The effect of intermittent pneumatic compression on fracture healing.
Continuously increased venous pressure has been shown to enhance bone growth, stimulate fracture healing, and prevent bone loss, but also causes soft-tissue breakdown as a result of chronic edema. This study was designed to test the hypothesis that intermittently increased venous pressure improves fracture healing without injuring soft tissue. An ostectomy was created in the right radius of 30 skeletally mature male beagles. On postoperative day 7, a pneumatic cuff was placed around the forelimb of each dog. In experimental animals (n = 13), the cuff compressed for 5 minutes followed by no compression for 2.5 minutes. This cycle was repeated 100 times per day for 8 weeks. Control animals (n = 15) wore a nonfunctional cuff. Fracture healing was assessed with dual-energy x-ray absorptiometry, histologic analysis, and biomechanical testing. No soft-tissue complications were noted. Bone mineral content at the ostectomy increased significantly more in the experimental group than in the control group (P < 0.05). Histology revealed that the bone defects in the experimental group were significantly more healed than those in the control group (P < 0.005). No differences were noted between groups in the biomechanical properties of the healing bones. Intermittently increased venous pressure proximal to a bone defect seems to enhance the formation of new bone without soft-tissue complications. These findings can potentially be applied to the clinical treatment of "difficult to heal" fractures. Further work is necessary to determine the most effective ratio of the presence and absence of pneumatic compression.


[Treatment of perforated appendicular peritonitis].
The article analyses the results of treatment of 104 patients with generalized appendicular peritonitis. Sixty-four patients were admitted for acute disease and 40 patients for chronic disease. Twenty-three patients had been previously subjected to appendectomy for destructive appendicitis at other clinics. Among 100 patients who were operated on 60 were treated by appendectomy: cecostomy was established in 5 and ileostomy in 3 patients with incompetence of the stump of the vermiform process; in nonviability of the wall of the small intestine (11 patients) the wall was resected and an anastomosis formed in 7 and enterostomy was performed in 4 cases. The method of "closed evisceration" was employed in 24 patients with neglected forms of peritonitis. Thirty-three hemosorption sessions were conducted in 30 patients in the terminal stage of peritonitis. Four patients died in the preoperative period and 12 died after the operation. Seventeen complications were encountered after the operation: intestinal fistulas 4, abscess of Douglas' space 2, suppuration of wounds 5, and pneumonia 6.


Endostar continuous intravenous infusion combined with S-1 and oxaliplatin chemotherapy could be effective in treating liver metastasis from gastric cancer.
Endostar is a new vascular epithelial inhibitor, which is reported to be effective in treating liver metastasis from gastric cancer. However, the optimal therapeutic regimen of Endostar remains unclear. Thus, our study aimed to examine the efficacy and safety of Endostar continuous intravenous infusion combined with S-1 and oxaliplatin (SOX) chemotherapy in treating such patients. A total of sixty patients with liver metastasis from gastric cancer admitted in our department were enrolled. The experimental group (n = 30) was treated with Endostar continuous intravenous infusion combined with SOX regimen chemotherapy, and the control group (n = 30) received SOX regimen chemotherapy alone. All patients received at least two cycles of treatment. The objective effective rate (ORR), disease control rate (DCR), progression-free survival (PFS), and adverse reactions were recorded and compared. The ORR of the experimental group and control group was 63.3% and 43.3% (P = 0.046), respectively. The DCR of the experimental group and the control group was 86.7% and 73.3% (P = 0.034). The median PFS in the experimental group was longer than that in the control group (15.3 months vs. 12 months). There was no significant difference in the incidence of common adverse reactions such as gastrointestinal reaction, bone marrow suppression, and cardiac toxicity between the two groups. No death was observed in the study period. Continuous infusion of Endostar combined with SOX chemotherapy could be recommended for the treatment of liver metastasis from gastric cancer due to its high effective rate, and Endostar did not increase the incidence of adverse reactions.


Canine Brief Pain Inventory scores for dogs with osteoarthritis before and after administration of a monoclonal antibody against nerve growth factor.
To determine changes in Canine Brief Pain Inventory scores for dogs with osteoarthritis after administration of a monoclonal antibody (mAb) against nerve growth factor (NGF) that was modified by use of a proprietary process for administration to dogs. 11 adult dogs. Dogs received the anti-NGF mAb (0.2 mg/kg, IV) at various evaluation times during the study period; at other evaluation times, dogs received an equivalent volume of PBS solution IV. Owners determined Canine Brief Pain Inventory pain severity (PS) and pain interference (PI) scores immediately before (baseline) and 2, 4, and 6 weeks after administration of the anti-NGF mAb; owners were unaware of the evaluation time at which the mAb had been administered. Compared with baseline PS scores (median, 4.75; range, 0.75 to 8.5), dogs had significantly lower PS scores 2 weeks (median, 3; range, 1 to 5.5) and 4 weeks (median, 2.25; range, 0.25 to 7.25) after administration of anti-NGF mAb. Compared with baseline PI scores (median, 5.33; range, 1.17 to 9.33), dogs had significantly lower PI scores 2 weeks (median, 3; range, 0.67 to 6.83) and 4 weeks (median, 3.33; range, 0.67 to 6.67) after administration of anti-NGF mAb. The PS and PI scores 6 weeks after mAb administration were lower than baseline scores, although values were not significantly different. Results of this study suggested the evaluated anti-NGF mAb decreased PS and PI scores for 4 weeks after administration. This treatment may be effective for alleviation of signs of pain in dogs with osteoarthritis for up to 4 weeks.


State and trait anxiety among medical staff during the first month of COVID-19 pandemic: A sample from Turkey.
During the COVID-19 pandemic, excessive workload, a rapidly changing workplace environment, the danger of carrying the virus and transmitting the disease to their families, relatives and those they live with creates stress for the medical workers. In our study, we aimed to evaluate the state and trait anxiety levels of healthcare professionals who encounter patients with suspected COVID-19 infection and related factors. Data were collected from healthcare professionals working with patients diagnosed or suspected with COVID-19 via online self-report questionnaire between 9-19 April 2020. The state (STAI-S) and trait anxiety (STAI-T) scale was used to measure anxiety. A total of 291 healthcare professionals, 216 women and 75 men, participated in the study. Women's state and trait anxiety were significantly higher than men's. 11 participants without any lifetime psychiatric illness experienced psychiatric symptoms and consulted to a psychiatrist. The state anxiety of those who have children, nurses and those working in branches directly related to the pandemic (Infectious Diseases, Respiratory Diseases, Emergency Medicine, Internal Medicine, Radiology, Anesthesiology and Reanimation) was higher than others. The state anxiety of those who thought they were not protected with personal protective equipment and those who did not stay in their own home was higher than others. At the forefront of the fight against COVID-19, there are medical personnel who pay a serious psychological cost. Especially in terms of anxiety, we should pay attention to women, workers with children, nurses and people working in branches that are directly related to pandemics.


Androgen regulation of immunological and biological activities of pituitary follicle-stimulating hormone isoforms in male rats.
Follicle-stimulating hormone (FSH) is involved in the regulation and maintenance of gametogenesis. It exists in multiple molecular forms with different oligosaccharide structures which in turn are influenced by the hormonal milieu. Previous studies from our laboratory demonstrated that antiandrogen administration to immature male rats altered the biological activity and the distribution profile of pituitary FSH isoforms. The aim of this study was to examine possible modifications in pituitary FSH polymorphism throughout sexual development (10-, 32- and 75-day-old rats). In addition, the effect of androgen deprivation by castration (32-day-old rats) and its replacement with a nonaromatizable androgen - dihydrotestosterone - on pituitary FSH polymorphism was determined. Concanavalin A affinity chromatography was used to isolate groups of FSH isoforms according to their carbohydrate inner structure. Radioimmunoassay and Sertoli cell bioassay were used to evaluate FSH immuno- and bioactivities. Androgen rise in serum was accompanied by a marked increase in pituitary bio- and immuno-FSH content in 32- and 75-day-old rats. However, FSH pituitary content did not vary despite the significant increment observed in serum FSH levels after castration and decrease to control levels after androgen replacement. The distribution profile of immuno- and bioactive FSH changed throughout sexual maturation. The proportion of pituitary FSH isoforms bearing complex oligosaccharide structures (triantennary, bisecting, complete and truncated biantennary) increased with age, with a concomitant decrease in the proportion of isoforms bearing incomplete carbohydrate chains. The distribution profile observed in castrated 32-day-old rats was similar to that determined in 10-day-old animals. Androgen replacement restored the distribution profile to normal. These results suggest that androgens regulate the incorporation of sugar residues to the carbohydrate chains of pituitary FSH favoring the biosynthesis of complex-type oligosaccharide structures.


Age, cognitive load, and multimodal effects on driver response to directional warning.
Inattention can be considered a primary cause of vehicular accidents or crashes, and in-car warning signals are applied to alert the driver to take action even in automated vehicles. Because of age related decline of the older driver's abilities, in-car warning signals may need adjustment to the older driver. We therefore investigated the effects of uni-, bi- and trimodal directional warnings (i.e., light, sound, vibration) on young and older drivers' responses in a driving simulator. A young group of 15 drivers (20-25 years of age) and an older group of 16 drivers (65-79 years of age) participated. In the simulations, warning signal was presented at the left, the center, or the right in front of the participant. With a warning at the left, the center, and the right the correct response was to steer to the right, brake, and steer to the left, respectively. The main results showed the older drivers' responses were slower for each type of warning compared with the young drivers' responses. Overall, the responses were slower with an added cognitively loading task. The only multimodal type of warning inducing overall faster response than its constituent warning types was the vibration-sound, and only for the older drivers. Additionally, with the groups' responses collapsed, such a true multimodal effect on response time also showed for the center vibration-sound warning (i.e., braking response). The only multimodal warning showing clear reduction in response errors compared with its constituent warning types was the vibration-sound for the older drivers during extra cognitive load. The main conclusion is that older drivers can benefit from bimodal warning, as compared with unimodal, in terms of faster and more accurate response. The potential superiority of trimodal warning is nevertheless argued.


The effects of tai chi in centrally obese adults with depression symptoms.
This study examined the effects of Tai Chi, a low-impact mind-body movement therapy, on severity of depression, anxiety, and stress symptoms in centrally obese people with elevated depression symptoms. In total, 213 participants were randomized to a 24-week Tai Chi intervention program or a wait-list control group. Assessments were conducted at baseline and 12 and 24 weeks. Outcomes were severity of depression, anxiety, and stress symptoms, leg strength, central obesity, and other measures of metabolic symptom. There were statistically significant between-group differences in favor of the Tai Chi group in depression (mean difference = -5.6 units, P < 0.001), anxiety (-2.3 units, P < 0.01), and stress (-3.6 units, P < 0.001) symptom scores and leg strength (1.1 units, P < 0.001) at 12 weeks. These changes were further improved or maintained in the Tai Chi group relative to the control group during the second 12 weeks of follow-up. Tai Chi appears to be beneficial for reducing severity of depression, anxiety, and stress and leg strength in centrally obese people with depression symptoms. More studies with longer follow-up are needed to confirm the findings. This trial is registered with ACTRN12613000010796.


Best practice of identification and proteomic analysis of extracellular vesicles in human health and disease.
Extracellular vesicles are emerging sources of biomarkers for modern preventive and precision medicine. Extracellular vesicles in body fluids offer a unique opportunity for integrative biomarker approaches due to their complex biocargo that includes proteins, lipids, nucleic acids and metabolites. Mass spectrometry-based proteomics data suggest that a significant portion of human proteins are sorted into extracellular vesicles and amenable for biomarker discovery schemes. Areas covered: this review focuses on key aspects of isolation, quality control and subsequent analysis of blood plasma- and conditioned medium-derived extracellular vesicle proteins, and summarizes the current state-of-the-art in the field. Furthermore, it provides introduction and guidelines for mass spectrometry-based proteomic analysis of extracellular vesicles. Expert commentary: Comparison of newly developed isolation and purification techniques with classical ultracentrifugation-based approaches are highly recommended. It is also essential to use multiple analytical approaches to characterize the isolated extracellular vesicles prior to characterization of their biocargo. Rigor in data reproducibility, critical data analysis, awareness of potential pitfalls, standardization and benchmarking are required for extracellular vesicle research to fulfil the current expectation that these subcellular structures can become a valid source of next generation biomarkers.


[Digital subtraction angiography and large-film angiography of the pelvic and leg arteries].
The diagnostic information and image quality of 1153 DSA studies of pelvic and lower limb arteries and of 104 conventional large film angiograms have been analysed. Using intra-arterial contrast, all large film angiograms and all DSA studies of the iliac, femoral, popliteal and upper calf arteries were satisfactory. For demonstrating the distal calf vessels and vessels in the foot, intra-arterial DSA was superior to large film angiography. Using intravenous DSA, 98% of the iliac, femoral and popliteal arteries were adequately demonstrated, although image quality was reduced.


Low magnetic field effects on embryonic bone growth.
Pulsed electromagnetic fields [EMF] and electric fields have been demonstrated to promote osteogenesis and wound healing. Pulsed EMF's have been approved since 1979 by the FDA, and are highly effective in the treatment of non-union fractures. Increased linear growth, cellular proliferation, cAMP and uptake of tritiated thymidine have been documented on short term exposure. Yet the mechanisms and the changes that occur have been difficult to quantify. Fluorescence, light, and electron microscopy were utilized in this study to assess any histological changes in bone. During incubation chick embryos were exposed to magnets oriented in various positions. Controls were oriented similarly using galvanized steel plugs. Field density in the center of the field was measure by a gaussmeter with a transverse probe. Each chick embryo in its magnetic field was isolated from the magnetic fields of others by being encased in a steel box. Intramembranous [calvaria] and endochondral [tibia] ossification were studied. Fluorescent dyes were micropipetted intravascularly at various stages of chick development. The tissues were fixed in methacrylate and stained for histomorphological study.


Characterization of the active site properties of CYP4F12.
Cytochrome P450 4F12 is a drug-metabolizing enzyme that is primarily expressed in the liver, kidney, colon, small intestine, and heart. The properties of CYP4F12 that may impart an increased catalytic selectivity (decreased promiscuity) were explored through in vitro metabolite elucidation, kinetic isotope effect experiments, and computational modeling of the CYP4F12 active site. By using astemizole as a probe substrate for CYP4F12 and CYP3A4, it was observed that although CYP4F12 favored astemizole O-demethylation as the primary route of metabolism, CYP3A4 was capable of metabolizing astemizole at multiple sites on the molecule. Deuteration of astemizole at the site of O-demethylation resulted in an isotope effect of 7.1 as well as an 8.3-fold decrease in the rate of clearance for astemizole by CYP4F12. Conversely, although an isotope effect of 3.8 was observed for the formation of the O-desmethyl metabolite when deuterated astemizole was metabolized by CYP3A4, there was no decrease in the clearance of astemizole. Development of a homology model of CYP4F12 based on the crystal structure of cytochrome P450 BM3 predicted an active site volume for CYP4F12 that was approximately 76% of the active site volume of CYP3A4. As predicted, multiple favorable binding orientations were available for astemizole docked into the active site of CYP3A4, but only a single binding orientation with the site of O-demethylation oriented toward the heme was identified for CYP4F12. Overall, it appears that although CYP4F12 may be capable of binding similar ligands to other cytochrome P450 enzymes such as CYP3A4, the ability to achieve catalytically favorable orientations may be inherently more difficult because of the increased steric constraints of the CYP4F12 active site.


Spontaneous diseases in captive ratites (Struthioniformes) in northwestern Germany: A retrospective study.
A retrospective study was carried out to define the spectrum of spontaneous diseases in ostriches and few other captive ratites, order Struthioniformes, in northwestern Germany. The investigation included 71 ratites necropsied between 1968 and 2014. They consisted of 54 ostriches, 5 emus, and 12 rheas with 37 adults, 23 juveniles and 11 neonates and embryonated eggs. Necropsy reports were reviewed, histologic preparations were re-examined and additional histochemical and immunohistochemical stains were carried out in selected cases. In many animals more than one morphologic diagnosis attributable to different disease processes was found. In adult animals (n = 37), the most commonly altered organ systems were the musculoskeletal system (49%), the digestive system (46%), and the cardiovascular system (46%) affected by traumatic lesions, inflammatory and degenerative changes, respectively. A spongy degeneration was found in the brain (35%); however, immunohistochemistry and western blotting failed to detect pathological prion protein. In juvenile animals (n = 23), the musculoskeletal (44%) and the digestive system (43%) were mainly affected by traumatic and inflammatory lesions, respectively. In embryonated eggs and neonates (n = 11) the major cause of death was circulatory failure associated with generalized subcutaneous edema as described for improper incubation conditions (64%). Summarized, most of the findings observed in adult and juvenile ratites in northwestern Germany are related to trauma, inflammatory and degenerative disorders, whereas death in embryonated eggs and neonates was most likely related to breeding conditions. A spongy encephalopathy awaits further studies to elucidate cause and pathogenesis.


Evaluation of Wearable Haptic Systems for the Fingers in Augmented Reality Applications.
Although Augmented Reality (AR) has been around for almost five decades, only recently we have witnessed AR systems and applications entering in our everyday life. Representative examples of this technological revolution are the smartphone games "Pokémon GO" and "Ingress" or the Google Translate real-time sign interpretation app. Even if AR applications are already quite compelling and widespread, users are still not able to physically interact with the computer-generated reality. In this respect, wearable haptics can provide the compelling illusion of touching the superimposed virtual objects without constraining the motion or the workspace of the user. In this paper, we present the experimental evaluation of two wearable haptic interfaces for the fingers in three AR scenarios, enrolling 38 participants. In the first experiment, subjects were requested to write on a virtual board using a real chalk. The haptic devices provided the interaction forces between the chalk and the board. In the second experiment, subjects were asked to pick and place virtual and real objects. The haptic devices provided the interaction forces due to the weight of the virtual objects. In the third experiment, subjects were asked to balance a virtual sphere on a real cardboard. The haptic devices provided the interaction forces due to the weight of the virtual sphere rolling on the cardboard. Providing haptic feedback through the considered wearable device significantly improved the performance of all the considered tasks. Moreover, subjects significantly preferred conditions providing wearable haptic feedback.


Outcomes after arthroscopic fixation of tibial eminence fractures with bioabsorbable nails in skeletally immature patients.
The aim of this paper is to report the outcomes and any complications with arthroscopic bioabsorbable nail fixation of tibial eminence fractures in skeletally immature patients. We retrospectively reviewed all surgically treated tibial eminence fractures treated by a single surgeon and seven patients were identified with a minimum 2-year follow-up. Mean deficits of flexion and extension were minimal. Satisfactory Tegner levels, Lysholm knee scores, and International Knee Documentation Committee subjective scores were reported. Arthroscopic fixation of tibial eminence fractures with bioabsorbable nails yields satisfactory outcomes for this uncommon injury and obviates the need for future hardware removal.


Does a neutropenic diet reduce adverse outcomes in patients undergoing chemotherapy?
This study aimed to compare clinical outcomes of chemotherapy patients who received either a neutropenic diet (ND) or liberalised diet (LD) and to investigate associations between ND and infectious outcomes. A retrospective case note audit of patients admitted to Flinders Medical Centre from 2013 to 2017 was conducted. Patients were eligible if they were aged 18 years and above, received chemotherapy and were neutropenic during admission. Demographic and clinical data were collected from medical records. Primary outcomes were occurrence of infections and fever. Secondary outcomes include hospital length of stay and infection-related mortality. Seventy-nine patients received ND while 75 patients received LD. The ND group had more patients with acute myeloid leukaemia (p < .001) and receiving high-toxicity chemotherapy (p = .005). Incidence of febrile neutropenia (p = .016), bacteraemia (p = .044) and number of febrile days (p = .033) was higher in the ND group. ND was not independently associated with occurrence of febrile neutropenia or infections. Subsample analysis of 20 pairs of patients matched on age, sex and cancer diagnosis found no significant differences in clinical outcomes between groups. ND was not associated with the prevention of adverse outcomes in chemotherapy patients.


Synthesis of (Z)-β-halo α,β-unsaturated carbonyl systems via the combination of halotrimethylsilane and tetrafluoroboric acid.
A convenient and broadly applicable method for the hydrohalogenation of ynones is described, by the combination of halotrimethylsilanes and tetrafluoroboric acid. Practically, one equivalent of HX (Brønsted acid) and BF3 (Lewis acid) is smoothly generated, which activates the carbonyl compounds. Through this protocol, 42 examples of (Z)-β-halovinyl carbonyl compounds (Cl, Br and I) were obtained, in good yields and high stereoselectivity having 2-MeTHF as a solvent.


Airway count and emphysema assessed by chest CT imaging predicts clinical outcome in smokers.
Recently, it has been shown that emphysematous destruction of the lung is associated with a decrease in the total number of terminal bronchioles. It is unknown whether a similar decrease is visible in the more proximal airways. We aimed to assess the relationships between proximal airway count, CT imaging measures of emphysema, and clinical prognostic factors in smokers, and to determine whether airway count predicts the BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index. In 50 smokers, emphysema was measured on CT scans and airway branches from the third to eighth generations of the right upper lobe apical bronchus were counted manually. The sum of airway branches from the sixth to eighth generations represented the total airway count (TAC). For each subject, the BODE index was determined. We used logistic regression to assess the ability of TAC to predict a high BODE index (≥ 7 points). TAC was inversely associated with emphysema (r = -0.54, P < .0001). TAC correlated with the modified Medical Research Council dyspnea score (r = -0.42, P = .004), FEV(1)% predicted (r = 0.52, P = .0003), 6-min walk distance (r = 0.36, P = .012), and BODE index (r = -0.55, P < .0001). The C-statistics, which correspond to the area under the receiver operating characteristic curve, for the ability of TAC alone and TAC, emphysema, and age to predict a high BODE index were 0.84 and 0.92, respectively. TAC is lower in subjects with greater emphysematous destruction and is a predictor of a high BODE index. These results suggest that CT imaging-based TAC may be a unique COPD-related phenotype in smokers.


The schizophrenia phenotype in 22q11 deletion syndrome.
This study investigated the schizophrenia phenotype in 24 subjects with 22q11 deletion syndrome (22qDS) and schizophrenia (22qDS-schizophrenia), a rare but relatively homogenous genetic subtype of schizophrenia associated with a microdeletion on chromosome 22. Individuals with 22qDS are at genetically high risk for schizophrenia. Standard measures of signs, symptoms, and course of schizophrenia were assessed in 16 adults with 22qDS-schizophrenia who did not meet criteria for mental retardation and in 46 adults with schizophrenia without evidence of 22qDS from a community familial sample. There were no significant differences in age at onset, lifetime or cross-sectional core positive and negative schizophrenic symptoms, or global functioning between the two groups of patients with schizophrenia. Patients with 22qDS-schizophrenia had higher excitement subscale scores and less lifetime substance use than the comparison patients with schizophrenia, but no significant differences in anxiety-depression symptom severity were found between the groups. These findings indicate that the core clinical schizophrenia phenotype would not distinguish individuals with a 22qDS subtype from those with schizophrenia who did not have the 22qDS subtype. The results provide further support for the utility of 22qDS-schizophrenia as a neurodevelopmental model of schizophrenia as well as support for prospective studies of individuals with 22qDS to help identify precursors of schizophrenia.


Cytogenetic and molecular identification of a wheat-Leymus mollis alien multiple substitution line from octoploid Tritileymus x Triticum durum.
Leymus mollis (Trin.) Pilger (NsNsXmXm, 2n = 28), a wild relative of common wheat, possesses many traits that are potentially valuable for wheat improvement. In order to exploit and utilize the useful genes of L. mollis, we developed a multiple alien substitution line, 10DM50, from the progenies of octoploid Tritileymus M842-16 x Triticum durum cv. D4286. Genomic in situ hybridization analysis of mitosis and meiosis (metaphase I), using labeled total DNA of Psathyrostachys huashanica as probe, showed that the substitution line 10DM50 was a cytogenetically stable alien substitution line with 36 chromosomes from wheat and three pairs of Ns genome chromosomes from L. mollis. Simple sequence repeat analysis showed that the chromosomes 3D, 6D, and 7D were absent in 10DM50. Expressed sequence tag-sequence tagged sites analysis showed that new chromatin from 3Ns, 6Ns, and 7Ns of L. mollis were detected in 10DM50. We deduced that the substitution line 10DM50 was a multiple alien substitution line with the 3D, 6D, and 7D chromosomes replaced by 3Ns, 6Ns, and 7Ns from L. mollis. 10DM50 showed high resistance to leaf rust and significantly improved spike length, spikes per plant, and kernels per spike, which are correlated with higher wheat yield. These results suggest that line 10DM50 could be used as intermediate material for transferring desirable traits from L. mollis into common wheat in breeding programs.


Not Who You Are, But Who You Are With: Re-examining Women's Less Satisfying Sexual Debuts.
Gender differences in appraisals of first intercourse are among the largest in sexuality research, with women indicating less satisfying "sexual debuts" than men. Dispositional or "actor-level" explanations for this gender gap are pervasive, yet research has largely examined heterosexual debuts in which actor gender and partner gender are confounded. We assessed whether women's less satisfying sexual debuts are better explained by actor gender or partner gender, comparing experiences of women who debuted with men (WDM) with those of men and women who debuted with women (MDW, WDW). Retrospective accounts of sexual debut were collected from 3033 adults. At first intercourse, we found that WDW had equal physical and emotional satisfaction to MDW, and more satisfaction than WDM, suggesting satisfaction gaps owing to partner gender, not actor gender. This pattern did not extend to a comparison event (first masturbation), where WDW and WDM had similar satisfaction, but less satisfaction than MDW, suggesting an actor gender gap. To identify sources of satisfaction gaps, we probed for corresponding differences in the circumstances of sexual debut. Sexual circumstances were more strongly implicated than nonsexual ones, with relative deprivation of glans stimulation explaining relative dissatisfaction at first intercourse, but not first masturbation, and orgasm explaining it at both. Findings challenge the view that the satisfaction gap at first intercourse reflects an inherent difference between genders. Indeed, they demonstrate similarities when partner gender does not differ and suggest strategies for ensuring equal sexual satisfaction-and equal sexual rights realization-at (hetero) sexual debut.


Ocular ischemic syndrome; A case report.
Ocular ischemic syndrome is not a common condition so most of these cases are often misdiagnosed or treated as a different entity. Therefore, it is very important for the ophthalmologists to have this condition in mind as a differential so that the patients can be diagnosed and treated as early as possible. A 42 years female presented with painless, progressive diminution of vision in right eye over the period of 1 month. She doesn't give any history of redness of eyes, fever or trauma. There is no history of diabetes mellitus or hypertension as well. On examination, vision in right and left eyes was 1.78 and 0.30 Log Mar Units respectively. On anterior segment examination, revascularization of iris (1o 4 'o'clock hrs) in right eye was noted. On dilated fund us copy, revascularization of disc (1/3rd) was present in right eye. Cotton wool spots blot hemorrhages and micro aneurysms were also noted in right eye. Likewise, attenuation of arteries were noted on both sides. Fund us fluorescent angiography revealed delayed artery covetous and venous phase. Carotid Doppler was done which showed complete occlusion of right common carotid and bilateral internal carotid artery. These findings lead to the diagnosis as ocular ischemic syndrome so she was then referred to the cardiologist who further confirmed that no active intervention was required at present. The patient was planned for right eye pan retinal photocoagulation (PRP) and was completed in 2 sittings and was asked to follow up regularly. Early diagnosis and management is very important for uncommon conditions such as ocular ischemic syndrome to prevent further complications.


Evaluating the importance of demographic connectivity in a marine metapopulation.
Recently researchers have gone to great lengths to measure marine metapopulation connectivity via tagging, genetic, and trace-elemental fingerprinting studies. These empirical estimates of larval dispersal are key to assessing the significance of metapopulation connectivity within a demographic context, but the life-history data required to do this are rarely available. To evaluate the demographic consequences of connectivity we constructed seasonal, size-structured metapopulation matrix models for two species of mytilid mussel in San Diego County, California, USA. The self-recruitment and larval exchange terms were produced from a time series of realized connectivities derived from trace-elemental fingerprinting of larval shells during spring and fall from 2003 to 2008. Both species exhibited a strong seasonal pattern of southward movement of recruits in spring and northward movement in fall. Growth and mortality terms were estimated using mark-recapture data from representative sites for each species and subpopulation, and literature estimates of juvenile mortality. Fecundity terms were estimated using county-wide settlement data from 2006-2008; these data reveal peak reproduction and recruitment in fall for Mytilus californianus, and spring for M. galloprovincialis. Elasticity and life-stage simulation analyses were employed to identify the season- and subpopulation-specific vital rates and connectivity terms to which the metapopulation growth rate (lambda) was most sensitive. For both species, metapopulation growth was most sensitive to proportional changes in adult fecundity, survival and growth of juvenile stages, and population connectivity, in order of importance, but relatively insensitive to adult growth or survival. The metapopulation concept was deemed appropriate for both Mytilus species as exchange between the subpopulations was necessary for subpopulation persistence. However, highest metapopulation growth occurred in years when a greater proportion of recruits was retained within the predominant source subpopulation. Despite differences in habitat and planktonic duration, both species exhibited similar overall metapopulation dynamics with respect to key life stages and processes. However, different peak reproductive periods in an environment of seasonal current reversals led to different regional (subpopulation) contributions to metapopulation maintenance; this result emphasizes the importance of connectivity analysis for spatial management of coastal resources.


Cdk2-null mice are resistant to ErbB-2-induced mammary tumorigenesis.
The concept of targeting G(1) cyclin-dependent kinases (CDKs) in breast cancer treatments is supported by the fact that the genetic ablation of Cdk4 had minimal impacts on normal cell proliferation in majority of cell types, resulting in near-normal mouse development, whereas such loss of Cdk4 completely abrogated ErbB-2/neu-induced mammary tumorigenesis in mice. In most human breast cancer tissues, another G(1)-regulatory CDK, CDK2, is also hyperactivated by various mechanisms and is believed to be an important therapeutic target. In this report, we provide genetic evidence that CDK2 is essential for proliferation and oncogenesis of murine mammary epithelial cells. We observed that 87% of Cdk2-null mice were protected from ErbB-2-induced mammary tumorigenesis. Mouse embryonic fibroblasts isolated from Cdk2-null mouse showed resistance to various oncogene-induced transformation. Previously, we have reported that hemizygous loss of Cdc25A, the major activator of CDK2, can also protect mice from ErbB-2-induced mammary tumorigenesis [Cancer Res (2007) 67(14): 6605-11]. Thus, we propose that CDC25A-CDK2 pathway is critical for the oncogenic action of ErbB-2 in mammary epithelial cells, in a manner similar to Cyclin D1/CDK4 pathway.


Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein.
Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial evidence that Pgp is expressed both as an acquired mechanism (e.g., in leukemias, lymphomas, myeloma, and breast and ovarian carcinomas) and constitutively (e.g., in colorectal and renal cancers) and that its expression is of prognostic significance in many types of cancer. Clinical trials of MDR modulation are complicated by the presence of multiple-drug-resistance mechanisms in human cancers, the pharmacokinetic interactions that result from the inhibition of Pgp in normal tissues, and, until recently, the lack of potent and specific inhibitors of Pgp. A large number of clinical trials of reversal of MDR have been undertaken with drugs that are relatively weak inhibitors and produce limiting toxicities at doses below those necessary to inhibit Pgp significantly. The advent of newer drugs such as the cyclosporin PSC 833 (PSC) provides clinicians with more potent and specific inhibitors for MDR modulation trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental for the design of therapeutic trials of MDR modulation. Our studies of combinations of high-dose cyclosporin (CsA) or PSC 833 with etoposide, doxorubicin, or paclitaxel have produced data regarding the role of Pgp in the clinical pharmacology of these agents. Major pharmacokinetic interactions result from the coadministration of CsA or PSC 833 with MDR-related anticancer agents (e.g., doxorubicin, daunorubicin, etoposide, paclitaxel, and vinblastine). These include increases in the plasma area under the curve and half-life and decreases in the clearance of these cytotoxic drugs, consistent with Pgp modulation at the biliary lumen and renal tubule, blocking excretion of drugs into the bile and urine. The biological and medical implications of our studies include the following. First, Pgp is a major organic cation transporter in tissues responsible for the excretion of xenobiotics (both drugs and toxins) by the biliary tract and proximal tubule of the kidney. Our clinical data are supported by recent studies in mdr-gene-knockout mice. Second, modulation of Pgp in tumors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting as inhibition of the disposition of MDR-related cytotoxins (which are transport substrates for Pgp). Third, these pharmacokinetic interactions of Pgp modulation are predictable if one defines the pharmacology of the modulating agent and the combination. The interactions lead to increased toxicities such as myelosuppression unless doses are modified to compensate for the altered disposition of MDR-related cytotoxins. Fourth, in serial studies where patients are their own controls and clinical resistance is established, remissions are observed when CsA or PSC 833 is added to therapy, even when doses of the cytotoxin are reduced by as much as 3-fold. This reversal of clinical drug resistance occurs particularly when the tumor cells express the mdr1 gene. Thus, tumor regression can be obtained without apparent increases in normal tissue toxicities. In parallel with these trials, we have recently demonstrated in the laboratory that PSC 833 decreases the mutation rate for resistance to doxorubicin and suppresses activation of mdr1 and the appearance of MDR mutants. These findings suggest that MDR modulation may delay the emergence of clinical drug resistance and support the concept of prevention of drug resistance in the earlier stages of disease and the utilization of time to progression as an important endpoint in clinical trials. Pivotal phase III trials to test these concepts with PSC 833 as an MDR modulator are under way or planned for patients with acute myeloid leukemias, multiple myeloma, and ovarian carcinoma.


Diagnosis of tuberculosis by Amplicor Mycobacterium tuberculosis test: a multicenter study.
The Amplicor Mycobacterium tuberculosis test is a new PCR assay for the direct detection of Mycobacterium tuberculosis from clinical samples. A multicenter study that included six laboratories was done to evaluate the Amplicor test in comparison with direct microscopy and culture (solid or radiometric media), and the culture method was used as the "gold standard." A total of 2,073 specimens, i.e., 1,749 respiratory specimens and 324 other specimens, were tested. A total of 184 cultures yielded M. tuberculosis. Of these 184 cultures, 77 (42%) were smear negative and 23 (12.5%) concerned extrapulmonary specimens. The sensitivity of the Amplicor test for all of the specimens and for extrapulmonary, smear-positive, and smear-negative specimens was 86, 83, 94.5, and 74%, respectively. The sensitivity of direct microscopy in comparison with that of culture was 58%. A total of 95% of patients with culture-proven tuberculosis were diagnosed by the Amplicor test, whereas direct microscopy detected mycobacteria in only 72% of these patients. The Amplicor test exhibited a high degree of specificity (98%). The assay was very rapid and easy to perform.


Types A and F Clostridium perfringens in healthcare wastewater from Ghana.
Clostridium perfringens causes gas gangrene and food poisoning in humans, and monitoring this bacterium is important for public health. Although whole-genome sequencing is useful to comprehensively understand the virulence, resistome, and global genetic relatedness of bacteria, limited genomic data from environmental sources and developing countries hamper our understanding of the richness of the intrinsic genomic diversity of this pathogen. Here, we successfully accumulated the genetic data on C. perfringens strains isolated from hospital effluent and provided the first evidence that predicted pathogenic C. perfringens may be disseminated in the clinical environment in Ghana. Our findings suggest the importance of risk assessment in the environment as well as the clinical setting to mitigate the potential outbreak of C. perfringens food poisoning in Ghana.


Histologic Anatomy of the Anterior Vagina and Urethra.
Vaginal and urethral histology is important to understanding the pathophysiology of the pelvic floor. En bloc removal of 4 female cadaveric pelvises was performed, with 18 to 25 serial sections obtained from each. The vaginal and urethral lengths were divided into distal and proximal sections; urethra was divided into anterior and posterior segments as well. Innervation and vasculature were qualified as small and large and quantified per high-power field. The mean vaginal length was 7.45 cm, and the mean urethral length was 3.38 cm. A distinct vaginal fibromuscular layer was noted, without evidence of a dense sheet of continuous collagen. An epithelial, lamina propria, and muscular layer surrounded the urethral lumen. Adipose and loose fibroconnective tissue separated the urethra from the anterior vagina in 41% of slides. Nerves and vasculature were concentrated in the lamina propria. More small nerves and vessels were grossly seen compared with larger counterparts in both the vagina and urethra. No significant differences in layer thickness, innervation, or vasculature were observed along the vaginal length. The posterior urethra had greater innervation than did the anterior (P = 0.012). The distal posterior urethra had more large vessels than did the proximal posterior urethra (P = 0.03). No other differences were noted in urethral sections. A vaginal fibromuscular layer was confirmed, refuting a true fascia. Innervation and vasculature were quantitatively the same along the anterior vagina. However, the posterior urethra had greater innervation than did anterior and is most innervated proximally. Nerve and vascular histology may relate to pelvic floor disorder etiology.


Cyclosporine Broadens the Therapeutic Potential of Lenalidomide in Myeloid Malignancies.
The immunomodulatory drug lenalidomide is used for the treatment of certain hematologic malignancies, including myelodysplastic syndromes (MDS). Lenalidomide interacts with cereblon (CRBN), a component of the CRL4CRBN E3 ubiquitin ligase complex, leading to ubiquitination and subsequent degradation of substrates, such as transcription factor Ikaros (Ikaros family zinc finger 1, IKZF1). With a genome loss of function screen, we recently identified two novel pathways mediated by lenalidomide in MDS. In this review, we summarized the major findings of these two pathways and their clinical implications. Depletion of G protein-coupled receptor 68 (GPR68) or an endogenous calcineurin (CaN) inhibitor, regulator of calcineurin 1 (RCAN1), reversed the inhibitory effect of lenalidomide on MDSL cells, an MDS cell line. Intriguingly, both GPR68 and RCAN1 expression levels were upregulated in MDSL cells after treatment with lenalidomide that was dependent on diminishment of IKZF1, indicating that IKZF1 functioned as a transcription repressor for GPR68 and RCAN1. Mechanistic studies revealed that upregulation or activation of GPR68 induced a Ca2+/calpain pro-apoptotic pathway, while upregulation of RCAN1 inhibited the CaN pro-survival pathway in MDSL cells. Notably, the pharmacological CaN inhibitor, cyclosporine, enhanced the sensitivity to lenalidomide in MDS as well as acute myeloid leukemia (AML). Surprisingly, pretreatment with lenalidomide reversed the immunosuppressive effects of cyclosporine on T lymphocytes. Our studies suggest that lenalidomide mediates degradation of IKZF1, leading to derepression of GPR68 and RCAN1 that activates the Ca2+/calpain pro- apoptotic pathway and inhibits the CaN pro-survival pathway, respectively. Our studies implicate that cyclosporine extends the therapeutic potential of lenalidomide to myeloid malignancies without compromising immune function.


PROTEIN TEMPLATES IN HARD TISSUE ENGINEERING.
Biomineralization processes such as formation of bones and teeth require controlled mineral deposition and self-assembly into hierarchical biocomposites with unique mechanical properties. Ideal biomaterials for regeneration and repair of hard tissues must be biocompatible, possess micro and macroporosity for vascular invasion, provide surface chemistry and texture that facilitate cell attachment, proliferation, differentiation of lineage specific progenitor cells, and induce deposition of calcium phosphate mineral. To expect in-vivo like cellular response several investigators have used extracellular matrix proteins as templates to recreate in-vivo microenvironment for regeneration of hard tissues. Recently, several novel methods of designing tissue repair and restoration materials using bioinspired strategies are currently being formulated. Nanoscale structured materials can be fabricated via the spontaneous organization of self-assembling proteins to construct hierarchically organized nanomaterials. The advantage of such a method is that polypeptides can be specifically designed as building blocks incorporated with molecular recognition features and spatially distributed bioactive ligands that would provide a physiological environment for cells in-vitro and in-vivo. This is a rapidly evolving area and provides a promising platform for future development of nanostructured templates for hard tissue engineering. In this review we try to highlight the importance of proteins as templates for regeneration and repair of hard tissues as well as the potential of peptide based nanomaterials for regenerative therapies.


Cloning, sequence analysis and expression of the major outer capsid protein gene of an aquareovirus.
The nucleotide and deduced amino acid sequences of genome segment 10 of aquareovirus strain SBR, encoding the major outer capsid protein (VP7), have been determined. Genome segment 10 of SBR virus is 986 nucleotides long and encodes a polypeptide of 298 amino acids with a predicted molecular mass of 32,430 Da. There are 26 non-translated nucleotides at the 5' end and 66 non-translated nucleotides at the 3' end. Using a recombinant baculovirus system, the VP7 protein of SBR virus was expressed to a high level. The baculovirus-produced VP7 protein was similar both in its size and antigenic properties to the authentic aquareovirus VP7 protein. Antiserum from a rabbit immunized with the baculovirus-produced VP7 protein failed to neutralize the homologous aquareovirus strain. As determined by Western blotting, this antiserum reacted with aquareovirus strains belonging to the same genogroup as SBR virus, but did not react with aquareovirus strains belonging to the other genogroups.


Poly(amidoamine) Dendrimers as a Pharmaceutical Excipient. Are We There yet?
Drug solubility could affect the therapeutic use of a drug because the biological activity of a drug is only possible if some fraction of a dissolved drug can permeate and overcome biological membranes to reach its site of action. The solubility-permeation interplay is therefore, probably the most important factor in determining a successful therapeutic outcome of any drug because more than 40% of marketed drugs and more than 70% of pipeline drugs show poor water solubility. Several solubilization techniques are used and include, balancing of pH-pKa properties, employment of cosolvents, and the solubilization by host-guest carriers. A relatively new addition to the polymer plethora of solubilizers are the poly(amidoamine) dendrimers. These highly branched, "tree-like" nanocarriers have a significant solubilization capacity for drugs in their cavities and also potentially via their terminals. Despite their successful solubilization capability, they are still plagued by some undesired properties such as cytotoxicity. Poly(amidoamine) however, seems to be a very lucrative target to develop into a pharmaceutical excipient, which will ultimately be confirmed by an official pharmacopeial monograph.


Competition between siRNA duplexes: impact of RNA-induced silencing complex loading efficiency and comparison between conventional-21 bp and Dicer-substrate siRNAs.
Cotransfection of a mixture of siRNAs species is typically used when simultaneous targeting of more than one mRNA is required. However, competition between siRNAs could occur and reduce the activity of some siRNAs within the mixture. To further study the factors affecting the degree of competition between siRNAs, we cotransfected luciferase targeting siRNAs with various irrelevant (ie, nonluciferase targeting) siRNAs into cells and examined differences in their competition profiles by assessing the effect on luciferase expression. We show that the degree of competition varies between irrelevant siRNAs and occurs at the point of RISC loading. Although the competition profile appears to be related to the calculated RNA-induced silencing complex (RISC) loading potential, empirical testing is required to confirm the competitive effects. We also observed reduced competition with siRNAs in the Dicer-substrate format, presumably due to more efficient RISC loading as a consequence of the physical transfer of the processed siRNA from Dicer.


A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage.
SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single nucleotide polymorphism in SH2B3 (rs3184504) results in substitution of tryptophan (Trp) for arginine (Arg) at amino acid 262 and is a top association signal for hypertension in human genome-wide association studies. Whether this variant is causal for hypertension, and if so, the mechanism by which it impacts pathogenesis is unknown. We used CRISPR-Cas9 technology to create mice homozygous for the major (Arg/Arg) and minor (Trp/Trp) alleles of this SH2B3 polymorphism. Mice underwent angiotensin II (Ang II) infusion to evaluate differences in blood pressure (BP) elevation and end-organ damage including albuminuria and renal fibrosis. Cytokine production and Stat4 phosphorylation was also assessed in Arg/Arg and Trp/Trp T cells. Trp/Trp mice exhibit 10 mmHg higher systolic BP during chronic Ang II infusion compared to Arg/Arg controls. Renal injury and perivascular fibrosis are exacerbated in Trp/Trp mice compared to Arg/Arg controls following Ang II infusion. Renal and ex vivo stimulated splenic CD8+ T cells from Ang II-infused Trp/Trp mice produce significantly more interferon gamma (IFNg) compared to Arg/Arg controls. Interleukin-12 (IL-12)-induced IFNg production is greater in Trp/Trp compared to Arg/Arg CD8+ T cells. In addition, IL-12 enhances Stat4 phosphorylation to a greater degree in Trp/Trp compared to Arg/Arg CD8+ T cells, suggesting that Trp-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFNg production. Finally, we demonstrated that a multi-SNP model genetically predicting increased SH2B3 expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans.. Taken together, these results suggest that the Trp encoding allele of rs3184504 is causal for BP elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T cell IL-12 signaling leading to enhanced IFNg production.


Does low-level laser therapy enhance the efficacy of intravenous regional anesthesia?
The use of intravenous regional anesthesia (IVRA) is limited by pain resulting from the application of tourniquets and postoperative pain. To assess the efficacy of low-level laser therapy added to IVRA for improving pain related to surgical fixation of distal radius fractures. The present double-blinded, placebo-controlled, randomized clinical trial involved 48 patients who were undergoing surgical fixation of distal radius fractures. Participants were randomly assigned to either an intervention group (n=24), who received 808 nm laser irradiation as 4 J⁄point for 20 s over ipsilateral three nerve roots in the cervical region corresponding to C5-C8 vertebrae, and 808 nm laser irradiation as 0.1 J⁄cm2 for 5 min in a tangential scanning mode over the affected extremity; or a control group (n=24), who underwent the same protocol and timing of laser probe application with the laser switched off. Both groups received the same IVRA protocol using 2% lidocaine. The mean visual analogue scale scores were significantly lower in the laser-assisted group than in the lidocaine-only group on all measurements during and after operation (P<0.05). The mean time to the first need for fentanyl administration during the operation was longer in the laser group (P=0.04). The total amount of fentanyl administered to patients was significantly lower in the laser-assisted group (P=0.003). The laser group needed significantly less pethidine for pain relief (P=0.001) and at a later time (P=0.002) compared with the lidocaine-only group. There was no difference between the groups in terms of mean arterial pressure and heart rate. The addition of gallium-aluminum-arsenide laser irradiation to intravenous regional anesthesia is safe, and reduces pain during and after the operation.


IMS-MS and IMS-IMS investigation of the structure and stability of dimethylamine-sulfuric acid nanoclusters.
Recent studies of new particle formation events in the atmosphere suggest that nanoclusters (i.e, the species formed during the early stages of particle growth which are composed of 10(1)-10(3) molecules) may consist of amines and sulfuric acid. The physicochemical properties of sub-10 nm amine-sulfuric acid clusters are hence of interest. In this work, we measure the density, thermostability, and extent of water uptake of <8.5 nm effective diameter dimethylamine-sulfuric (DMAS) nanoclusters in the gas phase, produced via positive electrospray ionization. Specifically, we employ three systems to investigate DMAS properties: ion mobility spectrometry (IMS, with a parallel-plate differential mobility analyzer) is coupled with mass spectrometry to measure masses and collision cross sections for <100 kDa positively charged nanoclusters, two differential mobility analyzers in series (IMS-IMS) are used to examine thermostability, and finally a differential mobility analyzer coupled to an atmospheric pressure drift tube ion mobility spectrometer (also IMS-IMS) is used for water uptake measurements. IMS-MS measurements reveal that dry DMAS nanoclusters have densities of ∼1567 kg/m(3) near 300 K, independent of the ratio of dimethylamine to sulfuric acid originally present in the electrospray solution. IMS-IMS thermostability studies reveal that partial pressures of DMAS nanoclusters are dependent upon the electrospray solution concentration ratio, R = [H2SO4]/[(CH3)2NH]. Extrapolating measurements, we estimate that dry DMAS nanoclusters have surface vapor pressures of order 10(-4) Pa near 300 K, with the surface vapor pressure increasing with increasing values of R through most of the probed concentration range. This suggests that nanocluster surface vapor pressures are substantially enhanced by capillarity effects (the Kelvin effect). Meanwhile, IMS-IMS water uptake measurements show clearly that DMAS nanoclusters uptake water at relative humidities beyond 10% near 300 K, and that larger clusters uptake water to a larger extent. In total, our results suggest that dry DMAS nanoclusters (in the 5-8.5 nm size range in diameter) would not be stable under ambient conditions; however, DMAS nanoclusters would likely be hydrated in the ambient (in some cases above 20% water by mass), which could serve to reduce surface vapor pressures and stabilize them from dissociation.


Rovibrationally state-specific collision model for the O2(Σg-3) + O(P3) system in DSMC.
A rovibrationally state-specific collision model for the O2(Σg-3)+O(P3) system is presented for direct simulation Monte Carlo, including rotation-vibration-translation energy transfer, exchange, dissociation, and recombination processes. The two-step binary collision approach is employed to model recombination reactions. Two available cross section databases by Andrienko/Boyd and Esposito/Capitelli are employed for the rovibrationally resolved model (rv-STS) and vibrationally resolved model (v-STS), respectively. The difference between rv-STS and v-STS comes from two contributions: the multisurface factor of dissociation (fMS) and the rotational averaging process. The dissociation cross section with the constant fMS is typically larger than with the variable fMS, especially for the low vibrational energy states. On the other hand, the cross sections resulting from the rotationally averaged database are found to underpredict the dissociation rate coefficient at low temperatures. In the rovibrational heating case, the rv-STS predicts faster relaxation than the v-STS, which also shows a lower quasi-steady-state temperature than v-STS. In the rovibrational cooling case, the rv-STS shows a faster relaxation than v-STS, which also presents a thermal non-equilibrium between rovibrational and translational mode during the cooling process.


Physical Origins of Codon Positions That Strongly Influence Cotranslational Folding: A Framework for Controlling Nascent-Protein Folding.
An emerging paradigm in the field of in vivo protein biophysics is that nascent-protein behavior is a type of nonequilibrium phenomenon, where translation-elongation kinetics can be more important in determining nascent-protein behavior than the thermodynamic properties of the protein. Synonymous codon substitutions, which change the translation rate at select codon positions along a transcript, have been shown to alter cotranslational protein folding, suggesting that evolution may have shaped synonymous codon usage in the genomes of organisms in part to increase the amount of folded and functional nascent protein. Here, we develop a Monte Carlo-master-equation method that allows for the control of nascent-chain folding during translation through the rational design of mRNA sequences to guide the cotranslational folding process. We test this framework using coarse-grained molecular dynamics simulations and find it provides optimal mRNA sequences to control the simulated, cotranslational folding of a protein in a user-prescribed manner. With this approach we discover that some codon positions in a transcript can have a much greater impact on nascent-protein folding than others because they tend to be positions where the nascent chain populates states that are far from equilibrium, as well as being dependent on a complex ratio of time scales. As a consequence, different cotranslational profiles of the same protein can have different critical codon positions and different numbers of synonymous mRNA sequences that encode for them. These findings explain that there is a fundamental connection between the nonequilibrium nature of cotranslational processes, nascent-protein behavior, and synonymous codon usage.


Polyelectrolyte Translocation through a Tortuous Nanopore.
Although nanopores have shown tremendous promise for use in DNA sequencing, the rate of translocation through most pores studied previously is too rapid for the genetic information to be read accurately. In this study, dissipative particle dynamics simulations were employed to investigate the feasibility of using tortuous nanopores to control the rate of polyelectrolyte translocation. Unlike many previous studies, our simulation method incorporates the effects of hydrodynamic and electrostatic interactions and the spatial variation of electric field strength. The average translocation time, ⟨τ⟩, increases with the pore length and tortuosity but decreases as the pore width increases. For the longest pore investigated, the introduction of tortuosity results in ⟨τ⟩ increasing by as much as 187% as compared to a straight pore. The temporal variation of bond tension indicates that slower translocation in tortuous nanopores is caused by inhibition of tension propagation.


Decentralized collection of iodinated x-ray contrast media in hospitals-results of the feasibility study and the practice test phase.
Iodinated x-ray contrast media are unmetabolized and almost completely with the urine in 24 hours emitted in the wastewater after their application by human being. These very polar, hydrophilic and hardly biodegradable substances have already been detected in the water cycle. The objective of this R&D project is the collection of the x-ray contrast media already at the source in the hospital and so the avoidance of an emission in the water cycle. Three concepts have been developed in the scope of this R&D project: a centralized collection concept with a no-mix toilet in the radiology unit, a decentralized collection concept featuring a no-mix toilet for every of the ward and another decentralized collection concept with mobile urine containers for the wards. The evaluation of the collection concepts has taken systematically into consideration costs, acceptance and a value benefit analysis. The feasibility study has shown that a separated collection of iodinated x-ray contrast media in hospitals is possible through the implementation of a decentralized urine collection concept using mobile urine containers. This decentralised collection concept was tested in each case on one main focus ward of two representative German hospitals for 20 weeks. In both wards of the hospitals around 60% of patients with an examination of x-ray contrast media took part in the voluntary urine collection. The AOX arose from the iodinated x-ray contrast media in the collected urine. The averaged measured AOI concentration in the patient's urine was 18 g/l. The total costs, formed by the costs for staff, material and disposal, were estimated at 10 euro per patient, 7 euro per litre urine and approximate 380 euro per kilogramme iodine for the separated urine collection in hospitals. The main part of the total costs is formed by the costs for staff with around 80%. This R&D project has shown that the separated collection of the patients' urine with a simple and decentralised collection concept with mobile urine containers in hospitals can be carried out hygienically and safely. A transfer of this decentralised collection concept to pharmaceuticals which are excreted with urine is possible.


Laboratory diagnosis of thrombophilic states: where do we stand?
Until recently the laboratory diagnosis of thrombophilia consisted on investigation of the plasmatic anticoagulant pathways and the search for dysfibrinogenemia and antiphospholipid antibodies/lupus anticoagulants. More recently, the laboratory investigation has been expanded by including activated protein C (APC) resistance, due or not to the presence of the factor V Leiden mutation; hyperprothrombinemia, due to the presence of the prothrombin mutation G20210A and hyperhomocysteinemia, due to impairment of the relevant metabolic pathway because of enzymatic and/or vitamin deficiency. Testing for thrombophilia may be useful for many reasons. First, the results of testing may provide valuable information to assess the risk of recurrence in the proband. Second, testing family members is useful for prophylactic and diagnostic purposes. Third, the identification of patients bearing combined defect helps to identify those at increased risk for thrombosis. Testing is recommended for patients with a past history of thrombosis and should be extended to their first-degree family members. Since most of the tests are not reliable during anticoagulation, it is preferable to postpone laboratory testing until after discontinuation of the treatment. Whenever possible testing should be performed by means of functional assays. DNA analysis is required for the prothrombin mutation G20210A. Laboratory diagnosis for antiphospholipid antibodies/lupus anticoagulant should be performed by a combination of tests including phospholipid-dependent clotting assays and solid phase anticardiolipin antibodies. Hyperhomocysteinemia may be assessed by high-pressure liquid chromatography methods, or by fluorescence polarization immunoassays.


Antineuronal antibodies in neuropsychiatric systemic lupus erythematosus.
The diagnosis of neuropsychiatric systemic lupus erythematosus (NP-SLE) is clinical and one of exclusion. Brain cross-reactive lymphocytotoxins or neuronal antibodies have been proposed as a mechanism underlying NP-SLE. We assessed the clinical relevance of neuronal cell binding antibodies using a standardized clinical definition of NP-SLE. Serum from 54 SLE patients and 77 controls were tested for binding to 3 neuroblastoma and 3 glioblastoma cell lines. Thirty-three SLE patients (61%) fulfilled clinical criteria for the diagnosis of NP-SLE; of these, 55% had serum binding activity to both neuroblastoma and glioblastoma cell lines, compared with 33% of the other SLE patients. When reactivity to neuroblastoma cell lines only was assessed, 43% of NP-SLE patient sera demonstrated binding activity, versus 14% of sera from the remaining SLE patients. Control subjects' reactivity to neuroblastoma cell lines was positive in 12% of sera. Analysis of serum reactivity using non-neuronal cell lines revealed that neuroblastoma, but not glioblastoma, cell binding was specific. NP-SLE patients with evidence of diffuse symptomatology had a higher mean titer of neuroblastoma cell line binding than those with focal symptomatology. Using a panel of substrates, one can identify a significant proportion of patients who are independently defined as having NP-SLE, who demonstrate specific serum neuronal antibodies.


Anosognosia for amnesia as a clue to understand the nature of dementia.
Dementia is a clinical syndrome characterized by a loss of intelligence once possessed by an individual. Clinically intelligence can be defined as an ability of an individual to get involved in social life as a responsible and independent member by employing his/her own cognitive resources in the most effective way. This ability has been attributed either to a unique faculty called g-factor or to the sum of several slave mental faculties such as memory, language, spatio-manual capacity and so on. Dementia is thus thought to be caused either by a loss of g-factor, or by the simultaneous loss of two or three slave faculties. Based on a long term observation of a couple of cases of senile degenerative dementia and many cases of Korsakoff amnesic syndrome, the author refutes both interpretation and proposes a qualitatively different hypothesis that senile degenerative dementia is a manifestation of the disorganization of the structure of consciousness, one of whose function is to bring up the stored mental contents to the state of awareness and make them available to the conscious manipulation. In degenerative dementia, slowly progressive dissolution of the structure of consciousness causes the breakdown of the integrity of social activity as well as personality. It is hard to confirm whether the mental resources themselves are destroyed or not in this process.


Noise-induced hearing loss and symphony orchestra musicians: risk factors, effects, and management.
Although industrial and recreational noise have been recognized as potential causes of noise-induced hearing loss for quite some time, it is only recently that the sound levels within a symphony orchestra have been implicated as possible sources of harmful noise levels. Many studies have concluded that not only are dangerous levels of noise present within the symphony orchestra, but there is evidence of noise-induced hearing loss among symphony orchestra musicians. Although hearing protection designed for industrial use may not be appropriate for the special listening needs of professional musicians, recent advances in hearing protection design have made hearing protection practical for this population. Suggestions are made for monitoring and protecting the professional ear.


A comprehensive evaluation of rhythm monitoring strategies for the detection of atrial fibrillation recurrence: insights from 647 continuously monitored patients and implications for monitoring after therapeutic interventions.
Intermittent rhythm monitoring (IRM) to detect atrial fibrillation (AF) recurrence is employed to evaluate the success of therapeutic interventions. In a large population of patients with continuous monitoring (CM), we investigated the sensitivity of various frequencies and durations of IRM strategies on the detection of AF recurrence, the dynamics behind AF recurrence detection, and we describe measures to evaluate temporal AF recurrence. Rhythm histories of 647 patients (mean AF burden, 0.12±0.22; median, 0.014; 687 patient-years) with implantable CM devices were reconstructed and analyzed. With the use of computationally intensive simulation, the sensitivity of IRM of various frequencies and durations on the identification of AF recurrence was evaluated. Prolonged-duration IRM was superior to shorter IRM (P<0.0001). However, even with aggressive IRM strategies, AF recurrence was not detected in a great proportion of patients. The temporal AF burden aggregation (AF density) was directly related to IRM sensitivity (P<0.0001). Even at similar AF burdens, patients with high-density AF required higher-frequency or prolonged-duration IRM to achieve the same sensitivity as in low-density AF (P<0.0001). Patients with high-density, low-burden AF benefit the most from CM for detection of AF recurrence. IRM follow-up is significantly inferior to CM. IRM strategies will not identify AF recurrence in a great proportion of patients at risk. Temporal AF characteristics play a significant role in AF recurrence detection with the use of IRM. For the scientific, evidence-based evaluation of AF treatments, CM should be strongly recommended. Prospective studies are required to evaluate whether CM to guide clinical management can also improve patient outcomes. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00806689.


Water diffusion, T(2), and compartmentation in frog sciatic nerve.
A potential relationship between structural compartments in neural tissue and NMR parameters may increase the specificity of MRI in diagnosing diseases. Nevertheless, our understanding of MR of nerves and white matter is limited, particularly the influence of various water compartments on the MR signal is not known. In this study, components of the (1)H transverse relaxation decay curve in frog peripheral nerve were correlated with the diffusion characteristics of the water in the nerve. Three T(2) values were identified with nerve. Water mobility was found to be unrestricted on the timescale of 100 msec in the component of the signal with the intermediate T(2) time, suggesting some contribution from the interstitial space to this T(2) component. Restricted diffusion was observed in the component with the longest T(2) time, supporting the assignment of at least part of the spins contributing to this component to an intracellular compartment. The observed nonexponential behavior of the diffusion attenuation curves was investigated and shown to be potentially caused by the wide range of axon sizes in the nerve. Magn Reson Med 42:911-918, 1999.


Improvement in the quality of frozen dough for fried flour products by electrostatic field-assisted freezing.
With the development of the food industry, frozen dough technology has gradually become an indispensable part of dough processing but its quality is often reduced due to freezing during the production process. Electrostatic field-assisted freezing (EF) technology, a key research project in recent years, reduces the physical damage to food materials by reducing or changing the size of ice crystals in frozen products. In this study, different intensities of electrostatic fields were used to assist in the repeated freezing and thawing of dough. The effects of electrostatic fields on the freezing nucleation process were evaluated by measuring dough freezing curves, low field nuclear magnetic resonance, and melting enthalpy. It was found that the freezing time of frozen dough added with electrostatic field-assisted freezing processing was shortened, the rate at which hardness, viscosity, and elasticity decreased was reduced, and the indicators of water distribution and protein secondary structure components were closer to those of fresh dough. This experiment used electrostatic field-assisted freezing to reduce the damage to the dough structure during the freezing process, improve the quality of frozen dough and fried products, and improve the freezing efficiency of frozen dough. It provides a new idea for the study of frozen dough. © 2023 Society of Chemical Industry.


Ontological Foundations for Tracking Data Quality through the Internet of Things.
Amongst the positive outcomes expected from the Internet of Things for Health are longitudinal patient records that are more complete and less erroneous by complementing manual data entry with automatic data feeds from sensors. Unfortunately, devices are fallible too. Quality control procedures such as inspection, testing and maintenance can prevent devices from producing errors. The additional approach envisioned here is to establish constant data quality monitoring through analytics procedures on patient data that exploit not only the ontological principles ascribed to patients and their bodily features, but also to observation and measurement processes in which devices and patients participate, including the, perhaps erroneous, representations that are generated. Using existing realism-based ontologies, we propose a set of categories that analytics procedures should be able to reason with and highlight the importance of unique identification of not only patients, caregivers and devices, but of everything involved in those measurements. This approach supports the thesis that the majority of what tends to be viewed as 'metadata' are actually data about first-order entities.


Challenges faced by informal caregivers of hospice patients in Uganda.
Serious illness can cause economic devastation for families. Locally run patient day care programs, or programs for training caregivers for future caregiving employment, could provide a measure of economic resilience. We sought to gather pilot data on the circumstances of informal caregivers and the desirability of such programs. In a convenience sample of patients' informal caregivers (ICs) visiting Hospice Africa Uganda in January 2006, face-to-face, survey interviews in local languages were conducted by hospice volunteers. Sixty-two surveys were completed. Eighty-seven percent of ICs were family members. Frequent needs reported by ICs were financial assistance (89%), free medications (77%), opportunities for income (52%), and caregiver training (44%). Caring for a terminally ill family member pressured ICs to stop attending school (51%), marry (32%), take embarrassing jobs (47%), or take jobs with health risks (42%). If a local day care center existed, 94% of respondents stated they would use it; 80% reported they would consider hiring a caregiver. Barriers to hiring a caregiver included costs (98%), patient preference (54%), and discomfort with a nonrelative caregiver (42%). Importantly, 96% reported interest in becoming a trained and certified caregiver. A minority of respondents felt that paid caregiving would go against their cultural traditions. Most ICs in this survey faced financial and personal hardships. A large majority reported that they would use day care or hired home care for their patients if it existed, and also reported interest in becoming certified, paid caregivers. These data suggest that an economic resilience option for families based on IC training in palliative care might work at Hospice Africa Uganda.


Zebrafish GSDMEb Cleavage-Gated Pyroptosis Drives Septic Acute Kidney Injury In Vivo.
The bacteria LPS is one of the leading endotoxins responsible for sepsis; its sensing pathway-induced pyroptosis plays an important role in innate immunity. However, excessive pyroptosis might cause immunological diseases, even multiple organ failure and death by undefined mechanisms. Given that the development of acute kidney injury (AKI) in patients with sepsis causes significant morbidity and mortality, the mechanism of pyroptosis in regulating septic AKI remains unknown. In this study, we establish a zebrafish crispant in vivo analysis model and reveal that both caspy2 and gasdermin Eb (GSDMEb) contribute to lethal LPS-induced septic shock. Meanwhile, the in vitro analysis reveals that caspy2 activation can specifically cleave GSDMEb to release its N terminus to mediate pyroptosis, which functions as GSDMD in mammals. Interestingly, we establish an in vivo propidium iodide-staining method and reveal that the caspy2-GSDMEb signaling cascade is essential for enhancing renal tubular damage during lethal LPS-induced septic shock, whereas administration of the zebrafish-specific GSDMEb-derived peptide inhibitor Ac-FEID-CMK can attenuate mortality and septic AKI in vivo. Moreover, we confirm that either caspase-11 or GSDMD deficiency decreases both inflammatory cytokines and kidney dysfunction enzyme release and prolongs survival in a murine model of septic shock. Taken together, these findings demonstrate an evolutionary executor for pyroptosis in zebrafish and reveal that the pyroptosis of renal tubular cells is a major cause of septic AKI, and also provide an ideal in vivo screening model for potential antisepsis therapeutic strategies.


Distinct gene expression profiles between primary breast cancers and brain metastases from pair-matched samples.
Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.


Modulation of insulin secretion by pancreatic ganglionic nicotinic receptors.
Autonomic ganglia may be regulated, in part, by nicotinic receptors. To test whether basal insulin secretion may be modulated by an endogenous pancreatic ganglionic mechanism, the effects of ganglionic pre- and postsynaptic nicotinic receptor antagonism were studied in the in vitro canine pancreas. Combined infusion of atropine, phentolamine, and propranolol had no affect on insulin secretion (P less than .30). Presynaptic nicotinic receptor blockade by beta-bungarotoxin (beta-BuTX) in combination with atropine and phentolamine reduced mean insulin secretion (78 +/- 18 U/ml, P less than .0025) from preinfusion concentrations (287 +/- 43 U/ml). The decrease in insulin secretion resulting from BuTX, atropine, and phentolamine was prevented by the addition of either specific postsynaptic nicotinic receptor blockade by alpha-bungarotoxin (P less than .05) or propranolol (P less than .005). Because it is known that postsynaptic nicotinic receptor agonism may stimulate the intraganglionic release of norepinephrine, these results suggest that nicotinic receptors are present at the ganglionic level in the pancreas and modulate insulin secretion by a complex intraganglionic mechanism. The postulated ganglionic nicotinic receptor-mediated mechanism may operate by the interaction of a beta-adrenergic inhibitory component, which may be activated by intraganglionic norepinephrine, and a stimulatory nonmuscarinic nonadrenergic (possibly peptidergic) component, which may be activated in the absence of intraganglionic norepinephrine.


Dental caries.
Dental caries is a biofilm-mediated, sugar-driven, multifactorial, dynamic disease that results in the phasic demineralization and remineralization of dental hard tissues. Caries can occur throughout life, both in primary and permanent dentitions, and can damage the tooth crown and, in later life, exposed root surfaces. The balance between pathological and protective factors influences the initiation and progression of caries. This interplay between factors underpins the classification of individuals and groups into caries risk categories, allowing an increasingly tailored approach to care. Dental caries is an unevenly distributed, preventable disease with considerable economic and quality-of-life burdens. The daily use of fluoride toothpaste is seen as the main reason for the overall decline of caries worldwide over recent decades. This Primer aims to provide a global overview of caries, acknowledging the historical era dominated by restoration of tooth decay by surgical means, but focuses on current, progressive and more holistic long-term, patient-centred, tooth-preserving preventive care.


reduced ocelli encodes the leucine rich repeat protein Pray For Elves in Drosophila melanogaster.
The ocelli are three simple photoreceptors on the vertex of the fruit fly head. We sought to identify the gene encoded by the classical ocellar mutant, reduced ocelli (rdo). Deficiency and inversion breakpoint mapping and P-element induced male recombination analyses were performed and Pray For Elves (PFE; CG15151; Fbgn0032661) emerged as a promising candidate for the rdo phenotype. The PFE locus maps to polytene region 36E on chromosome 2L between elfless (Fbgn0032660) and Arrestin 1 (Fbgn0000120). FlyBase annotation predicts that PFE encodes a serine/threonine kinase, yet protein prediction programs revealed no kinase domain. These analyses suggest that PFE simply encodes a leucine rich repeat molecule of unknown function, but presumably functions in nervous system protein-protein interaction. Two classical spontaneous alleles of rdo, rdo(1) and rdo(2), were characterized and the underlying mutations result from a small deletion spanning exon 1/intron 1 and a B104/roo insertion into the 3'UTR of PFE, respectively. Transposase-mediated excisions of several P-elements inserted into the PFE locus revert the rdo phenotype and a full-length PFE cDNA is sufficient to rescue rdo. A Gal4 enhancer trap reveals a broad adult neural expression pattern for PFE. Our identification and initial characterization of the rdo locus will contribute to the understanding of neurogenesis and neural development in the simple photoreceptors of the Drosophila visual system.


Assignment of epidemiological lineages in an emerging pandemic using the pangolin tool.
The response of the global virus genomics community to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been unprecedented, with significant advances made towards the 'real-time' generation and sharing of SARS-CoV-2 genomic data. The rapid growth in virus genome data production has necessitated the development of new analytical methods that can deal with orders of magnitude of more genomes than previously available. Here, we present and describe Phylogenetic Assignment of Named Global Outbreak Lineages (pangolin), a computational tool that has been developed to assign the most likely lineage to a given SARS-CoV-2 genome sequence according to the Pango dynamic lineage nomenclature scheme. To date, nearly two million virus genomes have been submitted to the web-application implementation of pangolin, which has facilitated the SARS-CoV-2 genomic epidemiology and provided researchers with access to actionable information about the pandemic's transmission lineages.


Cognition-emotion interaction as a predictor of adolescent depressive symptoms.
Given the sharp increase in rates of depression during adolescence, especially in girls, it is important to identify which youth are at greatest risk across this critical developmental transition. During the present research, we examined whether (a) individual differences in cognition-emotion interaction, as reflected in cognitive control (CC) deficits and trait negative emotionality (NE), predict depression levels across a 1-year period (sixth-seventh grades); and (b) these temperamental traits create a particularly strong risk in girls. Youth (338 girls, 298 boys; M age in 6th grade = 11.96, SD = .37) reported on their trait NE and depressive symptoms; teachers reported on CC deficits. As hypothesized, compromised CC predicted subsequent depressive symptoms in girls with high, but not average or low, trait NE. This research informs efforts to identify which adolescents are at heightened risk for depression during the adolescent transition and points to possible candidates for early intervention. (PsycINFO Database Record


Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older multimorbid community-dwellers: Results from the ilSIRENTE study.
The C-terminal agrin fragment (CAF), a circulating byproduct of neuromuscular junction disassembly, has been proposed as a possible biomarker for sarcopenia. However, its validity in "real-world", multimorbid older persons is currently unknown. The present study was undertaken to verify if serum CAF levels were associated with sarcopenia in a population of old and very old persons living in the community. Data were from the ilSIRENTE Aging and Longevity Study, a prospective cohort study conducted in all persons aged 80years and older residing in the Sirente geographic area (Italy; n=332). The identification of sarcopenia was based on the criteria elaborated by the European Working Group on Sarcopenia in Older People (EWGSOP). Serum levels of CAF were determined using a commercial ELISA kit. Sarcopenia was identified in 101 participants (30.8%). Serum levels of CAF were significantly higher in older adults with sarcopenia compared with non-sarcopenic participants (96.99±5.40pmol/L vs. 76.54±2.15pmol/L; p<0.001). The association remained significant in both genders after adjustment for several possible confounding factors, including age, cognition, disability status, body mass index, congestive heart failure, lung diseases, diabetes, renal failure, and plasma levels of C-reactive protein and interleukin 6. Our results obtained from a fairly large sample of old and very old, multimorbid community-dwellers show that elevated serum CAF levels are associated with sarcopenia, independent of age, gender and several clinical, functional, anthropometric, and biochemical variables. The determination of serum CAF concentration may therefore be proposed as a simple screening test for sarcopenia in the community.


Hospital clonal dissemination of Enterobacter aerogenes producing carbapenemase KPC-2 in a Chinese teaching hospital.
Carbapenems are first-line agents for the treatment of serious nosocomial infections caused by multidrug-resistant Enterobacteriaceae. However, resistance to carbapenems has increased dramatically among Enterobacteriaceae in our hospital. In this study, we report clonal dissemination caused by carbapenem-resistant Enterobacter aerogenes (CREA). In 2011, CREA was identified from 12 patients admitted to the neurosurgical ward. All 12 clinical isolates were non-susceptible to cefotaxime, ceftazidime, cefoxitin, ertapenem, imipenem or meropenem. All isolates carried the gene encoding Klebsiella pneumoniae carbapenemase-2 (KPC-2), except for the isolate E4. However, a remarkably lower expression level of the porin OmpF was detected in the non-KPC-2-producing isolate E4 on SDS-PAGE compared with the carbapenem-susceptible isolate. Epidemiological and molecular investigations showed that a single E. aerogenes strain (PFGE type A), including seven KPC-2-producing clinical isolates, was primarily responsible for the first isolation and subsequent dissemination. In a case-control study, we identified risk factors for infection/colonization with CREA. Mechanical ventilation, the changing of sickbeds and previous use of broad-spectrum antibiotics were identified as potential risk factors. Our findings suggest that further studies should focus on judicious use of available antibiotics, implementation of active antibiotic resistance surveillance and strict implementation of infection-control measures to avoid the rapid spread or clonal dissemination caused by carbapenem-resistant Enterobacteriaceae in healthcare facilities.


Influence of all-trans retinoic acid on sperm metabolism and oxidative stress: Its involvement in the physiopathology of varicocele-associated male infertility.
The mechanisms by which varicocele affects fertility remain undetermined. Vitamin A (all-trans retinoic acid [ATRA]) is required for fertility and normal spermatogenesis; however, the mechanisms driving its action are not defined yet. Previously, we demonstrated in varicocele sperm a reduced RARα expression and that ATRA influence sperm performance. To further define vitamin A significance in male gamete and in the physiopathology of varicocele, we tested for the first time ATRA action on human sperm metabolism and antioxidant defense systems. Evaluating triglycerides content and lipase activity, in normal sperm ATRA had a lipid lowering effect, which was not observed in varicocele sperm. The modulation of the glucose-6-phosphate dehydrogenase activity, concomitantly with a reduction of the glucose content, highlight an ATRA role on glucose metabolism. ATRA induced the superoxide dismutase (SOD) and glutathione transferase activities, while it reduced the malondialdehyde and reactive oxygen species (ROS) production both in healthy and varicocele sperm. Interestingly, SOD1 and SOD2 have been localized in the acrosome and midpiece, glutathione- S-transferase omega 2 (GSTO2) in the acrosome, equatorial, and subacrosomial regions. SOD1, SOD2, and GSTO2 levels were significantly lower in varicocele with respect to healthy sperm. Herein, we discovered that ATRA treatment was able to reprogram sperm metabolism toward that of the capacitation status. The retinol protected human sperm from ROS damage enhancing the antioxidant enzymes activity, providing evidence toward the efficacy of vitamin A as therapeutic tool in improving sperm quality. These novel findings further confirm the importance of vitamin A in male fertility adding new insights into the retinoids complex biological framework.


LncRNA DANCR Promotes Sorafenib Resistance via Activation of IL-6/STAT3 Signaling in Hepatocellular Carcinoma Cells.
Hepatocellular carcinoma (HCC) is one of the major malignancies and the second most common cause of cancer-related death worldwide. Sorafenib, an approved first-line systematic treatment agent for HCC, is capable to effectively improve the survival of patients with advanced HCC. The long-noncoding RNA (lncRNA) differentiation antagonizing non-protein coding RNA (DANCR) has been reported to exert oncogenic functions in several kinds of human cancers. However, the role of lncRNA DANCR in sorafenib resistance in HCC remains unknown. The expression levels of DANCR in HCC tissues were detected by qRT-PCR. DANCR overexpression and knockdown models were established and utilized to investigate the functional role of DANCR on sorafenib resistance in HCC cells. The MS2-binding sequences-MS2-binding protein-based RNA immunoprecipitation assay, RNA pull-down and luciferase reporter assay was used to detect the association between DANCR and PSMD10 mRNA. The activation of DANCR transcription mediated by STAT3 was assessed by luciferase reporter and chromatin immunoprecipitation assays. We found that DANCR was significantly overexpressed in HCC tissues and associated with prognosis of HCC patients. Overexpression and knockdown experiments demonstrated that DANCR promoted sorafenib resistance in HCC cells in vitro and in vivo. Mechanistically, the role of DANCR relied largely on the association with PSMD10. DANCR stabilized PSMD10 mRNA through blocking the repressing effect of several microRNAs on PSMD10. Besides, DANCR activated IL-6/STAT3 signaling via PSMD10. Furthermore, we revealed that DANCR transcription was enhanced by the activation of IL-6/STAT3 signaling, indicating a positive feedback loop of DANCR and IL-6/STAT3 signaling. Collectively, our study is the first to elucidate the mechanism of DANCR-mediated sorafenib resistance via PSMD10-IL-6/STAT3 signaling axis, which provides a promising target for developing new therapeutic strategy for sorafenib tolerance of HCC.


Polymorphisms in the methylenetetrahydrofolate reductase and methionine synthase reductase genes and homocysteine levels in Brazilian children.
Hyperhomocysteinemia is a risk factor for thrombosis, and methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms, folate, and B12 levels could contribute to plasma homocysteine (Hcy) variation. Although well established in adults, few studies have been performed in childhood. In this study, we investigated association of polymorphisms C677T and A1298C in the MTHFR gene and A66G in the MTRR gene with Hcy levels in children. These polymorphisms, as well as Hcy, folate, and vitamin B12 levels were investigated in 220 normal children with ages ranging from 1 to 8 years. Plasma Hcy, folate, and vitamin B12 levels were normal in all children. None of the polymorphisms could be considered an independent risk factor for hyperhomocysteinemia during childhood. The median Hcy levels in 37 children (17%) doubly heterozygous for C677T and A1298C mutations in the MTHFR gene were not different from the other genotypes. However, the association of the different genotypes with Hcy, folate, and vitamin B12 levels demonstrated significant P-values. The folate levels demonstrated a statistically significant decrease (P = 0.0477) from the C677T mutation in the MTHFR gene (TT genotype) when compared to the other groups. Folate was the only independent risk factor for hyperhomocysteinemia. Thus, monitoring the concentrations of folate would be more helpful for evaluating hyperhomocysteinemia and for preventing cardiovascular disease.