Development of chondroitin sulfate proteoglycans in the central auditory system of rats correlates with acquisition of mature properties.
Chondroitin sulfate proteoglycans (CSPGs) are macromolecules which regulate the structural organization of the extracellular matrix and can mediate cell migration and axonal growth. Here the spatiotemporal distribution of CSPGs in the central auditory system of rats was investigated using a polyclonal antiserum. In adult brains, CSPGs surrounded many neuronal cell bodies and proximal dendrites at all stations of the auditory pathway except the medial geniculate body. During development, CSPG expression became visible at postnatal day (P) 4 in the superior olivary complex, at P8 in the midbrain, and at P18 in the cortex. Immunoreactivity increased strongly until P12 in the brainstem and until P24 in the cortex. The adult-like pattern in the pontine nuclei, the midbrain, and the cortex was seen at P12, P29, and P35, respectively. The relatively late expression of strong immunoreactivity indicates that the CSPGs are involved in the maturation of axonal connections, but not in early processes such as cell migration or neurite outgrowth.


Resonance Raman spectroscopic study on chiral aggregation of bilirubin-bovine serum albumin complex formed at liquid/liquid interface.
Resonance Raman spectroscopy assisted by centrifugal liquid membrane/circular dichroism (CLM-CD) and UV/Vis absorption spectroscopies was applied to measure the binding state of bilirubin (BR) in the complex with bovine serum albumin (BSA) formed at a heptane/water interface. The bisignate Cotton effects in the interfacial CD spectra and the red shift and linewidth increase of the BR absorption band around 450 nm indicated the formation of the BR-BSA complex at the interface and the chiral conversion of BR molecules in the aggregates. The resonance Raman spectra of BR observed at the interface suggested that the interfacial BR-BSA complex formed during the initial 15 min after the contact of the two phases had a similar structure with that in solution, but after 15 min were forming aggregates coexisting with solid micro-particles. These experimental results strongly suggested that the chiral interconversion of BR from (P+) conformation to (M-) conformation in the interfacial complex was accompanied by aggregation of the BR-BSA complexes. In the present study, resonance Raman microscopic spectrometry was proved to be highly useful for characterizing the solid like aggregate formed at the liquid/liquid interface.


Manufacture and quality of iron-fortified yogurt.
Yogurts (nonfat and low fat) were manufactured and fortified with 10, 20, and 40 mg of iron/kg of yogurt. Growth of starter culture bacteria and nonstarter culture bacteria as well as lipid oxidation of the yogurts were monitored over 30 d of storage at 4 degrees C. Sensory characteristics of the yogurts were determined during that time by a trained panel of judges, and consumer panels were used to test acceptability of iron-fortified yogurt. Counts of Lactobacillus delbrueckii ssp. bulgaricas and Streptococcus thermophilus after 1 d of storage in iron-fortified skim yogurts were 7.0 x 10(8) cfu/ml, which were not significantly different from numbers in unfortified yogurts. Counts decreased to 2.5 x 10(8) and 1.9 x 10(8) cfu/ml for L. delbrueckii ssp. bulgaricus and S. thermophilus, respectively, after 30 d of storage. Fortifying yogurt with iron did not support the growth of Pseudomonas fluorescens or Escherichia coli. No significant increases in chemical oxidation, as measured using the thiobarbituric acid assay, were detected as a consequence of iron fortification. Trained panelists scored all yogurts for oxidized, metallic, bitter, and other off-flavors in the range of "not perceptible" to "very slightly perceptible". Iron-fortified yogurts had slightly higher oxidized flavor scores than did the control yogurt. There was no increase in metallic, bitter, or other off-flavors. The consumer panel did not detect any significant differences in the appearance, mouthfeel, flavor, or overall quality between fortified and unfortified flavored yogurts. All yogurt samples were liked by the consumer panelists, suggesting that yogurt is a suitable vehicle for iron fortification.


Understanding the context of novel interventions for self-injurious thoughts and behaviors: A reply to Nielsen et al.
In this response to the commentary by Nielsen, Kirtley, & Townsend (in press), the authors note several points of agreement related to further testing of therapeutic evaluative conditioning (TEC) for self-injurious thoughts and behaviors (SITBs), navigating logistical and ethical issues surrounding mobile interventions, and integrating such interventions into traditional practice. They also note a common mission held by Nielsen et al., themselves, and the SITB research community more broadly: the large-scale reduction of SITBs. Given that national rates of SITBs have never declined appreciably and have been on the rise in recent decades, there is an urgent need for progress toward this goal. However, they also highlight several unsupported or inaccurate assumptions and specific points made by Nielsen et al. that are important to correct for the sake of accuracy and progress in the prediction and prevention of SITBs. These include an overly narrow conceptualization of what constitutes an intervention; an unsupported model of the causes of SITBs and how to best prevent them; an erroneous belief about the iatrogenic effects of SITB stimulus exposure; and inaccuracies in their description of the development, testing, and release of TEC. The authors hope that this brief discussion of the evidence will facilitate progress toward the mission of large-scale reductions in SITBs. (PsycINFO Database Record


Prevention of Incident Hypertension in Patients With Obstructive Sleep Apnea Treated With Uvulopalatopharyngoplasty or Continuous Positive Airway Pressure: A Cohort Study.
To determine whether treatment with uvulopalatopharyngoplasty (UPPP) or continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) prevents hypertension, compared to those not receiving any treatment. A retrospective cohort study was conducted among 413 patients with OSA (age ≥ 35 years) at the Shuang Ho Hospital between 2009 and 2016. The patients were divided into three groups: UPPP, CPAP, and non-treatment groups. Data about the personal characteristics, history of comorbidities, and polysomnography (PSG) reports were collected at baseline. A Cox model with inverse probability of treatment weighting was used to adjust for confounders and baseline diversity. After multivariate adjustment and weighting for incident hypertension, patients in both the CPAP and UPPP groups showed a significant preventive effect on hypertension than in the non-treatment group. Moreover, patients in the CPAP group had lower event rates than those in the UPPP group. UPPP can prevent the development of new-onset hypertension in patients with OSA. CPAP had a better preventive effect than UPPP. UPPP might be a good alternative for reducing the risk of the onset of hypertension when compliance to CPAP is poor.


Effectiveness and safety of a disposable elastomeric continuous infusion pump for outpatient parenteral antimicrobial therapy (OPAT) in a UK setting.
We evaluated the effectiveness and safety of continuous antimicrobial infusion using a disposable elastomeric device in an outpatient parenteral antimicrobial therapy (OPAT) setting. We conducted a retrospective analysis of all patients who received either flucloxacillin (n = 131 episodes) or piperacillin/tazobactam (n = 301 episodes) as continuous infusion via elastomeric devices over 5 years (January 2018-December 2022) at a tertiary referral hospital in Derbyshire, UK. Overall, 81 adverse events were recorded in 77 (18%; 77/432) patient-episodes. Most adverse events were vascular access-related (59%; 4.6 events per 1000 OPAT-days), including one line-related infection (0.2%; 0.1 events per 1000 OPAT-days). 165 (38%) patient-episodes experienced at least one incident of incomplete infusion. Successful outcome (cure or improvement) occurred in 364 (84%) episodes. Our findings suggest that elastomeric infusion pumps are safe and effective for administering selected antimicrobial agents in OPAT. However, close monitoring of patients and the device are essential to ensure optimal delivery of prescribed therapy.


Recognition of early mortality in multiple myeloma by a prediction matrix.
Early mortality (EM; death ≤ 6 months from diagnosis) has been reported in several newly diagnosed multiple myeloma (NDMM) trials. Before the era of novel agents, the incidence was 10%-14%. Causes of death included infections/pneumonia, renal failure, refractory disease, and cardiac events. Staging systems, such as the revised International Staging System (r-ISS), and prognostic factors including cytogenetics, lactate dehydrogenase levels, and myeloma-specific factors, are useful to assess overall prognosis; however, they cannot predict EM. We evaluated patients treated with novel agents in the Connect MM® Registry and identified risk factors of the EM cohort. Eligible patients were enrolled in the registry within 60 days of diagnosis. Univariate and multivariate analyses were conducted to evaluate associations between baseline characteristics and EM. Prediction matrices for EM were constructed from a logistic model. Between September 2009 and December 2011, 1493 patients were enrolled in the registry and had adequate follow-up. Of these patients, 102 (6.8%) had EM and 1391 (93.2%) survived for > 180 days. Baseline factors significantly associated with increased EM risk included age > 75 years, higher Eastern Cooperative Oncology Group performance status, lower EQ-5D mobility score, higher ISS stage, lower platelet count, and prior hypertension. Renal insufficiency trended toward increased EM risk. These risk factors were incorporated into a prediction matrix for EM. The EM prediction matrix uses differential weighting of risk factors to calculate EM risk in patients with NDMM. Identifying patients at risk for EM may provide new opportunities to implement patient-specific treatment strategies to improve outcomes.


Morphine in cow and human milk: could dietary morphine constitute a ligand for specific morphine (mu) receptors?
Morphine has been found in cow and human milk at concentrations of 200 to 500 nanograms per liter. Multistep purification yields a material that has immunological, biological, pharmacological, and chemical properties identical to those of morphine. Similar morphine-like material, which has been tentatively identified in some common plant sources, may be a ubiquitous dietary constituent and a possible source for the material in milk. Since morphine (mu) receptors have a low affinity for enkephalins, and since morphine-like materials have been described in brain and intestine, it is possible that morphine in food may be the source of this material and a normal ligand specific for mu receptors.


Targeting Long Non-Coding RNAs in Cancer Therapy using CRISPR-Cas9 Technology: A Novel Paradigm for Precision Oncology.
Cancer is the second leading cause of death worldwide, despite recent advances in its identification and management. To improve cancer patient diagnosis and care, it is necessary to identify new biomarkers and molecular targets. In recent years, long non-coding RNAs (lncRNAs) have surfaced as important contributors to various cellular activities, with growing proof indicating their substantial role in the genesis, development, and spread of cancer. Their unique expression profiles within specific tissues and their wide-ranging functionalities make lncRNAs excellent candidates for potential therapeutic intervention in cancer management. They are implicated in multiple hallmarks of cancer, such as uncontrolled proliferation, angiogenesis, and immune evasion. This review article explores the innovative application of CRISPR-Cas9 technology in targeting lncRNAs as a cancer therapeutic strategy. The CRISPR-Cas9 system has been widely applied in functional genomics, gene therapy, and cancer research, offering a versatile platform for lncRNA targeting. CRISPR-Cas9-mediated targeting of lncRNAs can be achieved through CRISPR interference, activation or the complete knockout of lncRNA loci. Combining CRISPR-Cas9 technology with high-throughput functional genomics makes it possible to identify lncRNAs critical for the survival of specific cancer subtypes, opening the door for tailored treatments and personalised cancer therapies. CRISPR-Cas9-mediated lncRNA targeting with other cutting-edge cancer therapies, such as immunotherapy and targeted molecular therapeutics can be used to overcome the drug resistance in cancer. The synergy of lncRNA research and CRISPR-Cas9 technology presents immense potential for individualized cancer treatment, offering renewed hope in the battle against this disease.


An investigation of the ability of elemene to pass through the blood-brain barrier and its effect on brain carcinomas.
Elemene is a chemical extracted from plants. It has demonstrated anti-tumour capability. Although widely studied, there has been little reported regarding its tissue distribution. Our aim was to rectify this. The tissue distribution of elemene was studied after intragastric or intravenous administration in rats. The effectiveness of elemene in treating brain tumours was studied using the G-422 tumour cell model in mice. Elemene had a higher concentration in the lungs, spleen and livers than other tissues of normal rats after intragastric and intravenous administration, while the concentration in the gastrointestinal tract was greater after intragastric administration. Elemene molecules were also detected in the rats' brain tissue. Elemene had a therapeutic effect on mice inoculated with G-422 cells both intracranially and subcutaneously. The best life-extending rate and the best tumour-inhibiting rate of elemene were 64.43% and 34.46%, respectively, when 80 mg/kg elemene was used for treatment. The results from the tissue distribution study showed that elemene can pass through the blood-brain barrier. The therapeutic experiments showed that elemene is effective in treating cerebral malignancy.


TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India.
Polymorphisms in thiopurine methyltransferase (TPMT) and Nudix hydrolase-15 (NUDT15) have been implicated as the predominant cause of thiopurine induced leukopenia in the Western countries and East Asia respectively. Exact role of these polymorphisms in South Asian population with inflammatory bowel disease (IBD) is uncertain. We included consecutive patients with IBD who were initiated on thiopurines at a center in North India. The dosage of thiopurines was titrated using regular monitoring of hemogram and liver function tests. Three TPMT polymorphisms (c.238 G > C, c.460 G > A, and c.719A > G) and one NUDT15 polymorphism (c.415 C > T) were assessed. Comparison regarding incidence of leukopenia and maximum tolerated thiopurine dosage was performed between those with wild polymorphism and those with TPMT and NUDT15 polymorphisms, respectively. Of the 119 patients (61 males, mean age 36.8 ± 13.5 years), 105 (88.2%) had ulcerative colitis and 14 (11.8%) had Crohn's disease. Leukopenia was noted in 33 (27.7%), gastrointestinal intolerance in 5 (4.2%) and pancreatitis in 2 (1.6%). TPMT polymorphisms were detected amongst five patients of whom 1 developed leukopenia. NUDT15 polymorphism was noted in 13 patients of whom 7 had leukopenia. The odds of developing leukopenia in TPMT polymorphism were non-significant (0.77, 95% CI:0.0822 to 7.2134, P = 0.819) but were significantly higher in those with NUDT15 polymorphism (3.5933, 1.1041 to 11.6951, P value: = 0.0336). NUDT15 polymorphism was more frequent than TPMT polymorphisms and was associated with thiopurine induced leukopenia. However, the tested polymorphisms account for only 24.2% of the risk of thiopurine induced leukopenia.


Financial Analysis of Preoperative Nasal Decolonization With Povidone-Iodine in Closed Pilon Fracture Definitive Fixation.
The purpose of this study is to determine the financial practicality for the use of nasal povidone-iodine (NP-I) in the preoperative holding area in attempt to decrease the rate of infection that is associated with operative fixation of closed pilon fractures. Institutional costs for treating postoperative infection following a closed pilon fracture, along with costs associated with preoperative NP-I use, were obtained. A break-even equation was used to analyze these costs to determine if the use of NP-I would decrease the current infection rate (17%) enough to be financially beneficial for routine use preoperatively. The total cost of treating a postoperative infection was found to be $18,912, with the cost of NP-I being $30 per patient dose. Considering a 17% infection rate and utilizing the break-even equation, NP-I was found to be economically viable if it decreased the current infection rate by 0.0016% (Number Needed to Treat = 63,051.7). This break-even model suggests that the use of NP-I in the preoperative holding area is financially beneficial for decreasing the rate of infection associated with the treatment of closed pilon fractures.


Functional Quails Eggs using Enriched Spirulina during the Biosorption Process.
Spirulina platensis was included at 2.5%, 5%, and 7.5% of the diet as a phytobiotic either as a crude preparation or after enrichment by a biosorption process and fed to 126 Japanese quail and the eggs collected and examined for 6 weeks. Assessments were made of physical and chemical characteristics of the eggs. All treatments with added Spirulina increased unsaturated fatty acids and decreased saturated fatty acids with the largest responses for linolenic (omega 3) and oleic (omega 9) acids. The changes in fatty acids were greater with enriched than crude Spirulina. These results suggest that eggs from quail fed with Spirulina may have positive effects on human health.


Biofilms of Listeria monocytogenes produced at 12 °C either in pure culture or in co-culture with Pseudomonas aeruginosa showed reduced susceptibility to sanitizers.
The biofilm-forming ability of 21 Listeria monocytogenes isolates, previously pulsotyped and corresponding to 16 strains, from different origins was evaluated using the Calgary Biofilm Device, at 37 °C. Biofilms of 4 selected strains were also produced either on pure cultures or on co-cultures with Pseudomonas aeruginosa (PAO1), at 12 °C and at 37 °C. For these biofilms, the minimum biofilm eradication concentrations (MBECs) of 4 commercial dairy sanitizers (1 alkyl amine acetate based--T99, 2 chlorine based--T66 and DD, and 1 phosphoric acid based--BP) were determined. Listeria monocytogenes biofilms grown, either at 37 °C or 12 °C, were able to achieve similar cell densities by using different incubation periods (24 h and 7 d, respectively). In co-culture biofilms, P. aeruginosa was the dominant species, either at 37 °C or at 12 °C, representing 99% of a total biofilm population of 6 to 7 log CFU/peg. Co-culture biofilms were generally less susceptible than L. monocytogenes pure cultures. More interestingly, the biofilms produced at 12 °C were usually less susceptible to the sanitizers than when produced at 37 °C. Single or co-culture biofilms of L. monocytogenes and PAO1, particularly produced at 12 °C, retrieved MBEC values for agents T99 and BP that were, at times, above the maximum in-use recommended concentrations for these agents. The results presented here reinforce the importance of the temperature used for biofilm formation, when susceptibility to sanitizers is being assessed. Since most food plants have cold wet growth niches in production and storage areas, susceptibility testing should be performed on biofilms produced at refrigeration temperatures. Moreover, the efficiency of the sanitizers used in food industries should be performed on mixed culture biofilms, since in field conditions these will predominate. The results presented here highlight the importance of the temperature used for biofilm formation, when susceptibility to disinfectants is being assessed, as biofilms produced at lower temperature were less susceptible to sanitizers.


The DISABLED protein functions in CLATHRIN-mediated synaptic vesicle endocytosis and exoendocytic coupling at the active zone.
Members of the DISABLED (DAB) family of proteins are known to play a conserved role in endocytic trafficking of cell surface receptors by functioning as monomeric CLATHRIN-associated sorting proteins that recruit cargo proteins into endocytic vesicles. Here, we report a Drosophila disabled mutant revealing a novel role for DAB proteins in chemical synaptic transmission. This mutant exhibits impaired synaptic function, including a rapid activity-dependent reduction in neurotransmitter release and disruption of synaptic vesicle endocytosis. In presynaptic boutons, Drosophila DAB and CLATHRIN were highly colocalized within two distinct classes of puncta, including relatively dim puncta that were located at active zones and may reflect endocytic mechanisms operating at neurotransmitter release sites. Finally, broader analysis of endocytic proteins, including DYNAMIN, supported a general role for CLATHRIN-mediated endocytic mechanisms in rapid clearance of neurotransmitter release sites for subsequent vesicle priming and refilling of the release-ready vesicle pool.


Novel resistance functions uncovered using functional metagenomic investigations of resistance reservoirs.
Rates of infection with antibiotic-resistant bacteria have increased precipitously over the past several decades, with far-reaching healthcare and societal costs. Recent evidence has established a link between antibiotic resistance genes in human pathogens and those found in non-pathogenic, commensal, and environmental organisms, prompting deeper investigation of natural and human-associated reservoirs of antibiotic resistance. Functional metagenomic selections, in which shotgun-cloned DNA fragments are selected for their ability to confer survival to an indicator host, have been increasingly applied to the characterization of many antibiotic resistance reservoirs. These experiments have demonstrated that antibiotic resistance genes are highly diverse and widely distributed, many times bearing little to no similarity to known sequences. Through unbiased selections for survival to antibiotic exposure, functional metagenomics can improve annotations by reducing the discovery of false-positive resistance and by allowing for the identification of previously unrecognizable resistance genes. In this review, we summarize the novel resistance functions uncovered using functional metagenomic investigations of natural and human-impacted resistance reservoirs. Examples of novel antibiotic resistance genes include those highly divergent from known sequences, those for which sequence is entirely unable to predict resistance function, bifunctional resistance genes, and those with unconventional, atypical resistance mechanisms. Overcoming antibiotic resistance in the clinic will require a better understanding of existing resistance reservoirs and the dissemination networks that govern horizontal gene exchange, informing best practices to limit the spread of resistance-conferring genes to human pathogens.


Patterns and correlates of sexual initiation, sexual risk behaviors, and condom use among secondary school students in Ethiopia.
This study explored the patterns and socio-demographic correlates of sexual initiation, subsequent risk behaviors, and condom use among secondary school youth across Ethiopia. A total of 1,102 students were selected on convenience basis from five urban schools (in Baher Dar, Dessie, Awassa, Jimma, and Dire Dawa) and surveyed about their sexual and preventive behaviors using an extensive questionnaire. Data were analyzed using bivariate and multivariate statistical procedures. One third (33.3%) of the youth reported to have had sexual intercourse prior to the study. Mean age of sexual initiation was 15.3 (SD = 2.5) years. Two-thirds of the sexual initiations were unprotected and some occur with higher risk groups, including much older (15.5%) or casual/commercial sex partners (9.1%). Multi-partnered sex (52.7%) and sex with casual (30.4%) or commercial (25.3%) partners were the most commonly reported lifetime risk behaviors. Although 56.7% of the youth ever used condoms, only less than half of these used them regularly. On the positive note, 83.4% of the youth expressed intentions to use condoms in the future. Socio-demographic characteristics, particularly gender, location, and age, were significantly correlated with sexual and preventive behaviors. Implications of these findings to health education programs for youth are discussed.


A randomized, double-blind, placebo-controlled trial of Chinese herbal medicine capsules for the treatment of premature ovarian insufficiency.
This study was conducted to evaluate the treatment effectiveness of Chinese herbal medicine capsules containing the Yangyin Shugan formula (YYSG) in premature ovarian insufficiency (POI). One-hundred forty-six women with POI participated in this stratified, randomized, double-blind, placebo-controlled clinical trial. Participants in two groups (n = 73 in each)-the YYSG group and control group-underwent treatment for 12 weeks. Outcome measures included the Chinese version Menopause-Specific Quality of Life questionnaire (CMS), serum levels of basal follicle-stimulating hormone (bFSH), basal estradiol, and anti-Mullerian hormone (AMH), the antral follicle count (AFC), and ovarian peak systolic velocity (PSV; cm/s). Treatment with YYSG significantly reduced the total scores of the CMS at the end of the 12th week with statistical significance (P < 0.01); the vasomotor, psychosocial, physical, and sexual domains significantly improvement after treatment (P < 0.01). Compared with the baseline hormone levels, YYSG markedly decreased the bFSH level with statistical significance (P < 0.01) and improved the AMH level (P < 0.01). Furthermore, YYSG greatly improved the participants' AFC and ovarian PSV, compared with placebo (P < 0.01). There were no serious adverse events, and the safety indices of whole blood counts, renal function, and liver function were within the normal range, both before and after treatment. Treatment with YYSG was more effective than placebo for improving menopausal symptoms, basal hormone levels, and ovarian function in women with POI in Guangdong, China.


On-farm comparison of keel fracture prevalence and other welfare indicators in conventional cage and floor-housed laying hens in Ontario, Canada.
The objective of this study was to compare the flock-level prevalence of healed keel bone fractures and to benchmark other indicators of well-being in laying hens housed in conventional cages and single-tier floor housing systems at several points during the production period. Commercial farms in Ontario, Canada, that housed hens in cages (n=9) or floor barns (n=8) were included. Flocks were beak-trimmed brown hens of various strains. Each flock was visited at 20, 35, 50, and 65 wk of age. At each visit, 50 hens were weighed, palpated for healed keel fractures, and feather scored over 4 areas of the body. Data were collected from the farm records on cumulative mortality. Keel fracture prevalence was higher in floor-housed flocks compared to cage-housed flocks (48.3±0.04% vs. 24.8±0.03%; P<0.001). The majority of keel fractures occurred by 50 wk. Cumulative mortality tended to be higher in floor-housed flocks compared to cage-housed flocks (2.13±0.42% vs. 1.29±0.19%; P=0.078). Mean BW was lower (1,827±28.8 g vs. 1,888±26.8 g; P=0.02) yet more uniform (CV of BW 9.43±0.40% vs. 10.10±0.32%; P<0.001) in floor-housed flocks compared to cage-housed flocks. Feather condition was not affected by housing system type (P=0.618), although it declined with age (P<0.001). Individual hen factors assessed using Pearson partial correlations indicated that hens with fractures were heavier at 65 wk in both housing types (P<0.05) and that heavier hens housed on the floor had better feather scores (P<0.001) from 35 wk onward. Floor-housed hens with fractures had lower feather scores at 35 wk (P<0.05) but not at 50 or 65 wk. Housing hens in single-tier floor systems increased the flock-level prevalence of keel fractures and resulted in a lower, yet more uniform, BW compared to hens in conventional cages under commercial conditions in Ontario. Benchmarking welfare indicators from alternative housing systems for laying hens is important to ensure that progress is made in improving their well-being.


Adjunctive Use of the Dermocartilaginous Ligament for Dorsal Irregularities in Primary Rhinoplasty.
Nasal dorsal irregularity is a common postrhinoplasty complication in spite of meticulous smoothing. Utilization of the dermocartilaginous ligament in 2 different fashions for different purposes was described before. A novel utilization of the dermocartilaginous ligament as a flattened and pedicled flap from the cephalic attachment for nasal dorsal irregularities was presented in this article. This surgical technique was applied in 11 cases. Eight of them had thin skin, 2 had skin with medium thickness, and 1 had thick skin. They were followed on an average for 27 months (between 6 and 37 months). All of the patients had satisfactory esthetic results, and there was no apparent irregularities observed over the nasal dorsum. No complications such as infection or hematoma occurred during the early or late follow-up periods. Instead of discarding the dermocartilaginous ligament, it can be used adjunctively to conceal the nasal dorsal irregularities to attain a smoother dorsal nasal surface by increasing soft tissue cushion over the osseocartilaginous dorsum. Transposing of the dermocartilaginous ligament also relieves dynamic drooping of the nasal tip, shortening of the upper lip, and undesirable gingival display.


The living aortic valve: From molecules to function.
The aortic valve lies in a unique hemodynamic environment, one characterized by a range of stresses (shear stress, bending forces, loading forces and strain) that vary in intensity and direction throughout the cardiac cycle. Yet, despite its changing environment, the aortic valve opens and closes over 100,000 times a day and, in the majority of human beings, will function normally over a lifespan of 70-90 years. Until relatively recently heart valves were considered passive structures that play no active role in the functioning of a valve, or in the maintenance of its integrity and durability. However, through clinical experience and basic research the aortic valve can now be characterized as a living, dynamic organ with the capacity to adapt to its complex mechanical and biomechanical environment through active and passive communication between its constituent parts. The clinical relevance of a living valve substitute in patients requiring aortic valve replacement has been confirmed. This highlights the importance of using tissue engineering to develop heart valve substitutes containing living cells which have the ability to assume the complex functioning of the native valve.


The challenges of implementing pharmacogenomic testing in the clinic.
Pharmacogenomic testing has the potential to greatly benefit patients by enabling personalization of medication management, ensuring better efficacy and decreasing the risk of side effects. However, to fully realize the potential of pharmacogenomic testing, there are several important issues that must be addressed. Areas covered: In this expert review we discuss current challenges impacting the implementation of pharmacogenomic testing in the clinical practice. We emphasize issues related to testing methods, reporting of the results, test selection, clinical interpretation of the results, cost-effectiveness, and the long-term use of pharmacogenomic results in clinical practice. We identify opportunities and future directions to facilitate clinical implementation. Expert commentary: Several key elements are necessary to optimally integrate pharmacogenomic testing into clinical practice. Collaborative efforts among laboratories are needed to improve standardization of testing and reporting of the results. Clinicians need educational opportunities to improve understanding of which test to order and how to interpret the results. The electronic health records and other clinical systems need to improve their storage of the pharmacogenomics test results and interoperability to facilitate the use of clinically actionable results to improve patient care.


Hepatic glucose autoregulation: responses to small, non-insulin-induced changes in arterial glucose.
The purpose of this study was to determine whether the sedentary dog is able to autoregulate glucose production (R(a)) in response to non-insulin-induced changes (<20 mg/dl) in arterial glucose. Dogs had catheters implanted >16 days before study. Protocols consisted of basal (-30 to 0 min) and bilateral renal arterial phloridzin infusion (0-180 min) periods. Somatostatin was infused, and glucagon and insulin were replaced to basal levels. In one protocol (Phl +/- Glc), glucose was allowed to fall from t = 0-90 min. This was followed by a period when glucose was infused to restore euglycemia (90-150 min) and a period when glucose was allowed to fall again (150-180 min). In a second protocol (EC), glucose was infused to compensate for the renal glucose loss due to phloridzin and maintain euglycemia from t = 0-180 min. Arterial insulin, glucagon, cortisol, and catecholamines remained at basal in both protocols. In Phl +/- Glc, glucose fell by approximately 20 mg/dl by t = 90 min with phloridzin infusion. R(a) did not change from basal in Phl +/- Glc despite the fall in glucose for the first 90 min. R(a) was significantly suppressed with restoration of euglycemia from t = 90-150 min (P < 0.05) and returned to basal when glucose was allowed to fall from t = 150-180 min. R(a) did not change from basal in EC. In conclusion, the liver autoregulates R(a) in response to small changes in glucose independently of changes in pancreatic hormones at rest. However, the liver of the resting dog is more sensitive to a small increment, rather than decrement, in arterial glucose.


[Differential characteristics of the I and II phases and R-form of Sh. sonnei].
Characteristics of various phases of Sh. sonnei were determined on the standard strains of Sh. sonnei of phases I and II and R-form used for the industrial production of agglutinating monoreceptor sera. Bacteria of phase I displayed a distinct morphological, cultural and serological differences. For the differentiation of Sh. sonnei of the II phase and R-form, representing the greatest difficulty in this respect, it is recommended to use phages RFfm and 6-SR, and also indirect immunofluorescence method with the application of agglutinating monophasic serum against the II phase of Sh. sonnei. In addition, a study was made of over 20 various Sh. sonnei strains at different dissociative process phases. Verification data completely confirmed the specificity of phages RFfm and 6-SR for Sh. sonnei in the II phase. The efficacy of the immunofluorescence method was confirmed on 6 strains.


On the evolution of premating isolation after a founder event.
We present a new simple model for the evolution of premating reproductive isolation. Using this model we first analyze the level of genetic variability maintained by mutation in a large stable population. Then we consider the plausibility of the evolution of strong premating reproductive isolation after a founder event. We demonstrate that after a founder event a new adaptive combination of genes may rise to high frequencies in the presence of an old combination of genes. We compare the probabilities of speciation after a founder event with those in a stable population and with those when reproductive isolation is due to viability selection against hybrids. We argue that premating reproductive isolation is more efficient than postmating reproductive isolation in maintaining the integrity of sympatric species. This might have contributed to the pattern of stronger premating isolation than postmating isolation between closely related pairs of sympatric species.


Fast Marching based Tissue Adaptive Delay Estimation for Aberration Corrected Delay and Sum Beamforming in Ultrasound Imaging.
Conventional ultrasound (US) imaging employs the delay and sum (DAS) receive beamforming with dynamic receive focus for image reconstruction due to its simplicity and robustness. However, the DAS beamforming follows a geometrical method of delay estimation with a spatially constant speed-of-sound (SoS) of 1540 m/s throughout the medium irrespective of the tissue in-homogeneity. This approximation leads to errors in delay estimations that accumulate with depth and degrades the resolution, contrast and overall accuracy of the US image. In this work, we propose a fast marching based DAS for focused transmissions which leverages the approximate SoS map to estimate the refraction corrected propagation delays for each pixel in the medium. The proposed approach is validated qualitatively and quantitatively for imaging depths of upto ∼ 11 cm through simulations, where fat layer-induced aberration is employed to alter the SoS in the medium. To the best of the authors' knowledge, this is the first work considering the effect of SoS on image quality for deeper imaging.Clinical relevance- The proposed approach when employed with an approximate SoS estimation technique can aid in overcoming the fat-induced signal aberrations and thereby in the accurate imaging of various pathologies of liver and abdomen.


Domestication does not narrow MHC diversity in Sus scrofa.
The Major Histocompatibility Complex (MHC) is a multigene family of outstanding polymorphism. MHC molecules bind antigenic peptides in the peptide-binding region (PBR) that consists of five binding pockets (P). In this study, we compared the genetic diversity of domestic pigs to that of the modern representatives of their wild ancestors, the wild boar, in two MHC loci, the oligomorphic DQA and the polymorphic DRB1. MHC nucleotide polymorphism was compared with the actual functional polymorphism in the PBR and the binding pockets P1, P4, P6, P7, and P9. The analysis of approximately 200 wild boars collected throughout Europe and 120 domestic pigs from four breeds (three pureblood, Pietrain, Leicoma, and Landrace, and one mixed Danbred) revealed that wild boars and domestic pigs share the same levels of nucleotide and amino acid polymorphism, allelic richness, and heterozygosity. Domestication did not appear to act as a bottleneck that would narrow MHC diversity. Although the pattern of polymorphism was uniform between the two loci, the magnitude of polymorphism was different. For both loci, most of the polymorphism was located in the PBR region and the presence of positive selection was supported by a statistically significant excess of nonsynonymous substitutions over synonymous substitutions in the PBR. P4 and P6 were the most polymorphic binding pockets. Functional polymorphism, i.e., the number and the distribution of pocket variants within and among populations, was significantly narrower than genetic polymorphism, indicative of a hierarchical action of selection pressures on MHC loci.


Evaluation of mass spectral library search algorithms implemented in commercial software.
Performance of several library search algorithms (against EI mass spectral databases) implemented in commercial software products ( acd/specdb, chemstation, gc/ms solution and ms search) was estimated. Test set contained 1000 mass spectra, which were randomly selected from NIST'08 (RepLib) mass spectral database. It was shown that composite (also known as identity) algorithm implemented in ms search (NIST) software gives statistically the best results: the correct compound occupied the first position in the list of possible candidates in 81% of cases; the correct compound was within the list of top ten candidates in 98% of cases. It was found that use of presearch option can lead to rejection of the correct answer from the list of possible candidates (therefore presearch option should not be used, if possible). Overall performance of library search algorithms was estimated using receiver operating characteristic curves.


Differentiation-associated expression of prostaglandin H and thromboxane A synthases in monocytoid leukemia cell lines.
To elucidate the differentiation-associated expression of enzymes catalyzing arachidonic acid metabolism, we measured arachidonate metabolites by reverse-phase high pressure liquid chromatography in monocytoid leukemia (ML-1, THP-1, and U937) and myeloid leukemia (KG-1) cell lines. Undifferentiated ML-1 or THP-1 cells produced trace amounts of eicosanoids via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Upon differentiation induced by phorbol ester (phorbol 12-myristate 13-acetate [PMA]), metabolites via the COX pathway were increased by 100-fold in ML-1 and THP-1 cells, while the LOX products remained barely detectable. All the COX metabolites were elevated, but thromboxane A2 (TXA2) formation was threefold higher in ML-1 cells than in THP-1 cells. Similar time-related increases in COX metabolites were observed in THP-1 cells induced to differentiate with retinoic acid. Undifferentiated U937 cells were capable of generating a much higher quantity of COX products than ML-1 or THP-1 cells, but, upon PMA-induced differentiation, COX products were increased by only two-fold to threefold over the undifferentiated cells and the total COX products in differentiated U937 cells were only one-seventh of those produced by differentiated ML-1 or THP-1 cells. KG-1 cells had an entirely different metabolic profile. They produced a large quantity of a metabolite coeluted with prostaglandin D2, and PMA had no effect on inducing changes in arachidonic acid (AA) metabolism. Increased COX metabolite formation in differentiated THP-1 and ML-1 cells was due to an enhanced level of prostaglandin H synthase enzyme mass, as measured by Western blot analysis. The TXA synthase activity was also increased by approximately 100-fold in PMA-induced ML-1 cells and 10-fold in THP-1 cells. These findings indicate that increased expression of prostaglandin H and TXA synthase enzymes is a feature of differentiated monocytoid leukemia cell lines.


Sequential extraction procedure for the determination of some trace elements in fertilizer samples.
Total concentration of metal ions at trace levels does not give sufficient information about toxicity and biological availability of these elements in fertilizer samples. In the presented work, a sequential extraction procedure modified by the European Community Bureau of Reference (BCR) was applied to fractionate Cd, Cr, Co, Cu, Fe, Pb, Mn, Ni, and Zn levels in two fertilizer samples collected from cooperative agricultural retailers. The fractions extracted were exchangeable/dilute acid soluble, reducible bound to Fe/Mn oxides, oxidizable bound to organic matter and sulfides, and residual. The determination of analyte elements was done by flame atomic absorption spectrometry. The accuracy of the procedure was validated with BCR-701 sediment certified reference material. The RSD of the procedure was less than 10%.


Contractile ring mechanosensation and its anillin-dependent tuning during early embryogenesis.
Cytokinesis plays crucial roles in morphogenesis. Previous studies have examined how tissue mechanics influences the position and closure direction of the contractile ring. However, the mechanisms by which the ring senses tissue mechanics remain largely elusive. Here, we show the mechanism of contractile ring mechanosensation and its tuning during asymmetric ring closure of Caenorhabditis elegans embryos. Integrative analysis of ring closure and cell cortex dynamics revealed that mechanical suppression of the ring-directed cortical flow is associated with asymmetric ring closure. Consistently, artificial obstruction of ring-directed cortical flow induces asymmetric ring closure in otherwise symmetrically dividing cells. Anillin is vital for mechanosensation. Our genetic analysis suggests that the positive feedback loop among ring-directed cortical flow, myosin enrichment, and ring constriction constitutes a mechanosensitive pathway driving asymmetric ring closure. These findings and developed tools should advance the 4D mechanobiology of cytokinesis in more complex tissues.


Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion.
To investigate whether published results of industry funded trials of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion match underlying trial data by comparing three different data sources: individual participant data, internal industry reports, and publicly available journal publications and conference abstracts. The manufacturer of rhBMP-2 products (Medtronic; Minneapolis, MN) provided complete individual participant data and internal reports for all its studies of rhMBP-2 in spinal fusion. We identified publications and conference abstracts through comprehensive literature searches. We compared outcomes provided in the individual participant data against outcomes reported in publications. For effectiveness outcomes, we compared meta-analyses of randomised controlled trials based on each of the three data sources. For adverse events, meta-analysis of the published aggregate data was not possible and we compared the number and type of adverse events reported between data sources. 32 publications reported outcomes from 11 of the 17 existing manufacturer sponsored studies. For individual randomised controlled trials, 56% (9/16) to 88% (15/17) of effectiveness outcomes known to have been collected were reported in the published literature. Meta-analyses of effectiveness data were almost identical for pain outcomes and similar for fusion across the three data sources. A minority of adverse event data known to have been collected were reported in the published literature. Several journal articles reported only "serious," "related," or "unanticipated" adverse events, without defining these terms. Others reported a small proportion of the collected adverse event categories. Around 23% (533/2302) of the total adverse events collected in published randomised controlled trials have been reported in the literature, with randomised controlled trials evaluating the licensed preparation (Infuse) reporting around 11% (122/1108) of collected adverse events. The published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. This did not lead to substantially different results for meta-analysis of effectiveness outcomes. In contrast, reporting of adverse event data in trial publications was inadequate and inconsistent to the extent that any systematic review based solely on the publicly available data would not be able to properly evaluate the safety of rhBMP-2. Analysis of individual participant data enabled the most complete, detailed, and in-depth analysis and was not more resource intensive than extracting, collating, and analysing aggregate data from multiple trial publications and conference abstracts. Confidential internal reports presented considerably more adverse event data than publications, and in the absence of individual participant data access to these reports would support more accurate and reliable investigation, with less time and effort than relying on incomplete published data.


First Description of Male and Larval Female of Parasitic Mite Eutarsopolipus abdominis (Acari: Podapolipidae) with Redescription of the Adult Female.
Male and larval female of the parasitic mite Eutarsopolipus abdominis Regenfuss, 1968 (Acari: Prostigmata: Podapolipidae) belonging to the myzus species group are described and illustrated for the first time on the basis of the materials recovered from under elytra of Agonum sp. (Coleoptera: Carabidae) from Mazandaran Province, northern Iran. A redescription of the adult female is also provided. It is the first record of this species from Asia and fourth representative of parasitic mites of the myzus species group found from Iran. Furthermore, this finding revealed the first record of the association between tribe Platynini (Coleoptera: Carabidae: Harpalinae) and mites of myzus species group, and one of the highest levels of polyxeny among mites of the genus Eutarsopolipus.


Cannabinoids and the endocannabinoid system in immunotherapy: helpful or harmful?
Numerous studies in various cancer models have demonstrated that ingredients of cannabis can influence tumor growth through the endocannabinoid system (ECS), a network of molecules (mediators, receptors, transporters, enzymes) that maintains homeostasis and protection in many tissues. The main constituents of the ECS are the classical cannabinoid (CB) receptors, such as CB1 and CB2, their endogenous ligands (endocannabinoids), and the endocannabinoids' synthesizing and degrading enzymes. The role of the ECS in cancer is still unclear and its effects often depend on the tumor entity and the expression levels of CB receptors. Many studies have highlighted the tumor cell-killing potential of CB1 agonists. However, cannabis is also known as an immunosuppressant and some data suggest that the use of cannabis during immunotherapy worsens treatment outcomes in cancer patients. CB receptors are widely present in immune cells, and together with monoacylglycerol lipase, the 2-arachidonoylglycerol degrading enzyme, they could be critically involved in the regulation of the immune cell profile of the tumor microenvironment (TME), and hence in tumor progression. So far, data on the impact of the ECS in the immune-TME are still vague. In this review, we discuss the current understanding of the ECS on immunoregulation during tumor growth, and how it might affect the outcome of cancer immunotherapy.


Environmental Sustainability in Orthopaedic Surgery.
Climate change has been increasingly recognized in the healthcare sector over recent years, with global implications in infrastructure, economics, and public health. As a result, a growing field of study examines the role of healthcare in contributing to environmental sustainability. These analyses commonly focus on the environmental impact of the operating room, due to extensive energy and resource utilization in surgery. While much of this literature has arisen from other surgical specialties, several environmental sustainability studies have begun appearing in the field of orthopaedic surgery, consisting mostly of waste audits and, less frequently, more comprehensive environmental life cycle assessments. The present study aims to review this limited evidence. The results suggest that methods to reduce the environmental impact of the operating room include proper selection of anesthetic techniques that have a smaller carbon footprint, minimization of single use instruments, use of minimalist custom-design surgical packs, proper separation of waste, and continuation or implementation of recycling protocols. Future directions of research include higher-level studies, such as comprehensive life cycle assessments, to identify more opportunities to decrease the environmental impact of orthopaedic surgery.


Individual and combined effect of acrylamide, fumitremorgin C and penitrem A on human neuroblastoma SH-SY5Y cells.
Acrylamide (AA) is a chemical compound that can be formed in certain foods during high-temperature cooking processes such as frying, baking, and roasting. Exposure to AA has been linked to several neurological effects, including peripheral neuropathy, ataxia, and impaired cognitive function. Penitrem A (PEN A) and Fumitremorgin C (FTC) are toxic mycotoxins produced by certain species of fungi, such as Penicillium Crustosum, Aspergillus Fumigatus and Neosartorya Fischeri. Both mycotoxins are commonly found in contaminated foods and animal feeds and have been linked to several adverse health effects in humans and animals, including the ability to disrupt normal functioning of the nervous system, tremors, seizures, muscle spasms, and convulsions. AA, PEN A, and FTC are all chemical contaminants. Understanding their toxicity and how they may affect human cells can help food safety authorities to establish safe exposure levels for these compounds through food and develop strategies to reduce their presence. The aim of this study was to explore the combined in vitro toxicological effects of AA, PEN A and FTC in SH-SY5Y cells. For this purpose, cells were treated with AA, FTC, and PEN A as an individual and combined treatment. The types of interactions were assessed by the isobologram analysis. The cell cycle was performed by flow cytometry. Additive effect in binary and tertiary combinations was the major effect according to isobologram graphics. Our results demonstrate that PEN A possessed the highest potential in disturbing cell cycle progression by disrupting cell density in G0/G1 phase.


Effects of exercise training on oxygen uptake kinetic responses in women with type 2 diabetes.
Women with uncomplicated type 2 diabetes have both a decreased maximal oxygen consumption (VO2max) and slowed oxygen uptake (VO2) kinetics at the onset of exercise compared with nondiabetic women. These abnormalities are seen not only at maximal workloads, but also at the onset of low-level exercise. To evaluate the hypothesis that VO2max and VO2 kinetics would improve with exercise training in untrained people with type 2 diabetes, we measured these parameters in premenopausal sedentary women before and after 3 months of supervised exercise training. A total of 8 women with type 2 diabetes, 9 overweight nondiabetic women, and 10 lean nondiabetic women were studied. At baseline and after 3 months of exercise training, subjects underwent bicycle ergometer testing to obtain VO2max and VO2 kinetics data. On entry, women with type 2 diabetes had the lowest VO2max and slowest VO2 kinetics of the three groups. After exercise training, the women with type 2 diabetes improved their VO2max more than the lean and overweight control women: 28 vs. 5 and 8%, respectively (P < 0.05 for the diabetic group vs. both control groups). In the group with diabetes, VO2 kinetics improved by 39 and 22% at 20 and 30 W, respectively. For the control subjects, VO2 kinetics did not improve at any workload in either group. Despite beginning with the lowest VO2max and slowest VO2 kinetics, subjects with type 2 diabetes benefited more from an exercise training program than did control subjects. These findings suggest that in addition to its known metabolic effects, exercise training in individuals with type 2 diabetes may be an effective therapy to improve the cardiovascular response to exercise and to overcome low-level exercise impairment as reflected by improved VO2max and VO2 kinetics. If the ability to make circulatory adjustments at the beginning of exercise at low workloads is improved by an exercise training program, as suggested by the VO2 kinetics data, the clinical significance of exercise for people with type 2 diabetes is clear.


Hematoporphyrin monomethyl ether mediated sonodynamic antimicrobial chemotherapy on porphyromonas gingivalis in vitro.
This study aimed to evaluate the efficacy of hematoporphyrin monomethyl ether (HMME)-mediated sonodynamic antimicrobial chemotherapy (SACT) on Porphyromonas gingivalis (P. gingivalis). P. gingivalis (ATCC 33277) was used in the present study. The bacterial suspension was randomly divided into five groups: Group 1 was incubated for 2 h in the dark with HMME in various concentrations (10, 20, 30 and 40 μg/mL). Then exposed to 1 MHz ultrasound frequency with 3 W/cm2 ultrasound intensity for 10 min. Group 2 was incubated with 40 μg/mL HMME and then irradiated with 2, 4, 6, 8 and 10 min ultrasonic time. Group 3 received different HMME concentration (10, 20, 30 and 40 μg/mL) treatment alone with no ultrasound as the HMME control group. Group 4 received ultrasound treatment alone in different ultrasonic time (2, 4, 6, 8 and 10 min) with no HMME as the ultrasound control group. Group 5 received no treatment as the no treatment control group. After the SACT, the bactericidal effect was determined by the colony forming unit assay. The intracellular content of reactive oxygen species (ROS) was detected using the laser scanning confocal microscope based on DCFH-DA. 4.7 lg reduction in CFU, When P. gingivalis was treated with ultrasound (3 W/cm2 for 10 min) at 40 μg/mL HMME concentration (P < 0.01). The intracellular ROS in SDT group had a significant difference in comparison with the no treatment control group (P < 0.01). HMME mediated SACT can be a potential antibacterial therapy to significantly inhibit P. gingivalis growth.


Demographic characteristics, medical needs and utilisation of antenatal care among pregnant undocumented migrants living in Denmark between 2011 and 2017.
Introduction: An estimated 22,900-28,900 individuals live undocumented in Denmark, of whom many are women of reproductive age. Undocumented migrants in Denmark who are pregnant only have legal rights to health care in emergencies, which may lead to under-utilisation of antenatal care, despite the possibility of these women seeking antenatal care through informal networks. This study aimed to describe the demographics, general medical needs and prevalence of induced abortions among pregnant undocumented migrant women. Further, we aimed to investigate if the women received antenatal services as recommended, focusing on the timing of their first entry to antenatal care and the number of antenatal visits. Methods: This was a retrospective cross-sectional study. We used data from medical records at a health clinic managed by non-governmental organisations (NGOs) in Denmark from 1 January 2011 to 31 December 2017. Data regarding 679 pregnant women were included in descriptive and regression analyses. Results: The women had a mean age of 28.7 years, originated from 78 different countries and had diverse migration backgrounds. Among the 679 included women, there were 119 pregnancy-related complications. Regarding the utilisation of antenatal services, 52.6% had a late first attendance to antenatal care, and the likelihood of a late first attendance was highest among 35- to 44-year-olds. The majority (92.6%) of the women did not have the recommended number of antenatal care visits, and this was evident across all regions of origin. Logistic regression showed variation in utilisation of antenatal services according to age and region of origin. Conclusions: A quarter of the study population attended the health clinic requesting pregnancy termination. The pregnant undocumented migrants had few medical complications and predominantly attended the health clinic for antenatal care. However, some did attend the clinic with general or pregnancy-related medical conditions. Almost half of the study population had a late first attendance to antenatal care, and the vast majority did not have the recommended number of antenatal care visits. These results call for consideration as to whether health care for pregnant undocumented migrants should be formally available and free of charge.


Dysarthria, progressive parkinsonian features and symmetric necrosis of putamen in a family with painful lipomas (Dercum disease variant).
We describe painful subcutaneous lipomatosis in four members of a two-generation family. Lipomas appeared in adulthood, were circumscribed, painful on touch and mainly localized to the trunk and proximal parts of the extremities. The disorder was associated with dysarthria, visual pursuit defect and progressive dystonia. MRI showed bilateral increasing cystic lesions in the basal parts of the putamen. No other abnormalities were detected. The lesions corresponded well with the clinical presentation in the patients. Investigation for mitochondrial disease with muscle biopsy and mitochondrial DNA gave normal results. No consistent biochemical changes were found. The disorder in this family was considered to differ from MERRF with lipomatous lesions and multiple symmetric lipomatosis but compatible with a Dercum disease variant.


Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein expression at post-transcriptional level. We hypothesized that a specific pool of endothelial miRNAs could be selectively regulated by flow conditions and inflammatory signals, and as such be involved in the development of atherosclerosis. To identify miRNAs, called atheromiRs, which are selectively regulated by shear stress and oxidized low-density lipoproteins (oxLDL), and to determine their role in atherogenesis. Large-scale miRNA profiling in HUVECs identified miR-92a as an atheromiR candidate, whose expression is preferentially upregulated by the combination of low shear stress (SS) and atherogenic oxLDL. Ex vivo analysis of atheroprone and atheroprotected areas of mouse arteries and human atherosclerotic plaques demonstrated the preferential expression of miR-92a in atheroprone low SS regions. In Ldlr(-/-) mice, miR-92a expression was markedly enhanced by hypercholesterolemia, in particular in atheroprone areas of the aorta. Assessment of endothelial inflammation in gain- and loss-of-function experiments targeting miR-92a expression revealed that miR-92a regulated endothelial cell activation by oxLDL, more specifically under low SS conditions, which was associated with modulation of Kruppel-like factor 2 (KLF2), Kruppel-like factor 4 (KLF4), and suppressor of cytokine signaling 5. miR-92a expression was regulated by signal transducer and activator of transcription 3 in SS- and oxLDL-dependent manner. Furthermore, specific in vivo blockade of miR-92a expression in Ldlr(-/-) mice reduced endothelial inflammation and altered the development of atherosclerosis, decreasing plaque size and promoting a more stable lesion phenotype. Upregulation of miR-92a by oxLDL in atheroprone areas promotes endothelial activation and the development of atherosclerotic lesions. Therefore, miR-92a antagomir seems as a new atheroprotective therapeutic strategy.


Functional analysis of cystathionine gamma-synthase in genetically engineered potato plants.
In plants, metabolic pathways leading to methionine (Met) and threonine diverge at the level of their common substrate, O-phosphohomoserine (OPHS). To investigate the regulation of this branch point, we engineered transgenic potato (Solanum tuberosum) plants affected in cystathionine gamma-synthase (CgS), the enzyme utilizing OPHS for the Met pathway. Plants overexpressing potato CgS exhibited either: (a) high transgene RNA levels and 2.7-fold elevated CgS activities but unchanged soluble Met levels, or (b) decreased transcript amounts and enzyme activities (down to 7% of wild-type levels). In leaf tissues, these cosuppression lines revealed a significant reduction of soluble Met and an accumulation of OPHS. Plants expressing CgS antisense constructs exhibited reductions in enzyme activity to as low as 19% of wild type. The metabolite contents of these lines were similar to those of the CgS cosuppression lines. Surprisingly, neither increased nor decreased CgS activity led to visible phenotypic alterations or significant changes in protein-bound Met levels in transgenic potato plants, indicating that metabolic flux to Met synthesis was not greatly affected. Furthermore, in vitro feeding experiments revealed that potato CgS is not subject to feedback regulation by Met, as reported for Arabidopsis. In conclusion, our results demonstrate that potato CgS catalyzes a near-equilibrium reaction and, more importantly, does not display features of a pathway-regulating enzyme. These results are inconsistent with the current hypothesis that CgS exerts major Met metabolic flux control in higher plants.


Generation of human induced pluripotent stem cell lines derived from four patients with a pathogenic ALPK3 variant associated with adult-onset hypertrophic cardiomyopathy (HCM).
Loss of function variants in ALPK3 have been associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). However, the underlying pathomechanism remain largely unknown. Here, we generated human iPSC lines from four HCM patients carrying the heterozygous pathogenic variant in ALPK3 (c.2023delC p.Gln675fs). Peripheral blood mononuclear cells (PBMCs) from patients were reprogrammed to induced pluripotent stem cells (iPSCs) with the Sendai virus-based reprogramming method. All four lines display typical iPSC morphology, normal karyotype, expression of pluripotency-associated markers, and trilineage differentiation potential. These iPSC lines represent a valuable resource of ALPK3 patient-derived iPSC lines to the study ALPK3-associated cardiomyopathy.


[Localization of islet cell tumors using sonography, computed tomography, arteriography and selective transhepatic venous sampling for hormone assay (author's transl)].
Of 29 patients examined operation revealed a malignant tumor in 9 and a benign insulinoma in 18, 2 insulinomas were not found. The problems of preoperative tumor localization were limited to small insulinomas (size 7-35 mm). Ultrasound detected all of 3 insulinomas as low echogenic structures (size 7, 8, 17 mm). Computed tomography demonstrated 4 of 5 insulinomas (size 7, 8, 15, 17 mm) due to contrast enhancement following bolus injection. Arteriography localized 12 of 18 insulinomas preoperatively and 14 of 18 retrospectively. Selective transhepatic venous sampling for insulin assay identified 7 of 8 tumors. Real-time ultrasound and dynamic CT are promising in the diagnostics of insulinomas over 7 mm and should precede arteriography. Selective transhepatic venous sampling as the last diagnostic step is a major procedure and most specific, but not always without problems in interpretation.


Mechanism for transition from initial to stable cell-cell adhesion: kinetic analysis of E-cadherin-mediated adhesion using a quantitative adhesion assay.
A centrifugal force-based adhesion assay has been used to quantitatively examine the kinetics of formation of cell-cell contacts mediated specifically by expression of E-cadherin under the control of a glucocorticoid-inducible promoter in mouse fibroblasts. Analysis of cells expressing maximal or minimal levels of E-cadherin showed that the strength of E-cadherin-mediated adhesion developed in a single exponential step over a short time (half-maximal adhesion, 13-17 min). At 37 degrees C, adhesion strength increased rapidly in the first 20 min without an apparent lag phase. After 90 min, adhesion strength reached a plateau. Differences in final strengths of adhesion were commensurate with the level of E-cadherin expression. Strengthening of adhesion was temperature dependent. At 19 degrees C, strengthening of adhesion was delayed and subsequently developed with a slower rate compared to adhesion at 37 degrees C. At 4 degrees C, adhesion was completely inhibited. Strengthening of adhesion was absolutely dependent on a functional actin cytoskeleton since adhesion did not develop when cells were treated with cytochalasin D. Together, our current and previous (McNeill et al., 1993.J. Cell Biol. 120:1217-1226) studies indicate that the rate of initial strengthening of E-cadherin-mediated adhesion is neither dependent on the amount of E-cadherin expressed nor on long-range protein diffusion in the membrane to the adhesion site. However, initial strengthening of adhesion is dependent on temperature-sensitive cellular activities that may locally couple clusters of E-cadherin to the actin cytoskeleton.


Low expression of ZFP36L1 in osteosarcoma promotes lung metastasis by inhibiting the SDC4-TGF-β signaling feedback loop.
ZFP36L1, which is a negative regulator of gene transcripts, has been proven to regulate the progression of several carcinomas. However, its role in sarcoma remains unknown. Here, by using data analyses and in vivo experiments, we found that ZFP36L1 inhibited the lung metastasis of osteosarcoma (OS). Knockdown of ZFP36L1 promoted OS cell migration by activating TGF-β signaling and increasing SDC4 expression. Intriguingly, we observed a positive feedback loop between SDC4 and TGF-β signaling. SDC4 protected TGFBR3 from matrix metalloproteinase (MMP)-mediated cleavage and therefore relieved the inhibition of TGF-β signaling by soluble TGFBR3, while TGF-β signaling positively regulated SDC4 transcription. We also proved that ZFP36L1 regulated SDC4 mRNA decay through adenylate-uridylate (AU)-rich elements (AREs) in its 3'UTR. Furthermore, treatment with SB431542 (a TGF-β receptor kinase inhibitor) and MK2 inhibitor III (a MAPKAPK2 inhibitor that increases the ability of ZFP36L1 to degrade mRNA) dramatically inhibited OS lung metastasis, suggesting a promising therapeutic approach for the treatment of OS lung metastasis.


Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis.
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A.


How I do it: Prescribing abiraterone acetate for metastatic castration resistant prostate cancer.
Abiraterone acetate (AA) is a selective irreversible inhibitor of CYP 17, a key enzyme in androgen biosynthesis. The efficacy and safety of AA in improving survival and quality of life in metastatic castration resistant prostate cancer (mCRPC) has been demonstrated in two landmark clinical trials (COU-AA-301 and COU-AA-302). This article will review the rationale, pharmacology, clinical indications and contraindications, administration, and adverse effects of AA administration in mCRPC.


Fast curvature matrix-vector products for second-order gradient descent.
We propose a generic method for iteratively approximating various second-order gradient steps - Newton, Gauss-Newton, Levenberg-Marquardt, and natural gradient - in linear time per iteration, using special curvature matrix-vector products that can be computed in O(n). Two recent acceleration techniques for on-line learning, matrix momentum and stochastic meta-descent (SMD), implement this approach. Since both were originally derived by very different routes, this offers fresh insight into their operation, resulting in further improvements to SMD.


Leg blood flow is impaired during small muscle mass exercise in patients with COPD.
Skeletal muscle blood flow is regulated to match the oxygen demand and dysregulation could contribute to exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). We measured leg hemodynamics and metabolites from vasoactive compounds in muscle interstitial fluid and plasma at rest, during one-legged knee-extensor exercise, and during arterial infusions of sodium nitroprusside (SNP) and acetylcholine (ACh), respectively. Ten patients with moderate to severe COPD and eight age- and sex-matched healthy controls were studied. During knee-extensor exercise (10 W), leg blood flow was lower in the patients compared with the controls (1.82 ± 0.11 vs. 2.36 ± 0.14 l/min, respectively; P < 0.05), which compromised leg oxygen delivery (372 ± 26 vs. 453 ± 32 ml O2/min, respectively; P < 0.05). At rest, plasma endothelin-1 (vasoconstrictor) was higher in the patients with COPD (P < 0.05) and also tended to be higher during exercise (P = 0.07), whereas the formation of interstitial prostacyclin (vasodilator) was only increased in the controls. There was no difference between groups in the nitrite/nitrate levels (vasodilator) in plasma or interstitial fluid during exercise. Moreover, patients and controls showed similar vasodilatory capacity in response to both endothelium-independent (SNP) and endothelium-dependent (ACh) stimulation. The results suggest that leg muscle blood flow is impaired during small muscle mass exercise in patients with COPD possibly due to impaired formation of prostacyclin and increased levels of endothelin-1.NEW & NOTEWORTHY This study demonstrates that chronic obstructive pulmonary disease (COPD) is associated with a reduced blood flow to skeletal muscle during small muscle mass exercise. In contrast to healthy individuals, interstitial prostacyclin levels did not increase during exercise and plasma endothelin-1 levels were higher in the patients with COPD.


Simultaneous sizing and preoperative risk stratification for thoracic endovascular aneurysm repair: role of gated computed tomography.
Risk factors are similar for the development of both thoracic aortic aneurysms (TAA) and other cardiovascular diseases. Coronary artery disease is highly prevalent in patients with TAA, with a reported prevalence of 30% to 70%. Knowledge of the underlying cardiac pathology can minimize perioperative risk and improve patient selection. This study investigated the feasibility of simultaneous assessment of thoracic aortic pathology and cardiac structures and function, including the coronary arteries, using electrocardiogram-gated 64-slice computed tomography (CT) angiography. ECG-gated 64-detector row CT examinations of 11 patients (8 men, 3 women; mean age, 67 +/- 16; range, 41-83 years) with thoracic aortic pathology, including aneurysms and dissections, were reviewed. Images were assessed for coronary artery disease, calcifications, cardiac function, and valve characteristics. Simultaneous assessment and measurements of thoracic aortic pathology were performed with the same scan. All images of the patients could be successfully assessed for calcium scores, coronary artery stenoses, coronary artery anomalies, interventricular septal wall thickness, myocardial scar, left ventricular ejection fraction, muscle mass, and aortic and mitral valve calcification, mobility, and valve anatomy. Diagnostic image quality was also achieved in all patients for the underlying thoracic aortic disease. This study introduces the feasibility of dynamic imaging of the thoracic aorta and cardiac structures and function, including the coronary arteries, with just one CT scan. The images could be successfully assessed for thoracic aorta pathology, cardiac disease, and extracardiac pathology. With further developments of CT scanners-and more detailed insight in the prognosis of patients based on ECG-gated CTA findings-this new technique may become the initial imaging modality for preoperative cardiac risk stratification in patients with TAAs or dissections.


Prokaryotic communities adapted to microhabitats on the Indian lotus (Nelumbo nucifera) growing in the high-altitude urban Dal Lake.
Indian lotus (Nelumbo nucifera) is one of the dominant aquatic plants cultivated in Dal Lake, situated at 1586 m above mean sea level (MSL) in the northeast of Srinagar, Kashmir. Despite their economic and ecological role, the microbial communities associated with the lotus plant are still unexplored. In this study, we investigated the prokaryotic communities on surfaces of different lotus microhabitats (roots, rhizome, leaves, flowers, and fruits), lake water, and sediments using 16S rRNA gene amplicon sequencing. Overall, prokaryotic diversity decreased significantly on the surface of lotus microhabitats in comparison to the lake water and sediments. Among the microhabitats of lotus, roots and leaves harbored more diverse communities in comparison to rhizomes, fruits, and flowers. A total of 98 genera were shared by lotus and the Dal Lake sediments and water. However, significant differences were found in their relative abundance; for example, Pseudomonas was the most dominant genus on the majority of lotus microhabitats. On the other hand, Flavobacterium was highly abundant in the lake water, while a higher abundance of Acinetobacter was recorded in sediments. Additionally, we also noted the presence of potential human pathogenic genera including Escherichia-Shigella, Enterobacter, Pantoea, Raoultella, Serratia, and Sphingomonas on the lotus microhabitats. Predicted functions of prokaryotic communities revealed a higher abundance of genes associated with nutrient uptake in the microhabitats of the lotus. This study offered first-hand information on the prokaryotic communities harbored by lotus plants and water and sediments of the Dal Lake and demonstrated the adaptation of diverse communities to microhabitats of lotus.


Resorcinol-formaldehyde resin "Russian Red" endodontic therapy.
Resorcinol-formaldehyde resin is a material used in endodontic therapy in many foreign countries. With immigration to the United States increasing, American dentists need to become familiar with resorcinol-formaldehyde therapy. It contains two potentially toxic components, formaldehyde (liquid) and resorcinol (powder). Zinc oxide or barium sulfate may be used for radiopacity. When 10% sodium hydroxide is added to the mixture, polymerization occurs, which can form a brick-hard red material that has no known solvent. Several variations in technique exist. The catalyst can be mixed in before insertion into the tooth, added after the mixture is inserted, or not used. Providers believe pulp tissue will be fixed and bacteria destroyed apical to the level of resorcinol-formaldehyde resin placement. Canals are frequently not instrumented or obturated to their full length. Few success-failure studies have been published and results are contradictory. Consequently, providers have little guidance regarding when to retreat or for predicting the difficulty of retreatment.


The three moments of skin cream application: an evidence-based proposal for use of skin creams in the prevention of irritant contact dermatitis in the workplace.
Contact dermatitis is one of the most common occupational diseases, with serious impact on quality of life, lost days at work and a condition that may be chronically relapsing. Regular prophylactic skin cream application is widely acknowledged to be an effective prevention strategy against occupational contact dermatitis; however, compliance rates remain low. To present a simple programme for skin cream application in the workplace with focus on implementation to drive down the rate of occupational irritant contact dermatitis, an expert panel of eight international dermatologists combined personal experience with extensive literature review. The recommendations are based on clinical experience as supported by evidence-based data from interventional studies. The authors identified three moments for skin cream application in the work place: (i) before starting a work period; (ii) after washing hands; and (iii) after work. Affecting behaviour change requires systematic communications, monitoring and reporting, which is proposed through Kotter's principles of organizational change management. Measurement tools are provided in the appendix. Interventional data based on application of this proposal is required to demonstrate its effectiveness.


Age of transfused blood in critically ill adults.
Fresh red cells may improve outcomes in critically ill patients by enhancing oxygen delivery while minimizing the risks of toxic effects from cellular changes and the accumulation of bioactive materials in blood components during prolonged storage. In this multicenter, randomized, blinded trial, we assigned critically ill adults to receive either red cells that had been stored for less than 8 days or standard-issue red cells (the oldest compatible units available in the blood bank). The primary outcome measure was 90-day mortality. Between March 2009 and May 2014, at 64 centers in Canada and Europe, 1211 patients were assigned to receive fresh red cells (fresh-blood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group). Red cells were stored a mean (±SD) of 6.1±4.9 days in the fresh-blood group as compared with 22.0±8.4 days in the standard-blood group (P<0.001). At 90 days, 448 patients (37.0%) in the fresh-blood group and 430 patients (35.3%) in the standard-blood group had died (absolute risk difference, 1.7 percentage points; 95% confidence interval [CI], -2.1 to 5.5). In the survival analysis, the hazard ratio for death in the fresh-blood group, as compared with the standard-blood group, was 1.1 (95% CI, 0.9 to 1.2; P=0.38). There were no significant between-group differences in any of the secondary outcomes (major illnesses; duration of respiratory, hemodynamic, or renal support; length of stay in the hospital; and transfusion reactions) or in the subgroup analyses. Transfusion of fresh red cells, as compared with standard-issue red cells, did not decrease the 90-day mortality among critically ill adults. (Funded by the Canadian Institutes of Health Research and others; Current Controlled Trials number, ISRCTN44878718.).


Performance of SHOX2 and RASSF1A methylation assay in supernatants and matched cell pellets for the diagnosis of malignant pleural effusion.
It is difficult to distinguish between malignant pleural effusion (MPE) and benign pleural effusion (BPE). The purpose of this study was to determine the best specimen type by evaluating the DNA methylation status of SHOX2 and RASSF1A in 3 matched PE components. In total, 94 patients were enrolled, including 45 MPE, 35 BPE, and 14 undefined PE (UPE) with malignancies. PE samples were processed into supernatants, fresh-cell pellets, and formalin-fixed and paraffin-embedded (FFPE) cell blocks, respectively. A quantitative real-time PCR was used to detect the methylation status of SHOX2 and RASSF1A. SHOX2 and RASSF1A methylation levels were significantly higher in the 3 MPE sample types than those of BPE (P < 0.05). The area under the curve using cell-free DNA (cf-DNA) was the highest. The detection sensitivity of SHOX2 and RASSF1A in fresh-cell DNA, cf-DNA and FFPE cell-block were 71.1% (32/45), 97.8% (44/45) and 66.7% (28/42), respectively, with specificities of 97.1% (34/35), 94.3% (33/35), and 96.9% (31/32). Notably, a combination of the cytological analysis and cf-DNA methylation assay showed an increase in positivity rate from 75.6% to 100%. The SHOX2 and RASSF1A methylation assay using cf-DNA, the primary recommended specimen type, can excellently increase the diagnostic sensitivity of MPE. A combination of methylation assay with cytological analysis can be used for auxiliary diagnosis of PE.


Intakes and Food Sources of Dietary Fibre and Their Associations with Measures of Body Composition and Inflammation in UK Adults: Cross-Sectional Analysis of the Airwave Health Monitoring Study.
The purpose of this study was to investigate the associations between intakes of fibre from the main food sources of fibre in the UK diet with body mass index (BMI), percentage body fat (%BF), waist circumference (WC) and C-reactive protein (CRP). Participants enrolled in the Airwave Health Monitoring Study (2007-2012) with 7-day food records (n = 6898; 61% men) were included for cross-sectional analyses. General linear models evaluated associations across fifths of fibre intakes (total, vegetable, fruit, potato, whole grain and non-whole grain cereal) with BMI, %BF, WC and CRP. Fully adjusted analyses showed inverse linear trends across fifths of total fibre and fibre from fruit with all outcome measures (ptrend < 0.0001). Vegetable fibre intake showed an inverse association with WC (ptrend 0.0156) and CRP (ptrend 0.0005). Fibre from whole grain sources showed an inverse association with BMI (ptrend 0.0002), %BF (ptrend 0.0007) and WC (ptrend 0.0004). Non-whole grain cereal fibre showed an inverse association with BMI (Ptrend 0.0095). Direct associations observed between potato fibre intake and measures of body composition and inflammation were attenuated in fully adjusted analyses controlling for fried potato intake. Higher fibre intake has a beneficial association on body composition, however, there are differential associations based on the food source.


Development of a real-time enzymatic recombinase amplification assay for rapid detection of infectious hypodermal and hematopoietic necrosis virus (IHHNV) in shrimp Penaeus vannamei.
Infectious hypodermal and hematopoietic necrosis virus (IHHNV) is classified as a reportable crustacean disease by the World Organisation for Animal Health (WOAH), which causes poor growth in Penaeus vannamei. According to genome sequence alignment analysis, enzymatic recombinase amplification (ERA) primers and probe were designed based on the ORF1 region of IHHNV, and a real-time ERA assay for IHHNV detection (IHHNV-ERA) was established. The experimental results show that IHHNV-F2/IHHNV-R2 and IHHNV-Probe can effectively amplify the target gene, and the sensitivity is 1.4 × 101 copies/μL within 14.97 ± 0.19 min, while the qPCR using primers 309F/309R could reach the detection limit of 1.4 × 101 copies/μL within 21.76 ± 0.63 min, and the sensitivity results of one-step PCR could be as low as 1.4 copies/μL with expense of time and false positives. The IHHNV-ERA system can effectively amplify the target gene at 42 ℃ within 20 min, and has no cross-reaction with white spot syndrome virus (WSSV), Ecytonucleospora hepatopenaei (EHP), Vibrio parahaemolyticus causing acute hepatopancreatic necrosis disease (VpAHPND), and healthy shrimp genomic DNA. Test results of practical samples showed that the detection rate of IHHNV-ERA (18/20) was better than the industrial standard qPCR assay (17/20). Compared with the existing technology, the useful results of this detection assay are: (1) get rid of the dependence on the thermal cycle instrument in the PCR process; (2) the experimental procedure is simple, time-consuming and fast; (3) the detection sensitivity is high. This study provides an ERA based detection assay for IHHNV, which can be used not only for the rapid detection of IHHNV infection, but also for the field screening of pathogens. This assay can also be applied to clinical inspection, customs detection, enterprise quality inspection and other fields, and has obvious practical application value.


Shear elasticity probe for soft tissues with 1-D transient elastography.
Important tissue parameters such as elasticity can be deduced from the study of the propagation of low frequency shear waves. A new method for measuring the shear velocity in soft tissues is presented in this paper. Unlike conventional transient elastography, in which the ultrasonic transducer and the low frequency vibrator are two separated parts, the new method relies on a probe that associates the vibrator and the transducer, which is built on the axis of the vibrator. This setup is easy to use. The low frequency shear wave is driven by the transducer itself that acts as a piston while it is used in pulse echo mode to acquire ultrasonic lines. The results obtained with the new method are in good agreement with those obtained with the conventional one.


Genetical distance and dermatoglyphic characters. I. Interpopulation distance coefficients.
The distance coefficients between two relatively isolated population groups in Poland, based on various combinations of dermatoglyphic non-measurable characters were estimated. These were compared with the overall dermatoglyphic distance coefficients estimated separately for left and right, as well as with the serologic distance coefficient, based on ABO, Rh and Duffy blood groups. Dermatoglyphic distance coefficients, estimated from quantitative variables (pattern intensities) using Penrose's C2H analysis of variance method, were also introduced for a comparison. The differences in frequencies between two populations, separately for each character, were also compared with its heritability values.


Does the definition of a novel environment affect the ability to detect cryptic genetic variation?
Anthropogenic change exposes populations to environments that have been rare or entirely absent from their evolutionary past. Such novel environments are hypothesized to release cryptic genetic variation, a hidden store of variance that can fuel evolution. However, support for this hypothesis is mixed. One possible reason is a lack of clarity in what is meant by 'novel environment', an umbrella term encompassing conditions with potentially contrasting effects on the exposure or concealment of cryptic variation. Here, we use a meta-analysis approach to investigate changes in the total genetic variance of multivariate traits in ancestral versus novel environments. To determine whether the definition of a novel environment could explain the mixed support for a release of cryptic genetic variation, we compared absolute novel environments, those not represented in a population's evolutionary past, to extreme novel environments, those involving frequency or magnitude changes to environments present in a population's ancestry. Despite sufficient statistical power, we detected no broad-scale pattern of increased genetic variance in novel environments, and finding the type of novel environment did not explain any significant variation in effect sizes. When effect sizes were partitioned by experimental design, we found increased genetic variation in studies based on broad-sense measures of variance, and decreased variation in narrow-sense studies, in support of previous research. Therefore, the source of genetic variance, not the definition of a novel environment, was key to understanding environment-dependant genetic variation, highlighting non-additive genetic variance as an important component of cryptic genetic variation and avenue for future research.


Transplantation of Gelatin Microspheres Loaded with Wharton's Jelly Derived Mesenchymal Stem Cells Facilitates Cartilage Repair in Mice.
Knee osteoarthritis (KOA) is a prevalent chronic joint disease caused by various factors. Mesenchymal stem cells (MSCs) therapy is an increasingly promising therapeutic option for osteoarthritis. However, the chronic inflammation of knee joint can severely impede the therapeutic effects of transplanted cells. Gelatin microspheres (GMs) are degradable biomaterial that have various porosities for cell adhesion and cell-cell interaction. Excellent elasticity and deformability of GMs make it an excellent injectable vehicle for cell delivery. We created Wharton's jelly derived mesenchymal stem cells (WJMSCs)-GMs complexes and assessed the effects of GMs on cell activity, proliferation and chondrogenesis. Then, WJMSCs loaded in GMs were transplanted in the joint of osteoarthritis mice. After four weeks, joint tissue was collected for histological analysis. Overexpressing-luciferase WJMSCs were performed to explore cell retention in mice. In vitro experiments demonstrated that WJMSCs loaded with GMs maintained cell viability and proliferative potential. Moreover, GMs enhanced the chondrogenesis differentiation of WJMSCs while alleviated cell hypertrophy. In KOA mice model, transplantation of WJMSCs-GMs complexes promoted cartilage regeneration and cartilage matrix formation, contributing to the treatment of KOA. Compared with other groups, in WJMSCs+GMs group, there were fewer cartilage defects and with a more integrated tibia structure. Tracking results of stable-overexpressing luciferase WJMSCs demonstrated that GMs significantly extended the retention time of WJMSCs in knee joint cavity. Our results indicated that GMs facilitate WJMSCs mediated knee osteoarthritis healing in mice by promoting cartilage regeneration and prolonging cell retention. It might potentially provide an optimal strategy for the biomaterial-stem cell based therapy for knee osteoarthritis.


[Immunohistochemical identification of olfactory esthesioneuromas. Apropos of 16 cases].
We report anatomoclinical and immunohistochemical analysis of sixteen cases of esthesioneuroblastomas. Microscopic study confirm difficulty of diagnostic for this tumors. Results of S 100 protein reaction for Schwann cells identification, NSE and HNK1 reaction for nervous cells and KL1 reaction for epithelial cells drawn from olfactory mucosa, allow definition of immunologic ENO profile. Pattern immunologic criteria are defined by S 100, NSE or/and HNK1, and eventually KL1 positive reactions permit differential diagnosis with other nervous tumors or undifferentiated carcinomas of nasal fossa. Histo-prognostic patterns are defined by S 100 reactivity distributed in neoplastic cells and cytoplasmic process of cells, to form a continuous network in well differentiated ENO and discontinuous network in undifferentiated forms of ENBO. These results confirm histogenesis of this tumor derived from olfactory mucosa and emphasized only two distinct types: neuro epithelial tumors corresponding to ENEO and cases of ENBO and nervous tumors grouping ENCO and any cases of ENBO.


A physical map of human Alu repeats cleavage by restriction endonucleases.
Alu repetitive elements are the abundant sequences in human genome. Diversity of DNA sequences of these elements makes difficult the construction of theoretical patterns of Alu repeats cleavage by restriction endonucleases. We have proposed a method of restriction analysis of Alu repeats sequences in silico. Simple software to analyze Alu repeats database has been suggested and Alu repeats digestion patterns for several restriction enzymes' recognition sites have been constructed. Restriction maps of Alu repeats cleavage for corresponding restriction enzymes have been calculated and plotted. Theoretical data have been compared with experimental results on DNA hydrolysis with restriction enzymes, which we obtained earlier. Alu repeats digestions provide the main contribution to the patterns of human chromosomal DNA cleavage. This corresponds to the experimental data on total human DNA hydrolysis with restriction enzymes.


Poldip2 controls vascular smooth muscle cell migration by regulating focal adhesion turnover and force polarization.
Polymerase-δ-interacting protein 2 (Poldip2) interacts with NADPH oxidase 4 (Nox4) and regulates migration; however, the precise underlying mechanisms are unclear. Here, we investigated the role of Poldip2 in focal adhesion turnover, as well as traction force generation and polarization. Poldip2 overexpression (AdPoldip2) in vascular smooth muscle cells (VSMCs) impairs PDGF-induced migration and induces a characteristic phenotype of long cytoplasmic extensions. AdPoldip2 also prevents the decrease in spreading and increased aspect ratio observed in response to PDGF and slightly impairs cell contraction. Moreover, AdPoldip2 blocks focal adhesion dissolution and sustains H2O2 levels in focal adhesions, whereas Poldip2 knockdown (siPoldip2) significantly decreases the number of focal adhesions. RhoA activity is unchanged when focal adhesion dissolution is stimulated in control cells but increases in AdPoldip2-treated cells. Inhibition of RhoA blocks Poldip2-mediated attenuation of focal adhesion dissolution, and overexpression of RhoA or focal adhesion kinase (FAK) reverses the loss of focal adhesions induced by siPoldip2, indicating that RhoA and FAK mediate the effect of Poldip2 on focal adhesions. Nox4 silencing prevents focal adhesion stabilization by AdPoldip2 and induces a phenotype similar to siPoldip2, suggesting a role for Nox4 in Poldip2-induced focal adhesion stability. As a consequence of impaired focal adhesion turnover, PDGF-treated AdPoldip2 cells are unable to reduce and polarize traction forces, a necessary first step in migration. These results implicate Poldip2 in VSMC migration via regulation of focal adhesion turnover and traction force generation in a Nox4/RhoA/FAK-dependent manner.


Action and gait recognition from recovered 3-D human joints.
A common viewpoint-free framework that fuses pose recovery and classification for action and gait recognition is presented in this paper. First, a markerless pose recovery method is adopted to automatically capture the 3-D human joint and pose parameter sequences from volume data. Second, multiple configuration features (combination of joints) and movement features (position, orientation, and height of the body) are extracted from the recovered 3-D human joint and pose parameter sequences. A hidden Markov model (HMM) and an exemplar-based HMM are then used to model the movement features and configuration features, respectively. Finally, actions are classified by a hierarchical classifier that fuses the movement features and the configuration features, and persons are recognized from their gait sequences with the configuration features. The effectiveness of the proposed approach is demonstrated with experiments on the Institut National de Recherche en Informatique et Automatique Xmas Motion Acquisition Sequences data set.


A functional role for an opiate system in snail thermal behavior.
The terrestrial snail Cepaea nemoralis, when placed on a 40 degrees C hot plate, lifts the anterior portion of its foot. The latency of this response is influenced by morphine and by naloxone in a dose-dependent and time-dependent manner. Morphine increases the time taken to respond, whereas naloxone reduces it. Furthermore, naloxone abolishes the effect of morphine. These results indicate that an opiate system may have a role in this behavior, which resembles that reported in vertebrates.