Peripheral Vein Thrombophlebitis in the Upper Extremity: A Systematic Review of a Frequent and Important Problem.
The acceptable incidence of thrombophlebitis following intravenous cannulation is 5%, as recommended by the Intravenous Nurses Society guidelines, but publications have reported startling figures of 20% to 80%. Given the frequency of intravenous lines, this presents a potential clinical problem. We aimed to determine the predisposing patient, catheter, and health care-related factors of peripheral vein thrombophlebitis in the upper extremity. In this systematic review, we used a comprehensive search strategy to identify risk factors of thrombophlebitis from inception to May 20, 2019. Studies reporting risk factors of peripheral vein thrombophlebitis of adult patients admitted to the hospital and receiving an intravenous cannulation were included. The Quality of Prognostic Studies tool was used in the assessment for risk of bias to determine the study quality. Of the 6910 studies initially identified, 25 were eligible for inclusion. Qualitative syntheses revealed that patient-related factors that confer a higher risk included intercurrent illness, immunocompromised state, comorbidities such as diabetes mellitus, malignancy, previous thrombophlebitis, burns, and higher hemoglobin levels. Catheter-related risk factors included catheter size, duration, and site of insertion. Intravenous antibiotics and potassium chloride predisposed to thrombophlebitis. Cannulation by an intravenous therapy team and more nursing care were associated with a decreased risk. A P-value < .5 was considered to be statistically significant. Recognition of the predisposing factors would allow for targeted strategies to aid in the prevention of this iatrogenic infection, which may include closer monitoring of patients who are identified to be vulnerable. Based on this systematic review, we developed an algorithm to guide clinical management. Further research is warranted to validate this algorithm.


Online mindfulness-based intervention for women with pregnancy distress: A randomized controlled trial.
Pregnancy distress among childbearing women is common and can negatively affect both mother and infant. Mindfulness-based interventions (MBIs) may have a positive effect on pregnancy distress but randomized controlled trials with sufficient power are lacking. The current study examined the effectiveness of an online self-guided MBI in pregnant women with pregnancy distress. Pregnant women with elevated pregnancy distress levels at 12 weeks of pregnancy, measured with the Edinburgh Depression Scale (EDS) and Tilburg Pregnancy Distress Scale negative affect (TPDS-NA), were randomized into an intervention group (online MBI, N = 109) or control group (care as usual, N = 110). The primary outcome was the change in pregnancy distress post-intervention and at eight-weeks-follow-up. Secondary outcomes were mindfulness skills (Three Facet Mindfulness Questionnaire-Short Form), rumination (Rumination-Reflection Questionnaire), and self-compassion (Self-Compassion Scale-Short Form) at post-intervention and follow-up in the intervention group. Significant improvements were found in pregnancy distress scores, but no significant differences between intervention and control group appeared. The MBI group showed improvements in mindfulness skills, rumination, and self-compassion. Low adherence to the intervention and assessment of secondary outcome measures in the intervention group only. An intervention trial with one of the largest samples (N = 219) provided no evidence of a significant effect of an online self-guided MBI in distressed pregnant women. An online MBI may be associated with an improvement in mindfulness skills, rumination, and self-compassion. Future research should address the effectiveness of MBI's with different formats (online and group-based combined) and examine a possible delayed effect. ClinicalTrials.gov: NCT03917745, registered on 4 March 2019.


Gold nanorods: their potential for photothermal therapeutics and drug delivery, tempered by the complexity of their biological interactions.
Gold nanorods have promising applications in the fields of drug delivery and photothermal therapy. These promises arise from the nanorods' unique optical and photothermal properties, the availability of synthetic protocols that can tune the size and shape of the particles, the ability to modify the surface and conjugate drugs/molecules to the nanorods, and the relative biocompatibility of gold nanorods. In this review, current progress in using gold nanorods as phototherapeutic agents and as drug delivery vehicles is summarized. Issues of dosage, toxicity and biological interactions at three levels (biological media alone; cells; whole organisms) are discussed, concluding with recommendations for future work in this area.


The importance of functional impairment to mental health outcomes: a case for reassessing our goals in depression treatment research.
Outcomes in depression treatment research include both changes in symptom severity and functional impairment. Symptom measures tend to be the standard outcome but we argue that there are benefits to considering functional outcomes. An exhaustive literature review shows that the relationship between symptoms and functioning remains unexpectedly weak and often bidirectional. Changes in functioning often lag symptom changes. As a result, functional outcomes might offer depression researchers more critical feedback and better guidance when studying depression treatment outcomes. The paper presents a case for the necessity of both functional and symptom outcomes in depression treatment research by addressing three aims-1) review the research relating symptoms and functioning, 2) provide a rationale for measuring both outcomes, and 3) discuss potential artifacts in measuring functional outcomes. The three aims are supported by an empirical review of the treatment outcome and epidemiological literatures.


Multiple cranial neuropathies: presenting signs of systemic lymphoma.
A 58-year-old man four years after orthototic liver transplantation presented with a mental neuropathy, multiple ocular motor nerve palsies, and an upper extremity motor neuropathy. Serial neuroimaging, cerebrospinal fluid analysis, total body computerized tomography and paraesophageal needle biopsy failed to reveal the underlying etiology. Sural nerve biopsy showed endoneurial perivascular infiltration with lymphoid cells, and bone marrow biopsy confirmed the diagnosis of a Burkitt's-type lymphoma. Systemic lymphoma with neural infiltration should be suspected in the immunosuppressed patient who presents with cranial or peripheral neuropathies.


Influence of high-heeled shoe parameters on biomechanical performance of young female adults during stair ascent motion.
High-heeled shoes are currently preferred by women due to contemporary aesthetics. However, high-heeled shoes may increase the effort required to ascend stairs and, hence, alter biomechanical performance. How do high-heel shoe parameters affect the pelvis position, lower extremities kinematics, and ground reaction force in young women during stair ascent motion? Stair ascent experiments were performed with 20 healthy adult women. The participants were instructed to ascend a 3-step staircase, wearing heeled shoes of different heel heights and heel types and one pair of flat shoes as the control group. Changes in lower body biomechanics were analyzed with kinematics and ground reaction force variables collected from the dominant limb. A two-way repeated ANOVA was performed to determine which variables were affected by heel type and which were affected by heel height or a combination of both. As the heel height increased, an increased range of ankle dorsiflexion-plantarflexion, as well as pelvic rotation, was observed(P = 0.039 and P = 0.003, respectively). A thinner heel type displayed a larger pelvic forward tilt movement(P = 0.026)and 1st peak vertical force(P = 0.025), as well as a smaller 2nd peak vertical force (P = 0.002). With high heels, increased external rotation of the knee, inversion and plantar flexion, and flexion values of the knee were observed. We also observed decreased external rotation of the pelvis, ankle eversion, varum, and dorsiflexion. To stabilize body posture during stair ascent motion with high-heeled shoes, compensatory response including increasd pelvic range of motion and changing the joint angles of the lower extremities.


Intramuscular DNA immunization with in vivo electroporation induces antigen-specific cellular and humoral immune responses in both systemic and gut-mucosal compartments.
Mucosal delivery of antigens induces antigen-specific immune responses in both systemic and mucosal compartments, and is an attractive approach for preventing initial infection with mucosal pathogens. It has been shown that the intramuscular (i.m.) immunization of plasmid DNA by in vivo electroporation (DNA e.p.) induces both cellular and humoral immune responses in the airway-mucosal compartment as well as in the systemic compartment, implying there is a mechanism that bridges between the systemic and mucosal immune responses. An important question is whether the i.m. DNA e.p.-immunization alone can induce antigen-specific immune responses in the gut-mucosal compartment. Here, we investigated the induction of antigen-specific CD8(+) T cells and antibodies in both systemic and gut-mucosal compartments following i.m. DNA e.p.-immunization to mice. Surprisingly, the i.m. DNA e.p.-immunization induced the antigen-specific CD8(+) T cells and antigen-specific antibodies in the gut-mucosal as well as the systemic compartment. These results suggest that the i.m. DNA e.p.-immunization should be considered as an effective vaccine strategy for the prevention of gut-mucosal infectious diseases.


Associations between vitamin D-binding protein (DBP) gene polymorphism (TAAA)n and development of osteoporosis in the Volga-Ural region of Russia.
Study of DBP gene (TAAA) n polymorphism in women of postmenopausal age revealed a significantly lower incidence of DBP(*) 10 allele and a higher incidence of DBP(*) 11 allele in Russian women with bone fractures in comparison with the relevant controls (χ(2) = 4.47, p = 0.034 and χ(2) = 4.28, p = 0.038, respectively). Allele DBP(*) 11 is a high risk marker (OR = 1.93; 95%CI 1.06-3.48), while allele DBP(*)10 a marker of low risk of bone fractures (OR = 0.59; 95%CI 0.37-0.94). A trend to a reduction of mineral density of the femoral neck and of the lumbar vertebrae in women with DBP(*) 10(*) 8 genotype of DBP gene polymorphic locus (TAAA) n in comparison with DBP(*) 10(*) 10 and DBP(*) 10(*) 11 genotype carriers is traced.


Can surgical performance benchmarking be generalized across multiple outcomes databases: a comparison of University HealthSystem Consortium and National Surgical Quality Improvement Program.
Surgeon's performance is tracked using patient outcomes databases. We compared data on patients undergoing laparoscopic cholecystectomy from 2 large databases with significant institutional overlap to see if either patient characteristics or outcomes were similar enough to accurately compare performance. Data from 2009 to 2011 were collected from University HealthSystem Consortium (UHC) and National Surgical Quality Improvement Program (NSQIP). UHC and NSQIP collect data from over 200 and 400 medical centers, respectively, with an overlap of 70. Patient demographics, pre-existing medical conditions, operative details, and outcomes were compared. Fifty-six thousand one hundred ninety-seven UHC patients and 56,197 NSQIP patients met criteria. Groups were matched by age, sex, and pre-existing comorbidities. Outcomes for NSQIP and UHC differed, including mortality (.20% NSQIP vs .12% UHC; P < .0001), morbidity (2.0% vs 1.5%; P < .0001), wound infection (.07% vs .33%; P < .0001), pneumonia (.38% vs .75%; P < .0001), urinary tract infections (.62% vs .01%; P < .0001), and length of hospital stay (1.8 ± 7.5 vs 3.8 ± 3.7 days; P = .0004), respectively. Surgical outcomes are significantly different between databases and resulting performance data may be significantly biased. A single unified national database may be required to correct this problem.


In situ hybridization studies using a molecular probe that maps to Xq27-Zq28.
The locus DXS98, which is recognized by the sequence p4D-8, is closely linked to the FRAXA locus. In this study we present data that confirm the existing mapping data, sublocalizing this sequence to the Xq27 region immediately proximal to the fragile site at Xq27.3.


Ivermectin for the Treatment of Coronavirus Disease 2019: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
We systematically assessed benefits and harms of the use of ivermectin (IVM) in patients with coronavirus disease 2019 (COVID-19). Published and preprint randomized controlled trials (RCTs) assessing the effects of IVM on adult patients with COVID-19 were searched until 22 March 2021 in 5 engines. Primary outcomes were all-cause mortality rate, length of hospital stay (LOS), and adverse events (AEs). Secondary outcomes included viral clearance and severe AEs (SAEs). The risk of bias (RoB) was evaluated using the Cochrane Risk of Bias 2.0 tool. Inverse variance random effect meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods. Ten RCTs (n = 1173) were included. The controls were the standard of care in 5 RCTs and placebo in 5. COVID-19 disease severity was mild in 8 RCTs, moderate in 1, and mild and moderate in 1. IVM did not reduce all-cause mortality rates compared with controls (relative risk [RR], 0.37 [95% confidence interval, .12-1.13]; very low QoE) or LOS compared with controls (mean difference, 0.72 days [95% confidence interval, -.86 to 2.29 days]; very low QoE). AEs, SAEs, and viral clearance were similar between IVM and control groups (low QoE for all outcomes). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality rates in 3 RCTs at high RoB were reduced with IVM. Compared with the standard of care or placebo, IVM did not reduce all-cause mortality, LOS, or viral clearance in RCTs in patients with mostly mild COVID-19. IVM did not have an effect on AEs or SAEs and is not a viable option to treat patients with COVID-19.


Cadherins and catenins in breast cancer.
Recent studies show that cadherins and catenins are hormonally regulated and carry out physiological roles during mammary development but have pathological effects when deregulated. E-cadherin expression is irreversibly lost in invasive lobular breast cancer (ILC). Animal models of ILC provide mechanistic insight, confirming that E-cadherin serves as both a tumor suppressor and an invasion suppressor in ILC. Ductal breast cancer involves complex, reversible, epigenetic modulation of multiple cadherins. Transcriptional regulators of E-cadherin have been identified that induce epithelial-to-mesenchymal transitions. Catenins are lost or mislocalized in tumors lacking cadherins. However, beta-catenin signaling is upregulated by numerous pathways in >50% of breast tumors and animal models suggest its oncogenic function in breast relates to its role in mammary progenitor cell expansion.


Noninvasive neuromonitoring in the operating room and its role in the prevention of delirium.
Delirium is a frequent and serious complication after surgery. It has a variable incidence between 20% and 40% with the highest incidence in elderly people undergoing major or cardiac surgery. The development of postoperative delirium (POD) is associated with increased hospital stay lengths, morbidity, the need for home care, and mortality. Studies have appeared in the last decade that evaluate the use of noninvasive monitoring to prevent its development. The evaluation of the depth of anesthesia with processed EEG allows to avoid awareness and burst suppression events. The cessation of brain activity is associated with the development of delirium. Another noninvasive monitoring technique is NIRS for cerebral tissue hypoxia detection by measuring regional oxygen saturation. The reduction of this parameter does not seem to be associated with the development of POD but with postoperative cognitive dysfunction. There are few studies in the literature and with conflicting results on the use of the pupillometer and transcranial Doppler in predicting the development of postoperative delirium.


Lung Ultrasound Protocol and Quality Control of Image Interpretation Using an Adjudication Panel in the Household Air Pollution Intervention Network (HAPIN) Trial.
Lung ultrasound (LUS) is an alternative to chest radiography to confirm a diagnosis of pneumonia. For research and disease surveillance, methods to use LUS to diagnose pneumonia are needed. In the Household Air Pollution Intervention Network (HAPIN) trial, LUS was used to confirm a clinical diagnosis of severe pneumonia in infants. We developed a standardized definition of pneumonia, protocols for recruitment and training of sonographers, along with LUS image acquisition and interpretation. We use a blinded panel approach to interpretation with LUS cine-loops randomized to non-scanning sonographers with expert review. We obtained 357 lung ultrasound scans: 159, 8 and 190 scans were collected in Guatemala, Peru and Rwanda, respectively. The diagnosis of primary endpoint pneumonia (PEP) required an expert tie breaker in 181 scans (39%). PEP was diagnosed in 141 scans (40%), not diagnosed in 213 (60%), with 3 scans (<1%) deemed uninterpretable. Agreement among the two blinded sonographers and the expert reader in Guatemala, Peru and Rwanda was 65%, 62% and 67%, with a prevalence-and-bias-corrected kappa of 0.30, 0.24 and 0.33, respectively. Use of standardized imaging protocols, training and an adjudication panel resulted in high confidence for the diagnosis of pneumonia using LUS.


COVID-19 and the differential dilemma.
The conundrums of choosing candidate genes, via differential expression between treated and mock specimens, are tackled by Ghandikota et al. in this issue of Patterns in their efforts to tease out genetic patterns that are characteristic of coronavirus disease 2019 (COVID-19) outcomes.


Clinical characteristics and survival outcomes in patients with primary ovarian carcinoid: A historical cohort study.
Primary ovarian carcinoids are extremely rare ovarian tumors, and there is limited data available on their clinical characteristics and survival outcomes. We conducted a historical cohort study of 56 patients to investigate their clinical characteristics. The overall survival, disease-specific survival, recurrence-free survival, and potential prognostic factors of these patients were also evaluated. The median age of these patients was 42.0 years (range: 20-71). The average mass and carcinoid size was 7.3 and 0.4 cm, respectively. Elevated tumor marker levels and ascites were observed in 15 and 10 patients, respectively. In 98.2% of the patients, tumors were confined to the ovary, while only one had metastatic disease. Surgery was the mainstay therapy: 37.5% of the patients underwent unilateral salpingo-oophorectomy, 25.0% underwent hysterectomy with bilateral salpingo-oophorectomy, 21.4% underwent ovarian cystectomy, 10.7% underwent comprehensive staging surgery, and 5.4% underwent bilateral salpingo-oophorectomy. Appendectomy and lymphadenectomy were performed in eight and five patients, respectively, but none showed tumor involvement. Chemotherapy was the only adjuvant treatment utilized, and was administered in four patients. Pathological analysis showed that strumal carcinoid was the most predominant subtype, occurring in 66.1% of the patients. The Ki-67 index was reported in 39 patients, 30 of which had an index of no more than 3%, with a maximum of only 5%. Only one relapse occurred after the initial treatment, and that patient experienced recurrences on two occasions, maintaining stable disease after surgery and octreotide therapy. After a median follow-up of 3.6 years, 96.4% of the patients achieved no evidence of disease, while 3.6% were alive with the disease. The 5-year recurrence-free survival rate was 97.9% and no death occurred. No risk factors for recurrence-free survival, overall survival, or disease-specific survival were identified. The Ki-67 indices were extremely low and prognoses were excellent in patients with primary ovarian carcinoids. Conservative surgery, especially unilateral salpingo-oophorectomy, is preferred. Individualized adjuvant therapy may be considered for patients with metastatic diseases.


A Robust Observation, Planning, and Control Pipeline for Autonomous Rendezvous with Tumbling Targets.
Accumulating space debris edges the space domain ever closer to cascading Kessler syndrome, a chain reaction of debris generation that could dramatically inhibit the practical use of space. Meanwhile, a growing number of retired satellites, particularly in higher orbits like geostationary orbit, remain nearly functional except for minor but critical malfunctions or fuel depletion. Servicing these ailing satellites and cleaning up "high-value" space debris remains a formidable challenge, but active interception of these targets with autonomous repair and deorbit spacecraft is inching closer toward reality as shown through a variety of rendezvous demonstration missions. However, some practical challenges are still unsolved and undemonstrated. Devoid of station-keeping ability, space debris and fuel-depleted satellites often enter uncontrolled tumbles on-orbit. In order to perform on-orbit servicing or active debris removal, docking spacecraft (the "Chaser") must account for the tumbling motion of these targets (the "Target"), which is oftentimes not known a priori. Accounting for the tumbling dynamics of the Target, the Chaser spacecraft must have an algorithmic approach to identifying the state of the Target's tumble, then use this information to produce useful motion planning and control. Furthermore, careful consideration of the inherent uncertainty of any maneuvers must be accounted for in order to provide guarantees on system performance. This study proposes the complete pipeline of rendezvous with such a Target, starting from a standoff estimation point to a mating point fixed in the rotating Target's body frame. A novel visual estimation algorithm is applied using a 3D time-of-flight camera to perform remote standoff estimation of the Target's rotational state and its principal axes of rotation. A novel motion planning algorithm is employed, making use of offline simulation of potential Target tumble types to produce a look-up table that is parsed on-orbit using the estimation data. This nonlinear programming-based algorithm accounts for known Target geometry and important practical constraints such as field of view requirements, producing a motion plan in the Target's rotating body frame. Meanwhile, an uncertainty characterization method is demonstrated which propagates uncertainty in the Target's tumble uncertainty to provide disturbance bounds on the motion plan's reference trajectory in the inertial frame. Finally, this uncertainty bound is provided to a robust tube model predictive controller, which provides tube-based robustness guarantees on the system's ability to follow the reference trajectory translationally. The combination and interfaces of these methods are shown, and some of the practical implications of their use on a planned demonstration on NASA's Astrobee free-flyer are additionally discussed. Simulation results of each of the components individually and in a complete case study example of the full pipeline are presented as the study prepares to move toward demonstration on the International Space Station.


Efferent connections of area 20 in the cat: HRP-WGA and autoradiographic studies.
Following injections of horseradish peroxidase-wheat germ agglutinin conjugate (HRP-WGA) and tritiated leucine into area 20 of the cat, terminal labeling was observed in visual areas 19, 21, the splenial visual area, the lateral suprasylvian area as well as in premotor, association and limbic related cerebral cortical regions. Labeled terminals in the subcortex were distributed in the caudate nucleus, the claustrum, the putamen, the anterior ventral nucleus, the intralaminar nuclei, the caudal division of the intermediate lateral nucleus, the lateralis posterior-pulvinar complex, the parvocellular C laminae of the dorsal lateral geniculate nucleus and the ventral lateral geniculate nucleus. In HRP-WGA preparations, retrogradely labeled somata were observed in these regions with the exception of certain subcortical structures. The projections are discussed with respect to the possible role area 20 plays in the cortical control of pupillary constriction.


Adaptation and factor structure of three psychometric instruments measuring behavioral aspects of medication prescribing in physician assistants.
(1) Present the factor structure of two psychometric instruments for self-efficacy and one for outcome expectations of medication prescribing; (2) evaluate the reliability of the scales, and (3) present preliminary evidence of validity. Physician assistants (PA) and PA students completed a survey evaluating three psychometric instruments: (1) Self-Efficacy in Prescribing (SEP), (2) Self-Efficacy in Prescribing-Geriatric (SEPG), and (3) Outcomes Expectations of Prescribing Errors (OEP). Students also evaluated 3 hypothetical prescriptions, two of which contained a prescribing error. Students were instructed to identify (1) if an error occurred and (2) what type of error. The data were analyzed using parallel analysis with a varimax rotation, Cronbach's α, Pearson and Spearman correlations. One hundred eighty five (n = 185) respondents completed the survey (response rate = 63.8%). The parallel analysis found that the SEP had one 7-item factor with α = 0.94 (M = 5.7 (SD = 1.9) out of 10). The SEPG also had one 7-item factor with α = 0.95 (M = 5.5 (1.9). The OEP had one 6-item factor with α = 0.89 (M = 3.5 (SD = 0.8) out of 5). The SEP and SEPG, were correlated to the OEP each other (both p < 0.01). Actively practicing PAs had the highest composite mean SEP and SEPG scores. First-year PA students had the highest mean scores for the OEP. There was a weak association between the mean SEPG score and the number of correctly identified prescriptions (rs = 0.18, p = 0.04). The SEP, SEPG, and OEP show preliminary evidence of reliability and structural, construct, and known-group validities using simulated prescriptions. These tools may be able to be used by educators and implementation scientists as one method to show the effectiveness of future interventions to reduce incidence of prescribing errors.


The clinical utility of precision medicine: properly assessing the value of emerging diagnostic tests.
Assessments of the clinical utility of biomarkers and genomic tests often ignore individual utility and fail to account for downstream changes to the care delivery model. Tests that identify outliers are often undervalued in favor of those that help direct treatment for the "average" patient. By reducing uncertainty, these tests also enable lower-cost providers and even patients to assume increased responsibility for care in more convenient and affordable settings.


The clinical efficacy of acupoint sticking combined with massage to treatment functional dyspepsia: A protocol of systematic review and meta-analysis.
The objective of this meta-analysis was to summarize and identify the available evidence from studies to estimate the clinical value of acupoint sticking combined with massage (ASM) in the treatment of functional dyspepsia (FD), and provide clinicians with evidence on which to base their clinical decision making. This review will include all studies comparing clinical efficacy of ASM in the treatment of FD. The search strategy will be performed in 10 databases. We will not establish any limitations to language and publication status, published from inception to the August 2020. Two reviewers will screen, select studies, extract data, and assess quality independently. Outcome is alleviation of global dyspeptic symptoms, alleviation of individual dyspeptic symptoms, quality-of-life improvement, and safety. The methodological quality including the risk of bias of the included studies will be evaluated. We will carry out statistical analysis using RevMan 5.3 software. This study will summarize current evidence to assess the efficacy and safety of ASM in the treatment of FD. The findings of this study will provide helpful evidence for the clinician, and will promote further studies, as well as studying the value of ASM. INPLASY2020110072 (DOI number: 10.37766/inplasy2020.11.0072).


The mechanism and function of super enhancer RNA.
Super enhancer (SE) is a cluster of enhancers that has a stronger ability to promote transcription compared to the typical enhancer (TE). Similar to TE, which can transcribe enhancer RNA (eRNA), SE produces super enhancer RNA (seRNA). The activation of SE is cell and tissue-specific, and the SE-associated genes are mostly linked to the cell fate. This is demonstrated by the important role-played by SE in the embryonic stem cell (ESC) and multiple cancer development. SeRNA regulates transcription in both cis and trans configuration, and those located in the cytoplasm mediates various cell activities. However, the functions of seRNAs are unclear, and most of them have a synergistic effect with SE and SE-associated genes. In this mini review, we summarized the mechanisms of seRNA and functions of both SE and seRNA.


Cellular retinol-binding protein.
1. A protein which binds retinol in vitro with high affinity and specificity was detected by sucrose gradient centrifugation or by gel filtration after preincubating rat tissue cytosols with all-trans-[3H]retinol. This protein sediments in the 2 S region of sucrose gradients. Molecular size determination by gel filtration indicates a molecular weight of 16 000. 2. Competition studies revealed that only all-trans-retinol, not retinal or retinoic acid, competes for binding. The binding of radioactive retinol is reversible. 3. This protein was detected in cytosols of rat liver, lung, spleen, brain, testis, ovaries, uterus and intestinal mucosa whereas heart or gastrocnemius muscle seem to lack this protein. 4. The cellular retinol binding protein was found in fetuses as early as day 12 of the gestation period and possessed the same specificity for the ligand as the one in adult tissues. 5. This binding component was not detected in cytosols prepared from Novikoff hepatoma, ascites hepatoma AS-30D, mouse Ehrlich ascites tumor and mouse pituitary tumor cell line AtT 20. 6. The cellular retinol binding protein seems to be different from that described to be present in the serum as suggested by difference in size and by the inability of the antisera against the serum retinol binding protein to remove the cellular binding protein from the cytosol preparations.


Coproduction of KPC-2 and IMP-10 in Carbapenem-Resistant Serratia marcescens Isolates from an Outbreak in a Brazilian Teaching Hospital.
We describe an outbreak caused by KPC-2- and IMP-10-producing Serratia marcescens isolates in a Brazilian teaching hospital. Tigecycline was the only active antimicrobial agent tested. The blaIMP-10 gene was located in a new class 1 integron, named In990, carried by a nonconjugative plasmid, in contrast to blaKPC-2.


A methodological approach to rapid and sensitive monoamine histofluorescence using a modified glyoxylic acid technique: the SPG method.
A modified approach of the glyoxylic acid (GA) condensation reaction for the visualization of biogenic amines in tissue is described. Cryostat sections are used from brain or extracerebral tissue in dog, monkey, rat and mouse and exposed for 3 s to a room temperature solution containing sucrose-potassium phosphate-glyoxylic acid (SPG). The tissues are air dried and heated in an oven for 5 min. The complete precessing time from fresh tissue to microscopic examineation takes 18 min. Morphologically sharp and brightly fluorescent monoamine-containing neurons, pre- and terminal axons are seen against a dark parenchymal background without drug pre-treatment. The SPG method retains the high specific sensitivity for monoamines previously described in the original technique but is, in addition, more rapid and simple and is easily accissible as a research tool to investigators inexperienced in histofluoresecence techniques.


Transverse dentoalveolar response of mandibular arch after rapid maxillary expansion (RME) with tooth-borne and bone-borne appliances.
To assess and compare spontaneous expansion of mandibular posterior teeth between tooth-borne (TB) and bone-borne (BB) rapid maxillary expansion (RME). This study included 36 adolescents with bilateral maxillary crossbite receiving tooth-borne (average age: 14.4 ± 1.3 years) or bone-borne (average age: 14.7 ± 1.4 years) maxillary expansion. Cone beam computed tomography was acquired before expansion (T1) and after 6 months' retention (T2). Specific linear and angular measurements were performed in the coronal view to assess buccal inclinations and widths of mandibular posterior units. All data were statistically analyzed. In both groups there was a significant increase in buccal-lingual inclination of mandibular posterior teeth ranging from 1.67° to 2.30° in the TB group and from 1.46° to 2.11° in BB group. Mandibular posterior widths showed an increase ranging from 0.80 mm to 1.33 mm in TB group and from 0.64 mm to 0.96 mm in the BB group. No differences between groups were found for linear or angular measurements. A clinically significant gain of space in the mandibular arch should not be expected after RME.


Activation of extracorporeal membrane oxygenation: a therapeutic approach to be considered.
To describe the epidemiological profile of victims of cardiac arrest assisted using a nontransporting emergency medical service vehicle and to determine whether these patients met the criteria for the use of extracorporeal membrane oxygenation. This study employed a retrospective, cohort, descriptive, and exploratory design. Data were collected in January 2018 in northern Portugal by consulting the records of nontransporting emergency medical service vehicles that provided assistance between 2012 and 2016. An observation grid was prepared that was supported by the instrument used for collecting data from the national registry of out-ofhospital cardiac arrests. After applying the inclusion criteria, the sample consisted of 36 victims. Extracorporeal membrane oxygenation could have been applied to 24 victims during the period analyzed, which might have increased the odds for transplantation, survival, or both, for either the victim or other individuals. Nontransporting emergency medical service vehicles have the potential for inclusion in the extracorporeal membrane oxygenation network of the study area.


Totally Percutaneous Transfemoral Transcatheter Aortic Valve Replacement Despite Failure to Deploy a Vascular Closure Device: A Single-Centre Case Series.
Transcatheter aortic valve replacement (TAVR) is preferably performed as a completely percutaneous procedure via transfemoral access. Suture-mediated vascular closure devices are deployed prior to sheath insertion (pre-closure). Inability to perform pre-closure may necessitate surgical vascular repair of the femoral artery. Patients at increased risk of vascular surgery complications may benefit from a percutaneous method for achieving access site haemostasis. Stent graft implantation is commonly used for treating access site injury following TAVR. This study assessed the feasibility of a strategy of planned stent graft implantation within the femoral artery for achieving access site haemostasis in patients undergoing transfemoral TAVR and in whom vascular pre-closure was not possible. A prospective institutional TAVR registry was retrospectively analysed and a cohort of patients were identified who were selected for transfemoral valve delivery and in whom pre-closure failed and access site haemostasis was achieved by stent graft implantation. This strategy was used for achieving access site haemostasis in 11 patients (1.5% of 744 patients undergoing transfemoral TAVR). These patients were considered to be at increased risk of vascular surgery complications due to advanced age, frailty, comorbidities, or immobility. Stent graft implantation achieved access site haemostasis in all patients. During follow-up, 30-day mortality was zero, 1-year mortality was 27%, and none of the patients required additional vascular interventions. The preliminary data suggest that planned stent graft implantation within the femoral artery may achieve access site haemostasis and enable a totally percutaneous TAVR procedure, despite failure to perform pre-closure with a suture-based vascular closure device.


SPATA2: more than a missing link.
The assembly of the TNFR1 signalling complex (TNF-RSC) depends on K63- and M1-linked ubiquitylation, promoting the recruitment of complex constituents and the stability of the complex. Ubiquitylation is a dynamic process, controlled by E3 ubiquitin ligases as well as deubiquitinases, such as CYLD and OTULIN. A novel molecule, SPATA2, which is crucial for recruiting and activating the deubiquitinase CYLD within the TNF-RSC, has now been identified by four different studies. Loss of SPATA2 was shown to result in increased TNF-, but also NOD2-mediated proinflammatory signalling. Importantly, SPATA2 is instrumental for TNF-induced cell death, and a closer look at these findings suggests that SPATA2 possibly has functions beyond promoting the activity of CYLD.


Thermal picks for anchoring on icy moons.
Europa, Enceladus, and other icy moons are exciting science targets, but our capabilities to adequately explore these planetary bodies needs to be developed. Gripping the surface ice may aid the stability and mobility of surface landers and mobile explorers that are sent to the surface of an icy moon. This paper presents an approach to anchoring into the surface of an icy moon using a heated pick. The proposed thermodynamic approach contrasts with the traditional mechanical approach to inserting terrestrial ice anchors. This thermodynamic approach maintains the ice structure to provide a reliable hold. The low temperatures and lack of a significant atmosphere on most of the icy moons cause surface conditions to stay below the triple point of water, the primary constituent of the surface ice for both Europa and Enceladus. Under these conditions the surface water ice will sublimate when sufficiently heated. The thermal pick concept presented in this paper is used to study the nature of the sublimation that results from forced insertion of an object into ice, which could then be used as an anchor for stability and mobility. While the surfaces of the icy moons are composed primarily of water ice at cryogenic and vacuum conditions, the nature of a sublimation process can be more readily examined with frozen CO2, which sublimates under atmospheric conditions. This paper explores the physical phenomena and thermodynamic design considerations of a heated device that uses a sublimation based insertion into frozen CO2 under atmospheric conditions. This approach was found to allow for proper insertion of thermal picks with energetic efficiencies of up to 90%.


[Immediate and long-term outcomes after "Ephesos" coronary stent implantation in patients with stable or unstable angina].
An open non-randomized trial was initiated to assess clinical and angiographic results of using the coronary stent "Ephesos" in 457 patients with stable or unstable angina pectoris and native coronary affections. 268 stents have been implanted in 231 patients with stable angina (SA) and 271 stents--in 226 patients with unstable angina (UA). 46% lesions were complicated. The length of stenosis was 12.9 +/- 6.7 mm in the group SA and 14.1 +/- 7.4 mm in the group UA, 30% stenoses were long. Successful stenting was stated in 99% without cases of acute thrombosis. Non-fatal myocardial infarction took place in hospital in 1.3% of SA patients and in 2.6% of UA patients. Incidence of cardiac complications (death, recurrent angina pectoris, myocardial infarction, restenosis, repeated revascularization) for 6-month follow-up was 15.6% in SA group and 18.1% in UA group. At angiographic control, the index of vascular diameter loss made up 0.22 +/- 0.2 in SA group and 0.3 +/- 0.27 in UA group. Incidence of restenosis was 12 and 14%, respectively. 18-month follow-up found no differences in frequency of complications: 21.6 and 22.6% in groups SA and UA, respectively. Implantation of the stent "Ephesos" is effective in prevention of thrombosis and restenosis in patients with stable or unstable angina pectoris at high risk of intervention.


The yeast aminoacyl-tRNA synthetases. Methodology for their complete or partial purification and comparison of their relative activities under various extraction conditions.
Several fractionation steps are described which can be applied to the partial purification of the 20 aminoacyl-tRNA synthetases from commercial baker's yeast. Comparative experiments performed in the presence or absence of protease inhibitors revealed that some enzymes prepared in the presence of the inhibitor exhibit much higher specific activities than the proteins extracted in the absence of the inhibitor. The methodology reported can be used for the simultaneous preparation of several pure aminoacyl-tRNA synthetases. As examples, the large scale purification of phenylalanyl-and valyl-tRNA synthetases are described.


A high-quality cucumber genome assembly enhances computational comparative genomics.
Genetic variation is expressed by the presence of polymorphisms in compared genomes of individuals that can be transferred to next generations. The aim of this work was to reveal genome dynamics by predicting polymorphisms among the genomes of three individuals of the highly inbred B10 cucumber (Cucumis sativus L.) line. In this study, bioinformatic comparative genomics was used to uncover cucumber genome dynamics (also called real-time evolution). We obtained a new genome draft assembly from long single molecule real-time (SMRT) sequencing reads and used short paired-end read data from three individuals to analyse the polymorphisms. Using this approach, we uncovered differentiation aspects in the genomes of the inbred B10 line. The newly assembled genome sequence (B10v3) has the highest contiguity and quality characteristics among the currently available cucumber genome draft sequences. Standard and newly designed approaches were used to predict single nucleotide and structural variants that were unique among the three individual genomes. Some of the variant predictions spanned protein-coding genes and their promoters, and some were in the neighbourhood of annotated interspersed repetitive elements, indicating that the highly inbred homozygous plants remained genetically dynamic. This is the first bioinformatic comparative genomics study of a single highly inbred plant line. For this project, we developed a polymorphism prediction method with optimized precision parameters, which allowed the effective detection of small nucleotide variants (SNVs). This methodology could significantly improve bioinformatic pipelines for comparative genomics and thus has great practical potential in genomic metadata handling.


Immersive virtual reality is effective in the rehabilitation of older adults with balance disorders: A randomized clinical trial.
What are the effects of immersive virtual reality (IVR) training compared to conventional physiotherapy on body balance and risk of falls in older adults with balance disorders? A randomized controlled trial with two intervention arms, concealed allocation, per-protocol analysis, and blinded assessment. Thirty-seven older adults with balance disorders and risk of falling. Participants were randomized into two groups: a control group, which received balance training with conventional physiotherapy using multimodal circuit exercises, and an experimental group, which received balance training using immersive virtual reality. Both groups received 16 individual sessions, twice a week. The primary outcome was functional balance. Secondary outcomes were static balance, gait speed, functional range, dizziness symptoms, and fear of falling. Safety was ensured by assessing any adverse events during the intervention. After 16 sessions, in the intragroup analysis, the functional balance score in the experimental group increased by 3.00 (95% CI 1.42 to 4.57) and in the control group by 3.88 (95% CI 2.16 to 5.59). Both groups improved in assessments of sensory interaction and anterior reach. Only the experimental group presented increased mobility and reduced dizziness. After two months, there was a maintenance of gains in functional balance and a reduction of the gains in functional reach for both groups. In the intergroup comparison, there was no significant difference. Immersive Virtual Reality training proved to be effective for balance-related outcomes, although it was not superior to conventional therapy. RBR-3tk7fw.


Effects of allergy, intestinal helminthic infestation and sex on serum IgE concentrations and immediate skin hypersensitivity in three ethnic groups.
Serum IgE concentrations were measured in 232 blood donors resident in the Western Cape, South Africa. Subjects were interviewed for histories of allergy and skin tested with a variety of common allergens. Faecal specimens were collected for microscopic examination. Results confirmed that Cape Coloureds and Africans tend to have elevated serum IgE concentrations and showed that African males have a high prevalence of immediate skin hypersensitivity. Cape Coloureds and Africans had high prevalences of helminthic infestation and relatively low prevalence of allergic symptoms. Only in Whites were elevated serum IgE concentrations associated with positive allergic histories; in this group, results suggested that the sex difference in serum IgE concentrations observed previously is owing to differences in the IgE responses of allergic males and females.


Cortical bone stress distribution in mandibles with different configurations restored with prefabricated bar-prosthesis protocol: a three-dimensional finite-element analysis.
To evaluate stress distribution in different horizontal mandibular arch formats restored by protocol-type prostheses using three-dimensional finite element analysis (3D-FEA). A representative model (M) of a completely edentulous mandible restored with a prefabricated bar using four interforaminal implants was created using SolidWorks 2010 software (Inovart, São Paulo, Brazil) and analyzed by Ansys Workbench 10.0 (Swanson Analysis Inc., Houston, PA) to obtain the stress fields. Three mandibular arch sizes were considered for analysis, regular (M), small (MS), and large (ML). Three unilateral posterior loads (L) (150 N) were used: perpendicular to the prefabricated bar (L1); 30° oblique in a buccolingual direction (L2); 30° oblique in a lingual-buccal direction (L3). The maximum and minimum principal stresses (σ(max), σ(min)), the equivalent von Mises (σ(vM)), and the maximum principal strain (σ(max) ) were obtained for type I (M.I) and type II (M.II) cortical bones. Tensile stress was more evident than compression stress in type I and II bone; however, type II bone showed lower stress values. The L2 condition showed highest values for all parameters (σ(vM), σ(max), σ(min), ɛ(max)). The σ(vM) was highest for the large and small mandibular arches. The large arch model had a higher influence on σ(max) values than did the other formats, mainly for type I bone. Vertical and buccolingual loads showed considerable influence on both σ(max) and σ(min) stresses.


High-throughput multimodal automated phenotyping (MAP) with application to PheWAS.
Electronic health records linked with biorepositories are a powerful platform for translational studies. A major bottleneck exists in the ability to phenotype patients accurately and efficiently. The objective of this study was to develop an automated high-throughput phenotyping method integrating International Classification of Diseases (ICD) codes and narrative data extracted using natural language processing (NLP). We developed a mapping method for automatically identifying relevant ICD and NLP concepts for a specific phenotype leveraging the Unified Medical Language System. Along with health care utilization, aggregated ICD and NLP counts were jointly analyzed by fitting an ensemble of latent mixture models. The multimodal automated phenotyping (MAP) algorithm yields a predicted probability of phenotype for each patient and a threshold for classifying participants with phenotype yes/no. The algorithm was validated using labeled data for 16 phenotypes from a biorepository and further tested in an independent cohort phenome-wide association studies (PheWAS) for 2 single nucleotide polymorphisms with known associations. The MAP algorithm achieved higher or similar AUC and F-scores compared to the ICD code across all 16 phenotypes. The features assembled via the automated approach had comparable accuracy to those assembled via manual curation (AUCMAP 0.943, AUCmanual 0.941). The PheWAS results suggest that the MAP approach detected previously validated associations with higher power when compared to the standard PheWAS method based on ICD codes. The MAP approach increased the accuracy of phenotype definition while maintaining scalability, thereby facilitating use in studies requiring large-scale phenotyping, such as PheWAS.


Construction and assessment of individualized proteogenomic databases for large-scale analysis of nonsynonymous single nucleotide variants.
Next-generation sequencing projects focusing on genomes and transcriptomes identify millions of single nucleotide variants (SNVs), many of which result in single amino acid substitutions. These nonsynonymous (ns) SNVs are typically not incorporated into protein sequence databases used to identify MS/MS data. Here, we perform a comparative analysis of the assembly of nsSNV-containing proteogenomic databases. We use a comprehensive transcriptome and proteome dataset of HeLa cells from the literature to derive and to incorporate SNVs into databases applicable to proteomics search engines, and to assess their performance in the identification of nsSNVs. We assemble the databases by (1) translation of SNV-containing transcripts into all possible reading frames, (2) translation of predicted reading frame, (3) prediction of nsSNVs and subsequent incorporation into canonical protein sequences. We show substantial differences between generated databases in terms of represented nsSNVs and theoretical search space, affecting sensitivity and specificity of database search. We query the databases with >2.2M high-resolution MS/MS spectra using MaxQuant software and identify 451 variant peptides, containing 401 nsSNVs. We conclude that prediction of reading frame and, if applicable, SNV effect result in comprehensive yet compact databases necessary to retain sensitivity in large-scale analysis of nsSNVs called from transcriptomics data.


SL 75 102 as a gama-aminobutyric acid agonist: experiments on dorsal root ganglion neurones in vitro.
1 In anticipation that centrally active gamma-aminobutyric acid (GABA)-mimetic drugs may be clinically useful, derivatives of GABA with an imine link (Schiff base) to a lipophilic carrier have recently been prepared. The present paper concerns the actions of [alpha(4-chlorophenyl)5-fluoro, 2-hydroxy benzilidene-amino]-4-butanoate Na+, SL 75 102. 2 To test one aspect of the GABA-mimetic properties of SL 75 102, this compound was compared with GABA for activity on intracellularly-recorded neurones in rat dorsal root ganglia in vitro. On these neurones GABA, administered either by microiontophoresis or direct into the superfusion medium, causes a depolarization, due to an increased chloride conductance, followed by a period of desensitization. 3 The actions of Sl 75 102 were in nearly all respects identical to those of GABA; parameters examined were the effects on membrane potential and input conductance, desensitization, dose-response characteristics and sensitivity to the GABA antagonists, bicuculline and picrotoxin. 4 SL 75 102 was less potent than GABA (mean relative potency 0.03:1). 5 SL 75 102 therefore appears to be a weak agonist at GABA receptors of these neurones.


An Update on Applications of Cattle Mesenchymal Stromal Cells.
Attention on mesenchymal stromal cells (MSCs) research has increased in the last decade mainly due to the promising results about their plasticity, self-renewal, differentiation potential, immune modulatory and anti-inflammatory properties that have made stem cell therapy more clinically attractive. Furthermore, MSCs can be easily isolated and expanded to be used for autologous or allogenic therapy following the administration of either freshly isolated or previously cryopreserved cells. The scientific literature on the use of stromal cells in the treatment of several animal health conditions is currently available. Although MSCs are not as widely used for clinical treatments in cows as for companion and sport animals, they have the potential to be employed to improve productivity in the cattle industry. This review provides an update on state-of-the-art applications of bovine MSCs to clinical treatments and reproductive biotechnologies.


The natural history of Alzheimer disease: a longitudinal presymptomatic and symptomatic study of a familial cohort.
Knowledge of the evolution of cognitive deficits in Alzheimer disease is important for our understanding of disease progression. Previous reports, however, have either lacked detail or have not covered the presymptomatic stages. To delineate the onset and progression of clinical and neuropsychological abnormalities in familial Alzheimer disease. Nineteen subjects with familial Alzheimer disease underwent serial clinical and neuropsychological assessments. Eight of these had undergone presymptomatic assessments. The follow-up period was 1 to 10 years (mean, 5 years). The relative timing of the occurrence of 3 markers of disease onset and progression (onset of symptoms, Mini-Mental State Examination score < or = 24, and impaired scores on a range of neuropsychological tests) were compared using the binomial exact test. Neurological abnormalities were not prominent, although myoclonus appeared early in some. Mini-Mental State Examination score was not sensitive to early disease. Memory and general intelligence deficits appeared at an earlier stage, in some patients when presymptomatic. Perceptual, naming, and especially spelling skills were preserved to a late stage. Familial Alzheimer disease may have a long prodromal phase of several years with subtle deficits initially of general intelligence and memory, while spelling, naming, and perception are relatively preserved until a late stage.


Risk factors of postoperative pancreatic fistula in patients after distal pancreatectomy: a systematic review and meta-analysis.
Postoperative pancreatic fistula (POPF) is a common complication following distal pancreatectomy (DP). However, the risk factors of this complication in patients after DP still remain controversial. The aim of our study is to estimate the association between potential risk factors and POPF. Relevant articles published up to June 21, 2016 were identified via PubMed, EMBASE, Web of Science, and The Cochrane Library. Studies that examined the risk factors of POPF following DP were enrolled. 20 articles (2070 patients) were finally included in this study. The pooled data suggested that patients with soft pancreas, higher Body Mass Index (BMI), blood transfusion, elevated intraoperative blood loss, and longer operative time had a decreased risk for POPF. However, age, gender, malignant pathology, types of stump closure, octreotide therapy, history of diabetes and chronic pancreatitis, splenectomy, multiorgan resection, main duct ligation, preoperative serum albumin levels, PGA felt wrapping, and extended lymphadenectomy could not be regarded as risk factors for POPF. Our analytic data demonstrated that pancreas texture, BMI, blood transfusion, intraoperative blood loss, and operative time were clinical predictor for POPF. This study may assist surgeons to screen patients with high risk of POPF and select appropriate treatment measures.


Conformational and ligand binding properties of the isolated domains from the beta 2 subunit of Escherichia coli tryptophan synthetase investigated by the reactivity of their cysteines.
A mild proteolytic treatment of the dimeric beta 2 subunit of Escherichia coli tryptophan synthetase (L-serine hydrolase (adding indole) EC 22.214.171.124) is known to nick each polypeptide chain into two complementary fragments, F1 and F2 (Högberg-Railbaud, A., and Goldberg, M.E. (1977) Proc. Natl. Acad. Sci. U.S.A. 74, 442-446). The reactivity of the cysteines in the isolated or associated fragments is studied and used to characterize the structural and functional properties of these fragments. It is shown that the total number of cysteines, their reactivity to dithiobisnitrobenzoate, and their protection by various ligands are the same in the nicked and intact enzyme, thus demonstrating the close structural analogy between these two proteins. In the isolated F1 fragments two cysteines are reactive and two are buried, thus confirming that this fragments has a compact, globular structure. Various ligands tested fail to produce any modification of the cysteines in the isolated fragments, thus suggesting that none of the fragments alone carries a binding site for the substrates and coenzyme.


Performance of aphasic and nonaphasic children on a sentence repetition task.
Aphasic and nonaphasic subjects repeated 24 sentences that varied according to grammatical complexity of the auxiliary. The results revealed that the repetition behavior of both groups was influenced by grammatical complexity. Sentences containing two or three optional auxiliary elements were more difficult to repeat than sentences with one or no optional auxiliary element. Similar patterns of repetition errors were observed in the responses of both groups. These findings suggest that grammatical complexity as well as length influence the retention span of aphasic children.


Spectroscopic insight for tablet compression.
Tablet compression process has been studied over the years from various perspectives. However what exactly happens to material during compression is still unknown. In this study a novel compression die which enables real-time spectroscopic measurements during the compression of material is represented. Both near infrared and Raman spectroscope probes can be attached to the die. In this study the usage of the die is demonstrated by using Raman spectroscopy. Eicosane, d-glucose anhydrate, α-lactose monohydrate and xylitol were used in the study because their compression behavior and bonding properties during compression were assumed to be different. The intensity of the Raman signal changed during compression with all of the materials. However, the intensity changes were different within the materials. The biggest differences were within the xylitol spectra. It was noticed that some peaks disappeared with higher compression pressures indicating that the pressure affected variously on different bonds in xylitol structure. These reversible changes were supposed to relate the changes in conformation and crystal structure. As a conclusion, the die was found to be a significant addition for studying compression process in real-time. It can help to reveal Process induced transformations (PITs) occurring during powder compaction.


Metastatic colorectal cancer: systemic treatment in the new millennium.
Colorectal cancer (CRC) is common in North America. Metastatic disease is present at diagnosis in 30% of the patients, and approximately half of early-stage patients will eventually present with metastatic disease. Until recently, few chemotherapy options were available to treat metastatic CRC. The authors review the results of recent clinical trials and the design of ongoing trials in the management of patients with metastatic colorectal cancer. Fluorouracil (5-FU) with leucovorin (LV) modulation has a marginal but positive effect on survival in those patients. The recent incorporation of irinotecan (CPT-11) and oxaliplatin for the management of advanced CRC has generated further improvement in survival. The development of oral fluoropyrimidines, mimicking continuous infusion 5-FU, is convenient. In randomized trials, capecitabine was equally effective to bolus 5-FU and LV in the management of metastatic CRC. Recently completed or ongoing clinical trials to study novel targeting agents have initiated a new era of drug development. Anti-angiogenesis drugs, tyrosine kinase inhibitors, and epidermal growth factor blockers are among this new generation of agents with encouraging preliminary data. Randomized trials will determine the impact of these newer agents on survival and quality of life of patients with metastatic CRC.


Short-term outcome of functional integrity of the auditory brainstem in term infants who suffer perinatal asphyxia.
To assess short-term outcome of impaired functional integrity of the auditory brainstem in term infants who suffer perinatal asphyxia. Maximum length sequence brainstem auditory evoked response (MLS BAER) was recorded and analyzed at a mean age of 3months in term infants after perinatal asphyxia. The data were compared with age-matched normal term infants. The infants after asphyxia showed an increase in the latency of MLS BAER wave III at 91, 455 and 910/s, and wave V at all click rates of 91-910/s. The interpeak intervals in the infants after asphyxia were increased at almost all click rates. The IV and I-III intervals were increased at all click rates, and the III-V interval was increased at 455 and 910/s. These increases were generally more significant at higher than at lower click rates. The amplitudes of waves I, III and V in the infants after asphyxia were reduced at all click rates. The V/I amplitude ratio was increased at 91-455/s clicks. The slope of III-V interval-rate function was abnormally increased. 17.1% of the infants after asphyxia had an abnormal increase in IV intervals. MLS BAER was moderately abnormal at 3months of age in term infants after perinatal asphyxia, suggesting moderate impairment in the functional integrity of the auditory brainstem. The impairment occurs in 17.1% of the infants. Compared with that found at term, the impairment has improved, but not completely recovered.


Discoidin Domain Receptor 1 Expression in Colon Cancer: Roles and Prognosis Impact.
Extracellular matrix components such as collagens are deposited within the tumor microenvironment at primary and metastatic sites and are recognized to be critical during tumor progression and metastasis development. This study aimed to evaluate the clinical and prognostic impact of Discoidin Domain Receptor 1 (DDR1) expression in colon cancers and its association with a particular molecular and/or morphological profile and to evaluate its potential role as a prognosis biomarker. Immunohistochemical expression of DDR1 was evaluated on 292 colonic adenocarcinomas. DDR1 was highly expressed in 240 (82.2%) adenocarcinomas. High DDR1 immunostaining score was significantly associated, on univariate analysis, with male sex, left tumor location, BRAF wild type status, KRAS mutated status, and Annexin A10 negativity. High DDR1 immunohistochemical expression was associated with shorter event free survival only. Laser capture microdissection analyses revealed that DDR1 mRNA expression was mainly attributable to adenocarcinoma compared to stromal cells. The impact of DDR1 expression on cell invasion was then evaluated by modified Boyden chamber assay using cell types with distinct mutational profiles. The invasion capacity of colon adenocarcinoma is supported by DDR1 expression. Thus, our results showed that DDR1 was highly expressed in most colon adenocarcinomas and appears as an indicator of worse event free survival.


Case Report of a Mare Diagnosed with a Metastatic Mammary Carcinoma after the Excision of a Recurrent Intraocular Neuroepithelial Tumor.
A 24-year-old Irish Cob mare was presented with a peripheral iris mass, which was surgically resected and diagnosed as an undifferentiated neuroepithelial tumor. A few months later, a relapse occurred with histological features characterized by a more solid appearance and squamous differentiation. Subsequently, the mare was presented with rapidly spreading multiple subcutaneous masses and, at the onset of neurological signs, was humanely euthanized and subjected to a complete post mortem examination. The necropsy confirmed the presence of numerous widespread masses in the subcutaneous tissue, several internal organs, and mammary gland. Histological and immunohistochemical (IHC) examinations were performed on all masses, allowing the diagnosis of mammary carcinoma with several visceral and subcutaneous metastases. Considering the post mortem findings, the second intraocular mass was submitted to histological and IHC re-evaluation to differentiate it from an intraocular metastasis of the mammary carcinoma. The results of the histological and IHC analyses confirmed the diagnosis of neuroepithelial tumor relapse. This is the first case of a metastatic mammary carcinoma concurrent with a recurrent intraocular neuroepithelial tumor in a mare. This case was a challenge for both clinicians and pathologists involved and highlighted the importance of post mortem and IHC evaluations.


[Some characteristics of mitochondrial multienzyme systems from rat liver mitochondria after heating of rats].
A character of rat liver mitochondria degradation after the heat treatment of animals is studied. It is found that mitochondria under the effect of elevated temperature do not considerably change their functional characteristics and thus they are capable to provide the normal rate of ATP synthesis, the rate of succinate oxidation being slightly increased. At the same time the heating caused the degradation of mitochondria which results in the decrease of their thermostability, in the increased susceptibility to lytic effect of trypsin and phospholipase D, and in the activation of succinate dehydrogenase and cytochrome c oxidase. The mitochondria degradation is due to the formation of "latent impairments" in the structure of mitochondria.


A three-dimensional A549 cell culture model to study respiratory syncytial virus infections.
Respiratory syncytial virus (RSV) is a primary cause of morbidity and mortality worldwide, affecting infants, young children, and immune-compromised patients; however, currently no vaccine is available for prevention of RSV infections. The overwhelming majority of our knowledge of how RSV causes infection is based upon studies that have been carried out using traditional 2D methods, with cells cultured on flat plastic dishes. Although these simplified culture systems are essential to gain an insight into the fundamentals of host-pathogen interactions, cells in 2D are not exposed to the same conditions as cells in 3D tissues in the body and are therefore a poor representation of thein vivo microenvironment. In this study, we aim to develop the first 3D culture model for RSV infection using A549 cells to test its utility for RSV pathogenesis. To generate spheroids, A549 cells were cultured using ultra-low attachment plates to generate 25 × 103 cell spheroids. The viability of the spheroids was assessed by trypan blue exclusion assay and flow cytometry showing prominent live cells throughout the spheroids confirming high viability over seven days of incubation. Immunostaining of A549 spheroids inoculated with RSV, showed time-dependent dissemination of the viral antigen RSV-F within the spheroid, resulting in syncytia formation and a 3-fold increase in mucin secretion compared to the uninfected cells. Additionally, RSV successfully replicated in the spheroids producing infectious virus as early as day one post-inoculation and was sustained for up to 7 days post-inoculation. Results show that A549 spheroids are susceptible and permissive for RSV since they exhibit the characteristics of RSV infection including syncytia formation and mucin overexpression, suggesting that A549 spheroids can be used a promising model for studying RSV in vitro.


α-Mangostin decreases β-amyloid peptides production via modulation of amyloidogenic pathway.
β-amyloid (Aβ) aggregation and deposition play a central role in the pathogenic process of Alzheimer's disease (AD). α-Mangostin (α-M), a polyphenolic xanthone, have been shown to dissociate Aβ oligomers. In this study, we further investigated the effect of α-M on Aβ production and its molecular mechanism. The Aβ and soluble amyloid precursor protein α (sAPPα) in culture medium of cortical neurons were measured by ELISA. The activities of α-, β-, and γ-secretases were assayed, and the interaction between α-M and β- or γ-secretases was simulated by molecular docking. α-M significantly decreased Aβ40 and Aβ42 production. α-M did not affect the expression of enzymes involved in nonamyloidogenic and amyloidogenic pathways, but significantly decreased the activities of β-secretase and likely γ-secretase with IC50 13.22 nmol·L-1 and 16.98 nmol·L-1 , respectively. Molecular docking demonstrated that α-M interacted with β-site amyloid precursor protein cleaving enzyme 1 and presenilin 1 to interfere with their active sites. Our data demonstrate that α-M decreases Aβ production through inhibiting activities of β-secretase and likely γ-secretase in the amyloidogenic pathway. The current data together with previous study indicated that α-M could be a novel neuroprotective agent through intervention of multiple pathological processes of AD.


Capsaicin and carbon dioxide act by distinct mechanisms on sensory nerve terminals in the cat cornea.
The discharge of single afferent units recorded from filaments of the mixed ciliary nerve of anaesthetised cats was used to study the effects of CO2, capsaicin and the capsaicin antagonist, capsazepine, on sensory nerve terminals in the cornea. Units were selected on the basis of their sensitivity to CO2 (98.5% applied to the cornea for 30 s in a moist gas stream). Of these units, about 50% (18/38) also responded to capsaicin (0.1 microM applied as droplet and washed off after 20 s), with a discharge of similar magnitude to that produced by CO2. The other CO2-sensitive units (20/38) did not respond to capsaicin. Capsaicin-sensitive units responded more rapidly to CO2 (mean latency to first spike 0.7 +/- 0.2 s) than capsaicin-insensitive units (mean latency to first spike 5.1 +/- 1.2 s). On the basis of their conduction velocity, both the capsaicin-sensitive and the capsaicin-insensitive groups included both A- and C-fibres. Application of capsazepine (10 microM for 5-20 min) to the cornea reversibly blocked the response of the units to capsaicin without affecting responses to CO2. Units that were acutely desensitised by exposure to capsaicin (0.1 microM) for 30 s, during which time the discharge evoked by capsaicin declined to zero, still responded to CO2, though the response was reduced by 44% compared with controls. It is concluded that activation of sensory afferents in the cat cornea by capsaicin and by CO2 appear to involve distinct mechanisms, since: (a) many CO2- sensitive units are not excited by capsaicin; (b) capsazepine selectively blocks excitation by capsaicin without affecting responses to CO2; and (c) desensitisation to capsaicin impairs only partially the responsiveness to CO2.


Simultaneous determination of clodronate and its partial ester derivatives by ion-pair reversed-phase high-performance liquid chromatography coupled with evaporative light-scattering detection.
A new ion-pair HPLC method coupled with evaporative light-scattering detection (ELSD) for the simultaneous determination of clodronate and its partial esters has been developed. The simultaneous chromatographic separation was achieved on a reversed-phase C8 column with a gradient system and butylamine as an ion-pair reagent. This method provides good enough reproducibility and sensitivity for in vitro determinations of clodronate and its ester derivatives. The method is applied for hydrolysis studies of clodronate monoesters which have been described as possible prodrugs of clodronate.


[Occupational contact of women with methylmethacrylate and the negative tendency in the process of child-bearing].
The study of women exposed to methyl methacrylate (MMA) in the workplace revealed the increased incidence of spontaneous abortions (SA). When women contacted with MMA at the MAC levels, the incidence of SA did not exceed the control levels, but the newborns were recorded to have congenital malformations, cases of hypoxia, signs of prematurity, hypotrophy, which necessitates to make stricter specifications for MAC in the workplace air and/or to lead women of childbearing age from the enterprises manufacturing MMA- and its based acrylic plastic.


An index to quantify an individual's scientific research output.
I propose the index h, defined as the number of papers with citation number > or =h, as a useful index to characterize the scientific output of a researcher.


Factors mediating child abuse as a response to stress.
Twenty-three abusing couples were compared with a matched group of 23 non-abusing couples in terms of stress levels and factors that mediate their responses to stress. Parents who had physically abused their children were found to have significantly greater stress, but when compared with non-abusing couples under equally high stress, they also were much more likely to use violence as a socially scripted response or as an attempt to "solve" a problem. Significant differences also were found between the two groups in terms of the abusing parents scoring higher on symbiosis or attempts to force others to meet their emotional needs.


Language-to-music transfer effects depend on the tone language: Akan vs. East Asian tone languages.
Recent research suggests that speaking a tone language confers benefits in processing pitch in nonlinguistic contexts such as music. This research largely compares speakers of nontone European languages (English, French) with speakers of tone languages in East Asia (Mandarin, Cantonese, Vietnamese, Thai). However, tone languages exist on multiple continents-notably, languages indigenous to Africa and the Americas. With one exception (Bradley, Psychomusicology, 26(4), 337-345, 2016), no research has assessed whether these tone languages also confer pitch processing advantages. Two studies presented a melody change detection task, using quasirandom note sequences drawn from Western major scale tone probabilities. Listeners were speakers of Akan, a tone language of Ghana, plus speakers from previously tested populations (nontone language speakers and East Asian tone language speakers). In both cases, East Asian tone language speakers showed the strongest musical pitch processing, but Akan speakers did not exceed nontone speakers, despite comparable or better instrument change detection. Results suggest more nuanced effects of tone languages on pitch processing. Greater numbers of tones, presence of contour tones in a language's tone inventory, or possibly greater functional load of tone may be more likely to confer pitch processing benefits than mere presence of tone contrasts.


One-year outcomes of combined phacoemulsification and viscogoniosynechialysis with and without endoscopic cyclophotocoagulation in primary angle-closure glaucoma.
To compare the outcomes of combined phacoemulsification and viscogoniosynechialysis (VGSL) with and without endoscopic cyclophtocoagulation (ECP) in primary angle-closure glaucoma (PACG). In this prospective interventional case series 52 eyes of 50 patients were enrolled. Twenty-seven eyes underwent combined phacoemulsification and VGSL (PV group) and 25 eyes underwent the same procedure plus circumferential ECP (PVE group). All eyes were followed 1 day, 1 week, 3 months, 6 months, and 1 year after the procedure. Intraocular pressure and antiglaucoma medications were compared between and within groups using generalized estimating equations. Kaplan-Meier survival analysis was carried out to compare intensity to failure between groups. The mean ± SD age was 63.23 ± 6.87 years and 50% of the cases were male in the entire group. Intraocular pressure (IOP) and antiglaucoma medications were significantly reduced at all time points in comparison with the baseline in both groups (p < 0.05). There was no significant difference between groups in either IOP or medications at specific time points (p > 0.05). One eye in each group developed a fibrinous reaction in the postoperative period. There was no statistically significant difference between groups regarding the intensity to failure (P = 0.169). There were no significant differences in IOP and medication reduction between groups. Also, the complications were comparable between groups.


Extracorporeal shockwave lithotripsy: urine cytology findings.
To describe the urine cytology findings before and after stone therapy with extracorporeal shock wave lithotripsy (ESWL) and discuss its importance. The study consisted of 100 patients with a urinary tract stone (79 renal pelvic stones and 21 upper ureteric stones), 74 were male and 26 were female. The ages ranged 30-55 years. The average duration of symptoms was 3-8 years. The size of the stones varied from case to case ranging from 10.2 to 40 mm. Urine samples were obtained on three consecutive days before and after lithotripsy. The smears were stained by the Papanicolaou method. The smears before lithotripsy revealed a few red blood cells, inflammatory cells, epithelial cells and crystals (calcium oxalate, uric acid and triple phosphate). Atypical malignant looking cells and epithelial cell clusters were not noticed. After lithotripsy, the urine samples were examined at different periods, 24 hours, 2 weeks, 1 month, 2 months and 3 months. The smears revealed papillary clusters in all 100 patients within 24 hours and were always associated with inflammation. Atypical malignant looking cells appeared later, within 1-2 months in 21 patients, and were associated with inflammation (19 patients), RBC, crystals and papillary clusters. Most of the papillary clusters and atypical malignant looking cells disappeared before 3 months. The epithelial cell clusters and atypical cells were seen in urine smears after ESWL. Without knowing the previous history these findings can be confused with urothelial neoplasms.


Case study of rainfall and temperature assessment through trend and homogeneity analyses in Vadodara and Chhotaudepur district of Gujarat State, India.
This study aims to assess the climate change impact on the rainfall and temperature data of the Vadodara-Chhotaudepur district of India and to focus on the environmental challenges related to the rainfall and temperature in the present state of development, land use, industrialization, and urbanization. The study utilized nine trend analysis methods, namely linear regression (LR), Sen's robust slope estimator (SS), Mann-Kendall test (MK), Spearman's rank correlation (SRC), the trend-free pre-whitening (TFPW), variance correction approach by Hamed and Rao (1998) with MK test (MK-CF1), variance correction approach by Yue and Wang (2004) with MK test (MK-CF2), block bootstrap with MK test (BBS-MK), and graphical method as innovative trend analysis (ITA), applied on monthly, annual, and seasonal scales. Additionally, the study also employed four homogeneity analysis methods, including Pettitt's test, standard normal homogeneity test (SNHT), Buishand's test, and Von Neumann Ratio test (VNRTs). The IMD (Indian meteorological department) gridded long-term rainfall data from 1901 to 2019 and temperature data from 1951 to 2019 are used in the present study to assess the homogeneity and trends of the data series. Results showed a warming trend of maximum temperature (MaxT) and minimum temperature (MinT) at the monthly, annual, and seasonal time scale and significant (at 5%) warming trend in annual MinT in the entire study area. Annual rainfall showed negative trend in the study area with significant (at 5%) negative trend in eastern deforested area western industrial and area adjacent to thermal power station. The change point is detected in annual rainfall time series in eastern forest area in 1959 and western area in 1983, i.e., after development of the industries and commissioning of thermal power station in the western study area. The trend rate of MaxT and MinT has been recognized as 0.004 °C/year and 0.019 °C/year, respectively, for the data period of 1951 to 2019. The annual rainfall trend rate has been observed as -0.743 mm/year for the data range 1901 to 2019. All trend analysis methods revealed consistent results except MK-CF2 method, which portraits greater number of significant trends in trend analysis methods.


[Ultrastructural-morphometric analysis of liver biopsies in patients with intrahepatic cholestasis. I. Correlations between morphometry of bile canaliculi and so-called "marker enzymes of cholestasis" (author's transl)].
Reports on correlations between the activity of so-called "marker enzymes of cholestasis" in serum and the ultrastructural changes of the liver are rare. Therefore studies of ultrastructural changes were carried out in 40 patients with intrahepatic cholestasis. In the patients' serum activity of alkaline phosphatase, bile duct alkaline phosphatase, leucine-aminopeptidase (LAP), and 5'-nucleotidase (5'-Nu) as well as the concentration of bilirubin were determined. The results showed a significant correlation between the morphometry of the bile canaliculi and the serum activity of LAP and 5'-Nu. In patients with elevated LAP, an enlargement of the bile canaliculi could be proved. An increased serum activity of 5'-Nu correlated with a higher incidence of bile canaliculi in the ultrastructural picture. The results suggest an investigation of the ultrastructure of bile canaliculi and the determination of marker enzymes of cholestasis in the serum may both contribute to the assessment of cholestatic liver disease.


Usefulness of a new indicator test for the diagnosis of peripheral and autonomic neuropathy in patients with diabetes mellitus.
The aim of the present study was to assess the performance of a new indicator test (NIT), based on the measurement of sweat production after exposure to dermal foot perspiration, in the diagnosis of both peripheral sensorimotor polyneuropathy (PSN) and autonomic neuropathy in patients with diabetes. One hundred and seventeen diabetic patients were examined. PSN was assessed using the neuropathy symptoms score, the neuropathy disability score and the vibration perception threshold. Cardiac autonomic neuropathy (CAN) was assessed using the battery of the four classical standardized tests proposed by Ewing et al., Diabetes Care 1985; 8: 491-498. Sudomotor dysfunction was assessed using the NIT. Fifty patients (42.7%) had PSN and 44 patients (37.6%) had CAN. Of the 50 patients with PSN, 43 had a positive NIT (sensitivity 86%) and, out of the 67 patients without PSN, a negative NIT was obtained in 45 patients (specificity 67%). The positive and the negative predictive value of the NIT in detecting PSN were 66.2 and 86.5%, respectively. The sensitivity and specificity of NIT in detecting CAN was 59.1 and 46.5%, respectively. In the case of severe CAN, the sensitivity was increased to 80.9% and the specificity to 50%. The NIT has good sensitivity and negative predictive value for diagnosis of PSN and can be used as a screening method for detection of this complication in patients with diabetes. In addition, the test has a low sensitivity for detection of autonomic neuropathy in patients with milder forms of CAN.


Author Correction: Baroreceptor denervation reduces inflammatory status but worsens cardiovascular collapse during systemic inflammation.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Effects of castration on female rabbit bladder physiology and morphology.
To determine the effect of ovariectomy on bladder blood flow and oxygen tension. Women are subject to bladder dysfunctions that occur less frequently in men. These include interstitial cystitis (syndrome of urgency, frequency, and pain on distension), incontinence, and bladder infections. It is believed that alterations in female sex hormones play a major role in mediating these abnormalities. We believe that alterations in estrogen can have marked effects on the blood flow to the bladder. We divided 20 female rabbits into two equal groups: ovariectomized and sham operated. Six weeks later, the bladder of each rabbit was evaluated for bladder capacity, compliance, permeability, blood flow, tissue hypoxia, morphology, and smooth muscle contraction. Ovariectomy resulted in decreased bladder compliance; decreased blood flow to the bladder mucosa and uterus, a smaller decrease in blood flow to the bladder smooth muscle, and mucosal hypoxia; and statistically significant thinning of the bladder mucosa and increased mucosal permeability. Ovariectomy resulted in decreased blood flow and hypoxia to the bladder mucosa and a mildly decreased blood flow to the smooth muscle. The decreased blood flow and hypoxia may be related to the age-related uropathologic findings in postmenopausal women.


L-carnitine alleviated acute lung injuries induced by potassium dichromate in rats: involvement of Nrf2/HO-1 signaling pathway.
The activation of the Nrf2/HO-1 signaling pathway regulates cellular antioxidant stress and exerts anti-inflammatory and cytoprotective effects against acute lung injury (ALI). The present study aimed to evaluate the therapeutic role of L-carnitine (LC) against potassium dichromate (PD) - induced acute lung injury in adult male albino rats via modulation of Nrf2/HO-1 signaling pathway. For this purpose, forty rats were randomly allocated into 5 groups (8 rats each). The normal group received intranasal (i.n.) saline, while the ALI group received intranasal instillation of PD as a single dose of 2 mg/kg. The 3d - 5th groups received PD then after 24 h administered L-carnitine (25, 50 and 100 mg/kg; orally) for 3 consecutive days. The therapeutic effect of L-carnitine was evaluated by assessment of serum levels of glutathione (GSH) and malondialdehyde (MDA) along with measurement of lung contents of transforming growth factor β1 (TGFβ1), protein kinase B (AKT), Nuclear factor erythroid-2 related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 enzyme (NQO1) and glutathione cysteine ligase modifier subunit (GCLM) expression. Post-treatment with L-carnitine effectively increased the levels of GSH and AKT, elevated Nrf2 and its target genes and decreased the levels of MDA and TGFβ1 in comparison with PD control rats. Additionally, L-carnitine effectively reduced the number of goblet cell, inhibited the mucus formation in bronchioles and interstitial inflammatory infiltrate as well as alleviated the destruction of alveolar walls, and the congestion of blood vessels in lung tissue induced by PD. Our findings showed that L-carnitine may be a promising therapeutic agent against PD-induced acute lung injury.


Combining spatial distribution with oral bioaccessibility of metals in smelter-impacted soils: implications for human health risk assessment.
Geostatistical analysis and GIS-based spatial mapping have been widely used for risk assessment of environmental pollution. The objectives of this study were to: (1) investigate the spatial variability of pseudototal concentrations of Cd, Pb, and Zn; (2) estimate the degree of contamination on the basis of pollution indexes; and (3) combine geostatistical analysis with oral bioaccessibility to better assess the population's exposure to metals in smelter-impacted soils. Implications for human health risks were assessed by considering soil as a contaminant source, a release mechanism of contaminated soil to the hands, ingestion as an exposure route, and metal bioaccessibility. The bioaccessibility data in the gastric (G) and gastrointestinal (GI) phases were integrated into the standard hazard quotient-based risk assessment method. Using pollution indices showed that the entire area studied was highly polluted in terms of soil metal concentrations. However, the spatial pattern of health risk levels did not coincide with the spatial distribution of the degree of soil contamination. Introducing the bioaccessible fraction of metals from soils into the exposure calculations resulted in a substantial decrease in calculated risk (HI, hazard index) and provided a more realistic estimate of exposure to the three metals. For the highly exposed population, 46% of the soils studied provided an HI-G > 1.0 and 15% provided an HI-GI > 1.0, suggesting probable adverse health effects in children. The present study highlights the importance of conducting studies taking into account metal bioaccessible values in risk assessment.


Selective overproduction of human dihydrofolate reductase in a methotrexate-resistant human-mouse somatic cell hybrid.
The development of methotrexate (MTX) resistance in cultured cells results in increased levels of the drug's target enzyme dihydrofolate reductase (DHFR). Stepwise-selected MTX-resistant sublines originating from an MTX-sensitive human-mouse hybrid expressed elevated DHFR levels and human-DHFR specific gene sequence amplification. By high resolution two-dimensional polyacrylamide gradient electrophoresis, human DHFR was shown to be selectively overproduced in VB2a-100 MTX-resistant cells whereas mouse DHFR protein "spots" present in MTX-sensitive parental hybrid were absent in these cells exhibiting 100 microM MTX resistance. These findings and those in a parallel study indicate that concurrent with overproduction of human DHFR and amplification DHFR sequences in VB2a-100, a loss of mouse-specific DHFR gene sequences occurred.


The lack of inactivation of tobramycin by cefazolin, cefamandole, and moxalactam in vitro.
We examined the effects of mixing tobramycin with three cephalosporins, cefazolin, cefamandole, and moxalactam. Each cephalosporin was prepared from standard powder and diluted with human serum to concentrations of 50, 250, and 500 micrograms/ml and added to 10 micrograms/ml of tobramycin in human serum. Temperature environments of 4 degrees C (refrigeration), 24 degrees C (room temperature), and 37 degrees C (body temperature) were used and sampled at 0 hours (control), and at 8, 24, and 48 hours. The results indicated no inactivation of tobramycin by any of the cephalosporins, regardless of temperature, concentration, or contact time. These results indicate that significant inactivation of tobramycin does not occur when it is combined in vitro with moxalactam, cefamandole, or cefazolin.


The intervention of intestinal Wnt/β-catenin pathway alters inflammation and disease severity of CIA.
Autoreactive T cell is one of the leading causes of immunological tolerance defects in the chronic inflammatory lesions of rheumatoid arthritis (RA). There have been several extracellular signals and intracellular pathways reported in regulating this process but largely remain unknown yet. In this study, we explored the roles of intestinal Wnt/β-catenin on disease severity during collagen-induced arthritis model (CIA), an animal model of RA. We first testified the activity pattern Wnt/β-catenin shifted by intragastric administration of LiCl and DKK-1 in the intestine by real-time PCR and WB analysis. The arthritis scores showing the disease severity in the DKK-1 group was significantly ameliorated compared with the control group at the late stage of the disease, while in the LiCl group, the scores were significantly elevated which was consistent with pathology score analysis of H&E staining. Next, ELISA was performed and showed that TNF-α and IL-17 in the LiCl group were significantly higher than that of the control group. IL-10 in the DKK-1 group was significantly higher than that in the LiCl-1 group and control group, P < 0.05. Flow cytometry of spleen T cells differentiation ratio showed that: Th1 from the DKK-1 and LiCl groups and Th17 from the LiCl group was significantly different from that of the blank model group, P < 0.05. Finally, we explored the effects of intestinal Wnt/β-catenin on T cell differentiation regulator ROR-γt and TCF1 and found that both transcription factors were up-regulated in the LiCl group. Together, these data suggested the pro-information role of Wnt/β-catenin pathway from the intestine in the CIA mouse, implying its use as a potential therapeutic target for the treatment of inflammatory diseases such as RA.


Renal replacement treatment initiation with twice-weekly versus thrice-weekly haemodialysis in patients with incident dialysis-dependent kidney disease: rationale and design of the TWOPLUS pilot clinical trial.
The optimal haemodialysis (HD) prescription-frequency and dose-for patients with incident dialysis-dependent kidney disease (DDKD) and substantial residual kidney function (RKF)-that is, renal urea clearance ≥2 mL/min/1.73 m2 and urine volume ≥500 mL/day-is not known. The aim of the present study is to test the feasibility and safety of a simple, reliable prescription of incremental HD in patients with incident DDKD and RKF. This parallel-group, open-label randomised pilot trial will enrol 50 patients from 14 outpatient dialysis units. Participants will be randomised (1:1) to receive twice-weekly HD with adjuvant pharmacological therapy for 6 weeks followed by thrice-weekly HD (incremental HD group) or outright thrice-weekly HD (standard HD group). Age ≥18 years, chronic kidney disease progressing to DDKD and urine output ≥500 mL/day are key inclusion criteria; patients with left ventricular ejection fraction <30% and acute kidney injury requiring dialysis will be excluded. Adjuvant pharmacological therapy (ie, effective diuretic regimen, patiromer and sodium bicarbonate) will complement twice-weekly HD. The primary feasibility end points are recruitment rate, adherence to the assigned HD regimen, adherence to serial timed urine collections and treatment contamination. Incidence rate of clinically significant volume overload and metabolic imbalances in the first 3 months after randomisation will be used to assess intervention safety. The study has been reviewed and approved by the Institutional Review Board of Wake Forest School of Medicine in North Carolina, USA. Patient recruitment began on 14 June 2019, was paused between 13 March 2020 and 31 May 2020 due to COVID-19 pandemic, resumed on 01 June 2020 and will last until the required sample size has been attained. Participants will be followed in usual care fashion for a minimum of 6 months from last individual enrolled. All regulations and measures of ethics and confidentiality are handled in accordance with the Declaration of Helsinki. NCT03740048; Pre-results.


Enzyme-labelled immunosorbent assay techniques in foot-and-mouth disease virus research.
The indirect ELISA technique has been developed successfully to measure antibodies to foot-and-mouth disease virus (FMDV) in cattle sera. Preliminary studies using a standard serum assay show that reproducible results are obtained. The method should prove useful for the examination of antibody titres in sera from large numbers of cattle or other animals.


Eigenanatomy: sparse dimensionality reduction for multi-modal medical image analysis.
Rigorous statistical analysis of multimodal imaging datasets is challenging. Mass-univariate methods for extracting correlations between image voxels and outcome measurements are not ideal for multimodal datasets, as they do not account for interactions between the different modalities. The extremely high dimensionality of medical images necessitates dimensionality reduction, such as principal component analysis (PCA) or independent component analysis (ICA). These dimensionality reduction techniques, however, consist of contributions from every region in the brain and are therefore difficult to interpret. Recent advances in sparse dimensionality reduction have enabled construction of a set of image regions that explain the variance of the images while still maintaining anatomical interpretability. The projections of the original data on the sparse eigenvectors, however, are highly collinear and therefore difficult to incorporate into multi-modal image analysis pipelines. We propose here a method for clustering sparse eigenvectors and selecting a subset of the eigenvectors to make interpretable predictions from a multi-modal dataset. Evaluation on a publicly available dataset shows that the proposed method outperforms PCA and ICA-based regressions while still maintaining anatomical meaning. To facilitate reproducibility, the complete dataset used and all source code is publicly available.


Basket clinical trial design for targeted therapies for cancer: a French National Authority for Health statement for health technology assessment.
During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.