Complete Surgical Metastasectomy of Renal Cell Carcinoma in the Post-Cytokine Era.
Data supporting complete metastasectomy of metastatic renal cell carcinoma were derived primarily from the era of cytokine therapy. Whether complete metastasectomy remains beneficial in patients who receive more recently approved systemic therapies has not been well studied. The objective of this study was to examine survival outcomes among patients treated with complete metastasectomy in the era of targeted therapy and checkpoint blockade availability. We queried our institutional nephrectomy registry and identified 586 patients who underwent partial or radical nephrectomy of unilateral, sporadic renal cell carcinoma with a first occurrence of metastasis between 2006 and 2017. Of these patients 158 were treated with complete metastasectomy. Associations of complete metastasectomy with cancer specific and overall survival were assessed using Cox proportional hazards models. Median followup after the diagnosis of metastasis was 3.9 years, during which 403 patients died, including 345 of renal cell carcinoma. Of the patients treated with complete metastasectomy 147 (93%) did not receive any systemic treatment of the index metastatic lesion(s). Two-year cancer specific survival was significantly greater in patients with vs without complete metastasectomy (84% vs 54%, p <0.001). After adjusting for age, gender, and the timing, number and location of metastases complete metastasectomy was associated with a significantly reduced likelihood of death from renal cell carcinoma (HR 0.47, 95% CI 0.34-0.65, p <0.001). Complete surgical resection of metastases of renal cell carcinoma was associated with improved cancer specific survival in the post-cytokine era. It may be considered in appropriate patients after a process of shared decision making.


Best methods for identification and treatment of PCOS.
The polycystic ovarian syndrome (PCOS) includes a wide spectrum of clinical symptoms and signs. Three different diagnostic classifications have been proposed to define this disease. The first one, published in 1990, known as the "NIH criteria" requires the simultaneous presence of hyperandrogenism and menstrual dysfunction in order to diagnose PCOS. Later on, in 2003, an expert panel met in Rotterdam and added to the previous criteria the presence of polycystic ovarian morphology detected by transvaginal ultrasonography. The later classification broadened the spectrum of PCOS and also included women with oligomenorrhea and PCO without hyperandrogenism or hyperandrogenism and PCO without menstrual dysfunction. Finally, the Androgen Excess Society, published in 2006 new diagnostic criteria which required the presence of clinical or biochemical hyperandrogenism, with either PCO or menstrual dysfunction to diagnose PCOS. This review focuses on the diagnostic techniques and methods of treatment for PCOS patients. Special attention is given to the role of insulin resistance and the potential utility of insulin sensitizers in management of the syndrome. The benefit and utmost importance of lifestyle modification for the long-term health of these women is stressed as well. It is hoped that some clarity in this regard will allow more women to not only be diagnosed and managed properly for their presenting symptoms (hirsutism, irregular menses, etc.), but also to be educated and managed for the continuing health risk of insulin resistance throughout their lives.


Prebiotic and probiotic treatment of nonalcoholic fatty liver disease: a systematic review and meta-analysis.
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent and underdiagnosed comorbidity of many chronic diseases that is associated with altered intestinal bacterial communities. This association has prompted research into alternative treatments aimed at modulating intestinal microbiota. Given the novelty of these treatments, scarce evidence regarding their effectiveness in clinical populations exists. This meta-analysis sought to systemically review and quantitatively synthesize evidence on prebiotic, probiotic, and synbiotic therapies for patients with NAFLD in randomized controlled trials. PRISMA guidelines ensured transparent reporting of evidence. PICOS criteria defined the research question for the systematic review. A systematic keyword search in PubMed and EMBASE identified 25 studies: 9 assessed prebiotic, 11 assessed probiotic, and 7 assessed symbiotic therapies for a total of 1309 patients. Basic population characteristics, the primary variables of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (utilized for NAFLD diagnosis), and the secondary variables of body mass index (BMI), gamma-glutamyl transferase (γ-GT), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglyceridges (TAG) were extracted. Pooled effect sizes of these variables were calculated by meta-analysis. No publication bias was identified using Begg's and Egger's tests or Cochrane bias assessment tool. Meta-analysis indicated that microbial therapies significantly reduced BMI (-0.37 kg/m2; 95% confidence interval [CI], -0.46 to -0.28; P < 0.001), hepatic enzymes (ALT, -6.9 U/L [95%CI, -9.4 to -4.3]; AST, -4.6 U/L [95%CI, -6.6 to -2.7]; γ-GT, -7.9 U/L [95%CI, -11.4 to -4.4]; P < 0.001), serum cholesterol (-10.1 mg/dL 95%CI, -13.6 to -6.6; P < 0.001), LDL-c (-4.5 mg/dL; 95%CI, -8.9 to -0.17; P < 0.001), and TAG (-10.1 mg/dL; 95%CI, -18.0 to -2.3; P < 0.001), but not inflammation (TNF-α, -2.0 ng/mL; [95%CI, -4.7 to 0.61]; CRP, -0.74 mg/L [95%CI, -1.9 to 0.37]). Subgroup analysis by treatment category indicated similar effects of prebiotics and probiotics on BMI and liver enzymes but not total cholesterol, HDL-c, and LDL-c. This meta-analysis supports the potential use of microbial therapies in the treatment of NAFLD and sheds light on their potential mode of action. Further research into these treatments should consider the limitations of biomarkers currently used for the diagnosis and progression of NAFLD, in addition to the inherent challenges of personalized microbial-based therapies.


Linear scleroderma "en coup de sabre" coexisting with plaque-morphea: neuroradiological manifestation and response to corticosteroids.
A 24 year old woman in the 33rd week of pregnancy developed progressive neurological complications with right sided hemiparesis in association with the occurrence of linear scleroderma "en coup de sabre" (LSCS) and pre-existing plaque-morphea, already being treated by balneophototherapy. Further progression of neurological symptoms led to a caesarean section with the delivery of a healthy child. Brain magnetic resonance imaging (MRI) showed focal T2 signal increases in the left frontoparietal region directly adjacent to the area of LSCS. Cerebrospinal fluid analysis revealed oligoclonal bands, suggesting an intracerebral inflammatory process. Subsequent pulsed corticosteroid treatment led to a remission of neurological symptoms and to a marked resolution of the MRI lesions.


TAPER: Time-Aware Patient EHR Representation.
Effective representation learning of electronic health records is a challenging task and is becoming more important as the availability of such data is becoming pervasive. The data contained in these records are irregular and contain multiple modalities such as notes, and medical codes. They are preempted by medical conditions the patient may have, and are typically recorded by medical staff. Accompanying codes are notes containing valuable information about patients beyond the structured information contained in electronic health records. We use transformer networks and the recently proposed BERT language model to embed these data streams into a unified vector representation. The presented approach effectively encodes a patient's visit data into a single a distributed representation, which can be used for downstream tasks. Our model demonstrates superior performance and generalization on mortality, readmission and length of stay tasks using the publicly available MIMIC-III ICU dataset.


The neural correlates of desire.
In an event-related fMRI study, we scanned eighteen normal human subjects while they viewed three categories of pictures (events, objects and persons) which they classified according to desirability (desirable, indifferent or undesirable). Each category produced activity in a distinct part of the visual brain, thus reflecting its functional specialization. We used conjunction analysis to learn whether there is a brain area which is always active when a desirable picture is viewed, regardless of the category to which it belongs. The conjunction analysis of the contrast desirable > undesirable revealed activity in the superior orbito-frontal cortex. This activity bore a positive linear relationship to the declared level of desirability. The conjunction analysis of desirable > indifferent revealed activity in the mid-cingulate cortex and in the anterior cingulate cortex. In the former, activity was greater for desirable and undesirable stimuli than for stimuli classed as indifferent. Other conjunction analyses produced no significant effects. These results show that categorizing any stimulus according to its desirability activates three different brain areas: the superior orbito-frontal, the mid-cingulate, and the anterior cingulate cortices.


Brains from non-Alzheimer's individuals containing amyloid deposits accelerate Aβ deposition in vivo.
One of the main features of Alzheimer's disease (AD) is the presence of Aβ deposits, which accumulate in the brain years before the onset of symptoms. We and others have demonstrated that cerebral Aβ-amyloidosis can be induced in vivo by administration of AD-brain extracts into transgenic mice. However, it is currently unknown whether amyloid formation can be induced using extracts from individuals harboring Aβ deposits, but not clinical disease. In this study we analyzed the amyloid-inducing capability of samples from individuals affected by mild cognitive impairment (MCI) and Non-Demented persons with Alzheimer's disease Neuropathology (NDAN). Our results show that inoculation of transgenic mice with MCI and NDAN brain samples accelerated Aβ pathology in a similar way as extracts from confirmed AD. This data demonstrate that the sole presence of Aβ aggregates in a given sample, regardless of the clinical condition, is capable to accelerate Aβ deposition in vivo. These findings indicate that the amyloid-inducing activity may be present in the brain of people during pre-symptomatic or a-symptomatic stages of AD.


Angiotensin II-induced Ca(2+) influx in renal afferent and efferent arterioles: differing roles of voltage-gated and store-operated Ca(2+) entry.
Angiotensin II (Ang II)-induced Ca(2+) signaling was studied in isolated rat renal arterioles using fura-2. Ang II (10 nmol/L) caused a sustained elevation in [Ca(2+)](i), which was dependent on [Ca(2+)](o) in both vessel types. This response was blocked by nifedipine in only the afferent arteriole. Using the Mn(2+) quench technique, we found that Ang II stimulates Ca(2+) influx in both vessels. Nifedipine blocked the Ang II-induced Ca(2+) influx in afferent arterioles but not in efferent arterioles. In contrast to Ang II, KCl-induced depolarization stimulated Ca(2+) influx in only the afferent arteriole. Cyclopiazonic acid (CPA, 30 micromol/L) was used to examine the presence of store-operated Ca(2+) entry in myocytes isolated from each arteriole. In efferent myocytes, CPA induced a sustained Ca(2+) increase that was dependent on [Ca(2+)](o) and insensitive to nifedipine. This mechanism was absent in afferent myocytes. SKF 96365 inhibited Ang II-induced Ca(2+) entry in efferent arterioles and CPA-induced Ca(2+) entry in efferent myocytes over identical concentrations. Our findings thus indicate that Ang II activates differing Ca(2+) influx mechanisms in pre- and postglomerular arterioles. In the afferent arteriole, Ang II activates dihydropyridine-sensitive L-type Ca(2+) channels, presumably by membrane depolarization. In the efferent arteriole, Ang II appears to stimulate Ca(2+) entry via store-operated Ca(2+) influx.


Stability Evaluation of Ivermectin-Loaded Biodegradable Microspheres.
A stability study was performed on ivermectin (IVM)-loaded biodegradable microparticles intended for injection in dogs. The rational was to evaluate the performances upon irradiation of a drug, such as IVM, with a few criticalities with respect to its stability, and toxicity. The goal was to provide valuable information for pharmaceutical scientists and manufacturers working in the veterinary area. The microspheres based on poly(D,L-lactide) and poly-(ε-caprolactone) and loaded with IVM and with the addition of alpha-tocopherol (TCP) as antioxidant were prepared by the emulsion solvent evaporation method and sterilized by gamma irradiation. Microsphere characterization in term of size, shape, polymer, and IVM stability upon irradiation was performed. The results show that the type of polymer significantly affects microsphere characteristics and performances. Moreover, suitably stable formulations can be achieved only by TCP addition.


Synthesis of new steroidal inhibitors of P-glycoprotein-mediated multidrug resistance and biological evaluation on K562/R7 erythroleukemia cells.
A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/β-pregnane-3,20-dione or 5β-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2'R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/β-pregnane-3,20-dione, among which the 5β-H-7α-benzoyloxy-11α-(2'R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index 2.9, IC50 0.5 μM versus 1.2 and 10.6 μM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5β-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index 3.8, IC50 0.2 μM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.


New sensitive competitive enzyme-linked immunosorbent assay using a monoclonal antibody against nonstructural protein 1 of West Nile virus NY99.
An anti-West Nile virus (anti-WNV) monoclonal antibody, SHW-7A11, was developed for competitive enzyme-linked immunosorbent assays (c-ELISAs). SHW-7A11 reacted with nonstructural protein 1 in Western blot analysis. SHW-7A11 was relatively specific for the WNV strain NY99 and recognized Kunjin and Eg101 strains in indirect ELISAs. Two c-ELISAs were developed for sera diluted 10 and 100 times and named c-ELISA10 and c-ELISA100, respectively. Both c-ELISAs detected antibodies against WNV NY99 and Kunjin strains. Little cross-reactivity was observed for antibodies against Japanese encephalitis virus and St. Louis encephalitis virus in these assays. Using the cutoff point for the St. Louis encephalitis virus, all WNV-infected chickens were found to be positive on day 21 after infection in both c-ELISAs. On the other hand, all infected chickens were found to be positive on day 35 after infection in a virus neutralization test. Our newly developed SHW-7A11-based c-ELISA can detect WNV infection with sera diluted 10 to 100 times. Therefore, this c-ELISA can be used for WNV serosurveillance of chickens and wild birds.


Using administrative healthcare data to evaluate drug repurposing opportunities for cancer: the possibility of using beta-blockers to treat breast cancer.
Introduction: Cancer registries and hospital electronic medical records are commonly used to investigate drug repurposing candidates for cancer. However, administrative data are often more accessible than data from cancer registries and medical records. Therefore, we evaluated if administrative data could be used to evaluate drug repurposing for cancer by conducting an example study on the association between beta-blocker use and breast cancer mortality. Methods: A retrospective cohort study of women aged ≥50 years with incident breast cancer was conducted using a linked dataset with statewide hospital admission data and nationwide medication claims data. Women receiving beta blockers and first-line anti-hypertensives prior to and at diagnosis were compared. Breast cancer molecular subtypes and metastasis status were inferred by algorithms from commonly prescribed breast cancer antineoplastics and hospitalization diagnosis codes, respectively. Subdistribution hazard ratios (sHR) and corresponding 95% confidence intervals (CIs) for breast cancer mortality were estimated using Fine and Gray's competing risk models adjusted for age, Charlson comorbidity index, congestive heart failure, myocardial infraction, molecular subtype, presence of metastasis at diagnosis, and breast cancer surgery. Results: 2,758 women were hospitalized for incident breast cancer. 604 received beta-blockers and 1,387 received first-line antihypertensives. In total, 154 breast cancer deaths were identified over a median follow-up time of 2.7 years. We found no significant association between use of any beta-blocker and breast-cancer mortality (sHR 0.86, 95%CI 0.58-1.28), or when stratified by beta-blocker type (non-selective, sHR 0.42, 95%CI 0.14-1.25; selective, sHR 0.95, 95%CI 0.63-1.43). Results were not significant when stratified by molecular subtypes (e.g., triple negative breast cancer (TNBC), any beta blocker, sHR 0.16, 95%CI 0.02-1.51). Discussion: It is possible to use administrative data to explore drug repurposing opportunities. Although non-significant, an indication of an association was found for the TNBC subtype, which aligns with previous studies using registry data. Future studies with larger sample size, longer follow-up are required to confirm the association, and linkage to clinical data sources are required to validate our methodologies.


Learning curves of robotic extended totally extraperitoneal (eTEP) hernia repair among two surgeons at a high-volume community hospital: a cumulative sum analysis.
Robotic extended totally extraperitoneal hernia (eTEP) repair is a novel technique for minimally invasive ventral hernia repair with retromuscular placement of mesh. This study aimed to evaluate the learning curve for robotic eTEP hernia repair using risk-adjusted cumulative sum (RA-CUSUM) analysis for two general surgeons-one with dedicated fellowship training in robotic eTEP technique (surgeon 2) and another without robotic eTEP-specific training (surgeon 1). We conducted a retrospective analysis of 98 patients undergoing robotic eTEP hernia repair from July 2020 to February 2022 for two surgeons. RA-CUSUM method was applied to the overall operative time (OT) in minutes, adjusting for transversus abdominis release (TAR). Figures 3 (surgeon 1) and 4 (surgeon 2) illustrate the three phases in the RA-CUSUM graphs of OT. For surgeon 1, the cases for each phase were determined: phase 1 (1 to 12), phase 2 (13 to 24), and phase 3 (25 to 51). For surgeon 2, the three phases were similarly determined as 1 to 8, 9 to 32, and 33 to 47, respectively. A significant (p = 0.017) difference existed for the OTs between phases 1 (262 ± 69) and 3 (192 ± 63.0) for surgeon 1. OT compared to the risk-adjusted value stabilized after case 12 and decreased after case 24 for surgeon 1; it began to decrease after case 8 for surgeon 2. The initial learning curve for surgeon 1 reached its plateau after 12 cases, shorter than comparable studies. This was likely due to the surgeon's intentional focus on learning this technique through courses, proctoring, and active mentorship. The flat learning curve seen in surgeon 2's series illustrates the value of experience gained during fellowship training. Our data support that, given the right resources and support, a short learning curve for eTEP is attainable for community surgeons without prior training in the technique.


Influence of vitamin E on organic matter fermentation, ruminal protein and fatty acid metabolism, protozoa concentrations and transfer of fatty acids.
Vitamin E (Vit. E) is discussed to influence ruminal biohydrogenation. The objective of this study was to investigate the influence of a Vit. E supplementation on rumen fermentation characteristics, ruminal microbial protein synthesis as well as ruminal organic matter fermentation. Furthermore, we aimed to investigate the influence of Vit. E supplementation on short-chain fatty acids (SCFA) and protozoa concentrations in the rumen and, in addition, on transfer rates of middle-chain and long-chain fatty acids into the duodenum in lactating dairy cows. Eight rumen and duodenum fistulated German Holstein cows were assigned to either a group receiving 2,327 IU/d Vit. E (138.6 IU/kg DM DL-α-tocopherylacetate; n = 4) or a control group (23.1 IU/kg DM; n = 4). Neither ruminal protein synthesis nor organic matter fermentation was influenced by treatment. Vit. E did not act on the concentrations of short-chain fatty acids and protozoa in rumen fluid. Duodenal flow of C13:0 (1.3 versus 0.2 g/d, p = 0.014) and iso-C14:0 (1.0 versus 0.5 g/d, p = 0.050) was higher in the Vit. E group. We observed a trend for higher duodenal flows for C12:0 (1.6 versus 0.9 g/d, p = 0.095) and anteiso-C15:0 (12.2 versus 8.9 g/d, p = 0.084). Transfer rate of C12:0 tended to be higher in the Vit. E group (125.61 versus 73.96, p = 0.082). No other transfer rates were affected by treatment. Further studies are necessary to investigate the influence of Vit. E on rumen microbiota and their fatty acid production as well as on the impact of different doses of Vit. E supplementation on variables of protein synthesis efficiency.


Virtual Body Ownership Illusions for Mental Health: A Narrative Review.
Over the last 20 years, virtual reality (VR) has been widely used to promote mental health in populations presenting different clinical conditions. Mental health does not refer only to the absence of psychiatric disorders but to the absence of a wide range of clinical conditions that influence people's general and social well-being such as chronic pain, neurological disorders that lead to motor o perceptual impairments, psychological disorders that alter behaviour and social cognition, or physical conditions like eating disorders or present in amputees. It is known that an accurate perception of oneself and of the surrounding environment are both key elements to enjoy mental health and well-being, and that both can be distorted in patients suffering from the clinical conditions mentioned above. In the past few years, multiple studies have shown the effectiveness of VR to modulate such perceptual distortions of oneself and of the surrounding environment through virtual body ownership illusions. This narrative review aims to review clinical studies that have explored the manipulation of embodied virtual bodies in VR for improving mental health, and to discuss the current state of the art and the challenges for future research in the context of clinical care.


Elevation of plasma 1-deoxy-sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?
Diabetic distal sensorimotor polyneuropathy (DSPN) is a frequent, disabling complication of diabetes mellitus. There is increasing evidence that sphingolipids play a role in insulin resistance and type 2 diabetes (T2DM). Whether neurotoxic 1-deoxy-sphingolipids are elevated in DSPN patients' plasma and whether levels correlate to the DSPN stage were examined. The plasma profile of 12 sphingoid bases in patients with DSPN and T2DM(n = 39) were cross-sectionally compared to other nerve disorders including chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 13), transthyretin-related familial amyloid polyneuropathy (FAP) (n = 10), amyotrophic lateral sclerosis (ALS) (n = 13) and small fibre neuropathy (n = 12) by liquid chromatography mass spectrometry. Correlations to the DSPN stage were additionally performed. Furthermore, the sphingoid base distribution in sural nerve specimens was measured in patients with DSPN (n = 6) compared to CIDP (n = 3). A significantly increased amount of 1-deoxy-sphingolipids [1-deoxy-sphinganine (0.11 ± 0.06 μmol/l), 1-deoxy-sphingosine (0.24 ± 0.16 μmol/l)] in patients with DSPN was observed compared to age-matched healthy controls (0.06 ± 0.03 μmol/l; 0.12 ± 0.05 μmol/l) and to the other groups. (Para)clinical parameters including sensory loss, neuropathic pain, weakness, vibration perception, nerve conduction velocity, sensory nerve action potentials (sural nerve) and duration of T2DM did not correlate with plasma 1-deoxy-sphingolipid levels, neither did the clinical stage according to the Dyck classification for DSPN. Sphingolipid levels in sural nerve biopsies showed no differences between DSPN and CIDP. Contrarily, patients with a small fibre neuropathy had decreased C₂₀-sphingosine plasma levels. 1-deoxy-sphingolipid plasma levels are significantly elevated in DSPN. They are already detectable in early disease stages but do not correlate with the clinical course. Further knowledge on 1-deoxy-sphingolipids might lead to a better pathophysiological understanding and future treatment options in DSPN.


Live-virus serum neutralization after bivalent SARS-CoV-2 mRNA vaccination in hemodialysis patients.
The development of bivalent booster vaccines addresses the ongoing evolution of the emerging B.1.1.529 (omicron) variant subtypes that are known to escape vaccine-induced neutralizing antibody response. Little is known about the immunogenicity and reactogenicity of bivalent mRNA vaccines in hemodialysis patients with impaired vaccine response. In this prospective, observational cohort study, we analyzed SARS-CoV-2 anti-S1 IgG, surrogate neutralizing antibodies (SNA), and live-virus neutralization against the SARS-CoV-2 wildtype and the BA.5 variant in 42 hemodialysis patients with and without prior SARS-CoV-2 infection before and after an additional fifth bivalent vaccine dose. Anti-S1 IgG and SNA were significantly higher in hemodialysis patients with prior infection than in patients without infection (p < 0.001 and p < 0.01, respectively). In patients without prior infection, both antibody levels increased, and live-virus neutralizing antibodies against the wildtype and the BA.5 variant were correspondingly significantly higher after bivalent booster vaccination (p < 0.001 for both). Conversely, in patients with prior infection, anti-S1 IgG and SNA did not alter significantly, and bivalent booster vaccination did not induce additional humoral immune response against the SARS-CoV-2 wildtype and the BA.5 variant. Thus, bivalent mRNA vaccines might increase humoral responses in hemodialysis patients without prior infection. Larger clinical trials are needed to help guide vaccination strategies in these immunocompromised individuals.


Sequence-selective binding of phleomycin to DNA.
The binding of phleomycin and bleomycin to DNA has been investigated by studying their effects on cleavage by DNAase I and micrococcal nuclease. In the presence of cobalt, cleavage of DNA by the antibiotics is suppressed, yet they still provide protection from nuclease attack in regions surrounding the drug cleavage sites. We conclude that cleavage by phleomycin occurs at bonds around which the antibiotic is already selectively bound.


Miniature endoscopic optical coherence tomography probe employing a two-axis microelectromechanical scanning mirror with through-silicon vias.
We present the design and experimental results of a new MEMS-based endoscopic optical coherence tomography (OCT) probe. The uniqueness of this miniature OCT imaging probe is a two-axis MEMS mirror with through-silicon vias (TSVs) for interconnecting. The TSV interconnection enables ultracompact probe design, successfully reducing the probe size to only 2.6 mm in diameter. The MEMS mirror is actuated by an electrothermal actuator that is capable of scanning ± 16° at only 3.6 V DC. Two-dimensional and three-dimensional OCT images of microspheres embedded in PDMS and acute rat brain tissue have been obtained with this miniature probe in a time-domain OCT system.


Emergence of Time from Quantum Interaction with the Environment.
The nature of time as emergent for a system by separating it from its environment has been put forward by Page and Wootters [Phys. Rev. D 27, 2885 (1983)PRVDAQ0556-282110.1103/PhysRevD.27.2885] in a quantum mechanical setting neglecting interaction between system and environment. Here, we add strong support to the relational concept of time by deriving the time-dependent Schrödinger equation for a system from an energy eigenstate of the global Hamiltonian consisting of system, environment, and their interaction. Our results are consistent with concepts for the emergence of time where interaction has been taken into account at the expense of a semiclassical treatment of the environment. Including the coupling between system and environment without approximation adds a missing link to the relational time approach opening it to dynamical phenomena of interacting systems and entangled quantum states.


A systematic literature review on the use of platelet transfusions in patients with thrombocytopenia.
Objective: Investigate globally, current treatment patterns, benefit-risk assessments, humanistic, societal and economic burden of platelet transfusion (PT). Methods: Publications from 1998 to June 27, 2018 were identified, based on databases searches including MEDLINE®; Embase and Cochrane Database of Systematic Reviews. Data from studies meeting pre-specified criteria were extracted and validated by independent reviewers. Data were obtained for efficacy and safety from randomized controlled trials (RCTs); data for epidemiology, treatment patterns, effectiveness, safety, humanistic and societal burden from real-world evidence (RWE) studies; and economic data from both. Results: A total of 3425 abstracts, 194 publications (190 studies) were included. PT use varied widely, from 0%-100% of TCP patients; 1.7%-24.5% in large studies (>1000 patients). Most were used prophylactically rather than therapeutically. 5 of 43 RCTs compared prophylactic PT with no intervention, with mixed results. In RWE studies PT generally increased platelet count (PC). This increase varied by patient characteristics and hence did not always translate into a clinically significant reduction in bleeding risk. Safety concerns included infection risk, alloimmunization and refractoriness with associated cost burden. Discussion: In RCTs and RWE studies there was significant heterogeneity in study design and outcome measures. In RWE studies, patients receiving PT may have been at higher risk than those not receiving PT creating potential bias. There were limited data on humanistic and societal burden. Conclusion: Although PTs are used widely for increasing PC in TCP, it is important to understand the limitations of PTs, and to explore the use of alternative treatment options where available.


DrugComboRanker: drug combination discovery based on target network analysis.
Currently there are no curative anticancer drugs, and drug resistance is often acquired after drug treatment. One of the reasons is that cancers are complex diseases, regulated by multiple signaling pathways and cross talks among the pathways. It is expected that drug combinations can reduce drug resistance and improve patients' outcomes. In clinical practice, the ideal and feasible drug combinations are combinations of existing Food and Drug Administration-approved drugs or bioactive compounds that are already used on patients or have entered clinical trials and passed safety tests. These drug combinations could directly be used on patients with less concern of toxic effects. However, there is so far no effective computational approach to search effective drug combinations from the enormous number of possibilities. In this study, we propose a novel systematic computational tool DRUGCOMBORANKER: to prioritize synergistic drug combinations and uncover their mechanisms of action. We first build a drug functional network based on their genomic profiles, and partition the network into numerous drug network communities by using a Bayesian non-negative matrix factorization approach. As drugs within overlapping community share common mechanisms of action, we next uncover potential targets of drugs by applying a recommendation system on drug communities. We meanwhile build disease-specific signaling networks based on patients' genomic profiles and interactome data. We then identify drug combinations by searching drugs whose targets are enriched in the complementary signaling modules of the disease signaling network. The novel method was evaluated on lung adenocarcinoma and endocrine receptor positive breast cancer, and compared with other drug combination approaches. These case studies discovered a set of effective drug combinations top ranked in our prediction list, and mapped the drug targets on the disease signaling network to highlight the mechanisms of action of the drug combinations. The program is available on request.


An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs.
The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.


Room-temperature weak ferromagnetism induced by point defects in alpha-Fe2O3.
Unusual room-temperature weak ferromagnetism alpha-Fe(2)O(3) was prepared by heating the mixture of commercial alpha-Fe(2)O(3) (as raw material) and tartaric acid at a mild temperature of 250 degrees C. This reaction involves a fast heating and cooling process resulting from the self-catalyzed oxidation of tartaric acid. Careful chemical analyses confirmed that no any ferromagnetic impurities, such as Fe, Fe(3)O(4), amorphous iron oxide and gamma-Fe(2)O(3,) were present in the treated sample. The unusual weak ferromagnetism was then attributed to the formation of a large amount of point defects in the treated sample during the peculiar synthetic process. Such a mechanism is supported by the result of annealing, which reduces the amount of point defects and thereby reestablishes the original antiferromagnetism in alpha-Fe(2)O(3).


Determining the sigma-donor ability of the cyclopropane C-C bond.
The low temperature crystal structures of ester and ether derivatives of varying electron demand, derived from cyclopropylmethanol and dicyclopropylmethanol , have been determined. These structures show a very strong response of the C-OR bond distance to the electron demand of the OR substituent, demonstrating the strong sigma-donor ability of the strained C-C bonds in the cyclopropane ring.


Age-Associated Failure To Adjust Type I IFN Receptor Signaling Thresholds after T Cell Activation.
With increasing age, naive CD4 T cells acquire intrinsic defects that compromise their ability to respond and differentiate. Type I IFNs, pervasive constituents of the environment in which adaptive immune responses occur, are known to regulate T cell differentiation and survival. Activated naive CD4 T cells from older individuals have reduced responses to type I IFN, a defect that develops during activation and that is not observed in quiescent naive CD4 T cells. Naive CD4 T cells from young adults upregulate the expression of STAT1 and STAT5 after activation, lowering their threshold to respond to type I IFN stimulation. The heightened STAT signaling is critical to maintain the expression of CD69 that regulates lymphocyte egress and the ability to produce IL-2 and to survive. Although activation of T cells from older adults also induces transcription of STAT1 and STAT5, failure to exclude SHP-1 from the signaling complex blunts their type I IFN response. In summary, our data show that type I IFN signaling thresholds in naive CD4 T cells after activation are dynamically regulated to respond to environmental cues for clonal expansion and memory cell differentiation. Naive CD4 T cells from older adults have a defect in this threshold calibration. Restoring their ability to respond to type I IFN emerges as a promising target to restore T cell responses and to improve the induction of T cell memory.


Iron is a substrate of the Plasmodium falciparum chloroquine resistance transporter PfCRT in Xenopus oocytes.
The chloroquine resistance transporter of the human malaria parasite Plasmodium falciparum, PfCRT, is an important determinant of resistance to several quinoline and quinoline-like antimalarial drugs. PfCRT also plays an essential role in the physiology of the parasite during development inside erythrocytes. However, the function of this transporter besides its role in drug resistance is still unclear. Using electrophysiological and flux experiments conducted on PfCRT-expressing Xenopus laevis oocytes, we show here that both wild-type PfCRT and a PfCRT variant associated with chloroquine resistance transport both ferrous and ferric iron, albeit with different kinetics. In particular, we found that the ability to transport ferrous iron is reduced by the specific polymorphisms acquired by the PfCRT variant as a result of chloroquine selection. We further show that iron and chloroquine transport via PfCRT is electrogenic. If these findings in the Xenopus model extend to P. falciparum in vivo, our data suggest that PfCRT might play a role in iron homeostasis, which is essential for the parasite's development in erythrocytes.


Outcome of chickenpox in 66 pediatric renal transplant recipients.
Although chickenpox can cause severe morbidity and mortality in pediatric renal transplant recipients, published reports describing treatment of these patients are few, especially in the cyclosporine era. Sixty-nine episodes of chickenpox occurring in 66 patients were diagnosed in our transplant population between January 1984 and May 1996. Immunosuppression consisted of prednisone and azathioprine (30 cases); prednisone, azathioprine, and cyclosporine (38 cases); or prednisone alone (1 case). Azathioprine was temporarily discontinued in 66 of 68 cases. Cyclosporine was continued at the preexisting dose in 36 of 38 cases. Acyclovir was administered parenterally in 62 of 69 cases. Sixty-five of 66 patients survived. Cyclosporine use did not increase the incidence of severe disease (p > 0.1). Acute allograft rejection occurred in three patients and responded to prednisone. Chickenpox in children with renal transplants can be successfully treated with intravenous acyclovir and temporary withdrawal of azathioprine. Allograft rejection is uncommon with this approach. Patients receiving cyclosporine do not appear to experience increased morbidity or mortality with chickenpox.


KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size.
Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms of the gut wall that express the receptor tyrosine kinase KIT. Somatic mutations that result in constitutive activation of KIT kinase have been identified in a number of studies of GISTs, although the reported frequency of these mutations has varied over a wide range (20 to 92%). Several reports have suggested that KIT gene mutations are more common in malignant GISTs than in benign lesions, and it has been proposed that mutations in exon 11 of KIT are a negative prognostic factor. To maximize sensitivity for KIT mutations we have adapted denaturing high-pressure liquid chromatography as a method for screening polymerase chain reaction amplimers of exons 9, 11, 13, and 17 from GIST genomic DNA. This approach was used to assess the frequency of KIT mutations in 13 morphologically benign, incidentally discovered, GISTs identified at autopsy, endoscopy, or laparotomy for unrelated disease. Representing the smallest pathologically recognizable GISTs, these lesions ranged in size from 4 to 10 mm in diameter and were all immunohistochemically positive for KIT. Eleven of the 13 tumors had sequence-confirmed mutations in KIT, including 10 mutations in exon 11 (77%) and one mutation in exon 9 (7.7%). The remaining two tumors were wild type for exons 9, 11, and 17; one of these was also analyzed for exon 13 and was wild type in this exon as well. The mutations found in the incidental GISTs were identical to those that have been documented in larger GISTs. In addition, the overall frequency of mutations in the incidental tumors (85%) did not differ significantly from that we previously reported in a series of 72 advanced/metastatic GISTs (86%), strongly supporting the view that activating mutations in KIT are acquired very early in the development of most GISTs. The findings suggest that KIT mutations per se are of little prognostic importance in GISTs.


Methylphenidate does not improve cognitive function in healthy sleep-deprived young adults.
Abuse of methylphenidate, a treatment of attention-deficit/hyperactivity disorder, is reported to be increasing among students for the purpose of improving cognition. A single capsule, containing methylphenidate (20 mg) or placebo, was administered to healthy young adults orally following 24 hours of sleep deprivation. Measurements included percent change in score from sleep-deprived baseline on four standardized tests of cognitive function: Hopkins Verbal Learning, Digit Span, Modified Stroop, and Trail Making tests. Measurements also included percent changes in blood pressure and heart rate from sleep-deprived baseline and plasma methylphenidate concentration. Differences in cognitive test performance were not observed between intervention groups. In subjects receiving methylphenidate, mean percent changes from baseline for systolic blood pressure and heart rate were increased relative to placebo between 90 and 210 minutes following capsule administration (maximum increases of 9.45% and 11.03%, respectively). The timing of peak differences in physiologic measures did not correlate with peak serum methylphenidate concentrations. Exit questionnaire ratings of "capsule effect" and perceived performance on the postcapsule administration of the most challenging cognitive test were both higher (p = .044 and p = .009, respectively) for the methylphenidate group than for the placebo group. Cognitive improvement among sleep-deprived young adults was not observed following methylphenidate administration. Benefits perceived by abusers may relate to increased confidence and sense of well-being, as well as to sympathetic nervous system stimulation. Moreover, methylphenidate administration results in physiologic effects that could be harmful to certain individuals.


Modification of liposomes with N-substituted polyacrylamides: identification of proteins adsorbed from plasma.
Liposomes prepared from DMPC (80%) and cholesterol (20%) were modified with a series of hydrophobically modified N-substituted polyacrylamides, namely, poly[N-isopropylacrylamide] (PNIPAM), poly[N,N-bis(2-methoxyethyl) acrylamide] (PMEAM), and poly[(3-methoxypropyl)acrylamide] (PMPAM). The hydrophobic group, N-[4-(1-pyrenylbutyl)-N-n-octadecylamine was attached to one end of the polymer chains to serve as an anchor for incorporation into the liposome bilayer. Liposome-polymer interactions were confirmed using fluorescence spectroscopy and chemical analysis. Microscopy revealed differences in aggregation tendency between unmodified and polymer-modified liposomes. Proteins adsorbed to liposome surfaces during exposure to human plasma were identified by immunoblot analysis. It was found that both unmodified and polymer-modified liposomes adsorb a wide variety of plasma proteins. Contact phase coagulation proteins, complement proteins, cell-adhesive proteins, serine protease inhibitors, plasminogen, antithrombin III, prothrombin, transferrin, alpha(2)-microglobulin, hemoglobin, haptoglobin and beta-lipoprotein as well as the major plasma proteins were all detected. Some differences were found between the unmodified and polymer-modified liposomes. The unmodified liposomes adsorbed plasminogen mainly as the intact protein, whereas on the modified liposomes plasminogen was present in degraded form. Also, the liposomes modified with PNIPAM in its extended conformation (below the lower critical solution temperature) appeared to adsorb less protein than those containing the 'collapsed' form of PNIPAM (above the LCST).


Free range eggs does not mean safe eggs: an outbreak of Salmonella Typhimurium linked to free range eggs.
An outbreak of Salmonella enterica serovar Typhimurium with closely related Multiple Locus Variable-number Tandem Repeat Analysis (MLVA) patterns was detected by routine surveillance by the Australian Capital Territory Health Protection Service in May 2018. The outbreak consisted of three cases in 2018 (MLVA 03-10-10-09-496) and one in 2016 (MLVA 03-10-09-09-496), who reported eating home-cooked eggs from the same local producer. Environmental investigations found significant problems with egg cleaning, hand hygiene and documentation of food safety procedures on farm. Environmental samples collected from the farm were found to have the same MLVA pattern as the 2018 cases. Although poor farm practices most likely led to contamination of the eggs, this outbreak highlights the need for consumer education about safe handling of eggs in the home.


Cardiac Profile of Filipino Patients With Liver Cirrhosis: A 10-Year Study.
Cardiac complications among patients with liver cirrhosis have not yet been described among Filipinos. Cirrhotic cardiomyopathy is a rarely described complication that has not been extensively described in literature. This is the first study to describe the electrocardiographic and echocardiographic findings of Filipino patients with liver cirrhosis. A retrospective analytical study of 148 patients with liver cirrhosis from 2007 to 2016 at the Philippine Heart Center was done. The clinical characteristics, median QTc interval, systolic and diastolic functions on echocardiography of these patients were described. Spearman rho correlation was employed to determine the rank order correlation between QTc prolongation and the severity of liver cirrhosis. Fisher's Exact test was used to test the association of the echocardiographic parameters with the severity of liver cirrhosis. The 10-year prevalence rate of liver cirrhosis at the Philippine Heart Center was 0.001% (148/137,584). The mean age was 72.4 ± 14 years with a female/male ratio of 1.1:1. The most common etiology of cirrhosis was hepatitis B or C infection (20%, 29). The Child-Pugh Classification (CPC) and Model for End-Stage Liver Disease (MELD) score were used to determine the severity of liver cirrhosis and to assess their prognosis. There were 31 patients (24%) with CPC-A, 84 patients (64%) with CPC-B and 15 patients (11%) with CPC-C. Fifty-five percent (n = 69) had a MELD score of 16 and below. Prolongation of the QTc interval was only seen among those with CPC A (median QTc of 470 ms) and a MELD score of 9 and below (median QTc of 485 ms). The mean left ventricular ejection fraction was 54.40±28.63%. There were five patients with a left ventricular ejection fraction of < 55%. The mean cardiac output (6.04 ± 5.24 L/min/m2) and cardiac index (2.92 ± 1.47 L/min/m2) were normal. There were 44 patients who had evidence of diastolic dysfunction based on an E/A ratio < 1, prolongation of isovolumic relaxation time (IVRT) of > 80 ms and prolongation of deceleration time (DT) of > 200 ms. There were only five patients who fulfilled the criteria for cirrhotic cardiomyopathy. A majority of the patients were discharged improved (82%). There were 26 cases who expired (18%). A higher mean age of Filipinos with liver cirrhosis was reported in our study. Prolongation of the QTc interval was seen among those with early and late stage of cirrhosis (CPC A or MELD score ≤ 9 and CPC C). Most of these patients had normal left ventricular systolic function precluding the presence of cirrhotic cardiomyopathy.


Tumor-Associated CD19+CD39- B Regulatory Cells Deregulate Class-Switch Recombination to Suppress Antibody Responses.
B cells are an essential component of humoral immunity. Their primary function is to mount antigen-specific antibody responses to eliminate pathogens. Despite an increase in B-cell number, we found that serum-IgG levels were low in patients with breast cancer. To solve this conundrum, we used high-dimensional flow cytometry to analyze the heterogeneity of B-cell populations and identified a tumor-specific CD19+CD24hiCD38hi IL10-producing B regulatory (Breg)-cell subset. Although IL10 is a Breg-cell marker, being an intracellular protein, it is of limited value for Breg-cell isolation. Highly expressed Breg-cell surface proteins CD24 and CD38 also impede the isolation of viable Breg cells. These are hurdles that limit understanding of Breg-cell functions. Our transcriptomic analysis identified, CD39-negativity as an exclusive, sorting-friendly surface marker for tumor-associated Breg cells. We found that the identified CD19+CD39‒IL10+ B-cell population was suppressive in nature as it limited T helper-cell proliferation, type-1 cytokine production, and T effector-cell survival, and augmented CD4+FOXP3+ regulatory T-cell generation. These tumor-associated Breg cells were also found to restrict autologous T follicular helper-cell expansion and IL21 secretion, thereby inhibiting germinal transcript formation and activation-induced cytidine deaminase expression involved in H-chain class-switch recombination (CSR). This isotype-switching abnormality was shown to hinder B-cell differentiation into class-switched memory B cells and subsequent high-affinity antibody-producing plasma B cells, which collectively led to the dampening of IgG-mediated antibody responses in patients with cancer. As low IgG is associated with poor prognosis in patients with cancer, Breg-cell depletion could be a promising future therapy for boosting plasma B cell-mediated antibody responses.


Highly Efficient and Stable Inverted Perovskite Solar Cell Using Pure δ-FAPbI3 Single Crystals.
Pure δ-formamidinium lead triiodide (δ-FAPbI3 ) single crystal for highly efficient perovskite solar cell (PCS) with long-term stability is prepared by a new method consisting of liquid phase reaction of FAI and PbI2 in N,N-dimethyl formamide and antisolvent crystallization using acetonitrile. In this method, the incorporation of any impurity into the crystal is excluded by the molecular recognition of the crystal growth site. This pure crystal is used to fabricate α-FAPbI3 inverted PSCs which showed excellent power conversion efficiency (PCE) due to much-reduced trap-states. The champion device exhibited a high PCE of 23.48% under the 1-Sun condition. Surface-treated devices with 3-(aminomethyl)pyridine showed a significantly improved PCE of 25.07%. In addition, the unencapsulated device maintained 97.22% of its initial efficiency under continuous 1-Sun illumination for 1,000 h at 85 °C in an N2 atmosphere ensuring long-term thermal and photo stabilities of PSCs, whereas the control device kept only 89.93%.


Replacement of terminal cysteine with histidine in the metallothionein alpha and beta domains maintains its binding capacity.
To generate novel forms of metal-binding proteins, six mutant mouse metallothionein (MT) 1 fragments, in which a terminal cysteine residue was replaced by histidine, were expressed in Escherichia coli. The spectroscopic and analytical results showed that the alphaMT (C33H, C36H, C41H, C57H) and betaMT (C5H, C13H) mutant forms bound 4 and 3 Zn(II) atoms per molecule of protein to the nearest integer, even though in C41H and C5H, species of lower stoichiometry were also detected. In Cd(II) titrations, all the Zn(II) ions bound to the mutant proteins were displaced from the binding sites, giving rise to Cd-mutated MT forms with 4 and 3 Cd(II), respectively. However, although Cys-to-His substitutions maintained the binding capacity of the MT fragments, they caused structural changes with respect to the wild-type proteins. While C13H, C36H and C57H seem to contain Zn(II)-aggregates that are closely related to those of the wild-type proteins, only C41H and C57H gave rise to Cd(II)-aggregates similar to those of Cd4-alphaMT, where the His residue plays the role of the substituted Cys. Despite the structural implications of the Cys-to-His replacement, the dissociation constants showed no major decrease in the Cd-binding affinity in any of the mutants assayed compared with the wild-type.


Frequency-dependent and correlational selection pressures have conflicting consequences for assortative mating in a color-polymorphic lizard, Uta stansburiana.
Genetically determined polymorphisms incorporating multiple traits can persist in nature under chronic, fluctuating, and sometimes conflicting selection pressures. Balancing selection among morphs preserves equilibrium frequencies, while correlational selection maintains favorable trait combinations within each morph. Under negative frequency-dependent selection, females should mate (often disassortatively) with rare male morphotypes to produce conditionally fit offspring. Conversely, under correlational selection, females should mate assortatively to preserve coadapted gene complexes and avoid ontogenetic conflict. Using controlled breeding designs, we evaluated consequences of assortative mating patterns in color-polymorphic side-blotched lizards (Uta stansburiana), to identify conflict between these sources of selection. Females who mated disassortatively, and to conditionally high-quality males in the context of frequency-dependent selection, experienced highest fertility rates. In contrast, assortatively mated females experienced higher fetal viability rates. The trade-off between fertility and egg viability resulted in no overall fitness benefit to either assortative or disassortative mating patterns. These results suggest that ongoing conflict between correlational and frequency dependent selection in polymorphic populations may generate a trade-off between rare-morph advantage and phenotypic integration and between assortative and disassortative mating decisions. More generally, interactions among multiple sources of diversity-promoting selection can alter adaptations and dynamics predicted to arise under any of these regimes alone.


Validation of a single factor representing the indicators of metabolic syndrome as a continuous measure of metabolic load and its association with health and cognitive function.
The metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease associated with reduced physical fitness, higher disease burden, and impaired cognitive functions. Little is known about the operation of these risk factors in older adults when considered comprehensively without relying on the cut-off values of the single MetS components. The three main aims of the current study were to: (i) establish a latent metabolic load factor (MetL), using confirmatory factor analysis (CFA), and representing a continuous measure of MetL, defined by indicators that are commonly used to separate MetS groups from healthy individuals; (ii) examine the associations of this MetL factor with objective health, and cognitive function in men and women; (iii) compare the magnitude of these associations to those observed for the individual indicators used to define the MetL factor as well to the classical categorized MetS vs. non-MetS groups. The current analysis is based on cross-sectional data from 1,609 participants of the Berlin Aging Study II (mean age = 68.5 years, SD (3.7); 50.1% female). We applied structural equation modeling (SEM) to establish a latent MetL factor defined by the five indicators commonly used to diagnose MetS. The latent MetL factor was associated with physician-assessed morbidity and kidney function (estimated glomerular filtration rate, eGFR) in both men and women, but not with hand grip strength and lung function (Forced Expiratory Volume in 1 Second (FEV1)). In addition, we found a negative association between MetL and fluid intelligence among men. A continuous latent variable approach representing the common variance of MetS indicators is well suited to foster our understanding of human aging as a systemic phenomenon in which risk factors are operating on either side of the normal versus pathological divide.


Interventions for preventing falls in the elderly.
Fractures in the elderly often result from a simple fall. To assess the effects of programmes designed to reduce the incidence of falls in community dwelling, institutionalised, or hospitalised elderly people. We searched MEDLINE, EMBASE, CINAHL, PsycLIT, Social Science Citation Index, Dissertation Abstracts, Index to UK Theses, the Cochrane Register of Controlled Trials, and bibliographies of identified studies. We contacted known workers in the field. Trials were also obtained from the Cochrane Musculoskeletal Injuries Group trials register. Date of the most recent search: May 1997. Randomised trials of interventions designed to minimise the effect of, or prevent exposure to, any putative risk factor for falling in elderly individuals living in the community, in institutional care, or in hospital. The main outcomes of interest were number of fallers or falls, or the number sustaining a fall resulting in injury. Trials that focused on intermediate outcomes such as improved balance or did not report fall outcomes, were excluded. Two reviewers selected trials for inclusion. For each included trial, quality assessment and data extraction was carried out independently by two reviewers. Results of trials of similar design were pooled. Eighteen trials and one pre-planned meta-analysis were included. The analysis of four trials which studied the effect of exercise alone did not establish protection against falling (Peto odds ratio 1.05; 95% confidence interval 0.74 to 1.48). Based on one trial, there was no evidence to support exercise in conjunction with health education classes (Peto odds ratio 1.72; 95% confidence interval 0.78 to 3.75), or of health education classes alone (Peto odds ratio 1.25; 95% confidence interval 0.51 to 3.03) for the prevention of falls. However, significant protection against falling was apparent from interventions which targeted multiple, identified, risk factors in individual patients (Peto odds ratio 0.77; 95% confidence interval 0. 64 to 0.91), and from interventions which focused on behavioural interventions targeting environmental hazards plus other risk factors (Peto odds ratio 0.81; 95% confidence interval 0.71 to 0.93). Health care purchasers and providers contemplating fall prevention programmes should consider health screening of at risk elderly people, followed by interventions which are targeted at both intrinsic and environmental risk factors of individual patients. There is inadequate evidence for the effectiveness of single interventions such as exercise alone or health education classes for the prevention of falls.


[Colostoma with reflex evacuation--a new approach in rehabilitation of stoma patients].
Involuntary evacuation of the stoma is the problem of social rehabilitation of stomed patients. In 17 patients during formation of colostoma reservoir-holding mechanism was created. Strain of parietal peritoneum led to subjective feelings predicting colostoma evacuation that were seen 10-20 min before defecation and presented as heaviness in projection of external end of stoma in 15 (88.2%) or elements of intestinal colic in 2 (11.8%) patients. This permitted 9 patients to control colostoma evacuation. Five (29.4%) patients demonstrated ability to control defecation for 10-15 min with tension of the muscles of the anterior abdominal wall.


Overall survival is improved in mucinous adenocarcinoma of the colon.
Debate persists regarding the relationship between mucin expression and outcome in colon cancer. This arises due to discrepancy in the definition of mucinous adenocarcinoma and the combination of both colon and rectal cancers in analyses. This study examines the relationship between increased mucin production and outcomes in colon cancer. Cases were classified according to the World Health Organization classification of mucinous adenocarcinoma of the colon. Accordingly, tumors were categorized as either (a) mucinous adenocarcinoma of the colon (greater than 50% of the extracellular matrix occupied by mucin) or (b) non-mucinous adenocarcinoma of the colon. Overall survival and disease-free survival were calculated. A stepwise Cox proportional hazards regression model was employed to determine the risk of death/disease recurrence. Kaplan-Meier estimates of overall survival and disease-free survival were plotted for each group and compared using a log-rank test. On univariate analysis, mucinous adenocarcinoma was associated with reduced risk of death (P = 0.01). On multivariate analysis, mucinous adenocarcinoma was also associated with reduced risk of death (hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14-0.79, P = 0.01). Kaplan-Meier estimates confirmed improved rate of survival in the mucinous vs. non-mucinous group (P = 0.01). Mucinous adenocarcinoma did not affect disease-free survival (HR 0.75, 95% CI 0.46-1.21, P = 0.22). A comparison of Kaplan-Meier estimates for systemic recurrence demonstrated significant increases in systemic recurrence in the group with no mucin production (P = 0.04) but not for locoregional recurrence (P = 0.24). Histopathological evidence of mucinous adenocarcinoma in colon cancer is associated with improved outcomes.


Insulin-mimetic effects of vanadate in primary cultures of rat hepatocytes.
To evaluate possible mechanisms by which insulin inhibits hepatic apolipoprotein B (apoB) secretion, we incubated primary cultures of rat hepatocytes with sodium orthovanadate, a phosphotyrosine phosphatase inhibitor and insulin-mimetic agent. Vanadate (10 microM) and insulin (10 nM) inhibited the medium accumulation of apoB (secretion) by 21 and 37%, respectively, without increasing intracellular apoB. The effects of insulin and vanadate together were not additive. Both insulin and vanadate enhanced intracellular glycogen accumulation by 82 and 37%, respectively. Unlike insulin, vanadate, at a concentration that inhibited apoB secretion (10 microM), had no effect on intracellular lipogenesis, inhibited the secretion of newly synthesized hepatic proteins, and had a delayed onset and termination of action on inhibition of apoB secretion. At higher concentrations (40 and 80 microM), vanadate stimulated intracellular lipogenesis. In conclusion, our data indicate that vanadate mimics insulin action in hepatocytes with regard to the inhibition of medium accumulation of apoB. These data are consistent with the hypothesis that inhibition of apoB secretion may be secondary to an increase in phosphotyrosine content at its site of synthesis. The kinases responsible for this effect have not been identified. Several effects of vanadate, however, are different from those of insulin, suggesting a differential sensitivity to vanadate, a divergence of the signal transfer by insulin and vanadate at the insulin-receptor or postreceptor level, or both.


Metabolic Clinic Atlas: Organization of Care for Children with Inherited Metabolic Disease in Canada.
Nearly all children in Canada with an inherited metabolic disease (IMD) are treated at one of the country's Hereditary Metabolic Disease Treatment Centres. We sought to understand the system of care for paediatric IMD patients in Canada in order to identify sources of variation and inform future research priorities. Treatment centres were contacted by email and invited to complete a web-based survey. The questionnaire addressed, for each centre, the population size served and scope of practice, available human resources and clinic services and research capacity. Survey responses were analyzed descriptively. We received responses from 13 of the 14 treatment centres invited to participate. These centres represent at least 85% of the Canadian population, with over half of the centres located in southern Ontario and Quebec. All centres reported paediatric patients with IMDs as their main patient population. A variety of dedicated staff was identified; every centre reported having at least one physician and one dietician. The most common ancillary services available included telehealth (11/12 respondents) and biochemical genetic laboratory testing (10/12), with a high variability of access to on-site laboratory tests. A majority of centres indicated access to additional off-site services, but barriers to these were reported. All but one centre indicated previous experience with research. The variation we identified in the organization of care highlights the need to investigate the association between practice differences and health outcomes for paediatric IMD patients to inform policies that establish equitable access to services that are beneficial.


[Simultaneous infusion of vinorelbin and taxol as first-line chemotherapy in metastasized breast cancer].
To evaluate the activity and toxicity of simultaneous infusion of vinorelbine (VNB) and paclitaxel (T) as first line chemotherapy in advanced breast cancer patients (pts). 33 pts with histologically proven advanced breast cancer were treated with VNB 25 mg/m2 and T 150 mg/m2, both drugs given by i.v. infusion over 3 hours, with cycles repeated every 3 weeks. Granulocyte-colony-stimulating factor (G-CSF), 300 micrograms subcutaneously, was given on days 7 to 12 of each cycle in the first 10 patients. From October 1995 to July 1996, 33 untreated pts entered the study. Characteristics of the pts were the following: median age 53 years (29-71); median WHO performance status 1 (0-3); pre/postmenopausal 8/25; prior adjuvant chemotherapy 16; prior radiotherapy 8; dominant disease sites: soft tissue in 6; bone in 7, viscera in 19; number of metastatic sites: 1 in 18, 2 in 9, 3 in 6 pts. In 31 evaluable pts we observed: 1 CR (3%) and 14 PR (45%), for an overall response rate of 48%. Median time to response was 2 months; median time to progression and median survival were 7 and 22+ months, respectively. Median number of cycles was 6. Myelosuppression was the dose-limiting toxicity, with G 4 neutropenia occurring in 22% of the pts and neutropenic fever in 6% of the pts. Other toxicities were generally mild with nausea in 52% of the pts; mucositis in 15%; constipation in 12%; peripheral neuropathy in 46.5%. Alopecia was universal. Simultaneous infusion of VNB and T is well tolerated and active in untreated patients with advanced breast cancer. Median survival (22+ months) is similar to that reported with anthracycline-containing regimens, although response rate appears to be lower. It is likely that higher response rates may be achieved with a higher dose-intensity.


The kidney in potassium depletion. I. Na+-K+-ATPase activity and [3H]ouabain binding in MCT.
The effect of potassium depletion on renal Na+-K+-ATPase was studied in rats. K depletion produced a striking, time-dependent increase in Na+-K+-ATPase activity of the outer medullary collecting tubules (inner stripe; MCTis). After 3 wk on the K-free diet, when the urine was almost potassium-free, Na+-K+-ATPase activity in MCTis was over fourfold higher than in control animals (2,964 +/- 185 vs. 645 +/- 108 pmol X mm-1 X h-1). Repletion of potassium restored enzyme activity to base line within 7 days (t1/2 = 3.8 days), which corresponds to the catabolic rate of the renal enzyme, suggesting the cessation of enhanced synthesis that took place during K deprivation. Changes in Na+-K+-ATPase activity and aldosterone levels during both K depletion and repletion occurred in opposite directions and were therefore independent of each other. [3H]Ouabain binding to intact MCTis, reflecting the number of pump sites on the basolateral membrane, was similar in K-depleted and control animals; in contrast, tubule permeabilization that exposes additional pump units to the ligand, unmasked a nearly fourfold increase in [3H]ouabain binding (50.0 +/- 6.8 vs. 13.2 +/- 1.7 fmols X mm-1) in K-depleted rats, comparable to the increment in Na+-K+-ATPase activity. These results show that K depletion leads to a marked increase in Na+-K+-ATPase activity of MCTis, and suggest that the new enzyme units are located at a ouabain-inaccessible site in the intact tubule, i.e., either in an intracellular compartment or at the luminal membrane, where they may be involved in potassium reabsorption.


Are women better mindreaders? Sex differences in neural correlates of mentalizing detected with functional MRI.
The ability to mentalize, i.e. develop a Theory of Mind (ToM), enables us to anticipate and build a model of the thoughts, emotions and intentions of others. It has long been hypothesised that women differ from men in their mentalizing abilities. In the present fMRI study we examined the impact of (1) gender (women vs. men) and (2) game partner (human vs. computer) on ToM associated neural activity in the medial prefrontal cortex. Groups of men (n = 12) and women (n = 12) interacted in an iterated classical prisoner's dilemma forced choice situation with alleged human and computer partners who were outside the scanner. Both the conditions of playing against putative human as well as computer partners led to activity increases in mPFC, ACC and rTPJ, constituting the classic ToM network. However, mPFC/ACC activity was more pronounced when participants believed they were playing against the alleged human partner. Differences in the medial frontal lobe activation related to the sex of the participants could be demonstrated for the human partner > computer partner contrast. Our data demonstrate differences in medial prefrontal brain activation during a ToM task depending on both the gender of participants and the game partner.


[Cholinergic mechanisms of the hypothalamus medial preoptic area in control of thermoregulation and of wakefulness-sleep states in pigeons].
The data obtained show that cholinergic mechanisms of the medial preoptic area of hypothalamus participate in control of wakefulness-sleep states and thermoregulation parameters in pigeons. Muscarinic and nicotinic cholinergic receptors are established to be involved in the wakefulness maintenance. The muscarinic cholinergic receptor activation of the medial preoptic area is accompanied by an elevation of the brain temperature, by development of peripheral vasoconstriction, and by an in increase in level of the muscle contractile activity. During the nicotinic cholinergic receptor activation of the area, a decrease in the brain temperature and an increase in level of the muscle contractile activity are found. A comparative analysis of experiments and early investigation suggests that during the cholinergic receptors activation changes in the brain temperature of pigeons depend on type of the cholinergic receptors but not on their localization in the preoptic area of hypothalamus.


Ornithine alpha-ketoglutarate improves wound healing in severe burn patients: a prospective randomized double-blind trial versus isonitrogenous controls.
To compare the effectiveness on wound healing time in severe burn patients of ornithine alpha-ketoglutarate supplementation of enteral feeding vs. an isonitrogenous control. Previous clinical and experimental studies suggest a beneficial effect of enterally administered ornithine alpha-ketoglutarate supplementation on protein metabolism in burn patients, but few data deal with clinical outcome. Prospective double-blind randomized trial. Burn treatment center of an army hospital. Forty-seven severe burn patients with total burned body surface areas of 25% to 95% and presence of full thickness burn who were prescribed early exclusive enteral nutrition. Either ornithine alpha-ketoglutarate or isonitrogenous control (soy protein mixture, Protil-1) were administered twice a day as a bolus (2 x 10 g) at 9 am and 9 pm for 3 wks. The patients were evaluated for wound healing time (primary end point), antibiotic use, tolerance, duration of enteral nutrition, and nutritional status. Serial blood samples were collected in each patient for determination of serum transthyretin and plasma phenylalanine, and urine sampling was performed for determination of 3-methylhistidine excretion at day 4 and day 21 after burn injury. Wound healing times in patients receiving ornithine alpha-ketoglutarate or Protil-1 were 60 +/- 7 and 90 +/- 12 days, respectively (p < .05) for similar grafted surfaces. Based on increased serum transthyretin concentrations, both groups showed an improvement of nutritional status at day 21 after burn. Taking a cut-off value of 110 unit burn standard for severity of injury, plasma phenylalanine concentrations, and urinary 3-methylhistidine/creatinine ratio were significantly reduced (p < .05) in the less severe burn patients (<110 unit burn standard) supplemented with ornithine alpha-ketoglutarate. Ornithine alpha-ketoglutarate supplementation of enteral feeding significantly shortens wound healing time in severe burn patients. In addition, ornithine alpha-ketoglutarate administration was safe and well tolerated and decreased protein hypercatabolism in the less severe burn patients.


Psychometric properties of the Portuguese teacher-version of the Inventory of Callous-Unemotional Traits.
Callous unemotional (CU) traits refer to specific deficits in affective experience and interpersonal style, characterized by absence of guilt, constrictive display of emotion and failure to show empathy, callous use of others for one's own gain. The Inventory of Callous-Unemotional Traits (ICU) was developed to measure CU traits in children and adolescents. The aim of this study was to analyze the factorial structure of the Portuguese version of teacher-report ICU for children in school age and examine psychometric properties such as internal consistency and convergent validity in a community sample. Thirty-six teachers provided behavioral ratings of 100 and 78 children of elementary school, 88 boys and 90 girls, aged between 6 and 10 years old. Confirmatory factor analyses provided further support to a 2-factor structure, comprising the following dimensions: callous and uncaring. This study showed that the ICU seems a reliable an accessible tool that can be used in the Portuguese educational context to evaluate CU traits with low time consumption.


Destructive effect of HIFU on rabbit embedded endometrial carcinoma tissues and their vascularities.
To evaluate damage effect of High-intensity focused ultrasound on early stage endometrial cancer tissues and their vascularities. Rabbit endometrial cancer models were established via tumor blocks implantation for a prospective control study. Ultrasonic ablation efficacy was evaluated by pathologic and imaging changes. The target lesions of experimental rabbits before and after ultrasonic ablation were observed after autopsy. The slides were used for hematoxylin-eosin staining, elastic fiber staining and endothelial cell staining; the slides were observed by optical microscopy. One slide was observed by electron microscopy. Then the target lesions of experimental animals with ultrasonic ablation were observed by vascular imaging, one group was visualized by digital subtract angiography, one group was quantified by color Doppler flow imaging, and one group was detected by dye perfusion.SPSS 19.0 software was used for statistical analyses. Histological examination indicated that High-intensity focused ultrasound caused the tumor tissues and their vascularities coagulative necrosis. Tumor vascular structure components including elastic fiber, endothelial cells all were destroyed by ultrasonic ablation. Digital subtract angiography showed tumor vascular shadow were dismissed after ultrasonic ablation. After ultrasonic ablation, gray-scale of tumor nodules enhanced in ultrasonography, tumor peripheral and internal blood flow signals disappeared or significantly reduced in color Doppler flow imaging. Vascular perfusion performed after ultrasonic ablation, tumor vessels could not filled by dye liquid. High-intensity focused ultrasound as a noninvasive method can destroy whole endometrial cancer cells and their supplying vascularities, which maybe an alternative approach of targeted therapy and new antiangiogenic strategy for endometrial cancer.


Fluoroquinolones for treating tuberculosis.
Fluoroquinolones are sometimes used to treat multiple-drug-resistant and drug-sensitive tuberculosis. The effects of fluoroquinolones in tuberculosis regimens need to be assessed. To assess fluoroquinolones as additional or substitute components to antituberculous drug regimens for drug-sensitive and drug-resistant tuberculosis. In July 2007, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2007, Issue 3), MEDLINE, EMBASE, LILACS, Science Citation Index, Database of Russian Publications, and metaRegister of Controlled Trials. We also scanned reference lists of all identified studies and contacted researchers. Randomized controlled trials of antituberculous regimens containing fluoroquinolones in people diagnosed with bacteriologically positive (sputum smear or culture) pulmonary tuberculosis. Two authors independently applied inclusion criteria, assessed methodological quality, and extracted data. We used relative risk (RR) for dichotomous data, weighted mean difference (WMD) for continuous data (both with 95% confidence intervals (CI)), and the random-effects model if we detected heterogeneity and it was appropriate to combine data. Eleven trials (1514 participants) met the inclusion criteria. No statistically significant difference was found in trials substituting ciprofloxacin, ofloxacin or moxifloxacin for first-line drugs in relation to cure (416 participants, 3 trials), treatment failure (388 participants, 3 trials), or clinical or radiological improvement (216 participants, 2 trials). Substituting ciprofloxacin into first-line regimens in drug-sensitive tuberculosis led to a higher incidence of relapse (RR 7.17, 95% CI 1.33 to 38.58; 384 participants, 3 trials) and longer time to sputum culture conversion (WMD 0.50 months, 95% CI 0.18 to 0.82; 168 participants, 1 trial), although this was confined to HIV-positive participants. Substituting for ethambutol in first-line regimens led to a higher incidence of total number of adverse events (RR 1.34, 95% CI 1.05 to 1.72; 492 participants, 2 trials). Adding or substituting levofloxacin to basic regimens in drug-resistant areas had no effect. A comparison of sparfloxacin versus ofloxacin added to regimens showed no statistically significant difference in cure (184 participants, 2 trials), treatment failure (149 participants, 2 trials), or the total number of adverse events (253 participants, 3 trials). Only ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin and moxifloxacin have been tested in randomized controlled trials for treating tuberculosis. We cannot recommend ciprofloxacin in treating tuberculosis. Trials of newer fluoroquinolones for treating tuberculosis are needed and are on-going. No difference has been demonstrated between sparfloxacin and ofloxacin in drug-resistant tuberculosis.


Maternal temperament and character: associations to child behavior at the age of 3 years.
The influence of maternal temperament on child behavior, and whether maternal temperament impact boys and girls differently is not thoroughly studied. The aim was to investigate the impact of maternal temperament and character on child externalizing and internalizing problems at age 3. A birth-cohort of 1723 mothers and their children were followed from birth to age 3. At the child's age of 3 months, the mothers filled out standardized instruments on their temperament and character using the Temperament and Character Inventory (TCI) and depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS). At the child's age of 3 years, the mothers reported on child behavior using the Child Behaviour Checklist (CBCL). Maternal temperamental trait novelty seeking was positively associated with externalizing problems in the total population and in girls. Harm avoidance was positively associated with externalizing problems in the total population and in boys, and with internalizing problems in the total population and boys and girls respectively. Maternal character traits of self-directedness and cooperativeness were negatively associated with both externalizing and internalizing problems in the total population and in boys and girls respectively. Maternal character traits were more influential on child behavior than were temperamental traits, and thus the opportunities for intervention targeted at parental support are good. Maternal mental health and socioeconomic aspects also increased the risk for child behavior problems, indicating the need for recognition and support in clinical settings.


Changes of blood levels of several hormones, catecholamines, prostaglandins, electrolytes and cAMP in man during emotional stress.
The levels of several hormones (ACTH, GH, TSH, FSH, LH, parathyroid hormone--PTH, insulin, thyroxine--T4, triiodothyronine--T3, cortisol, testosterone, aldosterone, renin), catecholamines (epinephrine, norepinephrine, dopamin), prostaglandins (F1 alpha, F2 alpha, A + E), electrolytes (Na, K, Ca, Mg), cAMP and glucose in blood were measured before and immediately after the examination in 15 male students aged 28 to 35 years. Simultaneously the blood pressure was measured and hemodynamic measures were registered with the aid of echocardiography. A remarkable increase of catecholamines, ACTH, renin, T3, PTH, cAMP, PG F1 alpha, PG F2 alpha and Ca was found before the examination together with the increase of blood pressure. After the examination the levels of catecholamines, renin, aldosterone, T3, PTH, GH, FSH, LH, testosterone, PG A + E, glucose and Ca were found to be increased, while these of insulin, Na, PG F1 alpha, PG F2 alpha were decreased. The decrease of blood pressure was also found.


COVID-19 Exposes the Cracks in Our Already Fragile Mental Health System.
The coronavirus pandemic has caused enormous concern among many people. Every morning, we are met with an increasing deluge of dire news about the most recent number of people to contract COVID-19 and to die from it, decreases in the stock market, and countries implementing broad travel restrictions and stay-at-home orders.1,2 The current state of affairs is having a negative effect on the mental well-being of our country's residents. It also highlights the policy gaps in our current system that inhibit the vital conditions for well-being and resiliency.3 Although the primary focus has rightfully been on stopping the spread of COVID-19, we should also quickly prepare to address the mental toll the pandemic is taking on individuals and communities across the country. (Am J Public Health. Published online ahead of print May 21, 2020: e1-e2. doi:10.2105/AJPH.2020.305699).


Effect of lactate and palmitate on substrate utilization of isolated rat soleus.
The effects of exogenous lactate and palmitate on the metabolism of rat soleus muscle were studied. In the presence of glucose and insulin, the addition of 8 mM lactate resulted in a decrease in the oxidation of both glucose and other substrates. Lactate accounted for 70% of the oxygen consumption under these conditions. Glycogen accumulation and the incorporation of exogenous palmitate into triglycerides were stimulated by lactate addition, whereas the utilization of exogenous glycerol was depressed. The addition of 1 mM palmitate in either the presence or absence of lactate resulted in an inhibition of both glycolysis and the utilization of exogenous glucose. The results are discussed in terms of the effect of lactate levels on recovery from exercise.


Archaeal flagellin combines a bacterial type IV pilin domain with an Ig-like domain.
The bacterial flagellar apparatus, which involves ∼40 different proteins, has been a model system for understanding motility and chemotaxis. The bacterial flagellar filament, largely composed of a single protein, flagellin, has been a model for understanding protein assembly. This system has no homology to the eukaryotic flagellum, in which the filament alone, composed of a microtubule-based axoneme, contains more than 400 different proteins. The archaeal flagellar system is simpler still, in some cases having ∼13 different proteins with a single flagellar filament protein. The archaeal flagellar system has no homology to the bacterial one and must have arisen by convergent evolution. However, it has been understood that the N-terminal domain of the archaeal flagellin is a homolog of the N-terminal domain of bacterial type IV pilin, showing once again how proteins can be repurposed in evolution for different functions. Using cryo-EM, we have been able to generate a nearly complete atomic model for a flagellar-like filament of the archaeon Ignicoccus hospitalis from a reconstruction at ∼4-Å resolution. We can now show that the archaeal flagellar filament contains a β-sandwich, previously seen in the FlaF protein that forms the anchor for the archaeal flagellar filament. In contrast to the bacterial flagellar filament, where the outer globular domains make no contact with each other and are not necessary for either assembly or motility, the archaeal flagellin outer domains make extensive contacts with each other that largely determine the interesting mechanical properties of these filaments, allowing these filaments to flex.


New asymmetric AB(n)-shaped amphiphilic poly(ethylene glycol)-b-[poly(l-lactide)](n) (n = 2, 4, 8) bridged with dendritic ester linkages: I. Syntheses and their characterization.
This study presents new investigations on chemical syntheses and characterization of new asymmetric AB(n)-shaped amphiphilic diblock methoxy poly(ethylene glycol)-b-[poly(l-lactide)](n), MPEG-b-(PLLA)(n) (n = 2, 4, and 8), bridged with dendritic ester linkages. First, a new series of A(OH)(n)-shaped hydroxy end-capped MPEG-(OH)(2), MPEG-(OH)(4), and MPEG-(OH)(8) bearing corresponding one- to three-generation dendritic ester moieties were efficiently derived from the starting MPEG (M(n) = 2 KDa) and 2,2'-bis(hydroxymethyl)propionic acid (Bis-HMPA) via ester coupling and a facile hydroxy protection-deprotection cycle, and then, chemical structures of these functional MPEG-(OH)(n) were characterized by nuclear magnetic resonance spectrometry (NMR) and MALDI-FTMS. Subsequently, by employing these MPEG-(OH)(n) as functional macroinitiators, new asymmetric AB(n)()-shaped amphiphilic MPEG-b-(PLLA)(2) S1, MPEG-b-(PLLA)(4) S2, and MPEG-b-(PLLA)(8) S3 bridged with dendritic Bis-HMPA ester linkages of L1-L3 as well as linear structural MPEG-b-PLLA references (R1-R3) were synthesized through the SnOct(2)-catalyzed ring-opening polymerization (ROP) of l-lactide at 130 degrees C in m-xylene solution, and their structures were further examined by NMR and gel permeation chromatography (GPC). It was demonstrated that the functional MPEG-(OH)(n) efficiently initiated the ROP of LLA, finally leading to successful formation of the AB(n)-shaped amphiphilic MPEG-b-(PLLA)(n) (n = 2, 4, and 8) with each PLLA arm weight close to 2 KDa and very narrow molecular weight distribution. Moreover, thermal history, crystallization, and spherulite morphologies were studied by means of differential scanning calorimeter (DSC), thermal gravimetric analyzer (TGA), and polarized microscope (POM) for these new structural amphiphilic S1-S3 as well as the linear R1-R3, intriguingly indicating a strong molecular architecture dependence of segmental crystallizability, spherulite morphology, and apparent crystal growth rate. Due to the favorable biodegradability and biocompatibility of the PLLA and MPEG, these results may therefore create new possibilities for these novel structural AB(n)-shaped amphiphilic MPEG-b-(PLLA)(n) as potential biomaterials.


Seronegative myasthenia gravis.
Some myasthenia gravis (MG) patients do not have detectable acetylcholine receptor (AChR) antibodies and have been termed "seronegative" (SNMG) in many previous studies. A high proportion of patients with purely ocular symptoms, ocular MG, are seronegative; this may be because the sensitivity of the assay is insufficient to detect low levels of circulating AChR antibodies and because of intrinsic differences in the ocular muscles that make them more susceptible to circulating factors. Seronegative generalized myasthenia is proving to be heterogeneous both clinically and immunologically. Plasma from SNMG patients often contains a factor, probably an immunoglobulin M antibody, that alters AChR function in in vitro assays, but its target is not yet clear. A variable proportion of SNMG patients have antibodies to the muscle-specific tyrosine kinase (MuSK). These antibodies are directed against the extracellular domain of MuSK and inhibit agrin-induced AChR clustering in muscle myotubes. Although the role of these antibodies in causing myasthenic symptoms in vivo has not been elucidated, MuSK antibodies appear to define a group of patients who are often female with bulbar weakness, contrasting with MuSK antibody-negative SNMG patients who are more likely to have generalized weakness. MuSK antibody-positive patients may also differ in the distribution of their electrophysiological abnormalities and their responses to treatments.


The relationship between alcohol consumption patterns and injury.
A case-control design was employed to quantify the risk of injury after the recent consumption of alcohol. A total of 797 cases and 797 controls were interviewed throughout 1997. A response rate of 82% was calculated for eligible cases who were approached by an interviewer. The rate for interviews conducted of all people presenting with an injury during the study period was 67%. Cases were injured patients from a hospital emergency unit. Controls were matched on suburb and were interviewed at home regarding activities leading up to the time of their matched case's injury. Cases and controls were questioned about the injury event and alcohol and other drug use consumed in the 6 hours prior to the injury. They were also breath-tested and medical records were checked for validation purposes. Logistic regression analysis produced an odds ratio of 3.4 (95% CI: 1.8-6.4) for the risk of sustaining an injury after consuming more than 60 g of alcohol in a 6-hour period, after controlling for demographic variables. The risk of injury at different levels of alcohol use was substantially higher for females with a significant odds ration of 9.6 at greater than 60 g of alcohol compared to 2.1 for men. These results need to be interpreted cautiously, but provide additional support that the risk of injury increases with the quantity of alcohol consumed and that the risk of injury is significantly higher for women.


Accident flying squad.
This paper describes the organization, evaluation, and costing of an independently financed and operated accident flying squad. 132 accidents involving 302 casualties were attended, six deaths were prevented, medical treatment contributed to the survival of a further four, and the condition or comfort of many other casualties was improved. The calls in which survival was influenced were evenly distributed throughout the three-and-a-half-year survey and seven of the 10 so aided were over 16 and under 30 years of age, all 10 being in the working age group.The time taken to provide the service was not excessive and the expense when compared with the overall saving was very small. The scheme was seen to be equally suitable for basing on hospital or general practice or both, and working as an integrated team with the ambulance service. The use of specialized transport was found to be unnecessary. Other benefits of the scheme included use of the experience of attending accidents to ensure relevant and realistic training for emergency service personnel, and an appreciation of the effect of ambulance design on the patient.


Human Myt1 is a cell cycle-regulated kinase that inhibits Cdc2 but not Cdk2 activity.
Activation of the Cdc2.cyclin B kinase is a pivotal step of mitotic initiation. This step is mediated principally by the dephosphorylation of residues threonine 14 (Thr14) and tyrosine 15 (Tyr15) on the Cdc2 catalytic subunit. In several organisms homologs of the Wee1 kinase have been shown to be the major activity responsible for phosphorylating the Tyr15 inhibitory site. A membrane-bound kinase capable of phosphorylating residue Thr14, the Myt1 kinase, has been identified in the frog Xenopus laevis and more recently in human. In this study, we have examined the substrate specificity and cell cycle regulation of the human Myt1 kinase. We find that human Myt1 phosphorylates and inactivates Cdc2-containing cyclin complexes but not complexes containing Cdk2 or Cdk4. Analysis of endogenous Myt1 demonstrates that it remains membrane-bound throughout the cell cycle, but its kinase activity decreased during M phase arrest, when Myt1 became hyperphosphorylated. Further, Cdc2. cyclin B1 was capable of phosphorylating Myt1 in vitro, but this phosphorylation did not affect Myt1 kinase activity. These findings suggest that human Myt1 is negatively regulated by an M phase-activated kinase and that Myt1 inhibits mitosis due to its specificity for Cdc2.cyclin complexes.


Influence of different sized files on the accuracy of two electronic apex locators.
The aim of this study was to evaluate the impact of different file sizes on the accuracy of two electronic apex locators (EALs). Thirty extracted human single-rooted permanent mandibular incisors were used. A #10 K-file was inserted in the root canal until its end could be observed (using a light microscope) through the apical foramen. One millimetre was subtracted to establish working length (WL). Electronic readings were performed using MiniApex Locator or Root ZX II, from #10 K-file to #130 K-file. Statistical analysis was performed by two-way anova and Tukey test (P ≤ 0.05). From #60 to #130 K-file, observed differences were noted between the values obtained with both EALs and WL (P ≤ 0.05). The MiniApex Locator showed increased means when measurements were made with #50 to #70 and with #120 (P = 0.008) and #130 (P = 0.005) K-files. File sizes influenced the accuracy of EALs - the greater the instrumentation size, the higher mean differences compared to WL.


Research Note: Association of insulin-like growth factor 1 receptor gene polymorphism with production performance in Savimalt and French Giant meat-type quails.
This study aimed to investigate the association of insulin-like growth factor 1 receptor (IGF-1R) gene single nucleotide polymorphisms (SNPs) with growth traits and carcass traits of quail by PCR amplification and direct sequencing technology. Genomic DNA was extracted from blood samples collected from 49 female French Giant (FG) quails and 36 female Savimalt (SV) quails as part of this study. Growth traits and carcass traits were measured and assessed for IGF-1R gene analysis in the 2 meat-type quail strains. The results showed that 2 SNPs (A57G and A72T) of the IGF-1R gene were detected in the 2 quail strains. The A57G (P = 0.002) and A72T (P = 0.026) were significantly associated with breastbone length (BBL) in FG. Whereas A57G was significantly associated with chest weight (CW, P = 0.004), BBL (P = 0.009), and body length (BL, P = 0.009) in SV, while A72T was significantly associated with BBL (P = 0.014) and BL (P = 0.028) in SV. Haplotypes based on these 2 SNPs showed significant effects on BBL in FG strain (P = 0.000), and they also had significant effects on CW (P = 0.007), BBL (P = 0.004), and BL (P = 0.001) in SV strain. Additionally, A57G was significantly associated with liver rate (LR) in FG strain (P = 0.017). A72T showed significant associations with dressed carcass weight (DCW, P = 0.048) and breast muscle weight (BMW, P = 0.018) in FG strain. A57G was significantly associated with DCW (P = 0.048), whole net carcass weight (WNCW, P = 0.048), BMW (P = 0.036), and liver muscle rate (LMR, P = 0.003) in SV strain. Haplotypes also displayed significant effects on BMW (P = 0.029) and LMR (P = 0.010) in FG strain. These findings indicated that the IGF-1R gene could serve as a valuable molecular genetic marker for enhancing growth traits and carcass traits in meat-type quails.