MTA2 enhances colony formation and tumor growth of gastric cancer cells through IL-11.
We have preliminarily reported MTA2 expression in gastric cancer and its biological functions by using knockdown cell models, while the molecular mechanisms of MTA2 in regulating malignant behaviors are still unclear. MTA2 overexpression models were established by transfection assay in gastric cancer cells BGC-823 and MKN28. Cell proliferation assay, colony formation in soft agar, wound-healing assay and transwell migration assay were performed with MTA2 overexpression and negative control (NC) cells. Subcutaneous xenografts and pulmonary metastasis models by BGC-823/MTA2 and BGC-823/NC cells were used to observe the capacity of growth and metastasis in vivo. Differential gene expression in MTA2 knockdown and overexpression cells was analyzed by microarrays. IL-11, which demonstrated as differential expression in microarray, was detected by real-time PCR, western blot, ELISA and immunohistochemistry staining. Recombinant human IL-11 (rhIL-11) was administrated in cell proliferation and colony formation as rescue assay. The numbers of colonies in soft agar were significantly more in BGC-823/MTA2 and MKN28/MTA2 cells, comparing with those in their NC cells. Capabilities of cell proliferation, wound-healing and cell migration were not significantly changed in MTA2 overexpression cells. The sizes of subcutaneous xenografts and pulmonary metastases of BGC-832/MTA2 cells were significantly larger than those in BGC-823/NC group. Differential expression of IL-11 was identified by genome expression microarray both in MTA2 knockdown and overexpression cells. IL-11 expression was elevated in BGC-823/MTA2 cells, whereas reduced in SGC-7901/shMTA2 cells. Administration of rhIL-11 recovered colony formation capacity of SGC-7901/shMTA2 cells. MTA2 overexpression enhances colony formation and tumor growth of gastric cancer cells, but not plays important role in cancer cell migration and metastasis. IL-11 is one of the downstream effectors of MTA2 in regulating gastric cancer cells growth.


Phase I evaluation of thio-TEPA in combination with cisplatin for advanced gynecologic malignancies.
Thirty-five patients with advanced gynecologic malignancies were entered into a phase I study evaluating thio-TEPA in combination with cisplatin (50 mg/m2) intravenously every 4 weeks. Thirty-four patients were evaluable for toxicity and response, and one was evaluable for toxicity only. Median age was 53 years (range 28-72), and performance status less than or equal to 2. Prior treatment included chemotherapy in 21 patients, radiation in 15, hormonal therapy in 3, and immunotherapy in 1. Thio-TEPA was given to three or more patients at each of the following dose levels: 15, 20, 25, 30, 40, 50, and 60 mg/m2. Thio-TEPA's primary toxicity was myelosuppression; at 50 mg/m2, grade 3 or 4 granulocytopenia occurred in 13 of 17 cycles, and grade 3 or 4 thrombocytopenia occurred in 8 of 17 cycles. The maximum tolerated dose (MTD) of thio-TEPA was 40 mg/m2; in 35 cycles at this dose, grade 3 or 4 granulocytopenia occurred in 19, and grade 3 or 4 thrombocytopenia occurred in 10 cycles; median granulocyte nadir was 1100 (range 110 to 3600) and median platelet nadir was 90,000 (range 10,000 to 289,000). Fifteen patients received three or more cycles at one dose level; cumulative myelosuppression was observed in 11. Two cases of partial alopecia occurred at 40 and 60 mg/m2 thio-TEPA. Responses were as follows: complete response, 5; partial response, 7; stable disease, 14; progressive disease, 8. In 16 patients with ovarian cancer (15 of whom had previously received cisplatin), there were 4 complete responses and 5 partial responses (overall response rate of 56%). The thio-TEPA dose recommended in combination with cisplatin (50 mg/m2) in phase II trials is 40 mg/m2. Cumulative hematologic toxicity may occur with this regimen.


Association of prostate cancer susceptibility variant (MSMB) rs10993994 with risk of spermatogenic failure.
β-Microseminoprotein (MSMB) is one of the most abundant proteins in human seminal plasma. It has been identified that MSMB increased significantly in oligoasthenoteratozoospermic patients compared with fertile controls. We hypothesized that the functional polymorphism (rs10993994) of MSMB gene could be a risk factor for spermatogenic failure. For this study, 338 patients with idiopathic oligozoospermia or azoospermia and 382 fertile controls were recruited from an infertility clinic. Semen analysis was performed by computer-assisted semen analysis system. The functional polymorphism of MSMB gene was genotyped using TaqMan method. Sixty three seminal plasma samples were used to test the expression of MSMB by enzyme-linked immunosorbent assay (ELISA). The TT genotype and T allele were associated with an increased risk of idiopathic infertility with azoospermia (TT genotype: OR, 1.75; 95% CI, 1.03-2.95; T allele: OR, 1.34; 95% CI, 1.03-1.75). However, no differences were found in risk for the TT genotype or T allele among men with oligozoospermia. In addition, idiopathic infertile males have significantly higher MSMB expression levels than fertile controls. We present the first epidemiologic evidence supporting the involvement of common genetic polymorphism in MSMB gene in spermatogenic failure. These results suggest that men carrying the variant have an increased risk of spermatogenic failure associated with male infertility. Further studies are needed to confirm the roles of the polymorphism in idiopathic azoospermia and investigate the biological mechanism of elevated MSMB expression in infertile males.


Root exudates drive the soil-borne legacy of aboveground pathogen infection.
Plants are capable of building up beneficial rhizosphere communities as is evidenced by disease-suppressive soils. However, it is not known how and why soil bacterial communities are impacted by plant exposure to foliar pathogens and if such responses might improve plant performance in the presence of the pathogen. Here, we conditioned soil by growing multiple generations (five) of Arabidopsis thaliana inoculated aboveground with Pseudomonas syringae pv tomato (Pst) in the same soil. We then examined rhizosphere communities and plant performance in a subsequent generation (sixth) grown in pathogen-conditioned versus control-conditioned soil. Moreover, we assessed the role of altered root exudation profiles in shaping the root microbiome of infected plants. Plants grown in conditioned soil showed increased levels of jasmonic acid and improved disease resistance. Illumina Miseq 16S rRNA gene tag sequencing revealed that both rhizosphere and bulk soil bacterial communities were altered by Pst infection. Infected plants exhibited significantly higher exudation of amino acids, nucleotides, and long-chain organic acids (LCOAs) (C > 6) and lower exudation levels for sugars, alcohols, and short-chain organic acids (SCOAs) (C ≤ 6). Interestingly, addition of exogenous amino acids and LCOA also elicited a disease-suppressive response. Collectively, our data suggest that plants can recruit beneficial rhizosphere communities via modification of plant exudation patterns in response to exposure to aboveground pathogens to the benefit of subsequent plant generations.


Actual status of patient information sharing among healthcare delivery facilities: a survey by the third subcommittee, committee on academic research, the Japanese society of hospital pharmacists.
Information sharing among medical professionals is important for providing quality medical care. The purpose of the present study was to elucidate the actual status of information sharing between hospitals and other healthcare delivery facilities by surveying information sharing among the pharmaceutical departments of Japanese hospitals in 2020 conducted by the Japanese Society of Hospital Pharmacists. Responses were received from 3612 (43.6%) of the 8278 target medical institutions between May 2020 and August 2020. The proportions of hospitals that shared information with community pharmacies, other hospitals, and long-term nursing homes were 40.6%, 36.4%, and 27.3%, respectively. While tracing reports were the most common tool used by hospitals for information sharing with community pharmacies (54.3%), drug summaries were used for sharing information with other hospitals and long-term nursing homes (77.4% and 78.0%, respectively). The proportion of hospitals sharing information with community pharmacies and other hospitals showed a tendency to increase as the number of hospital beds increased. No relationship could be established between the number of hospital beds and the proportion of hospitals sharing information with long-term nursing homes. Information between hospitals and community pharmacies was shared primarily using tracing reports, whereas information between hospitals and other hospitals and long-term nursing homes was primarily shared via drug summaries.


The mining chemical Polydadmac is cytotoxic but does not interfere with Cu-induced toxicity in Atlantic salmon hepatocytes.
To speed up sedimentation of suspended solids the mining industry often uses flocculent chemicals. In this work we evaluated the cytotoxic and mechanistic effects of Polydadmac, and its basic component Dadmac, on fish cells. Dose-response effects, temperature-dependent effects and impact of Dadmac and Polydadmac on Cu toxicity were studied in Atlantic salmon hepatocytes. We used the xCELLigence system and the MTT test for cytotoxicity assessments, and real-time RT-qPCR to evaluate molecular effects. The results showed a cytotoxic response for Polydadmac but not for Dadmac. Elevated levels of Cu were cytotoxic. Moderately cytotoxic concentrations of Cu (100-1000 μM) induced significant responses on the transcription of a number of genes in the cells, i.e. cuznsod (sod1), cat, mnsod (sod2), nfe2l2, hmox1, mta, casp3b, casp6, bclx, cyp1a, ccs, atp7a, app, mmp13, esr1, ppara, fads2 and ptgs2. A factorial PLS regression model for mnsod transcription showed a synergistic effect between Dadmac and Cu exposure in the cells, indicating an interaction effect between Dadmac and Cu on mitochondrial ROS scavenging. No interaction effects were seen for Polydadmac on Cu toxicity. In conclusion, Polydadmac is cytotoxic at elevated concentrations but appears to have low ability to interfere with Cu toxicity in Atlantic salmon liver cells.


Staphylococcus lugdunensis: an important cause of endocarditis. A case report.
Staphylococcus lugdunensis endocarditis was diagnosed in a 55-year-old woman maintained on chronic haemodialysis. S. lugdunensis was isolated from blood and a Gore-Tex graft fistula at admission, and vegetations with Gram-positive cocci were found on the mitral cusps at autopsy.


Self-reported sleep in relation to risk of dementia a quarter of a century later at age 90+: The 90+ Study.
To examine sex-specific associations of sleep duration and napping self-reported at mean age of 69 years (range: 53-81) with risk of incident dementia 24 years later at age 90 +. Analytic sample included individuals from a population-based study who reported sleep and napping once in the 1980s and 24 years later (range: 16-38) joined The 90+ Study and were evaluated in-person. Those without dementia at baseline of The 90+ Study were prospectively followed. Hazard ratios [HR] and 95% confidence intervals [CI] of dementia risk were estimated by Cox regression. Of 574 participants 71% were women, mean age at start of dementia follow-up with The 90+ Study was 93 years (range: 90-102). After 3.3 years (range: 0.4-13.8) of follow-up 47% developed dementia. Higher risk of dementia at age 90+ was seen in women with <6 hours of self-reported sleep per night (adjusted HR = 2.00; 95% CI = 1.15-3.50; p = .01) compared with 8 hours. Lower risk of dementia at 90+ was seen in men with short-to-moderate (<60 minutes) self-reported naps compared with no naps (HR = 0.33; 95% CI = 0.18-0.63; p < .01). Sleep and nap 24 years earlier are important risk factors for dementia after age 90.


Long-Term Outcome of ICD Therapy in Patients With Noncompaction Cardiomyopathy Compared With DCM and HCM.
Implantable cardioverter-defibrillators (ICDs) are frequently used for primary and secondary prevention in patients with cardiomyopathies due to different etiologies. However, long-term outcome studies in patients with noncompaction cardiomyopathy (NCCM) are scarce. This study summarizes the long-term outcome of ICD therapy in patients with NCCM compared with those with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM). Prospective data from our single-center ICD registry were used to analyze the ICD interventions and survival in patients with NCCM (n = 68) compared with patients with DCM (n = 458) and patients with HCM (n = 158) from January 2005 to January 2018. This NCCM population with an ICD for primary prevention comprised 56 (82%) patients with a median age of 43 years and 52% males, compared with 85% in patients with DCM and 79% in patients with HCM (P = 0.20). During a median follow-up of 5 years (IQR: 2.0-6.9 years), appropriate and inappropriate ICD interventions were not significantly different. Nonsustained ventricular tachycardia during Holter monitoring in patients with NCCM was the only significant risk factor for appropriate ICD therapy in patients with NCCM, with a HR of 5.29 (95% CI: 1.12-24.96). The long-term survival was significantly better in the univariable analysis in the NCCM group. However, there was no difference in multivariable Cox regression analyses between the cardiomyopathy groups. At 5 years of follow-up, the rate of appropriate and inappropriate ICD interventions in NCCM was comparable to that in DCM or HCM. In multivariable analysis, no differences in survival were found between the cardiomyopathy groups.


KSHV infection of B-cell lymphoma using a modified KSHV BAC36 and coculturing system.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of two B cell lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KSHV infection of B cell lymphoma in vitro has been a long-standing battle in advancing human KSHV biology. In this study, a modified form of KSHV BAC36 named BAC36A significantly increased the fidelity of gene-targeted site-directed mutagenesis in the KSHV genome. This modification eliminates tedious screening steps required to obtain mutant clones when a KSHV BAC36 reverse genetic system is used. Coculturing B-cell lymphoma BJAB cells with KSHV BAC36A stably transfected 293T cells enabled us to infect BJAB cells with a KSHV virion derived from the KSHV BAC36A. The coculture system produced substantial amounts of KSHV infection to BJAB, meaning that KSHV virions were released from 293T cells and then infected neighboring BJAB cells. Owing to our success with the KSHV BAC36A and coculture system, we propose a new genetic system for the study of KSHV gene expression and regulation in B-cell lymphoma.


[The superior vena cava syndrome secondary to a benign intrathoracic goiter: a case report and review of the literature].
The clinical case of a female patient suffering a benign retrosternal goitre which first appeared as a superior vena cava syndrome, is presented. After confirming the diagnosis with an intrathoracic CT scan, a subtotal bilateral thyroidectomy was performed resulting in a complete remission of the clinical picture. A literature review is performed commenting on some clinical, diagnostic and therapeutical aspects.


Distinct geographic distributions of hepatitis B virus genotypes in patients with acute infection in Japan.
Genotypes of hepatitis B virus (HBV) were determined in 145 patients with acute hepatitis B from various districts in Japan to establish their geographic distribution and evaluating the influence on the clinical illness and outcome. Genotypes were A in 27 (19%) patients, B in 8 (5%), C in 109 (75%) and mixed with B and C in the remaining one (1%). Genotype A was more frequent in metropolitan than the other areas (21/69 (30%) vs. 6/76 (8%), P < 0.001). On phylogenetic analysis, seven of the nine (78%) HBV/A isolates selected at random clustered with those from Europe and the United States, while the remaining two with those of subgroup A' prevalent in Asia and Africa. Maximum ALT levels were lower (2069 +/- 1075 vs. 2889 +/- 1867 IU/L, P = 0.03) and baseline HBV DNA titers were higher (5.90 +/- 1.45 vs. 5.13 +/- 1.36 log genome equivalents (LGE)/ml, P = 0.002) in patients infected with genotype A than C. Hepatitis B surface antigen persisted longer in patients infected with genotype A than C (1.95 +/- 1.09 vs. 1.28 +/- 1.42 months, P = 0.02). HBV infection became chronic in one (4%) patient with genotype A and one (1%) with genotype C infection. Fulminant hepatic failure developed in none of the patients with genotype A, one (13%) with genotype B and five (5%) with genotype C. The point mutation in the precore region (A1896) or the double mutations in the basic core promoter (BCP) region (T1762/A1764) were detected in none of the patients with genotype A, two (25%) with genotype B and 27 (26%) with genotype C. In conclusion, genotype A is frequent in patients with acute hepatitis B in metropolitan areas of Japan, probably reflecting particular transmission routes, and associated with longer and milder clinical course than genotype C.


Loss and regeneration of the microvilli of human placental syncytiotrophoblast.
In order to explore the functional role of microvilli of the syncytiotrophoblast of the human full-term placenta, 16 placentas were examined by scanning electron microscopy (SEM). Our results showed that the microvilli projecting from the apical portion of the syncytiotrophoblast appeared to be highly pleomorphic and showed regional variations in their distribution. This has been correlated to the difference in the stage of growth of microvilli following certain obvious examples of loss. Such a process of distortion and renewal or regeneration may suggest a dynamic functional activity of the microvilli on the villous surface.


Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression.
The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated. Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2'-deoxycytidine was used to demethylate the MGMT promoter and O(6)-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed. Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229) and high (SF268 and SK-N-SH) basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines. These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma multiforme patients.


Development of contractile properties in the fetal porcine urinary bladder.
BackgroundIn early fetal life, the bladder is merely a conduit allowing urine to pass through freely into the amniotic cavity. As the striated external urethral sphincter evolves, the bladder acquires its reservoir and voiding functions. We characterized the myogenic and neurogenic contractions of the normal fetal porcine bladder from midterm until close to full-term gestation.MethodsContractile responses were measured in vitro using bladder strips from fetuses at 60 (N=23) and 100 days (N=21) of gestation. Spontaneous activity, and the responses to potassium chloride (KCl) solution, electrical field stimulation (EFS), and receptor activation were recorded. The smooth muscle content was evaluated histologically.ResultsHistological studies revealed that the fractional content of smooth muscle doubled between the two time points, and passive tension was adjusted to take that into account. Spontaneous activity was regular at 60 days, changing toward an irregular pattern at 100 days. Contractile force elicited by KCl and carbachol increased significantly with gestational age, while contractions to the purinergic agonist, α-β-methylene adenosine 5'-triphosphate did not. The responses to EFS were almost completely blocked by atropine.ConclusionSpontaneous myogenic contractions become irregular and contractile responses to muscarinic receptor stimulation increase during gestation, as the bladder reservoir and voiding functions develop.


Infliximab in young paediatric IBD patients: it is all about the dosing.
Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10-18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 μg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3); p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01); p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56).Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known? •Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers. •In 4.5-30% of the paediatric IBD patients, infliximab treatment was stopped within the first year. What is New? •The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment. •Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment. •The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).


CuS nanoparticles as a mimic peroxidase for colorimetric estimation of human blood glucose level.
CuS nanoparticles (NPs) was synthesized through a simple and green method using water soluble precursor complex [CuL2(H2O)2]Cl2 (L=pyridine 2-carboxamide) and was characterized by X-ray diffraction analysis (XRD), transmission electron microscopy (TEM) and UV-Vis spectroscopic techniques. The as-prepared CuS NPs (covellite) was demonstrated to possess intrinsic peroxidase-like activity using 3,3',5,5'-tetramethylbenzidine (TMB), as a peroxidase substrate, in presence of H2O2 which show good affinity towards both TMB and H2O2. Using this TMB-H2O2 catalyzed color reaction; the CuS NPs was exploited as a new type of biosensor for detection and estimation of glucose through a simple, cheap and selective colorimetric method in a linear range from 2 to 1800 μM with a detection limit of 0.12 μM. On the basis of the developed reaction process, we can easily monitor human blood glucose level.


Synthesis of enterolactone and enterodiol precursors as potential inhibitors of human estrogen synthetase (aromatase).
A series of variably substituted derivatives of lignan lactones and diols were prepared using tandem conjugate addition reaction as a key step. These theoretical precursors of the mammalian lignans enterolactone 1 and enterodiol 3 are moderate or weak inhibitors of human aromatase activity.


Initial Report of Pencil Beam Scanning Proton Therapy for Posthysterectomy Patients With Gynecologic Cancer.
To report the acute toxicities associated with pencil beam scanning proton beam radiation therapy (PBS) for whole pelvis radiation therapy in women with gynecologic cancers and the results of a dosimetric comparison of PBS versus intensity modulated radiation therapy (IMRT) plans. Eleven patients with posthysterectomy gynecologic cancer received PBS to the whole pelvis. The patients received a dose of 45 to 50.4 Gy relative biological effectiveness (RBE) in 1.8 Gy (RBE) daily fractions. Acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 4. A dosimetric comparison between a 2-field posterior oblique beam PBS and an IMRT plan was conducted. The Wilcoxon signed rank test was used to assess the potential dosimetric differences between the 2 plans and PBS target coverage robustness relative to setup uncertainties. The median patient age was 55 years (range 23-76). The primary site was cervical in 7, vaginal in 1, and endometrial in 3. Of the 11 patients, 7 received concurrent cisplatin, 1 each received sandwich carboplatin and paclitaxel chemotherapy, both sandwich and concurrent chemotherapy, and concurrent and adjuvant chemotherapy, and 1 received no chemotherapy. All patients completed treatment. Of the 9 patients who received concurrent chemotherapy, the rate of grade 2 and 3 hematologic toxicities was 33% and 11%, respectively. One patient (9%) developed grade 3 acute gastrointestinal toxicity; no patient developed grade ≥3 genitourinary toxicity. The volume of pelvic bone marrow, bladder, and small bowel receiving 10 to 30 Gy was significantly lower with PBS than with intensity modulated radiation therapy (P<.001). The target coverage for all PBS plans was robust relative to the setup uncertainties (P>.05) with the clinical target volume mean dose percentage received by 95% and 98% of the target volume coverage changes within 2% for the individual plans. Our results have demonstrated the clinical feasibility of PBS and the dosimetric advantages, especially for the low-dose sparing of normal tissues in the pelvis with the target robustness maintained relative to the setup uncertainties. Future studies with larger patient numbers are planned to further validate our preliminary findings.


A low-calcemic vitamin D analog (Ro 25-4020) inhibits the growth of LNCaP human prostate cancer cells with increased potency by producing an active 24-oxo metabolite (Ro 29-9970).
In this study, we have characterized a novel less-calcemic vitamin D analog Ro 25-4020 (1alpha, 25 dihydroxy-16-ene-5,6-trans-vitamin D3) and investigated the mechanisms underlying its enhanced growth inhibitory properties. We found that Ro 25-4020 (IC50 = 0.3 nM) exhibited greater inhibitory activity than 1,25(OH)2D3 (IC50 = 1 nM) on LNCaP human prostate cancer cell growth. However, Ro 25-4020 was tenfold less active than 1,25(OH)2D3 in receptor-binding assays, ligand-induced heterodimerization and transactivation assays using VDR. HPLC and GC-MS analyses revealed that 1,25(OH)2D3 is converted to a 24-hydroxy metabolite, which has been shown to be less potent than 1,25(OH)2D3. In contrast, Ro 25-4020 was converted to a major 24-oxo metabolite that was more stable. Ligand-binding assays reveal that both Ro 25-4020 and its 24-oxo metabolite have similar affinity for VDR. Synthetic 24-oxo-Ro 25-4020, however, inhibited LNCaP cell proliferation as potently as 1,25(OH)2D3 and was more potent in transactivation of two out of three vitamin D target genes tested. These results suggest that conversion of Ro 25-4020 into an active and more stable 24-oxo metabolite with longer half-life contributes significantly to its potent antiproliferative actions on the LNCaP cells.


Alternative NF-κB Signaling Discriminates Induction of the Tumor Marker Fascin by the Viral Oncoproteins Tax-1 and Tax-2 of Human T-Cell Leukemia Viruses.
Transcriptional regulation of the actin-bundling protein and tumor marker Fascin is highly diverse depending on cell and tumor type. Previously, we discovered that the viral oncoprotein Tax-1 of human T-cell leukemia virus type 1 (HTLV-1) considerably enhances Fascin expression in T-cells, depending on classical NF-κB signaling. In this study, we asked if the non-oncogenic Tax-2 of the related HTLV-2 is still able to induce Fascin by using luciferase assays, immunoblot, and qPCR. We found that Tax-2 only slightly induces Fascin expression compared to Tax-1; however, both Tax-1 and Tax-2 comparably activated a 1.6 kb fragment in the human Fascin promoter including Tax-responsive elements. Furthermore, we identified a link between Tax-induced activity of the alternative NF-κB pathway and Fascin induction. While treatment with the second mitochondria-derived activator of caspases (SMAC)-mimetic AZD5582, a compound known to robustly activate alternative NF-κB signaling, did not induce Fascin, combination of AZD5582 with activation of classical NF-κB signaling by Tax-2 significantly induced Fascin expression. In conclusion, our data demonstrate that both classical and alternative NF-κB activity are necessary for strong Fascin induction by the viral Tax oncoproteins, thus, shedding new light on the regulation of Fascin in T-cells and during viral transformation.


Patent ductus arteriosus occlusion using detachable coils.
Occlusion of patent ductus arteriosus was performed using detachable coils in 193 cases, with 181 successful implants and a low embolization rate. This technique is safe and effective for occlusion of ductuses of various sizes, and is low cost.


Autologous blood transfusion in radical hysterectomy with and without erythropoietin therapy.
To investigate whether preoperative treatment with erythropoietin facilitates the collection of a sufficient amount of autologous blood in a short period of time. Forty-one women scheduled for radical hysterectomy were randomized to preoperative autologous blood donation with or without preoperative recombinant human erythropoietin therapy. All patients were scheduled to deposit three units of blood within 2 weeks before surgery. Hemoglobin, erythrocyte volume fraction, blood cells, iron status, and hemolysis were analyzed before and after surgery. Hemoglobin levels decreased continuously in both groups after the first autologous donation until day 1 postoperatively. With erythropoietin therapy, the erythrocyte volume fraction and hemoglobin levels were significantly higher during precollection and day 1 after surgery. Preoperatively, the drop was 12 g/L less in the erythropoietin-treated group. The additional use of erythropoietin therapy reduced the inability of patients to predeposit blood from 17.8% to 3.4%. Most women can predeposit three units of whole blood in only 2 weeks without obtaining severe anemia. By treating women with erythropoietin, one out of seven can be prevented from a hemoglobin level below the 100 g/L limit for donation.


Changes in immune responses to antigen applied to tape-stripped skin with CpG-oligodeoxynucleotide in NC/Nga mice.
CpG-oligodeoxynucleotide (CpG-ODN) plays a critical role in immunity via the augmentation of Th1 and the suppression of Th2 responses. We examined here the effect of CpG-ODN on the immune response to an antigen applied to a tape-stripped skin of NC/Nga mouse, a human atopic dermatitis (AD) model, by evaluating the production of cytokines and immunoglobulin isotypes. Model antigen, ovalbumin (OVA), and CpG-ODN were applied on to the shaved skin. The penetration of OVA and CpG-ODN was evaluated using confocal laser scanning microscopy (CLSM). Secretion of cytokine from splenocytes and changes in immunoglobulin isotype levels were determined by enzyme-linked immunosorbent assay (ELISA). Through CLSM it was revealed that the model antigen, OVA, and CpG-ODN easily penetrated the tape-stripped skin. Coadministration of CpG-ODN and OVA to the skin elicited an antigen-specific, Th1-predominant immune response and enhanced the production of IFN-gamma. On the other hand, the production of a Th2-type cytokine, IL-4, was drastically suppressed. In terms of antigen-specific antibody production, the level of IgG2a regulated by IFN-gamma was increased by CpG-ODN, but IgE production regulated by IL-4 was suppressed. Administration of CpG-ODN with antigen through the skin may shift the immune response from a Th2- to Th1-like response. These results suggested that administration of CpG-ODN via skin is a simple strategy for patients with diseases such as AD, which is characterized by Th2-dominated inflammation.


α-Glucosylated 6-gingerol: chemoenzymatic synthesis using α-glucosidase from Halomonas sp. H11, and its physical properties.
6-Gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one] is a biologically active compound and is abundant in the rhizomes of ginger (Zingiber officinale). It has some beneficial functions in healthcare, but its use is limited because of its insolubility in water and its heat-instability. To improve these physical properties, the glucosylation of 6-gingerol was investigated using α-glucosidases (EC. 18.104.22.168) from Aspergillus niger, Aspergillus nidulans ABPU1, Acremonium strictum, Halomonas sp. H11, and Saccharomyces cerevisiae, and cyclodextrin glucanotransferases (CGTase, EC. 220.127.116.11) from Bacillus coagulans, Bacillus sp. No. 38-2, Bacillus clarkii 7364, and Geobacillus stearothermophilus. Among these, only α-glucosidase from Halomonas sp. H11 (HaG) transferred a glucosyl moiety to 6-gingerol, and produced glucosylated compounds. The chemical structure of the reaction product, determined by nuclear magnetic resonance spectroscopy and mass spectrometry, was (S)-5-(O-α-D-glucopyranosyl)-1-(4-hydroxy-3-methoxyphenyl)decan-3-one (5-α-Glc-gingerol). Notably, the regioisomer formed by glucosylation of the phenolic OH was not observed at all, indicating that HaG specifically transferred the glucose moiety to the 5-OH of the β-hydroxy keto group in 6-gingerol. Almost 60% of the original 6-gingerol was converted into 5-α-Glc-gingerol by the reaction. In contrast to 6-gingerol, 5-α-Glc-gingerol, in the form of an orange powder prepared by freeze-drying, was water-soluble and stable at room temperature. It was also more stable than 6-gingerol under acidic conditions and to heat.


Determinants, self-management strategies and interventions for hope in people with mental disorders: systematic search and narrative review.
Developing a recovery focus in mental health services is a policy goal internationally, and hope is a central component of recovery. Yet determinants of hope of people with mental disorders are not well known, nor are strategies and interventions that increase hope. This study aims to systematically summarise the available evidence to fill four relevant knowledge gaps: (1) hope scales used in psychiatric research, (2) determinants of hope, (2) hope-fostering self-management strategies, and (3) interventions to increase hope for people with mental disorders. We conducted a systematic literature search in April 2011 and a narrative synthesis of publications including qualitative and quantitative studies. Results for the first time provide a comprehensive overview of existing evidence and identify important scientific knowledge gaps: (1) Hope scales used do slightly vary in focus but are overall comparable. (2) Most published research used cross-sectional designs resulting in a high number of potential determinants of hope. No studies prospectively investigated the influence of these determinants. (3) Hope fostering self-management strategies of people with mental disorders were described in qualitative studies only with experimental studies completely missing. (4) While some recovery oriented interventions were shown to increase hope as a secondary outcome, there are no successful interventions specifically aimed at increasing hope. This review provides the basis for both practical and research recommendations: The five most promising candidate interventions to improve hope in people with mental disorders are (i) collaborative strategies for illness management, (ii) fostering relationships, (iii) peer support, (iv) helping clients to assume control and to formulate and pursue realistic goals, and (v) specific interventions to support multiple positive factors such as self-esteem, self-efficacy, spirituality and well-being. These may serve to directly improve care and to develop theory-based models and testable interventions to improve hope in mental health as well as in allied fields.


The execution of the Grooved Pegboard test in a Dual-Task situation: A pilot study.
Manual dexterity is an important aspect in everyday life, which is widely studied through the Grooved Pegboard Test (GPT). Since Dual-Tasks (DT) activities are widely investigated and important to simulate everyday life situations, the objectives of the present pilot study were the evaluation of the effect of a cognitive task and a motor task during the performance of the GPT and the feasibility of the GPT in a DT contest. A secondary objective was to evaluate the training effect of the GPT. A total of 31 young adults (20 man and 11 woman, age (SD): 27.7 (2.5)) performed the GPT eight times to understand the presence of a training effect before performing the GPT in DT. The additional tasks were a secondary cognitive task and a secondary motor task. All participants were able to complete the required conditions. The GPT performed in motor DT were significantly slower than those performed singularly (p < 0.01). The GPT performed with the cognitive task was slower than the secondary motor task (p < 0.05). A training effect was present up to the 4th consecutive trial. The GPT can be executed with a cognitive or motor task to increase the difficulty of the trial to better evaluate manual dexterity and cognitive capacities.


The OpdQ porin of Pseudomonas aeruginosa is regulated by environmental signals associated with cystic fibrosis including nitrate-induced regulation involving the NarXL two-component system.
Pseudomonas aeruginosa is a versatile opportunistic pathogen that causes chronic infections in immunocompromised hosts. Multiple porins modulate outer membrane permeability under various environmental conditions. The lung environment of cystic fibrosis (CF) patients is unique with changes occurring in nutrient availability, osmolarity, and oxygen content. Although P. aeruginosa gene expression is modified under these conditions, little is known about how they influence porin regulation. In this study, we evaluated the regulation of the outer membrane porin OpdQ, a member of the OprD family of porins, with regard to oxygen, nitrate, and/or NaCl levels. We demonstrated using promoter::fusion clones of P. aeruginosa PAO1 and clinical strains collected from CF patients that OpdQ was transcriptionally repressed under low oxygen but increased in the presence of nitrate. The nitrate-induced regulation of OpdQ was found to be dependent on the transcription factor NarL via the NarXL two-component system. In addition, NaCl-induced osmotic stress increased OpdQ production among most of the clinical strains evaluated. In conclusion, these data identify for the first time that specific environmental cues associated with the CF microenvironment influence porin regulation, and that the nitrate-induced regulation of OpdQ is associated with nitrate metabolism via the NarXL two-component system of P. aeruginosa.


Diagnostic and therapeutic thoracoscopy: lessons from the learning curve.
A variety of video-assisted thoracic operations are being reported with increasing frequency. Problems encountered during the development of this technology have received less attention. During the course of 27 months, 69 consecutive patients underwent minimally invasive procedures at our institution. Conversion to thoracotomy was required in 16 of 49 (33%) patients undergoing diagnostic procedures and 1 of 20 (5%) patients undergoing therapeutic interventions. Fewer complications occurred in those patients with diagnostic procedures (10 of 49, 20%) versus therapeutic interventions (10 of 20, 50%; p = 0.01). Logistic regression analysis showed chronic obstructive pulmonary disease to be an independent risk factor for complications. The mean postoperative stay was 7.9 +/- 6.8 days for diagnostic and 12.8 +/- 9.7 days for therapeutic interventions (p = 0.02). As new technologic improvements were introduced, the mean hospital stay decreased (first 10 months: 14.6 +/- 10.0 days, 10 to 20 months: 9.8 +/- 9.6 days, more than 20 months: 5.2 +/- 3.0 days, p < 0.004). The surgeon's thoracoscopic experience was not as strongly predictive (5 or fewer cases: 8.9 +/- 5.9 days, 6 to 15 cases: 13.1 +/- 12.6 days, more than 15 cases: 5.0 +/- 2.0 days). Although thoracoscopic surgery is promising, the potential for problems requires careful surgical judgment and expertise in dealing with thoracic complications.


Incidence and prognosis of distant metastasis in malignant peripheral nerve sheath tumors.
Malignant peripheral nerve sheath tumors (MPNSTs) are a type of soft tissue sarcomas (STS) with recurrence and metastatic potential. We aimed to investigate the risk factors for developing distant metastases (DM) and to identify the prognostic factors in patients with DM. Based on the Surveillance, Epidemiology, and End Result (SEER) database, MPNST patients diagnosed between 2010 and 2016 were extracted in our study. The logistic regression model was performed for predicting DM development while the Cox proportional hazard regression model was conducted for revealing the prognostic factors. Eventually, 764 patients diagnosed with MPNSTs were included with 109 cases presenting with metastases at initial diagnosis. Larger tumor size and lymph node metastases were independent risk factors for developing DM. The median overall survival (OS) for patients with metastases was 8.0 (95% CI: 6.1-9.9) months. Multiple metastatic sites and no surgical treatment were prognostic factors for worse survival. Tumors located in non-head and neck region were related with better survival. The incidence of DM was 14.3% with a dismal median OS of 8.0 months for metastatic MPNSTs. More evaluation should be applied for patients with large tumor size and lymph metastases. Tumors located in head and neck region and the presence of multiple metastases predicted worse survival outcome. Surgical treatment can significantly improve the survival of MPNST patients with distant metastasis.


The projections of single thalamic neurons onto multiple visual cortical areas in the cat.
Fluorescent dyes Fast Blue and Nuclear Yellow injected into pairs of visual cortical and parietal 'association' cortical areas in the cat revealed the presence of retrogradely double-labeled cells in the intralaminar nuclei and lateral posterior-pulvinar complex of the thalamus. These results demonstrate the projection of individual thalamic neurons onto multiple cortical areas.


The Spectrum of Nontraumatic Convexity Subarachnoid Hemorrhage.
Nontraumatic convexity subarachnoid hemorrhage (cSAH) is a nonaneurysmal variant that is associated with diverse etiologies. With IRB approval, we retrospectively reviewed consecutive nontraumatic cSAH from July 1, 2006 to July 1, 2016. Data were abstracted on demographics, medical history, neuroimaging, etiology, and clinical presentation. We identified 94 cases of cSAH. The cases were classified according to the following etiologies: reversible cerebral vasoconstriction syndrome (RCVS) 17 (18%), cerebral amyloid angiopathy (CAA) 15 (16%), posterior reversible encephalopathy syndrome 16 (17%), cerebral venous thrombosis 10 (11%), large artery occlusion 7 (7%), endocarditis 6 (6%), and cryptogenic 25 (27%). Early rebleeding occurred in 9 (10%) patients. Time from initial imaging to CT rebleeding was 40 hours (range, 5-74). CAA was associated with the highest mean age at 75.8 and RCVS the lowest at 47.6 years (P< .0001). Among patients with RCVS, initial vascular imaging was negative in 6 (35%), and repeat imaging documented vasoconstriction at a mean delay of 5 days (range, 3-16). There were significant differences among the subgroups in cSAH, with CAA presenting as older men with transient neurological deficits, and RCVS presenting as younger women with thunderclap headache. Rebleeding was seen in 10% of cSAH patients. One-third of RCVS patients with cSAH required repeat vascular imaging to diagnose vasoconstriction.


Long-term quality of life after surgery of head and neck cancer with microvascular reconstruction: a prospective study with 4.9-years follow-up.
The aim of this study was to evaluate the long-term health-related quality of life (HRQoL) of head and neck cancer patients with microvascular surgery. Surgical treatment causes great changes in patient HRQoL. Studies focusing on long-term HRQoL after microvascular reconstruction for head and neck cancer patients are scarce. We conducted a prospective study of 93 patients with head and neck cancer and microvascular reconstruction in Helsinki University Hospital Finland. HRQoL was measured using the 15D instrument at baseline and after a mean 4.9-years follow up. Results were compared with those of an age-standardized general population. Of the 93 patients, 61 (66%) were alive after follow-up; of these, 42 (69%) answered the follow-up questionnaire. The median time between surgery and HRQoL assessment was 4.9 years (range 3.7-7.8 years). The mean 15D score of all patients (n = 42) at the 4.9-years follow up was statistically significantly (p = 0.010) and clinically importantly lower than at baseline. The dimensions of "speech" and "usual activities" were significantly impaired at the end of follow up. There was a significant difference at the 4.9-years follow-up in the mean 15D score between patients and the general population (p = 0.014). After follow up, patients were significantly (p < 0.05) worse off on the dimensions of "speech," "eating," and "usual activities." Long-term HRQoL was significantly reduced in the whole patient cohort. Speech and usual activities were the most affected dimensions in head and neck cancer patients with microvascular reconstruction at the end of the 4.9-years follow up.


Design and membrane-disruption mechanism of charge-enriched AMPs exhibiting cell selectivity, high-salt resistance, and anti-biofilm properties.
Cationic antimicrobial peptides (AMPs) are essential components of the innate immune system, offering protection against invading pathogenic bacteria. In nature, AMPs serve as antibiotics with broad-spectrum antimicrobial and anti-biofilm properties. However, low effective stability in high-salt environments and physiological instability in biological membranes limit the applicability of naturally occurring AMPs as novel therapeutics. We therefore designed short synthetic cationic peptides by substituting key residues in myxinidin, an AMP derived from the epidermal mucus of hagfish, with lysine (Lys, K), arginine (Arg, R), and tryptophan (Trp, W). The resultant myxinidin analogs exhibited strong antimicrobial activity against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains, even under high-salt conditions. Moreover, these peptides showed high binding affinity for both lipopolysaccharides and lipoteichoic acids and inhibited biofilm formation by most bacteria, but did not cause significant lysis of human red blood cells and were not cytotoxic to normal human keratinocytes. Circular dichroism analysis revealed that myxinidin and its analogs assumed α-helical or β-sheet structures within artificial liposomes and bacterial membranes. In addition, bacterial killing and membrane permeation experiments demonstrated that the myxinidin analogs permeated through bacterial membranes, leading to cytoplasmic disruption and cell death. Taken together, these findings suggest myxinidin analogs may be promising candidate antibiotic agents for therapeutic application against antibiotic-resistant bacteria.


Histological prognostic factors in children with Henoch-Schönlein purpura nephritis.
The management of IgA vasculitis with nephritis (IgAVN) remains controversial because of the difficulty to identify prognostic factors. This study reports the prognosis of children with IgAVN in relation to histological parameters. All children with IgAVN diagnosed between 2000 and 2015 in three pediatric nephrology centers were included. The following histological parameters were analyzed: mesangial proliferation (MP), endocapillary proliferation (EP), crescents, active, or chronic tubular and interstitial lesions (TIa lesions/TIc lesions), and segmental glomerulosclerosis (GS). Clinical and biological data were collected at the time of renal biopsy. The primary endpoint was IgAVN remission defined as a proteinuria < 200 mg/l without renal failure. One hundred fifty-nine children were included with a median age of 7.6 years. Acute glomerular or TI lesions including MP, EP, crescents, and TIa lesions were observed, respectively, in 81%, 86%, 49%, and 21% of patients. Chronic glomerular lesions including GS and TIc lesions were observed in 6 and 7% of patients. Median initial proteinuria was 330 mg/mmol, albuminemia 32 g/l, and eGFR 110 ml/min/1.73 m2. One hundred twelve (70%) patients were in remission at the end of a median follow-up of 37.4 months. Chronic lesions were significantly associated with the absence of remission in multivariate analysis, whereas EP, crescents and TIa were not associated with a poor prognosis. Of children with IgAVN, 30% present a persistent renal disease at the end of a 3-year follow-up. Chronic histological lesions, but not EP or crescents, are associated with a bad prognosis and must be evaluated in IgAVN histological classification.


Effects of the COVID-19 pandemic on diet and physical activity and the possible influence factors among Saudi in Riyadh.
The COVID-19 pandemic has been spreading throughout the world, having a significant impact on people's lifestyles and health through social isolation and home confinement. The purpose of this study is to look into the impact of COVID-19 on diet and physical activity, as well as the possible influence factors, among ≥ 13-year-olds in Riyadh, Saudi Arabia. In the present study data were collected from 2,649 participants via an online survey. The Google online questionnaire was available from April 23 to May 6, 2020. During the COVID-19 lockdown, the survey asked respondents about their demographic characteristics (gender, age, education, economic income, and occupation), anthropometric data, physical activity, and diet habits. The study included 2,649 respondents, with 23.3% being male and 76.7% female. The majority of them were in good health and ranged in age from 21 to 29 years. 31% of those polled were overweight, and 14.3% were obese. The majority of respondents have a bachelor's degree, diploma, or the equivalent, and a monthly family income of ≤ 25.000 SR. Those who were following a healthy diet (32.3%) were unable to maintain it during confinement, with males being affected more than females (42.7%, 29.3%, respectively, P = 0.004), and those most impacted were aged 21-29 years (38.0%, P = 0.046). Furthermore, 59.5% of males significantly failed to continue exercising during confinement compared to females who exercised consistently (P = 0.01). In terms of age, females aged less than 40 increased their exercise rate by about 23.4%, while males aged 40 and up decreased their exercise rate by 25.7% (P = 0.000). Moreover, 40.5% of the subjects' weight increased, according to the findings. However, there was no significant effect on body mass index, despite the fact that 51% of participants were overweight or obese. The data showed that the COVID-19 lockdown had a negative impact on maintaining a healthy diet (p = 0.023*) and physical activity (p = 0.000**).


Bioadhesive pellets increase local 5-aminosalicylic acid concentration in experimental colitis.
Topical delivery of 5-aminosalicylic acid (5-ASA) to the colonic mucosa is important in order to achieve effective drug concentration in the site of inflammation and to minimize its systemic availability. 5-ASA loaded pellets were prepared by an extrusion/spheronization method. Mucoadhesive biopolymer chitosan was incorporated into the pellets, and drug delivery to the colon was controlled by the pH-sensitive polymer Eudragit® FS. Dissolution profiles of coated pellets revealed no drug release at pH 1.2 within 2h and release as intended in the simulated distal ileum and colon. In vivo, chitosan-core drug loaded pellets (AMCh) showed 2.5-fold higher drug metabolite concentration than after chitosan free pellets (AM) administration in the inflamed colonic tissue. Additionally, AMCh demonstrated decreased in AUC in colitis group (1507 ± 400 ng h/ml) compared with AM (1907 ± 122 ng h/ml). In terms of therapeutic efficiency, administration of pellets markedly decreased the colon/body weight ratio (colitis: 0.0355 ± 0.0028; AM 0.0092 ± 0.0033; AMCh 0.0086 ± 0.0022) and myeloperoxidase activity (colitis: 3212 ± 294 U/g tissue; AM 796 ± 211 U/g; AMCh 552 ± 319 U/g). Bioadhesive chitosan pellets showed additional beneficial properties for colonic 5-ASA delivery in the treatment of inflammatory bowel disease by increasing the drug concentration locally.


Herbivore-Algal relationships on a coastal rock platform (Cape Banks, N.S.W.).
A fifty-three metre inter-tidal transect on a headland near Sydney, New South Wales, has been studied. Its profile, fauna and flora are illustrated and described.Figures were prepared indicating the herbivore standing crop on this transect at various seasons, and some evidence of seasonal changes in the marine algal flora is presented.All macroscopic herbivorous animals were removed from the transect at two-weekly intervals during a twelve month period. After the initiation of this treatment no species of alga in the transect appeared outside the zone in which it normally occurred. There was thus no indication that animal browsing normally restricts algae to particular (vertical) zones on this rock platform. The abundance of certain species was, however, affected by the removal of the herbivores. First to flourish were the green algae; contrary to results obtained in other parts of the world, brown algae did not then become established to form a climax community. It is suggested that the rapid reinvasion by herbivores noted at Cape Banks may account for differences in these results from those recorded elsewhere.Some algal taxonomic notes are appended.


Development of psychophysiological motoric reactivity is influenced by peripubertal pharmacological inhibition of gonadotropin releasing hormone action--results of an ovine model.
This study reports the effects of peripubertal GnRH receptor inactivation on development of psychophysiological motoric reactivity (PMR; sometimes also called emotional reactivity), plasma cortisol concentrations and the relationship between plasma cortisol and PMR in male and female sheep. The study formed part of a larger trial and utilised 46 same sex twins. One twin remained untreated (control) while the other received a subcutaneous GnRH agonist (GnRHa Goserelin-Acetate) implant every 4th week, beginning at 8 and 28 weeks of age, in males and females, respectively (different, due to sex specific age of puberty). PMR, a measure of an animals' response to social isolation, was measured over a two minute period at 8, 28 and 48 weeks of age, using a three axis accelerometer. During the test period vocalisation rate was recorded. Cortisol was assayed in blood samples collected on a single day when animals were 40 weeks of age. PMR and vocalisation rate were significantly higher in females than males at all ages tested. At 28 weeks of age (20 weeks treatment) PMR was increased in treated males to the level seen in control females, by 48 weeks of age treated males' PMR was significantly less than controls. In females, 20 weeks of GnRHa treatment (28-48 weeks of age) was not associated with differences in PMR. Cortisol concentrations were significantly higher in females than males but were not affected by treatment. Plasma cortisol concentrations were positively correlated with PMR; this relationship being driven by the treated animals in both sexes. The results demonstrate that PMR is sexually dimorphic and cortisol dependent in sheep from at least 8 weeks of age. Importantly, they also demonstrate that long-term treatment of males with a GnRH agonist results in changes in age-dependent development of PMR.


CD40L-null NKT cells provide B cell help for specific antibody responses.
CD1d-binding glycolipids exert potent adjuvant effects on T-dependent Ab responses. The mechanisms include cognate interaction between CD1d-expressing B cells and TCR-expressing Type I CD1d-restricted natural killer T cells (NKTs). However, the critical NKT-derived factors that stimulate B cells are poorly understood. We tested the hypothesis that CD1d-driven CD40L expression by NKT cells influences humoral immunity. Bone marrow chimeras with CD40L(+/+) or CD40L(-/-) NKT cells were immunized with Ag plus CD1d ligand before measuring Ab responses. CD40L(-/-) NKT cells stimulated higher endpoint Ab titers than controls expressing CD40L. In contrast, immunization of CD40L(-/-) mice revealed that CD40L(-/-) NKT cells could not provide B cell help when Th cells lacked CD40L. We report that CD40L(-/-) NKT cells can provide help for Ab production and do so cooperatively with CD40L(+/+) Th cells. We suggest that the manner in which NKT cells provide B cell help is distinct from that of Th cells.


The evaluation of traditional and early driver training with simulated accident scenarios.
We assessed the driving skills of novice traditionally trained, novice early-trained, and experienced drivers to evaluate whether supervised early training could improve young drivers' skills. The overall representation of young male drivers in car crashes is a recurrent problem in developed countries.To prevent this overrepresentation, France institutes an early driver training program from the age of 16 with the supervision of an adult. However, evidence of the positive effects of this system is still lacking. Three groups of drivers (12 participants each) were confronted with five prototypical accident scenarios introduced in a simulated urban circuit. Drivers' response time, speed, and vehicle position in the lane were analyzed. No difference was detected across groups regarding obstacle detection, as revealed by the analysis of response times. But in some unexpected scenarios, position control by traditionally trained drivers was more conservative than for more experienced drivers, and early-trained drivers were far more likely to respond with efficient evasive action. The exposure gained by an early training program could thus increase the development of visuomotor coordination and involve better skills in challenging situations. The supplementary driving experience gained with the supervision of an adult during early training could promote the skills necessary to deal with risky situations. Driving simulators could be used to confront young drivers with a broad range of hazardous scenarios not commonly encountered in natural driving.


Pharmacology of the fluoroquinolones: a perspective for the use in domestic animals.
The fluoroquinolones are a class of compounds that comprise a large and expanding group of synthetic antimicrobial agents. Structurally, all fluoroquinolones contain a fluorine molecule at the 6-position of the basic quinolone nucleus. Despite the basic similarity in the core structure of these molecules, their physicochemical properties, pharmacokinetic characteristics and microbial activities can vary markedly across compounds. The first of the fluoroquinolones approved for use in animals, enrofloxacin, was approved in the late 1980s. Since then, five other fluoroquinolones have been marketed for use in animals in the United States, with others currently under investigation. This review focuses on the use of fluoroquinolones within veterinary medicine, providing an overview of the structure-activity relationship of the various members of the group, the clinical uses of fluoroquinolones in veterinary medicine, their pharmacokinetics and potential interspecies differences, an overview of the current understanding of the pharmacokinetic/pharmacodynamic relationships associated with fluoroquinolones, a summary of toxicities that have been associated with this class of compounds, their use in both in human and veterinary species, mechanisms associated with the development of microbial resistance to the fluoroquinolones, and a discussion of fluoroquinolone dose optimization. Although the review contains a large body of basic research information, it is intended that the contents of this review have relevance to both the research scientist and the veterinary medical practitioner.


Insulin resistance and preeclampsia.
Insulin resistance appears to be a causative mechanism for the development of essential hypertension. Insulin resistance syndrome consists of a cluster of abnormalities that aggravate preexisting tendencies to develop hypertension, resulting in a cascade of physiologic alterations and ultimately leading to increased rates of heart attack, stroke, and peripheral vascular disease. Like hypertension, NIDD is mediated by insulin resistance and is expressed in individuals with limited beta-cell reserve. Episodes of increased insulin resistance, such as aging, weight gain, and pregnancy, cannot be compensated for in these states, and glucose intolerance results. In the case of pregnancy, the temporary state of insulin resistance unmasks individuals with an early beta-cell defect and allows for identification of high-risk groups at a time when therapeutic interventions could result in primary prevention of disease. Evidence is beginning to accumulate that preeclampsia is at least partially mediated by insulin resistance as well, and that individuals with preeclampsia may have clinically silent but persistent alterations in insulin resistance. If this condition proves a corollary to gestational diabetes, there may be an opportunity to intervene for primary prevention of some forms of essential hypertension as well. The availability of new pharmacologic agents to enhance insulin sensitivity represents a true opportunity effectively to prevent the long-term complications associated with insulin resistance and hyperinsulinemia. To achieve this goal, early and accurate identification of populations at risk is essential. A complete understanding of the role of insulin resistance in the generation of preeclampsia will aid significantly in the discovery of the genetic polymorphisms and intracellular pathways by which insulin resistance is translated into cardiovascular disease, stroke, and nephropathy.


Physiological incidents during 39 years of hypobaric chamber training in Japan.
Hypobaric chamber training for military aircrew is very important for flight safety. Since we began hypobaric training in our laboratory in 1960, some trainees have suffered physiological incidents. This study will characterize the physiological incidents during hypobaric chamber training at the Japan Air Self-Defense Force (JASDF). All available training records from 1960-1998 were reviewed and the frequency of physiological incidents counted and analyzed. There were 29,677 trainees and 58,454 exposures. Overall frequency of physiological incidents was 6.3%. Physiological incidents included ear pain, paranasal sinus pain, abdominal pain, hypoxia, hyperventilation, joint pain, and toothache. Decompression sickness (DCS-I, simple joint pain only) was rare. In cases of DCS-I, joint pain was easily relieved with controlled descent. During the last three decades, overall prevalence of physiological incidents has gradually increased from 5.3 to approximately 6.1% before 1991, to 6.8-9.9% after 1991. However, prevalence rate showed no change through out the period when ear pain was factored out. The increase in prevalence was entirely due to an increased frequency of ear pain: 3.6 to approximately 4.6% before 1991, and 5.4 to approximately 7.2% after 1991. DCS has not been a problem in the JASDF hypobaric chamber training experience. The majority of physiological incidents during hypobaric chamber training in JASDF have been ear pain, a minor but frequent obstacle to hypobaric training. The exact cause of the observed increase in frequency of Eustachian tube dysfunction currently remains unclear.


Circumferential web of the upper esophagus.
Two patients with circumferential webs of the upper esophagus are presented. Both patients had a long history of intermittent dysphagia, particularly with solid food. The clinical, endoscopic, and radiologic features of these webs are discussed.


Postnatal outcome of fetal bradycardia without significant cardiac abnormalities.
A heart rate <100 beats/min may be present in 5% of fetuses with arrhythmia. In this study, we sought to define the feasibility of in utero diagnosis of the underlying mechanisms and the postnatal outcome. The types of fetal bradycardia were defined by fetal echocardiogram. Fetuses with transient sinus bradycardia were excluded. From 1995-2000, a total of 18 fetuses were found to have bradycardia. Postnatal 12-lead electrocardiograms made at least 3 times during follow-up confirmed the cardiac rhythm in all except those terminated during pregnancy. Sick sinus bradycardia was noted in 4 patients (22 %), of whom 1 had a positive family history and 2 received permanent pacemakers at age 4 and 5 years. Frequent nonconducted atrial premature beats or nonconducted atrial bigeminy or trigeminy were noted in 5 (28%). All of them revealed normal sinus rhythm after birth. Atrioventricular (AV) block was noted in 6 (33%), of whom 3 were terminated due to severe heart failure, and another 2 fetuses received permanent pacemaker implantation soon after birth. Only 1 fetus whose mother showed normal levels of C3 and C4 recovered at late gestation. Most importantly, 3 patients (17%) developed intermittent bradycardia (AV block) and ventricular tachycardia during the fetal stage. They were found to have long QT syndrome. Two of them died during early infancy. One received in utero propranolol and postnatal propranolol and nicorandil with satisfactory control. The mechanisms responsible for fetal bradycardia were diverse and could be characterized by fetal echocardiography. The prognosis was poor in those with long QT syndrome manifested as intermittent fetal bradycardia and tachycardia with AV dissociation.


Real-time three-dimensional transesophageal echocardiography to predict artificial chordae length for mitral valve repair.
Artificial chordae replacement is an effective technique for mitral valve repair, however, it is difficult to accurately determine the length of artificial chordae. This study aimed to assess the reliability and accuracy of real-time three-dimensional transesophageal echocardiography (TEE) to predict the length of artificial chordae preoperatively. From December 2008 to December 2010, 48 patients with severe mitral regurgitation successfully underwent mitral valve repair using artificial chordae replacement. The patients were divided into a TEE pre-measurement group (n = 26) and a direct measurement group (n = 22), according to the method used to determine the length of artificial chordae. Cardiopulmonary bypass time, aortic cross-clamp time, and the recurrence rate of moderate or severe mitral regurgitation were compared between the two groups. There were no operative deaths in either group. The mean cardiopulmonary bypass time was 113.0 ± 18.7 min and 127.0 ± 28.9 min (p < 0.05), and the aortic cross-clamp time was 70.0 ± 16.6 min and 86.0 ± 20.7 min (p < 0.05) in the TEE pre-measurement group and direct measurement group, respectively. The difference between the pre-measured artificial chordal length and actual constructed artificial chordal length was not significant in the TEE pre-measurement group (p > 0.05). Although the difference in the incidence of moderate or severe mitral regurgitation between the two groups was not significant (p > 0.05), the incidence in the TEE pre-measurement group (3.8%) was lower than that in the direct measurement group (18.2%). Real-time three-dimensional transesophageal echocardiography can accurately predict the length of artificial chordae required for mitral valve repair, and shortens cardiopulmonary bypass time and aortic cross-clamp time while improving the results of mitral valve repair.


Determination of o-phthalaldehyde for dose verification of the clinical disinfectant by fluorescent sequential injection analysis.
A new automated, generic analytical approach for determining the clinical disinfectant o-phthalaldehyde (OPA) is reported in this study. The proposed sequential injection analysis (SIA) is based on the online reaction of the OPA with glycine/N-acetylcysteine (NAC) in a neutral medium (pH = 7.0) to form a highly fluorescent isoindole derivative. All critical flow and reaction variables were investigated, while validation was carried out in the linearity detection range (0.0075-0.02%). As a result, excellent linearity (R2 > 0.99) and precision (1.5-2.4% for repeatability and 0.7-2.2% for reproducibility) were achieved for the reference OPA solutions. Furthermore, reasonable concentration verification of OPA disinfection (0.2-0.6%) in healthcare institutes can be achieved using the developed fluorescent SIA due to its good sensitivity (0.111 V/%) and precision (1.0-2.3% for intermediate precision) around the minimum effective concentration (MEC) of 0.3% for Cidex-OPA disinfectant.


A versatile simulator of evoked potentials.
A simple electronic device is described which simulates evoked potentials with variable amounts of superimposed noise to facilitate routine checking and testing of apparatus and computer programs in an evoked potential laboratory.


Multifunctional MXene/C Aerogels for Enhanced Microwave Absorption and Thermal Insulation.
Two-dimensional transition metal carbides and nitrides (MXene) have emerged as promising candidates for microwave absorption (MA) materials. However, they also have some drawbacks, such as poor impedance matching, high self-stacking tendency, and high density. To tackle these challenges, MXene nanosheets were incorporated into polyacrylonitrile (PAN) nanofibers and subsequently assembled into a three-dimensional (3D) network structure through PAN carbonization, yielding MXene/C aerogels. The 3D network effectively extends the path of microcurrent transmission, leading to enhanced conductive loss of electromagnetic (EM) waves. Moreover, the aerogel's rich pore structure significantly improves the impedance matching while effectively reducing the density of the MXene-based absorbers. EM parameter analysis shows that the MXene/C aerogels exhibit a minimum reflection loss (RLmin) value of - 53.02 dB (f = 4.44 GHz, t = 3.8 mm), and an effective absorption bandwidth (EAB) of 5.3 GHz (t = 2.4 mm, 7.44-12.72 GHz). Radar cross-sectional (RCS) simulations were employed to assess the radar stealth effect of the aerogels, revealing that the maximum RCS reduction value of the perfect electric conductor covered by the MXene/C aerogel reaches 12.02 dB m2. In addition to the MA performance, the MXene/C aerogel also demonstrates good thermal insulation performance, and a 5-mm-thick aerogel can generate a temperature gradient of over 30 °C at 82 °C. This study provides a feasible design approach for creating lightweight, efficient, and multifunctional MXene-based MA materials.


Dramatic improvement in FMD DNA vaccine efficacy and cross-serotype antibody induction in pigs following a protein boost.
To overcome the low and slow development of humoral antibody often observed with DNA vaccines we applied a prime-boost strategy. When FMD DNA vaccine P1-2A3C3D and pGM-CSF primed pigs were boosted with inactivated foot-and-mouth disease virus (FMDV) antigen and recombinant 3D (without adjuvant) an average 36-fold increase in the FMDV antibody response was observed compared to conventional vaccination, that included a log(10) virus neutralising titre increase. Most remarkably, a significant level of cross-serotype reactivity was observed against A, C and Asia1 in the virus neutralisation and ELISA tests. This prime-boost strategy fully protected pigs from a heterologous challenge.


The role of human perfusion techniques in the assessment of oral rehydration solutions.
Early human intestinal perfusion studies provided valuable information on gut transport procession in vivo. Subsequently, similar models have proved a useful means of assessing the efficacy of glucose-electrolyte oral rehydration solutions. In contrast to clinical trials they enable quantification of water and solute movement across the small intestine and, unlike animal studies, results are directly applicable to man. However, limitations exist, including the fact that a short, usually normal, segment of intestine is studied. Recent studies confirm the relationship between oral rehydration solution sodium concentration and sodium movement; the stimulatory effect of glucose on sodium and water movement; and the detrimental effect of high glucose content. Glycine, bicarbonate, citrate and acetate provide little additional benefit for water absorption when added to solutions containing glucose. Preliminary comparative studies of results obtained in the rat and in man show parallels between these models suggesting they may be complimentary methods of assessing new oral rehydration solutions.


A multicenter phase 2 study of risk-adjusted salvage chemotherapy incorporating vinorelbine and gemcitabine for relapsed and refractory lymphoma.
Administration of salvage chemotherapy to patients with relapsed or refractory lymphoma is associated with significant toxicity. Vinorelbine and gemcitabine are novel chemotherapeutic agents with minimal overlapping toxicity. We present a phase 2 study of vinorelbine and gemcitabine with or without ifosfamide administered in an ambulatory care setting for relapsed or refractory lymphoma. Ninety patients were enrolled. Group 1 comprised patients with "good" risk disease, Group 2 comprised patients with "high" risk disease, and Group 3 comprised patients relapsing after prior stem cell transplant. Patients in Group 1 and Group 3 received vinorelbine and gemcitabine with filgrastim support (VGF); those in Group 2 received the above regimen with ifosfamide (FGIV). We incorporated a standardized interim evaluation with dose escalation for patients with suboptimal response after 2 cycles. Toxicities were acceptable. Febrile neutropenia was uncommon: 7% after VGF (7 of 107 cycles) and 19% for FGIV (26 of 148 cycles). Unplanned admissions occurred in 23 of 107 cycles (21%) after VGF and 50 of 148 (34%) after FGIV. Overall response for Groups 1, 2 and 3, respectively was 76%, 39% and 50%, with median overall survival of 28, 9 and 30 months. Vinorelbine-based and gemcitabine-based chemotherapy is effective in the salvage setting against lymphoma and can be administered in an ambulatory setting.


Heterogeneity correction for intensity-modulated frameless SRS in pituitary and cavernous sinus tumors: a retrospective study.
Frameless immobilization allows for planning and quality assurance of intensity-modulated radiosurgery (IM-SRS) plans. We tested the hypothesis that IM-SRS planning with uniform tissue density corrections results in dose inaccuracy compared to heterogeneity-corrected algorithms. Fifteen patients with tumors of the pituitary or cavernous sinus underwent frameless IM-SRS. Treatment planning CT and MRI scans were obtained and fused to delineate the tumor, optic nerves, chiasm, and brainstem. The plan was developed with static gantry IM-SRS fields using a pencil beam (PB), analytical anisotropic (AAA), and Acuros XB (AXB) algorithms. We evaluated measures of target coverage as well as doses to organs at risk (OAR) for each algorithm. We compared the results of each algorithm in the cases where PTV overlapped OAR (n = 10) to cases without overlapping OAR with PTV (n = 5). Utilizing film dosimetry, we measured the dose distribution for each algorithm through a uniform density target to a rando phantom with non-uniform density of air, tissue, and bone. There was no difference in target coverage measured by DMaxPTV, DMinPTV, D95%PTV, or the isodose surface (IDS) covering 95% of the PTV regardless of algorithm. However, there were differences in dose to OAR. PB predicted higher (p < 0.05) Dmax for the brainstem, chiasm, right optic nerve, and left optic nerve. In cases of PTV overlapping an optic nerve (n = 7), PB was unable to limit dose to 8 Gy while achieving PTV coverage (PB 855 cGy vs. AAA 769 cGy, p = 0.05 vs. AXB 658 cGy, p = 0.03). Within the rando phantom, the PB and AAA algorithms over-estimated the dose delivered in the bone-tissue-air interface of the sinus (+17%), while the AXB algorithm closely predicted the actual dose delivered through the inhomogeneous tissue (+/- 1 % max, p < 0.05). Patients undergoing frameless SRS benefit from heterogeneity corrected dose plans when the lesion lies in areas of widely varying tissue density and near critical normal structures such as the skull base. Film dosimetry confirms that the AXB dose calculation algorithm more accurately predicts actual dose delivered though tissues of varying densities than PB or AAA dose calculation algorithms.


Anxiety and depression in the medical setting: an overview.
Many physicians fail to correctly diagnose, treat, or refer their patients with anxiety and depression. These are common and costly disorders, but many barriers often prevent effective care for them in medical settings. Greater knowledge about these disorders and closer working relationships with mental health specialists should lead to decreased morbidity and mortality.


Should we be performing more randomized controlled trials evaluating surgical operations?
The objective of this study was, first to determine what proportion of clinical treatment evaluation questions involving surgical operations could be answered by a randomized controlled trial (RCT). Second, for those questions not amenable to a RCT, to determine the problems that potentially preclude the initiation of RCT in an ideal clinical research setting. A sample of treatment evaluation questions involving a surgical procedure was obtained by a computerized search of the surgical literature. Problems precluding a RCT were defined. Their face validity and interobserver and intraobserver reliability were assessed. By use of these criteria, the sample questions were evaluated to determine whether a RCT could be performed and, if not, the predominant reasons precluding RCT of surgical procedures. Only 38.8% of treatment evaluation questions could have been answered by a RCT in an ideal clinical research setting. Patient preference was the most common precluding problem encountered (40% of all problems). The principal precluding problem was patient preference in 23.1%, an uncommon condition in 24.2%, and lack of community (clinical) equipoise in 10%. Methodologic issues (1.2%) and surgical preference (2.3%) were infrequent precluding problems. Questions evaluating therapy for malignant disease, comparing surgical with nonsurgical therapies, and where survival was the primary outcome were more likely to have problems precluding RCT. In the ideal situation RCT can be performed to evaluate only 40% of treatment questions involving surgical procedures. Patient preferences, uncommon conditions, and lack of surgical community equipoise appear to be the most common reasons precluding the of RCT of surgical operations.


A comparative study of immobilization techniques for urease on glass-pH-electrode and its application in urea detection in blood serum.
Different techniques have been used (physical adsorption, physically entrapped sandwich and microencapsulation) for the immobilization of urease enzyme in tetramethylorthosilicate (TMOS) derived sol-gel matrix on the sensing surface of glass-pH-electrode. No significant leaching of enzyme occurs from the microencapsulated and physically entrapped enzyme sandwich films. Potentiometric techniques have been used for the estimation of urea concentration in each instance. Various parameters of biosensor performance have been studied which indicates that microencapsulation technique is a better method of enzyme immobilization in sol-gel films derived from TMOS. The advantage of microencapsulated biosensor over others include higher sensitivity (dpH/dp(C)=2.4), lower detection limit of 52 microg mL(-1), larger linear range (0.01-30 mM) of urea determination and reasonably long-term stability of about 25 days with 80% response signal.


The emerging Fusarium toxin enniatin B: in-vitro studies on its genotoxic potential and cytotoxicity in V79 cells in relation to other mycotoxins.
The Fusarium metabolite enniatin B is now recognized as a frequent contaminant of grains used for human foods and animal feeds. Yet, so far very limited data are available on its toxicity and that of other emerging Fusarium mycotoxins (Jestoi M, 2008, Crit Rev Food Sci Nutr 48:21-49). Thus, the mutagenic/genotoxic potential of enniatin B was investigated in a battery of short-term tests, and its cytotoxicity compared with that of several other mycotoxins. No mutagenicity was detected in the Ames assay with four Salmonella typhimurium strains, and in the HPRT (hypoxanthine guanine phosphoribosyl transferase) assay with V79 cells, in either the presence or absence of an external metabolizing enzyme system (rat liver S9). For other types of genotoxicity, i.e., clastogenicity and chromosomal damage, studied in V79 cells by means of alkaline single-cell gel electrophoresis (Comet) assay and micronucleus assay, no significant genotoxic potential of enniatin B was revealed. However, the Fusarium metabolite exerts pronounced time- and concentration-dependent cytotoxic effects in V79 cells as determined by Alamar Blue reduction and by neutral red uptake assays. For instance, IC20 and IC50 values determined for enniatin B by neutral red assay for 48-h exposure are 1.5 μM and 4 μM. These values are higher than those of the more potent Fusarium toxin deoxynivalenol (IC20 0.7 μM, IC50 of 0.8 μM), but clearly lower than the IC values of several other mycotoxins tested in parallel. Their ranking of cytotoxicity in V79 cells was as follows: deoxynivalenol > enniatin B > patulin > ochratoxin A > zearalenone > citrinin. Moreover, enniatin B was found to induce nuclear fragmentation, a sign of apoptosis, already at low submicromolar concentrations. In summary, despite an apparent lack of mutagenic and genotoxic activity, enniatin B can cause pronounced cytotoxicity in mammalian cells, detectable at low micromolar concentrations.


Four new Entiminae from the Mediterranean region (Coleoptera: Curculionidae: Entiminae: Phyllobiini, Trachyphloeini), with additional data on the distribution of some poorly known species.
Argoptochus sappho sp. n. and Pelletierellus bryophilus sp. n. from Lesbos island, Greece, Cathormiocerus kostali sp. n. from Morocco, and C. meyeri sp. n. from Portugal are described. New faunistic data are presented for Argoptochus moraveci Borovec, 2006, Cathormiocerus inflatiscapus Escalera, 1918, C. jeani (Borovec, 1989), C. longiscapus Pic, 1912, C. tenuiscapus Fairmaire, 1884, Pelletierellus bosnicus (Apfelbeck, 1898) and P. neglectus (Borovec, 1992). Males of Cathormiocerus inflatiscapus Escalera, 1918 and C. tenuiscapus Fairmaire, 1884 are described for the first time and the penises of these species are illustrated.


Effect of roasting speed on the volatile composition of coffees with different cup quality.
This study investigated the volatile composition of coffee blends of different cup quality, roasted in an industrial-scale semi-fluidized bed roaster (SFBR) and in a lab-scale fluidized bed roaster (FBR), at three roasting speeds/profiles, to reach medium roast degree. Thirty volatile compounds were selectively investigated. Roasting the specialty coffee blend in both roasters produced lower concentrations of total volatile compounds, compared to the low cup quality blends. Higher concentrations of pyrazines and phenols were observed in low cup quality blends. In SFBR, quality and roasting speed affected all groups of compounds, including impact compounds such as 2,5-dimethylpyrazine, 2-ethylpyrazine, 2,3-dimethylpyrazine, 2-methoxyphenol and 4-ethyl-2-methoxyphenol. In FBR, only phenols were affected. The present results help explain why different roast profiles should be used for coffees with different cup quality for better sensory outcome and why blending should be performed after roasting of green seeds. They also show that results obtained in lab scale roasters are not necessarily reproduced in industry under the same settings.


Disorder and partial folding in the regulatory subunit hinge region of Trypanosoma brucei protein kinase A: The C-linker portion inhibits the parasite's protein kinase A.
Microbial pathogens, such as Trypanosoma brucei, have an enormous impact on global health and economic systems. Protein kinase A of T. brucei is an attractive drug target as it is an essential enzyme which differs significantly from its human homolog. The hinge region of this protein's regulatory domain is vital for enzymatic function, but its conformation is unknown. Here, the secondary structure of this region has been characterized using NMR and CD spectroscopies. More specifically, three overlapping peptides corresponding to residues T187-I211, G198-Y223 and V220-S245 called peptide 1, peptide 2 and peptide 3, respectively, were studied. The peptide 1 and peptide 2 are chiefly unfolded; only low populations (<10%) of α-helix were detected under the conditions studied. In contrast, the peptide 3 contains a long α-helix whose population is significantly higher; namely, 36% under the conditions studied. Utilizing the dihedral φ and ψ angles calculated on the basis of the NMR data, the conformation of the peptide 3 was calculated and revealed an α-helix spanning residues E230-N241. This α-helix showed amphiphilicity and reversible unfolding and refolding upon heating and cooling. Most fascinating, however, is its capacity to inhibit the activity of the catalytic domain of Trypanosoma equiperdum protein kinase A even though it is quite distinct from the canonical inhibitor motif. Based on this property, we advance that peptoids based on the peptide 3 α-helix could be novel leads for developing anti-trypanosomal therapeutics.


LncRNA TP73-AS1/miR-539/MMP-8 axis modulates M2 macrophage polarization in hepatocellular carcinoma via TGF-β1 signaling.
Our study aimed to study the role of lncRNA TP73-AS1/miR-539/MMP-8 axis in modulating M2 macrophage polarization in hepatocellular carcinoma (HCC). The gene expression levels of TP73-AS1, miR-539 and MMP-8 were modified by transfection with the overexpression or knockdown vectors. The patient survival rate was analyzed using Kaplan-Meier method. The levels of TP73-AS1, miR-539, MMP-8 and M1/2 macrophage polarization markers were analyzed by qRT-PCR, western blot, and flow cytometry. The release of TGF-β1 in the supernatant was determined by ELISA assay. The interaction between TP73-AS1, miR-539 and MMP-8 was analyzed by bioinformatics analysis and dual-luciferase reporter assays. Mouse xenograft model was further established to examine the therapeutic effects of the TP73-AS1 knockdown and miR-539 overexpression in vivo. We found TP73-AS1 and MMP-8 upregulation, and miR-539 downregulation in HCC tissues and cell lines. Lower TP73-AS1 and MMP-8 expressions and higher miR-539 expression were associated with higher survival rate of patients. M2-macrophage markers CD206, Arg-1 and CD163 were significantly upregulated in the tumor tissues. TP73-AS1 negatively and directly regulated miR-539 and knockdown of TP73-AS1 inhibited MMP-8 expression and M2 macrophage polarization. Also, overexpression of miR-539 suppressed M2 macrophage polarization by negatively regulating MMP-8. Furthermore, knockdown of MMP-8 also restrained M2 macrophage polarization via inhibiting TGF-β1 signaling. We also found knockdown of TP73-AS1 or overexpression of miR-539 inhibited HCC tumor growth and M2 macrophage infiltration in vivo. Our study demonstrated lncRNA TP73-AS1 negatively regulated miR-539 to promote MMP-8 expression, which activated TGF-β1 signaling to induce M2 macrophage polarization in HCC.


Risk of Melanoma and Nonmelanoma Skin Cancer in People with Vitiligo: United Kingdom Population-Based Cohort Study.
Although genetic studies have found an inverse relationship between vitiligo and skin cancer, epidemiological evidence is conflicting. We investigated the risk of skin cancer in adults with vitiligo using United Kingdom electronic primary care records from the Optimum Patient Care Research Database 2010-2020. Vitiligo cases were age, sex, and general practitioner practice matched to population controls without vitiligo. Incidence of melanoma, nonmelanoma skin cancers (squamous cell carcinoma and basal cell carcinoma), and actinic keratoses was compared between vitiligo cases and controls using Cox regression. A total of 15,156 vitiligo cases were matched to 60,615 controls. Vitiligo was associated with a 38% reduced risk of new-onset skin cancer (adjusted hazard ratio [aHR] = 0.62, 95% confidence interval [CI] = 0.52-0.75, P < 0.001) and skin cancer subtypes; melanoma (aHR = 0.39, 95% CI = 0.23-0.65, P < 0.001), squamous cell carcinoma (aHR = 0.67, 95% CI = 0.49-0.90, P < 0.01), basal cell carcinoma (aHR = 0.65, 95% CI = 0.51-0.83, P < 0.001). There was no significant association for actinic keratosis (aHR = 0.88, 95% CI = 0.77-1.01). People with vitiligo have a markedly reduced incidence of melanoma and nonmelanoma skin cancer. Given concerns that some treatments, such as phototherapy, may increase skin cancer risk, this finding provides reassurance to people with vitiligo and clinicians managing the condition.


[Conservative treatment of malignant intra-ocular tumours seen in Lausanne. First report (author's transl)].
Conservative treatment of malignant tumours situated within the eye, was begun in Lausanne eight years ago. Although the period of observation has been short and the number of patients limited, we can already note the first results, insisting particularly on the dangers and difficulties encountered during this plan of treatment.


Reduced serotonin content and uptake in platelets from patients with essential hypertension: is a ouabain-like factor involved?
Platelet serotonin (5-HT) content was investigated in 35 essential hypertensive patients and in 58 normotensive subjects. A significant decrease of platelet 5-HT content was observed in both hypertensive men and women in respect to normotensive controls. This decreased platelet 5-HT content appears to be linked to a reduced capacity of platelets to take up 5-HT. Maximal velocity of 5-HT uptake was shown to be reduced in platelets from hypertensive patients and significantly correlated to platelet 5-HT content. No concomitant change of uptake Michaelis constant (KM) was observed. The great sensitivity of human platelets to very low concentrations of ouabain was demonstrated when incubation times were prolonged. The decreased Vmax observed in platelets from hypertensive patients and reproduced by ouabain inhibition could conceivably be linked to the presence of a circulating ouabain-like factor in hypertension.


Early thermal aging detection in tin based perovskite solar cell.
Tin-based perovskite solar cells (T-PSCs) are introduced as the next generation of valid and environment-friendly photovoltaic (PV) cells for near-future commercialization. However, there are some issues limiting T-PSCs including their instability, low efficiency, and use of toxic processing solvents. Among all these barriers, instability and early aging under thermal stress conditions are considered as significant challenges to the development of the T-PSCs. In this study, the impact of different temperature levels on the performance of a T-PSC is investigated over time. It is observed that early degradation of the device occurs at higher temperatures. For timely detection of the early aging, an accurate adaptive estimation of the series resistance is obtained in the equivalent single-diode circuit model of the T-PSC. It is shown that the trend of changes in the series resistance is a reliable indication of the aging process in the T-PSC. Finally, a mathematical index is derived for early aging detection based on the relative variation of the gradient from its minimum value in the linear regression analysis. The proposed approach could be utilized for timely detection of early aging conditions and protection of the device from permanent damage.


Maternal Lifetime Trauma and Birthweight: Effect Modification by In Utero Cortisol and Child Sex.
To evaluate associations between maternal lifetime traumatic stress and offspring birthweight and examine modifying effects of third trimester cortisol and fetal sex. Analyses included 314 mother-infant dyads from an ethnically mixed pregnancy cohort. Maternal lifetime trauma was reported via the Life Stressor Checklist-Revised. Fenton birthweight for gestational age z-scores (BWGA-z) were calculated. A 3-cm scalp-nearest maternal hair segment collected at birth was assayed to reflect cumulative third trimester cortisol secretion. Multivariable regression was used to investigate associations between maternal lifetime trauma and BWGA-z and examine 2- and 3-way interactions with cortisol and fetal sex. Because subjects with low or high cortisol levels could represent susceptible populations, varying coefficient models that relax the linearity assumption on cortisol level were used to assess the modification of maternal lifetime trauma associations with BWGA-z as a function of cortisol. Women were primarily minorities (41% Hispanic, 26% black) with ≤12 years education (63%); 63% reported ≥1 traumatic event. Prenatal cortisol modified the association between maternal lifetime trauma and birthweight. Women with higher lifetime trauma and increased cortisol had significantly lower birthweight infants in males; among males exposed to the 90th percentile of cortisol, a 1-unit increase in trauma score was associated with a 0.19-unit decrease in BWGA-z (95% CI, -0.34 to -0.04). Associations among females were nonsignificant, regardless of cortisol level. These findings underscore the need to consider complex interactions among maternal trauma, disrupted in utero cortisol production, and fetal sex to fully elucidate intergenerational effects of maternal lifetime trauma.


Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51.
The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial. Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis. The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014). Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).