Glenohumeral joint lavage does not affect clinical outcomes in open reduction and internal fixation of displaced intracapsular proximal humeral fractures: a prospective, randomized, double-blinded trial.
This prospective, randomized, and double-blinded trial evaluates the effect of intraoperative glenohumeral joint lavage in open reduction and internal fixation of displaced intracapsular proximal humeral fractures. Between January 2016 and April 2018, 86 patients (mean age: 65.2 ± 16.3 years) with a displaced intracapsular proximal humeral fracture were treated by open reduction and internal fixation using locking plates. Patients were randomized to either locked plating followed by intraoperatively performed glenohumeral joint lavage (group L, n = 36) or locked plating without the lavage (group NL, n = 36). Functional outcome assessment included range of shoulder motion, strength, and the Constant score, obtained 6 weeks, 3 months, 6 months, and 12 months postoperatively. A total of 62 shoulders could be reviewed for final investigation (86% follow-up). One year after open reduction and internal fixation, the mean Constant score was 70 ± 14 (group L, n = 31) compared with 73 ± 14 (group NL, n = 31, P = .272). The mean forward flexion and abduction in group L was 134 ± 33 and 128 ± 33 as compared with 139 ± 32 and 135 ± 32 in group NL, respectively (P = .538, P = .427). The mean external rotation was 40 ± 16 (group L) compared with 44 ± 16 (group NL) (P = .210). The overall complication rate was 9.6% and did not differ significantly between the groups (P = .321). In group L, there were 2 cases of avascular necrosis (6.5%) and 1 case of secondary displacement (3.2%). In group NL, 1 case of avascular necrosis (3.2%) and 1 case of secondary displacement were noted (3.2%, P = .742). The results of this study do not demonstrate a need for glenohumeral joint lavage in open reduction and internal fixation of displaced intracapsular proximal humeral fractures with regard to shoulder function at 1-year follow-up.


Soft-Tissue Metastases From Esophageal Cancer.
Metastatic carcinoma to skeletal muscle and/or subcutaneous fat is a rare event. Only 27 cases of esophageal cancer to soft tissue have been described in the English-language literature. Our goal was to describe the prevalence and clinical characteristics of soft-tissue metastasis among patients with primary esophageal cancer at a single institution. We performed a retrospective review of all patients with primary esophageal cancer. Data points analyzed included histologic subtype, anatomic location, metastasis pattern, treatment, and survival. Kaplan-Meier curves were used to estimate survival time, and log-rank tests were used for comparisons. For all analyses, P < 0.05 was considered significant. Of 1341 patients with primary esophageal cancer, 25 (1.9%) had metastases to soft tissue. Soft-tissue metastases were diagnosed at a median age of 64 years, a median 9.6 months after esophageal cancer diagnosis. Adenocarcinoma was the predominant histopathological type, and soft-tissue metastasis was most common in the lower extremity. Local intervention was used for 10 symptomatic patients with favorable prognoses. Chemotherapy was the only treatment modality in 18 patients. Median survival time after diagnosis of soft-tissue metastasis was 8.9 months and was longer in patients with metastasis in soft tissue only (24.6 months, P = 0.007) and in those who received local intervention (11.1 months vs those who did not, P = 0.020). We estimate the prevalence of soft-tissue metastasis to be 1.9% among patients with esophageal cancer. Local intervention may be beneficial for patients in otherwise good health with symptomatic soft-tissue lesions.


Antioxidants and bioactivities of free, esterified and insoluble-bound phenolics from berry seed meals.
Phenolic compounds present in the free, soluble ester and insoluble-bound forms of blackberry, black raspberry and blueberry were identified and quantified using high-performance liquid chromatography-diode array detection-electrospray ionisation multistage mass spectrometry. The total phenolics, scavenging activity against hydroxyl and peroxyl radicals, the reducing power and chelating capacity were, in general, in the decreasing order of blackberry>black raspberry>blueberry. Amongst fractions, the order was insoluble-bound>esterified>free. These trends were the same as those found against copper-induced LDL-cholesterol oxidation and supercoiled plasmid DNA strand breakage inhibition induced by both peroxyl and hydroxyl radicals. Extracts were found to contain various levels of phenolic compounds that were specific to each berry seed meal type. Berry seed meals should be considered as a good source of phenolics with potential health benefits. Their full exploitation may be helpful for the food industry and consumers.


Factor Structure and Psychometric Properties of the Work-Family Balance Scale in an Urban Chinese Sample.
The purpose of this study was to explore the factor structure of the Work-Family Balance Scale (WFBS) and examine its reliability and validity in use in the urban Chinese population. The scale was validated using a sample of 605 urban Chinese residents from 7 cities. Exploratory factor analysis identified two factors: work-family conflict and work-family enrichment. The WFBS showed adequate reliability and concurrent validity. The WFBS is a reliable and valid instrument to measure work-family balance for Chinese working parents. However, further examination of the scale is needed.


Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil. Experience from the Helsinki Heart Study.
Coronary risk factors related to the insulin resistance syndrome tend to cluster in the same individual. Our previous studies have shown that the dyslipidemia characteristic of this syndrome--low HDL cholesterol and high triglyceride (TG) levels--responds well to treatment with gemfibrozil. Most factors related to insulin-resistance syndrome decrease fibrinolytic capacity, whereas a recent study showed that gemfibrozil improves it and thus may attenuate thrombotic events. To discover whether subjects with clustering of factors related to this resistance might in particular benefit from gemfibrozil, we reanalyzed the Helsinki Heart Study data. We used Cox regression models to explore the effects of gemfibrozil among overweight subjects with additional coronary risk factors in this hypercholesterolemic male population of 2046 subjects randomized to gemfibrozil and 2035 to placebo. The effect of gemfibrozil was largely confined to overweight subjects: among those with body mass index (BMI) > 26 kg/m2, the net difference in cardiac end points between gemfibrozil and placebo groups was 21 (25 of 1119 versus 46 of 1081), and in those with BMI < or = 26 kg/m2, it was 7 (31 of 927 versus 38 of 954). The risk reduction with gemfibrozil was 78% (P = .002) among those with BMI > 26 kg/m2 and dyslipidemia (TG > or = 2.3 mmol/L and HDL cholesterol < 1.08 mmol/L). Among those with BMI > 26 kg/m2 and three or four of the following factors present--smoking, sedentary lifestyle, blood pressure > or = 140/90 mm Hg, or blood glucose > 4.4 mmol/L--the risk reduction was 68% (P = .03). Gemfibrozil reduced the coronary risk mainly in overweight subjects with additional risk factors known to contribute to the insulin-resistance syndrome or predispose to it.


Diffusion-weighted imaging (DWI) signal intensity and distribution represent the amount of cancer cells and their distribution in primary lung cancer.
The aim of this study was to interpret diffusion-weighted imaging (DWI) signals in lung cancers. They were converted into several three-dimensional DWI signals patterns, which represent the degree of DWI signal intensity by height and the degree of distribution by area: flat, low elevation, irregular elevation, single-peak elevation, multiple-peak elevation, and nodular elevation. There were 39 adenocarcinomas and 21 squamous cell carcinomas. Three-dimensional DWI signals decreased significantly in order of cell differentiation. Tumor cellular densities were increased according to the increase in three-dimensional DWI signals. DWI signal intensity and distribution can represent the amount of cancer cells and their distribution in the carcinoma.


[Yes, we should keep ABO agglutination test within bedside transfusion checks].
ABO incompatible transfusions are still a frequent cause of serious adverse transfusion reactions. Bedside check is intended to detect patient errors and prevent ABO mismatch. France is one of the few countries that includes ABO agglutination test for red blood cells in bedside checks. Evaluation of this ABO agglutination test, performed with a special card, shows that, on the field, despite frequent users' mishandling, it can detect up to 93% of ABO incompatibilities. This is not enough to rely on this sole test for bedside checks. But, linking it with an another test, currently, checks that the right blood is given to the right patient, rises the sensitivity of the whole bedside procedure up to an estimated 99.65%, for detection of ABO incompatibilities. This linkage has been introduced in the French regulation in 2003. Since then, the incidence of ABO incompatible transfusions has decreased dramatically and faster than in any other country, so France has now, probably, the lowest rate of ABO incompatible transfusions. The investigation of the few ABO accidents that still occur, shows that professionals have always bypassed this linkage. On the other hand, introducing bedside recipient and blood products barcode or radio-chip checks in all the 1500 French hospitals, though technically possible, would provide very little enhancement and lead to major difficulties and expenses. Linkage of ABO agglutination test to patient and blood checks within the bedside procedure has proved to be efficient and should be kept.


An investigation of jogging biomechanics using the full-body lumbar spine model: Model development and validation.
The ability of a biomechanical simulation to produce results that can translate to real-life situations is largely dependent on the physiological accuracy of the musculoskeletal model. There are a limited number of freely-available, full-body models that exist in OpenSim, and those that do exist are very limited in terms of trunk musculature and degrees of freedom in the spine. Properly modeling the motion and musculature of the trunk is necessary to most accurately estimate lower extremity and spinal loading. The objective of this study was to develop and validate a more physiologically accurate OpenSim full-body model. By building upon three previously developed OpenSim models, the full-body lumbar spine (FBLS) model, comprised of 21 segments, 30 degrees-of-freedom, and 324 musculotendon actuators, was developed. The five lumbar vertebrae were modeled as individual bodies, and coupled constraints were implemented to describe the net motion of the spine. The eight major muscle groups of the lumbar spine were modeled (rectus abdominis, external and internal obliques, erector spinae, multifidus, quadratus lumborum, psoas major, and latissimus dorsi), and many of these muscle groups were modeled as multiple fascicles allowing the large muscles to act in multiple directions. The resulting FBLS model׳s trunk muscle geometry, maximal isometric joint moments, and simulated muscle activations compare well to experimental data. The FBLS model will be made freely available (https://simtk.org/home/fullbodylumbar) for others to perform additional analyses and develop simulations investigating full-body dynamics and contributions of the trunk muscles to dynamic tasks.


Recent advances on the role of tumor exosomes in immunosuppression and disease progression.
Exosomes are endosomal-derived nanovesicles released by most cells types, including tumor cells, and principally involved in intercellular communication in physiology and disease. Tumor exosomes are gaining increasing interest in medicine and oncology as efficient tools for the delivery of defined signals. Representing the acellular replicas of tumor cells, they contain a great variety of bioactive molecules, such as proteins, RNA, miRNA and DNA. Their great ability to recirculate in body fluids and their structure allow them to transport their cargo to distant targets. Major studies have shown that tumor exosomes convey information not only between tumor cells but also to other cell types, including different immune cell components. There is increasing evidence that these nanovesicles may contribute to cancer progression by influencing different immune cell types, likely blunting specific T cell immunity and skewing innate immune cells toward a pro-tumorigenic phenotype. Because of this function and the additional property to deliver molecular signals modulating neoangiogenesis and stroma remodeling, tumor exosomes are believed to play a role in tumor progression by favoring metastatic niche onset. This review outlines the recent knowledge on immune suppressive mechanisms mediated by tumor exosomes. We will discuss our view on the role of these nanovesicular structures in cancer progression and how their presence could interfere with cancer therapy.


Atmospheric Concentrations and Air-Soil Exchange of Polycyclic Aromatic Hydrocarbons (PAHs) in Typical Urban-Rural Fringe of Wuhan-Ezhou Region, Central China.
During the summer of 2015, polycyclic aromatic hydrocarbons (PAHs) in the atmosphere were collected by passive air samplers in typical urban-rural fringe of Wuhan-Ezhou region, Central China. The results showed that 16 kinds of PAHs were ubiquitous with the concentrations of ∑16PAHs from 14.69 to 136.30 ng·m-3 and the mean concentration of 43.03 ng·m-3. Phenanthrene (Phe), fluoranthene (Fla) and pyrene (Pyr) were major components, which accounted for 81% of ∑16PAHs. PAHs atmospheric concentrations presented obvious spatial variation, being significantly related to geographical environment and influenced by anthropogenic activity. Air-soil exchange status of PAHs was discussed according to the fugacity fraction (ff). The results showed that HMW-PAHs behaved as net deposition, while LMW-PAHs were more likely to establish dynamic equilibrium between atmosphere and soil than MMW-PAHs and HMW-PAHs. For some PAHs, such as acenaphthylene (Acy) and anthracene (Ant), the soil acted as second sources of them.


Reliability and minimal detectable change of nonlinear analysis measure of postural control in older adults with mild cognitive impairment.
Evaluating quiet stance under various conditions using nonlinear analysis may be an effective method of measuring postural control in older adults with mild cognitive impairment (MCI). However, no studies have examined the reliability of using sample entropy (SampEn) in older adults with MCI. What are the within- and between-session reliability and minimal detectable change (MDC) of a nonlinear analysis measure of postural control during quiet stance in older adults with MCI? Fourteen older adults with MCI performed static standing under four conditions, and the center of pressure signal was calculated and applied to SampEn nonlinear analysis. The within- and between-session reliability and MDC were explored. Within-session reliability was found to be fair to good and excellent (ICC = 0.527-0.960), and between-session reliability was excellent (ICC = 0.795-0.979). MDC values were less than 0.15. The between-session reliability of SampEn in all conditions demonstrates SampEn's stable performance. This method may be useful in assessing postural control in older adults with MCI, and MDC values may be helpful in detecting subtle changes in patient performance.


Non-enzymatic detection of glucose using poly(azure A)-nickel modified glassy carbon electrode.
A simple, sensitive and selective non-enzymatic glucose sensor was constructed in this paper. The poly(azure A)-nickel modified glassy carbon electrode was successfully fabricated by the electropolymerization of azure A and the adsorption of Ni(2+). The Ni modified electrode, which was characterized by scanning electron microscope, cyclic voltammetry, electrochemical impedance spectra and X-ray photoelectron spectroscopy measurements, respectively, displayed well-defined current responses of the Ni(III)/Ni(II) couple and showed a good activity for electrocatalytic oxidation of glucose in alkaline medium. Under the optimized conditions, the developed sensor exhibited a broad linear calibration range of 5 μM-12mM for quantification of glucose and a low detection limit of 0.64μM (3σ). The excellent analytical performance including simple structure, fast response time, good anti-interference ability, satisfying stability and reliable reproducibility were also found from the proposed amperometric sensor. The results were satisfactory for the determination of glucose in human serum samples as comparison to those from a local hospital.


Gender Facial Affirmation Surgery; Techniques for Feminizing the Chin.
The shape and size of the chin are very important in feminizing the lower third of the face, and osseous genioplasty is commonly used in FFS. Different variations of the osseous genioplasty can be used to feminize the chin. The 1-piece genioplasty reduces the size and rounds the chin. 2-piece genioplasty reduces or increases the projection of the chin, but retains the same shape. 3-piece genioplasty also reduces or increases the projection, but has the additional benefit of narrowing the chin. This narrowing helps to create the "V" shaped lower face that is often desired by patients seeking facial feminization. Protection of the mental nerve and resuspension of the mentalis muscle is essential to prevent permanent lower lip numbness and ptosis respectively.


Serum miRNA Panel in Egyptian Patients with Chronic Hepatitis C Related Hepatocellular Carcinoma.
Primary hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. MicroRNAs (miRNAs) have great HCC diagnostic potential and circulating miRNAs have been reported as promising biomarkers for various pathologic conditions. To explore the potential benefit of serum miR-126, miR-129, miR-155, miR-203 and miR-223 as non-invasive diagnostic markers of hepatitis C virus (HCV)-related HCC. The expression of miRNA was evaluated using real-time quantitative RT-PCR in 78 serum samples (30 treatment-naive chronic HCV, 25 post-HCV compensated cirrhosis and 23 treatment- naive HCC cases). Comparing miRNA fold changes in the HCC group vs the non HCC groups, there was significant fold decrease in miR-126 (P= 0.034), miR-129 (P= 0.006), miR-155 (P= 0.011), miR-203 (<0.001) and miR-223 (P= 0.013). The highest AUC to differentiate HCC patients from non-HCC was 0.76 for miR-203. Among studied miRNAs, serum miR-203 has the highest potential as a non-invasive biomarker of HCC.


[Effect of short-term cerebral ischemia on the microcirculation in the rat mesentery].
The effect of brain ischemia, produced by constriction of the common carotid arteries, on microcirculation in the mesentery was studied in experiments on rats. The spreading and intensity of microcirculatory disturbances were dependent on duration of ischemia and post-ischemia. The state of systemic hemodynamics and microcirculation in the mesentery was compared. Possible mechanisms of the microcirculatory disturbances are discussed.


Engineering cell fate: Applying synthetic biology to cellular reprogramming.
Cellular reprogramming drives cells from one stable identity to a new cell fate. By generating a diversity of previously inaccessible cell types from diverse genetic backgrounds, cellular reprogramming is rapidly transforming how we study disease. However, low efficiency and limited maturity have limited the adoption of in vitro-derived cellular models. To overcome these limitations and improve mechanistic understanding of cellular reprogramming, a host of synthetic biology tools have been deployed. Recent synthetic biology approaches have advanced reprogramming by tackling three significant challenges to reprogramming: delivery of reprogramming factors, epigenetic roadblocks, and latent donor identity. In addition, emerging insight from the molecular systems biology of reprogramming reveal how systems-level drivers of reprogramming can be harnessed to further advance reprogramming technologies. Furthermore, recently developed synthetic biology tools offer new modes for engineering cell fate.


Engaging street-involved youth using an evidence-based intervention: A preliminary report of findings.
Street-involved youth experience many barriers to accessing health and social services. There is a literature gap in the literature regarding evidence-based interventions to facilitate engagement with street-involved youth. A qualitative descriptive study of preliminary findings from a large mixed-methods study was undertaken to assess the impact of a resilience-based motivational intervention. This intervention was grounded in frameworks including strengths-based and resilience-based communication using the Seven C's Model of Resilience, positive youth development, and motivational interviewing that are particularly relevant to youth. Individual interviews were conducted with two subsets of youth who participated (n = 3) or did not participate (n = 3) in the intervention. Thematic analysis was conducted to identify themes between the intervention and comparison groups. Preliminary themes identified across the sample include (1) establishing a trusting relationship, (2) strengthening self-worth and resilience, (3) focusing on goals, and (4) perceiving a sense of hope and possibility. The themes identified the importance of positive relationships with care providers built upon a foundation of trust to engage youth to remain motivated and focused on their goals.


Dancing through the pain. Physician executive launches new business to treat patients with chronic pain.
Wilhelmina Korevaar's career path as a physician executive has taken many twists and turns. Early on, she didn't even want to be a doctor. Now, she's foxtrotting down yet another path, trying to use dance to help patients relieve their pain.


Arrested development of Nematodirus species in grazing lambs.
Spring born lambs grazing in initially clean pasture for two successive years acquired low levels of Nematodirus species infection which showed a progressive increase in the level of arrested development, reaching 70 to 90 per cent of the total worm burden in lambs slaughtered in November. Similar levels were recorded in worm free tracer lambs allowed only one month access to contaminated pastures. Results suggested that both seasonal environmental conditions and host age may play an important role in larval inhibition for this genus and that this phenomenon was not density dependent, nor associated with host immunity.


Clinicopathological study on 100 early gastric cancer cases.
Clinicopathological study was given to 100 early gastric cancer cases. The cases included 50 intramucosal lesions (m-group) and 62 submucosal lesions (sm-group), and the share is 17% of whole cases treated surgically. The sex ratio is about 2:1 (male : female). According to the classification by location, the occurrence rate of lesion on anterior wall is 18.8%. This fact suggests the impotance of roentgenscopy by compression technique and double contrast in a prone position focussed on anterior wall. In addition, endoscopy is essential in order to detect minute cancers. The rates of metastasis of early gastric cancers is 2.4% of m-group and 16.1% of sm-group. No metastasis occurs in protruded or elevated type as far as cancer cells remain within the mucosa. Once cancer cells infiltrate into the submucosa, metastasis is observed in 36%. In the present cases, 9 (9%) out of 100 cases of early gastric cancers are the multiple cases. In order to avoid oversight of cancer foci, the portion of stomach to be remained after surgery should be throughly examined prior to operation and again under direct vision after gastric incision.


Prognostic value of the combination of uric acid and NT-proBNP in patients with chronic heart failure.
Hyperuricemia is associated with poor outcomes in chronic heart failure (HF). We aimed to evaluate whether uric acid (UA) alone or in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a good predictor of all-cause mortality, HF hospitalization, and the composite endpoint of HF hospitalization or all-cause mortality in chronic HF. UA and NT-proBNP levels were evaluated retrospectively in 861 chronic HF patients with a left ventricular ejection fraction of ≤50%. The patients were compared by dividing them into 4 groups according to the cut-off values of UA and NT-proBNP. Serum UA concentrations were ≥ 7.0 mg/dL in 46.5% of the subjects. With a median follow-up of 30 months, 201 (23.3%) patients died and 308 (35.8%) patients were hospitalized during the study. The all-cause mortality rate was higher in the hyperuricemic group than that of the normouricemic group (p < 0.001). A multivariate Cox regression model revealed that UA and NT-proBNP were independent predictors of all-cause mortality (HR: 1.105, 95% CI: 1.019-1.198, p = 0.016 and HR: 3.743, CI: 2.647-5.292, p < 0.001, respectively). Patients were divided into 4 groups based on UA (≥ 7 and < 7 mg/dL) and NT-proBNP (≥ 2279 and < 2279 ng/L) levels. All-cause mortality, HF hospitalization, and the composite endpoint of HF hospitalization or all-cause mortality rates were higher in the group with high UA and NT-proBNP levels (p < 0.001, p < 0.001, p < 0.001, respectively). Hyperuricemia alone is an independent predictor of all-cause mortality in chronic HF. However, the combination of UA and NT-proBNP appears to be a stronger predictor of poor outcomes.


Rim plating for a rare variant of posteromedial tibial condyle fracture; partial coronal split, akin to Hoffa's fracture, associated with multi-ligament injuries and central depression.
Proximal tibia intra-articular fractures are commonly associated with ligamentous injuries and require early diagnosis and intervention. An array of fracture patterns can be encountered, and Schatzker's classification is a standard description to identify them. However, several patterns have been described that fall outside the ambits of this classification. We present a rare fracture pattern of partial posteromedial condyle coronal split associated with depression of the anterolateral plateau and mid substance tear of medial collateral ligament (MCL) and avulsions of anterior and posterior cruciate ligaments(ACL/PCL). A 45 year old male presented with swelling and severe pain in his right knee after an accident. He was diagnosed with a posteromedial tibial condyle coronal split with two fragments, along with multi-ligament injuries. He was operated with cannulated screws and a rim plate for the larger fragment. The fractures united and patient was doing well in his daily activities at final follow up of 15 months. Proximal tibia fractures can present as an array of fracture patterns and require prompt diagnosis and surgical management. The one described in the present case is a rarest of rare pattern and rim plating could be a cheaper alternative to the anatomical plates.


Object-based attention in complex, naturalistic auditory streams.
In vision, objects have been described as the 'units' on which non-spatial attention operates in many natural settings. Here, we test the idea of object-based attention in the auditory domain within ecologically valid auditory scenes, composed of two spatially and temporally overlapping sound streams (speech signal vs. environmental soundscapes in Experiment 1 and two speech signals in Experiment 2). Top-down attention was directed to one or the other auditory stream by a non-spatial cue. To test for high-level, object-based attention effects we introduce an auditory repetition detection task in which participants have to detect brief repetitions of auditory objects, ruling out any possible confounds with spatial or feature-based attention. The participants' responses were significantly faster and more accurate in the valid cue condition compared to the invalid cue condition, indicating a robust cue-validity effect of high-level, object-based auditory attention.


Carpentier-Edwards pericardial aortic valve in middle-aged patients: comparison with the St. Jude Medical valve.
The objective of the present study was to compare long-term results of single aortic valve replacement (AVR) with mechanical (St. Jude Medical valves: standard) and biologic (the Carpentier-Edwards pericardial) prostheses. Between 1995 and 2002, 95 patients who underwent single AVR with mechanical (n= 46) or biologic (n= 49) prostheses were enrolled in this study. The mean age at the operation was 54.0 +/- 9.6 years (range: 20 to 69 years) with the mechanical and 68.8 +/- 7.1 years (range: 44 to 85 years) with the biologic prosthesis. The 9-year actuarial survival rate, which was calculated by taking perioperative mortality into account, was 90.3 +/- 4.6% for patients with mechanical valves and 87.6 +/- 4.8% for patients with bioprostheses, with no difference between the two groups (p=0.342). The 9-year freedom rate from thromboembolism, reoperation, endocarditis was 94.8 +/- 3.6%, 100% and 97.8 +/- 2.2% for patients with mechanical valves and 98.0 +/- 2.0%, 97.5 +/- 3.4% and 95.0 +/- 3.4% for those with bioprostheses, respectively. After 9 years, freedom from cardiac death averaged 97.8% in the group with mechanical valves compared with 95.3% in those with bioprostheses (p=0.541). We conclude that the mid-term durability of the Carpentier-Edwards pericardial valve in the aortic position for the elderly is excellent. Nevertheless, the risk of tissue valve reoperation progressively increases with time, and a longer follow-up may be necessary to provide its value compared with the mechanical valves in a country like Japan with a high life expectancy.


The American anthropometric norms are not suitable to assess the nutritional status of a French population.
Weight: height2 ratio (W/H2), triceps skinfold thickness (TSF), and mid-upper arm circumference (MAC) were recorded in 254 blood donors aged 20 to 59 yrs (123 men and 131 women), to establish anthropometric data in a healthy sample of the French population. When compared with the American anthropometric norms (HANES I & II), we noted that: (1) the percentiles distribution values of W/H2 were nearly identical; (2) the age and sex-related values of TSF were lower in our study (p < 0.003); (3) our percentiles distribution values of MAC were lower in our study (p < 0.03), except in women 20-39 yrs of age. The variations of TSF and MAC with age and sex were identical in both the French and the American populations: i.e. the MAC values increased with age in both men and women, and the TSF values increased with age only in women. We conclude that the differences noted between the American norms and our anthropometric data plead in favour of the determination of French national anthropometric norms.


Targeting TLK2 inhibits the progression of gastric cancer by reprogramming amino acid metabolism through the mTOR/ASNS axis.
Several recent studies have suggested that TLKs are related to tumor progression. However, the function and mechanism of action of TLK2 in gastric cancer (GC) remain elusive. In this study, TLK2 was found to be significantly upregulated in patients with GC and was identified as an independent prognostic factor for GC. Consistently, TLK2 knockdown markedly reduced the aggressiveness of GC, whereas its overexpression had the opposite effect. IP-MS revealed that the effects of TLK2 on GC were mainly associated with metabolism reprogramming. TLK2 knockdown suppressed amino acid synthesis by downregulating the mTORC1 pathway and ASNS expression in GC cells. Mechanistically, mTORC1 directly interacts with the ASNS protein and inhibits its degradation. Further experiments validated that the ASNS protein was degraded via ubiquitination instead of autophagy. Inhibiting and activating the mTORC1 pathway can upregulate and downregulate ASNS ubiquitination, respectively, and the mTORC1 pathway can reverse the regulatory effects of TLK2 on ASNS. Furthermore, TLK2 was found to regulate the mRNA expression of ASNS. TLK2 directly interacted with ATF4, a transcription factor of ASNS, and promoted its expression. The kinase inhibitor fostamatinib significantly inhibited the proliferative, invasive, and migratory capabilities of GC cells by inhibiting TLK2 activity. Altogether, this study reveals a novel functional relationship between TLK2 and the mTORC1/ASNS axis in GC. Therefore, TLK2 may serve as a potential therapeutic target for GC.


Orosomucoid (ORM) typing by isoelectric focusing: evidence for gene duplication of ORM1 and genetic polymorphism of ORM2.
It has been demonstrated that the genetic polymorphism of human serum orosomucoid (ORM) is controlled by polymorphic ORM1 and monomorphic ORM2 loci. In this study a Japanese family was encountered in which several members had puzzling electrophoretic patterns consisting of four bands. The ORM patterns were due to the products of a duplicated ORM1 locus haplotype (ORM1 2.1) or the products of new variant alleles at the ORM2 locus. The ORM1 2.1 haplotype is very common in the Japanese population, occurring at an allele frequency of 0.16. The increased occurrence of ORM12-1 and the heterogeneity in band intensity among ORM12-1 phenotypes could be explained in terms of a duplicated gene ORM1 2.1. The ORM2 locus proved to be polymorphic, with six alleles in the Japanese population.


Detection of radicals produced by reaction of hydroperoxides with rat liver microsomal fractions.
EPR spin trapping using the spin traps 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and 3,5-dibromo-4-nitrosobenzene sulphonic acid (DBNBS) has been employed to examine the generation of radicals produced on reaction of a number of primary, secondary and lipid hydroperoxides with rat liver microsomal fractions in both the presence and absence of reducing equivalents. Two major mechanisms of radical generation have been elucidated. In the absence of NADPH or NADH, oxidative degradation of the hydroperoxide occurs to give initially a peroxyl radical which in the majority of cases can be detected as a spin adduct to DMPO; these radicals can undergo further reactions which result in the generation of alkoxyl and carbon-centered radicals. In the presence of NADPH (and to a lesser extent NADH) alkoxyl radicals are generated directly via reductive cleavage of the hydroperoxide. These alkoxyl radicals undergo further fragmentation and rearrangement reactions to give carbon-centered species which can be identified by trapping with DBNBS. The type of transformation that occurs is highly dependent on the structure of the alkoxyl radical with species arising from beta-scission, 1,2-hydrogen shifts and ring closure reactions being identified; these processes are in accord with previous chemical studies and are characteristic of alkoxyl radicals present in free solution. Studies using specific enzyme inhibitors and metal-ion chelators suggest that most of the radical generation occurs via a catalytic process involving haem proteins and in particular cytochrome P-450. An unusual species (an acyl radical) is observed with lipid hydroperoxides; this is believed to arise via a cage reaction after beta-scission of an initial alkoxyl radical.


On-line synthesis utilizing immobilized enzyme reactors based upon immobilized dopamine beta-hydroxylase.
Immobilized enzyme reactors (IMERs) based upon dopamine beta-hydroxylase (DBH) have been developed. Immobilized artificial membrane (IAM) and glutaraldehyde-P (Glut-P) stationary phases have been used to immobilize DBH. When DBH is immobilized on the Glut-P interphase the enzyme is outside the stationary phase whereas with the IAM interphase the enzyme is embedded within the interphase surroundings. The activity of each IMER and their ability for on-line hydroxylation has been investigated. The resulting IMERs are enzymatically active and reproducible. The IMERs can be utilized through the use of coupled chromatography to characterize the cytosolic (DBH-Glut-P-IMER) and membrane-bound (DBH-IAM-IMER) forms of the enzyme. The substrate is injected onto the individual IMERs and the reactants and products are eluted onto a phenylboronic acid column for on-line extraction. The substrates and products are then transported via a switching valve to coupled analytical columns. The results demonstrate that enzyme-substrate and enzyme-inhibitor interactions can be investigated with the on-line system. These IMERs can be utilized for the discovery and characterization of new drug candidates specific for the soluble form and membrane-bound form of DBH. The effects of flow-rate, contact time, pH and temperature have also been investigated.


Structure of a unique twofold symmetric haem-binding site.
Bacterioferritin of Escherichia coli, also known as cytochrome b1, is a hollow, nearly spherical shell made up of 24 identical protein subunits and 12 haems. We have solved this structure in a tetragonal crystal form at 2.9 A resolution. We find that each haem is bound in a pocket formed by the interface between a pair of symmetry-related subunits. The quasi-twofold axis of the haem is closely aligned with the local twofold axis relating these subunits. The axial ligands of the haem are sulphurs of two equivalent methionyl residues (Met 52) from the symmetry-related subunits. A cluster of four water molecules is trapped in the gap between the upper edge of the haem and two extended protein loops which close off the haem from the outer aqueous environment. This is the first structure of a bis-methionine ligated haem-binding site and the first case of a twofold symmetric haem-binding site.


Evolution and Targeting of Myeloid Suppressor Cells in Cancer: A Translational Perspective.
In recent years, the immune system has emerged as a critical regulator of tumor development, progression and dissemination. Advanced therapeutic approaches targeting immune cells are currently under clinical use and improvement for the treatment of patients affected by advanced malignancies. Among these, anti-PD1/PD-L1 and anti-CTLA4 immune checkpoint inhibitors (ICIs) are the most effective immunotherapeutic drugs at present. In spite of these advances, great variability in responses to therapy exists among patients, probably due to the heterogeneity of both cancer cells and immune responses, which manifest in diverse forms in the tumor microenvironment (TME). The variability of the immune profile within TME and its prognostic significance largely depend on the frequency of the infiltrating myeloid cells, which often represent the predominant population, characterized by high phenotypic heterogeneity. The generation of heterogeneous myeloid populations endowed with tumor-promoting activities is typically promoted by growing tumors, indicating the sequential levels of myeloid reprogramming as possible antitumor targets. This work reviews the current knowledge on the events governing protumoral myelopoiesis, analyzing the mechanisms that drive the expansion of major myeloid subsets, as well as their functional properties, and highlighting recent translational strategies for clinical developments.


Tumour-associated isoenzymes of gamma-glutamyl transferase in the serum of patients with hepatocellular carcinoma.
Sera from 391 southern African Blacks with hepatocellular carcinoma, matched controls, patients with other malignant tumours, and with various forms of hepatobiliary disease were fractionated by polyacrylamide gradient gel electrophoresis to determine the prevalence of tumour-associated gamma-glutamyl transferase isoenzymes in Black patients with hepatocellular carcinoma. One or more tumour-associated isoenzymes (I', I'' or II') were present in 58.6% of the patients with hepatocellular carcinoma: I' in 54.5%, I'' in 27.1%, and II' in 34%. These isoenzymes were detected in one patient with prostatic cancer, occasionally in patients with acute viral hepatitis, but in no normal individuals. The presence of tumour-associated isoenzymes was not related to patient age, sex or hepatitis-B virus status or to the tumour burden. Isoenzymes were present in 42 percent of hepatocellular carcinoma patients with a normal serum alpha-foetoprotein concentration and in 50% of those with a non-diagnostic value. gamma-glutamyl transferase isoenzymes may be supplementary to alpha-foetoprotein in the diagnosis of hepatocellular carcinoma.


Genetic and molecular risk factors within the newly identified primate-specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia-associated locus.
The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.


Ravulizumab: A Review in Generalised Myasthenia Gravis.
Ravulizumab (ULTOMIRIS®) is the first long-acting complement C5 inhibitor (administered intravenously every 8 weeks) to be approved in several countries globally, for adults with generalised myasthenia gravis (gMG) who are anti-acetylcholine receptor antibody-positive (AChR Ab+). In the phase III CHAMPION MG trial, intravenous ravulizumab was associated with statistically significant improvements in the MG-Activities of Daily Living scale at week 26 of treatment compared with placebo in adults with AChR Ab+ gMG. Improvements in the Quantitative MG scale total score were also statistically significantly higher in ravulizumab than placebo recipients. These improvements were sustained to week 26 of treatment. Ravulizumab was generally well tolerated; the most common treatment-emergent adverse events were headache, diarrhoea and nausea. Efficacy and tolerability data for up to 1 year from the ongoing open-label extension phase are consistent with those from the randomized, placebo-controlled phase; further results are awaited with interest. Thus, ravulizumab is an efficacious, generally well tolerated and convenient treatment option in adults with AChR Ab+ gMG, expanding the options available for gMG management.


Ventricular Tachycardia (VT) Storm After Cryoballoon-Based Pulmonary Vein Isolation.
BACKGROUND Following catheter ablation of atrial fibrillation, increased incidence of ventricular arrhythmia has been observed. We report a case of sustained ventricular arrhythmia in a patient who underwent cryoballoon-based pulmonary vein isolation for symptomatic persistent atrial fibrillation. CASE REPORT A 57-year-old patient with dilated cardiomyopathy underwent CB-based pulmonary vein isolation for symptomatic persistent AF. On the day following an uneventful procedure, the patient for the first time experienced a sustained ventricular tachycardia that exacerbated into VT storm. Each arrhythmia was terminated by the ICD that had been implanted for primary prevention. Antiarrhythmic treatment with amiodarone was initiated immediately. The patient remained free from sustained ventricular arrhythmia during follow-up. CONCLUSIONS After pulmonary vein isolation, physicians should be vigilant for ventricular arrhythmia. The influence of atrial autonomic innervation on ventricular electrophysiology is largely unknown.


1H, 15N and 13C backbone and side chain solution NMR assignments of the TPM domain-containing protein of the thermophilic bacterium Rhodothermus marinus.
The InterPro family IPR007621 TPM_phosphatase is a widely conserved family of protein domains found in prokaryotes, plants and invertebrates. Despite similar predicted protein folding, members of this family are involved in different cellular processes. In recent years, the structural and biochemical characterization of evolutionarily divergent TPM domains has shown their ability to hydrolyze phosphate groups of different substrates. However, there are still inaccurate functional annotations and uncertain relationships between the structure and function of this domain family. We here report the 1H, 13C, and 15N backbone and sidechain resonances of the TPM domain of a predicted TPM domain-containing protein of the thermophilic bacterium Rhodothermus marinus. These data will lay the groundwork for future NMR-based investigations, contributing to a thorough comprehension of the intricate aspects governing the interplay between structure and function of TPM domains. Additionally, they will unlock opportunities to explore dynamic structural changes, providing valuable insights into the molecular mechanisms underlying the evolutionary adaptations to extreme environmental conditions within this protein family.


High-level expression of functional cGMP-dependent protein kinase using the baculovirus system.
The understanding of the structure and function of cGMP-dependent protein kinase (cGMP kinase) has been hindered by the difficulty to obtain large quantities of functional enzyme. A recombinant baculovirus encoding bovine cGMP kinase I alpha was constructed and purified. Infected insect cells synthesized large amounts of soluble and biologically active cGMP kinase I alpha representing up to 10% of the total cell extract protein. The recombinant enzyme had an identical apparent molecular mass, cGMP affinity and kinase activity as the native bovine lung enzyme. The high-level expression of functional cGMP kinase I alpha should provide an excellent tool to study further the structure and function of cGMP kinase.


Radiographic Incidence of Knee Osteoarthritis After Isolated ACL Reconstruction Versus Combined ACL and ALL Reconstruction: A Prospective Matched Study From the SANTI Study Group.
Combined anterior cruciate ligament (ACL) reconstruction (ACLR) and anterolateral ligament reconstruction (ALLR) have demonstrated reduced risk of graft rerupture as compared with isolated ACLR. However, concerns remain that the risk of osteoarthritis (OA) may be increased by the addition of ALLR. The aim of this study was to evaluate the incidence of OA with isolated ACLR in comparison with ACLR + ALLR at medium-term follow-up. We hypothesized that there would be no differences between the groups. Cohort study; Level of evidence, 3. Patients who underwent ACLR + ALLR with hamstring tendon autograft between January 2011 and March 2012 were propensity matched to patients who underwent isolated ACLR with bone-patellar tendon-bone (BPTB) or hamstring tendon autograft in the same period. Medium-term radiographic evaluation was performed using the International Knee Documentation Committee (IKDC) radiographic OA grading scale, modified Kellgren-Lawrence grade, and the surface fit method to assess percentage of joint space narrowing. Clinical outcomes were assessed with the following measures: IKDC, Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm, Tegner, and ACL Return to Sport after Injury. A total of 80 patients (42 ACLR + ALLR and 38 isolated ACLR) were analyzed with a mean follow-up of 104 months. There was no significant difference between groups for joint space narrowing in the medial or lateral tibiofemoral or lateral patellofemoral (PF) compartment. However, 36.8% in the isolated ACLR group versus 11.9% in the ACLR + ALLR group had narrowing of the medial PF compartment (P = .0118). A lateral meniscal tear increased the risk of lateral tibiofemoral narrowing by nearly 5 times (odds ratio, 4.9; 95% CI, 1.547-19.367; P = .0123). The risk of medial PF narrowing was >4-fold with an isolated ACLR (odds ratio, 4.8; 95% CI, 1.44-19.05; P = .0179). Between the isolated ACLR group and the ACLR + ALLR group, the secondary meniscectomy rate was 13.2% versus 11.9% (not significantly different). There was no difference between groups in KOOS, Tegner, or IKDC scores. There was also no difference between groups for grades of osteoarthritic change for any classification system. Patients who received a BPTB graft had medial PF joint narrowing in 66.7% of cases as compared with 11.9% in those who received ACLR + ALLR (P = 0.118). ACLR + ALLR did not increase the risk of OA in the lateral tibiofemoral compartment when compared with an isolated ACLR at medium-term follow-up. Isolated ACLR using BPTB was associated with a significantly increased risk of medial PF joint space narrowing. NCT05123456 (ClinicalTrials.gov identifier).


A new assay for the discovery of Bcl-XL inhibitors.
The Bcl-2 family of antiapoptotic proteins is commonly over expressed in many types of human cancer and remains one of the few validated targets. Antiapoptotic family proteins such as Bcl-2 and Bcl-XL function, at least in part, by binding proapoptotic members such as Bax and Bak and thereby prevent release of the apoptotic cascade of events. "BH3-only" members of the family disrupt this interaction by binding, via their BH3 domain, to a hydrophobic pocket on the surface of the antiapoptotic members. Disruption of heterodimerization could be used to modulate cell death reinstating apoptosis in cancer cells. An affinity displacement assay based on Bcl-XL/BH3 interaction has been developed. This assay makes use of soluble His-tagged Bcl-XL and fluorescein tagged BH3. Binding is measured as fluorescence associated with magnetic beads. The assay was miniaturized to 96-well microtiter plates and can be employed in high throughput screening (HTS), in addition it is robust enough to be applied to microbial fermentation extracts.


Adaptive Radiotherapy Enabled by MRI Guidance.
Adaptive radiotherapy (ART) strategies systematically monitor variations in target and neighbouring structures to inform treatment-plan modification during radiotherapy. This is necessary because a single plan designed before treatment is insufficient to capture the actual dose delivered to the target and adjacent critical structures during the course of radiotherapy. Magnetic resonance imaging (MRI) provides superior soft-tissue image contrast over current standard X-ray-based technologies without additional radiation exposure. With integrated MRI and radiotherapy platforms permitting motion monitoring during treatment delivery, it is possible that adaption can be informed by real-time anatomical imaging. This allows greater treatment accuracy in terms of dose delivered to target with smaller, individualised treatment margins. The use of functional MRI sequences would permit ART to be informed by imaging biomarkers, so allowing both personalised geometric and biological adaption. In this review, we discuss ART solutions enabled by MRI guidance and its potential gains for our patients across tumour types.


Late Mortality After Myocardial Injury in Critical Care Non-Cardiac Surgery Patients Using Machine Learning Analysis.
Myocardial injury after noncardiac surgery (MINS) increases mortality within 30 days. We aimed to evaluate the long-term impact of myocardial injury in a large cohort of patients admitted to intensive care after noncardiac surgery. All patients who stayed, at least, overnight with measurement of high-sensitive cardiac troponin were included. Clinical characteristics and occurrence of MINS were assessed between patients who died and survivors using chi-square test and Student t test. Variables with p <0.01 in the univariate model were included in the Cox regression model to identify predictor variables. Survival decision tree (SDT), a machine learning model, was also used to find the predictors and their correlations. We included 2,230 patients with mean age of 63.8±16.3 years, with most (55.6%) being women. The prevalence of MINS was 9.4% (209 patients) and there were 556 deaths (24.9%) in a median follow-up of 6.7 years. Univariate analysis showed variables associated with late mortality, namely: MINS, arterial hypertension, previous myocardial infarction, atrial fibrillation, dementia, urgent surgery, peripheral artery disease (PAD), chronic health status, and age. These variables were included in the Cox regression model and SDT. The predictor variables of all-cause death were MINS (hazard ratio [HR] 2.21; 95% confidence interval [CI] 1.77 to 2.76), previous myocardial infarction (HR 1.47; 95% CI 1.14 to 1.89); urgent surgery (HR 1.24; 95% CI 1.01 to 1.52), PAD (HR 1.83; 95% CI 1.23 to 2.73), dementia (HR 2.54; 95% CI 1.86 to 3.46) and age (HR 1.05; 95% CI 1.04 to 1.06). SDT had the same predictors, except PAD. In conclusion, increased high-sensitive troponin levels in patients who underwent noncardiac surgery raised the risk of short and late mortality.


Synthesis and Structure-Activity Relationships of N-(4-Benzamidino)-Oxazolidinones: Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6.
Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high-throughput screen within the European Lead Factory program. Structure-guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)-3-(4-carbamimidoylphenyl)-N-((S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) and 34 ((5R)-3-(6-carbamimidoylpyridin-3-yl)-N-((1S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) have single-digit nanomolar potency against KLK6, with over 25-fold and 100-fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6-dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.


Inhibition of HDAC increases BDNF expression and promotes neuronal rewiring and functional recovery after brain injury.
Brain injury causes serious motor, sensory, and cognitive disabilities. Accumulating evidence has demonstrated that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults to the central nervous system (CNS). In this study, we investigated the effects of the HDAC inhibition on the expression of brain-derived neurotrophic factor (BDNF) and functional recovery after traumatic brain injury (TBI) in mice. Administration of class I HDAC inhibitor increased the number of synaptic boutons in rewiring corticospinal fibers and improved the recovery of motor functions after TBI. Immunohistochemistry results showed that HDAC2 is mainly expressed in the neurons of the mouse spinal cord under normal conditions. After TBI, HDAC2 expression was increased in the spinal cord after 35 days, whereas BDNF expression was decreased after 42 days. Administration of CI-994 increased BDNF expression after TBI. Knockdown of HDAC2 elevated H4K5ac enrichment at the BDNF promoter, which was decreased following TBI. Together, our findings suggest that HDAC inhibition increases expression of neurotrophic factors, and promote neuronal rewiring and functional recovery following TBI.


Cyclosporine-pancuronium interaction in a patient with a renal allograft.
A case is described of a 54-year-old 55 kg patient who presented for clipping of a middle cerebral aneurysm two years after a successful renal allograft. Immunosuppression was maintained with azathioprine 100 mg daily, cyclosporine 300 mg daily and prednisone 10 mg daily. The patient had chronic hypertension controlled with nifedipine 40 mg daily and furosemide 20 mg daily. The cyclosporine level taken on the morning of surgery was 166 micrograms.L-1. Induction of anaesthesia consisted of fentanyl 350 micrograms, thiopentone 125 mg and pancuronium 5.5 mg. Anaesthesia was maintained with nitrous oxide 70 per cent in oxygen and isoflurane 0.5-1.5 per cent. No additional doses of pancuronium were given during the four hour surgical procedure. At the end of surgery, four twitches were present with train-of-four stimulation, but evidence of residual muscle paralysis was present. Residual neuromuscular blockade was reversed with atropine 1.2 mg and neostigmine 2.5 mg. Residual paralysis was present in the Recovery Room and edrophonium 10 mg was given prior to extubation. Clinical testing demonstrated adequate reversal of neuromuscular blockade. Twenty minutes following extubation, increasing respiratory distress was noted. There was clinical evidence of muscle paralysis. The patient was re-intubated. It is proposed that cyclosporine potentiated the pancuronium blockade producing prolonged neuromuscular relaxation resulting in residual paralysis following surgery. The potential interactions of cyclosporine and muscle relaxants deserve further study.


Medical certificate for older drivers - an analysis of the Norwegian parliamentary debate.
In February 2021, the Storting decided to abolish the mandatory medical certificate required for driving licence renewals for drivers over the age of 80. The decision will affect older drivers, traffic safety in general, and the everyday work of GPs in particular. A content analysis was performed of the parliamentary debates and supporting documentation on the issue of medical certificates for older drivers, from the time of the motion in December 2020 up to the debate on when to implement the decision in May 2021. The majority decision was founded on an anti-discrimination argument with undertones of district politics, in which the traffic safety element was relativised. A minority argued for a traffic safety policy based on a health authority decision and with an emphasis on the added overall health value. Cognitive screening tests were unanimously rejected. The parties that represent the majority decision framed cognitive testing in a way that suggests the decision is a reaction to these tests rather than to the medical certificate requirement as such. There was little discussion on how the decision will affect GPs' ability to identify impaired fitness to drive among the older population.


No robust evidence for an interaction between early-life adversity and protective factors on global and regional brain volumes.
Childhood adversity is associated with brain morphology and poor psychological outcomes, and evidence of protective factors counteracting childhood adversity effects on neurobiology is scarce. We examined the interplay of childhood adversity with protective factors in relation to brain morphology in two independent longitudinal cohorts, the Generation R Study (N = 3008) and the Mannheim Study of Children at Risk (MARS) (N = 179). Cumulative exposure to 12 adverse events was assessed across childhood until age 9 years in Generation R and 11 years in MARS. Protective factors (temperament, cognition, self-esteem, maternal sensitivity, friendship quality) were assessed at various time-points during childhood. Global brain volumes and volumes of amygdala, hippocampus, and the anterior cingulate, medial orbitofrontal and rostral middle frontal cortices were assessed with anatomical scans at 10 years in Generation R and at 25 years in MARS. Childhood adversity was related to smaller cortical grey matter, cerebral white matter, and cerebellar volumes in children. Also, no buffering effects of protective factors on the association between adversity and the brain outcomes survived multiple testing correction. We found no robust evidence for an interaction between protective factors and childhood adversity on broad brain structural measures. Small interaction effects observed in one cohort only warrant further investigation.


Paraoxonase 1 and HDL subfractions in hypercholesterolemic children and adolescents.
Assessment of the cardiovascular disease (CVD) risk factors in children can predict clinical manifestations of atherosclerosis in adulthood. The arylesterase (PON1-A) and lactonase (PON1-L) activities of paraoxonase 1 (PON1) and lipid parameters (Total cholesterol (TCH), VLDL-cholesterol (VLDL), triacylglycerols (TAG), HDL-cholesterol (HDL), LDL-cholesterol (LDL) and LDL- and HDL-subfractions and their mutual associations in 27 hypercholesterolemic children and adolescents were investigated. Serum levels of TCH and TAG were determined using a Hitachi 911 analyser (Roche Diagnostics, Switzerland). LDL- and HDL-subfractions were determined by Lipoprint® system (Quantimetrix, Corp., USA). PON1-A and PON1-L activities were determined according to Gan et al. (1991) and Aviram and Rosenblat (2008). PON1-A activity was higher compared to healthy children (134.1±26.2 vs. 118.16±7.05 U/ml) and PON1-L was not different from healthy controls. Increased levels of atherogenic risk factors TCH, VLDL, IDL1 subfraction and decreased levels of the antiatherogenic IDL3 and LDL1 subfractions were observed in the hypercholesterolemic children compared to reference values. Increased levels of large HDL subfractions, comparable levels of intermediate HDL and lower levels of small HDL subfractions were observed in hypercholesterolemic children compared to healthy adults (in absence of data available for healthy children). No significant correlation between PON1-A and HDL subfractions was found. PON1-L activity positively correlated with antiatherogenic large HDL1 subfraction and negatively correlated with intermediate HDL4, 5 and 6 subfractions. The findings suggest that the PON1-L activity rather than PON1-A activity play a protective role in atherosclerosis. We confirmed atheroprotective effect of large and atherogenic properties of small HDL subfractions. The intermediate HDL subfractions probably play no atheroprotective role.


Retinal nerve fibre layer thickness profile in normal eyes using third-generation optical coherence tomography.
To establish four normal retinal nerve fibre layer (RNFL) thickness radial profiles based on third-generation optical coherence tomography (OCT) and to compare them with previously reported histologic measurements. A total of 20 normal eyes were studied. A circular scan was adjusted to the size of the optic disc and three scans were performed with this radius and every 200 microm thereafter, up to a distance of 1400 microm. Four different radial sections (superotemporal, superonasal, inferonasal, and inferotemporal) were studied to establish RNFL thickness OCT profiles. Additionally, two radial scans orientated at 45 and 135 degrees crossing the optic disc centre were performed in six of 20 eyes, and RNFL thickness was measured at disc margin. Quadrant location and distance from disc margin interaction in RNFL thickness was statistically significant (P<0.001). The RNFL thickness decreased (P<0.001) as the distance from the disc margin increased for all sections. The measurements automatically generated by the OCT built-in software were thinner (P<0.001) than histologic ones close to the disc margin. Four normal OCT RNFL profiles were established and compared with histological data obtained from the same area. RNFL measurements assessed by OCT 3 were significantly thinner close to the optic disc margin.


Enhanced rheological and tribological properties of nanoenhanced greases by tuning interparticle contacts.
Despite the wide spectrum of available nanoparticles, their utilization in lubricant and grease formulations remains challenging. To enhance their performance, an improved link between the interparticle contacts, brittleness of the resulting particle network, time-dependent rheology and tribology is required. We systematically changed interparticle contacts and examined their effect on the colloidal stability, microstructure, rheological and tribological behavior of model greases by investigating four types of nanoclays: montmorillonite (Cloisite Na+), oleic-acid functionalized Cloisite Na+ (OA-Cloisite Na+), organomodified montmorillonite (C20A) and oleic-acid functionalized C20A (C20A-OA). We observed a range of behaviors, starting from the lack of colloidal stability in greases derived with Cloisite Na+ and OA-Cloisite Na+ to semi-solid type systems with C20A and C20A-OA. Consistent with previous studies, the rheological and tribological properties of C20A systems scale with nanoclay loadings. Surprisingly, the functionalized C20A-OA system exhibited a delayed transition towards hydrodynamic lubrication, and enhanced lubrication properties, both of which were largely independent of nanoclay loadings. Coupled microstructural investigation and time-dependent rheology reveal that this behavior is governed by increasing repulsive forces, decreasing inter-particle friction between C20A-OA nanoparticles, and faster reorganization of the C20A-OA nanoparticle network under shear. Increased interparticle repulsion enables C20A-OA nanoclays to pass each other under shear and align in direction of shear, which reduces the overall viscosity, while the presence of OA on nanoclays decreases inter-particle friction and particle-steel surface friction.


Effectiveness and safety of normoxic allogenic umbilical cord mesenchymal stem cells administered as adjunctive treatment in patients with severe COVID-19.
Inflammatory response in COVID-19 contributes greatly to disease severity. Mesenchymal Stem Cells (MSCs) have the potential to alleviate inflammation and reduce mortality and length of stay in COVID-19 patients. We investigated the safety and effectiveness of normoxic-allogenic umbilical cord (NA-UC)-MSCs as an adjunctive treatment in severe COVID-19 patients. A double-blind, multicentric, randomized, placebo-controlled trial involving severe COVID-19 patients was performed from January to June 2021 in three major hospitals across Java, Indonesia. Eligible participants (n = 42) were randomly assigned to two groups (1:1), namely the intervention (n = 21) and control (n = 21) groups. UC-MSCs dose was 1 × 106 /kg body weight on day D0, D3, and D6. The primary outcome was the duration of hospitalization. Meanwhile, the secondary outcomes were radiographical progression (Brixia score), respiratory and oxygenation parameters, and inflammatory markers, in addition to the safety profile of NA-UC-MSCs. NA-UC-MSCs administration did not affect the length of hospital stay of severe COVID-19 patients, nor did it improve the Brixia score or mMRC dyspnoea scale better than placebo. Nevertheless, NA-UC-MSCs led to a better recuperation in oxygenation index (120.80 ± 72.70 baseline vs. 309.63 ± 319.30 D + 22, p = 0.038) and oxygen saturation (97.24 ± 4.10% vs. 96.19 ± 3.75% in placebo, p = 0.028). Additionally, compared to the placebo group, the treatment group had a significantly smaller increase in PCT level at D + 22 (1.43 vs. 12.76, p = 0.011). No adverse effects, including serious ones, were recorded until D + 91. NA-UC-MSCs therapy is a very safe adjunct for COVID-19 patients. It improves the oxygenation profile and carries potential to suppress inflammation.


Phosphorus footprint in China over the 1961-2050 period: Historical perspective and future prospect.
The phosphorus footprint (PF) is a novel concept to analyze human burdens on phosphorus resources. However, research on PF approach is still limited, and current several PF studies include incomplete phosphorus sources and have limited quantitative interpretation about the drivers of PF changes, which can help understand future trends of PF. This study develops a more comprehensive PF model by considering crop, livestock and aquatic food, and non-food goods, which covers the mainly phosphorus containing products consumed by human. The model is applied to quantify China's PF from 1961 to 2014, and the results of the model are also used to analyze the factors driving the PF changes and explored China's PF scenarios for 2050 using an econometric analysis model (STIRPAT). The result shows that China's PF increased over 11-fold, from 0.9 to 10.6 Tg between 1961 and 2014. The PF of livestock food dominated China's PF, accounting for 57% of the total in 1961 and 45% in 2014. The key factors driving the increase in China's PF are the increase in population and urbanization rate, with contributions of 38% and 33%, respectively. We showed that in the baseline scenario, China's PF would increase by 70% during 2014-2050 and cause the depletion of China's phosphate reserves in 2045. However, in the best case scenario, China's PF would decrease by 15% in 2050 compared with that in 2014, and it would have 50% of current phosphate reserve remaining by 2050. Several mitigation measures are then proposed by considering China's realities from both production and consumption perspective, which can provide valuable policy insights to other rapid developing countries to mitigate the P footprint.


Effect of metformin on the long non-coding RNA expression levels in type 2 diabetes: an in vitro and clinical trial study.
It has been suggested that the anti-hyperglycemic effect of metformin could be associated with its impact on long non-coding RNA (lncRNA) expression levels. Accordingly, in the current study, we evaluated the effect of metformin on the expression of H19, MEG3, MALAT1, and GAS5 in in vitro and in vivo situations. The effect of hyperglycemia and metformin treatment on the lncRNAs expression level was evaluated in HepG2 cells. A total of 179 age- and sex-matched subjects, including 88 newly diagnosed patients with type 2 diabetes (T2D) and 91 healthy volunteers, were included in the case-control phase of the study. Moreover, 40 newly diagnosed patients participated in the study's open-labeled non-controlled clinical trial phase. The expression levels of lncRNA in HepG2 cells and whole blood samples were determined using QRT-PCR. In vitro results showed that hyperglycemia induced H19 and MALAT1 and decreased GAS5 expression levels. Moreover, metformin decreased H19 and increased GAS5 expression in high glucose-treated cells. Case-control study findings revealed that the circulating levels of H19, MALAT1, and MEG3 were significantly elevated in T2D patients compared to the control subjects. Finally, results showed that the level of circulating H19 levels decreased while GAS5 increased in T2D patients after taking metformin for 2 months. The results of the current study provided evidence that metformin could exert its effect in the treatment of T2D by altering the expression levels of H19 and GAS5.


IL-17 sustains the plasma cell response via p38-mediated Bcl-xL RNA stability in lupus pathogenesis.
Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Currently, both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear. In this study, we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A (IL-17) stimulation in SLE patients and lupus mice. Using a humanized lupus mouse model, we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs. Moreover, long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU+ subsets among IL-17 receptor-expressing plasma cells. Lupus mice deficient in IL-17 or IL-17 receptor C (IL-17RC) exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage, while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice. In reconstituted chimeric mice, IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells. Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization. Together, our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis, which may provide new therapeutic strategies for the treatment of SLE.


Quantitative Proteome Analysis Reveals Increased Content of Basement Membrane Proteins in Arteries From Patients With Type 2 Diabetes Mellitus and Lower Levels Among Metformin Users.
The increased risk of cardiovascular diseases in type 2 diabetes mellitus has been extensively documented, but the origins of the association remain largely unknown. We sought to determine changes in protein expressions in arterial tissue from patients with type 2 diabetes mellitus and moreover hypothesized that metformin intake influences the protein composition. We analyzed nonatherosclerotic repair arteries gathered at coronary bypass operations from 30 patients with type 2 diabetes mellitus and from 30 age- and sex-matched nondiabetic individuals. Quantitative proteome analysis was performed by isobaric tag for relative and absolute quantitation-labeling and liquid chromatography-mass spectrometry, tandem mass spectrometry analysis on individual arterial samples. The amounts of the basement membrane components, α1-type IV collagen and α2-type IV collagen, γ1-laminin and β2-laminin, were significantly increased in patients with diabetes mellitus. Moreover, the expressions of basement membrane components and other vascular proteins were significantly lower among metformin users when compared with nonusers. Patients treated with or without metformin had similar levels of hemoglobin A1c, cholesterol, and blood pressure. In addition, quantitative histomorphometry showed increased area fractions of collagen-stainable material in tunica intima and media among patients with diabetes mellitus. The distinct accumulation of arterial basement membrane proteins in type 2 diabetes mellitus discloses a similarity between the diabetic macroangiopathy and microangiopathy and suggests a molecular explanation behind the alterations in vascular remodeling, biomechanical properties, and aneurysm formation described in diabetes mellitus. The lower amounts of basement membrane components in metformin-treated individuals are compatible with the hypothesis of direct beneficial drug effects on the matrix composition in the vasculature.


Seeking a geochemical identifier for authigenic carbonate.
Authigenic carbonate was recently invoked as a third major global carbon sink in addition to primary marine carbonate and organic carbon. Distinguishing the two carbonate sinks is fundamental to our understanding of Earth's carbon cycle and its role in regulating the evolution of atmospheric oxygen. Here, using microscale geochemical measurements of carbonates in Early Triassic strata, we show that the growth of authigenic carbonate follows a different trajectory from primary marine carbonate in a cross-plot of uranium concentration and carbon isotope composition. Thus, a combination of the two geochemical variables is able to distinguish between the two carbonate sinks. The temporal distribution of authigenic carbonates in the Early Triassic strata suggests that the increase in the extent of carbonate authigenesis acted as a negative feedback to the elevated atmospheric CO2 concentration.


Disordered eating behaviors among Turkish adolescents with and without Type 1 diabetes.
The aim of this comparative study was to determine the prevalence of disordered eating behaviors (DEBs) and its affecting factors among adolescents with Type 1 diabetes. Subjects were 45 diabetic adolescents and 55 nondiabetic healthy control subjects. The main outcome measures used were the Eating Attitudes Test and the Body Image Scale (BIS). Findings suggest that DEBs are almost four times as common in diabetic adolescents as in their nondiabetic peers (p < .001). Strict diet restriction and insulin misuse (p < .01) were related to DEBs. Disordered eating behaviors make a significant contribution to menstrual problems (p < .001) and poor metabolic control (p < .001). There was a nonsignificant negative correlation between DEBs and the BIS score. Health care professionals should be aware of the potential effect of subclinical and clinical DEBs including insulin misuse and strict diet in weight-conscious people with Type 1 diabetes who have poor metabolic control and menstrual problems.


Risk of venous thromboembolism in Chinese pregnant women: Hong Kong venous thromboembolism study.
Previous Caucasian studies have described venous thromboembolism in pregnancy; however, little is known about its incidence during pregnancy and early postpartum period in the Chinese population. We investigated the risk of venous thromboembolism in a "real-world" cohort of pregnant Chinese women with no prior history of venous thromboembolism. In this observational study, 15,325 pregnancies were identified in 14,162 Chinese women at Queen Mary Hospital, Hong Kong between January 2004 and September 2016. Demographic data, obstetric information, and laboratory and imaging data were retrieved and reviewed. The mean age at pregnancy was 32.4±5.3 years, and the median age was 33 years (interquartile range, 29-36 yr). Pre-existing or newly diagnosed diabetes mellitus was present in 627 women (4.1%); 359 (0.7%) women had pre-existing or newly detected hypertension. There was a small number of women with pre-existing heart disease and/or rheumatic conditions. Most deliveries (86.0%) were normal vaginal; the remaining were Cesarean section 2,146 (14.0%). The incidence of venous thromboembolism was 0.4 per 1,000 pregnancies, of which 83.3% were deep vein thrombosis and 16.7% were pulmonary embolism. In contrast to previous studies, 66.7% of venous thrombosis occurred in the first trimester. Chinese women had a substantially lower risk of venous thromboembolism during pregnancy and the postpartum period compared to that of Caucasians. The occurrence of pregnancy-related venous thromboembolism was largely confined to the early pregnancy period, probably related to the adoption of thromboprophylaxis, a lower rate of Cesarean section, and early mobilization.


Productive and reproductive performance of females F1 Holstein x Gir daughters of proven bulls.
Records of 234 lactations from F1 Holstein x Gyr daughters of proven bulls were used in this study for the evaluation of productive and reproductive characteristics of cows. Data were collected from a private farm located in the municipality of Santo Antônio do Monte, MG, Brazil. The objective of this study was to evaluate the effects of Holstein bull's PTA milk (predicted transmitting ability) calving year, season, and parity on the productive and reproductive characteristics of F! cows. The productive characteristics analyzed were total milk production (TMP), average daily production (ADP), days in milk (DIM), and milk yield per day of calving interval (MYDCI). The studied reproductive characteristics were service interval (SI), calving interval (CI), and gestation length (GL). The results were subjected to statistical analysis and means for significant effects were compared using Duncan's test at a significance level of 5%. F1 animals efficiently expressed their genetic potential for milk production with an average total milk production of 7842.61 kg and average daily production of 24.53 kg. Means for days in milk, milk yield per day of calving interval, service interval, calving interval, and gestation length were 322.52 days, 20.73 kg, 106.0 days, 383.23 days, and 276.18 days, respectively. Properly managed F1 Holstein x Gyr daughters of proven bulls fed a balanced diet efficiently expressed their genetic potential for milk production without adverse effects on reproduction. Moreover, Holstein x Gyr cows should be selected based on parents' PTA for milk traits and other factors such as environmental conditions and management.


Quality of life after transoral laser microresection of laryngeal cancer: a longitudinal study.
In the treatment of early to moderate laryngeal carcinoma, both, transoral laser surgery and radiation-based protocols have demonstrated good survival and preservation rates. In this scenario, quality of life (QOL) may become an important tool for treatment planning. We aimed to evaluate QOL changes after transoral laser microsurgery (TLM). Prospective longitudinal study. Ninety-three consecutive disease-free patients were evaluated using UW-QOL v4 and SF-12, before and 12 months after treatment. Changes over time were assessed according to age, gender, location, tumor size, and adjuvant treatment. UW-QOL improved from 1,051.5 ± 133.7 to 1,121.7 ± 92.1 (P = 0.000), suggesting that the impact of the treatment was favorable in most of the patients. Voice quality significantly improved after TLM, but speech was still the most important variable for 46% of the patients. Tumor location (P = 0.002) was an independent factor for preoperative total score of UW-QOL, whereas adjuvant radiation (P = 0.03) and neck dissection (P = 0.02), were the only postoperative negative factors. One year after TLM patients present a very good QOL. Relevant voice impairment is detected especially in locally advanced tumors, reinforcing the necessity of preoperative counseling and postoperative rehabilitation. Adjuvant radiotherapy and neck dissection negatively influenced disease-specific QOL.


Metabolic engineering of Escherichia coli for high production of 1,5-pentanediol via a cadaverine-derived pathway.
1,5-Pentanediol (1,5-PDO) is a high value-added chemical which is widely used as a monomer in the polymer industry. There are no natural organisms that could directly produce 1,5-PDO from renewable carbon sources. In this study, we report metabolic engineering of Escherichia coli for high-level production of 1,5-PDO from glucose via a cadaverine-derived pathway. In the newly proposed pathway, cadaverine can be converted to 1,5-PDO via 5-hydroxyvalerate (5-HV) by introducing only one heterologous enzyme in E. coli. Different endogenous genes of E. coli were screened and heterologous carboxylic acid reductase genes were tested to build a functional pathway. Compared to the previously reported pathways, the engineered cadaverine-based pathway has a higher theoretical yield (0.70 mol/mol glucose) and higher catalytic efficiency. By further combining strategies of pathway engineering and process engineering, we constructed an engineered E. coli strain that could produce 2.62 g/L 1,5-PDO in shake-flask and 9.25 g/L 1,5-PDO with a yield of 0.28 mol/mol glucose in fed-batch fermentation. The proposed new pathway and engineering strategies reported here should be useful for developing biological routes to produce 1,5-PDO for real application.


Expression of ultraviolet-induced restriction alleviation in Escherichia coli K-12. Detection of a lambda phage fraction with a retarded mode of DNA injection.
Ultraviolet-induced restriction alleviation is an SOS function which partially relieves the K-12-specific DNA restriction in Escherichia coli. Restriction alleviation is determined by observing elevated survival of unmodified phage lambda in cells irradiated with ultraviolet prior to infection. We demonstrate that restriction of lambda is also relieved when log-phase cells are irradiated as late as 50 min after adsorption of lambda. At this time more than 60% of the lambda DNA is already released as acid-soluble material from the cells. Experiments involving reextraction of lambda DNA from infected cells and a mild detergent treatment removing absorbed phages from the cellular surface showed that only a small specific fraction of all lambda infections is destined to escape restriction due to restriction alleviation. This fraction (10-20%) has a retarded mode of DNA injection (60 min or longer) after adsorption which allows the expression of the restriction alleviation function before the phage DNA is exposed to restriction endonucleases. This behaviour of a fraction of lambda phages explains why the SOS function restriction alleviation could initially be discovered. We show that the retarded mode of DNA injection is not required for another SOS function acting on lambda DNA, the increased repair of ultraviolet-irradiated DNA (Weigle reactivation).


Haemodynamic and renal effects of a novel prostaglandin analogue (L644,122(+isomer)) in sheep.
1. Merino-cross ewes were given an intravenous injection of a prostaglandin analogue, (+)-4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]- propyl) benzoic acid, at doses of 0.01, 0.05 and 0.10 mg/kg, on separate days, to determine renal and haemodynamic responses. 2. Peripheral vasodilatory effects, indicated by increases in heart rate and cardiac output, and falls in total peripheral resistance, peaked at 20 min at the two highest doses. By 60 min most values had returned to pre-injection levels. There were no changes in mean arterial pressure. 3. At the highest dose of 0.10 mg/kg there was a fall in glomerular filtration rate, renal blood flow and effective renal plasma flow within 20 min. Urinary sodium and potassium excretion also fell with all three doses tested. 4. Plasma renin concentration increased at the 0.05 and 0.10 mg/kg doses and was still elevated at 60 min. 5. The results of this study in the sheep contrast with others in the dog, where renal blood flow is increased and the rat, where blood pressure is increased, and indicate a species specificity in regard to the analogue's actions.


Enantioselective N-heterocyclic carbene-catalyzed synthesis of trifluoromethyldihydropyridinones.
The enantioselective N-heterocyclic carbene-catalyzed [4 + 2] cyclocondensation of α-chloroaldehydes and trifluoromethyl N-Boc azadienes was developed, giving the corresponding 3,4-disubstituted-6-trifluoromethyldihydropyridin-2(1H)-ones in good yields with exclusive cis-selectivities and excellent enantioselectivities.


Elucidating chromatin and nuclear domain architecture with electron spectroscopic imaging.
Electron microscopy has been the 'gold standard' of spatial resolution for studying the structure of the cell nucleus. Electron spectroscopic imaging (ESI) offers advantages over conventional transmission electron microscopy by eliminating the need for heavy-atom contrast agents. ESI also provides mass-dependent and element-specific information at high resolution, permitting the distinguishing of structures that are primarily composed of protein, DNA, or RNA. The technique can be applied to understand the structural consequences of epigenetic modifications, such as modified histones, on chromatin fiber morphology. ESI can also be applied to elucidate the multifunctional behavior of subnuclear 'organelles' such as the nucleolus and promyelocytic leukemia nuclear bodies.


Perinatal mental illness and maternal autoimmune disease: A review of current evidence and avenues for future research.
This review summarizes evidence on the association between perinatal mental illness and maternal autoimmune disease and identifies avenues for future research. Perinatal mental illness has several characteristics in common with autoimmune disease, including increased incidence in the early postpartum period, recurrence across pregnancies, evidence of elevated immune-mediated cytokines, and familial risk, as well as the general predominance of mental illness in females versus males. Several studies have demonstrated elevated risk of maternal autoimmune disease in women with perinatal mental illness, and of perinatal mental illness in those with autoimmune dysfunction, suggesting a bi-directional relationship. Further research is needed to elucidate the importance of the specific diagnosis, severity, and timing of perinatal mental illness and specific diagnosis of autoimmune disease, as well as the relative importance of perinatal versus non-perinatal mental illness. Such research could have implications for prevention, treatment, and follow-up of perinatal mental illness.


Photochemistry of oxidized Hg(I) and Hg(II) species suggests missing mercury oxidation in the troposphere.
Mercury (Hg), a global contaminant, is emitted mainly in its elemental form Hg0 to the atmosphere where it is oxidized to reactive HgII compounds, which efficiently deposit to surface ecosystems. Therefore, the chemical cycling between the elemental and oxidized Hg forms in the atmosphere determines the scale and geographical pattern of global Hg deposition. Recent advances in the photochemistry of gas-phase oxidized HgI and HgII species postulate their photodissociation back to Hg0 as a crucial step in the atmospheric Hg redox cycle. However, the significance of these photodissociation mechanisms on atmospheric Hg chemistry, lifetime, and surface deposition remains uncertain. Here we implement a comprehensive and quantitative mechanism of the photochemical and thermal atmospheric reactions between Hg0, HgI, and HgII species in a global model and evaluate the results against atmospheric Hg observations. We find that the photochemistry of HgI and HgII leads to insufficient Hg oxidation globally. The combined efficient photoreduction of HgI and HgII to Hg0 competes with thermal oxidation of Hg0, resulting in a large model overestimation of 99% of measured Hg0 and underestimation of 51% of oxidized Hg and ∼66% of HgII wet deposition. This in turn leads to a significant increase in the calculated global atmospheric Hg lifetime of 20 mo, which is unrealistically longer than the 3-6-mo range based on observed atmospheric Hg variability. These results show that the HgI and HgII photoreduction processes largely offset the efficiency of bromine-initiated Hg0 oxidation and reveal missing Hg oxidation processes in the troposphere.


Insulin-induced hypoglycaemic response and release of growth hormone in depressed patients and healthy controls.
As part of the Collaborative Study of the Psychobiology of Depression, we have examined the pretreatment growth hormone response (delta GH) to insulin (0.1 U/kg) and the magnitude of the hypoglycaemic response in a large number of well-defined depressed patients (N = 132) and healthy controls (N = 80). After applying rigorous exclusion criteria, data were analysed from 93 patients and 66 controls for blood glucose response and from 56 patients and 52 controls for delta GH. Depressed patients, either unipolar or bipolar, showed less of a fall in glucose than controls. A weak association was found between the magnitude of the fall in glucose and the severity of depression. No significant differences were found in values for delta GH between the unipolar or bipolar depressed patients and controls either for males, pre-menopausal or post-menopausal females, or the total female group. These data do not support previous claims of a lowered delta GH response to insulin in depressed patients. However, the resistance to hypoglycaemia seen in the depressed patients is consistent with previous reports.


SOCS3 Silencing Promotes Activation of Vocal Fold Fibroblasts via JAK2/STAT3 Signaling Pathway.
Suppressor of cytokine signaling 3 (SOCS3) is a negative regulatory protein that has been identified as a key inhibitory regulator of JAK/STAT signaling pathway. However, the mutual regulatory relationship between SOCS3 and JAK2/STAT3 signaling pathway after vocal fold injury remains unclear. In this study, we used small interfering RNA (siRNA) to investigate the mechanism of SOCS3 regulating of fibroblasts through JAK2/STAT3 signaling pathway after vocal fold injury. Our data shows that SOCS3 silencing promotes the transformation of normal vocal fold fibroblasts (VFFs) into an fibrotic phenotype and activates the JAK2/STAT3 signaling pathway. JAK2 silencing significantly inhibits the increase in type I collagen and α-smooth muscle actin (α-SMA) secretion in VFFs induced by TGF-β but has no significant effect on normal VFFs. The silencing of SOCS3 and JAK2 reverses the fibrotic phenotype of VFFs induced by SOCS3 silencing. Therefore, we suggest that SOCS3 can affect the activation of vocal fold fibroblasts by regulating the JAK2/STAT3 signaling pathway after vocal fold injury. It provides a new insight for promoting the repair of vocal fold injury and preventing the formation of fibrosis.


Perinatal lethality of Par4-/- mice delivered by primiparous dams reveals spontaneous bleeding in mice without platelet thrombin receptor function.
Protease-activated receptor 4 (PAR4) is a cell surface G protein-coupled receptor for serine proteases, such as thrombin. Par4-/- mice have platelets that are unresponsive to thrombin and thereby allow examination of the importance of thrombin-induced platelet activation in (patho)physiology. Par4-/- mice are protected against arterial thrombosis but show no evidence of spontaneous bleeding. This contrasts with the bleeding experienced by mice with marked thrombocytopenia, such as those with genetic deficiency of the transcription factor, nuclear factor erythroid 2 (Nfe2-/-), that have high rates of perinatal death due to hemorrhage. Given this discrepancy in spontaneous perinatal bleeding between mice without platelets and those without thrombin-induced platelet activation mechanisms, we examined in detail the immediate postnatal survival of Par4-/- pups. We observed significant postpartum loss of Par4-/- pups derived from Par4+/- intercrosses that was restricted to a dam's first litter; only 9% of surviving pups genotyped as Par4-/- in first litters and this normalized from the second litter onward (26%). A similar perinatal lethality in pups delivered by primiparous dams occurred in mice lacking platelets (Nfe2-/-; 10%) but not in those lacking fibrinogen (Fga-/-; 26%). These data,, provide the first evidence of spontaneous bleeding in Par4-/- mice, suggest that a dam's first litter provides a greater hemostatic challenge than subsequent litters, and uncovers an important role for platelets-and more specifically thrombin-induced platelet activation-in hemostasis during these more traumatic births.


Effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice.
Dutasteride is a 5alpha-reductase inhibitor in clinical use to treat endocrine conditions. The present study investigated the neuroprotective mechanisms of action of dutasteride in intact and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice using a low dose of MPTP not affecting motor activity modeling early stages of Parkinson's disease (PD). We hypothesized that dutasteride neuroprotection is due to altered steroids levels. Dutasteride pre-treatment prevented loss of striatal dopamine (DA) and its metabolite DOPAC. Dutasteride decreased effects of MPTP on striatal dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2) and D2 DA receptor specific binding while D1 receptor specific binding remained unchanged. Dutasteride enhanced DAT specific binding and the glycosylated form of DAT in intact mice. MPTP-lesioned mice had plasma and brain testosterone and dihydrotestosterone levels lower than control mice whereas progesterone and its metabolites (dihydroprogesterone, isopregnanolone and tetrahydroprogesterone) pathway showed increases. Dutasteride treatment by inhibiting transformation of progesterone and testosterone to its metabolites elevated plasma and brain concentrations of testosterone compared to MPTP mice and decreased DHT levels in intact mice. Plasma and brain estradiol levels were low and remained unchanged by MPTP and/or dutasteride treatment. Dutasteride treatment did not affect striatal phosphorylation of Akt and its downstream substrate GSK3β as well as phosphorylation of ERK1/2 in intact and MPTP lesioned MPTP mice. Striatal glial fibrillary acidic protein (GFAP) levels were markedly elevated in MPTP compared to control mice and dutasteride reduced GFAP levels in MPTP mice. Treatment with dutasteride post-lesion left unchanged striatal DA levels. These results suggest dutasteride as promising drug for PD neuroprotection.


Planetary protection guidelines for outer planet missions.
Facilities, techniques, and operational procedures used to implement Planetary Protection (PP) requirements for the Viking Project are reviewed in order to better define the COSPAR resolution which proposes that Outer Planet spacecraft be assembled using Viking-like clean room technology. It is concluded that, for such missions, PP requirements can be met by adopting Viking clean room standards, personnel and operation procedures, and by establishing PP as an official entity in project management.


Maternal care as a model for experience-dependent chromatin plasticity?
It is widely acknowledged that the nature of the maternal care a child receives can have long-term repercussions, and that children raised in deprived environments can have severe cognitive and behavioural difficulties that last into adulthood. The mechanisms underlying these effects are not understood, but recent data from rodents provide insight into a potential molecular mechanism. Like humans, rodent maternal behaviour towards offspring can effect long-term changes in responses of the offspring to stress throughout the rest of their lives. Remarkably, these changes reflect permanently altered gene expression, so-called "environmental programming", and its downstream effects on the hypothalamic-pituitary-adrenal axis. This review discusses the nature of this environmental programming--the mechanism by which it occurs in rats, its long-term implications, and opportunities for its reversal in rodents and ultimately in humans.