the very early phase of clinical development, some of the molecular alterations identified in prostate cancer are being translated into clinical practice. The purpose of this review is to update the practicing surgical pathologist, and residents-in-training in pathology, regarding recent findings in the molecular pathobiology of prostate cancer. We will highlight some of the somatic molecular alterations associated with prostate cancer development and progression, with a focus on newer discoveries. In addition, recent studies in which new molecular diagnostic approaches have been applied in the clinic will be discussed.


Extracellular Vesicles Released From Articular Chondrocytes Play a Major Role in Cell-Cell Communication.
The purpose of this investigation was to determine the role of extracellular vesicles (EVs), released from articular chondrocytes in a physiological or pathological state, in cell-cell communication with other articular chondrocytes or chondrocyte precursor cells. The conditioned medium from interleukin-1β (IL-1β)-treated human articular chondrocytes stimulated catabolic events and inhibited type II collagen expression in articular chondrocytes to a much greater degree than medium from IL-1β-treated chondrocytes after complete removal of EVs. The vehicle-treated and IL-1β-treated human articular chondrocytes released EVs of similar size; however, the number of EVs released by IL-1β-treated chondrocytes was markedly higher than the number of EVs released from the vehicle-treated cells. Furthermore, our findings demonstrate that similar to medium from IL-1β-treated chondrocytes containing EVs, EVs isolated from medium of IL-1β-treated chondrocytes stimulated catabolic events in articular chondrocytes, whereas EVs isolated from the medium of vehicle-treated chondrocytes inhibited catabolic events and increased messenger RNA levels of aggrecan and type II collagen in IL-1β-treated chondrocytes. Furthermore, the medium containing EVs from vehicle-treated articular chondrocytes or EVs isolated from this medium stimulated chondrogenesis of C3H10T1/2 cells, whereas medium containing EVs from IL-1β-treated chondrocytes or EVs isolated from this medium inhibited chondrogenesis. Our findings suggest that EVs released by articular chondrocytes play a key role in the communication between joint cells and ultimately in joint homeostasis, maintenance, pathology, and repair. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:731-739, 2020.


Impaired visual cortical plasticity in schizophrenia.
Impaired cortical plasticity may be part of the core pathophysiology of schizophrenia (SZ). Long-term potentiation is a form of neuroplasticity that has been recently demonstrated in humans by showing that repetitive visual stimulation produces lasting enhancement of visual evoked potentials (VEP). Using this paradigm, we examined whether visual cortical plasticity is impaired in SZ. Electroencephalographic data were recorded from 19 SZ and 22 healthy control (HC) subjects during a visual long-term potentiation paradigm. Visual evoked potentials were elicited by standard visual stimuli (∼.83 Hz, 2-minute blocks) at baseline and at 2, 4, and 20 minutes following exposure to visual high-frequency stimulation (HFS) (∼8.8 Hz, 2 minutes) designed to induce VEP potentiation. To ensure attentiveness during VEP assessments, subjects responded with a button press to infrequent (10%) target stimuli. Visual evoked potentials were subjected to principal components analysis. Two negative-voltage components prominent over occipital-parietal electrode sites were evident at 92 msec (C1) and at 146 msec (N1b). Changes in C1 and N1b component scores from baseline to the post-HFS assessments were compared between groups. High-frequency stimulation produced sustained potentiation of visual C1 and N1b in HCs but not in SZs. The HCs and SZs had comparable HFS-driven electroencephalographic visual steady state responses. However, greater visual steady state responses to the HFS predicted greater N1b potentiation in HCs but not in SZs. Schizophrenia patients with greater N1b potentiation decreased their reaction times to target stimuli. Visual cortical plasticity is impaired in schizophrenia, consistent with hypothesized deficits in N-methyl-D-aspartate receptor function.


Azilsartan compared to ACE inhibitors in anti-hypertensive therapy: one-year outcomes of the observational EARLY registry.
Azilsartan medoxomil (AZL-M), has been demonstrated to be more effective than the other sartans currently in use; however, there is insufficient information available comparing it with ACE-inhibitors. Therefore, we aimed to compare the efficacy, safety, and tolerability of AZL-M with that of ACE-inhibitors in a real life clinical setting. The EARLY registry is a prospective, observational, national, multicentre registry with a follow-up period of 12 months. There were two principal objectives: 1) documentation of the achievement of target BP values set according to recent national and international guidelines, and 2) description of the safety profile of AZL-M. A total of 3 849 patients with essential arterial hypertension were recruited from primary care offices in Germany. Patients who initiated monotherapy at baseline comprising either AZL-M or an ACE-inhibitor were included at a ratio of seven to three. Results demonstrated that a blood pressure target of <140/90 mmHg was achieved by a significantly greater proportion of patients in the AZL-M group (61.1 %) compared with the ACE-inhibitor group (56.4 %; p < 0.05; OR, 1.21; 95 % CI, 1.03-1.42), with this finding maintained after adjusting for differences in baseline characteristics. AZL-M appeared to have an equivalent safety profile to the ACE-inhibitors, with a similar incidence of adverse events in the two patient groups (p = 0.73). These data add to the results of previous randomized controlled clinical trials suggesting that, compared with other agents that target the renin-angiotensin system, AZL-M provides statistically significant albeit small improvements in blood pressure control.


Amphetamine radioimmunoassay: chemical tuning of specificity.
Four [125I]iodine labelled amphetamine derivatives were synthesised. Three of these proved useful in the development of radioimmunoassays for amphetamine. The assays, all using the same antiserum, had widely differing specificities for compounds closely related to amphetamine. Thus, chemical modification of the radiotracer was used to tune radioimmunoassay specificity without recourse to the production of different antisera.


Comparative study of BacT/Alert FAN bottles and standard BacT/Alert bottles.
A total of 5,230 paired blood cultures were studied. One sample was divided between aerobic and anaerobic BacT/Alert standard bottles, and the other divided between aerobic and anaerobic BacT/Alert FAN bottles. There were 44 occasions where Staphylococcus aureus was recovered only from the FAN bottles, compared to six where only the standard bottles were positive (p < 0.001), and 21 occasions where Escherichia coli was isolated only from FAN bottles, compared to eight occasions where only the standard bottles were positive for this organism (p < 0.05). In 21 of 28 cases reviewed where S. aureus was isolated from FAN bottles only the patient had been receiving anti-staphylococcal antibiotics. However, only 2 of 30 cases where Gram-negative bacilli were isolated from FAN bottles had documented recent appropriate antibiotic therapy. Patients in whom FAN bottles are more likely to recover organisms cannot be selected on the basis of documented antibiotic treatment.


Loss of dsRNA-based gene silencing in Entamoeba histolytica: implications for approaches to genetic analysis.
The ability to regulate gene expression in the protozoan parasite Entamoeba histolytica is critical in determining gene function. We previously published that expression of dsRNA specific to E. histolytica serine threonine isoleucine rich protein (EhSTIRP) resulted in reduction of gene expression [MacFarlane, R.C., Singh, U., 2007. Identification of an Entamoeba histolytica serine, threonine, isoleucine, rich protein with roles in adhesion and cytotoxicity. Eukaryotic Cell 6, 2139-2146]. However, after approximately one year of continuous drug selection, the expression of EhSTIRP reverted to wild-type levels. We confirmed that the parasites (i) contained the appropriate dsRNA plasmid, (ii) were not contaminated with other plasmids, (iii) the drug selectable marker was functional, and (iv) sequenced the dsRNA portion of the construct. This work suggests that in E. histolytica long term cultivation of parasites expressing dsRNA can lead to the loss of dsRNA based silencing through the selection of "RNAi" negative parasites. Thus, users of the dsRNA silencing approach should proceed with caution and regularly confirm gene down regulation. The development and use of constructs for inducible expression of dsRNA may help alleviate this potential problem.


Myeloid-derived suppressor cells in patients with myeloproliferative neoplasm.
Although BCR-ABL negative myeloproliferative neoplasms (MPN)--and especially myelofibrosis (MF)--are recognized to be associated with autoimmune phenomena, immune derangements in MPN have been much less studied. Myeloid-derived suppressor cells (MDSC) are one type of important immune modulator cell. Therefore, we studied MDSCs in MPN disease. MDSCs were studied in two cohorts: the first cohort was 55 patients including 16 primary myelofibrosis (PMF), 7 post-polycythemia vera (PV)-MF, 2 post-essential thrombocythemia (ET)-MF, 11 ET, 17 PV, 2 undefined MPN disorder, and 23 normal controls; the second cohort included 38 patients: 17 ET, 7 PMF, 3 ET-MF, 2 PV-MF, 9 PV patients, and 20 normal volunteers. The second cohort was studied using freshly collected specimens and a comparable age group as controls. CD11b(+), CD14(-), and CD33(+) cells were defined as MDSCs in both cohorts by flow cytometry. Since there are no differences in MDSC levels among different MPN categories, they were grouped as MPNs. The results showed that MDSCs were significantly elevated in MPNs compared with controls in both cohorts. We also performed RT-PCR and found that MPN patients have significantly elevated arginase-1 mRNA compared with controls, and sorted MDSCs were found to have suppressor T cell activity in MPNs, substantiating the hypothesis that levels of MDSCs are, in fact, deranged in MPNs. MDSC levels were not correlated with JAK2 status, white blood cells, Hb levels, platelet counts, splenomegaly, or the degree of bone marrow fibrosis (in MF). Further studies in immune therapy involving MDSC inhibitors or differentiation may be developed to treat MPN disease.


Paraquat-induced cytoskeletal injury in cultured cells.
Although the redox cycling of paraquat (PQ) and the resultant "activated oxygen" generation are important in toxicity development, the intracellular events leading to cell injury remain unclear. To understand the mechanism of PQ-induced cell injury, we have studied the effects of PQ on DNA synthesis, cell proliferation, the cytoskeletal organization, particularly microtubules (MT) and microfilaments (MF), and the synthesis and composition of cytoskeletal proteins in mouse 3T3 cells. PQ treatment produced a dose-dependent inhibition of DNA synthesis and cell growth. Exposure of cells to PQ (313 microM, 20 hr) resulted in MT aggregation and bundling as well as MF redistribution in the perinuclear area as revealed by fluorescence microscopy. Although this PQ dose inhibited DNA synthesis by 95%, it caused only a 22% decrease in protein synthesis of the cytoskeletal fraction. Higher doses of PQ (1250 microM, 20 hr) caused (a) dramatic thinning out and loss of MT and (b) marked loss of MF cables and the appearance of numerous pine needle-like structures much finer and shorter than normal MF. Under these conditions, the synthesis of cytoskeletal proteins was decreased by about 83%. Further analysis of the cytoskeletal fraction from PQ-treated cells by sodium dodecyl sulfate gel electrophoresis showed (a) that tubulin was greatly diminished, in agreement with microscopic observations; (b) that two new protein bands appeared; and (c) another protein band which was also reduced considerably. These results indicate that the PQ-induced dose-dependent cytoskeletal injury may be important to the mechanism of cytotoxicity of this herbicide.


Pharmacist-led medication education in cancer pain control: a multicentre randomized controlled study in Guangzhou, China.
To evaluate clinical pharmacist-led pain-medication education in patients with cancer. A controlled study was conducted prospectively at six tertiary hospitals in China. In-patients with cancer were randomized to receive conventional treatment plus medication education or no education (controls). Education consisted of access to information booklets and eight 30-min face-to-face counselling sessions given by clinical pharmacists over 4 weeks. Patients completed pain- and analgesic-knowledge assessments and a Brief Pain Inventory, pre- and post-study. A total of 123 and 114 patients in the education and control groups, respectively, completed follow-up. At the end of the study, patient knowledge regarding cancer pain and pain control was significantly increased in both groups; pain and analgesic knowledge scores were significantly higher in the education group compared with controls. In the control group, the increase in total pain-related knowledge was significantly greater in analgesic-naïve patients compared with those who were using/had used analgesics. Pain intensity scores and pain interference of daily activities were significantly reduced in the education group compared with controls. Clinical pharmacist-led medication education resulted in improved pain control in patients with cancer.


Peripheral benzodiazepine receptors and mitochondrial function.
For over 20 years, numerous investigations have focused on elucidating the function of the peripheral benzodiazepine receptor (PBR). This relatively small protein (18kDa) arouses great interest because of its association with numerous biological functions, including the regulation of cellular proliferation, immunomodulation, porphyrin transport and heme biosynthesis, anion transport, regulation of steroidogenesis and apoptosis. Although the receptor was first identified as a binding site for the benzodiazepine, diazepam, in peripheral organ systems, the PBR was subsequently found to be distinct from the central benzodiazepine receptor (CBR) in terms of its pharmacological profile, structure, subcellular localization, tissue distribution and physiological functions. The PBR is widely expressed throughout the body, with high densities found in steroid-producing tissues. In contrast, its expression in the CNS is restricted to ependymal cells and glia. The benzodiazepine Ro5-4864 and the isoquinoline carboxamide PK11195 exhibit nanomolar affinity for the PBR, and are the archtypic pharmacological tools for characterizing the receptor and its function. Primary among these functions are its regulation of steroidogenesis and apoptosis, which reflect its mitochondrial localization and involvement in oxidative processes. This review will evaluate the basic pharmacology and molecular biology of the PBR, and highlight its role in regulating mitochondrial function, the mitochondrial transmembrane potential and its sensitivity to reactive oxygen species (ROS), and neurosteroid synthesis, processes relevant to the pathogenesis of a number of neurological and neuropsychiatric disorders.


Establishing clinical end points of respiratory function in large animals for clinical translation.
Respiratory dysfunction due progressive weakness of the respiratory muscles, particularly the diaphragm, is a major cause of death in the neuromuscular disease (NMD) X-linked myotubular myopathy (XLMTM). Methods of respiratory assessment in patients are often difficult, especially in those who are mechanically ventilated. The naturally occuring XLMTM dog model exhibits a phenotype similar to that in patients and can be used to determine quantitative descriptions of dysfunction as clinical endpoints for treatment and the development of new therapies. In experiments using respiratory impedance plethysmography (RIP), XLMTM dogs challenged with the respiratory stimulant doxapram displayed significant changes indicative of diaphragmatic weakness.


Antiviral and antibacterial activity of sodium alginate/poly(diallyldimethylammonium chloride) polyelectrolyte film for packaging applications.
Pathogen agents, such as bacteria and virus, can contaminate plastic surfaces, particularly those used in food packaging. This study proposed to prepare a polyelectrolyte film with antiviral and antibacterial activity based on sodium alginate (SA) and poly(diallyldimethylammonium chloride) (PDADMAC), a cationic polymer with sanitizing properties. In addition, the physicochemical properties of the polyelectrolyte films were also evaluated. The polyelectrolyte films showed continuous, compact, and crack-free structures. The FTIR analysis confirmed the ionic interaction between SA and PDADMAC. Adding PDADMAC significantly affected the mechanical properties of the films (p < 0.05), increasing the maximum tensile strength (from 8.66 ± 1.55 MPa to 18.1 ± 1.77 MPa). However, polyelectrolyte films showed higher water vapor permeability values due to the strong hydrophilicity of PDADMAC, representing a 43 % average increase compared with the control film. Also, thermal stability improved with the incorporation of PDADMAC. The selected polyelectrolyte film inactivated 99.8 % of SARS-CoV-2 after 1 min in direct contact with the virus, in addition to having an inhibitory effect against Staphylococcus aureus and Escherichia coli bacteria. Therefore, this study demonstrated the efficacy of using PDADMAC in the preparation of polyelectrolyte sodium alginate-based films with improvements in physicochemical properties and especially with antiviral activity against SARS-CoV-2.


Evaluation of the body adiposity index against dual-energy X-ray absorptiometry for assessing body composition in children and adolescents.
It is important to clarify the association of lean and fat mass between children and adolescents considering the rising prevalence of overweight and obesity in this age group. The aim of this study was to verify the association between the body adiposity index (BAI) and dual-energy X-ray absorptiometry (DXA) methods for analyzing body composition, as well as analyzing the validity of BAI to verify the percentage of fat in children and adolescents. The sample was composed of 106 children and adolescents, 44 females (age: 11.5 ± 1.8 years) and 62 evils (13.6 ± 2.6 years). The body fat (%F) was measured using DXA and the doubly indirect BAI body fat estimation technique. The BAI and DXA estimates of %F were strongly correlated (boys: r = .71, P < .0001; girls: r = .72, P < .0001). The linear regression analyses showed that BAI is significant to estimate the %F in total sample (P < .0001). For boys, the %F analyzes performed by BAI and DXA did not show any differences when compared (P = .2). In addition, BAI pointed out a significant proportion bias for both sexes (P < .0001), which suggests its inefficiency in the analysis of %F. BAI and DXA correlate; however, there is low reliability and a high proportion bias for the analysis of %F by BAI.


Effectiveness of massage on flexibility of hamstring muscle and agility of female players: An experimental randomized controlled trial.
This study aimeded to examine acute and late effects of five consecutive sessions of Swedish massage on hamstring flexibility and agility of players. Arandom sample of 34 female players having bilateral tight hamstrings [passive straight leg raise ≤70° and active knee extension test ≥ 30°] was randomly allocated to two equal groups. Study design involved 7 minute massage given on each posterior thigh for 5 continuous days; followed by 5 days of no massage. Experimental group received classical Swedish massage whereas control group received only superficial stroking. Outcome measures were Passive straight leg raise [PSLR], Active knee extension test [AKET], Passive knee extension test [PKET], Back saver sit and reach test [BSSR] for flexibility and 5-0-5 change of direction test for agility measured pre and post intervention on each days of massage and also on 10th day. Two way ANOVA with post hoc t-test was the tool of statistical analysis with significance level 0.05. Significant [p ≤ 0.05] post intervention increase in all parameters of flexibility was observed each day in experimental group within PSLR (8%-12% ↑), AKET (10%24% ↓) and PKET (12%-30% ↓) and highly significant (p ≤ 0.001) increase on 5th and 10th day in BSSR (4%-21% ↑) for both legs. Pre and post intervention values for control group were not significantly different. No significant changes were observed in agility performance of both groups. Swedish massage of posterior thigh appears to acutely increase flexibility of hamstrings in female athletes, which persisted for 5 days even after cessation of massage.


Electrophysiologic identification and evaluation of stylohyoid and posterior digastricus muscle complex.
To identify the function of stylohyoid and posterior digastricus (STH-PD) muscle complex by the EMG techniques. Unaffected sides of the faces of 30 patients with facial paralysis or hemifacial spasm were investigated. A concentric needle electrode was inserted to the STH-PD muscle complex and another concentric needle electrode was inserted to the orbicularis oris (OO) muscle. Simultaneous recording were obtained from two muscles using electrical stimulation (ES) (in 25 cases) and magnetic coil stimulation (MS) (in 15 cases); and both in 10 cases. Afterwards, the function of STH-PD was studied such as whistling, lip pursing, swallowing, jaw opening and closing. (1) The motor latency of compound muscle action potential (CMAP) of the STH-PD muscle was shorter than that of OO. (2) When the facial nerve was stimulated more distally than the stylomastoid foramen, the CMAP elicited from the STH-PD muscle complex immediately disappeared. (3) Ipsilateral MS was able to elicit the motor evoked potential (MEP) from STH-PD either at intracranially (half of cases) or at the extracranially. While OO muscle was always stimulated intracranially by MS. (4) The STH-PD muscle complex could not be basically recruited by the mimicry except lip pursing. The main recruitment were provided by swallowing and jaw opening. Cortical MS were facilitated during swallowing (5) Late reflex responses appeared in the STH-PD muscle complex during infraorbital-trigeminal and facial nerve ES. The STH-PD muscle complex is identified electrophysiologically. Although it is innervated by the facial nerve, its functions are mainly related with jaw opening and oropharyngeal swallowing. However, it is activated by the lip pursing.


Monitoring CAR T cell generation with a CD8-targeted lentiviral vector by single-cell transcriptomics.
Quantifying gene expression in individual cells can substantially improve our understanding about complex genetically engineered cell products such as chimeric antigen receptor (CAR) T cells. Here we designed a single-cell RNA sequencing (scRNA-seq) approach to monitor the delivery of a CD19-CAR gene via lentiviral vectors (LVs), i.e., the conventional vesicular stomatitis virus (VSV)-LV and the CD8-targeted CD8-LV. LV-exposed human donor peripheral blood mononuclear cells (PBMCs) were evaluated for a panel of 400 immune response-related genes including LV-specific probes. The resulting data revealed a trimodal expression for the CAR and CD8A, demanding a careful distribution-based identification of CAR T cells and CD8+ lymphocytes in scRNA-seq analysis. The fraction of T cells expressing high CAR levels was in concordance with flow cytometry results. More than 97% of the cells hit by CD8-LV expressed the CD8A gene. Remarkably, the majority of the potential off-target cells were in fact on-target cells, resulting in a target cell selectivity of more than 99%. Beyond that, differential gene expression analysis revealed the upregulation of restriction factors in CAR-negative cells, thus explaining their protection from CAR gene transfer. In summary, we provide a workflow and subsetting approach for scRNA-seq enabling reliable distinction between transduced and untransduced cells during CAR T cell generation.


Is bipolar disorder specifically associated with aggression?
Several studies have suggested that bipolar disorder (BP) in adults is associated with aggressive behaviors. However, most studies have included only inpatients and have not taken into consideration possible confounding factors. The goal of the present study was to compare the prevalence of aggression in subjects with BP compared to subjects with other, non-BP psychopathology and healthy controls. Subjects with bipolar I disorder (BP-I) and bipolar II disorder (BP-II) (n = 255), non-BP psychopathology (n = 85), and healthy controls (n = 84) were recruited. Aggression was measured using the Aggression Questionnaire (AQ). Group comparisons were adjusted for demographic and clinical differences (e.g., comorbid disorders) and multiple comparisons. The effects of the subtype of BP, current versus past episode, polarity of current episode, psychosis, the presence of irritable mania/hypomania only, and pharmacological treatment were examined. Subjects with BP showed significantly higher total and subscale AQ scores (raw and T-scores) when compared to subjects with non-BP psychopathology and healthy controls. Exclusion of subjects with current mood episodes and those with common comorbid disorders yielded similar results. There were no effects of BP subtype, polarity of the current episode, irritable manic/hypomanic episodes only, or current use of pharmacological treatments. Independent of the severity of BP and polarity of the episode, those in a current mood episode showed significantly higher AQ scores than those not in a current mood episode. Subjects with current psychosis showed significantly higher total AQ score, hostility, and anger than those without current psychosis. Subjects with BP display greater rates of anger and aggressive behaviors, especially during acute and psychotic episodes. Early identification and management of these behaviors is warranted.


Pseudomonas maltophilia bacteremia associated with a prolapsed mitral valve.
A 53-year-old man had had recurrent episodes of transient visual loss, malaise and a heart murmur. Blood cultures repeatedly grew Pseudomonas maltophilia, a frequent opportunistic pathogen, and echocardiogram documented mitral-valve prolapse. The risk of bacterial endocarditis is stressed.