MicroRNA-29a induces insulin resistance by targeting PPARδ in skeletal muscle cells.
Intrauterine growth retardation (IUGR) induces metabolic syndrome, which is often characterized by insulin resistance (IR), in adults. Previous research has shown that microRNAs (miRNAs or miRs) play a role in the target genes involved in this process, but the mechanisms remain unclear. In the present study, we examined miRNA profiles using samples of skeletal muscles from both IUGR and control rat offspring whose mothers were fed either a protein-restricted diet or a diet which involved normal amounts of protein during pregnancy, respectively. miR‑29a was found to be upregulated in the skeletal muscles of IUGR offspring. The luciferase reporter assay confirmed the direct interaction between miR‑29a and peroxisome proliferator‑activated receptor δ (PPARδ). Overexpression of miR‑29a in the skeletal muscle cell line C2C12 suppressed the expression of its target gene PPARδ, which, in turn, influenced the expression of its coactivator, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thus, PPARδ/PGC-1α‑dependent signals together reduced insulin-dependent glucose uptake and adenosine triphosphate (ATP) production. Overexpression of miR‑29a also caused a decrease in levels of glucose transporter 4 (GLUT4), the most important glucose transporter in skeletal muscle, which partially induced a decrease insulin‑dependent glucose uptake. These findings provide evidence for a novel micro-RNA‑mediated mechanism of PPARδ regulation, and we also noted the IR-promoting actions of miR-29a in skeletal muscles of IUGR.


A Rapidly Growing Cervical Meningeal Melanocytoma with a Dumbbell-Shaped Extension.
Meningeal melanocytoma is a rare benign lesion found in the central nervous system. Preoperative diagnosis of meningeal melanocytoma is often a diagnostic challenge, as the clinical and neurologic features are often nonspecific. Various characteristics, including the natural course of this tumor, remain poorly understood. We report a case of a rapidly growing dumbbell-shaped melanocytoma compressing the spinal cord that manifested 2 years after a tumor was identified at the right C2-C3 foramen. A 40-year-old, right-handed man presented with a 2-month history of right palm and left leg numbness. Magnetic resonance imaging of the cervical spine showed a dumbbell-shaped tumor at the right C2-C3 foramen with extension into the central canal. The lesion was hyperintense on T1-weighted images and hypointense to isointense on T2-weighted images. Contrast enhancement was not visualized clearly. Fluorodeoxyglucose-positron emission tomography with computed tomography showed intense uptake in the lesion. The patient's history included a small lesion that had been localized at the right C2-C3 foramen 2 years before admission. The pathologic findings were consistent with melanocytoma. It is important to include meningeal melanocytoma in the differential diagnosis of dumbbell tumors, as meningeal melanocytomas may show rapid progression.


Autophagic mechanisms in diethylnitrosamine-induced tracheal papillomas of Syrian golden hamster.
Treatment with diethylnitrosamine induced tracheal papillomas in the Syrian golden hamster. Enlarged lysosomes (EL) occurred in a particular type of cells situated at the periphery of tumor lobules. The differentiated phenotype of these cells in secretory in nature. As to the significance of EL occurrence, two possibilities are considered: 1) EL formation is a part of disposal mechanisms after the autophagocytosis of undischarged secretory products by secondary lysosomes and 2) ELs are indicative of sublethal injury to cells of the outermost layer of tracheal papillomas.


Effective vaccine safety systems in all countries: a challenge for more equitable access to immunization.
Serious vaccine-associated adverse events are rare. To further minimize their occurrence and to provide adequate care to those affected, careful monitoring of immunization programs and case management is required. Unfounded vaccine safety concerns have the potential of seriously derailing effective immunization activities. To address these issues, vaccine pharmacovigilance systems have been developed in many industrialized countries. As new vaccine products become available to prevent new diseases in various parts of the world, the demand for effective pharmacovigilance systems in low- and middle-income countries (LMIC) is increasing. To help establish such systems in all countries, WHO developed the Global Vaccine Safety Blueprint in 2011. This strategic plan is based on an in-depth analysis of the vaccine safety landscape that involved many stakeholders. This analysis reviewed existing systems and international vaccine safety activities and assessed the financial resources required to operate them. The Blueprint sets three main strategic goals to optimize the safety of vaccines through effective use of pharmacovigilance principles and methods: to ensure minimal vaccine safety capacity in all countries; to provide enhanced capacity for specific circumstances; and to establish a global support network to assist national authorities with capacity building and crisis management. In early 2012, the Global Vaccine Safety Initiative (GVSI) was launched to bring together and explore synergies among on-going vaccine safety activities. The Global Vaccine Action Plan has identified the Blueprint as its vaccine safety strategy. There is an enormous opportunity to raise awareness for vaccine safety in LMIC and to garner support from a large number of stakeholders for the GVSI between now and 2020. Synergies and resource mobilization opportunities presented by the Decade of Vaccines can enhance monitoring and response to vaccine safety issues, thereby leading to more equitable delivery of vaccines worldwide.


Results of digital neurorrhaphy in adults.
Forty-two digital neurorrhaphies utilizing contemporary techniques and suture material are reviewed. 17% regained near normal function. Another 30% regained imperfect, but very pleasing function. Half of the patients were left with moderate to marked hypoaesthesia, but protective sensation. Protective sensation did not return to those nerves left unrepaired. Immediate repair did not allow better recovery than repair within six days. Delay up to eleven months did not obviate pleasing return of sensibility. Similarly, simultaneous tenorrhaphy did not seem to affect the quality of the result. Crushing, or avulsive injuries always resulted in "poor" return of sensibility. Testing two-point discrimination with the technique of Dellon will reveal recovery of epicritic sensation earlier than any other technique. After six months, few patients regained, or lost sensibility. The severed digital nerve must still carry a guarded prognosis in the adult.


New supramolecular trigonal prisms from zinc(II)- 1,4,7,10-tetraazacyclododecane (cyclen) complexes and trithiocyanurate in aqueous solution.
The multiple bonding between multinuclear zinc(II)-1,4,7,10-tetraazacyclododecane (cyclen, a 12-membered tetraamine) complexes and multidentate ligands is an effective method for constructing supramolecular complexes having well defined and distinct structures in aqueous solution. Herein we present examples of supramolecular D(3h) prisms formed by self-assembly of linearly dimeric or trimeric zinc(II)-cyclen complexes with a potentially trianionic C(3) subunit trithiocyanuric acid (TCA(3-)), wherein Zn(2+)-S(-) or Zn(2+)-N(-) coordination bonds and hydrogen bonds are responsible for stability of the multicomponent architectures in aqueous solution at neutral pH.


Protein inference: A protein quantification perspective.
In mass spectrometry-based shotgun proteomics, protein quantification and protein identification are two major computational problems. To quantify the protein abundance, a list of proteins must be firstly inferred from the raw data. Then the relative or absolute protein abundance is estimated with quantification methods, such as spectral counting. Until now, most researchers have been dealing with these two processes separately. In fact, the protein inference problem can be regarded as a special protein quantification problem in the sense that truly present proteins are those proteins whose abundance values are not zero. Some recent published papers have conceptually discussed this possibility. However, there is still a lack of rigorous experimental studies to test this hypothesis. In this paper, we investigate the feasibility of using protein quantification methods to solve the protein inference problem. Protein inference methods aim to determine whether each candidate protein is present in the sample or not. Protein quantification methods estimate the abundance value of each inferred protein. Naturally, the abundance value of an absent protein should be zero. Thus, we argue that the protein inference problem can be viewed as a special protein quantification problem in which one protein is considered to be present if its abundance is not zero. Based on this idea, our paper tries to use three simple protein quantification methods to solve the protein inference problem effectively. The experimental results on six data sets show that these three methods are competitive with previous protein inference algorithms. This demonstrates that it is plausible to model the protein inference problem as a special protein quantification task, which opens the door of devising more effective protein inference algorithms from a quantification perspective. The source codes of our methods are available at: http://code.google.com/p/protein-inference/.


Resistance Training and White Matter Lesion Progression in Older Women: Exploratory Analysis of a 12-Month Randomized Controlled Trial.
To assess whether resistance training (RT) slows the progression of white matter lesions (WMLs) in older women. Secondary analysis of a 52-week randomized controlled trial of RT, the Brain Power Study. Community center and research center. Of 155 community-dwelling women aged 65 to 75 enrolled in the Brain Power Study, 54 who had evidence of WMLs on magnetic resonance imaging (MRI) at baseline were included in this secondary analysis. Participants were randomized to once-weekly RT (1× RT), twice-weekly RT (2× RT), or twice-weekly balance and tone (BAT). Assessors were blinded to participant assignments. WML volume was measured using MRI at baseline and trial completion. At trial completion, the 2× RT group had significantly lower WML volume than the BAT group (P = .03). There was no significant difference between the BAT group and the 1× RT group at trial completion (P = .77). Among participants in the two RT groups, reduced WML progression over 12 months was significantly associated with maintenance of gait speed (correlation coefficient (r) = -0.31, P = .049) but not with executive functions (r = 0.30; P = .06). Engaging in progressive RT may reduce WML progression.


Paradoxical increase in left atrial strains early after Covid-19 infection, a result of comprehensive recovery phase four-chamber strains study.
Cardiac consequences of Covid-19 infection have been mentioned in various studies as a serious risk factor for in-hospital mortality. However, the existence of residual cardiac dysfunction after the acute phase is seldom investigated especially in people without a history of specific medical disease. One hundred health care workers with positive reverse transcription-polymerase chain reaction test underwent comprehensive 2D and 3D echocardiography six to eight weeks after infection. Patients were classified into Mild, Moderate, and Severe groups based on their clinical characteristics of covid-19 infection, and all echocardiographic parameters were compared between the three groups. Left ventricular (LV) stroke volume index was reduced in all groups compared to normal ranges and was more prominent in the severe group (P-value < 0.05). 3D-derived LV global longitudinal strain (GLS) was significantly lower in the severe group in comparison to the mild group (- 19.3 ± 1 Vs. - 22.2 ± 2, P-value < 0.001) and correlated with highly sensitive CRP level at the acute phase. Left atrial (LA) strains, including LA peak strain, LA contraction strain, and LA reservoir strain, were considerably higher and LA volume index was significantly lower in the clinically severe covid patients. Analysis based on the extent of lung involvement showed significantly increased 3D-derived right ventricular volumes in patients who experienced severe pneumonia despite normalized strains. Conclusion: subclinical LV dysfunction as reduced stroke volume index and GLS exists in the early recovery phase of normal individuals with severe course of covid-19. LA function indicated by LA strains paradoxically increases in severe covid-19 infection in this phase.


Comparison of estimators in nested case-control studies with multiple outcomes.
Reuse of controls in a nested case-control (NCC) study has not been considered feasible since the controls are matched to their respective cases. However, in the last decade or so, methods have been developed that break the matching and allow for analyses where the controls are no longer tied to their cases. These methods can be divided into two groups; weighted partial likelihood (WPL) methods and full maximum likelihood methods. The weights in the WPL can be estimated in different ways and four estimation procedures are discussed. In addition, we address modifications needed to accommodate left truncation. A full likelihood approach is also presented and we suggest an aggregation technique to decrease the computation time. Furthermore, we generalize calibration for case-cohort designs to NCC studies. We consider a competing risks situation and compare WPL, full likelihood and calibration through simulations and analyses on a real data example.


Extremity fractures in children: when is it an emergency?
Not all pediatric fractures require emergent orthopedic attention. The information needed to assess and provide the appropriate interventions to children and their families following an extremity fracture is discussed in this article. A case study is used to describe a fracture that requires emergent intervention. The role of the pediatric orthopaedic nurse practitioner in the emergency department, inpatient, and outpatient setting is also illustrated.


The antiocclusive effect of coronary dilatation with age.
Human coronary arteries were perfusion-fixed; sectioned and their external and lumenal circumferences measured by microscopic planimetry. They were found to dilate with increasing age, and this change seems to be more a degenerative process than a response to increasing heart weight. It is inferred that a moderate degree of coronary dilatation compensates for the tendency of atherosclerosis to occlude the lumen. Absence of any coronary dilatation might be hazardous in that the stenosing effects of atherosclerosis would be enhanced. By contrast over-dilatation (ectasia) is dangerous in that it causes a reduced flow-rate and, hence, promotes thrombosis.


The effect of lensectomy on the incidence of iris neovascularization and neovascular glaucoma after vitrectomy for diabetic retinopathy.
We analyzed a consecutive series of 596 eyes that underwent vitrectomy for complications of diabetic retinopathy to determine the postoperative incidence of iris neovascularization and neovascular glaucoma. Survival curves for various factors were plotted, showing the cumulative incidence of these complications at various postoperative times up to one year. Eyes in which the lens was removed during vitrectomy had a statistically significant (P less than .001 by log-rank test) increase in the postoperative incidence of both iris neovascularization and neovascular glaucoma compared to eyes in which the lens was not removed. Lens removal at vitrectomy increased the risk of postoperative iris neovascularization by a factor of more than three and the risk of neovascular glaucoma by a factor of more than four. Other factors associated with a significantly increased incidence of postoperative iris neovascularization were severe preoperative retinal neovascularization and the absence of preoperative scatter retinal photocoagulation. Neither of these two factors nor postoperative retinal detachment invalidated or reduced the effect of lensectomy on increased postoperative iris neovascularization when all factors were considered simultaneously. This study showed a statistically significant increase in the postoperative incidence of neovascular glaucoma in eyes undergoing combined lensectomy and vitrectomy compared to eyes in which the lens was not removed.


The Effect of taVNS on the Cerebello-Thalamo-Cortical Pathway: a TMS Study.
fMRI studies show activation of cerebellum during transcutaneous auricular vagal nerve stimulation (taVNS); however, there is no evidence whether taVNS induced activation of the cerebellum translates to the cerebellar closed loops involved in motor functions. We assessed the propensity of taVNS at 25 Hz (taVNS25) and 100 Hz (taVNS100) to modulate cerebello-thalamo-cortical pathways using transcranial magnetic stimulation. In our double blind within-subjects study thirty-two participants completed one visit during which cerebellar brain inhibition (CBI) was assessed at baseline (no stimulation) and in a randomized order during taVNS100, taVNS25, and sham taVNS (xVNS). Generalized linear mixed models with gamma distribution were built to assess the effect of taVNS on CBI. The estimated marginal means of linear trends during each taVNS condition were computed and compared in a pairwise fashion with Benjamini-Hochberg correction for multiple comparisons. CBI significantly increased during taVNS100 compared to taVNS25 and xVNS (p = 0.0003 and p = 0.0465, respectively). The taVNS current intensity and CBI conditioning stimulus intensity had no significant effect on CBI. taVNS has a frequency dependent propensity to modulate the cerebello-thalamo-cortical pathway. The cerebellum participates in closed-loop circuits involved in motor, cognitive, and affective operations and may serve as an entry for modulating effects of taVNS.


Virtual reality as a learning tool for improving infection control procedures.
Hand hygiene and donning personal protective equipment (PPE) are essential techniques for infection control; however, low compliance is an issue. The effectiveness of virtual reality (VR) in learning infection control procedures is unknown. To verify the effectiveness of VR, medical students were categorized into VR or lecture groups (n=21 each). Each group was given the same curricular content; one group received the training through VR learning using a fully-immersive 360-degree video and the other was conventional lecture-style learning. Before and after the training, they were evaluated for the implementation of hand hygiene and PPE using an Objective Structured Clinical Examination method. Post-test questionnaires were administered. The scores for hand hygiene, donning PPE, and the total score increased after learning in both groups. There was no difference between the pre-test total scores of the two groups (7 [5-9] vs 6 [5-7.5], P=.352); however, the VR group had significantly higher post-test total scores than the lecture group (12 [9.5-12] vs 9 [8-12], P=.024). More students in the VR group responded that they enjoyed the training and would like to use the same learning method next time. VR can be a useful tool for learning and practicing appropriate infection control procedures.


Repeat CyberKnife Radiosurgery for Trigeminal Neuralgia: Outcomes and Complications.
CyberKnife radiosurgery (RS), as an initial first treatment, is recognized as an efficient and safe modality for trigeminal neuralgia (TN). However, knowledge on repeat CyberKnife RS in refractory cases is limited. The objective was to evaluate the clinical outcomes of repeat CyberKnife RS for TN. A retrospective review of 33 patients with refractory TN treated a second time with CyberKnife RS from 2009 to 2021. The median follow-up period after the second RS was 26.0 months (range 0.3-115.8). The median dose for the repeat RS was 60 Gy (range 60.0-70.0). Pain relief after the intervention was assessed using the Barrow Neurological Institute scale for pain (I-V). Scores I to IIIb were classified as an adequate pain relief and scores IV-V were classified as a treatment failure. After the second RS, initial adequate pain relief was achieved in 87.9% of cases. The actuarial probabilities of maintaining an adequate pain relief at 6, 12, 24, and 36 months were 92.1%, 74.0%, 58.2%, and 58.2%, respectively. Regarding sustained pain relief, there was no significant difference between the first and the second RS. Sensory toxicity after the first RS was predictive of a better outcome following the second RS. The onset of hypesthesia rate was the same after the first or the second RS (21%). Repeat RS is an effective and safe method for the treatment of refractory TN.


Indirect comparison of the antiviral efficacy of peginterferon alpha 2a plus ribavirin used with or without simeprevir in genotype 4 hepatitis C virus infection, where common comparator study arms are lacking: a special application of the matching adjusted indirect comparison methodology.
The need to assess relative efficacy in the absence of comparative clinical trials is a problem that is often encountered in economic modeling. The use of matching adjusted indirect comparison (MAIC) in this situation has been suggested. We present the results of a MAIC used to evaluate the incremental benefit offered by adding simeprevir (SMV) to standard therapy in the treatment of patients infected with genotype 4 hepatitis C virus (HCV). Individual patient data for a single arm study evaluating the use of SMV with peginterferon alfa 2a + ribavirin (PR) in genotype 4 HCV were available (RESTORE study). A systematic literature review was used to identify studies of PR alone used in the same patient group. By applying the inclusion criteria for each study in turn to the RESTORE dataset and then applying the published MAIC covariate matching algorithm, a series of pseudosamples from RESTORE were generated. After assessment of the matching outcomes, the best matched comparisons were used to derive estimates of efficacy for SMV + PR in patients equivalent to those participating in the PR trial. Five potential comparator studies were identified. After applying the matching process, two emerged as offering the greatest equivalence with the generated RESTORE pseudosamples and were used to estimate SMV + PR efficacy, expressed as the percentage of patients achieving sustained viral response (SVR). In one comparison, SVR in the SMV + PR group was 85% versus 63% for PR alone. In the second comparison, the corresponding SVRs were 77% and 44% respectively. After matching for varying baseline characteristics, both comparisons of RESTORE versus studies of PR alone yielded a benefit for SMV + PR vs PR alone in genotype 4 HCV-infected patients. The incremental gain in SVR associated with use of SMV ranged from 22% to 33%. In the absence of direct comparative studies, the MAIC gives a better perspective than simple comparison of absolute SVR from individual studies.


Depressive symptoms are associated with DNA methylation age acceleration in a cross-sectional analysis of adults over age 50 in the United States.
Major depressive disorder affects mental well-being and accelerates DNA methylation age, a marker of biological aging. Subclinical depressive symptoms and DNA methylation aging have not been explored. To assess the cross-sectional association between depressive symptoms and accelerated DNA methylation aging among United States adults over age 50. We included 3,793 participants from the 2016 wave of the Health and Retirement Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale and operationalized as high versus low/no. Blood DNA methylation GrimAge was regressed on chronologic age to obtain acceleration. Multiple linear regression assessed the relationship between high depressive symptoms and GrimAge acceleration, controlling for demographic factors, health behaviors, and cell type proportions. We investigated sex and race/ethnicity stratified associations. Participants were 42% male, 14% had high depressive symptoms, 44% had accelerated GrimAge, and were mean age 70 years. In our fully adjusted model, those with high depressive symptoms had 0.40 (95%CI: 0.06, 0.73) years accelerated GrimAge, compared to those with low/no depressive symptoms. The association between depressive symptoms and GrimAge acceleration was larger in male participants ( P = 0.04). Higher depressive symptoms were associated with accelerated DNA methylation age among older adults.


The effects of preanesthetic, single-dose dexmedetomidine on induction, hemodynamic, and cardiovascular parameters.
To investigate the hemodynamic, cardiovascular, and recovery effects of dexmedetomidine used as a single preanesthetic dose. Randomized, prospective, double-blind study. University Hospital of Kirikkale, Kirikkale, Turkey. 40 ASA physical status I and II patients, aged 20 to 60 years, who were scheduled for elective cholecystectomy. Patients were randomly divided into two groups to receive 0.5 microg kg(-1) dexmedetomidine (group D, n = 20) or saline solution (group C, n = 20). Anesthesia was induced with thiopental sodium and vecuronium, and anesthesia was maintained with 4% to 6% desflurane. Mean arterial pressure (MAP), heart rate (HR), ejection fraction (EF), end-diastolic index (EDI), cardiac index (CI), and stroke volume index (SVI) were recorded at 10-minute intervals. The times for patients to "open eyes on verbal command" and postoperative Aldrete recovery scores were also recorded. In group C, an increase in HR and MAP occurred after endotracheal intubation. In group D, HR significantly decreased after dexmedetomidine was given. The EDI, CI, SVI, and EF values were similar in groups D and C. The modified Aldrete recovery scores of patients in the recovery room were similar in groups C and D at the 15th minute. A single dose of dexmedetomidine given before induction of anesthesia decreased thiopental requirements without serious hemodynamic effects or any effect on recovery time.


Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein in inflammation and tumor immunity.
Human Interleukin-18 (IL-18) is an omnipresent proinflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases and serves as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase of COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18-Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors are highly desirable; however, the structure of human IL-18BP in complex with IL-18 has been elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP toward IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecules from different complexes, resulting in a novel tetramer with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings provide a framework for innovative, structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease.


Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines.
The RET gene encodes a receptor tyrosine kinase whose function is essential during the development of kidney and the intestinal nervous system. Germline mutations affecting one of five cysteines (Cys609, 611, 618, 620 and 634) located in the juxtamembrane domain of the RET receptor are responsible for the vast majority of two cancer-prone disorders, multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC). These mutations lead to the replacement of a cysteine by an alternate amino acid. Mutations of the RET gene are also the underlying genetic cause of Hirschsprung disease (HSCR), a congenital aganglionosis of the hindgut. In a fraction of kindreds, MEN 2A cosegregate with HSCR and affected individuals carry a single mutation at codons 609, 618 or 620. To examine the consequences of cysteine substitution on RET function, we have introduced a Cys to Arg mutation into the wild-type RET at either codons 609, 618, 620, 630 or 634. We now report that each mutation induces a constitutive catalytic activity due to the aberrant disulfide homodimerization of RET. However, mutations 630 and 634 activate RET more strongly than mutations 609, 618 or 620 as demonstrated by quantitative assays in rodent fibroblasts and pheochromocytoma PC12 cells. Biochemical analysis revealed that mutations 618 and 620, and to a lesser extent mutation 609, result in a marked reduction of the level of RET at the cell surface and as a consequence decrease the amount of RET covalent dimer. These findings provide a molecular basis explaining the range of phenotype engendered by alterations of RET cysteines and suggest a novel mechanism whereby mutations of cysteines 609, 618 and 620 exert both activating and inactivating effects.


Comments on relationships between native seed preferences of shrub-steppe granivores and seed nutritional characteristics.
Kelrick et al. (1986) argued that seed preferences of desert granivores are strongly influenced by soluble carbohydrate contents of native seed species. They assumed that bitterbrush (Purshia tridentata) seeds are eaten in their entirety by rodents, but in fact these granivores eat only embryos of bitterbrush seeds. Embryos have a much lower percentage of soluble carbohydrate than whole bitterbrush seeds, and the correlation between preference and soluble carbohydrate content of seeds for six native species becomes non-significant when embryo values are substituted for whole-seed values.


Diabetic ketoacidosis in pregnancy - Case series, pathophysiology, and review of the literature.
Diabetic ketoacidosis (DKA) during pregnancy is a life-threatening emergency for both the mother and the fetus. The pathophysiology of DKA in pregnancy has its own characteristics due to multiple factors, such as insulin resistance, accelerated starvation and respiratory alkalosis, thus creating ketosis-prone state, with DKA occurring at milder degrees of hyperglycemia, even in normoglycemic levels, which can result in delayed diagnosis and treatment with potential for adverse metabolic consequences. In this article, we presented 8 clinical cases of DKA during pregnancy. We discuss the spectrum of the clinical picture, the entity of euglycemic DKA vs hyperglycemic DKA, the period of pregnancy in appearance of episode of DKA and triggers of DKA. The treatment of DKA in pregnant women must be started immediately and must be accentuated on intravenous fluids, insulin and electrolyte replacement. DKA in pregnancy may be euglycemic. Prevention, early recognition, immediate hospitalization, and aggressive management remain the cornerstones in DKA management in pregnancy.


The association between metabolic syndrome and the National Institutes of Health Chronic Prostatitis Symptom Index: results from 1673 men in China.
To investigate the association between metabolic syndrome (MetS) and the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) in a population-based sample of Chinese men. From October 2010 to July 2011, 1896 men, aged between 20 and 50 years, residing in Shijingshan district of Beijing, China, were selected to participate in the Male Reproductive Health Program (a random cross-sectional survey). The Chinese version of the NIH-CPSI questionnaire was used to identify men with prostatitis-like symptoms. The presence of MetS was determined according to the 2005 National Cholesterol Education Program-Adult Treatment Panel III criteria for Asian Americans. Complete data were available for 1673 men. The major domains of NIH-CPSI scores were significantly different among different body mass index (BMI) groups (P <.05). No significant differences were identified in the incidence of prostatitis-like symptoms or each NIH-CPSI scores between patients with MetS and those without MetS. When the age and BMI were adjusted, there was no significant correlation between the components of MetS and each NIH-CPSI scores. There was no significant correlation between MetS or components of MetS and chronic prostatitis/chronic pelvic pain syndrome. Age and BMI were identified as a risk factor for chronic prostatitis/chronic pelvic pain syndrome. Further studies are necessary to confirm our results.


The use of Taqman genotyping assays for rapid confirmation of β-thalassaemia mutations in the Malays: accurate diagnosis with low DNA concentrations.
In Malaysia, β-thalassaemia is a common inherited blood disorder in haemoglobin synthesis with a carrier rate of 4.5%. Currently, PCR-incorporating techniques such as amplification refractory mutation system (ARMS) or reverse dot blot hybridization (RDBH) are used in β-thalassaemia mutation detection. ARMS allows single-mutation identification using two reactions, one for wild type and another for mutant alleles. RDBH requires probe immobilization and optimization of hybridization and washing temperatures which is time consuming. The aim of our study was to investigate whether β-thalassaemia mutations can be identified in samples with low DNA concentrations. Genotype identification of common β-thalassaemia mutations in Malays was carried out using Taqman genotyping assays. Results show that the Taqman assays allow mutation detection with DNA template concentrations as low as 2-100 ng. In addition, consistent reproducibility was observed in the Taqman assays when repeated eight times and at different time intervals. The developed sensitive Taqman assays allow molecular characterization of β-thalassaemia mutations in samples with low DNA concentrations. The Taqman genotyping assays have potential as a diagnostic tool for foetal blood, chorionic villi or pre-implantation genetic diagnosis where DNA is limited and precious.


Highly sensitive oligosaccharide analysis in capillary electrophoresis using large-volume sample stacking with an electroosmotic flow pump.
To obtain high sensitivity in capillary electrophoresis of oligosaccharide without reducing the high resolution with an easy experimental procedure, large-volume sample stacking with an electroosmotic flow pump (LVSEP) was investigated. As a fundamental study, effect of the conductivity of a sample solution in LVSEP was examined. It was revealed that LVSEP was successfully carried out even in using a sample solution with the ionic strength of 150 μM and the conductivity ratio of 20, indicating a good applicability of LVSEP to the analysis of real samples containing salts. When glucose oligomer was analyzed as a model sample in LVSEP-capillary zone electrophoresis (CZE), all peaks were well resolved with decreasing only 5% of the peak-to-peak distance, which suggested 95% of the whole capillary could be used for the effective separation. In the analysis of maltoheptaose, a good calibration line with correlation coefficient of 0.9995 was obtained. The limit of detection was estimated as 2 pM, which was 500-fold lower than that in the conventional CZE. N-linked glycans released from three glycoproteins, bovine ribonuclease B, bovine fetuin, and human α(1)-acid glycoprotein were also analyzed by LVSEP-CZE. By the sample purification with a gel filtration column, further sample dilution to reduce the sample conductivity for LVSEP was not needed. All glycan samples were well concentrated and separated with up to a 770-fold sensitivity increase. The run-to-run repeatabilities of the migration time, peak height, and peak area were good with relative standard deviations of 0.1-1.3%, 1.2-1.7%, and 2.8-4.9%, respectively.


Surgical approach for appendicitis in neutropenia: a case report and review of the literature.
Acute appendicitis is a common abdominal pathology, particularly in younger patients presenting with abdominal pain. The clinical presentation is typically characterized by right lower quadrant pain (with local peritonitis) accompanied by fever and nausea. In neutropenic patients it is challenging to diagnose acute appendicitis. It is much more challenging because the characteristic symptoms are different, and diagnosis may be delayed or missed. We present the case of a 33-year-old Caucasian male patient with fever, abdominal pain, and an absolute granulocyte count of 0 × 109/L. Abdominal CT demonstrated an uncomplicated acute appendicitis. We initiated a conservative in-hospital treatment with intravenous antibiotic therapy and simultaneous bone marrow stimulation, with close monitoring. On day three, there was evidence of monocyte increase, one of the first signs of bone marrow regeneration, and delayed laparoscopic appendectomy was performed. The perioperative and postoperative course was uneventful. We discuss the different treatment strategies in patients with neutropenia presenting with acute appendicitis (i.e., conservative management, delayed appendectomy, and immediate appendectomy) based on our experience and a review of the literature. In summary, delayed laparoscopic appendectomy at the onset of granulocyte regeneration under antibiotic and G-CSF therapy represents a viable surgical option for adults as well as for children and should be discussed compared with conservative therapy.


A novel film based on gluten, pectin, and polyphenols and its potential application in high-fat food.
A novel film based on some natural ingredients (wheat gluten, pectin, and polyphenols) was used to improve the quality and storage stability of high-fat food due to their good sustainable, mechanical, and edible properties. With the addition of polyphenols from Cedrus deodara (in the form of pine-needle extract (PNE)), the physicochemical properties (thickness, moisture content, and color), mechanical properties (tensile strength and elongation), barrier properties (water vapor, oil, and oxygen permeability, transmittance), and thermal stability of the composite film were improved. According to the analysis of infrared spectroscopy and molecular docking, the main compounds of PNE interacted with wheat gluten by hydrogen bonds and hydrophobic forces to form a compact and stable structure. In addition, the composite film showed a remarkable antioxidant capability to scavenge free radicals, and the film matrix could effectively protect the antioxidant activity of PNE. Furthermore, using cured meat as a model, the composite film exhibited a fine packaging performance in high-fat food during storage, which could obviously inhibit the excessive oxidation of fat and protein of cured meat and was beneficial in forming its special flavor. Our results suggest that the composite film possessed good properties and had potential for packing of high-fat foods, which could improve the quality and safety of food during processing and storage. © 2023 Society of Chemical Industry.


[The neurophysiology of cataplexy].
Cataplexy and excessive daytime sleepiness are the leading symptoms of narcolepsy. Electrophysiological studies in humans do not show a clear association between cataplexy and rapid eye movement (REM) sleep. Even a decrement of the H reflex is not specific for cataplexy and may be caused by unspecific triggers such as coughing. Cholinomimetics, which may induce status cataplecticus, do not influence REM sleep, thus evidencing a REM-independent mechanism. Recent studies demonstrate a lack of the neuropeptide hypocretin in the CSF of narcoleptics. Hypocretin controls wakefulness and the motor and autonomous systems. In hypocretin-1 and -2 knockout mice, sudden stops of motor activity could be observed in emotional situations that were accompanied by sudden shifts from wakefulness to REM sleep and could be terminated by application of anticataplectic medication. The lack of hypocretin not only causes a noradrenergic-cholinergic imbalance in the midbrain but also influences motoneurons directly by juxtacellular hypocretin-containing membranes. Intravenous application of hypocretin in a dog with hypocretin deficiency in the CSF caused a dose-dependent decrease of cataplexies. An understanding of the neuronal mechanisms responsible for cataplexies is essential for the development of new anticataplectic medications.


A thermochromic dispersive electrode can measure the underlying skin temperature and prevent burns during radiofrequency ablation.
Evaluation of a thermochromic dispersive electrode. Burns at the dispersive electrode are serious complications of diathermy and radiofrequency (RF) ablation procedures. We aimed to create a new methodology to reduce the incidence of dispersive electrode related skin burns. We hypothesized that a dispersive electrode incorporating a thermochromic liquid crystal (TLC) layer could accurately measure underlying skin temperatures and help prevent burns. The TLC electrode was compared with a standard dispersive electrode in 12 male sheep. RF current was delivered with the dispersive electrode fully applied or partially detached to simulate different clinical scenarios. The temperature of the TLC layer, calculated from the hue (color) every 15 seconds, was compared with fluoroptic skin temperature probes. TLC electrodes with a temperature range of 45-58 degrees C were used in six sheep to assess the correlation of TLC temperature distribution with skin temperature and burns. TLC electrodes with a temperature range of 40-50 degrees C were used in another 6 sheep to simulate clinical conditions in which the ablation was stopped if the TLC temperature was >42 degrees C. The TLC measured temperatures correlated well with fluoroptic probes at the skin surface (r=0.94+/-0.05, mean of the absolute difference in temperature difference 0.9+/-0.58 degrees C). Ablations with partial application of standard dispersive electrodes consistently caused skin burns. There were no burns under the TLC electrode when ablations were ceased for temperatures>42 degrees C. TLC-equipped dispersive electrodes were able to accurately measure skin temperature under the electrode. This technology is likely to prevent dispersive electrode related burns.


Detection of osteoporosis by dual energy X-ray absorptiometry (DXA) of the calcaneus: is the WHO criterion applicable?
The study assessed the precision, sensitivity, and specificity of a recently developed peripheral dual-energy X-ray absorptiometry (DXA) scanner, applied to the calcaneus, in the identification of individuals with osteoporosis at axial sites by DXA. Two hundred and two women, aged 55.2 +/- l3.7 years (mean +/- SD), participated in the study. The precisions (coefficient of variation) of measurements in vitro (0.48%) and in vivo (1.40%) were very good. The in vivo precision was independent of the operator, foot size, foot width, weight, height, and body mass index. Calcaneus BMD correlated moderately (r = 0.494-0.690, P <0.001) with axial BMD measurements by DXA. Using the World Health Organization (WHO) criterion for defining osteoporosis (T score ? -2.5) the specificity of the calcaneus to identify patients with osteoporosis at total hip, femoral neck, spine, or any of these axial sites was excellent (97.0%, 97.0%, 96.5%, and 97.1%, respectively); however, the sensitivity was poor (58.8%, 36.4%, 21.8%, and 20.3%, respectively). Therefore, the WHO criterion is not appropriate for DXA calcaneus. Based on femoral neck BMD for detection of osteoporosis, a more appropriate calcaneus T score threshold would be -1.4 by analyses of receiver-operator characteristic curves; this might serve to select those patients who might appropriately be referred for axial DXA.


Synthesis and properties of Praziquantel, a novel broad spectrum anthelmintic with excellent activity against Schistosomes and Cestodes.
Synthesis and properties of 2-cyclohexylcarbonyl-1,3,4,6,7,11b-hexahydro-2H-pyrazino [2,1-a] isoquinolin-4-one, a novel anthelmintic with excellent activity against all species of Schistosomes pathogenic to man and a wide range of cestodes, will be reported.


The differential effects of prazosin and hydralazine on sympathoadrenal activity in conscious rats.
The ability of the vasodilator hydralazine and the alpha 1-adrenoceptor antagonist prazosin to increase sympathoadrenal outflow was compared by measuring plasma norepinephrine and epinephrine concentrations, norepinephrine clearance and norepinephrine spillover rate into plasma in conscious Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Even though the vasodepressor effect of 1 mg/kg (i.p.) of prazosin (-23 mm Hg) was significantly less than that caused by 1 mg/kg (i.p.) of hydralazine (-31 mm Hg) in normotensive rats, the increases in plasma norepinephrine concentration and norepinephrine spillover rate were significantly larger in prazosin-treated rats. In conscious SHR, 0.5 mg/kg (i.p.) of prazosin and 0.3 mg/kg (i.p.) of hydralazine lowered blood pressure to the same extent (-22 mm Hg), but prazosin again produced significantly larger increases in plasma norepinephrine concentration and norepinephrine spillover rate. Neither prazosin nor hydralazine affected norepinephrine clearance, and only prazosin elicited a significant rise in plasma epinephrine concentration. This differential effect of prazosin and hydralazine on sympathoadrenal activity is best explained by the differing effects of these drugs on venous return and thus the afferent activity of the cardiopulmonary baroreceptors.


Poor agreement between respiratory variations in pulse oximetry photoplethysmographic waveform amplitude and pulse pressure in intensive care unit patients.
To identify fluid responsiveness, a correlation between respiratory variations in pulse pressure (DeltaPP) and respiratory variations in pulse oximetry photoplethysmographic waveform amplitude (DeltaPOP) in mechanically ventilated patients has been demonstrated. To evaluate the agreement between the two methods, knowledge about the repeatability of the methods is imperative. However, no such data exist. Based on knowledge of slow oscillation in skin blood flow, the authors hypothesized that the variability of DeltaPOP would be larger than that of DeltaPP when calculations were performed continuously over a long recording period. Respiration, continuous invasive blood pressure, pulse oximetry, and skin microcirculation were recorded in 14 mechanically ventilated intensive care unit patients. No intravenous fluid challenges were given, and no other interventions were performed during the measurements. Seventy consecutive comparisons between DeltaPP and DeltaPOP were calculated for each of the 14 patients. For all patients, DeltaPOP was 13.7 +/- 5.8% and DeltaPP was 5.8 +/- 2.6% (P < 0.001). There was a larger intraindividual (8.94 vs. 1.29; P < 0.001) and interindividual (26.01 vs. 5.57; P < 0.001) variance of DeltaPOP than of DeltaPP. In six patients, there was no significant correlation between DeltaPP and DeltaPOP. A Bland-Altman plot showed poor agreement between the two methods. A large variability of DeltaPOP and a poor agreement between DeltaPP and DeltaPOP limits DeltaPOP as a tool for evaluation of fluid responsiveness in intensive care unit patients. This is in contrast to DeltaPP, which shows a small variability.


Characterization of motility and piliation in pathogenic Neisseria.
The type IV pili (Tfp) of pathogenic Neisseria (i.e., N. gonorrhoeae and N. meningitidis) are essential for twitching motility. Tfp retraction, which is dependent on the ATPase PilT, generates the forces that move bacteria over surfaces. Neisseria motility has mainly been studied in N. gonorrhoeae whereas the motility of N. meningitidis has not yet been characterized. In this work, we analyzed bacterial motility and monitored Tfp retraction using live-cell imaging of freely moving bacteria. We observed that N. meningitidis moved over surfaces at an approximate speed of 1.6 μm/s, whereas N. gonorrhoeae moved with a lower speed (1.0 μm/s). An alignment of the meningococcal and gonococcal pilT promoters revealed a conserved single base pair variation in the -10 promoter element that influence PilT expression. By tracking mutants with altered pilT expression or pilE sequence, we concluded that the difference in motility speed was independent of both. Live-cell imaging using total internal reflection fluorescence microscopy demonstrated that N. gonorrhoeae more often moved with fewer visible retracting filaments when compared to N. meningitidis. Correspondingly, meningococci also displayed a higher level of piliation in transmission electron microscopy. Nevertheless, motile gonococci that had the same number of filaments as N. meningitidis still moved with a lower speed. These data reveal differences in both speed and piliation between the pathogenic Neisseria species during twitching motility, suggesting a difference in Tfp-dynamics.


Effects of oral losartan administration on homeostasis of articular cartilage and bone in a rabbit model.
Previous work has shown that oral losartan can enhance microfracture-mediated cartilage repair in a rabbit osteochondral defect injury model. In this study, we aimed to determine whether oral losartan would have a detrimental effect on articular cartilage and bone homeostasis in the uninjured sides. New Zealand rabbits were divided into 4 groups including normal uninjured (Normal), contralateral uninjured side of osteochondral defect (Defect), osteochondral defect plus microfracture (Microfracture) and osteochondral defect plus microfracture and losartan oral administration (10 mg/kg/day) (Losartan). Rabbits underwent different surgeries and treatment and were sacrificed at 12 weeks. Both side of the normal group and uninjured side of treatment groups tibias were harvested for Micro-CT and histological analysis for cartilage and bone including H&E staining, Herovici's staining (bone and cartilage) Alcian blue and Safranin O staining (cartilage) as well as immunohistochemistry of losartan related signaling pathways molecules for both cartilage and bone. Our results showed losartan oral treatment at 10 mg/kg/day slightly increase Alcian blue positive matrix as well as decrease collagen type 3 in articular cartilage while having no significant effect on articular cartilage structure, cellularity, and other matrix. Losartan treatment also did not affect angiotensin receptor type 1 (AGTR1), angiotensin receptor type 2 (AGTR2) and phosphorylated transforming factor β1 activated kinase 1 (pTAK1) expression level and pattern in the articular cartilage. Furthermore, losartan treatment did not affect microarchitecture of normal cancellous bone and cortical bone of tibias compared to normal and other groups. Losartan treatment slightly increased osteocalcin positive osteoblasts on the surface of cancellous bone and did not affect bone matrix collagen type 1 content and did not change AGTR1, AGTR2 and pTAK1 signal molecule expression. Oral losartan used as a microfracture augmentation therapeutic does not have significant effect on uninjured articular cartilage and bone based on our preclinical rabbit model. These results provided further evidence that the current regimen of using losartan as a microfracture augmentation therapeutic is safe with respect to bone and cartilage homeostasis and support clinical trials for its application in human cartilage repair.


Serum Zinc, Selenium and Total Antioxidant Contents of Nigerian Children with Asthma: Association with Disease Severity and Symptoms Control.
Micronutrients and antioxidants may ameliorate oxidative stress. This study aimed to determine the serum Zinc (Zn), Selenium (Se) and Total Antioxidant Contents (TAC) of Nigerian children with asthma and relate these to disease severity and symptoms control. Children aged 2-15 years with asthma and age and sex matched controls were consecutively recruited. The children's serum Zn, Se and TAC were assayed and compared. Eighty children each with asthma and controls participated in the study. Serum Zn (71.0 ± 30.3 µg/dl vs. 84.2 ± 31.7 µg/dl; p = 0.008), Se (67.3 ± 29.8 µg/l vs. 80.0 ± 31.7 µg/l; p = 0.033) and TAC [median (interquartile range) 5.2 (3.8-6.8) ng/dl vs. 6.2 (4.3-8.0) ng/dl; p = 0.019] were lower in children with asthma. Serum Se (65.7 ± 29.1 µg/l vs. 92.4 ± 28.6 µg/l; p = 0.001) was lower in those with moderate/severe than mild disease, but no association with symptoms control (p > 0.05). Micronutrient supplementation may be beneficial in Nigerian children with asthma as they have relatively lower antioxidant micronutrients than nonasthmatics.


Gc and C3 polymorphisms in South Sardinia.
The distribution of phenotypes and gene frequencies of the group-specific component (Gc) and C3 complement were studied in South Sardinia. The gene frequencies were: Gc1 = 0.7346; C3F = 0.1963.


Waist circumference cutoff points and action levels for Asian Indians for identification of abdominal obesity.
To test the validity of internationally accepted waist circumference (WC) action levels for adult Asian Indians. Analysis of data from multisite cross-sectional epidemiological studies in north India. In all, 2050 adult subjects >18 years of age (883 male and 1167 female subjects). Body mass index (BMI), WC, waist-to-hip circumference ratio, blood pressure, and fasting samples for blood glucose, total cholesterol, serum triglycerides, and high-density lipoprotein cholesterol. In male subjects, a WC cutoff point of 78 cm (sensitivity 74.3%, specificity 68.0%), and in female subjects, a cutoff point of 72 cm (sensitivity 68.7%, specificity 71.8%) were appropriate in identifying those with at least one cardiovascular risk factor and for identifying those with a BMI >21 kg/m(2). WC levels of > or =90 and > or =80 cm for men and women, respectively, identified high odds ratio for cardiovascular risk factor(s) and BMI level of > or =25 kg/m(2). The current internationally accepted WC cutoff points (102 cm in men and 88 cm in women) showed lower sensitivity and lower correct classification as compared to the WC cutoff points generated in the present study. We propose the following WC action levels for adult Asian Indians: action level 1: men, > or =78 cm, women, >/=72 cm; and action level 2: men, > or =90 cm, women, > or =80 cm.


Endovascular Coiling of Wide-Neck and Wide-Neck Bifurcation Aneurysms: A Systematic Review and Meta-Analysis.
We present the results of a systematic review and meta-analysis examining outcomes of endovascular coiling of wide-neck and wide-neck bifurcation aneurysms with and without stent assistance. The aim of our study was to assess angiographic and clinical outcomes. We performed a comprehensive literature search for all articles on the endovascular coiling of wide-neck and wide-neck bifurcation aneurysms. Studies meeting our inclusion criteria and abstracted data were selected by 2 independent reviewers. Primary outcomes were >6-month complete or near-complete angiographic occlusion, aneurysm recanalization, and aneurysm retreatment. Secondary outcomes included initial complete or near-complete occlusion, long-term good neurologic outcome, procedure-related morbidity, and procedure-related mortality. Data were analyzed by using random-effects meta-analysis. In total, 38 studies including 2446 patients with 2556 aneurysms were included. For all wide-neck aneurysms, immediate complete or near-complete occlusion rate was 57.4% (95% CI, 48.1%-66.8%). Follow-up near-complete occlusion rate was 74.5% (95% CI, 68.0%-81.0%). Recanalization and retreatment rates were 9.4% (95% CI, 7.1%-11.7%) and 5.8% (95% CI, 4.1%-7.5%), respectively. Long-term good neurologic outcome was 91.4% (95% CI, 88.5%-94.2%). For wide-neck bifurcation aneurysms, initial complete or near-complete occlusion rate was 60.0% (95% CI, 42.7%-77.3%), long-term complete or near-complete occlusion rate was 71.9% (95% CI, 52.6%-91.1%), and the recanalization and retreatment rates were 9.8% (95% CI, 7.1%-12.5%) and 5.2% (95% CI, 1.9%-8.4%), respectively. Our study of angiographic and clinical outcomes for patients with wide-neck aneurysms demonstrates that endovascular coiling with or without stent-assisted coiling is safe, with low rates of perioperative morbidity and mortality. Initial and long-term angiographic outcomes were generally satisfactory, but not ideal. These data provide some baseline comparisons against which emergent technologies can be assessed.


Initiation of the Fixed Combination IDegLira in Patients with Type 2 Diabetes on Prior Injectable Therapy: Insights from the EASY French Real-World Study.
Combining basal insulin (BI) with glucagon-like peptide-1 receptor agonist (GLP-1RA) is recognized as a relevant option to optimize glucose control in type 2 diabetes (T2D). The EASY real-world study aimed to evaluate the modalities of initiation and the effectiveness of the insulin Degludec plus Liraglutide (IDegLira) fixed-ratio combination in the French health care system. A retrospective analysis included all patients with T2D and prior injectable therapy (GLP1-RA and/or insulin) who started treatment with IDegLira from September 2016 to December 2017 in 11 French diabetes centers. Baseline characteristics, reasons for IDegLira initiation, and modes of implementation were collected from the medical records. Changes in HbA1c and body weight were determined in patients with available follow-up data (nearest 6-month visit). IDegLira was initiated in 629 patients previously treated with GLP-1RA alone (11.6%), insulin alone (31.5% including 16.5% with BI and 14.9% with multiple daily injections [MDI]) or a free combination of GLP-1RA and insulin (56.9% including 44.8% with BI and 12.1% with MDI), associated or not with oral agents. IDegLira starting dose (mean of 29 ± 11 dose steps) most often exceeded the recommended dose, and was significantly correlated with prior BI but not GLP-1RA dosage. At initiation, mean age, body mass index (BMI) and HbA1c were 60.1 ± 10.2 years, 33.4 ± 6.2 kg/m2 and 8.8 ± 1.7%, respectively. In 461 patients with available follow-up (median 178 days), HbA1c decreased in all subgroups submitted to treatment intensification (- 1.7 ± 1.8% [p < 0.0001], - 1.2 ± 1.8% [p < 0.001] and - 0.8 ± 1.8% [p = 0.0026] in patients with prior GLP-1RA, BI or MDI therapy, respectively) but also in those switching from BI and GLP-1RA free combination (- 0.2 ± 0.9%, p = 0.0419). Significant body weight gain occurred in patients previously treated with GLP-1RA alone (+ 1.5 ± 5.8 kg, p = 0.0572) or combined to BI (+ 1.0 ± 3.1 kg, p < 0.0001) while those on BI (- 1.4 ± 4.6 kg, p = 0.0139) or MDI (- 1.4 ± 5.0 kg, p = 0.0484) experienced weight loss. While providing new information on the use of IDegLira in the French healthcare system, these data confirm the effectiveness of this fixed-ratio combination in the management of T2D.


Laparoscopic ureterolithotomy: our experience with 74 cases.
We retrospectively evaluated our experience with a relatively uncommon procedure, the laparoscopic ureterolithotomy, for the treatment of ureteral stones. Between April 2002 and October 2006, a total of 74 patients (56 males, 18 females) with upper (54 cases), middle (18 cases) and lower (two cases) ureteral stones underwent laparoscopic ureterolithomy. The mean age was 39.4 years (range, 19-74). The stones were in the right side in 44 cases (59.5%) and in the left side in 30 (40.5%) cases. The mean stone size was 1.8 cm (range 1.5-2.8). The procedure was retroperitoneal in 66 cases (89.2%) and transperitoneal in eight (10.8%) cases. Laparoscopic guided flexible ureterorenoscopic extraction of kidney stone was carried out in one case as an adjuvant procedure. The ureter was stented and not sutured in 64 cases (86.5%). The procedure was successfully completed in 94.6% of cases and an open conversion was carried out in four (5.4%) patients. The mean operative time was 58.7 min, and the mean blood loss was 90.6 mL. No major complications were encountered. Prolonged urinary leakage occurred in one patient. The mean hospital stay was 6.4 days. One patient developed ureteral stricture during follow up and was treated by endoscopic dilatation and stenting. In our experience laparoscopic ureterolithotomy represents a safe and effective treatment option for ureteral stones either as primary for large impacted stones or as a salvage procedure after failed shock wave lithotripsy or ureteroscopy. This procedure fulfills the advantages of minimal blood loss and analgesia requirements, good cosmetic appearance, short hospital stay and convalescence period.


A new lineage of halophilic, wall-less, contractile bacteria from a brine-filled deep of the Red Sea.
A novel strictly anaerobic bacterium designated strain SSD-17B(T) was isolated from the hypersaline brine-sediment interface of the Shaban Deep, Red Sea. Cells were pleomorphic but usually consisted of a central coccoid body with one or two "tentacle-like" protrusions. These protrusions actively alternated between a straight, relaxed form and a contracted, corkscrew-like one. A peptidoglycan layer was not detected by electron microscopy. The organism forms "fried-egg"-like colonies on MM-X medium. The organism is strictly anaerobic and halophilic and has an optimum temperature for growth of about 30 to 37 degrees C and an optimum pH of about 7. Nitrate and nitrite are reduced; lactate is a fermentation product. The fatty acid profile is dominated by straight saturated and unsaturated chain compounds. Menaquinone 4 is the major respiratory quinone. Phylogenetic analysis demonstrated strain SSD-17B(T) represents a novel and distinct lineage within the radiation of the domain Bacteria. The branching position of strain SSD-17B(T) was equidistant to the taxa considered to be representative lineages of the phyla Firmicutes and Tenericutes (with its sole class Mollicutes). The phenotypic and phylogenetic data clearly show the distinctiveness of this unusual bacterium, and we therefore propose that strain SSD-17B(T) (= DSM 18853 = JCM 14575) represents a new genus and a new species, for which we recommend the name Haloplasma contractile gen. nov., sp. nov. We are also of the opinion that the organism represents a new order-level taxon, for which we propose the name Haloplasmatales.


Epigenetic and transcriptional mechanisms for the regulation of IL-10.
IL-10 is a critical immunoregulatory cytokine expressed in virtually all immune cell types. Maintaining a delicate balance between effective immune response and tolerance requires meticulous and dynamic control of IL-10 expression both epigenetically and transcriptionally. In this Review, we describe the epigenetic mechanisms controlling IL-10 expression, including chromatin remodeling, 3D chromatin loops, histone modification and DNA methylation. We discuss the role of transcription factors in directing chromatin modifications, with a special highlight on the emerging concept of pioneer transcription factors in setting up the chromatin landscape in T helper cells for IL-10 induction. Besides summarizing the recent progress on transcriptional regulation in specialized IL-10 producers such as type 1 regulatory T cells, regulatory B cells and regulatory innate lymphoid cells, we also discuss common transcriptional mechanisms for IL-10 regulation that are shared with other IL-10 producing cells.


Posttraumatic lumbar intraspinal extradural-intradural ossification.
A case of intraspinal calcification having mainly the configuration of an intradural cast is presented. The traumatic etiology is obvious, and we consider, that the dural sac and nerve root lacerations were associated with intradural as well as extradural hematomas, which later became calcified.


Generation of an RNF1-deficient human pluripotent stem cell line using CRISPR/Cas9 technology.
RNF1 (RING1A) is a catalytic component of the polycomb repressive complex 1 (PRC1) involved in regulation of, among others, embryonic development and disease progression. However, the exact role of RNF1 in self-renewal and differentiation of human embryonic stem cells (ESCs) remains unknown. Here, we derive one RNF1 knockout human ESC line using CRISPR/Cas9 system. The cell line retains the canonical stem cell morphology and normal karyotype. Moreover, the cell line highly expresses pluripotency genes and has three germ-layer differentiation potential. The RNF1 -/- cell line will be useful for studies on the function and role of RNF1 in human embryonic stem cell fate decisions.


Comprehensive analysis of candidate signatures of long non-coding RNA LINC01116 and related protein-coding genes in patients with hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a long-term malignancy that causes high morbidities and mortalities worldwide. Notably, long non-coding RNAs (LncRNAs) have been identified as candidate targets for malignancy treatments. LncRNA LINC01116 and its Pearson-correlated genes (PCGs) were identified and analyzed in HCC patients. The diagnostic and prognostic value of the lncRNA was evaluated using data from The Cancer Genome Atlas (TCGA). Further, we explored the target drugs of LINC01116 for clinical application. Relationships between immune infiltration and PCGs, methylation and PCGs were explored. The diagnostic potentials were then validated by Oncomine cohorts. LINC01116 and the PCG OLFML2B are differentially and highly expressed in tumor tissues (both P ≤ 0.050). We found that LINC01116, TMSB15A, PLAU, OLFML2B, and MRC2 have diagnostic potentials (all AUC ≥ 0.700, all P ≤ 0.050) while LINC01116 and TMSB15A have prognostic significance (both adjusted P ≤ 0.050). LINC01116 was enriched in the vascular endothelial growth factor (VEGF) receptor signaling pathway, mesenchyme morphogenesis, etc. After that, candidate target drugs with potential clinical significance were identified: Thiamine, Cromolyn, Rilmenidine, Chlorhexidine, Sulindac_sulfone, Chloropyrazine, and Meprylcaine. Analysis of immune infiltration revealed that MRC2, OLFML2B, PLAU, and TMSB15A are negatively associated with the purity but positively associated with the specific cell types (all P < 0.050). Analysis of promoter methylation demonstrated that MRC2, OLFML2B, and PLAU have differential and high methylation levels in primary tumors (all P < 0.050). Validation results of the differential expressions and diagnostic potential of OLFML2B (Oncomine) were consistent with those obtained in the TCGA cohort (P < 0.050, AUC > 0.700). Differentially expressed LINC01116 could be a candidate diagnostic and an independent prognostic signature in HCC. Besides, its target drugs may work for HCC therapy via the VEGF receptor signaling pathway. Differentially expressed OLFML2B could be a diagnostic signature involved in HCC via immune infiltrates.


Prevalence and distribution of hypertension in overweight and obese subjects in an urban community in Enugu, South East Nigeria. A post hoc analysis.
Most recent studies in Nigeria have documented high prevalence of hypertension, diabetes, and obesity. Several mechanisms may link hypertension and obesity hence the high prevalences of both disorders in Nigeria. There are however no studies on the prevalence of hypertension among the obese in urban settings. The aim of this study was to describe the prevalence and pattern of hypertension in overweight/obese individuals in a community. We conducted a post-hoc analysis on obese subjects 20 years and above from two urban settlements within Enugu metropolis. For database management and statistical analyses, we used the SPSS version 22. Data from a total of 301 individuals with obesity who met the selection criteria were re-analyzed. A total of 198 (65.8%) individuals were found to have hypertension most of whom were newly diagnosed 110 (55.6%). The prevalence of hypertension was 65.8% and increased with age and BMI. Individuals with overweight/obesity have very high rates of hypertension. The prevalence of hypertension also increased with and BMI. Thus, there is need for targeted health education in adults to address the burden of obesity and hypertension to reduce the burden of cardiovascular disease in the community.


Accurately predicting the risk of unfavorable outcomes after endovascular coil therapy in patients with aneurysmal subarachnoid hemorrhage: an interpretable machine learning model.
Despite endovascular coiling as a valid modality in treatment of aneurysmal subarachnoid hemorrhage (aSAH), there is a risk of poor prognosis. However, the clinical utility of previously proposed early prediction tools remains limited. We aimed to develop a clinically generalizable machine learning (ML) models for accurately predicting unfavorable outcomes in aSAH patients after endovascular coiling. Functional outcomes at 6 months after endovascular coiling were assessed via the modified Rankin Scale (mRS) and unfavorable outcomes were defined as mRS 3-6. Five ML algorithms (logistic regression, random forest, support vector machine, deep neural network, and extreme gradient boosting) were used for model development. The area under precision-recall curve (AUPRC) and receiver operating characteristic curve (AUROC) was used as main indices of model evaluation. SHapley Additive exPlanations (SHAP) method was applied to interpret the best-performing ML model. A total of 371 patients were eventually included into this study, and 85.4% of them had favorable outcomes. Among the five models, the DNN model had a better performance with AUPRC of 0.645 (AUROC of 0.905). Postoperative GCS score, size of aneurysm, and age were the top three powerful predictors. The further analysis of five random cases presented the good interpretability of the DNN model. Interpretable clinical prediction models based on different ML algorithms have been successfully constructed and validated, which would serve as reliable tools in optimizing the treatment decision-making of aSAH. Our DNN model had better performance to predict the unfavorable outcomes at 6 months in aSAH patients compared with Yan's nomogram model.


Responses of NFR/N inbred mice to very low-dose infections with Ascaris suum.
Mice were evaluated for immunological responses and resistance to challenge infections after single infections. When given infections simultaneously with thiabendazole, larval migration to the liver and lungs was blocked but not when mice were given infections only. Enlargement of Peyer's patches was observed after infection followed by increased numbers of IgA-containing cells in the lamina propria of the intestines and increased levels of hepatobiliary IgA. Ig-containing cells were variable in the spleens during the early phase of infection. The observed changes quickly returned to normal control levels and did not change throughout the rest of the experiment. Serum Ig levels did not change dramatically. Challenge with high doses of eggs indicated that mice given single very low-dose infections became highly resistant.


Tissue-type plasminogen activator in plasma from breast cancer patients determined by enzyme-linked immunosorbent assay.
An enzyme-linked immunosorbent assay (ELISA) using monoclonal and polyclonal antibodies against t-PA was used to measure the concentration of tissue-type plasminogen activator (t-PA) in plasma from 34 healthy donors and 92 breast cancer patients with a varying extent of disease. The mean value of t-PA in plasma for the healthy donors was 2.4 +/- 2.1 ng ml-1 (s.d.). The mean value for the breast cancer patients was 5.3 +/- 4.3 ng ml-1. This increase was statistically significant at the 1% level. There was a positive correlation between the mean t-PA plasma concentration and the extent of disease in different groups of patients. Taking 5.0 ng ml-1 as cut-off point, about 40% of the patients were positive, and 6% of the normal controls were false positive. Twenty-five per cent of the patients in complete remission, 28% of the patients with minimal tumour burden, 60% of the patients with moderate tumour burden, and 90% of the patients with massive tumour burden were positive. It is possible that the patients with an elevated plasma t-PA represent a group with a particularly bad prognosis.


Validation of the illustrated questionnaire on eating and sedentary behaviors (QUICAS) for seven to ten-year-old children.
The Illustrated Questionnaire on Eating and Sedentary Behaviors (QUICAS) was developed and validated for schoolchildren seven to ten years old. It used previous day recall and was illustrated with ten eating behaviors (referring to the act of eating without distractions, with company, on a regular basis, the type of food eaten, and participation in tasks involved in meal preparation) and five sedentary behaviors (related to the use of television, computer, tablet, cell phone, and video game). The instrument was validated in four stages: (1) Its content was developed based on literature review and expert evaluation; (2) Items were validated by comparing the responses of children and their parents, through a questionnaire on Google Forms. At this stage, a convenience sample was adopted, consisting of 145 parent-child dyads. High sensitivity (average of 90.7%); high specificity (mean of 87.9%); low number of false positives (mean of 12.1%); low number of false negatives (mean of 9.3%); almost perfect agreement between the child's and the parent's reports (k = 0.81); and low disagreement (≤22%) were found. In addition, the child's gender and age did not significantly influence the child's report. (3) The illustrations were validated in a focus group with 18 children, who satisfactorily described all the eating and sedentary behaviors of the illustrations. (4) In the pretest of the questionnaire on Google Forms, with the participation of 15 children, the majority (86.7%) judged the questionnaire as excellent or good. Therefore, the QUICAS is valid to assess eating and sedentary behaviors in schoolchildren seven to ten years old.


Glycaemic and non-glycaemic efficacy of once-weekly GLP-1 receptor agonists in people with type 2 diabetes.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may confer a range of benefits for people with type 2 diabetes (T2D), which is reflected through their position within diabetes treatment guidelines. The objective of this narrative review is to explore the efficacy data of once-weekly (QW) GLP-1 RAs in terms of glycaemic control, body weight reduction, cardiovascular (CV) outcomes and potential renal protective effects to assist pharmacists and other healthcare professionals (HCPs) in treatment discussions with patients. This a narrative review focused on 31 clinical trials involving the Phase 3 clinical programmes of the QW GLP-1 RAs dulaglutide, exenatide extended-release (ER) and semaglutide subcutaneous (s.c.). The clinical trials were divided by their comparator arms and examined for trends. All QW GLP-1 RAs were superior to placebo for reductions in glycated haemoglobin (HbA1c ) and body weight. Data regarding QW GLP-1 RAs versus metformin were limited, likely due to metformin's use as the first-line pharmacologic for T2D. In the robust head-to-head trials of QW versus QW GLP-1 RAs, semaglutide s.c. was superior to both dulaglutide and exenatide ER regarding HbA1c and body weight; however, QW versus once-daily GLP-1 RA trials had mixed results depending on the comparators. Finally, in QW GLP-1 RA versus insulin trials, all QW GLP-1 RAs were as effective as insulin, particularly when hypoglycaemia and body weight were also considered. CV outcome trials demonstrated benefits in major adverse CV events and renal outcomes for semaglutide and dulaglutide. This review collates recently published data and previously published Phase 3 results to allow pharmacists and other HCPs to understand all of the efficacy data available and the corresponding impact on treatment guidelines. QW GLP-1 RAs are emerging as important therapeutic options for people with T2D as they offer a spectrum of benefits extending beyond glycaemic control, but it is important to be aware of their efficacy differences when prescribing and discussing them with patients.


Plant viral vectors for delivery by Agrobacterium.
Plant viral vectors delivered by Agrobacterium are the basis of several manufacturing processes that are currently in use for producing a wide range of proteins for multiple applications, including vaccine antigens, antibodies, protein nanoparticles such as virus-like particles (VLPs), and other protein and protein-RNA scaffolds. Viral vectors delivered by agrobacterial T-DNA transfer (magnifection) have also become important tools in research. In recent years, essential advances have been made both in the development of second-generation vectors designed using the 'deconstructed virus' approach, as well as in the development of upstream manufacturing processes that are robust and fully scalable. The strategy relies on Agrobacterium as a vector to deliver DNA copies of one or more viral RNA/DNA replicons; the bacteria are delivered into leaves by vacuum infiltration, and the viral machinery takes over from the point of T-DNA transfer to the plant cell nucleus, driving massive RNA and protein production and, if required, cell-to-cell spread of the replicons. Among the most often used viral backbones are those of the RNA viruses Tobacco mosaic virus (TMV), Potato virus X (PVX) and Cowpea mosaic virus (CPMV), and the DNA geminivirus Bean yellow dwarf virus. Prototypes of industrial processes that provide for high yield, rapid scale up and fast manufacturing cycles have been designed, and several GMP-compliant and GMP-certified manufacturing facilities are in place. These efforts have been successful as evidenced by the fact that several antibodies and vaccine antigens produced by magnifection are currently in clinical development.


Flerobuterol: a potential antidepressant drug related to beta-adrenergic agonists. Experimental profile in mice.
The potential antidepressant effect of flerobuterol (dl-(fluoro-2 phenyl)-1 t-butylamino-2 ethanol), a new drug related to beta-adrenoceptor agonists, was evaluated and compared with imipramine and salbutamol using classical psychopharmacological tests in mice. Like imipramine and salbutamol, flerobuterol (0.5-32 mg kg-1, ip) fully prevented apomorphine (16 mg kg-1, sc)- and partly reversed reserpine- and oxotremorine-induced hypothermia. At higher doses (16-32 mg kg-1), flerobuterol enhanced the toxic effects of yohimbine. Unlike imipramine, flerobuterol and salbutamol did not reduce immobility duration in the behavioural despair test. Salbutamol and flerobuterol decreased locomotor activity. Flerobuterol did not induce mydriasis, did not prevent oxotremorine-induced tremors or salivary and lacrimal gland secretion and did not reduce reserpine-induced palpebral ptosis. Propranolol (8 mg kg-1, ip) but not alpha-methyl-paratyrosine (75 mg kg-1, ip) prevented the flerobuterol-induced antagonism of apomorphine-induced hypothermia. Our results suggest that flerobuterol demonstrates potential antidepressant activity, which could be related to beta-adrenoceptor activation in mice.


Evaluating the male and female reproductive toxicity of high-boiling petroleum substances.
To meet the EPA HPV Chemical Challenge Program requirement for reproductive toxicity data on sponsored high-boiling petroleum substances (HBPS), an analysis was conducted using the results of 39 repeat-dose and 59 developmental rat dermal toxicity studies on HBPS samples spanning the boiling range of the sponsored substances, and the results of three one-generation reproductive toxicity studies on two samples spanning the concentration range of polycyclic aromatic compounds of sponsored substances. The analysis found little evidence of male or female reproductive tract toxicity based on histopathology, reproductive organ weight, and sperm parameters, and no evidence of effects on fertility, while significant developmental toxicity and/or systemic repeat-dose toxicity were frequently observed. Among 14 samples of HBPS tested in both repeat-dose toxicity and developmental toxicity studies, there were no studies in which an adverse reproductive tract finding occurred at a dose lower than that producing developmental toxicity or other adverse effects in repeat-dose toxicity studies. The current analysis supports the hypothesis that effects in developmental and/or repeat-dose toxicity studies of HBPS occur at doses lower than those that might affect fertility in rat one-generation reproductive studies. When adequate developmental and repeat-dose toxicity studies are available, a reproductive toxicity study of HBPS appears unnecessary.


Endoscopic management of acute sigmoid volvulus in high risk surgical elderly patients: a randomized controlled trial.
Most patients with sigmoid volvulus are of old age with multiple comorbidities. So, the risk of surgery for those elderly patients is usually associated with increased rates of morbidity and mortality. Early intervention is required for managing sigmoid volvulus to avoid its serious complications; therefore, early endoscopic untwist of sigmoid colon can be performed followed by endoscopic fixation of sigmoid colon under sedation in this category of the patients to avoid development of high risk surgical complications following surgical fixation of sigmoid colon or sigmoidectomy after initial simple loop colostomy procedure to relieve obstruction. This prospective randomized controlled clinical trial included all patients who developed acute sigmoid volvulus and were referred to the Zagazig University Hospital Emergency Department between December 2020 and August 2022. The study was prospectively approved by Zagazig University Faculty of Medicine Institutional Review Board (Approval Number: 9989/23-10-2022) and was retrospectively submitted in http://clinicaltrials.gov in November 2022 ( http://clinicaltrials.gov ID: NCT05620446). Included eligible patients were simply randomized at a 1:1 ratio to "Endoscopic Group (EG)" or "Surgical Group (SG)" via drawing of sealed envelopes containing computer-generated random numbers prepared by a third party before start of intervention. Sample size included 18 patients divided into 2 equal groups. (1) Endoscopic group included 9 patients who were subjected to endoscopic untwist of sigmoid colon followed by endoscopic fixation of sigmoid colon under sedation; (2) Surgical group included 9 patients who were subjected to surgical fixation of sigmoid colon or sigmoidectomy after initial simple loop colostomy under general anesthesia. In comparison between both groups, there were statistically significant differences regarding length of hospital stay and procedure time. Unfortunately, there were no statistically significant differences regarding postoperative complications and co-morbidities. Eight patients in the endoscopy group demonstrated excellent quality of life, and one demonstrated good quality of life; unlike the surgical group, there were 3 patients with excellent quality of life, 5 patients with good quality of life, and 1 patient with poor quality of life. So there was statistically significant difference regarding quality of life between both groups. During the 9-month follow-up period, both groups demonstrated no cases of recurrence post-fixation. Endoscopic management of acute sigmoid volvulus is effective and safe in elderly high risk surgical patients (either in managing the intestinal obstruction caused by volvulus or in definitive treatment of volvulus).


Changes in antioxidant and antiinflammatory activity of black bean (Phaseolus vulgaris L.) protein isolates due to germination and enzymatic digestion.
Germination is an inexpensive process to improve the nutritional properties of legumes. The effect of germinating black bean seeds on the production of cotyledon protein hydrolysates (CPH) with antioxidant and antiinflammatory activities was analyzed in this research. After simulated enzymatic digestion, the oxygen radical absorbance capacity (ORAC) of CPH obtained from germinated black beans was lower than that observed for raw cotyledons. There were no significant differences among CPH cellular antioxidant activities (CAA), except for the high CAA of the 120 min hydrolysate obtained from one day germinated black bean cotyledons. The most significant changes due to germination and enzymatic hydrolysis were observed for the inhibition of nitric oxide (NO) production in macrophages. The NO synthesis inhibition observed for raw CPH was reduced after simulated gastrointestinal digestion but for germinated samples the inhibition was doubled. Peptides derived from cell wall proteins produced during germination could be responsible of antiinflammatory activity.


[Production of patulin in a liquid medium by moulds belonging to the genera: Aspergillus and Penicillium (author's transl)].
The toxinogenesis of 10 strains of Penicillium granulatum, 5 of P. expansum, 4 of Aspergillus terreus, 2 of A. clavatus, P. thomii, P. urticae, P. italicum and 1 of P. claviforme was tested at 26 degrees C in Czapek's enriched liquid medium (8 p. 1000 glucose + 2 p. 1000 yeast extract). 6 strains of P. granulatum, 5 of P. expansum, 1 of P claviforme and P. thomii produced patulin after 9 days of culture. Mycotoxin concentrations recovered was between 0.2 ppm and 3127 ppm. Highly toxinogenic strains are Penicillium granulatum; but patulin in silages was not associated with P. granulatum.


Is the combined application of both drain-clamping and tranexamic acid superior to the single use of either application in patients with total-knee arthroplasty?: A meta-analysis of randomized controlled trials.
To compare the efficacy and safety of the combined application of both drain-clamping and tranexamic acid (TXA) versus the single use of either application in patients with total-knee arthroplasty (TKA). Databases (EMBASE, PubMed, Cochrane Library, Web of Sciences, the Google database, and the Ovid database) were searched from their inception through April 2018 for randomized controlled trials (RCTs) comparing the combined application of both drain-clamping and TXA versus single use of either application in patients with TKA. The Cochrane risk of bias (ROB) tool was used to assess the methodologic quality. The primary outcomes were blood loss in drainage, total blood loss, transfusion rate, and hemoglobin decline. The secondary outcomes were postoperative complications, the Knee Society Score (KSS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. The statistical analysis was performed with RevMan 5.3.5 software. A total of five RCTs (479 participants) were included in our meta-analysis. The present meta-analysis indicated that significant differences existed in the total blood loss (mean difference [MD] = -145.86, 95% confidence interval [CI]: -228.64 to -63.08, P = .0006), blood loss in drainage (MD = -169.06, 95% CI: -248.56 to -89.57, P < .0001), hemoglobin decline (MD = -0.66, 95% CI: -1.00 to -0.33, P = .0001), and transfusion rate (MD = 0.44, 95% CI: 0.26-0.75, P = .002) between the groups. However, regarding postoperative complications, no significant differences were found between the 2 groups in the KSS and the WOMAC score (P > .05). Combined application of both drain-clamping and TXA was associated with significant reductions in blood loss in drainage, total blood loss, hemoglobin decline, and the need for transfusion. However, high-quality, well-designed RCTs with long-term follow-up are still required.


Cognitive mediators of adaptive functioning outcomes in survivors of pediatric brain tumors treated with proton radiotherapy.
Cranial radiotherapy (RT) is associated with risk for cognitive and adaptive dysfunction. Proton RT (PRT) is a technique hypothesized to spare cognition by reducing exposure to nontarget brain tissue. However, little is known regarding functional outcomes in survivors of pediatric brain tumor (BT) treated with PRT. The present study examined the relationship between cognitive and adaptive outcomes in pediatric BT survivors post-PRT. Survivors treated with either focal (n = 33) or craniospinal irradiation (CSI; n = 37) PRT completed neurocognitive evaluations approximately 5 years post-treatment. Results of intelligence testing and ratings of adaptive functioning are reported. Mediation models examined the relationship among radiation field, cognition, and adaptive functioning. The PRT CSI group demonstrated worse cognitive outcomes than the PRT Focal group across each cognitive index (Cohen's d = 0.56-0.70). Parent ratings of adaptive functioning were also worse in the PRT CSI group than the PRT Focal group (Global Adaptive Composite, d = 0.53; conceptual skills, d = 0.67). Cognitive performance fully mediated the relationship between radiation field and adaptive outcomes, while controlling for group differences in tumor histology and RT dose. Focal PRT survivors demonstrated generally positive outcomes with weaknesses in processing speed and aspects of adaptive functioning. CSI exposure was associated with more consistently poor cognitive and adaptive outcomes. The increased risk for adaptive dysfunction in the PRT CSI group appeared due to the effects of CSI on cognition. Efforts to reduce the volume of tissue exposure to RT remain important.


Combination of ultrasonic and acidic pretreatments for enhancing biohythane production from tofu processing residue via one-stage anaerobic digestion.
Tofu processing residues (TPR) have received more attention as a source of bioenergy. However, their low solubility has hindered biohythane generation. Consequently, the ultrasonic and H2SO4 pretreatments were combined and compared for the first time to improve the hydrolysis of organic matter and carbohydrate and increase free amino nitrogen generation from TPR. Besides, the impact of pretreatments on biohythane generation was investigated. Under the optimal conditions of 7.54% substrate level, 8% H2SO4 concentration, 80 °C and 50 min, the coincident ultrasonic-H2SO4 pretreatment enriched the contents of soluble chemical oxygen demand, reducing sugar, and free amino nitrogen to 49675 mg/L, 26 g/L, and 1721 mg/L, respectively, greater than individual pretreatments. Also, Biohythane yield increased by 4.24-13.61% over control (389.42 ± 23.7 ml/g-VSfed). Furthermore, hydrogen yield at 42.5 ± 2.08 and 28.1 ± 1.07 ml/g-VSfed and sulfate removal efficiency at 93 and 92% were significantly improved with ultrasonic-H2SO4 and H2SO4 pretreatments, respectively, indicating acidogenic and sulfidogenic activity enhancement.


Sexual differentiation in three unconventional mammals: spotted hyenas, elephants and tammar wallabies.
The present review explores sexual differentiation in three non-conventional species: the spotted hyena, the elephant and the tammar wallaby, selected because of the natural challenges they present for contemporary understanding of sexual differentiation. According to the prevailing view of mammalian sexual differentiation, originally proposed by Alfred Jost, secretion of androgen and anti-Mullerian hormone (AMH) by the fetal testes during critical stages of development accounts for the full range of sexually dimorphic urogenital traits observed at birth. Jost's concept was subsequently expanded to encompass sexual differentiation of the brain and behavior. Although the central focus of this review involves urogenital development, we assume that the novel mechanisms described in this article have potentially significant implications for sexual differentiation of brain and behavior, a transposition with precedent in the history of this field. Contrary to the "specific" requirements of Jost's formulation, female spotted hyenas and elephants initially develop male-type external genitalia prior to gonadal differentiation. In addition, the administration of anti-androgens to pregnant female spotted hyenas does not prevent the formation of a scrotum, pseudoscrotum, penis or penile clitoris in the offspring of treated females, although it is not yet clear whether the creation of masculine genitalia involves other steroids or whether there is a genetic mechanism bypassing a hormonal mediator. Wallabies, where sexual differentiation occurs in the pouch after birth, provide the most conclusive evidence for direct genetic control of sexual dimorphism, with the scrotum developing only in males and the pouch and mammary glands only in females, before differentiation of the gonads. The development of the pouch and mammary gland in females and the scrotum in males is controlled by genes on the X chromosome. In keeping with the "expanded" version of Jost's formulation, secretion of androgens by the fetal testes provides the best current account of a broad array of sex differences in reproductive morphology and endocrinology of the spotted hyena, and androgens are essential for development of the prostate and penis of the wallaby. But the essential circulating androgen in the male wallaby is 5alpha androstanediol, locally converted in target tissues to DHT, while in the pregnant female hyena, androstenedione, secreted by the maternal ovary, is converted by the placenta to testosterone (and estradiol) and transferred to the developing fetus. Testicular testosterone certainly seems to be responsible for the behavioral phenomenon of musth in male elephants. Both spotted hyenas and elephants display matrilineal social organization, and, in both species, female genital morphology requires feminine cooperation for successful copulation. We conclude that not all aspects of sexual differentiation have been delegated to testicular hormones in these mammals. In addition, we suggest that research on urogenital development in these non-traditional species directs attention to processes that may well be operating during the sexual differentiation of morphology and behavior in more common laboratory mammals, albeit in less dramatic fashion.


Measurement of effects of the Chinese herbal medicine higenamine on left ventricular function using a cardiac probe.
The effects of the Chinese herbal medicine higenamine on left ventricular function were studied by means of an external radiation detector in 15 patients with heart disease. Higenamine, administered intravenously, markedly increased the ejection fraction of LV, as well as the ejection rate. The LVEF increased from 46% +/- 9% to 60% +/- 15% and 61% +/- 12% (P less than 0.005) after a 30- and 60-min infusion of higenamine, respectively. The percentage increase in LVEF paralleled the increase in the heart rate. The effects of higenamine on LV function were similar to the response obtained with isoproterenol. These results document the pharmacologic effect of the Chinese herbal medicine, higenamine, on heart function.


Clinical spectrum of septic pulmonary embolism and infarction.
Management of septic pulmonary embolism now suggests a predictability of the clinical course which often allows an early decision regarding the need for definitive thoracotomy. Sixty patients have been treated within the past 5 years. Antibiotics were employed in all patients, administered whenever possible according to cultures. In 12 patients thoracotomy was required. This involved decortication and varying amounts of pulmonary resection from wedge excision to pneumonectomy. Early appreciation of septic pulmonary embolism and prompt thoracotomy can frequently obviate the need for tardy open drainage procedures with consequent prolonged recovery. Sources of emboli must be controlled. Interruption of the inferior vena cava, vein excision, aggressive control of peripheral abscesses, and excision of the tricuspid valve may be required. Reliance on antiocagulants alone to control emboli is dangerous, and proper surgical intervention and antibiotic therapy reduce the need for long-term anticoagulation.


Immunochemical studies of estrogen receptors.
Fusion of splenic lymphocytes from Lewis rats, immunized with affinity-purified estrogen receptor from the cytosol of MCF-7 human breast cancer cells, with two different mouse myeloma lines, has provided 13 monoclonal hybridoma lines secreting antiestrophilin antibodies, each of which (with one possible exception) recognizes a different antigenic determinant in the human receptor molecule. Of this library of monoclonal antibodies, some react with estrophilin from all sources tested, some react with mammalian but not avian receptors, whereas one preparation appears specific for estrophilin from primate sources. By proteolytic digestion under controlled conditions with mercury-deactivated papain, chymotrypsin, and trypsin, respectively, it is possible to remove sequentially the determinants recognized by one, two or three of the monoclonal antibodies, leaving the epitopes for the six remaining antibodies investigated on the steroid-binding portion of the receptor. The proteolytic fragment containing the epitope most readily removed (by mercuripapain) also contains the DNA-binding domain of the activated receptor molecule. Immunocytochemical staining, using the peroxidase procedure with various monoclonal antibody preparations, of frozen sections of human breast cancer tissue, fixed in ethanol or in picric acid-formaldehyde reagent, shows clearly that the majority of the native receptor, which appears in the cytosol after tissue homogenization, is actually localized within the nuclear compartment in the intact cell. The immunocytochemical technique also permits the identification of mixed populations of receptor-containing and non-containing cells in human breast cancers.