In vitro expansion of U87-MG human glioblastoma cells under hypoxic conditions affects glucose metabolism and subsequent in vivo growth.
Hypoxia is a characteristic feature of solid tumors leading to the over expression of hypoxia-inducible factor (HIF)-1α protein and therefore to a specific cellular behavior. However, even though the oxygen tension in tumors is low (<5 %), most of the cell lines used in cancer studies are grown under 21 % oxygen tension. This work focuses on the impact of oxygen conditions during in vitro cell culture on glucose metabolism using 1-(13)C-glucose. Growing U87-MG glioma cells under hypoxic conditions leads to a two- to threefold reduction of labeled glutamine and an accumulation of fructose. However, under both hypoxic and normoxic conditions, glucose is used for de novo synthesis of pyrimidine since the (13)C label is found both in the uracil and ribose moieties. Labeling of the ribose ring demonstrates that U87-MG glioma cells use the reversible branch of the non-oxidative pentose phosphate pathway. Interestingly, stereotactic implantation of U87-MG cells grown under normoxia or mild hypoxia within the striatum of nude mice led to differential growth; the cells grown under hypoxia retaining an imprint of the oxygen adaptation as their development is then slowed down.


Reducing Vocal Fatigue While Preserving Realism During Video Game Voice-Overs Using the Vocal Combat Technique: A Randomized Controlled Trial.
Vocal Combat Technique (VCT) teaches indirect and direct behavioral voice techniques to voice-over artists performing in violent video games. Although previous work on VCT has shown promise for mitigating dysphonia symptoms, a randomized clinical trial has yet to be undertaken. Therefore, we completed a randomized, controlled trial between a group of experienced video game voice-over actors receiving VCT and a control group comparison. A total of 24 video game voice-over actors completed this study. Participants were randomly assigned to receive VCT or indirect vocal hygiene training prior to completing an intensive 1-hour video game voice recording session. The primary outcome was a change in Voice Handicap Index-10 (VHI-10) preperformance/postperformance. Secondary measures included a modified version of the Evaluation of the Ability to Sing Easily (m-EASE), the Vocal Tract Discomfort Scale (VTDS), and questions regarding return to work. Participants were also rated on the realism of their vocal performance by a blinded video game director. The VCT group showed a significantly smaller change in VHI-10 and m-EASE scores postperformance, and a higher increased likelihood to return to work compared to the control group. There were no group differences for VTDS or realism ratings. Four participants from the control group exhibited outlier behavior with more pronounced phonotraumatic symptoms following performance than all other participants. VCT shows evidence of mitigating symptoms of dysphonia while preserving the realism of the vocal performance. More work is needed to understand performers at risk for more severe vocal symptoms following extreme voice-over work, so as to target them for preventative techniques and voice preservation.


Commentary on, 'Internal reliability of measures of substance-related cognitive bias'.
A recent paper published in Drug and alcohol dependence (Ataya et al., 2012) is the first systematic attempt to establish the internal reliability of measures of substance-related attentional bias, and it makes an important and long overdue contribution to this topic. The authors reported that the reliability of attentional bias indices derived from the visual probe task was very poor, and while the attentional bias index from the Stroop was a little better, it fell some way short of being acceptable, as α>0.70 in only two of six studies in which the task was used. In this commentary, we speculate on some of the factors that might have contributed to the poor reliability of the tasks, and how task reliability might be improved in future studies.


A look ahead to promote the early detection of lung cancer: technical and cost implications of a confirmed diagnosis before surgery.
To compare the costs and length of hospital stay among patients with a confirmed diagnosis of lung cancer (LC) prior to surgery versus those without confirmation. This retrospective, single-center study was conducted in patients who underwent a surgical procedure for LC, with or without a pathologically confirmed LC diagnosis prior to surgery, between March 2017 and December 2019. The main outcomes were costs and length of hospital stay (LOS). Among the 269 patients who underwent surgery for lung cancer between March 2017 and December 2019, 203 (75.5%) patients underwent surgery due to a histopathological diagnosis, and 66 (24.5%) because of a Multidisciplinary Cancer Committee indication. The unadjusted mean cost was significantly lower in Group II (patients with surgery based on Multidisciplinary Cancer Committee criteria) (Є2,581.80 ± Є1,002.50) than in Group I (patients with histopathological diagnosis) (Є4,244.60 ± Є2,008.80), P < 0.0001. Once adjusted for covariables, there was a mean difference of -Є1,437.20 in the costs of Group II, P < 0.0001. Unadjusted mean hospital stay was significantly longer in Group I (5.6 days) than in Group II (3.5 days). The results suggest that indicating surgical resection of lung cancer based on Multidisciplinary Cancer Committee criteria, rather than performing CT-guided percutaneous lung biopsy, may result in a significant decrease in cost and length of hospital stay.


Health care utilization in very advanced ages: A study on predisposing, enabling and need factors.
This study aims to examine the effects of predisposing, enabling, and need factors on healthcare utilization in advanced age. Data from a sample of 270 Portuguese community-dwelling persons aged ≥80 years was used. Face-to-face interviews were conducted and included the application of a research protocol addressing a set of sociodemographic and health-related variables that expressed the Andersen Behavioral model (i.e., predisposing, enabling, and need factors). Predictors of visits to general practitioners (GP) and specialist physicians, as well as emergency department (ED) use and hospitalizations were investigated. Multivariate linear and logistic regression analyzes were used to model the effects of predictor factors specified in the Andersen Behavioral model. Our findings underscore that younger age and having multimorbidity were significantly associated with having GP visits. Specialist physician visits were associated with younger age and a higher number of daily medications. ED use was associated with being male, having formal social support and a higher number of daily medications. Hospitalizations were associated with being younger, being male and having multimorbidity. Our findings revealed that need and predisposing factors determined the most healthcare use.


The contraceptive efficacy of Implanon: a review of clinical trials and marketing experience.
To evaluate the contraceptive efficacy of the etonogestrel-releasing implant Implanon as assessed in international studies and during nine years of marketing experience. The analysis included 11 international studies and data collected during nine years of marketing experience (1998--2007). Seven of these studies were noncomparative; the four other studies included the 6-rod levonorgestrel implant system or an intrauterine device as a comparator. All studies except one were of at least two years in duration, and all had contraceptive efficacy as the objective. Market data were provided unsolicited to Organon, part of Schering Plough. The integrated efficacy analysis included 923 non-breastfeeding women who were exposed to the implant for 24,100 cycles. No in-treatment or pretreatment pregnancies were reported. Fifty posttreatment pregnancies were reported, six of which occurred within 14 days of implant removal, indicating that fertility had quickly returned. Over a nine-year marketing period an overall pregnancy rate of 0.049 per 100 implants sold (estimated Pearl Index = 0.031 based on all pregnancies reported) was calculated. When only counting contraceptive method failures the pregnancy rate amounts to 0.010 per 100 implants sold (estimated Pearl Index = 0.006). Implanon is a highly effective and quickly reversible subdermal method of long-acting hormonal contraception for women. Typical use of this implant achieves a contraceptive protection exceeding 99%.


Inguinal bladder hernia with lipomatosis of the bladder wall: A potential clinical pitfall for cancer.
A 70-year-old man was referred to the Urology Service of our University Hospital for an irregular thickening of the left anterior-lateral urinary bladder wall found in a computed tomography scan following gross haematuria. In particular, the computed tomography scan showed irregularity of the mucosal aspect and an irregular thickening of the bladder wall in close proximity of an inguinal hernia. The computed tomography exam also showed an unusual little fatty seizure in the parietal planes. A magnetic resonance imaging confirmed the thickening in the same area as the hernia with a mainly extraluminal presentation and extension in the perivesical adipose tissue. Cystoscopy did not show alteration of the mucosal surface. Urine cytology showed normal urothelium cells. At the time of the left inguinal hernia repair, the bladder was isolated from the inguinal hernia fat tissue and then opened with median cystotomy. Biopsy of the anterior-lateral bladder wall showed normal urothelium and an abundant component of mature lobules of adipose tissue in the sub-epithelial connective tissue extending among the muscle bundles of muscularis propria, compatible with a diagnosis of lipomatosis, a very rare lesion in the urinary bladder.


Antiproliferative effects of the antiallergic agent azelastine on human aortic smooth-muscle cells: an in vitro study.
The aim of the study was to examine the effects of azelastine on proliferation, clonogenic activity, cell-cycle, and migration of human aortic smooth-muscle cells (haSMCs) in vitro. HaSMCs were treated for 4 days with azelastine (1 micromol/L, 25 micromol/L, 50 micromol/L). Half of the treated groups were incubated again with azelastine, the other half received azelastine-free medium every 4 days until day 20. The growth kinetics and clonogenic activity were assessed. The cell-cycle distribution was investigated by FACS -- analysis and the migratory ability was evaluated. Azelastine inhibited the proliferation and the clonogenic activity of haSMCs in a dose dependent manner. A G2/M-phase block was induced and the migratory ability was significantly impaired. Azelastine has the potential to inhibit the proliferation of haSMCs. If a sufficient dose can be applied either systemically or locally it could be a valuable substance to prevent restenosis.


Causes of blindness and visual impairment in the West of Scotland.
To determine the overall reported incidence and causes of registrable blindness and visual impairment in the West of Scotland and any trends that have occurred in the previous 16 years since data from the same area were published. Data for analysis were obtained from BP1 registration forms returned to the Resource Centre for the Blind serving the Strathclyde region in the West of Scotland between 1 April 1996 and 31 March 1997. A total of 1595 visually handicapped people were registered during the study year. Of these, 99 forms (6.2%) were excluded from further analysis because of insufficient information. The remaining 1496 completed BP1 Forms were in respect of 530 males and 966 females. Of these, 253 males and 450 females were legally blind (total 703 or 47.0%) and 277 males and 516 females were partially sighted (total 793 or 53.0%). The five leading causes of blindness, in decreasing frequency, were age-related macular degeneration (ARMD), glaucoma, diabetic retinopathy, myopic degeneration, and optic atrophy. ARMD and diabetic retinopathy were the most common causes of blindness in those over 65 years and persons of working age, respectively. In adults, cataract is no longer a significant cause of registrable visual impairment. The proportions of registrations owing to glaucoma, diabetic retinopathy, and myopia have not significantly changed since 1983 and the proportion owing to macular degeneration has increased. In children, congenital glaucoma, cataract, and corneal infection were no longer causes of registration, but impairment of vision caused by brain damage is now a significant contributor.


Filtering surgery with 5-fluorouracil: a second course.
In five glaucoma patients, a previous filtering surgery that was followed by sub-conjunctival injections of 5-Fluorouracil (5-FU) failed, due to filtering bleb scarring. A repetition of the filtering surgery with subsequent sub-conjunctival injections of 5 mg of 5-FU, administered once daily for 8-14 days, was undertaken. At the end of 6-19 months of follow-up, IOP levels in all five eyes were 20 mmHg or less with medication. A repeated course of filtering surgery plus 5-FU treatment seems to be a favourable surgical option in refractory glaucoma.


Prospective comparison of magnetic resonance angiography with selective renal angiography for living kidney donor assessment.
For years, the reference standard in the evaluation of living donor vascular anatomy has been selective renal angiography (SRA). Because of the potential morbidity associated with SRA, we prospectively evaluated magnetic resonance angiography (MRA) in the assessment of renal donors. All patients had SRA and 53 renal units were prospectively evaluated by MRA. We used SRA supplemented by findings at donor nephrectomy (DN) as our standard. We defined a positive test as the detection of any abnormality in the number of renal arteries. Selective renal angiography yielded a sensitivity of 86%, specificity of 95%, positive predictive value (PPV) of 75%, and negative predictive value (NPV) of 97% compared with findings at DN. MRA had a sensitivity of 64%, 88% specificity, 58% PPV, and 90% NPV. MRA correctly identified only 7 of 11 renal units with accessory arteries. MRA also incorrectly identified 5 accessory arteries not present on SRA or DN. Two patients diagnosed with fibromuscular dysplasia by SRA were missed using MRA. We have shown that MRA is not capable of replacing SRA as the reference standard in renal donor imaging.


Behavioral inhibition during a conflict state elicits a transient decline in hippocampal theta power.
Although it has been shown that hippocampal theta power transiently declines during response inhibition in a simultaneous feature negative (FN: A+, AB-) task, observations of additional changes after this initial decline have been inconsistent across subjects. We hypothesized that the cause of these inconsistencies might be that variations in the learning speed for the FN task differentially affect the changes in hippocampal theta activity observed during the task. In this study, we classified rats into three groups (fast, intermediate, and slow FN-learning groups) based on the number of sessions required to complete learning of the FN task. We then examined whether there was a difference in hippocampal theta power among the fast, intermediate, and slow FN-learning groups, and rats that learned a simple discrimination task (SD group). We observed that compared to the SD group, the slow FN-learning group, but not the fast FN-learning group, showed an increase in hippocampal theta power. In addition, a transient decline of hippocampal theta power occurred in the fast FN-learning group, but not in the slow FN-learning group. These results indicate that the hippocampal theta activity during response inhibition in the FN task differed between fast- and slow-learning rats. Thus, we propose that a difference in learning speed affected hippocampal theta activity during response inhibition under a conflict state.


MEK'ing the most of p53 reactivation therapy in melanoma.
Melanoma is one of the few tumor types in which p53 is functionally repressed without extraneous mutations. With the number of kinase-based drug targets rapidly declining, p53 represents a relatively untapped resource for therapeutic intervention. Studies in other tumor types have demonstrated that reactivation of p53 is a viable strategy to initiate sustained tumor regression; combining p53 reactivation while inhibiting traditional genetic targets, such as mitogen-activated protein kinase/extracellular signal-related kinase kinase (MEK), holds therapeutic promise.


Essential and non-essential trace elements among working populations in Ghana.
Lead battery repair workers (LBRW) and electronic repair workers (ERW) may be exposed to inorganic components during work. This study aimed at determining essential and non-essential trace elements in male LBRW, ERW, referents and a group of female petty traders (FPT) in Kumasi (Ghana), taking into account iron status and inflammation. Altogether 64 LBRW, 64 ERW, 65 referents and 26 FPT were investigated in this cross-sectional study. Urine, whole blood and serum were collected for determination of trace elements. C-reactive protein and ferritin were determined in serum. The LBRW had higher blood concentrations of manganese (B-Mn) and lead (B-Pb) and antimony in urine (U-Sb), and lower concentrations of cobalt in blood (B-Co). Being ERW was associated with higher concentrations of blood cadmium (B-Cd), urinary tin (U-Sn) and serum chromium (S-Cr). Concentrations of selenium (B-Se), Co and mercury (B-Hg) in whole blood and iodine in urine (U-I) were relatively high. Marginal iron status appeared to be a determinant for elevated concentrations of Co in particular, but also Mn and Cd in blood. Systemic inflammation was associated with the concentrations of copper and Se. The concentrations of Hg in whole blood were highly associated with Se and arsenic (As) in whole blood, indicating fish consumption as a common source of intake of these elements. However, Hg in whole blood was only slightly associated with Se in serum. The ERW had elevated concentrations of B-Cd, S-Cr, and U-Sn, while B-Mn, B-Pb, and U-Sb concentrations were higher among the LBRW. Iron status and inflammation had substantial impact on some element concentration. This population had high concentrations of B-Se, B-Hg and B-Co and U-I.


Isolation and characterization of β-transducin repeat-containing protein ligands screened using a high-throughput screening system.
β-transducin repeat-containing protein (β-TrCP) is an F-box protein subunit of the E3 Skp1-Cullin-F box (SCF) type ubiquitin-ligase complex, and provides the substrate specificity for the ligase. To find potent ligands of β-TrCP useful for the proteolysis targeting chimera (PROTAC) system using β-TrCP in the future, we developed a high-throughput screening system for small molecule β-TrCP ligands. We screened the chemical library utilizing the system and obtained several hit compounds. The effects of the hit compounds on in vitro ubiquitination activity of SCFβ-TrCP1 and on downstream signaling pathways were examined. Hit compounds NPD5943, NPL62020-01, and NPL42040-01 inhibited the TNFα-induced degradation of IκBα and its phosphorylated form. Hence, they inhibited the activation of the transcription activity of NF-κB, indicating the effective inhibition of β-TrCP by the hit compounds in cells. Next, we performed an in silico analysis of the hit compounds to determine the important moieties of the hit compounds. Carboxyl groups of NPL62020-01 and NPL42040-01 and hydroxyl groups of NPD5943 created hydrogen bonds with β-TrCP similar to those created by intrinsic target phosphopeptides of β-TrCP. Our findings enhance our knowledge of useful small molecule ligands of β-TrCP and the importance of residues that can be ligands of β-TrCP.


Renal sodium-D-glucose cotransport system. Involvement of tyrosine residues in sodium-transporter interaction.
Using brush-border membrane vesicles isolated from calf kidney cortex the effect of tyrosine-reactive reagents on sodium-dependent D-glucose transport was investigated. Treatment of the membranes for 60 min with NBD-Cl (7-chloro-4-nitrobenzo-2-oxa-1,3-diazole), N-acetylimidazole or tetranitromethane decreased D-glucose uptake 50, 70 and 40%, respectively. Tracer exchange experiments revealed that the inhibition of transport is due to a direct modification of the sodium-D-glucose cotransport system. The modification by NBD-Cl decreases the apparent Vmax of the transport system with respect to its interaction with sodium. In addition, the rate of inactivation of the transport system by NBD-Cl is reduced in the presence of high concentrations of sodium. The results indicate that tyrosine residues play an essential role in sodium-D-glucose cotransport and are probably involved in the binding and/or transport of sodium by the sodium-D-glucose cotransport system.


Independent Roles of Switching and Hypermutation in the Development and Persistence of B Lymphocyte Memory.
Somatic hypermutation (SHM) and class-switch recombination (CSR) increase the affinity and diversify the effector functions of antibodies during immune responses. Although SHM and CSR are fundamentally different, their independent roles in regulating B cell fate have been difficult to uncouple because a single enzyme, activation-induced cytidine deaminase (encoded by Aicda), initiates both reactions. Here, we used a combination of Aicda and antibody mutant alleles that separate the effects of CSR and SHM on polyclonal immune responses. We found that class-switching to IgG1 biased the fate choice made by B cells, favoring the plasma cell over memory cell fate without significantly affecting clonal expansion in the germinal center (GC). In contrast, SHM reduced the longevity of memory B cells by creating polyreactive specificities that were selected against over time. Our data define the independent contributions of SHM and CSR to the generation and persistence of memory in the antibody system.


Metasurface designed with quantitative field distributions.
A new method for designing metasurfaces has been proposed and demonstrated, which allows for the generation of precise quantitative field distributions. This unique approach involves combining a tandem neural network with an iterative algorithm to optimize the metasurface design, enabling accurate control over the intensity and polarization of the resulting field. This strategy is both efficient and robust and has the potential to accelerate the development of metasurface devices with complex functionalities.


Low pH-dependent Sindbis virus-induced fusion of BHK cells: differences between strains correlate with amino acid changes in the E1 glycoprotein.
Expression of alphavirus glycoproteins on the surface of infected cells leads to cell fusion after exposure to acidic pH. Two strains of Sindbis virus, AR339 (SV) and neuroadapted Sindbis virus (NSV), which differ in virulence for weanling mice, were found to differ in pH-dependent fusion. BHK-21 cells infected with SV fused maximally after shifting to pH 5.4, whereas cells infected with NSV required a lower pH, pH 4.8, for maximal fusion. No difference was noted in the optimal pH for agglutination of goose erythrocytes (5.75 for both viruses). To determine the molecular basis for the difference in fusion a series of recombinant viruses was constructed using a cDNA clone of Sindbis virus from which infectious RNA can be transcribed in vitro. Cells infected with a recombinant virus that had the SV E1 and NSV E2 genes had a fusion response curve as a function of pH like SV, while cells infected with recombinant virus with the NSV E1 and SV E2 genes fused like NSV. The E1 glycoproteins of SV and NSV differ at two positions: Val-72 in SV is Ala in NSV (a change near the putative fusion site), and Gly-313 in SV is Asp in NSV. Recombinant viruses which had Val-72 (SV) and Asp-313 (NSV) or Ala-72 (NSV) and Gly-313 (SV) had a lowered pH of fusion like NSV suggesting that both positions participate in determining some aspect of the conformational change in the E1-E2 heterodimer associated with pH-dependent fusion.


Knockout of spinophilin, an endogenous antagonist of arrestin-dependent alpha2-adrenoceptor functions, enhances receptor-mediated antinociception yet does not eliminate sex-related differences.
We have previously shown gonadal steroid-dependent, gender specific modulation of nociception by alpha(2)-adrenoceptors. Agonist activation of the receptor enhances its association with spinophilin that antagonizes arrestin functions both by diminishing receptor phosphorylation by G-protein-coupled receptor kinase 2 (GRK2) and by competing for receptor interactions with arrestin. Since spinophilin is highly enriched in dendritic spines, we investigated whether alpha(2)-adrenoceptor-induced antinociception as well as sex-related differences are modified in spinophilin knockout mice. We evaluated alpha(2)-adrenoceptor antinociception in a heat-evoked tail flick test in spinophilin wild type (Sp(+/+)) and knockout (Sp(-/-)) mice. Baseline tail flick latencies (TFLs) did not change between any groups. Interestingly, the alpha(2)-adrenoceptor agonist, clonidine, increased TFL in male and diestrous (low estrogen) Sp(-/-) as well as Sp(+/+) mice; in fact, this increase in TFL was significantly higher in Sp(-/-) male and diestrous groups than in their Sp(+/+) counterparts. This unexpected finding is consistent with enhanced alpha(2)-adrenoceptor-mediated sedation observed previously in Sp(-/-) mice, presumably due to accelerated endocytosis of desensitized receptors and recycling of refreshed receptors when arrestin is not competed for by spinophilin in Sp(-/-) mice. Despite modulation of alpha(2)-adrenoceptor effects in Sp(-/-) mice, sex-related differences were retained; thus, clonidine was ineffective in proestrous females (highest estrogen levels), in both Sp(-/-) and Sp(+/+) mice, reaffirming that estrogen suppresses alpha(2)-adrenoceptor-evoked antinociception. These findings show that elimination of spinophilin enhances alpha(2)-adrenoceptor-evoked antinociception in estrogen-deprived physiological settings, suggesting a role for spinophilin to suppress these effects, and yet this enhanced response cannot overcome the absence of antinociception with elevated estrogen levels.


Genopathomic profiling identifies signatures for immunotherapy response of lung adenocarcinoma via confounder-aware representation learning.
Immunotherapy shows durable response but only in a subset of patients, and test for predictive biomarkers requires procedures in addition to routine workflow. We proposed a confounder-aware representation learning-based system, genopathomic biomarker for immunotherapy response (PITER), that uses only diagnosis-acquired hematoxylin-eosin (H&E)-stained pathological slides by leveraging histopathological and genetic characteristics to identify candidates for immunotherapy. PITER was generated and tested with three datasets containing 1944 slides of 1239 patients. PITER was found to be a useful biomarker to identify patients of lung adenocarcinoma with both favorable progression-free and overall survival in the immunotherapy cohort (p < 0.05). PITER was significantly associated with pathways involved in active cell division and a more immune activating microenvironment, which indicated the biological basis in identifying patients with favorable outcome of immunotherapy. Thus, PITER may be a potential biomarker to identify patients of lung adenocarcinoma with a good response to immunotherapy, and potentially provide precise treatment.


Probiotics enhances anti-tumor immune response induced by gemcitabine plus cisplatin chemotherapy for urothelial cancer.
Chemotherapy drugs, such as gemcitabine and cisplatin (GC), are frequently administered to patients with advanced urothelial carcinoma, however the influence of the gut microbiota on their action is unclear. Thus, we investigated the effects of GC on the gut microbiome and determined whether oral supplementation with a probiotics mixture of Lactobacillus casei Shirota and Bifidobacterium breve enhanced the anti-tumor immune response. After subcutaneous inoculation with MBT2 murine bladder cancer cells, syngenic C3H mice were randomly allocated into eight groups. The gut microbiome cluster pattern was altered in both the GC and oral probiotics groups (p = 0.025). Both tumor-bearing conditions (no treatment) and GC chemotherapy influenced Pseudoclostridium, Robinsoniella, Merdimonas, and Phocea in the gut. Furthermore, comparison of the GC-treated and GC + probiotics groups revealed an association of four methyltransferase family enzymes and two short-change fatty acid-related enzymes with oral probiotics use. A significant difference in tumor volume was observed between the GC and GC + probiotics groups at week 2 of treatment. Additionally, decreased recruitment of cancer-associated fibroblasts and regulatory T cells, and activation of CD8+ T cells and dendritic cells were observed in the tumor microenvironment. Our findings reveal the positive effects of a probiotics mixture of Lactobacillus and Bifidobacterium in enhancing anti-tumor effects through the gut-tumor immune response axis. Future clinical trials are needed to evaluate the full benefits of this novel supplement with oral probiotics in patients with advanced urothelial carcinoma.


Total biomass of a single population in two-patch environments.
For the two-patch logistic model, we study the effect of dispersal intensity and dispersal asymmetry on the total population abundance and its distribution. Two complete classifications of the model parameter space are given: one concerning when dispersal causes smaller or larger total biomass than no dispersal, and the other addressing how the total biomass changes with dispersal intensity and dispersal asymmetry. The dependencies of the population abundance of each individual patch on dispersal intensity and dispersal asymmetry are also fully characterized. In addition, the maximal and minimal total population sizes induced by dispersal are determined for the logistic model with an arbitrary number of patches, and a weak order-preserving result correlated the local population abundances with and without dispersal is established.


Low frequency of community-acquired bacterial co-infection in patients hospitalized for COVID-19 based on clinical, radiological and microbiological criteria: a retrospective cohort study.
We defined the frequency of respiratory community-acquired bacterial co-infection in patients with COVID-19, i.e. patients with a positive SARS-CoV-2 PCR or a COVID-19 Reporting and Data System (CO-RADS) score ≥ 4, based on a complete clinical assessment, including prior antibiotic use, clinical characteristics, inflammatory markers, chest computed tomography (CT) results and microbiological test results. Our retrospective study was conducted within a cohort of prospectively included patients admitted for COVID-19 in our tertiary medical centres between 1-3-2020 and 1-6-2020. A multidisciplinary study team developed a diagnostic protocol to retrospectively categorize patients as unlikely, possible or probable bacterial co-infection based on clinical, radiological and microbiological parameters in the first 72 h of admission. Within the three categories, we summarized patient characteristics and antibiotic consumption. Among 281 included COVID-19 patients, bacterial co-infection was classified as unlikely in 233 patients (82.9%), possible in 35 patients (12.4%) and probable in 3 patients (1.1%). Ten patients (3.6%) could not be classified due to inconclusive data. Within 72 h of hospital admission, 81% of the total study population and 78% of patients classified as unlikely bacterial co-infection received antibiotics. COVID-19 patients are unlikely to have a respiratory community-acquired bacterial co-infection. This study underpins recommendations for restrictive use of antibacterial drugs in patients with COVID-19.


Fertility-Sparing Surgery for Early-Stage Cervical Cancer: A Systematic Review of the Literature.
This systematic review aimed to evaluate oncologic and reproductive outcomes after fertility-sparing surgery (FSS) for early-stage cervical cancer (early CC). Ovid MEDLINE, Ovid EMBASE, and Cochrane CENTRAL were searched from 1980 to the present using Medical Subject Headings terms; other controlled vocabulary terms; and keywords related to fertility, cervical cancer, and surgical techniques. A total of 2415 studies were screened, with 53 studies included. Studies reporting recurrences with a median follow-up of 12 months in early CC (International Federation of Gynecology and Obstetrics 2009 stages IA with lymphovascular space invasion, IB, or IIA) of traditional histologic type undergoing FSS were included. The studies were grouped by intervention, including vaginal radical trachelectomy (VRT), abdominal radical trachelectomy (ART), minimally invasive radical trachelectomy (MIS-RT), and conization or simple trachelectomy (ST), and studies involving neoadjuvant chemotherapy (NACT). Combined rates of recurrence (RR), cancer death (CDR), pregnancy (PR), and live birth (LBR) were calculated per procedure on the basis of all included studies that reported outcomes on that procedure. The results were as follows: VRT: RR 4%, CDR 1.7%, PR 49.4%, and LBR 65.0% ART: RR 3.9%, CDR 1.4%, PR 43.2%, and LBR 44.0% MIS-RT: RR 4.2%, CDR 0.7%, PR 36.2%, and LBR 57.1% Cone or ST: RR 4.2%, CDR 0.8%, PR 55.1%, and LBR 71.9% NACT: RR 7.5% and CDR 2.0% CONCLUSION: FSS of early CC with VRT, ART, or MIS-RT have comparable oncologic outcomes in carefully selected patients, with reproductive outcomes favoring VRT. Data on nonradical FSS with cone or ST are less robust but support similar oncologic outcomes to radical trachelectomy with fewer reproductive complications. NACT in this setting requires more investigation before routine implementation into practice.


Enhanced parainfluenza I (6/94) virus detection in latently infected human brain cell cultures by treatment with cytochalasin D and dimethyl sulfoxide.
The ability of cytochalasin D (CD) and dimethyl sulfoxide (DMSO) to enhance parainfluenza I (6/94) virus replication was studied in various cell culture systems. Treatment of CV1 cells with CD (1 microgram/ml) dissolved in DMSO prior to primary 6/94 virus exposure at 10(0)--10(5) multiplicities of infection did not substantially enhance virus replication. However, there was a transient increase in cell associated virus one day after infection of DMSO-treated cultures. CD treatment of cultures of human brain cells latently infected with 6/94 virus (LIHB cells) did not enhance 6/94 virus detection. Cocultivation of CV1 cells with CD-treated LIHB cell cultures, and cocultivation of LIHB cell cultures with CD-treated CV1 cells, resulted in the production of both cell-associated and cell-free 6/94 virus three and five days after cocultivation. No virus was detected after similar cocultivation of untreated LIHB cell cultures with untreated CV1 cells. The usefulness of CD-DMSO treatment in the rescue of virus from 6/94 LIHB cell cultures appears limited to a cocultivation system. The use of these techniques to enhance virus rescue from human tissues suspected of harboring latent viral genomes is discussed.


Inline blood gas analysis by gas chromatography in patients during and after coronary artery surgery.
A system was evaluated of measuring Pao2 and Pao2 by an inline sensor in the brachial artery and gas chromatography. Eight patients having coronary artery vein grafts were studied during anaesthesia, operation, perfusion and for 24 hours afterward. Compared to conventional blood gas analysis by polarography (electrodes), the chromatographic method gave readings for Pao2 which were not significantly different during normothermia. During hypothermic perfusion, the chromatographic system read significantly higher than the bench electrode, due at least in part to a difference in temperature correction. For Pao2 the correlation between the two methods was close and differences were clinically insignificant. The Sentorr blood-gas analyser provides a sensitive, accurate indicator of changes in oxygenation, ventilation and circulation during anaesthesia and in the intensive care unit.


The Natural Stories corpus: a reading-time corpus of English texts containing rare syntactic constructions.
It is now a common practice to compare models of human language processing by comparing how well they predict behavioral and neural measures of processing difficulty, such as reading times, on corpora of rich naturalistic linguistic materials. However, many of these corpora, which are based on naturally-occurring text, do not contain many of the low-frequency syntactic constructions that are often required to distinguish between processing theories. Here we describe a new corpus consisting of English texts edited to contain many low-frequency syntactic constructions while still sounding fluent to native speakers. The corpus is annotated with hand-corrected Penn Treebank-style parse trees and includes self-paced reading time data and aligned audio recordings. We give an overview of the content of the corpus, review recent work using the corpus, and release the data.


Sequence-specific 1H NMR assignments and secondary structure of a lipid-associating peptide from human ApoC-I: an NMR study of an amphipathic helix motif.
The conformation of a synthetic peptide corresponding to residues 35-53 (SAKM-REWFSETFQKVKEKL) of human apolipoprotein C-I (57 amino acids) was studied by nuclear magnetic resonance and circular dichroism spectroscopy in water and in perdeuterated dodecylphosphocholine solution at 37 degrees C and pH 4.8. The proton resonances of the peptide in both solutions were assigned from TOCSY, NOESY and DQF-COSY experiments. In water solution, the peptide is predominantly "random", although nuclear Overhauser connectivity patterns and H alpha secondary shifts show a threshold population of nascent helical conformers. Upon the addition of 40-fold molar excess dodecylphosphocholine to the water solution, the peptide adopts a helical structure that extends throughout the sequence.


Assessment of genetic damage induced by gadolinium-based radiocontrast agents.
Today, although gadolinium based contrast agents have been frequently used in the field of medicine, there is limited data available whether gadolinium based agents affect the genome. The present study aimed to investigate the genotoxic and cytotoxic potentials of gadoteric acid and gadoversetamide used as gadolinium-based contrast agents for magnetic resonance (MR) imaging. The cytokinesis-block micronucleus assay was applied to human peripheral blood lymphocytes to assess the genotoxicity measured as micronucleus (MN), nucleoplasmic bridge (NPBs) and nuclear bud (NBUDs) frequencies. Furthermore, cytokinesis-block proliferation index (CBPI) was calculated to determine cytostasis. Lymphocytes were treated with gadoteric acid at concentrations of 1.0, 2.5, 5.0, and 25 mM and with gadoversetamide at concentrations of 0.25, 1.0, 2.5, and 5.0 mM for 48 h. Gadoteric acid did not cause significant increase in MN, NBPs and NBUDs frequencies and CBPI values at any concentration. Gadoversetamide induced significantly increase MN formation at concentration of 2.5 mM, NBP formation at concentrations of 1.0 and 2.5 mM, and NBUD formation at concentrations of 0.25, 1.0 and 2.5 mM. Additionally, gadoversetamide exposure resulted in statistically significant decrease in CBPI values compared to the control at concentrations of 2.5 and 5.0 mM. In addition, CBPI levels in response to concentrations of gadoversetamide was negatively and significantly associated with concentration. These findings show that gadoteric acid does not have genotoxic or cytotoxic potential, while gadoversetamide might have both genotoxic and cytotoxic potential on human peripheral blood lymphocytes. As a comparison, gadoversetamide was found more genotoxic and cytotoxic.


Magnetic resonance imaging in childhood disseminated encephalomyelitis.
We report the magnetic resonance imaging features in two children with post-infectious disseminated encephalomyelitis. Magnetic resonance imaging dramatically demonstrated multiple white matter lesions in both children and resolution of lesions in conjunction with clinical recovery. These cases indicate that magnetic resonance imaging has considerable diagnostic utility in disseminated encephalomyelitis of childhood.


Modification of encephalomyocarditis virus-induced diabetes in mice by antiviral agents.
The current study used a murine model of diabetes induced by the D variant of encephalomyocarditis virus (DEMC) to determine the protective effect of exogenous antiviral agents. Antivirals, which were found to inhibit the development of DEMC virus cytopathic effect in L-929 cell monolayers, were administered intraperitoneally beginning 12 h prior to DEMC virus challenge. Arildone (500 mg/kg per day) or murine interferon (3.2 X 10(6) IU/kg per day) significantly reduced the incidence of hyperglycemia at 4 days after virus challenge. The incidences of hyperglycemia were 96% in untreated, 62% in arildone, and 0% in interferon treated mice. In other experiments we found that interferon (1.6 X 10(6) IU/kg per 12 h X 3) significantly protected mice against diabetes when administered at the time of virus infection or beginning 12 h afterwards. This effect was associated with reductions in average viral titers in the heart and pancreas of infected animals relative to untreated, infected mice. The results of these studies suggest that picornavirus induced diabetes may be prevented or ameliorated by the use of antiviral agents.


Ultrastructural study of cultured smooth muscle cells from uterine leiomyoma and myometrium under the influence of sex steroids.
Upon the hypothesis that the differentiation or development of smooth muscle cells in both myometrium and leiomyomas may be under the regulation of sex steroids, myometrial and myoma cells were cultured in the presence of sex steroids and their morphological changes were studied ultrastructurally. The cells from the explants of both leiomyoma and myometrium at the 14th day in either control or E (10(-8) M 17-beta-estradiol)-added medium showed extremely well-developed cytoplasmic organelles with few filaments located at the marginal portion of the cytoplasm. These ultrastructural features resembled those of a dedifferentiated stage of smooth muscle cells in vitro. At the 21st day, these cells showed a moderate number of cytoplasmic filaments with dense bodies. These ultrastructural features resembled those of a redifferentiated stage of smooth muscle cells in vitro. In both E- and P (10(-7) M progesterone)-added medium, the cultured smooth muscle cells from both leiomyoma and myometrium showed an increased number of myofilaments with dense bodies even at the 14th day to the 21st day of culture in comparison to the cells either in control or estrogen-added medium. Therefore, the cultured smooth muscle cells in the medium with E and P lacked their dedifferentiated phase in vitro and/or the differentiation or maintenance of their filaments might be under the influence of both estrogen and progesterone. On the observation that the cultured smooth muscle cells from both leiomyoma and myometrium showed very similar ultrastructural changes under the influence of sex steroids, it was suggested that leiomyoma may have the same progenitor cells as myometrium.


Exploring insulin analogue safety and effectiveness in a Maghrebian cohort with type 2 diabetes: results from the A₁chieve study.
To evaluate the safety and effectiveness of insulin analogues in patients with type 2 diabetes (T2D) from Morocco, Algeria and Tunisia that formed the Maghrebian cohort of the 24-week, non-interventional A₁chieve study. Patients starting biphasic insulin aspart, insulin detemir and insulin aspart, alone or in combination, were included. The primary outcome was the incidence of serious adverse drug reactions (SADRs), including major hypoglycaemic events. Secondary outcomes included hypoglycaemia, glycated haemoglobin A₁c (HbA₁c), fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), systolic blood pressure (SBP), body weight and lipids. Quality of life (QoL) was evaluated using the EQ-5D questionnaire. Overall, 3720 patients with a mean age of 58.6 years, body mass index of 27.7 kg/m(2) and diabetes duration of 11.5 years were enrolled. Pre-study, insulin-experienced patients had a mean ± SD dose of 0.54 ± 0.27 U/kg. In the entire cohort, the mean dose was 0.42 ± 0.27 U/kg at baseline, titrated to 0.55 ± 0.30 U/kg by Week 24. Twenty-six SADRs were reported during the study. There was a significant decrease in the proportion of patients reporting overall hypoglycaemia from baseline to Week 24 (18.3% to 13.8%, p < 0.0001). The mean HbA₁c improved significantly from 9.5 ± 1.8% to 7.9 ± 1.4% (p < 0.001). The mean FPG, PPPG, SBP, total cholesterol and QoL also improved significantly (all p < 0.001), while the mean body weight increased by 0.9 ± 3.9 kg (p < 0.001). Insulin analogue therapy was well-tolerated and was associated with improved glycaemic control.


The fate of mycotoxins during the distillation process of barley shochu, a distilled alcoholic beverage.
Mycotoxins are frequent contaminants of grains and critical risk substances for brewers. Fermented barley mash contaminated artificially with 13 representative mycotoxins was distilled with small-scale apparatuses to elucidate the possibility of mycotoxin transfer from mash to distillates. None of these were detected in the distillates. The distillation process can effectively reduce the contamination risk posed by mycotoxins in distilled alcoholic beverages.


Comparative binding properties of rat and human alpha-fetoproteins for arachidonic acid and estradiol.
Rat and human alpha-fetoproteins, (AFP) were able to bind arachidonic acid with high affinity (Ka = 10(7) to 10(8) M-1). Nevertheless, a great difference was found in the binding capacity of these two proteins. Rat AFP was shown to possess one high affinity binding site and several (12-13) low affinity sites while human AFP presented three equivalent binding sites for polyunsaturated fatty acids. Estrogenic hormones compete with fatty acids bound to the high affinity binding site of rat AFP but remained unable to displace arachidonic acid bound to the human one.


Vitamin B12 conveys a protective advantage to phycosphere-associated bacteria at high temperatures.
Many marine microbes require vitamin B12 (cobalamin) but are unable to synthesize it, necessitating reliance on other B12-producing microbes. Thus, phytoplankton and bacterioplankton community dynamics can partially depend on the production and release of a limiting resource by members of the same community. We tested the impact of temperature and B12 availability on the growth of two bacterial taxa commonly associated with phytoplankton: Ruegeria pomeroyi, which produces B12 and fulfills the B12 requirements of some phytoplankton, and Alteromonas macleodii, which does not produce B12 but also does not strictly require it for growth. For B12-producing R. pomeroyi, we further tested how temperature influences B12 production and release. Access to B12 significantly increased growth rates of both species at the highest temperatures tested (38 °C for R. pomeroyi, 40 °C for A. macleodii) and A. macleodii biomass was significantly reduced when grown at high temperatures without B12, indicating that B12 is protective at high temperatures. Moreover, R. pomeroyi produced more B12 at warmer temperatures but did not release detectable amounts of B12 at any temperature tested. Results imply that increasing temperatures and more frequent marine heatwaves with climate change will influence microbial B12 dynamics and could interrupt symbiotic resource sharing.


M-2 protocol for melphalan-resistant and relapsing multiple myeloma.
33 patients with advanced refractory multiple myeloma received a combination of vincristine, cyclophosphamide, carmustine, melphalan and steroids (M-2 protocol). 20 of them had failed prior chemotherapy with alkylating agents and the remaining 13 patients had relapsed after a response to these drugs. An objective tumour cell mass reduction (greater than or equal to 50%) was achieved in 17% of the patients (6% of previously nonresponders and 33% of previously relapsing), while 9 additional patients improved (30-50% tumour reduction), for an overall response rate of 47% (39% for previously nonresponders and 58% for previously relapsing). The median duration of response was 7 months. Thrombocytopenia was the most common toxicity encountered in the study (39% of cases). Our findings indicate that M-2 protocol is an effective salvage treatment for patients who relapse from previous chemotherapy with alkylating agents. In contrast, results in patients who are primarily resistant to these drugs justify the search for different treatment programmes which can produce greater degrees of tumour reduction.


Long-term systemic hypertension in children after successful repair of coarctation of the aorta.
The mechanisms responsible for long-term hypertension in children after successful repair of coarctation of the aorta have not yet been determined. We measured plasma renin activity and aldosterone, adrenalin, and noradrenalin concentrations both under basal conditions and in response to standing and treadmill exercise in 24 normal normotensive children, 16 normotensive postcoarctectomy children, eight hypertensive postcoarctectomy children, and seven children with essential hypertension. Exercise-induced changes in plasma renin activity, aldosterone, adrenalin, and noradrenalin were comparable in the four groups in spite of a significantly greater increase in systolic blood pressure in the children with hypertension. In response to standing, the plasma concentration of noradrenalin increased significantly in normotensive but not in hypertensive children. Hyperresponse of blood pressure to exercise in hypertensive postcoarctectomy children and children with essential hypertension is not related to abnormalities in the sympathetic nervous system or the angiotensin-aldosterone axis. Hypertension could be related to primary baroreceptor alterations, to structural changes in the arterial wall, or both. Twenty percent of normotensive postcoarctectomy children had a blood pressure hyperresponse to exercise and an abnormal noradrenalin response to standing similar to that seen in the hypertensive children. Follow-up of children after coarctectomy may elucidate whether these two abnormalities are indicators of an increased risk of developing long-term recurrent hypertension.


[Experimental artificial embolization in animals: consequences and clinical applications (author's transl)].
A fistula was created between the jugular vein and the common carotid artery in rabbits. The fistula was demonstrated by angiography and embolized using material labelled with iodine 131. The embolization material used was fibrin, Tabotamp, and Lyo-Dura. The migration of the emboli was registered by scintigraphy with an Anger camera. The experiment showed that the embolization material is transported from the small to the great circulation.


Effects of U50,488H on transient outward and ultra-rapid delayed rectifier K+ currents in young human atrial myocytes.
The effects of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate salt (U50,488H), a selective kappa-opioid receptor agonist, on transient outward K+ current (Ito1) and ultra-rapid delayed rectifier K+ current (IKur) in young human atrial myocytes were evaluated with a whole-cell patch-clamp technique. At +10 mV, U50,488H decreased Ito1 in a concentration-dependent manner (IC50=12.4+/-3.5 microM), while at +50 mV, U50,488H produced biphasic effects on Ito1-increasing and decreasing the current at 1-3 and 10-30 microM, respectively. U50,488H at 10 microM shifted the midpoint (V0.5) of Ito1 activation in a depolarizing direction by approximately 5 mV, accelerated the inactivation, and slowed the recovery from inactivation of Ito1. In addition, U50,488H inhibited IKur in a concentration-dependent manner (IC50=3.3+/-0.6 microM). The effects of U50,488H on the two types of K+ currents were not antagonized by either 5 microM nor-binaltorphimine or 300 nM naloxone. These results indicate that U50,488H affects both Ito1 and IKur in young human atrial myocytes in an opioid receptor-independent manner.


Treatment of relapsed B-cell non-Hodgkin's lymphoma with a combination of chimeric anti-CD20 monoclonal antibodies (rituximab) and G-CSF: final report on safety and efficacy.
Antibody-dependent cellular cytotoxicity (ADCC) is one of the possible mechanisms of action of the chimeric CD20 monoclonal antibody IDEC-C2B8 (rituximab). As granulocyte-colony stimulating factor (G-CSF) greatly enhances the cytotoxicity of neutrophils in ADCC, the efficacy of rituximab might be enhanced by the addition of G-CSF. In a phase I/II clinical trial, we investigated the safety and efficacy of the combination of rituximab and G-CSF (5 microg/kg/day, administered for 3 days, starting 2 days before each infusion) in 26 relapsed low-grade lymphoma patients. Adverse events occurred in 25/26 patients and mainly consisted of (grade I/II) fever (29%) and allergic reactions (19%). In phases I and II (375 mg/m(2) rituximab+G-CSF), 19 patients were evaluable for efficacy. The response rate was 42% (8/19; 95% CI 20-67%), with 16% (3/19) complete remissions and 26% (5/19) partial remissions. The median duration of response was 18 months, the median time to progression was 24 months. We conclude that the combination of rituximab and G-CSF is well tolerated. Although the overall response rate seems comparable to that reported for rituximab monotherapy, remission duration in this pilot phase II study is remarkably long. Randomized comparison with rituximab monotherapy should substantiate this promising finding.


Incidence of apparent Michaelis-Menten kinetic behavior of theophylline and its parameters (Vmax and Km) among asthmatic children and adults.
For assessing the clinical impact of nonlinearity in theophylline elimination, we examined the incidence of individuals with an apparent Michaelis-Menten kinetics (percent change in plasma concentration exceeding that in dose by at least 50%) among asthmatic children (n = 122) and adults (n = 50) screened through a two-step chart review. Forty-nine children and 21 adults had the apparent nonlinearity. When compared overall between the two groups, the maximum elimination rate (Vmax) differed significantly (mean +/- SD, 32.2 +/- 11.5 versus 21.8 +/- 6.7 mg/kg/day, p less than 0.001). The Vmax correlated with age (r = -0.459, p less than 0.001). Such a trend as found in Vmax was not observed in Km. Our results imply that a disproportionate relationship between dose and concentration of theophylline appears to be relatively common in asthmatic children and adults; the metabolic capacity in children is greater than in adults, if the nonlinearity could occur; and caution is needed with these certain susceptible individuals when using linear kinetics for the dosage modification of theophylline.


Multicohort genomewide association study reveals a new signal of protection against HIV-1 acquisition.
To date, only mutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility. We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10(-5) in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent. After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: P(combined) = 7.76 × 10(-8). We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation.


NF-κB decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model.
Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Wear particle-induced chronic inflammation is associated with the development of periprosthetic osteolysis. Modulation of NF-κB signaling in macrophages, osteoclasts, and mesenchymal stem cells could potentially mitigate this disease. In the current study, we examined the effects of local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) on wear particle-induced bone loss in a murine continuous femoral particle infusion model. Ultra-high molecular weight polyethylene particles (UHMWPE) with or without lipopolysaccharide (LPS) were infused via osmotic pumps into hollow titanium rods placed in the distal femur of mice for 4weeks. Particle-induced bone loss was evaluated by μCT, and immunohistochemical analysis of sections from the femur. Particle infusion alone resulted in reduced bone mineral density and trabecular bone volume fraction in the distal femur. The decoy ODN reversed the particle-associated bone volume fraction loss around the implant, irrespective of the presence of LPS. Particle-infusion with LPS increased bone mineral density in the distal femur compared with particle-infusion alone. NF-κB decoy ODN reversed or further increased the bone mineral density in the femur (3-6mm from the distal end) exposed to particles alone or particles plus LPS. NF-κB decoy ODN also inhibited macrophage infiltration and osteoclast number, but had no significant effects on osteoblast numbers in femurs exposed to wear particles and LPS. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced osteolysis. Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Chronic inflammation is crucial for the development of wear particle-associated bone loss. Modulation of NF-κB signaling in macrophages (pro-inflammatory cells), osteoclasts (bone-resorbing cells), and osteoblasts (bone-forming cells) could potentially mitigate this disease. Here we demonstrated that local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) mitigated ultra-high molecular weight polyethylene (UHMWPE) wear particle induced bone loss in a clinically relevant murine model. The protective effects of decoy ODN was associated with reduced macrophage infiltration and osteoclast activation, but had no significant effects on osteoblast numbers. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced bone loss.


Elderly patients treated with psychotropic medicines admitted to hospital: associated characteristics and inappropriate use.
The purpose of this study is to describe the characteristics of older patients treated with psychotropic medicines and the associated factors and to assess their inappropriate use. An observational, prospective study was carried out in 672 elderly patients admitted to seven hospitals for a year. A comparison of sociodemographic characteristics, geriatric variables, multimorbidity and the number of prescribed medicines taken in the preceding month before hospitalization between patients treated with psychotropics and those not treated was performed. To assess factors associated with psychotropics, multivariate logistic regression analyses were performed. Inappropriate use was assessed using the Beers and the STOPP criteria. A total of 57.5 % patients (median [Q1-Q3] age 81.7 [78.2-86.1], 65.7 % female) were treated with psychotropics (44.2 % anxiolytics, 22.6 % antidepressants and 10.8 % antipsychotics). Independent factors associated with the use of psychotropics were female gender (OR = 2.3; CI 95 %,1.6-3.5), some degree of disability on admission (slight [OR = 2.2; 1.2-4.2], moderate [OR = 3.2, 1.6-6.6], severe [OR = 3.4; 1.4-8] and very severe [OR = 5.1; 2.0-12.8]) and polypharmacy (5-9 medicines [OR = 3.0; 1.3-6.9] and ≥10 medicines [OR = 6.0; 2.7-13.6]). The associated factors varied depending on the different types of psychotropics. In patients treated with psychotropics, the percentage of those with at least one Beers (61.6 %) or at least one STOPP (71.4 %) criteria was significantly higher in comparison with those not treated with psychotropics (30.7 and 47.7 %, respectively, p < 0.001). Psychotropics are widely used in the elderly population and often their use is inappropriate. Female gender, a poor functional status and polypharmacy, are the characteristics linked to their use. Interventional strategies should be focused on patients with these characteristics.


Family perceptions of nurses' roles toward family members of critically ill patients: a descriptive study.
The purpose of this study was to examine the role of the nurse with families of critically ill patients as perceived by family members and whether meeting family expectations impact family satisfaction. A descriptive design was conducted with 29 family members from a 19-bed intensive care unit. Nonparametric statistics, known for their appropriateness for small samples, were used to examine the research questions. Overall, the expectations that family members held regarding nurses' roles with families were not different from their perceptions of what nurses actually did (P = .087). Family members were more satisfied with care when nurses' performance either met or exceeded their expectations (P = .046). Nurses did well with regard to meeting family members' expectations. Variations in expectations among family members reflect their diversity and highlight the importance of assessing family needs on a case-by-case basis.


Enhanced remedial reagents delivery in unsaturated anisotropic soils using surfactant foam.
Homogeneous delivery of solution of oxidant in unsaturated soils is limited by soil anisotropy and gravity. An innovative injection strategy using foam was developed to improve in situ delivery. Primary foam injection before oxidant solution enhanced both the lateral and uniform delivery of reactant in isotropic and anisotropic (permeability, contamination) soils. The oxidant spread isotropically through the foam water network. This sequential injection heavily improved the delivery radius of influence (ROI), while limiting contact between surfactant and solution of oxidant in order to preserve the selective oxidation of petroleum hydrocarbons contaminant (TPH). Prior foam injection allowed uniform delivery of the solution of oxidant across the region occupied by the foam, regardless of the soil permeability contrast (1:18), whereas poor ROI were observed for the direct injection of oxidant. Experiments in contamination contrasted soils showed that foam was able to propagate in highly TPH contaminated soils (max 60% velocity reduction for 22 g.kgdry soil-1). As for permeability contrast, foam is expected to enhance reagents delivery in such contexts. This novel strategy was proven to be efficient, even for complex anisotropic conditions, and should allow to cut field costs and uncertainties associated to poor reagents delivery.


First-line systemic treatment for hepatocellular carcinoma: A systematic review and network meta-analysis.
The rapid development of novel therapeutic options for advanced hepatocellular carcinoma (aHCC) has generated some uncertainty about the rational choice of the systemic upfront treatment. So far, a variety of therapeutic strategies have been investigated, including the combination of immunecheckpoint inhibitors and anti-VEGF. To identify the treatment that should be preferred as front-line approach, we compared the efficacy and toxicity of a variety of therapeutic strategies. With this aim, we performed a systematic review and a meta-analysis of randomized clinical trials. OS, PFS, ORR and tolerability outcomes were considered, and for each outcome the treatment ranking was evaluated by the surface under the cumulative rankings (SUCRAs). Combination of Camrelizumab + Rivoceranib scored the best in OS, followed by Sintilimab + Bevacizumab, whereas Lenvatinib + Pembrolizumab showed higher probability to be the best treatment in PFS and Sintilimab + Bevacizumab performed best in ORR. Finally, Durvalumab is the most tolerated treatment.


Unusual stab injury of the spinal cord.
To report an unusual penetrating stab injury of the spinal cord. Case report of a 13-year-old boy who sustained cervical trauma following an accident while playing. Spinal Cord Injuries Unit, Musgrave Park Hospital, Belfast, UK. Mechanism of injury was by a spear-like electric fence post entering the neck. Initial neurological examination revealed tetraplegia with C4 sensory level. Magnetic resonance imaging (MRI) of spinal cord demonstrates the penetrating injury. No ligamentous instability was demonstrated. In the absence of this, the penetrating injury by a short blade thrown at speed was felt to be responsible for the subsequent injury and resulting outcome at discharge of C4 American Spinal Injury Association (ASIA) grade D tetraplegia.


High prevalence of isolated sperm DNA damage in infertile men with advanced paternal age.
Sperm DNA damage is associated with male infertility, lower pregnancy rates and pregnancy loss. The primary aim of our study was to evaluate the prevalence of sperm DNA damage in younger and older men with normozoospermia. We obtained semen from 277 consecutive non-azoospermic men presenting for sperm DNA testing. The main outcome measures included sperm % DNA fragmentation index (%DFI, using sperm chromatin structure assay), sperm concentration, motility and morphology, and, paternal age. Sperm % DFI was positively correlated with paternal age (r = 0.20, P < 0.001) and inversely correlated % progressive motility (r = -0.16, P = 0.01). Sperm %DFI was significantly higher in older (≥40 years) compared to younger (<40 years) normozoospermic men (17 ± 13 vs. 12 ± 8, respectively P = 0.008), whereas, sperm concentration, progressive motility and morphology were not significantly different in these two groups. Moreover, the prevalence of high levels of sperm DNA damage (>30 % DFI) was significantly higher in older compared to younger normozoospermic men (17 % vs. 3 %, respectively, P < 0.001). The data indicate that a conventional semen analysis can often fail to detect a defect in spermatogenesis (high %DFI) in older men and suggest that infertile couples with advanced paternal age, including those with normal semen parameters, should consider sperm DNA testing as part of the couple evaluation.


Non-radioactive reverse transcriptase/polymerase chain reaction for quantification of myosin heavy chain mRNA isoforms in various rabbit muscles.
A method was established for measuring molecule numbers of three different myosin heavy chain (MHC) mRNA isoforms in total RNA preparations. The quantification was based on a combination of primer-directed reverse transcriptase and polymerase chain reactions with 5'-digoxigenin-labeled oligonucleotides, using external standards. The sensitivity of the method allowed the quantitation of mRNA amounts down to the range of 1,000 molecules (detection limit 50 molecules). The numbers determined for eight different rabbit muscles are in the range of 10(3)-10(9)/micrograms total RNA. In soleus muscle, the value of 1.11 x 10(9) MHCI mRNA molecules corresponds to approximately 8% of the total mRNA. With reference to myonuclei, this amount corresponds to 1-2 x 10(4) molecules/nucleus. A quantitative comparison of the two fast MHC mRNA isoforms with the distribution of different MHC isoforms at the protein level indicates that one of these two fast sequences is specific to MHCIIb and the other to MHCIId. However, our data point to the existence of additional MHCIId mRNA subtypes.


Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists.
A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and alpha-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50 approximately 1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.


Proinflammatory cytokine, chemokine, and cellular adhesion molecule expression during the acute phase of experimental brain abscess development.
Brain abscess represents the infectious disease sequelae associated with the influx of inflammatory cells and activation of resident parenchymal cells in the central nervous system. However, the immune response leading to the establishment of a brain abscess remains poorly defined. In this study, we have characterized cytokine and chemokine expression in an experimental brain abscess model in the rat during the acute stage of abscess development. RNase protection assay revealed the induction of the proinflammatory cytokines interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor-alpha as early as 1 to 6 hours after Staphylococcus aureus exposure. Evaluation of chemokine expression by reverse transcription-polymerase chain reaction demonstrated enhanced levels of the CXC chemokine KC 24 hours after bacterial exposure, which correlated with the appearance of neutrophils in the abscess. In addition, two CC chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha were induced within 24 hours after S. aureus exposure and preceded the influx of macrophages and lymphocytes into the brain. Analysis of abscess lesions by in situ hybridization identified CD11b+ cells as the source of IL-1beta in response to S. aureus. Both intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule expression were enhanced on microvessels in S. aureus but not sterile bead-implanted tissues at 24 and 48 hours after treatment. These results characterize proinflammatory cytokine and chemokine expression during the early response to S. aureus in the brain and provide the foundation to assess the functional significance of these mediators in brain abscess pathogenesis.


Infantile masturbation and paroxysmal disorders.
A recurrent paroxysmal presentation in children leads to different diagnoses and among them are neurologic and cardiac etiologies. Infantile masturbation is not a well known entity and cannot be differentiated easily from other disorders. Aim of this study is to elucidate and differentiate this condition from epileptic seizures. We report 3 cases of 10 to 30 mth old girls of infantile masturbation that their symptoms initiated at 2, 3 and 8 mth of age. These present with contraction and extension of lower extremities, scissoring of legs, perspiration, changing face color. In 2 cases body rocking and legs rubbing initiated then there after. Masturbation is one of the paroxysmal non-epileptic conditions of early infancy and is in differential diagnosis of epileptic seizures.


Components of left ventricular dysfunction discriminated noninvasively beat by beat.
Disturbed left ventricular contractility and synchrony were studied noninvasively beat by beat with simultaneous systolic time intervals and acceleration ballistocardiograms during quiet respiration. Thirty-six measures per beat, reduced to 7 by appropriate statistical methods, produced a linear discriminant function, based on a split training sample of 15 normal men (258 beats) and 9 men (149 beats) with proved myocardial infarctions. Validation tests on an independent set classified 89% of the beats from 12 tested normal subjects as "normal" and 96% of the beats from 6 tested men who had had infarction as "coronary-like," a physiologic, not etiologic, classification. In 14 hypertensive patients with no history or findings of coronary artery disease, 8 had 72 to 100% coronary-like beats per subject, suggesting unrecognized coronary artery disease, the cumulative effect of hypertension, or both. This method may help identify hypertensive patients at greater risk. Factor analysis found 4 discrete groups of the 7 discriminant variables that function together. Despite beat-to-beat variations due to respiration, myocardial dysfunction (when present) and individual differences, dysfunctional beats can be identified by these methods. They may also be applied to other multivariate data to extract the maximal information despite complex interactions.


Acquired B antigen, Tk activation and A1 destroying enzyme activity in a patient with septicaemia.
During the course of septicaemia, a group A1 patient developed several RBC antigenic modifications. Acquired B antigen, Tk transformation and a partial disappearance of A1 receptors associated with an increase of H reactivity were observed.


The impacts of adverse childhood experiences on socioeconomic disadvantage by sexual and gender identity in the U.S.
Adverse childhood experiences (ACEs) predict low education and low income, but this has scarcely been examined by sexual orientation and gender identity. We investigated prevalence and associations between ACEs, low income, and low education in sexual and gender diverse (SGD) and cisgender heterosexual (CGH) sub-groups. Data came from 14 states in the 2019 Behavioral Risk Factor Surveillance System survey (n = 79,303). Chi-square, logistic regression, and moderation analyses were implemented to examine the prevalence and associations between ACEs, low income, and low education. Sample stratification was used to examine differences between SGD and CGH sub-groups. SGD participants reported higher prevalence of ACEs, low income, and low education compared to CGH participants (p < 0.0001) with the highest proportions in transgender and queer/something else groups. ACEs were associated with low income (AOR 1.084, CI 1.067-1.102) and low education (AOR 1.056, CI 1.041-1.071) in the entire sample. Transgender and queer/something else groups had higher odds of low income (AOR 3.345, CI 1.975-5.665; AOR 1.702, CI 1.096-2.643) and low education (AOR 1.702, CI 1.096-2.643; AOR 3.552, CI 2.842-4.440) and gay/lesbian identity had reduced odds of low education (AOR 0.586, CI 0.457-0.751) compared to CGH males. The strength of associations between ACEs and low income and low education were weaker among SGD compared to CGH sub-groups. These findings highlight the importance of including categories of sexual identity cross-classified by gender identity in population-based analyses in order to facilitate a comprehensive characterization of the life course outcomes of SGD populations.


Preparation and application of irradiated polyvinyl alcohol/starch/pumice composites for adsorption of basic dye: Isotherm and kinetics study.
Even at low concentrations, organic dye pollution entering water resources from the textile, paper, and pharmaceutical industry sectors poses a serious hazard to human and aquatic life. One of the most significant remediation methods is the adsorption method. In the present study, the uptake of basic violet 7 (BV7) synthetic dye was investigated utilizing Poly (vinyl alcohol)/starch/Pumice [poly (PVA/St/Pu)] composite films prepared by a simple casting of both PVA and St with Pu and then irradiated by electron beam (EB) source to prompt curing. Numerous characterization methods, such as SEM, FTIR, X-ray diffraction (XRD, and other measurements, were examined on the prepared sample. The tensile strength (TS) of all composites was increased by increasing the radiation dose up to 10 kGy. TS was increased by 3 php of Pu, and an overload of Pu led to a decrease in TS values. The elongation at break (Eb) of the prepared composite increased at 3 Pu, then decreased as the quantity of the pumice increased, while the Eb was decreased by irradiation. The effects of the produced polymeric films' composition and irradiation dose on the basic violet 7 (BV 7) dye adsorption were studied. It was found that the adsorption capacity of poly (PVA/St/9 php Pu-10 kGy) toward the BV 7 dye was 64.9 mg/g at the optimal conditions: pH = 11, contact time = 480 min., adsorbent dosage = 0.2 g., concentration = 150 mg/l, and temperature = 298 K. The adsorption process fitted with the pseudo-second-order model, Freundlich adsorption isotherms were found to be spontaneous and endothermic.


Perspectives on handedness, life and physics.
In contrast to motion, matter will be conserved in all eternity. Structure and function will arise by the angular momentum of spinning spherical particles and their composites. Symmetry prevails in physics by equal amounts of left- and right-hand spinning entities, while life is asymmetric in this respect. Very rare deviations from the ubiquitous one-sided handedness in biology will probably explain the inert degradation resistant proteins in 'mad cow' type diseases. Velocities of physical events seems to be a most important feature and will explain for instance brain function and the true nature of neurodegenerative diseases. This biophysics of mind will in turn provide answers to many disputable aspects of physics such as the true nature of waves and gravity. Many current concepts in quantum physics will be invalidated, among them the uncertainty principle, the relativity to a fixed speed of light, the energy equation and the expansion of the Universe. Instead, decay and formation will balance each other in a continuum of matter in an intuitively cyclic Multiverse.


[Primary adenocarcinoma of the jejunum. Diagnostic challenge by a rare tumour].
A 75 year old patient presented for many years with nausea and vomiting. The exacerbation of clinical presentation caused further investigation of the small bowel. The source of nausea and vomiting had been achieved by double contrast enteroclysis in the upper jejunum and it was confirmed with a coloskop. Histological result was a primary small bowel adenocarcinoma. The primary definitive therapy was a radical resection of the jejunal neoplastic loop, also as an important prognostic factor. Because of the tumour stadium adjuvant chemotherapy was not necessary. Tumours of small bowel are always a diagnostic challenge. With the help of an primary small bowel adenocarcinoma we suggest an algorithm of diagnostic possibilities adjusted to the clinical situation.


Ingestion rate: An empirical model for aquatic deposit feeders and detritivores.
Published ingestion rates of total dry material (inorganic and organic) by benthic invertebrate deposit feeders and detritivores feeding at 15°C could be explained almost entirely by organic content of the ingested material and body size; the relation was consistent for 19 species from 3 phyla. Since ingestion rate of total dry material varied inversely with the organic content of the food, organic matter ingestion (C) was essentially a function of body size (W): [Formula: see text] where C is mg day-1 and W is mg dry weight. These animals may maintain a rate of intake of organic matter which is independent of the organic content of the food source by: (1) Actively adjusting their feeding rates according to some perception of food "quality", and/or (2) Adapting their feeding rates to different environments on an evolutionary time scale.


Reduction and standardization of surgical instruments in pediatric inguinal hernia repair.
To standardize and reduce surgical instrumentation by >25% within a 9-month period for pediatric inguinal hernia repair (PIHR), using "improvement science" methodology. We prospectively evaluated instruments used for PIHR in 56 consecutive cases by individual surgeons across two separate subspecialties, pediatric surgery (S) and pediatric urology (U), to measure actual number of instruments used compared with existing practice based on preference cards. Based on this evaluation, a single preference card was developed using only instruments that had been used in >50% of all cases. A subsequent series of 52 cases was analyzed to assess whether the new tray contained the ideal instrumentation. Cycle time (CT), to sterilize and package the instruments, and weights of the trays were measured before and after the intervention. A survey of operating room (OR) nurses and U and S surgeons was conducted before and after the introduction of the standardized tray to assess the impact and perception of standardization. Prior to creating the standardized tray, a U PIHR tray contained 96 instruments with a weight of 13.5 lbs, while the S set contained 51, weighing 11.2 lbs. The final standardized set comprised 28 instruments and weighed 7.8 lbs. Of 52 PIHRs performed after standardization, in three (6%) instances additional instruments were requested. CT was reduced from 11 to 8 min (U and S respectively) to <5 min for the single tray. Nurses and surgeons reported that quality, safety, and efficiency were improved, and that efforts should continue to standardize instrumentation for other common surgeries. Standardization of surgical equipment can be employed across disciplines with the potential to reduce costs and positively impact quality, safety, and efficiencies.


Econometric analysis of phase duration for blood morphology and basophil count alterations in chronic granulocytic leukaemia.
The retrospective analysis of 40 cases with chronic granulocytic leukemia revealed an average survival time of 39 months. Modal proportions between the chronic, accelerated and acute blastic crisis amounted to 25:6:8 months. The characteristic points and curves for peripheral white cell, blast cell, basophil cell and thrombocyte counts as well as haemoglobin levels were determined separately in 20 patients with long and in 20 with short survival time. Comparisons indicate among others that Busulphan sensitivity is an essential factor for a longer survival time of CGL patients.


Evaluation of 9 biomarkers for predicting 10-year cardiovascular risk in patients undergoing coronary angiography: findings from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study.
Conventional factors do not fully explain the distribution of cardiovascular outcomes. Biomarkers are known to participate in well-established pathways associated with cardiovascular disease, and may therefore provide further information over and above conventional risk factors. This study sought to determine whether individual and/or combined assessment of 9 biomarkers improved discrimination, calibration and reclassification of cardiovascular mortality. 3267 patients (2283 men), aged 18-95 years, at intermediate-to-high-risk of cardiovascular disease were followed in this prospective cohort study. Conventional risk factors and biomarkers were included based on forward and backward Cox proportional stepwise selection models. During 10-years of follow-up, 546 fatal cardiovascular events occurred. Four biomarkers (interleukin-6, neutrophils, von Willebrand factor, and 25-hydroxyvitamin D) were retained during stepwise selection procedures for subsequent analyses. Simultaneous inclusion of these biomarkers significantly improved discrimination as measured by the C-index (0.78, P = 0.0001), and integrated discrimination improvement (0.0219, P<0.0001). Collectively, these biomarkers improved net reclassification for cardiovascular death by 10.6% (P<0.0001) when added to the conventional risk model. In terms of adverse cardiovascular prognosis, a biomarker panel consisting of interleukin-6, neutrophils, von Willebrand factor, and 25-hydroxyvitamin D offered significant incremental value beyond that conveyed by simple conventional risk factors.


The role of peripheral opioid receptor subtypes in the modulation of gastric acid secretion and plasma gastrin in dogs.
The peripheral opioid receptor subtypes involved in the regulation of gastric acid secretion were studied in dogs with both a gastric fistula and a Heidenhain pouch, by using the putative mu-opioid receptor agonist dermorphin, the delta-opioid receptor agonist [D-Ala2,D-Leu5]enkephalin (DADLE) and the kappa-opioid receptor agonist dynorphin-(1-13). Dermorphin caused a significant increase in basal acid secretion from both the gastric fistula and the Heidenhain pouch, while DADLE and dynorphin-(1-13) did not. Acid secretion stimulated by 2-deoxy-D-glucose from the gastric fistula was not modified by dermorphin and dynorphin-(1-13), while DADLE significantly inhibited it; at the same time gastric secretion from the Heidenhain pouch was significantly increased by dermorphin and unmodified by DADLE and dynorphin-(1-13). Dermorphin, DADLE or dynorphin-(1-13) did not modify plasma gastrin during basal or 2-deoxy-D-glucose-stimulated conditions. Submaximal bethanechol-stimulated secretion was increased by dermorphin and DADLE but unaffected by dynorphin-(1-13). Acid secretion from the gastric fistula stimulated by pentagastrin was enhanced by dermorphin, inhibited by DADLE and unaffected by dynorphin-(1-13). Dermorphin and DADLE significantly increased acid secretion from the Heidenhain pouch stimulated by pentagastrin, while dynorphin-(1-13) was ineffective. Naloxone prevented the stimulatory effects of dermorphin and DADLE on the Heidenhain pouch, but it reduced acid secretion from the gastric fistula further when given with DADLE. The inhibitory effects of DADLE on secretion from the gastric fistula were prevented by naltrindole, a selective antagonist of delta-opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)


Predictors of sexual intercourse and rapid-repeat pregnancy among teenage mothers: an Australian prospective longitudinal study.
To examine the determinants of pregnancy within 2 years of a teenager giving birth for the first time (rapid-repeat pregnancy [RRP]) and resumption of sexual intercourse after the birth. Prospective cohort study between June 2004 and September 2006 at the sole tertiary obstetric hospital in Western Australia involving teenagers who gave birth for the first time. Data were collected using questionnaires at recruitment, 6 weeks and 3-monthly intervals for up to 2 years postpartum. RRP and time to a return to sexual intercourse after giving birth. Of the 147 participants, 49 (33%) experienced an RRP. Sexual intercourse was independently significantly associated with using an oral contraceptive (odds ratio [OR], 2.83; 95% CI, 1.38-5.82); living with the birth father (OR, 8.43; 95% CI, 5.12-13.86); intending to become pregnant (OR, 3.20; 95% CI, 1.53-6.65); smoking marijuana (OR, 2.60; 95% CI, 1.38-4.79); and using alcohol (OR, 1.93; 95% CI, 1.17-3.20). Use of long-acting contraceptives was associated with reduced odds of RRP (OR, 0.27; 95% CI, 0.12-0.62), while teenagers who used an oral contraceptive had a similar risk of RRP compared with those using barrier methods or no contraception. Other factors predicting RRP were: being sexually active for more than 3 months (OR, 8.96; 95% CI, 1.97-40.74); intending to become pregnant (OR, 2.39; 95% CI, 1.62-4.93); and being an Indigenous Australian (OR, 2.38; 95% CI, 1.38-4.11). There are two options available to health care providers for reducing the rate of RRP: to facilitate teenage mothers' access to long-acting contraceptives; and to gain clear understanding of their intention with regard to repeat pregnancy and to provide appropriate support.


Roles of conserved intracellular sequences regions for the proper expression of dopamine D(2) and D(3) receptors.
The dopamine D(2) receptor and D(3) receptor (D(2)R, D(3)R) have high homology in both their amino acid composition and signaling pathways. Virtually all signaling pathways reported thus far overlap between the two receptors with the exception that the D(3)R signals are 2 approximately 5 times less efficient than D(2)R. Previous studies have suggested that conformational constraints of D(3)R might be responsible for the poor coupling with the G protein. To this hypothesis, point mutations were introduced into some of the conserved regions between D(2)R and D(3)R, and their effects on receptor expression were investigated. Among the four conserved intracellular receptor regions examined (TTT motif in the 1(st) intracellular loop, SS motif in the 2(nd) intracellular loop, YxxL and TxxS/xS motifs in the 3(rd) intracellular loop), a mutation of the Thr-Thr-Thr (TTT) motif in the first intracellular loop or the LxxY motif in the 3(rd) intracellular loop markedly decreased the level of D(3)R expression compared with D(2)R. The TTT motif was further mutated individually or in combination to test which residue plays a critical role on the expression of the receptor proteins. Different amino acids between D(2)R and D(3)R in the 1(st) intracellular loop were exchanged to determine if the adjacent amino acid residues are responsible for the differences between D(2)R and D(3)R. The first two threonine residues become more important when the individual threonine residue is mutated. However, all three intact threonine residues are essential for proper expression of the receptor proteins. The neighboring sequences around the triplet threonine residues in the 1(st) loop of D(3)R are not important for proper positioning of the receptor proteins on the plasma membrane. It was concluded that D(2)R has a more flexible overall conformation that can accept mutated residues in the intracellular region than D(3)R, which might be partly responsible for the quantitative differences in the signaling efficiency between D(2)R and D(3)R.


Development and psychometric evaluation of a quality of life questionnaire for infertile women: a mixed method study.
Infertility is one of the most important issues that negatively influences women's quality of life, especially when the cause is associated with females. Given that no instruments have been designed to assess quality of life among infertile women with focus on female factors, this study was conducted to develop and evaluate the psychometric properties of a female-centric quality of life questionnaire for infertile women. This sequential exploratory study was conducted in two stages. First, the concept of quality of life and its dimensions as they relate to infertile women were elucidated through a qualitative inquiry accompanied with a content analysis. Accordingly, infertile women and key informants from a teaching hospital affiliated with the Mazandaran University of Medical Sciences and a private center for infertility treatment in Sari (north of Iran) were screened through purposive sampling until data saturation. Those who satisfied the inclusion criteria and exhibited maximum variance in terms of age, educational level, employment status, infertility duration, treatment type, and social class were recruited. The conventional content analysis was carried out in accordance with the steps proposed by Graneheim and Lundman, and the accuracy and robustness of the data were verified using Lincoln and Guba's criteria (credibility, transferability, dependability, confirmability and authenticity). Second, the psychometric properties of the instrument developed in the qualitative stage were evaluated using a quantitative method and on the basis of the results of a literature review. The content, face, and construct validity of the instrument was determined, and its test-retest reliability and stability were ascertained using internal correlation and Cronbach's alpha. The collected data were entered into the Statistical Package for the Social Sciences (version 22) for analysis, and descriptive statistics were calculated. Developing and evaluating the psychometric properties of a valid and reliable female factor-centric instrument that measures quality of life among infertile women will be very useful in the assessment of their future status.


In vivo and in vivo/in vitro kinetics of cyclophosphamide-induced sister-chromatid exchanges in mouse bone marrow and spleen cells.
In several acute and chronic exposures to various chemicals in vivo and in vitro, the average sister-chromatid exchange (SCE) frequencies in human, mouse, rat, and rabbit lymphocytes generally decrease with time following treatment. The rate of this decline varies, but little data have been published pertaining to the comparative kinetics of SCEs both in vivo and in vivo/in vitro (exposure of animals to the test compound and culturing of cells) simultaneously in the same tissues. In this study, a single dose of cyclophosphamide (40 mg/kg) was injected for varying periods (6-48 h) and its effects, as assessed by the induction of SCEs, were analyzed under both in vivo and in vivo/in vitro conditions in mouse bone marrow and spleen cells. In vivo, the cyclophosphamide-induced SCEs increased with increasing time up to 12 h, stayed at approximately the same level until 24 h, and then decreased with increase in post-exposure time. However, the SCE levels remained significantly higher than controls at 48 h post-exposure time in both bone marrow and spleen cells. Under in vivo/in vitro conditions, the SCEs in bone marrow decreased with increase in post-exposure time until reaching control values by 48 h post exposure. However, in spleen cells, the decrease in SCE level was gradual, and by 48 h post-exposure time, the cells still had approximately 6 times higher SCEs than the control values. These results suggest that there are pharmacokinetic differences for cyclophosphamide in mouse bone marrow and spleen. Also, there is a differential SCE response to cyclophosphamide under in vivo and in vivo/in vitro conditions.


Asymptomatic carriage of Plasmodium falciparum by individuals with variant blood groups and haemoglobin genotypes in southern Ghana.
The ABO and the Rhesus blood group systems, as well as various abnormal haemoglobin (Hb) variants (haemoglobinopathies) are known to influence malaria parasite carriage and disease severity in individuals living in malaria endemic areas. This study identified the blood group and Hb variant distribution and Plasmodium falciparum infection status of afebrile individuals living in southern Ghana. Afebrile participants were recruited from Obom (358) in the Greater Accra Region and Ewim (100) and Simiw (329) in the Central Region of Ghana. Venous blood (1 ml) was collected into EDTA vacutainer tubes. Three 20 μl drops of blood were used for blood group analysis using the tile method. Another 500 μl aliquot was used for the qualitative sickling test using sodium metabisulphite and haemoglobin electrophoresis. Genomic DNA was extracted from 100 μl of whole blood and used in P. falciparum species-specific PCR. The most abundant blood group and abnormal haemoglobin variant in both sites was blood group O + (47.4%) and HbAS (15.8%). A total of 13 (1.7%) of the participants had full haemoglobinopathies (SS, SC and CC), whilst 196 (25.4%) were carriers (AS and AC). Although there was a significantly higher prevalence of sickling positive participants from the Central Region, genotyping identified a similar prevalence of each of the abnormal haemoglobin genes in both sites. Asymptomatic parasite carriage estimated by PCR was 40.9% in the Central Region and 41.8% in the Greater Accra Region. Asymptomatic carriage of P. falciparum parasite in the study population was not associated with any particular blood group variant or haemoglobin genotype.


ANVCFV Score System: Assessment for Probability of New Vertebral Compression Fractures after Percutaneous Vertebroplasty in Patients with Vertebral Compression Fractures.
Percutaneous vertebroplasty (PVP) is widely used for the treatment of painful vertebral compression fractures (VCFs). However, new VCFs occur frequently after PVP. We aim to establish an objective risk score system to assess the possibility of new vertebral fractures in patients with VCFs undergoing PVP. This study was a retrospective study, and it was approved by the Institutional Review Board of our 2 institutions. This study consists of patients from 2 large academic centers. Patients with VCFs who underwent their first PVP and met the inclusion criteria between January 2007 and December 2013 at Hospital A (training cohort) and Hospital B (validation cohort) were included. In the training cohort, the independent risk factors for new VCFs after PVP were identified by multivariate stepwise backward Cox regression analysis from the risk factors selected by univariate analysis and Harrell's C-statistics and used to develop the score system (assessment for new VCFs after PVP [ANVCFV]) to predict the probability of new VCFs. In total, 397 patients (training cohort: n = 241; validation cohort: n = 156) were included in this study. In the training cohort, the ANVCFV score was developed based on 5 independent risk factors for the new VCFs after PVP, including lower computed tomography (CT) values, pre-existing old VCFs, intradiscal cement leakage, more than one vertebra treated, and superior or inferior marginal cement distribution in the vertebra. The patients were divided into 2 groups by the ANVCFV score of -1.5 to 8.5 vs. > 8.5 points in the probability of new VCFs (median fracture-free time: 1846 vs. 732 days; P < 0.001) in the training cohort. The accuracy of this score system was 77.4% for the training cohort and 85.3% for the validation cohort. The main limitations of this study are that it is a retrospective study and that there is a significant difference of the treated vertebrae of PVP per session between the 2 cohorts. Patients who underwent their first PVP with an ANVCFV score > 8.5 points may exhibit an increased chance of suffering from new VCFs.