A 10-year retrospective analysis of Toxoplasma gondii qPCR screening in allogeneic hematopoietic stem cell transplantation recipients.
Weekly blood Toxoplasma gondii DNA screening using real-time quantitative polymerase chain reaction (qPCR) has been implemented in all allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients at our hospital. We retrospectively analyzed the consequences of a positive blood qPCR in the management of Toxoplasma infection (TI) and disease (TD).From 2011 to 2020, 52 (4.13%) of 1 257 alloHSCT recipients had at least one positive qPCR, 45 (3.5%) with TI and seven (0.56%) with TD (central nervous system involvement). Forty-four patients were qPCR-positive before day 100, 30 without and 14 with anti-Toxoplasma prophylaxis. Twenty-five of them (56.8%) started or continued prophylactic dosage treatment: all became qPCR-negative, including 20 (80%) receiving only prophylactic dosage treatment. Twenty-four of them (54.5%) received non-prophylactic dosage treatment: qPCR became negative in 22/24 (91.7%), while TI contributed to death in two cases. Six of the eight patients diagnosed after D100 had breakthrough TI or TD. No death was attributable to TI or TD. qPCR kinetics available for 24 patients increased until anti-Toxoplasma treatment began, then decreased with all treatment regimens.Clinical follow-up and qPCR monitoring with quantification of the parasitic load appears a reasonable strategy to avoid TD and to use minimal effective dosage of anti-Toxoplasma treatments.


Poverty and Proximate Barriers to Learning: Vision Deficiencies, Vision Correction and Educational Outcomes in Rural Northwest China.
Uncorrected vision may present a significant barrier to educational mobility in poor communities in low and middle income countries. Focusing on the case of rural Northwest China, we analyze the Gansu Survey of Children and Families (2,000 children; 100 rural villages) and the Gansu Vision Intervention Project (a randomized trial; 19,185 students, 165 schools, two counties). Four main findings emerge: significant unmet need for vision correction; socioeconomic gradients in vision correction; somewhat greater vulnerability to vision problems among higher socioeconomic status and more academically engaged children; and significant favorable effects of vision correction on math and literacy performance and class failure.


De Novo Aneurysm Associated with Superficial Temporal Artery to Middle Cerebral Artery Bypass: Report of Two Cases and Review of Literature.
De novo aneurysm formation has been reported as a rare complication of superficial temporal artery (STA) to middle cerebral artery (MCA) bypass surgery. The first patient with intracerebral hemorrhage had a ruptured de novo aneurysm arising from the recipient MCA at 6 years after undergoing STA-MCA bypass for hemispheric hemodynamic insufficiency. In the second case, an enlarging unruptured STA aneurysm was detected by follow-up magnetic resonance angiography at 8 years after the patient underwent STA-MCA bypass for moyamoya disease. Both patients were successfully treated by surgical clipping. Persistent hemodynamic stress with hypertension in an artificial T-shaped vasculature and traumatic injury during surgical manipulation are the most important causes for de novo aneurysms after STA-MCA bypass. Follow-up magnetic resonance and computed tomography angiography examinations, along with appropriate blood pressure control, are recommended for patients who have undergone STA-MCA bypass surgery.


Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses.
Cyclin-dependent kinase 5 (Cdk5) is involved in proper neurodevelopment and brain function and serves as a switch between neuronal survival and death. Overactivation of Cdk5 is associated with many neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. It is believed that in those diseases Cdk5 may be an important link between disease-initiating factors and cell death effectors. A common hallmark of neurodegenerative disorders is incorrect folding of specific proteins, thus leading to their intra- and extracellular accumulation in the nervous system. Abnormal Cdk5 signaling contributes to dysfunction of individual proteins and has a substantial role in either direct or indirect interactions of proteins common to, and critical in, different neurodegenerative diseases. While the roles of Cdk5 in α-synuclein (ASN) - tau or β-amyloid peptide (Aβ) - tau interactions are well documented, its contribution to many other pertinent interactions, such as that of ASN with Aβ, or interactions of the Aβ - ASN - tau triad with prion proteins, did not get beyond plausible hypotheses and remains to be proven. Understanding of the exact position of Cdk5 in the deleterious feed-forward loop critical for development and progression of neurodegenerative diseases may help designing successful therapeutic strategies of several fatal neurodegenerative diseases. Cyclin-dependent kinase 5 (Cdk5) is associated with many neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. It is believed that in those diseases Cdk5 may be an important factor involved in protein misfolding, toxicity and interaction. We suggest that Cdk5 may contribute to the vicious circle of neurotoxic events involved in the pathogenesis of different neurodegenerative diseases.


Analysis of expression and comparative profile of normal placental tissue proteins and those in preeclampsia patients using proteomic approaches.
Preeclampsia (PE) is a complex and serious condition of pregnancy. Trophoblasts in human placenta can be separated and collected by laser capture micro-dissection (LCM). Protein in trophoblasts have been extracted and separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), finally 962 unique proteins are identified by liquid chromatography coupled to mass spectrometry (LC-MS/MS). Comparison of differential expressed proteins in normal and those in PE are investigated. Two-dimensional electrophoresis (2DE) and MS were used to identify differential expressed proteins. 13 differential expressed proteins include signal transduction protein, molecular chaperone, cell skeleton proteins are identified, in which 3 proteins are down-regulated and 10 proteins are up-regulated. They might be correlated with the cause of PE.


Comparison of angiographic findings among postmenopausal women using unopposed estrogen, estrogen/progestin combinations, and nonusers.
Studies of the effects of menopausal hormone therapy on coronary artery disease (CAD) in postmenopausal women have provided contradictory results. Although recent experimental studies have revealed no beneficial effect of combination therapy with estrogen (E) and progesterone (P), the effect of monotherapy with E remains unknown. We retrospectively examined the medical records of 843 consecutive women aged > or =55 years who underwent their first cardiac catheterization between January 1996 and December 1998. We compared the presence and severity of CAD, defined as > or =1 diseased coronary vessel (with stenosis > or =50%), in women who only took E, E+P, or no menopausal hormone therapy. In all, 210 women (33%) took hormones, of whom 47 (22%) used E+P and 163 (78%) used E only. Women who used any hormones tended to be healthier than nonusers, but E+P users had a lower prevalence of risk factors and co-morbidities than E users. In unadjusted analyses, both the E and E+P groups were significantly less likely to have CAD than nonusers (relative risk [RR] 0.71, 95% confidence interval [CI] 0.58 to 0.84 for the E group; RR 0.76, 95% CI 0.54 to 0.99 for the E+P group). Demographic factors, CAD risk factors, co-morbidities, and primary prevention medication use explained the association between E+P and the presence of CAD (RR 1.14, 95% CI 0.74 to 1.39). In contrast, adjustment for these factors had a minimal effect on the association between E and CAD compared with nonusers (RR 0.79, 95% CI 0.59 to 0.98). Thus, the apparent protective effect of combination menopausal hormone therapy with E+P on CAD is due to differences in other patient characteristics. In contrast, unopposed E therapy may have a protective effect on CAD.


Occult breast carcinoma--use of color Doppler in localization.
Occult breast carcinoma presenting with axillary metastases is a difficult clinical problem. Mammography is recommended as the diagnostic tool for detecting breast masses, but is very insensitive. In two consecutive patients with nonpalpable carcinoma of the breast, the detection of breast lesions was made by color Doppler sonography. The sensitivity of the technique makes it a useful diagnostic aid in patients with negative mammograms.


Prolactin secretion in posterior pituitary lobectomized rats: differential effects of 5-hydroxytryptophan and ether.
The objective of this study was to determine whether the posterior pituitary mediates the prolactin (PRL) releasing activities of serotonin and ether. Ovariectomized (OVEX) rats were subjected to posterior pituitary lobectomy (LOBEX) or sham surgery (SHAM). Either 1 or 12 days after surgery, rats were injected i.v. with 20 mg/kg b. wt. of 5-hydroxytryptophan (5-HTP), which is a precursor of serotonin. A second group of rats was exposed to ether vapors for 10 min. Blood was collected from a jugular cannula before and after the treatments and analyzed for PRL. On either 1 or 12 days after surgery, injection of 5-HTP increased plasma PRL levels 5-10 fold in both LOBEX and SHAM rats. This was followed by a decline to preinjection levels within 60-90 min. LOBEX and SHAM male rats which were injected i.p. with 50 mg/kg b. wt. of 5-HTP, also showed marked and similar elevations of plasma PRL levels 12 days after surgery. Exposure of OVEX rats to ether elicited a 2-3 fold rise in plasma PRL levels only on day 1, but not on day 12, after LOBEX. The ether-induced rise in PRL was similar in SHAM rats tested on both days. These results indicate that the 5-HTP-induced rise in plasma PRL levels is independent of the posterior pituitary, regardless of the sex, the route of drug administration or the length of time after surgery. In contrast, the PRL response to ether stress is diminished within 12 days after LOBEX. The evidence that the PRL responses to 5-HTP and to ether might be mediated via different neuronal mechanisms is discussed.


The role of extracorporeal membrane oxygenation in adult kidney transplant patients: A qualitative systematic review of literature.
A paucity of evidence exists regarding the risks and benefits of Extracorporeal Membrane Oxygenation (ECMO) in adult kidney transplantation. This was a systematic review conducted from Jan 1, 2000 to April 24, 2020 of adult kidney transplant recipients (pre- or post- transplant) and donors who underwent veno-arterial or veno-venous ECMO cannulation. Death and graft function were the primary outcomes, with complications as secondary outcomes. Twenty-three articles were identified that fit inclusion criteria. 461 donors were placed on ECMO, with an overall recipient 12-month mortality rate of 1.3% and a complication rate of 61.5%, the majority of which was delayed graft function. Fourteen recipients were placed on ECMO intraoperatively or postoperatively, with infection as the most common indication for ECMO. The 90-day mortality rate for recipients on ECMO was 42.9%, with multisystem organ failure and infection as the ubiquitous causes of death. 35.7% of patients experienced rejection within 6 months of decannulation, yet all were successfully treated. ECMO use in adult kidney transplantation is a useful adjunct. Recipient morbidity and mortality from donors placed on ECMO mirrors that of recipients from standard criteria donors. The morbidity and mortality of recipients placed on ECMO are also similar to other patient populations requiring ECMO.


Collection and use of autologous fetal blood.
A prospective study was completed to evaluate the feasibility of autologous fetal blood collection. Following puncture on the umbilical vein, fetal blood was drawn into sterile heparinized plastic syringes and aliquots were subjected to coagulation and culture studies. None of the blood samples exhibited significant growth of bacterial pathogens and all patients had normal coagulation studies at 24 hours of age. These data demonstrate that fetal blood can be safely collected and given to infants subjected to shock or iatrogenic blood loss.


A non-derivative method for the quantitative analysis of isosteroidal alkaloids from Fritillaria by high performance liquid chromatography combined with charged aerosol detection.
A non-derivative method was developed for the qualitative and quantitative analysis of isosteroidal alkaloids from Fritillaria thunbergii. During method development the performance of two universal detectors, the charged aerosol detector (CAD) and evaporative light scattering detector (ELSD), were evaluated. The CAD was found to be 30 to 55 times more sensitive than ELSD enabling the measurement of low levels of reference compound impurities that could not be detected by ELSD. The peak area percent of the reference compound, peimisine, obtained by CAD was 50.10%, but 91.66% by ELSD showing that CAD is suitable to estimate the presence of impurities. The CAD showed good reproducibility with overall intra- and inter-day peak area RSD values of less than 1.8% and 2.7%, respectively and had a linear dynamic range of up to 4 orders of magnitude (0.06-44mg/L) for peimine and peiminine. The optimized method was used for the quantitative analysis of peimine and peiminine from F. thunbergii.


Influence of assay conditions on ELISA determinations of anti-DNA antibodies.
The influence of assay conditions on anti-DNA determinations by an enzyme-linked immunosorbent assay (ELISA) was investigated to evaluate the detection of various DNA antigenic specificities. Among 4 monoclonal anti-DNA antibodies of MRL-lpr/lpr strain origin, 2 showed higher titers in 100 mM NaCl-50 mM Tris, pH 7.5 (Tris-NaCl) than in phosphate-buffered saline (PBS). The determination of 'polyspecificity' for these monoclonal products also depended on the set of conditions used for assay with inhibitory activity of polynucleotides differing in the 2 buffers. The buffer effects were not confined to the monoclonal antibodies as increases in anti-DNA titers were demonstrated for certain SLE patient sera when assayed in Tris-NaCl rather than PBS; sera of MRL-lpr/lpr mice showed an opposite effect, however, with enhancement of anti-DNA activity by PBS. These results suggest that the representation of antigenic sites on DNA may be variably affected by the conditions of assay, altering quantitative and qualitative assessment of this important serological marker.


Sedative and physiologic effects of low-dose intramuscular alfaxalone in dogs.
To describe the sedative and physiologic effects of two doses of alfaxalone administered intramuscularly in dogs. Randomized, blinded, crossover experimental trial. Ten adult mixed-breed dogs. Dogs were assigned randomly to be administered one of three intramuscular injections [saline 0.1 mL kg-1 (S), alfaxalone 1 mg kg-1 (A1) or alfaxalone 2 mg kg-1 (A2)] on three occasions. Heart rate (HR), respiratory rate (fR) and sedation score were assessed before injection (T0) and at 5 (T5), 10 (T10), 15 (T15), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes postinjection. Rectal temperature was determined at T0 and T60. Adverse events occurring between the time of injection and T60 were recorded. Sedation scores were higher in group A2 at T15 and T30 compared with group S. There were no additional differences between groups in sedation score. The A2 group had higher sedation scores at T15, T20 and T30 compared with T0. The A1 group had higher sedation scores at T10 and T30 compared with T0. Temperature was lower in groups A1 and A2 compared with S at T60, but was not clinically significant. There were no differences between or within groups in HR or fR. Adverse effects were observed in both A1 and A2 groups. These included ataxia (17/20), auditory hyperesthesia (5/20), visual disturbance (5/20), pacing (4/20) and tremor (3/20). While alfaxalone at 2 mg kg-1 intramuscularly resulted in greater median sedation scores compared with saline, the range was high and adverse effects frequent. Neither protocol alone can be recommended for providing sedation in healthy dogs.


Antigen-induced release of histamine from serosal mast cells, lung, and tracheal tissue: variation with tissue and rat strain in relation to serum IgE-antibody level.
Rats of the Brown Norway (BN)2, Fischer, PVG and Sprague Dawley (SD) strains were immunized intraperitoneally with graded doses of ovalbumin (OA) together with either alum or Silica gel. At specified times after immunization, in vitro histamine release from serosal mast cells and from chopped lung and tracheal tissue was determined after challenge with OA. The development of the capacity to respond in these tests seemed to vary within strain independently for mast cells, lung, and tracheal tissue with immunization dose of antigen and nature of adjuvant. These variations were not closely correlated to observed variations in serum levels of OA-IgE antibody or ratio OA-IgE to total IgE as determined by radioimmunoassay. Furthermore, variations between strains in response capacity did not correlate to inter strain variation in median serum OA-IgE antibody level. These results do not clearly conform to the possibility that one single class of IgE mediates anaphylactic reactivity of various tissues of the rat.


Association between nitric oxide synthase 3 genetic variant and acute kidney injury following pediatric cardiac surgery.
Acute kidney injury (AKI) complicates 30% to 50% of cardiac surgeries in pediatric patients. Genetic variants that affect renal blood flow and inflammation have been associated with AKI after cardiac surgery in diverse populations of adults but have not been studied in children. The objective of this study is to test the hypothesis that common candidate genetic variants are associated with AKI following pediatric cardiac surgery. This is a retrospective cohort study at a single tertiary referral children's hospital of 2,062 individual patients undergoing surgery for congenital heart disease from September 2007 to July 2020. Pre-specified variants in candidate genes (AGTR1, APOE, IL6, NOS3, and TNF) were chosen. AKI was defined using Kidney Disease: Improving Global Outcomes serum creatinine criteria in the first week following surgery. Outcomes were analyzed by univariate and multivariable analysis of demographic, clinical, and genetic factors. The study population had median age of 6 (interquartile range [IQR], 1-53) months, 759 (37%) of whom met criteria for postoperative AKI. In unadjusted analyses of each genetic variant, only NOS3 (rs2070744) was associated with lower risk for AKI (OR 0.75, 95% CI 0.62-0.9, P = .002). In logistic regression analyses adjusting for body surface area, previously identified genetic syndrome, Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) score, cardiopulmonary bypass time, and nephrotoxic medication exposure, the NOS3 variant remained protective against AKI (OR 0.7, 95% CI 0.58-0.85, P<.001). A common variant in NOS3 is associated with decreased incidence of AKI in children undergoing cardiac surgery. Further analysis of the genetic contributions to postoperative AKI may help identify individual risk in the pediatric population.


Global and Targeted miRNA Expression Profiling in Clear Cell Renal Cell Carcinoma Tissues Potentially Links miR-155-5p and miR-210-3p to both Tumorigenesis and Recurrence.
About 30% of patients undergoing nephrectomy for renal cell carcinoma (RCC) experience disease recurrence. We profiled miRNAs dysregulated in clear-cell (cc) RCC tumor tissues and predictive of recurrence. The expression levels of 800 miRNAs were assessed in paired tumor and normal tissues from a discovery cohort of 18 ccRCC patients. miRNAs found to be differentially expressed were examined in a validation set of 205 patients, using real-time quantitative PCR. Tumor-normal data from 64 patients in The Cancer Genome Atlas were used for external validation. Twenty-eight miRNAs were consistently dysregulated in tumor tissues. On dichotomized analysis, patients with high levels of miR-155-5p and miR-210-3p displayed an increased risk for ccRCC recurrence (hazard ratio, 2.64; 95% CI, 1.49 to 4.70; P = 0.0009; and hazard ratio, 1.80; 95% CI, 1.04 to 3.12; P = 0.036, respectively) and a shorter median recurrence-free survival time than did patients with low levels [P < 0.01 (log rank test)]. A risk score was generated based on the expression levels of miR-155-5p and miR-210-3p, and the trend test was significant (P = 0.005). On pathway analysis, target genes regulated by miR-155-5p and miR-210-3p were mainly enriched in inflammation-related pathways. We identified and validated multiple miRNAs dysregulated in ccRCC tissues; miR-155-5p and miR-210-3p were predictive of ccRCC recurrence, pointing to potential utility as biomarkers and underlying biological mechanisms.


Analytical comparability study of anti-CD20 monoclonal antibodies rituximab and obinutuzumab using a stability-indicating orthogonal testing protocol: Effect of structural optimization and glycoengineering.
Glycoengineering and biosimilarity are the key factors for growing, promising and progressive approaches in monoclonal antibodies development. In this study, the physicochemical stability of anti-CD20 rituximab (RTX); originator and biosimilar was compared to its glycoengineered humanized version; obinutuzumab (OBZ). An orthogonal stability-indicating protocol using a set of validated bioanalytical techniques; size exclusion high performance liquid chromatography (SE-HPLC), reversed phase liquid chromatography (RP-HPLC), quantitative gel electrophoresis by TapeStation, receptor binding assay and dynamic light scattering (DLS) was used to investigate the effect of different stress factors on the pattern and kinetics of degradation. SE-HPLC results supported with spectral purity showed similar degradation extent with a different pattern of degradation between RTX and OBZ. A lower tendency to form degraded fragments and a relatively higher favorability for degradation through aggregate formation has been revealed in case of OBZ. Results were in agreement with those of DLS and receptor binding assay which showed specificity to the intact antibodies in the presence of their degradation products. Furthermore, results were additionally confirmed through denaturing quantitative gel electrophoresis which suggested reducible covalent bonds as the mechanism for aggregates formation. RP-HPLC results showed two oxidized forms via excessive oxidation of RTX and OBZ with nearly the same degradation percent. Comparability data of RTX and OBZ using the applied methodologies showed that although glycoengineering; carried out to enhance the therapeutic and biological activity of OBZ altered the pattern of degradation but did not significantly affect the overall stability. Results showed also consistent stability profile between the biosimilar and its originator RTX products.


Localized delivery of Erlotinib using liposomal gel formulations for the treatment of oral squamous cell carcinoma.
Oral cancer accounts for more than 350,000 cases worldwide with 90% of them being oral squamous cell carcinomas (OSCC). The current treatment modalities of chemoradiation have poor outcomes along with harmful effects to neighbouring healthy tissues. The present study aimed to deliver Erlotinib (ERB), locally at the site of tumor arising in the oral cavity. ERB was encapsulated in liposomal formulations (ERB Lipo) and optimized using full factorial, 32 experimental design. The optimized batch was then coated with chitosan to obtain CS-ERB Lipo and were characterized further. Both liposomal ERB formulations had size <200 nm and PDI < 0.4. Zeta potential was upto -50 mV for ERB Lipo and upto +25 mV for CS-ERB Lipo indicating stable formulation. Liposomal formulations were freeze dried and loaded into gel to study in-vitro release and chemotherapeutic evaluation. CS-ERB Lipo showed sustained release upto 36 h from gel as compared to control formulation. In-vitro cell viability studies showed potent anti-cancer activity on KB-cells. In-vivo studies showed better pharmacological efficacy in terms of tumor volume reduction for ERB Lipo gel (49.19%) and CS-ERB Lipo gel (55.27%) as compared to plain ERB Gel (38.88%) applied locally. Histology also revealed that formulation could alleviate dysplasia condition to hyperplasia. The locoregional therapy of ERB Lipo gel and CS-ERB Lipo gel thus show promising outcome in improving pre-malignant and early-stage oral cavity cancers.


An oculo-cardiac hypothesis of sudden unexpected death in infants.
The oculo-cardiac hypothesis presented here draws attention to the evidence for links between Sudden Unexpected Death in Infants (SUD) - known in America as the Sudden Infant Death Syndrome, also as "cot death" or "crib death" - and the vagally mediated reflex slowing of the heart beat following pressure on the eye. A brief review is made of epidemiologic findings on SUD, including the fact that around 9000 infant fatalities per year are attributed to SUD in the U.S.A. alone. Evidence for excessive vagal discharge as a likely factor in SUD is discussed. The nature of the oculo-cardiac reflex discovered by Aschner is described, with particular attention to those factors which appear to make specific categories of sleeping infant more vulnerable to cardiac arrest in circumstances where this reflex is elicited. The factors include prematurity and an existing electrical instability of the heart. Regarding the manner in which such an oculo-cardiac reflex might in practice be set off, it is suggested that this could occur if the infant slept in such a position that the weight of the head could press the eye against any irregular surface which might exist on the mattress, or any object which was resting on the mattress. Evidence is cited for SUD infants being in fact more likely than controls to sleep in such a position. Children with exophthalmos would be more at risk in this respect. It is stressed that all this evidence is already published, but has not previously been drawn together to show the likelihood of a link between Sudden Dath and the oculo-cardiac reflex.


Expression of cancer stem cell markers in basal and penta-negative breast carcinomas--a study of a series of triple-negative tumors.
Breast cancer is a heterogeneous disease. Immunohistochemistry has given rise to triple-negative carcinoma (TNC). Concomitantly, biological origins of neoplasia and its heterogeneity has been strongly debated in cancer stem cells (CSC) theme. This study investigates the prevalence of basal (BCC) and penta-negative carcinomas (5NC) in TNC and establishes associations with CSC (CD44CD24). 94 TNC were tested for CK5/6, HER1, CD44 and CD24, evaluated by a simple immunohistochemistry score and correlated with clinicopathological and survival data. BCC had higher tumor grades than 5NC (p=0.004). CD44 negativity (p=0.007) and CD44(-)CD24(+) phenotype (p=0.013) were associated with less vascular invasion amongst TNC. CD44 expression was associated with BCC (p=0.007). CD44(-)CD24(-/low) phenotype was associated with 5NC. None of the variables were associated with clinical outcome. BCC and 5NC are closely related tumor subtypes. CD44(-)CD24(-/low) phenotype was associated with 5NC and CD44(-)CD24(+) phenotype was associated with vascular invasion. These results require histogenetic confirmation in larger studies.


A real-world study on the prevalence and risk factors of medication related osteonecrosis of the jaw in cancer patients with bone metastases treated with Denosumab.
Assessing the incidence of Medication Related Osteonecrosis of the Jaw (MRONJ) in cancer patients with bone metastases receiving Denosumab (Dmab) and identifying potential risk factors. A retrospective observational study on consecutive cancer patients with bone metastases, who received at least one dose of Dmab and one follow-up visit. MRONJ crude cumulative incidence (CCI) was estimated considering death without MRONJ as competing event. Multiple regression models were used to study the association between MRONJ incidence and potential risk factors: age, cancer diagnosis, previous bisphosphonates, dental treatments before starting Dmab, extraction or other dental treatment during Dmab, chemotherapy, hormone therapy, and antiangiogenic (AA) agents concurrent use. On 780 patients included (median follow-up 17 months), 54% and 18% had, respectively, breast and prostate cancer. The mean number of Dmab administration was 12. Fifty-six patients developed MRONJ with a 24- and a 48-month crude cumulative incidence of 5.7% (95% Cl: 4.2%-7.8%) and 9.8% (95% CI: 7.6%-12.7%), respectively. Higher MRONJ incidence was significantly associated with middle aged group (>56 and ≤73), both at univariate and multivariate analysis (p = 0.029 and 0.0106). Dental treatments (Hazard Ratio [HR] = 3.67; p = 0.0001), dental extractions (HR = 23.40; p < 0.0001), and previous BP administration (HR = 2.62; p = 0.0024) were significantly associated with higher MRONJ incidence at multivariate Cox analysis. Although not statistically significant, MRONJ incidence was lower for patients receiving chemotherapy or hormone therapy and higher for those receiving AAs. The results confirm a clinically relevant incidence of Dmab-induced MRONJ. Dental treatments, especially extraction, during and before Dmab, constitute a serious risk factor. The role of AA concurrent administration deserves further investigations.


Long-term treatment with nipradilol, a nitric oxide-releasing beta-adrenergic blocker, enhances postischemic recovery and limits infarct size.
This study examines whether the chronic administration of nipradilol, a nitric oxide-releasing beta-adrenergic blocker, decreases ischemia-reperfusion injury. Rats were treated with nipradilol (10 mg/kg per day orally) or a vehicle alone for 4 weeks. Isolated rat hearts were assigned to one of five groups (each n = 6): global ischemia groups treated with the vehicle or with nipradilol were subjected to 20 minutes of ischemia; ischemic preconditioning groups treated with the vehicle or with nipradilol were subjected to 3 minutes of ischemic preconditioning; and the L-arginine group treated with the vehicle received 1 mmol/L of L-arginine before global ischemia. Hemodynamic variables and coronary flow were recorded continuously. Nitrites and nitrates levels were measured 60 minutes after reperfusion, and the infarct size was determined. In another series (each n = 6), lipid peroxidation was investigated. In the nipradilol group, significant preservation of the left ventricular pressure and coronary flow, as well as the level of nitrates and nitrites, was observed, compared with the global ischemia group. The infarct size was also significantly reduced in the ischemic preconditioning (23.5%+/-5.47%), L-arginine (25.6%+/-5.59%), and especially the nipradilol (10.7%+/-1.65%) groups. However, in the nipradilol plus ischemic preconditioning group, the protective effects were eliminated. Lipid peroxidation after nipradilol treatment was significantly reduced before and after global ischemia, compared with the global ischemia group. The chronic administration of nipradilol improves postischemic functional recovery and infarct size, partly by preventing the formation of lipid peroxides. These cardioprotective effects were, however, abolished by ischemic preconditioning.


Honey bee toxicological responses do not accurately predict environmental risk of imidacloprid to a solitary ground-nesting bee species.
Honey bees (Apis mellifera) are the current model species for pesticide risk assessments, but considering bee diversity, their life histories, and paucity of non-eusocial bee data, this approach could underestimate risk. We assessed whether honey bees were an adequate risk predictor to non-targets. We conducted oral and contact bioassays for Leioproctus paahaumaa, a solitary ground-nesting bee, and A. mellifera, using imidacloprid (neonicotinoid) and dimethoate (organophosphate). The bees responded inconsistently; L. paahaumaa were 36 and 194 times more susceptible to oral and topically applied imidacloprid than A. mellifera, but showed comparable sensitivity to dimethoate. Furthermore, the proposed safety factor of ten applied to honey bee endpoints did not cover the interspecific sensitivity difference. Our standard-setting study highlights the urgent need for more comparative inter-species toxicity studies and the development of standardized toxicity protocols to ensure regulatory pesticide risk assessment frameworks are protective of diverse pollinators.


Cyclosporine and skin allografts for the treatment of thermal injury. II. Development of an experimental massive third-degree burn model demonstrating extensive graft survival.
We have previously reported the successful treatment and apparent development of skin allograft tolerance in a patient sustaining massive burns, utilizing skin allografts and cyclosporine. We now report the experimental correlate via successful achievement of a 75% body surface area (BSA) scald burn cyclosporine-skin allograft model in Lewis (LEW) rats. Cyclosporine (8 mg/kg/day) was given to the experimental animals daily for the first 20 days and then three times a week thereafter. Two experimental groups were studied: one received standard posttrauma care and the second critical posttrauma care. Controls (n = 22) and experimental groups 1 (n = 28) and 2 (n = 4) had average survival times of 13.8 +/- 12.8 days, 44.2 +/- 132.5 days, and 172.0 +/- 19.4 days, respectively. The allografts on the surviving experimental animals appeared normal and healthy and had nearly perfect hair growth. These results indicate that the model follows the clinical burn wound course, and treatment of massive burns with primary excision, skin allografts, and low doses of cyclosporine could provide immediate and complete functional repair of the burn wound.


The plant kinome.
Plant kinases are one of the largest protein families in Arabidopsis. There are almost 600 membrane-located receptor kinases and almost 400 soluble kinases with distinct functions in signal transduction. In this minireview we discuss phylogeny and functional context of prominent members from major protein kinase subfamilies in plants.


Technology-assisted anterior cruciate ligament reconstruction improves tunnel placement but leads to no change in clinical outcomes: a systematic review and meta-analysis.
To investigate the effect of technology-assisted Anterior Cruciate Ligament Reconstruction (ACLR) on post-operative clinical outcomes and tunnel placement compared to conventional arthroscopic ACLR. CENTRAL, MEDLINE, and Embase were searched from January 2000 to November 17, 2022. Articles were included if there was intraoperative use of computer-assisted navigation, robotics, diagnostic imaging, computer simulations, or 3D printing (3DP). Two reviewers searched, screened, and evaluated the included studies for data quality. Data were abstracted using descriptive statistics and pooled using relative risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CI), where appropriate. Eleven studies were included with total 775 patients and majority male participants (70.7%). Ages ranged from 14 to 54 years (391 patients) and follow-up ranged from 12 to 60 months (775 patients). Subjective International Knee Documentation Committee (IKDC) scores increased in the technology-assisted surgery group (473 patients; P = 0.02; MD 1.97, 95% CI 0.27 to 3.66). There was no difference in objective IKDC scores (447 patients; RR 1.02, 95% CI 0.98 to 1.06), Lysholm scores (199 patients; MD 1.14, 95% CI - 1.03 to 3.30) or negative pivot-shift tests (278 patients; RR 1.07, 95% CI 0.97 to 1.18) between the two groups. When using technology-assisted surgery, 6 (351 patients) of 8 (451 patients) studies reported more accurate femoral tunnel placement and 6 (321 patients) of 10 (561 patients) studies reported more accurate tibial tunnel placement in at least one measure. One study (209 patients) demonstrated a significant increase in cost associated with use of computer-assisted navigation (mean 1158€) versus conventional surgery (mean 704€). Of the two studies using 3DP templates, production costs ranging from $10 to $42 USD were cited. There was no difference in adverse events between the two groups. Clinical outcomes do not differ between technology-assisted surgery and conventional surgery. Computer-assisted navigation is more expensive and time consuming while 3DP is inexpensive and does not lead to greater operating times. ACLR tunnels can be more accurately located in radiologically ideal places by using technology, but anatomic placement is still undetermined because of variability and inaccuracy of the evaluation systems utilized. Level III.


Patient-specific factors, but neither regional anesthesia nor hip-specific cryotherapy, predict postoperative opioid requirements after hip arthroscopy for femoroacetabular impingement (FAI) syndrome.
We sought to determine whether regional nerve block, cryotherapy variant, or patient-specific factors predict postoperative opioid requirements and pain control following hip arthroscopy. 104 patients underwent hip arthroscopy with (n = 31) or without (n = 73) regional block and received cryotherapy with a universal pad [joint non-specific; no compression (n = 60)] or circumferential hip/groin wrap with intermittent compression (n = 44). Outcomes included total opioid prescription amounts, requests for refills, and unplanned clinical encounters for postoperative pain within 45 days of surgery. Multivariate modeling was used to determine the effect of perioperative regional nerve block and type of cryotherapy device on outcomes after adjusting for patient demographics, previous opioid use, mental health disorder history, and surgery length. The average amount of 5 mg oxycodone pill equivalents prescribed within 45 days of surgery was 40.5 (SD 14.8); 36% requested refills, 20% presented to another physician, and 21% called the surgeon's office due to pain. Neither the hip-specific cryotherapy pad nor regional block was predictive of opioid amounts prescribed, refill requests, or unplanned clinical encounters due to pain. Refill requests within 45 days were more common with baseline opioid use (p < 0.001), increased age (p = 0.007), and mental health disorder history (p = 0.008). Total opioid amounts prescribed within 45 days were higher with workers compensation (p = 0.03), a larger initial opioid prescription (p < 0.001), baseline opioid use (p < 0.001), history of mental health disorder (p = 0.02), and increased age (p = 0.02). Together, these variables explained 61% of the variance in opioid amounts prescribed. Patient factors are strong predictors of postoperative opioid requirements after hip arthroscopy. Postoperative opioid prescription amounts, opioid refill requests, and pain-related calls or office visits were not affected by use of a perioperative regional nerve block or type of cryotherapy delivery system. III, retrospective cohort study.


Distinct sleep-wake stages in rats depend differentially on age.
The objective was to study age-related changes in sleep-wake stages in the rat by using precise polyphysiograph criteria for stage identification. Cortical and hippocampal electroencephalogram, and ocular and myographic activities were recorded in young, middle-aged, and old male Wistar rats to define 6 stages: active and quiet wake (AW, QW); light and deep slow wave sleep (SWS: S1, S2); intermediate stage of sleep (IS); and paradoxical sleep (PS). The old rats displayed a decrease in S1, S2, and IS, accompanied by an enhancement of AW. No age changes were found for QW and PS. It is suggested that the consolidation of SWS is primarily disturbed in the old rats, which may lead to a facilitation of wake.


A clinical and epidemiological study of Loxosceles spider envenoming in Santa Catarina, Brazil.
A clinical and epidemiological study of 267 cases of envenomation by Loxosceles spp. (loxoscelism), notified to Centro de Informações Toxicológicas de Florianópolis (Santa Catarina State, Brazil), was conducted between January 1985 and December 1995. Most of the incidents occurred along the coast of the mid-southern region of the state, during the warmest months. L. laeta and L. intermedia were identified as the causative agents. Cutaneous loxoscelism was clinically diagnosed in 232 (86.9%) patients with local pain (86.5%), oedema (80.5%), hyperaemia (79.8%) and necrosis (56.9%). Cutaneous-visceral loxoscelism was detected in 35 patients (13.1%) with intravascular haemolysis, manifested by jaundice (68.6%), oliguria (45.7%), dark urine (28.6%), haemorrhage (25.7%), anuria (8.6%) and shock (2.9%), besides the cutaneous effects. Specific antivenom was given to 125 patients (46.8%) and only 8 (6.5%) had mild reactions. Acute renal failure was observed in 17 cases (6.4%); 4 patients (1.5%) died, all of whom were children under 14 years old.


Cylinder problems with AMS 700 inflatable penile prosthesis.
Six cases of cylinder problems encountered in 1986 with the AMS 700 Silastic inflatable penile prosthesis (IPP) were studied in detail. The problems included 1 case of significant penile bending, the development of a cylinder tear, and several cylinder aneurysms. Possible causes of the problems are explored, along with possibilities for prevention of future problems.


The health belief model and adherence with a community center-based, supervised coronary heart disease exercise program.
Some investigators have concluded that health beliefs do not influence the maintenance of coronary heart disease (CHD) exercise adherence. However, the beliefs tested have not been specific to CHD nor exercise. In addition, much of the research has been atheoretical. We conducted a retrospective study to explore the possible utility of the Health Belief Model (HBM) for explaining attendance at a supervised CHD exercise program, based in a community center. Two dimensions of the model, general health motivation and perceived severity of CHD, were associated with attendance in the theoretically predicted direction, while a third dimension, perceived benefits of exercise, was associated in a direction opposite that predicted by the model. The model as a whole accounted for 29% (adjusted R2) of the variance. This study provides some initial evidence that health beliefs are associated with CHD exercise adherence.


A multimodal therapeutic approach improves the clinical outcome of auricular keloid patients.
We retrospectively studied the efficacy of personalized therapy with surgical resection plus prophylactic management of postsurgical auricular keloids by intralesional injection of betamethasone and local pressure therapy using magnets in patients with auricular keloids. Surgical excision was performed in all patients, and surgical techniques including fusiform excision of the keloid scar, core excision of the keloid scar followed by flap repair, and scar graft were chosen. A total of 85 patients with 98 auricular keloids were eligible. Seventy-two (74%) patients had primary auricular keloids, and 13 patients had recurrent keloids after surgical excision. Keloids, were located in the helix in 28 (32.9%) cases, in the earlobe in 45 (52.9%) cases, and in the entire auricle in 12 (14.1%) cases. The size of auricular keloids ranged from 10 to 35 mm. Surgical resection was uneventful in all cases. Twenty-one (21.4%) patients received fusiform excision, 47 (47.9%) patients underwent core excision and flap repair, and 30 (30.6%) patients received skin grafts. The patients were followed up for median duration of 1 year (range: 12-24 months). The cure rate was 87.2%, and the recurrence rate was 12.8%. A personalized surgical approach based on the characteristics of auricular keloids in each patient and a multimodal therapeutic regimen including surgical excision, glucocorticoid blockade, and intralesional injection of glucocorticoids and pressure therapy improve the cure rate and reduce the recurrence rate of auricular keloids.


A prospective study of motor recovery following multiple subpial transections.
A prospective study of motor recovery was undertaken in a patient scheduled to undergo multiple subpial transections (MST) of right sensorimotor cortex. Pre-transection, functional MRI (fMRI) and cortical stimulation mapping confirmed left hand motor control within right primary motor cortex. Immediately post-transection, behavioral testing demonstrated preserved strength bilaterally but decreased dexterity in the left hand. Seven weeks post-transection, dexterity returned to normal and left hand finger tapping corresponded with multiple bilateral foci of fMRI activation. At 16 weeks, fMRI activation returned to pre-transection levels. These data indicate that cortical injury due to MST resulted in the temporary recruitment of distant cortical sites which presumably subserved normal motor function during recovery.


Antenatal care: selection of the high risk patient.
Despite the best antenatal care, complications may arise during the course of any pregnancy, labour or puerperium. Some groups of women are more likely to develop complications. A method of detecting these high risk patients is discussed.


Ocular manifestations and clinical outcomes in Tubulointerstitial Nephritis and Uveitis Syndrome (TINU).
To describe the various ocular clinical features and visual outcomes in Tubulointerstitial Nephritis and Uveitis Syndrome (TINU). The medical records of 13 patients (26 eyes) diagnosed with TINU were reviewed. Twenty-six (26) eyes of 13 patients with TINU were reviewed in this study. The median age at onset of uveitis was 14 (range, 9-45). Eight (61.5%) subjects were female. The median follow-up of patients was 30 months (range, 6-89 months). Posterior segment findings were seen in 18 eyes of 9 patients (69.2%). The most common posterior findings were optic nerve head inflammation (16 eyes, 88.8%) and retinal vasculitis (13 eyes, 72.2%). Other posterior findings included vitritis (8 eyes, 44.4%), macular edema (6 eyes, 33.3%), snowball (4 eyes, 22.2%), and chorioretinal lesions (2 eye, 11.1%). Eight patients had fluorescein angiography (FA) data available and most eyes had retinal capillary leakage (13 eyes, 81.2%) followed by optic disc staining/leakage (12 eyes, 75%). Twelve (12) patients (92.3%) were treated with immunomodulatory treatment (IMT) and/or biologics. Five patients (%38.4) required biologics to control intraocular inflammation. Posterior segment involvement may be common in patients with TINU syndrome. FA provides significant information for detecting posterior segment involvement and disease activity in TINU. The majority of patients required systemic treatment in order to control intraocular inflammation and prevent relapses.


Measuring provider well-being: initial validation of a brief engagement survey.
Measurement is one of the critical ingredients to addressing the well-being of health care professionals. However, administering an organization-wide well-being survey can be challenging due to constraints like survey fatigue, financial limitations, and other system priorities. One way to address these issues is to embed well-being items into already existing assessment tools that are administered on a regular basis, such as an employee engagement survey. The objective of this study was to assess the utility of a brief engagement survey, that included a small subset of well-being items, among health care providers working in an academic medical center. In this cross-sectional study, health care providers, including physicians and advanced clinical practitioners, employed at an academic medical center completed a brief, digital engagement survey consisting of 11 quantitative items and 1 qualitative item administered by Dialogue™. The emphasis of this study was on the quantitative responses. Item responses were compared by sex and degree, domains were identified via exploratory factor analysis (EFA), and internal consistency of item responses was assessed via McDonald's omega. Sample burnout was compared against national burnout. Of the 791 respondents, 158 (20.0%) were Advanced Practice Clinicians (APCs), and 633 (80.0%) were Medical Doctors (MDs). The engagement survey, with 11 items, had a high internal consistency with an omega ranging from 0.80-0.93 and was shown, via EFA, to have three domains including communication, well-being, and engagement. Significant differences for some of the 11 items, by sex and degree, in the odds of their agreement responses were found. In this study, 31.5% reported experiencing burnout, which was significantly lower than the national average of 38.2%. Our findings indicate initial reliability, validity, and utility of a brief, digital engagement survey among health care professionals. This may be particularly useful for medical groups or health care organizations who are unable to administer their own discrete well-being survey to employees.


The Saccharomyces cerevisiae CLB5 promoter contains two middle sporulation elements (MSEs) that are differentially regulated during sporulation.
The B-type cyclins Clb5 and Clb6 are essential activators of DNA replication during sporulation in Saccharomyces cerevisiae. The expression of CLB5 is maximally induced during the middle phase of sporulation by the transcription factor Ndt80. We have performed an analysis of the CLB5 promoter and have identified two middle sporulation elements (MSEs) that act as binding sites for Ndt80. Although both MSE sequences bind Ndt80 in vitro, they display differential effectiveness in their ability to function as cis-acting regulatory sequences in vivo. Mutation of both MSE sequences in the CLB5 promoter profoundly reduces the induction of CLB5 transcription during the middle phase of sporulation but results in no obvious defect in progression through meiosis and sporulation, implying that the Ndt80-dependent induction of CLB5 is not required for effective DNA replication or chromosome division.


The construction and expression of recombinant shuttle plasmid with OmpL1 gene from leptospira interrogans serovar Lai strain 017 in Bacille Calmette-Guerin.
To construct recombinant BCG against leptospirosis. We amplified the entire open reading frame of the OmpL1 gene from the genome of the leptospire serovar Lai strain 017. Two recombinant plasmids pBQ1 and pBQ2 were constructed by oriented ligation based on the E. coli-BCG shuttle plasmids pMV261 and pMV361 respectively. The recombinant plasmids were transformed into BCG by electroporation. The rBCGs bearing pBQ1 and pBQ2 were induced by high temperature of 45 degrees C. The expressed product, a 35kD protein was detected by SDS-PAGE. The result indicates that pBQ1 and pBQ2 can express OmpL1 in rBCG. The technical methods in this study may help detect the immunogenicity and immunoprotection of OmpL1 and develop more safe, highly effective rBCG bearing leptospiral antigen with long-lasting protection.


A rapid myelin stain for frozen sections: modification of the Heidenhain procedure.
A protocol has been established for the staining of myelin in frozen sections. While the new method is relatively fast and simple, it eliminates the problems routinely encountered with myelin stains such as blotchiness and uneven staining. Modifications were introduced into the procedures in order to obtain excellent fiber staining results on a wide variety of tissue.


Rapid uptake of early medical abortions in the Northern Territory: A family planning-based model.
Abortion law reform does not necessarily translate into services, especially for those in regional areas. Although abortion has been legal in the Northern Territory (NT) since 1974, prior to 2017 legislation change, early medical abortions (EMAs) were effectively prohibited in primary care. In July 2017, Family Planning Welfare Association of the Northern Territory (FPNT) was awarded funding to provide EMAs free of charge for Medicare eligible clients. To describe the demographics and clinical outcomes of clients accessing the EMA service in the first 12 months after legislation change. Retrospective audit of FPNT's Unplanned Pregnancy Database from 1 July 2017 to 30 June 2018 and analysis of the NT Government's Termination of Pregnancy 12 Month Data Report. Of 742 abortions in the NT in the first 12 months after legislation change, 426 were EMAs prescribed at FPNT. Eleven percent of these (47/426) were for Aboriginal or Torres Strait Islander women and 15% (64/426) were for women from Remote or Very Remote Australia. Outcomes were definitively documented for 326 (77%); 5% of these required further misoprostol and 99% had a complete abortion without surgical intervention. Eighty-six percent (281/326) commenced effective hormonal contraception following their EMA. Providing funding to a Family Planning service was effective in devolving the majority of abortions from tertiary to primary healthcare and increasing the use of effective contraception. Some women remain under-represented, particularly women from more remote areas of the NT. Further work is required to ensure equity of access to services for these women.


Thiacalix[4]arene-cinnamaldehyde derivative: ICT-induced preferential nanomolar detection of Ag+ among different transition metal ions.
A new thiacalix[4]arene-cinnamaldehyde derivative 3, which undergoes red shift in the fluorescence spectrum in the presence of Ag(+) ions, has been synthesized. This emission shift is attributed to the intramolecular charge transfer process in the presence of Ag(+) ions with a detection limit in the nanomolar range.


A systematic review of microbiome composition in osteoarthritis subjects.
Osteoarthritis (OA) started to be associated to shifted microbiota composition recently. This systematic review aims to elucidate if there is a common microbiota composition linked with OA between different studies. We screened PubMed, Scopus, Web of Science and Cochrane databases up to July 26th 2021 to identify original studies in which microbiome was assessed from OA individuals, both in human and laboratory animals' studies. Bacteria associated with OA were summarized to find common patterns between the studies. We identified 37 original studies where the microbiota composition was assessed in OA subjects. We identified some bacteria (Clostridium, Streptococcus, Bacteroides and Firmicutes) that were reported to be upregulated in OA subjects, whereas Lactobacillus and Bifidobacterium longum were associated with improved OA outcomes. The heterogeneity of sampling and analysis methods, different taxonomical levels reported and the lack of healthy controls in several studies made it difficult to compare the studies and reach conclusions about a potential causal link. The current study demonstrated that some bacteria were identified as regulators of OA. Future works following standardized methodologies with more proper controls are needed to elucidate our understanding of the role of the microbiota in OA pathogenesis and progress towards new treatments.


Characterization of carbapenem-resistant Acinetobacter baumannii ST540 and Klebsiella pneumoniae ST2237 isolates in a pneumonia case from China.
This study aimed to characterize the chromosome and plasmid sequences, and determine the transferability of plasmids in carbapenem-resistance Acinetobacter baumannii DD520 and Klebsiella pneumoniae DD521 isolates from the same patient who was co-infected in a hospital in China. Both isolates DD520 and DD521 exhibited multidrug resistance phenotype, especially the former isolate which was resistant to nine classes of antimicrobials including carbapenems, quinolones, penicillins, cephalosporins, tetracyclines, phenicols, fosfomycins, sulfanilamides and aminoglycosides. Carbapenem resistance genes of blaOXA-23 and blaOXA-66 were identified on the chromosome of A. baumannii DD520, and blaKPC-2 was found in the plasmid pDD521.2 from K. pneumoniae DD521. Phylogenetic analysis revealed that A. baumannii DD520 belonged to the ST540 clone, and K. pneumoniae DD521 belonged to the ST2237 clone. Plasmid analysis suggested that blaKPC-2 was embedded into plasmid pDD521.2, which might be resulted from IS26- and Tn1721-mediated transposition. Plasmid pDD521.2 carrying blaKPC-2 successfully transferred from K. pneumoniae DD521 into Escherichia coli C600, and carbapenems resistance also transferred in the conjugation. To our knowledge, it was the first report of A. baumannii ST540 and K. pneumoniae ST2237 in the same patient in China. Both these two isolates exhibited resistance to carbapenem, which was likely to have resulted from carbapenem-resistance genes blaOXA-23 -blaOXA-66 on the chromosome of A. baumannii ST540, and blaKPC-2 in the plasmid of K. pneumoniae ST2237. Our study highlighted that effective measures were urgent to prevent and control the co-infection caused by two or more carbapenem-resistance pathogens in the same patient.


[Capacity Building for Prevention and Health Promotion for Children and Parents in a Deprived Urban Quarter: Lenzgesund].
In 2005 the local health authority Hamburg-Eimsbüttel developed a prevention programme for the disadvantaged quarter "Lenzsiedlung" which has been implemented by the stakeholders committee "Round Table Lenzgesund" and other partners led by the health authority. The Department of Medical Sociology and Health Economics of the University Medical Centre had taken on the accompanying analysis and long-term evaluation with a mixture of qualitative and quantitative methods for health reporting and evaluation and a new instrument for measuring capacity building in the quarter (KEQ).


On the validity of hypotheses derived from the Rorschach: III. The relationship between shading and anxiety.
Research was reviewed in an attempt to assess the validity of the hypothesis that shading on the Rorschach is related to anxiety. This research turned out to be replete with inconsistent and contradictory findings. The reasons for this are discussed. However, as a consequence of the kind of research that has been conducted in this area, we are unable to draw any conclusions except that we need more research. The methodological and epistemological issues in this research are discussed with the hope of providing some direction for that new research by correcting for the errors in the research done to date.


Amine-enriched surface modification facilitates expansion, attachment, and maintenance of human cardiac-derived c-kit positive progenitor cells.
Stem cells have a low expansion rate and are difficult to maintain in vitro. To overcome the problems of cardiovascular regeneration, we developed a novel method of stem cell cultivation in culture vessels with amine and carboxyl coatings. We isolated cardiac stem/progenitor cells from infant-derived heart tissue by using c-kit antibody (human cardiac-derived c-kit positive progenitor cells; hCPC(c-kit+)); the cells differentiated into endothelial cells, smooth muscle cells, and cardiomyocytes. To characterize the effect of surface modification on hCPC(c-kit+) expansion, cellular attachment, c-kit expression maintenance, and cardiomyocyte differentiation, we tested hCPC(c-kit+) cultured on non-coated (control), amine-coated (amine), and carboxyl-coated (carboxyl) vessels. Ex vivo proliferation, c-kit maintenance, and cellular attachment were significantly enhanced in the amine group. The amine coating also increased procollagen type I (pro-COL1) expression and increased phosphorylation signals, such as focal adhesion kinase (FAK) and cytosolic Src, as well as enhanced ERK/CDK2 signaling. In addition, there was significant downregulation of the stress signal transducer, JNK, in the amine group. However, cardiomyogenesis remained unchanged in the control, amine, and carboxyl groups. Although surface modifications had no effect on early induction cardiomyogenesis, amine-enriched surface modification may increase hCPC(c-kit+) expansion. The amine-enriched surface improved cellular proliferation and attachment during ex vivo hCPC(c-kit+) expansion, possibly by modulating intracellular signal transducers.


The truncated ghrelin receptor polypeptide (GHS-R1b) is localized in the endoplasmic reticulum where it forms heterodimers with ghrelin receptors (GHS-R1a) to attenuate their cell surface expression.
The ghrelin receptor (GHS-R1a) is remarkable amongst G-protein-coupled receptors for its high degree of constitutive activity, and this agonist-independent activity may be important for its physiological function in the control of food intake and body weight. Ghrelin receptors form heterodimers with the truncated ghrelin receptor polypeptide (GHS-R1b), which has a dominant-negative effect on ghrelin receptor function. Here we show that GHS-R1b has an intracellular localization distinct from ghrelin receptors, being primarily localized in the endoplasmic reticulum. Immunocytochemical studies suggest that GHS-R1b decreases the plasma membrane expression of ghrelin receptors, but the overall distribution profile of ghrelin receptors in isolated subcellular fractions is unaffected by GHS-R1b. Using bioluminescence resonance energy transfer methods, we have shown that while ghrelin receptor homodimers are evenly distributed in all subcellular fractions, GHS-R1a/GHS-R1b heterodimers are concentrated within the endoplasmic reticulum and these results suggest that GHS-R1b traps ghrelin receptors within the endoplasmic reticulum by the process of oligomerization. Furthermore, ghrelin receptors constitutively activated extracellular signal-regulated kinases 1/2 in the endoplasmic reticulum, but this small response was not affected by GHS-R1b and its physiological relevance is uncertain. Taken together, these results suggest that ghrelin receptors can be retained in the endoplasmic reticulum by heterodimerization with GHS-R1b, and constitutive activation of phospholipase C is attenuated due to decreased cell surface expression of ghrelin receptors. However, sufficient ghrelin receptor homodimers can still be expressed on the cell surface for maximal responses to agonist stimulation.


Rhodium-/Iridium-Catalyzed Hydroamination for the Synthesis of 1,2-, 1,3-, or 1,4-Diamines.
An Ir-catalyzed regioselective hydroamination of allyl amines using aryl amines and catalyst-controlled regiodivergent hydroamination of allylic and homoallylic amines with aniline nucleophiles are reported. The directed hydroamination reactions afford a variety of 1,2-, 1,3-, and 1,4-diamines in good to excellent yields and high regio- and chemoselectivities. Mechanistic investigations suggests that the reactions are proceeding through an oxidative addition into the ArHN-H bond and that the observed regioselectivity is due to the selective formation of a 5- or 6-membered metalacyclic intermediate, depending on the catalyst employed.


Synthesis and "in Vitro" Trypanocidal Activity Evaluation of Some Organo-iron Compounds.
Eight organo-iron ferrocene derivatives and arenocenium salts were prepared and evaluated by "in vitro" assay against one strain of Trypanosoma cruzi (Y). Six of the eight organo-iron compounds assayed, piperazinium diferrocenoate 1, eta(6)-(o-xylene)-eta(5)-(cyclopentadienyl) Iron(II) hexafluorophosphate 3, eta(6)-(mesitylene)-eta(5)-(cyclopentadienyl) iron(II) hexafluorphosphate 5, eta(6)-(durene)-eta(5)-(cyclopentadienyl) iron(II) hexafluorphosphate 6, eta(6)-(rho-chlorotoluene)-eta(5)-(cyclopentadienyl) Iron(II) hexafluorphosphate 7 and eta(6)-(chlorobenzene)-eta(5)-(cyclopentadienyl) iron(II) picrate 8 , were poorly active in the "in vitro" assays. Only two compounds 1,1'-(N-pyperidinocarbonyl) ferrocene 2(IC(50)=2.4 mug/mL) and eta(6)-(o-xylene)-eta(5)(cyclopentadienyl) iron(II) picrate 4 (IC(50)=12.08 mug/mL), were more active. Thus, some of the compounds are promising to be used against Chagas' disease as a prophylactic agents.


Neurodevelopment at 11 months after starting antiretroviral therapy within 3 weeks of life.
Antiretroviral therapy (ART) started between 7 and 12 weeks of age improves neurodevelopmental outcomes in HIV-infected (HIV+) infants, but the impact of even earlier initiation is not yet described. We assessed the early neurodevelopment of HIV+ infants who started ART within 21 days of life. Participants were enrolled from the public sector birth HIV-diagnosis programme. Inclusion criteria included the following: birth weight > 2000 g, infant commencing ART < 6 weeks and no infant cytomegalovirus disease. Antiretroviral therapy included Zidovudine/Lamivudine/Nevirapine for the first 2 weeks, the latter then replaced by Lopinavir/Ritonavir. Once body weight > 3 kg and gestational age > 44 weeks, Abacavir replaced Zidovudine. The Griffiths mental development scales (GMDS) were administered at 10-12 months. Of 29 infants assessed, 23 (79%) were girls. Mean birth weight was 3002 ± 501 g. Twenty-four mothers (83%) received ART during pregnancy. Seven (24%) infants were diagnosed HIV+ within 48 h of birth. Median [interquartile range] viral load (VL) at diagnosis was 3904 [259-16 922] copies/mL, age starting ART was 6.0 [3-10] days and age at VL suppression was 19.1 [15-36] weeks. At the GMDS assessment, nine (31%) participants had detectable VL and 26 (90%) had World Health Organization (WHO) clinical stage I disease. The GMDS was performed at a mean age of 11.5 ± 0.8 months. Mean quotients were within the average range: Global Griffiths score was 103.6 ± 10.9 and mean quotients on the subscales ranged from lowest 95.9 ± 13.4 for locomotor to highest 112.8 ± 11.3 for hearing-and-language. Preliminary findings in this small group suggest that early neurodevelopmental scores are within the normal range in infants with perinatal HIV infection who started ART at a median of 6 days.


Impact of alcohol consumption on the outcome of ischemic stroke and thrombolysis: role of the hepatic clearance of tissue-type plasminogen activator.
Tissue-type plasminogen activator (tPA) is the only acute treatment for ischemic stroke. Unfortunately, the benefit of tPA-driven thrombolysis is not systematic, and understanding the reasons for this is mandatory. The balance between beneficial and detrimental effects of tPA might explain the limited overall efficiency of thrombolysis. Here, we investigated whether this balance could be influenced by excessive alcohol intake. We used a murine model of thromboembolic stroke, coupled to an array of biochemical assays, near-infrared or magnetic resonance imaging scans, 2-photon microscopy, hydrodynamic transfections, and immunohistological techniques. We found that 6 weeks of alcohol consumption (10% in drinking water) worsens ischemic lesions and cancels the beneficial effects of tPA-induced thrombolysis. We accumulate in vivo and in vitro evidence showing that this aggravation is correlated with a decrease in lipoprotein receptor-related protein 1-mediated hepatic clearance of tPA in alcohol-exposed mice. An efficient liver-driven clearance of tPA might influence the safety of thrombolysis after stroke.


Bone- and dentoalveolar-anchored dentofacial orthopedics for Class III malocclusion: new approaches, similar objectives? : a systematic review.
To analyze the scientific literature and compare in the results of conventional orthopedic appliances with those obtained from recent bone-anchored orthopedics for Class III malocclusion. The literature was systematically reviewed using PubMed/Medline, Scopus, and Scirus databases up to January 2012. Articles were selected by two different researchers (kappa index = 0.83), based on established inclusion/exclusion criteria. Methodologic quality was classified as high, medium, or low quality. The search strategy identified 1020 titles. Thirty studies were selected after applying the criteria (high quality = 9, medium quality = 21). Protraction rates differed within a range of one- to twofold between bone-anchored and dentoalveolar therapies (P < .001). All studies noted the effect of clockwise rotation on the mandible and an increase in inferior-anterior and total facial height; this was more obvious in dentoalveolar therapy than in bone-anchored orthopedics (P < .001). Dental parameters like overjet increased significantly with both sets of groups, ranging from 1.7 to 7.9 mm with dentoalveolar therapy and from 2.7 to 7.6 mm with bone-anchored orthopedics.


Investigating the potential of non-thermal microwave as a novel skin penetration enhancement method.
Microwaves (MW), a part of the electromagnetic spectrum at 0.3-300GHz, affect human body in different ways through its thermal and athermal effects, including fluidization of cell membranes and liquid crystalline systems. Due to presence of such structures in skin barrier, it was decided here to investigate the potential of athermal MW as skin penetration enhancer. In this investigation, nitrofurazone was chosen as the model penetrant and its permeation through rat skin was studied in vitro at 45 and 90min exposure intervals using MW intensities of 3, 15, 30, 60, 120W at 2450MHz. Results revealed that at 30°C and 45min exposure, 3W MW does not affect permeation of nitrofurazone (P=0.148), while higher intensities increased its flux significantly (P<0.05) in a intensity-dependent manner up to 2.7 times. When the duration of exposure increased to 90min, the enhancement ratio also increased to reach a maximum of 3.3. Applying 60W MW at 25, 30, 37 and 42°C resulted in a parabolic relationship between temperature and enhancement ratio. The present results reveal that microwave can act as a skin penetration enhancement method and that its effect depends on applied intensities, exposure time and temperature.


Detection of nitrous oxide in the neuronal nitric oxide synthase reaction by gas chromatography-mass spectrometry.
Using headspace gas chromatography-mass spectrometry, we detected significant amounts of nitrous oxide in the reaction products of the monooxygenase reaction catalyzed by neuronal nitric oxide synthase. Nitrous oxide is a dimerization product of nitroxyl anion; its presence in the reaction products indicates that the nitroxyl anion is a product of the neuronal nitric oxide synthase-catalyzed reaction.


1,25-Dihydroxycholecalciferol in human serum and its relationship with other metabolites of vitamin D-3.
A competitive protein binding assay for 1,25-dihydroxycholecalciferol has been developed using the hormone's nuclear receptor protein from chick intestinal mucosa. This nuclear receptor protein can be stored at -70 degrees C for several months and bound and free hormone can be separated easily with dextran coated charcoal. Results obtained using this assay agree well with those reported by other groups of workers. Serum levels of other vitamin D-3 metabolites, namely 25-hydroxycholecalciferol and 24,25-dihydroxycholecalciferol have also been measured and are shown in relation to 1,25-(OH)2D3 levels.


[Levels of polychlorinated dibenzo-p-dioxins and dibenzofurans in airborne fine particulate matter and inhalation risk assessment for local residents of Shenzhen].
To explore the levels and congener profiles of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in airborne fine particulate matter (PM25) in Shenzhen and roughly discuss its correlations between PM25 concentration and meteorological factors. The high volume air samplers were used to collect the samples in six sampling sites in respective winter and spring phase and summer and autumn phase. Referring to the US EPA TO-9A for dioxins detection methods, the concentrations of the 17 polychlorinated dibenzo-p-dioxins and dibenzofurans in airborne fine particulate matter were determined by HRGC/HRMS. The total concentrations of PCDD/Fs ranged from 0.32 to 9.35 pg/m3, with average of 2.45 pg/ m3. The TEQ concentrations ranged from 0.006 to 0.388 pg I-TEQ/m3, with average of 0.095 pg I-TEQ/m3. The four abundant congeners were found to be OCDD (36.49%), 1, 2, 3, 4, 6, 7, 8-HpCDF (14.89%), OCDF (13.34%) and 1, 2, 3, 4, 6, 7, 8-HpCDD (10.92%). 2, 3, 4, 7, 8-PeCDF was the dominant contributor to toxicity equivalent (TEQ), accounting for 34.65%. Positive relationship was found between the levels of fine particle-bound PCDD/Fs and PM2.5 concentration (r(s) = 0.794, P = 0.006), whereas no correlation was observed for temperature, humidity and atmospheric pressure. Inhalation exposure to PCDD/Fs were 0. 023 pg I-TEQ/(kg · d) for adult and 0.035 pg I-TEQ/(kg · d) for children during winter and spring and relatively higher than those during summer and autumn (0.014 pg I-TEQ/(kg · d). for adult and 0.021 pg I-TEQ/(kg · d) for children respectively). The levels of PCDD/Fs in airborne fine particle-bound samples collected in Shenzhen were lower than those in Hangzhou and Beijing.


Low beta-band suppression as a tool for DBS contact selection for akinetic-rigid symptoms in Parkinson's disease.
Suppression of pathologically altered activity in the beta-band has previously been suggested as a biomarker for feedback-based neurostimulation in subthalamic deep brain stimulation (STN-DBS) for Parkinson's Disease (PD). To assess the utility of beta-band suppression as a tool for contact selection in STN-DBS for PD. A sample of seven PD patients (13 hemispheres) with newly implanted directional DBS leads of the STN were recorded during a standardized monopolar contact review (MPR). Recordings were received from contact pairs adjacent to the stimulation contact. The degree of beta-band suppression for each investigated contact was then correlated to the respective clinical results. Additionally, we have implemented a cumulative ROC analysis, to test the predictive value of beta-band suppression on the clinical efficacy of the respective contacts. Stimulation ramping led to frequency-specific changes in the beta-band, while lower frequencies remained unaffected. Most importantly, our results showed that the degree of low beta-band suppression from baseline activity (stimulation off) served as a predictor for clinical efficacy of the respective stimulation contact. In contrast suppression of high beta-band activity yielded no predictive power. The degree of low beta-band suppression can serve as a time-saving, objective tool for contact selection in STN-DBS.


Programmed death-ligand 1 (PD-L1) may play a role in malignant glioma infiltration.
Infiltration is the main cause of death of malignant glioma patients. However, the mechanisms of the infiltration in the development of brain cancer (glioblastoma multiforme) are not completely understood. Here, we hypothesized that, in the development of human brain cancer, infiltration is primarily due to differentiated cancer cells and that the cell surface molecule programmed death-ligand 1 (PD-L1) may play an important role in brain tumor infiltration. PD-L1 is highly expressed in differentiated glioma cells in comparison to undifferentiated ones. As PD-L1 has both pro-survival and immunoinhibitory functions in tumor cells, the potential role of PD-L1 in tumor propagation suggest a new therapeutic target for preventing glioma infiltration and recurrence.


High lipid parenteral feeds raise plasma branched chain amino acid concentrations--a possible therapeutic approach to portasystemic encephalopathy?
The effect of varying the calorie source of parenteral feeding from an all glucose source to a high fat source has been studied in seven patients with normal liver function by randomised crossover trial. 'Intralipid' used as the major non-nitrogen calorie source (except for 400 kcal as glucose) was associated with significantly lower plasma concentrations of insulin and glucose, significantly higher plasma concentrations of the three branched chain amino acids, and a significantly higher urinary excretion of sodium. If these effects of a high fat parenteral feed were repeatable in patients with liver failure and portasystemic encephalopathy they might be of therapeutic benefit.


Suicidality in emergency medicine: Results from a retrospective analysis of emergency documentation forms.
To analyze suicidal care episodes in emergency medical responses in Germany. Anonymized data from emergency care episodes in Ulm from 2004 to 2013 were analyzed retrospectively. 158 of 933 psychiatric emergencies (16 %) were suicide related, including 14 completed suicides, 25 care episodes with suicidal ideation, and 119 suicide attempts. Significantly more men than women completed suicide (χ²(2,N = 934) = 12.70, p = 0.02). 93 % of the total psychiatric emergencies received any medication at all, and only about 33 % were transported to a psychiatric hospital. Psychiatric treatment for suicidality in emergency medicine requires improvement to ensure that patients receive adequate therapy.


Overexpression of MicroRNA-1 improves the efficacy of mesenchymal stem cell transplantation after myocardial infarction.
The aim of this research was to study whether transplantation of mesenchymal stem cells (MSCs) overexpressing microRNA-1 into mouse infarcted myocardium can enhance cardiac myocyte differentiation and improve cardiac function efficiently. Eight-week-old female C57BL/6 mice underwent ligation of the left coronary artery to produce models of myocardial infarction. The ligated animals were randomly divided into 4 groups (20 in each). One week later, they were intramyocardially injected at the heart infarcted zone with microRNA-1-transduced MSCs (MSC(miR-1) group), mock-vector-transduced MSCs (MSC(null) group), MSCs (MSC group) or medium (PBS group). At 4 weeks post-transplantation, transthoracic echocardiographic assessment, histological evaluation and Western blot were performed. The transplanted MSCs were able to differentiate into cardiomyocytes in the infarcted zone. Cardiac function in the MSC, MSC(null) and MSC(miR-1) groups was significantly improved compared to the PBS group (p < 0.01 or p < 0.001). However, treatment of MSCs expressing microRNA-1 was more effective for cardiac repair and improved cardiac function more efficiently by enhancing cell survival and cardiac myocyte differentiation compared to the MSC group or the MSC(null) groups (p < 0.05 or p < 0.01, respectively). Transplantation of microRNA-1-transfected MSCs was more conducive to repair of infarct injury and improved heart function by enhancing transplanted cells survival and cardiomyogenic differentiation.


Inability of Rous sarcoma virus to cause sarcomas in the avian embryo.
The injection of Rous sarcoma virus (RSV) into the wing web of newly hatched chicks causes a rapidly growing sarcomatous tumour which is palpable within 1 week of inoculation; and cultures of fibroblasts derived from chick embryos (CEF) and infected with RSV become rapidly transformed. Genetic studies have determined that expression of a single viral gene, designated v-src, is necessary for neoplastic transformation. This gene codes for a 60,000-molecular weight phosphoprotein termed pp60SPC , which possesses a protein kinase activity that phosphorylates polypeptides on tyrosine residues and is constitutively expressed in infected CEF cells. It has been suggested that transformation, and possibly tumorigenesis, may result solely from the consequences of this increase in tyrosine phosphorylations. The pathogenicity of RSV in chick embryos in ovo is less clear. Murphy and Rous suggested that RSV may have caused tumours in "various tissues" of "some embryos", but the subsequent studies of Milford and Duran - Reynals , as well as several other laboratories, failed to find any evidence of intraembryonic tumours in RSV-infected early embryos. The findings of Duran - Reynals , if correct, cannot be explained easily in view of our present understanding of RSV tumorigenicity. Thus, we have re-examined the interaction of RSV with the avian embryo and confirm here that RSV is nontumorigenic and non-teratogenic when microinjected into day 4 chicken embryos. In addition, we found that (1) the virus not only replicates in the embryo, but it also expresses an active src-specific protein kinase and (2) once the cells from the infected limbs are disrupted and placed in culture, they are capable of expressing the transformed phenotype after a 24-h delay.


A quality improvement project: Defining and operationalizing a holistic admission selection policy.
Nationwide, faculty in colleges of nursing are struggling to define practices surrounding holistic admission. Faculty may support the idea of holistic admissions however, little is known about how policies and procedures are developed, operationalized and applied across pools of applicants. The objective of this article is to describe the quality improvement (QI) process surrounding the development of a holistic admission selection policy by faculty in a college of nursing. The Experience-Attributes- Metrics Model was altered and adopted for use in our prelicensure programs. Selection criteria were defined and operationalized. Findings indicate that the QI process took approximately two years. The new policy and tiering are currently being applied to our pools of admission candidates.


A pediatric weight management program for high-risk populations: a preliminary analysis.
To determine whether a multidisciplinary pediatric weight management program effectively improves BMI, BMI z-score, and cardiovascular risk factors (CVRFs) in high-risk populations. A retrospective chart review was performed on children seen in the NEW Kids Program at the Children's Hospital of Wisconsin, a family-based clinic that treats pediatric obesity using medical management, nutrition education, behavioral intervention, and physical activity. Inclusion criteria were program participation for >or=9 months and >4 visits. Analyses were performed to identify factors associated with pre- to postintervention changes in BMI, BMI z-score, and CVRF laboratory values. A total of 66 patients met inclusion criteria; the mean age was 11 years (s.d.+/-3.4), 56% were racial/ethnic minorities, 45% were Medicaid recipients, 48% resided in impoverished communities, and 38% had a BMI >or=40 kg/m(2). Of the 66 patients, 91% had more than one weight-related comorbidity, 88% had CVRFs, and the preintervention mean BMI was 37 kg/m(2). After the intervention, there was an overall increase in absolute BMI, but a small, yet significant decrease in BMI z-score (mean -0.03+/-0.16; P<0.05). There were significant pregroup to postgroup improvements in total cholesterol, low-density lipoprotein, and triglycerides levels (P<0.05). Insurance coverage, race/ethnicity, gender, age, and initial BMI were not significantly associated with changes in BMI or BMI z-score. A multidisciplinary pediatric weight management program can improve the weight status of high-risk populations, including minorities, Medicaid recipients, patients with multiple comorbidities and CVRFs, and the severely obese.


Extensible carbon emission factor database: empirical study for the Chinese construction industry.
A carbon emission factor (CEF) database is required for the basis of carbon emission calculation in construction projects. However, the default values for existing CEF databases cannot cover the complex resources involved in a construction project. Therefore, this paper proposes a three-step method to guide the establishment of an extensible CEF database for the construction industry, including (1) data collection and parser, (2) data extension, and (3) data encoding and storage. The data extension mechanisms provide the supply chain perspective considering temporal issues and the accounting perspective to streamline the process. Aiming to address the lack of a comprehensive CEF database for the construction industry in China, this paper uses this method to establish a carbon emission factor database for the Chinese construction industry (CEFD for CCI). This database is open and free with 646 CEFs, including five parts: energy, human, material, machinery, and greenspace. This paper provides a way for developing and less developed countries to establish an expandable CEF database, which benefits the parser, extension, encoding, and storage of new resources, as well as computer access.


A novel metaheuristic algorithm inspired by COVID-19 for real-parameter optimization.
In this modern world, we are encountered with numerous complex and emerging problems. The metaheuristic optimization science plays a key role in many fields from medicine to engineering, design, etc. Metaheuristic algorithms inspired by nature are among the most effective and fastest optimization methods utilized to optimize different objective functions to minimize or maximize one or more specific objectives. The use of metaheuristic algorithms and their modified versions is expanding every day. However, due to the abundance and complexity of various problems in the real world, it is always necessary to select the most proper metaheuristic method; hence, there is a strong need to create new algorithms to achieve our desired goal. In this paper, a new and powerful metaheuristic algorithm, called the coronavirus metamorphosis optimization algorithm (CMOA), is proposed based on metabolism and transformation under various conditions. The proposed CMOA algorithm has been tested and implemented on the comprehensive and complex CEC2014 benchmark functions, which are functions based on real-world problems. The results of the experiments in a comparative study under the same conditions show that the CMOA is superior to the newly-developed metaheuristic algorithms including AIDO, ITGO, RFOA, SCA, CSA, CS, SOS, GWO, WOA, MFO, PSO, Jaya, CMA-ES, GSA, RW-GWO, mTLBO, MG-SCA, TOGPEAe, m-SCA, EEO and OB-L-EO, indicating the effectiveness and robustness of the CMOA algorithm as a powerful algorithm. As it was observed from the results, the CMOA provides more suitable and optimized solutions than its competitors for the problems studied. The CMOA preserves the diversity of the population and prevents trapping in local optima. The CMOA is also applied to three engineering problems including optimal design of a welded beam, a three-bar truss and a pressure vessel, showing its high potential in solving such practical problems and effectiveness in finding global optima. According to the obtained results, the CMOA is superior to its counterparts in terms of providing a more acceptable solution. Several statistical indicators are also tested using the CMOA, which demonstrates its efficiency compared to the rest of the methods. This is also highlighted that the CMOA is a stable and reliable method when employed for expert systems.


Consistent behavioral and electrophysiological evidence for rapid perceptual discrimination among the six human basic facial expressions.
The extent to which the six basic human facial expressions perceptually differ from one another remains controversial. For instance, despite the importance of rapidly decoding fearful faces, this expression often is confused with other expressions, such as Surprise in explicit behavioral categorization tasks. We quantified implicit visual discrimination among rapidly presented facial expressions with an oddball periodic visual stimulation approach combined with electroencephalography (EEG), testing for the relationship with behavioral explicit measures of facial emotion discrimination. We report robust facial expression discrimination responses bilaterally over the occipito-temporal cortex for each pairwise expression change. While fearful faces presented as repeated stimuli led to the smallest deviant responses from all other basic expressions, deviant fearful faces were well discriminated overall and to a larger extent than expressions of Sadness and Anger. Expressions of Happiness did not differ quantitatively as much in EEG as for behavioral subjective judgments, suggesting that the clear dissociation between happy and other expressions, typically observed in behavioral studies, reflects higher-order processes. However, this expression differed from all others in terms of scalp topography, pointing to a qualitative rather than quantitative difference. Despite this difference, overall, we report for the first time a tight relationship of the similarity matrices across facial expressions obtained for implicit EEG responses and behavioral explicit measures collected under the same temporal constraints, paving the way for new approaches of understanding facial expression discrimination in developmental, intercultural, and clinical populations.


Small Molecule Targeting of Specific BAF (mSWI/SNF) Complexes for HIV Latency Reversal.
The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1. Through this mechanism, these compounds are able to reverse HIV-1 latency in an in vitro T cell line, an ex vivo primary cell model of HIV-1 latency, and in patient CD4+ T cells without toxicity or T cell activation. These macrolactams represent a class of latency reversal agents with unique mechanism of action, and can be combined with other latency reversal agents to improve reservoir targeting.


Simultaneous determination of the three major monoamine metabolites in cerebrospinal fluid by high-performance liquid chromatography with electrochemical detection.
A simple method is described for the simultaneous determination of the three monoamine metabolites, 4-hydroxy-3-methoxyphenylacetic acid, 4-hydroxy-3-methoxyphenylethyleneglycol and 5-hydroxyindole-3-acetic acid, in cerebrospinal fluid by high-performance liquid chromatography with electrochemical detection. Quantitation is accomplished by the standard addition technique. Chromatographic peak heights are corrected for volume effects by comparison with the signal obtained for an added auxiliary reference substance. Sample preparation is kept to a minimum, involving precipitation of proteins by means of perchloric acid and subsequent neutralization. The reproducibility was estimated to be 10%. For one of the metabolites, 4-hydroxy-3-methoxyphenylethyleneglycol, a correlation between the results obtained by this method and a mass fragmentographic method was made, and a satisfactory correlation (r = 0.904, slope = 0.914, intercept 3.26 ng/ml) found. The sensitivity of the method is in the picogram range. The methodology has been applied to measure biogenic amine metabolites in both rabbit and human cerebrospinal fluid. The levels found are in agreement with previously reported values.


Dissociation of peptidyl-tRNA from ribosomes is perturbed by streptomycin and by strA mutations.
Peptidyl-tRNA may dissociate preferentially from ribosomes during protein synthesis when it is inappropriate to, does not correctly complement, the messenger RNA. To test this idea, growing cultures of Escherichia coli were treated with streptomycin to increase the frequency of errors during protein synthesis. Since the treated cells had a temperature-sensitive peptidyl-tRNA hydrolase and could not destroy dissociated peptidyl-tRNA, it was possible to measure the rate of its accumulation after raising the temperature to non-permissive conditions. Both low and high doses of streptomycin enhanced the rate of dissociation and accumulation of peptidyl-tRNA. The rank order of rates of dissociation/accumulation of various isoaccepting tRNA families was not significantly altered by the drug treatment. We concluded that streptomycin stimulated a normal pathway for dissociation of peptidyl-tRNA. Two streptomycin- resistant strains of E. coli had higher rates of dissociation of peptidyl-tRNA than did their sensitive parent strain. When treated with high doses of the drug, the resistant strains showed slightly reduced rates of dissociation of peptidyl-tRNA. These results were interpreted in terms of a two state, two site model for protein synthesis: streptomycin enhances the binding of aminoacyl-tRNA to a tight state of the ribosome A site; the strA mutation enhances translocation to a loose state of the ribosome P site.


Surgical management of a giant sternal chondromyxoid fibroma: a case report.
A primary chondromyxoid fibroma (CMF) arising from sternum is quite uncommon tumor in thoracic surgery. Removal of giant sternal tumors requires extensive resection of the anterior chest wall, and results in deformity and paradoxical movement. A 40-year-old female presented a progressively enlarging mass of her anterior chest wall. Computed tomography revealed an osteolytic lesion with discrete calcification in the bone marrow of the sternum. The tumor extended across the destroyed cortex to the parietal and visceral soft aspects, involving some of the costal cartilage and most of the sternal body. Partial sternal resection was performed successfully and an individual-specific stainless steel plate was used to reconstruct the anterior chest wall. The early result was good, however, nine months after the first surgery, fractures of plate were found at bilateral plate-clavicular junction. The plate had to be removed, and a titanium mesh was used to reconstruction of the chest wall. The patient has been of disease free for more than 18 month after the second surgery. Our experience indicated that the individual-specific plate may not be suitable for reconstructing both the anterior chest wall as well as the sternoclavicular joint after subtotal sternum resection.


Allosteric transitions of rabbit skeletal muscle lactate dehydrogenase induced by pH-dependent dissociation of the tetrameric enzyme.
Among the functions exerted by eukaryotic lactate dehydrogenases, it is of importance the generation of lactate in muscles subjected to fatigue or to limited oxygen availability, with both these conditions triggering a decrease of cellular pH. However, the mutual dependence between lactate dehydrogenase (LDH) catalytic action and lactic acidosis is far from being fully understood. Here we show that the tetrameric LDH from rabbit skeletal muscle undergoes allosteric transitions as a function of pH, i.e. the enzyme obeys Michaelis-Menten kinetics at neutral or slightly alkaline pH values, and features sigmoidal kinetics at pH 6.5 or lower. Remarkably, we also report that a significant dissociation of tetrameric rabbit LDH occurs under acidic conditions, with pyruvate/NAD+ or citrate counteracting this effect. Moreover, citrate strongly activates rabbit LDH, inducing the enzyme to feature Michaelis-Menten kinetics. Further, using primary rabbit skeletal muscle cells we tested the generation of lactate as a function of pH, and we detected a parallel decrease of cytosolic pH and secretion of lactate. Overall, our observations indicate that lactic acidosis is antagonized by LDH dissociation, the occurrence of which is regulated by citrate and by allosteric transitions of the enzyme induced by pyruvate.


Porphobilinogen-synthase (delta-aminolevulinic acid dehydratase) deficiency in bone marrow cells of two patients with porphobilinogen-synthase defect acute porphyria.
Two male patients aged 23 and 25 years with intermittent acute, frequently repeated porphyria syndromes presented an almost total deficiency of porphobilinogen-synthase [(PBG-S); synonym: delta-aminolevulinic acid dehydratase] in peripheral erythrocytes. PBG-S was investigated in bone marrow cells obtained by sternal puncture. A minimal enzyme activity of less than 3% of controls was established. Specific activity and protoporphyrin concentration decreased considerably during the course of erythropoiesis. Both patients are homozygous gene carriers; their parents (father and mother) as well as most of their brothers and sisters are heterozygotes with a PBG-S deficiency of approximately 50% of controls. All people with PBG-S deficiency are especially endangered by alcohol intake and lead exposure, because alcohol and lead toxically inhibit PBG-S.


Beneficial effects of Anadenanthera colubrina (Vell.) Brenan extract on the inflammatory and nociceptive responses in rodent models.
Anadenanthera colubrina (Vell.) Brenan, popularly known as "angico", is a plant that has been widely used in folk medicine due to its anti-inflammatory property. To evaluate the pharmacological activities of this plant, studies were performed on its antinociceptive and anti-inflammatory properties. The AE of Anadenanthera colubrina, made from the bark, was used in rodents via oral route (p.o.), at 100, 200, and 400mg/kg in classical models of nociception (acetic acid-induced writhing and hot-plate test) and inflammation evoked by carrageenan (e.g., paw edema, peritonitis, and synovitis). The acetic acid-induced abdominal writhes in mice were significantly reduced (P<0.001) by oral treatment with the extract (100, 200, and 400mg/kg), but the extract did not significantly increase the latency in the nociceptive hot-plate test. Anadenanthera colubrina aqueous extract reduced significantly the edema and, besides, diminished the mieloperoxidase activity (200 and 400mg/kg, P<0.01). The carrageenan-induced peritonitis was significantly reduced (P<0.05) by the aqueous extract at 100, 200, and 400mg/kg. The aqueous extract (200mg/kg) reduces the synovial leukocyte infiltration on carrageenan-induced synovitis in rats (P<0.01), but failed to significantly affect joint swelling and impaired mobility. We show for the first time that the anti-inflammatory and peripheral antinociceptive activities of Anadenanthera colubrina are consistent, at least in part, with the use of this plant in popular medicine practices.