[Study on the role of Wnt/beta-catenin signaling transduction pathway in hepatocellular carcinoma cell line HepG2 and L02 cell line].
To explore the possible mechanism of action of Wnt/beta-catenin signaling pathway in hepatocarcinogenesis by investigating the different expressions of the main members on this signaling pathway in hepatocellular carcinoma cell line HepG2 and L02 cell line. The mRNAs of Wnt1, Wnt4, beta-catenin, cyclinD1 and c-myc genes were amplified by means of semiquantitative reverse transcription polymerase chain reaction (RT-PCR) in normal liver cell line L02 and hepatocellular carcinoma cell line HepG2, respectively. At the same time, the proteins expression of beta-catenin which was the key member in the Wnt/beta-catenin signaling pathway was examined by immunocytochemical method and Western blot technique. In normal liver cell line L02, the mRNAs of Wnt1, Wnt4, cyclin D1 and c-myc genes were not detected except for the gene of beta-catenin. In hepatocellular carcinoma cell line HepG2, the mRNAs of Wnt1, beta-catenin, cyclin D1 and c-myc genes were detected except for the gene of Wnt4. Meanwhile, found that beta-catenin proteins were accumulated in the cytoplasm and/or nucleus in HepG2 but only in cell membrane in L02.Using Western blot technique, found that beta-catenin proteins expression was higher in HepG2 than in L02. The Wnt/beta-catenin signaling transduction pathway is activated with aberrant expression of Wnt1 in hepatocellular carcinoma cell line HepG2.


Analytical expressions for spreading resistance in lossy media and their application to the calibration of scanning microwave microscopy.
This paper presents the analytical derivation of spreading resistance expressions for diverse geometries of a conducting probe submerged in a lossy medium. Resulting equations can be used to calibrate scanning impedance/scanning microwave microscopes operating in liquid. The expressions are systematically validated through numerical and experimental methods for the calibration of an inverted Scanning Microwave Microscope (iSMM) when operating in a lossy saline medium, such as Dulbecco's Modified Eagle Medium (DMEM), a widely used medium for supporting the growth of biological cells. The calibration process within DMEM plays an important role in the quantitative local evaluation of electromagnetic properties of biological samples under physiological conditions. Additionally, measurements are performed in distilled water for comparative analysis.


Constraint-based modelling captures the metabolic versatility of Desulfovibrio vulgaris.
A refined Desulfovibrio vulgaris Hildenborough flux balance analysis (FBA) model (iJF744) was developed, incorporating 1016 reactions that include 744 genes and 951 metabolites. A draft model was first developed through automatic model reconstruction using the ModelSeed Server and then curated based on existing literature. The curated model was further refined by incorporating three recently proposed redox reactions involving the Hdr-Flx and Qmo complexes and a lactate dehydrogenase (LdhAB, DVU 3027-3028) indicated by mutation and transcript analyses to serve electron transfer reactions central to syntrophic and respiratory growth. Eight different variations of this model were evaluated by comparing model predictions to experimental data determined for four different growth conditions - three for sulfate respiration (with lactate, pyruvate or H2 /CO2 -acetate) and one for fermentation in syntrophic coculture. The final general model supports (i) a role for Hdr-Flx in the oxidation of DsrC and ferredoxin, and reduction of NAD+ in a flavin-based electron confurcating reaction sequence, (ii) a function of the Qmo complex in receiving electrons from the menaquinone pool and potentially from ferredoxin to reduce APS and (iii) a reduction of the soluble DsrC by LdhAB and a function of DsrC in electron transfer reactions other than sulfite reduction.


Quantum coherence of biophotons and living systems.
Coherence is a property of the description of the system in the classical framework in which the subunits of a system act in a cooperative manner. Coherence becomes classical if the agent causing cooperation is discernible otherwise it is quantum coherence. Both stimulated and spontaneous biophoton signals show properties that can be attributed to the cooperative actions of many photon-emitting units. But the agents responsible for the cooperative actions of units have not been discovered so far. The stimulated signal decays with non-exponential character. It is system and situation specific and sensitive to many physiological and environmental factors. Its measurable holistic parameters are strength, shape, relative strengths of spectral components, and excitation curve. The spontaneous signal is non-decaying with the probabilities of detecting various number of photons to be neither normal nor Poisson. The detected probabilities in a signal of Parmelia tinctorum match with probabilities expected in a squeezed state of photons. It is speculated that an in vivo nucleic acid molecule is an assembly of intermittent quantum patches that emit biophoton in quantum transitions. The distributions of quantum patches and their lifetimes determine the holistic features of biophoton signals, so that the coherence of biophotons is merely a manifestation of the coherence of living systems.


Guidance on feedback of outcome data to improve performance in vascular surgery.
Feedback of performance data is a well-established method of performance improvement in the health-care setting, although guidance has been limited in the context of surgical performance. This article outlines how optimal feedback can be achieved using surgeon outcome data.


Orthodontic Consideration in Patients with Beta-Thalassemia Major: Case Report and Literature Review.
Beta Thalassemia (βT) patients present a unique facial appearance and specific craniofacial, jaw and dental patterns. Although this anomaly often requires orthodontic management, βT patients have received scant attention in the orthodontic and dental literature over the past 50 years. The aim of this article is to review the characteristic craniofacial and dental manifestation pattern of βT patients and to emphasize their preferred orthodontic management protocol by presenting a βT orthodontic treated patient. A 10 year old patient presented with a complaint of severe esthetic and functional disorders due to her diagnosis of βT. We initiated orthodontic treatment including a combined orthopedic and functional treatment modality to improve facial appearance. Maxillary restraint and increased mandibular size during treatment along with an increase in the vertical dimension were achieved. The patient presented with Angle class I molar relationship, with reduction of the excessive overjet and deep overbite. Orthodontic treatment comprised of maxillary orthopedic treatment directed especially toward premaxilla with light forces, and mandibular modification by functional appliance along with fixed orthodontic treatment is recommended in βT patients.


Towards two decades of Atlantic Ocean mass and heat transports at 26.5° N.
Continuous measurements of the Atlantic meridional overturning circulation (AMOC) and meridional ocean heat transport at 26.5° N began in April 2004 and are currently available through December 2020. Approximately 90% of the total meridional heat transport (MHT) at 26.5° N is carried by the zonally averaged overturning circulation, and an even larger fraction of the heat transport variability (approx. 95%) is explained by the variability of the zonally averaged overturning. A physically based separation of the heat transport into large-scale AMOC, gyre and shallow wind-driven overturning components remains challenging and requires new investigations and approaches. We review the major interannual changes in the AMOC and MHT that have occurred over the nearly two decades of available observations and their documented impacts on North Atlantic heat content. Changes in the flow-weighted temperature of the Florida Current (Gulf Stream) over the past two decades are now taken into account in the estimates of MHT, and have led to an increased heat transport relative to the AMOC strength in recent years. Estimates of the MHT at 26.5° N from coupled models and various surface flux datasets still tend to show low biases relative to the observations, but indirect estimates based on residual methods (top of atmosphere net radiative flux minus atmospheric energy divergence) have shown recent promise in reproducing the heat transport and its interannual variability. This article is part of a discussion meeting issue 'Atlantic overturning: new observations and challenges'.


Cyclin-Dependent Kinase Regulation of Diurnal Transcription in Chlamydomonas.
We analyzed global transcriptome changes during synchronized cell division in the green alga Chlamydomonas reinhardtii. The Chlamydomonas cell cycle consists of a long G1 phase, followed by an S/M phase with multiple rapid, alternating rounds of DNA replication and segregation. We found that the S/M period is associated with strong induction of ∼2300 genes, many with conserved roles in DNA replication or cell division. Other genes, including many involved in photosynthesis, are reciprocally downregulated in S/M, suggesting a gene expression split correlating with the temporal separation between G1 and S/M. The Chlamydomonas cell cycle is synchronized by light-dark cycles, so in principle, these transcriptional changes could be directly responsive to light or to metabolic cues. Alternatively, cell-cycle-periodic transcription may be directly regulated by cyclin-dependent kinases. To distinguish between these possibilities, we analyzed transcriptional profiles of mutants in the kinases CDKA and CDKB, as well as other mutants with distinct cell cycle blocks. Initial cell-cycle-periodic expression changes are largely CDK independent, but later regulation (induction and repression) is under differential control by CDKA and CDKB. Deviation from the wild-type transcriptional program in diverse cell cycle mutants will be an informative phenotype for further characterization of the Chlamydomonas cell cycle.


Asian flus in ethnographic and political context: A biosocial approach.
This collection highlights some of the social, cultural, political and economic factors that must be considered in developing a biosocial approach to pandemic influenza control and prevention. To date, most discussions of the current spread of avian influenza and a predicted human influenza pandemic have lacked rigorous analysis of the local contexts in which flus arise and in which the effects of a pandemic would most strongly be felt. Such local engagement is necessary to the development of an effective and ethical programme of epidemic control. The papers in this special issue take a step towards filling this gap by exploring the local moral worlds associated with avian influenza in China, Indonesia and Thailand.


Acupressure in Management of Postoperative Nausea and Vomiting in High-Risk Ambulatory Surgical Patients.
The purpose of this randomized blinded placebo-controlled research study was to investigate the effect of acupressure over 24 hours postoperatively for ambulatory surgical patients who are identified as high risk for PONV. A randomized blinded placebo-controlled study design was implemented. Study enrollment criteria included four of five risk factors as defined in 2006 by American Society of PeriAnesthesia Nurses PONV/postdischarge nausea and vomiting guidelines: female, PONV history or motion sickness, nonsmoker, and volatile gas general anesthetic. One hundred ten patients were randomly assigned to an intervention (N = 57) acupressure bead patch or control (N = 53) sham acupressure patch group. Patients rated PONV on scale (0 to 10). Acupressure use at P6 preoperatively was statistically significant in reducing PONV in all three postoperative phases. One hundred ten patients were enrolled; 93 patients finished the study's three phases and nine were admitted postoperatively. Acupressure is an effective minimal risk and low-cost adjunctive therapy for prevention and treatment in ambulatory surgical patients at high risk for PONV. Further studies using other acupressure points should be conducted.


Exploring the significance of lipids in Alzheimer's disease and the potential of extracellular vesicles.
Lipids play a significant role in maintaining central nervous system (CNS) structure and function, and the dysregulation of lipid metabolism is known to occur in many neurological disorders, including Alzheimer's disease. Here we review what is currently known about lipid dyshomeostasis in Alzheimer's disease. We propose that small extracellular vesicle (sEV) lipids may provide insight into the pathophysiology and progression of Alzheimer's disease. This stems from the recognition that sEV likely contributes to disease pathogenesis, but also an understanding that sEV can serve as a source of potential biomarkers. While the protein and RNA content of sEV in the CNS diseases have been studied extensively, our understanding of the lipidome of sEV in the CNS is still in its infancy.


Prevalence and cost of nonadherence to antiepileptic drugs in elderly patients with epilepsy.
Retrospective insurance claims from the United States were analyzed to assess nonadherence to antiepileptic drugs (AEDs) and the association between AED nonadherence, seizures, and health care costs in elderly persons with epilepsy. Inclusion criteria were: age 65, epilepsy diagnosis between 1 January 2000 and 31 June 2006, 2 AED prescriptions, and insurance enrollment for 6 months pre- and 12 months post-AED initiation. Adherence was evaluated using the medication possession ratio (MPR), with MPR<0.8 defining nonadherence. Per-patient outcomes were evaluated over 12 months post-AED initiation. Of 1278 patients identified, 41% were nonadherent. Seizure, defined by epilepsy-related inpatient or emergency department admission, occurred in 12.1% of nonadherers versus 8.2% of adherers (P=0.0212). Nonadherers had higher inpatient (+$872, P=0.001), emergency department (+$143, P=0.0008), other outpatient ancillary (+$1741, P=0.0081), and total health care (+$2674, P=0.0059) costs. AED adherence among elderly patients with epilepsy is suboptimal and associated with increased seizures and health care costs.


Isofagomine- and 2,5-anhydro-2,5-imino-D-glucitol-based glucocerebrosidase pharmacological chaperones for Gaucher disease intervention.
Gaucher disease, resulting from deficient lysosomal glucocerebrosidase (GC) activity, is the most common lysosomal storage disorder. Clinically important GC mutant enzymes typically have reduced specific activity and reduced lysosomal concentration, the latter due to compromised folding and trafficking. We and others have demonstrated that pharmacological chaperones assist variant GC folding by binding to the active site, stabilizing the native conformation of GC in the neutral pH environment of the endoplasmic reticulum (ER), enabling its trafficking from the ER to the Golgi and on to the lysosome. The mutated GC fold is generally stable in the lysosome after pharmacological chaperone dissociation, owing to the low pH environment for which the fold was evolutionarily optimized and the high substrate concentration, enabling GC to hydrolyze glucosylceramide to glucose and ceramide. The hypothesis of this study was that we could combine GC pharmacological chaperone structure-activity relationships from distinct chemical series to afford potent novel chaperones comprising a carbohydrate-like substructure that binds in the active site with a hydrophobic substructure that binds in a nearby pocket. We combined isofagomine and 2,5-anhydro-2,5-imino-D-glucitol active site binding substructures with hydrophobic alkyl adamantyl amides to afford novel small molecules with enhanced ability to increase GC activity in patient-derived fibroblasts. The cellular activity of N370S and G202R GC in fibroblasts is increased by 2.5- and 7.2-fold with isofagmine-based pharmacological chaperones N-adamantanyl-4-((3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-1-yl)-butanamide (3) and N-adamantanyl-4-((3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-1-yl)pentanamide (4), respectively, the best enhancements observed to date.


Multiple keratomas in an equine foot.
A 19-year-old, Arabian gelding was presented for left hindlimb lameness and deviation of the hoof wall. Radiographs revealed a semicircular, radiolucent area in the lateral edge of the distal phalanx. Three distinct keratomas were successfully removed following hoof wall resection.


Waffle production: influence of batter ingredients on sticking of fresh egg waffles at baking plates-Part I: effect of starch and sugar components.
Fresh egg waffles are a sweet convenience product typically baked from eggs, water, sugar, flour, fat, leavening agents, emulsifiers, preservatives, and flavors. In industrial production, waffles are baked continuously in high amounts of up to 200 kg raw material per hour. Therefore, it is important that the waffles do not stick onto the baking plates, which can cause significant product loss and increased costs due to interruption of the baking process, required cleaning procedures, and restarting of the energy-consuming start-up phase. Sticking of waffles is greatly influenced not only by baking plate material, release agent, baking temperature, and time, but also by the batter ingredients. In this study, effects of different starches and sugar components were investigated. Within the selected starches, potato starch demonstrated the highest effects on increasing waffle stability and releasing properties compared to wheat and lupine flour (less than 7% sticking waffles). Rice flour performed worst, with almost 50% of sticking waffles. Most of these waffles were broken during take-off, due to their crumbly texture. Within the sugar components, glycerine was better suitable than sorbitol and crystal sugar was superior compared to powdered sugar. They required less take-off force. It could be demonstrated that waffles with increased stability and texture were those that showed the least number of sticking waffles, thus the main aim of batter ingredients was to improve waffle quality. Waffle quality was influenced by batter parameters, significant correlations could be found, for example, a positive correlation between pH- and L-value, negative correlations between pH- and a-value, or density and aw-value. This resulted in significant correlations with take-off-force, which was correlated with L*- and b*-value (negative) and positive to a*-value. Sticking behavior was strongly associated with b*-value (positive) and to a*-value (negative).


An interlocked dimer of the protelomerase TelK distorts DNA structure for the formation of hairpin telomeres.
The termini of linear chromosomes are protected by specialized DNA structures known as telomeres that also facilitate the complete replication of DNA ends. The simplest type of telomere is a covalently closed DNA hairpin structure found in linear chromosomes of prokaryotes and viruses. Bidirectional replication of a chromosome with hairpin telomeres produces a catenated circular dimer that is subsequently resolved into unit-length chromosomes by a dedicated DNA cleavage-rejoining enzyme known as a hairpin telomere resolvase (protelomerase). Here we report a crystal structure of the protelomerase TelK from Klebsiella oxytoca phage varphiKO2, in complex with the palindromic target DNA. The structure shows the TelK dimer destabilizes base pairing interactions to promote the refolding of cleaved DNA ends into two hairpin ends. We propose that the hairpinning reaction is made effectively irreversible by a unique protein-induced distortion of the DNA substrate that prevents religation of the cleaved DNA substrate.


Determining structure and action mechanism of LBF14 by molecular simulation.
The recently discovered, membrane-active peptide LBF14 contains several non-proteinogenic amino acids and is able to transform vesicles into tubule networks. The exact membrane interaction mechanism and detailed secondary structure are yet to be determined. We performed molecular dynamics simulations of LBF14 and let it fold de novo into its ensemble of native secondary structures. Histidine protonation state effects on secondary structure were investigated. An MD simulation of the peptide with a lipid bilayer was performed. Simulation results were compared to circular dichroism and electron paramagnetic resonance data of previous studies. LBF14 contains a conserved helical section in an otherwise random structure. Helical stability is influenced by histidine protonation. The peptide localized to the polar layer of the membrane, consistent with experimental results. While the overall secondary structure is unaffected by membrane interaction, Ramachandran plot analysis yielded two distinct peptide conformations during membrane interaction. This conformational change was accompanied by residue repositioning within the membrane. LBF14 only affected the local order in the membrane, and had no measurable effect on pressure. The simulation results are consistent with the previously proposed membrane interaction mechanism of LBF14 and can additionally explain the local interaction mechanism. Communicated by Ramaswamy H. Sarma.


Membrane interactions of dynorphins.
The dynorphins are primarily endogenous ligands to the kappa-opioid receptor, but a variety of non-opioid effects have also been observed, including direct effects on membranes. The peptides are rich in Arg residues, a characteristic feature of the cell-penetrating peptides. In this investigation, we have examined the interaction of the two peptides dynorphin A and dynorphin B with model membranes. A variety of NMR methods, as well as CD and fluorescence spectroscopy, have been used to characterize the structure of the two peptides and, more importantly, the position of the peptides in phospholipid bicelles. Both peptides interact to a large extent with both zwitterionic and partly negatively charged bicelles but are only marginally structured in either solvent. Dynorphin A was found to insert its N-terminus into the bilayer of the bicelle, while dynorphin B was found to reside on the surface of the bilayer. Despite the high degree of similarity in the sequence of the two peptides, it has previously been observed that dynorphin A has membrane perturbing effects and causes leakage of calcein from large unilamellar phospholipid vesicles while dynorphin B has no such effects. Our results provide a possible explanation for the difference in membrane perturbation.


Computation of, and rules relating to, medical loss ratio. Final regulations.
This document contains final regulations that provide guidance to Blue Cross and Blue Shield organizations, and certain other qualifying health care organizations, on computing and applying the medical loss ratio added to the Internal Revenue Code by the Patient Protection and Affordable Care Act.


[Diffuse pseudotumorous oncocytosis of the parotid gland. A case report].
Pseudotumorous oncocytosis of the parotid gland is very uncommon and frequently misdiagnosed since it generally presents as a true tumor. The clinical presentation and imaging features of a 6-cm diameter left parotid mass led to the diagnosis of a tumor in a 73-year-old man. At pathology examination of the partial parotidectomy specimen the "tumor" was found to be a metaplastic oncocytic lesion. We discuss the diagnostic criteria, differential diagnosis, and etiopathogeny of this lesion.


The construct validity of the Short Form-36 Health Survey for patients with nonspecific chronic neck pain.
Self-reported disability related to neck pain can be measured using general health questionnaires. The validity of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) in patients with nonspecific chronic neck pain (CNP) in a tertiary outpatient rehabilitation setting is unknown. This study investigates construct validity of the SF-36 in these patients using 16 a-priori formulated hypotheses. Ninety-one patients admitted for rehabilitation completed the SF-36 before the rehabilitation program. SF-36 domain scores of patients with CNP were compared with general population reference values and standardized differences were calculated. For both the SF-36 physical and the mental component summary (PCS and MCS), differences between primary and tertiary care setting, men and women, age groups, litigants and nonlitigants, patients with and without compensation, and with ≥3 versus≤2 concomitant complaints were analyzed using independent t-tests. Differences between PCS and MCS scores were analyzed using a paired t-test. Twelve hypotheses were not rejected and four were rejected. All SF-36 domain scores were significantly lower than the general population references values. The domain scores 'role physical', 'bodily pain', 'vitality', 'social functioning,' and 'role emotional' were relevantly (≥1 SD) lower. SF-36-PCS and SF-36-MCS scores were significantly lower in tertiary care. The SF-36-PCS score was significantly lower for patients with workers compensation and patients with at least three concomitant complaints. The SF-36-MCS score was significantly lower for the age group of at least 39 years. The SF-36 has good construct validity and can be used to measure self-reported general health in patients with nonspecific CNP in outpatient tertiary rehabilitation.


Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors.
Prostate-specific antigen (PSA) is one of the three most abundant prostatic-secreted proteins in human semen. It is a serine proteinase that, in its primary structure, manifests extensive similarities with that of the Arg-restricted glandular kallikrein-like proteinases. When isolated from semen by the addition of chromatography on aprotinin-Sepharose to a previously described procedure, PSA displayed chymotrypsin-like activity and cleaved semenogelin and the semenogelin-related proteins in a rapid and characteristic pattern, but had no trypsin-like activity. About one third of the purified protein was found to be enzymatically inactive, due to cleavage carboxy-terminal of Lys145. Active PSA formed SDS-stable complexes with alpha 1-antichymotrypsin, alpha 2-macroglobulin-analogue pregnancy zone protein. PSA formed inhibitory complexes with alpha 1-antichymotrypsin at a molar ratio of 1:1, a reaction in which PSA cleaved the inhibitor in a position identical to that reported from the reaction between chymotrypsin and alpha 1-antichymotrypsin. The formation of stable complexes between PSA and alpha 1-antichymotrypsin occurred at a much slower rate than that between chymotrypsin and alpha 1-antichymotrypsin, and at a similar or slightly slower rate than that between PSA and alpha 2-macroglobulin. When added to normal blood plasma in vitro, active PSA formed stable complexes both with alpha 2-macroglobulin and alpha 1-antichymotrypsin. This complex formation may be a crucial determinant of the turnover of active PSA in intercellular fluid or blood plasma in vivo.


A non-active site residue, cysteine 69, of glutathione S-transferase ADGSTD3-3 has a role in stability and catalytic function.
The Cys69 residue of an Anopheles dirus glutathione S-transferase isoform (adGSTD3-3), was characterized to elucidate its contribution in both catalysis and structural support. Nine mutants were generated at this position by replacing the residue with polar, non-polar and charged residues. The polar residues changed the Vm of the enzymes. With non-polar residues, the enzymes were unable to fold and were expressed in the insoluble inclusion form. With charged residues, the soluble enzyme yields were only 3% of the wild type protein. Molecular dynamics simulation also was performed to understand the changes in the enzyme structure. These findings are additional evidence of the importance of structural residues that affect the enzymatic properties such as Vm, Km and enzyme specificity.


Poor Appetite in Frail Older Persons-A Systematic Review.
Anorexia of aging is a common problem in older adults. Depending on the setting, its prevalence varies from about 10% (among community-dwelling older adults) to over 30% in acute wards and nursing homes. The objective of this systematic review was to establish the prevalence of poor appetite in frail persons ≥60 years of age. We performed a literature search for studies where the prevalence of anorexia of aging among frail and pre-frail old adults was reported. 957 articles on this topic were identified. After eligibility assessment, three articles were included in the review. The studies included 4657 community-dwelling older adults. The weighted total prevalence of anorexia of aging in all the included studies was 11.3%. Among frail and pre-frail participants, loss of appetite was reported in 20.5% (weighted estimate). Overall, robust status was associated with a 63% lower probability of concomitant anorexia of ageing (OR 0.37, 95%CI 0.21-0.65, p = 0.0005). Frailty or risk of frailty are associated with more prevalent anorexia of ageing. This has potential practical implications; however, more research, especially to elucidate the direction of the relation, is needed.


Effects of hormone treatment on hemostasis variables.
A survey was made of the changes in hemostasis and related inflammatory biomarkers for hormone treatments (HT) of women. Treatments included were oral and non-oral estrogens combined or not with progestogens, raloxifene, tamoxifene, tibolone and ethinylestradiol in oral contraceptives with non-androgenic progestogens. Special attention was given to dosages lower than the present standard dose and we explored how treatment variants approached a situation of minimal changes in biomarkers. For oral unopposed estrogens, dose reduction effectively reduced the changes in some hemostasis markers, but not in a specific set of anticoagulant variables (antithrombin, protein S, tissue factor pathway inhibitor, and the endogenous thrombin potential assay for resistance to activated protein C). Inflammation markers from the liver showed a dose-dependent reduction but effects were not nullified at the lowest dose tested. It was concluded that adequate reduction of estrogen dose for these effects will coincide with the dose-range of efficacy. Androgenic progestogens may be suitable for further reducing the impact of estrogens on some of the anticoagulant variables; reductions of estrogen-induced C-reactive protein increases appear possible with specific progestogens (medroxyprogesterone actate, nomegestrol acetate). For non-oral unopposed estrogens, all variables except inflammation biomarkers from the vascular wall showed minimal changes. Reduction in vascular inflammatory biomarkers, considered to mark anti-inflammatory effects, is augmented by medroxyprogesterone actate or norethisterone acetate. It was concluded that unopposed, non-oral estrogen treatment is the present best available option approaching minimal effects of treatment on biomarkers. Progestogen selection requires more data. We postulated that minimal effects on all cardiovascular biomarkers should define the HT with maximal safety for venous and arterial vascular events. The survey has identified specific biomarkers sensitive to low-dose unopposed and opposed estrogen which can be used to characterize future preparations for HT.


Bilateral Symmetric Gastrocnemius Myositis Secondary to COVID-19.
As the coronavirus disease 2019 (COVID-19) pandemic perseverates on, more insight into the multidisciplinary manifestations of COVID-19 is being brought to the forefront. Musculoskeletal presentations range from mild creatinine kinase elevation and myalgias to severe rhabdomyolysis. We present a case of a patient who presented with symmetric myositis of bilateral gastrocnemius muscles secondary group.


Remote Excitation of Tip-Enhanced Photoluminescence with a Parallel AgNW Coupler.
Tip-enhanced photoluminescence (TEPL) microscopy allows for the correlation of scanning probe microscopic images and photoluminescent spectra at the nanoscale level in a similar way to tip-enhanced Raman scattering (TERS) microscopy. However, due to the higher cross-section of fluorescence compared to Raman scattering, the diffraction-limited background signal generated by far-field excitation is a limiting factor in the achievable spatial resolution of TEPL. Here, we demonstrate a way to overcome this drawback by using remote excitation TEPL (RE-TEPL). With this approach, the excitation and detection positions are spatially separated, minimizing the far-field contribution. Two probe designs are evaluated, both experimentally and via simulations. The first system consists of gold nanoparticles (AuNPs) through photoinduced deposition on a silver nanowire (AgNW), and the second system consists of two offset parallel AgNWs. This latter coupler system shows a higher coupling efficiency and is used to successfully demonstrate RE-TEPL spectral mapping on a MoSe2/WSe2 lateral heterostructure to reveal spatial heterogeneity at the heterojunction.


Social preferences influence the short-term exchange of social grooming among male bonobos.
The emotional mediation hypothesis proposes a mediating role of social bonds in the exchange of services. This model predicts that the form of short-term exchange of services depends on the relationship between the individuals involved. Here, we test this prediction in the exchange of grooming among males in a wild bonobo community for which close relatedness could be excluded. As bonobo males hardly engage in food sharing or agonistic support, grooming is mainly exchanged for grooming. While overall grooming, both given and received, correlates across dyads and within sessions, the form of grooming exchange within a given session differs according to dyadic association preferences. Individuals with a higher tendency to associate, ergo more familiar individuals, exhibit larger time differences and reduced reciprocation in consecutive grooming bouts than less familiar individuals. These results support the idea that emotional components are involved in the exchange of services between unrelated individuals.


A case of Sotos syndrome (cerebral gigantism) and psychosis.
Sotos syndrome, or cerebral gigantism, is a syndrome of accelerated growth during early childhood, and a number of craniofacial and other physical abnormalities are commonly present. Behavioral and psychiatric manifestations of the disorder include attention deficits, aggressiveness, and social inhibition. The authors describe a case of psychosis that developed in a patient with Sotos syndrome.


Epidemiology of age-related maculopathy: a review.
Age-related maculopathy (ARM) is a degenerative disease of the retina and the leading cause of incurable blindness and visual impairment in industrialized countries. By definition, ARM is confined to the age-category above 50 years. The aetiology of ARM is still unknown, despite intensive research on many fronts. In this paper, we provide a review of the epidemiology of ARM. The most prominent findings were an exponential increase in frequency with age, a significant familial and genetic component, and a strong association with smoking. Other risk factors that were found less consistently were atherosclerosis, low intake of antioxidant nutrients, and cataract extraction. Future studies, both observational and experimental, will hopefully identify more risk factors that are amenable to prevention.


Three-dimensional-poly(lactic acid) scaffolds coated with gelatin/magnesium-doped nano-hydroxyapatite for bone tissue engineering.
Treatment of critical-sized bone defects has progressively evolved over the years from metallic implants to more ingenious three-dimensional-based scaffolds. The use of three-dimensional scaffolds for bone regeneration from biodegradable polymers like poly(lactic acid) (PLA) is gaining popularity. Scaffolds with surface functionalization using gelatin (Gel) have the advantages of biocompatibility and cell adhesion. Nano-hydroxyapatite (nHAp) is one of the most promising implant materials utilized in orthopaedics. The osteogenic potential of the nHAp can be improved by the substitution of magnesium (Mg) ions onto the crystal lattice of nHAp. Thus, the goal of this work was to make three-dimensional-PLA scaffolds covered with Gel/Mg-nHAp for osteogenic effect. The designed three-dimensional-PLA/Gel/Mg-nHAp scaffolds were attributed to various characterizations for the examination of their physicochemical, mechanical properties, cyto-compatibility, and biodegradability as well as their ability to promote osteogenesis in vitro. Mouse mesenchymal stem cells (mMSCs) were cytocompatible with these scaffolds. The osteogenic potential of three-dimensional-PLA/Gel/Mg-nHAp scaffolds employing mMSCs was validated at the cellular and molecular levels. The three-dimensional-PLA/Gel/Mg-nHAp scaffolds stimulated the differentiation of mMSCs towards osteoblastic lineage. Based on these findings, we suggest that the three-dimensional-PLA/Gel/Mg-nHAp scaffolds' osteogenic capability may be advantageous in the mending of bone defects in orthopedic applications.


Glucose homeostasis in rats treated with 4-vinylcyclohexene diepoxide is not worsened by dexamethasone treatment.
4-vinilcyclohexene diepoxide (4-VCD) causes premature ovarian failure and may result in estrogen deficiency, characterizing the transition to estropause in rodents (equivalent to menopause in women). Estropause/menopause is associated with metabolic derangements such as glucose intolerance and insulin resistance. Glucocorticoids (GCs) are known to exert diabetogenic effects. Thus, we aimed to investigate whether rats with premature ovarian failure are more prone to the diabetogenic effects of GC. For this, immature female rats received daily injections of 4-VCD [160mg/kg body weight (b.w.), intraperitoneally (i.p.)] for 15 consecutive days, whereas control rats received vehicle. After 168days of the completion of 4-VCD administration, rats were divided into 4 groups: CTL-received daily injections of saline (1mL/kg, b.w., i.p.) for 5days; DEX-received daily injections of dexamethasone (1mg/kg, b.w., i.p.) for 5days; VCD-treated as CTL group; VCD+DEX-treated as DEX group. Experiments and euthanasia occurred one day after the last dexamethasone injection. 4-VCD-treated rats exhibited ovary hypotrophy and reduced number of preantral follicles (p<0.05). Premature ovarian failure had no impact on the body weight gain or food intake, but both were reduced by the effects of dexamethasone. The increase in blood glucose, plasma insulin and triacylglycerol levels as well as the reduction in insulin sensitivity caused by dexamethasone treatment was not exacerbated in the VCD+DEX group of rats. Premature ovarian failure did change neither the hepatic content of glycogen and triacylglycerol nor the glycerol release from perigonadal adipose tissue. Glucose intolerance was observed in the VCD group after an ipGTT (p<0.05), but not after an oral glucose challenge. Glucose intolerance and compensatory pancreatic β-cell mass caused by GC were not modified by ovarian failure in the VCD+DEX group. We conclude that reduced ovarian function has no major implications on the diabetogenic effects promoted by GC treatment, indicating that other factors related to aging may make rats more vulnerable to GC side effects on glucose metabolism.


Oral Health Among Swedish Patients with Substance Use Disorders - A Comparative, Cross-Sectional Study.
This study explored the oral health of individuals with substance use disorders and examined the relationship between oral health and type and number of years of substance use disorder. This comparative cross-sectional study comprised patients with one of four groups of substance use disorders - alcohol, cannabis, central nervous system stimulants (CNSS), and opiates. All participants underwent a dental examination and were included in the study based on their clinical findings. Of 95 participants, 79 (83%) were male and 37 (39%) were homeless. Statistically significant difference between the groups was observed in 6-12-mm periodontal pocket depths (p <0.05), as were differences in oral mucosal changes (p <0.001). Statistically significantly lower proportions were observed in the cannabis group for Mob G:0 and Mob G:1 and Furcation G:1 compared to the CNSS and opiate groups; the proportion of Furcation G:0 was significantly lower in the alcohol group compared to the cannabis group. Analysis of variance (ANOVA) revealed statistically significant between-group differences in age, number of years of substance use disorder, number of teeth, and decayed, missing and filled teeth (DMFT). When controlling for age and gender, substance type was found to be a statistically significant predictor of number of teeth (B = -4.4; 95% CI: -8.1 to -0.38; p = 0.03) and DMFT (B = 2.1; 95% CI: 0.86 to 3.3; p = 0.001). These results indicate poor oral health among individuals with substance use disorders. It seems that oral health problems are lower among abusers of cannabis than of CNSS, alcohol and opiates.


Integrated arrays of air-dielectric graphene transistors as transparent active-matrix pressure sensors for wide pressure ranges.
Integrated electronic circuitries with pressure sensors have been extensively researched as a key component for emerging electronics applications such as electronic skins and health-monitoring devices. Although existing pressure sensors display high sensitivities, they can only be used for specific purposes due to the narrow range of detectable pressure (under tens of kPa) and the difficulty of forming highly integrated arrays. However, it is essential to develop tactile pressure sensors with a wide pressure range in order to use them for diverse application areas including medical diagnosis, robotics or automotive electronics. Here we report an unconventional approach for fabricating fully integrated active-matrix arrays of pressure-sensitive graphene transistors with air-dielectric layers simply formed by folding two opposing panels. Furthermore, this realizes a wide tactile pressure sensing range from 250 Pa to ∼3 MPa. Additionally, fabrication of pressure sensor arrays and transparent pressure sensors are demonstrated, suggesting their substantial promise as next-generation electronics.


Anti-thrombotic and anti-atherogenic action of eicosapentaenoic acid.
Effects of dietary supplementation with highly purified EPA (1.8-2.7 g/day) for 16 weeks on platelet and red blood cell function and serum lipids concentration were investigated in patients with various thrombotic diseases. Decreases in platelet aggregation, thromboxane formation in platelets, platelet retention and whole blood viscosity, increased red blood cell deformation and prolongation of bleeding time were observed in the present study. In addition a reduction in serum cholesterol and triglyceride concentrations was noted in patients with hyperlipidemia after EPA ingestion. Some clinical improvements such as improvement of diabetic gangrene or peripheral vascular occlusive disease were observed. These results indicate that dietary supplementation of purified EPA may be beneficial for prevention and treatment of cerebro- and cardiovascular diseases.


Neuroprotection of selenite against ischemic brain injury through negatively regulating early activation of ASK1/JNK cascade via activation of PI3K/AKT pathway.
To investigate whether selenite, a known antioxidant, could decrease the activation of apoptosis signal regulating kinase 1/c-jun N-terminal kinase (ASK1/ JNK) signaling cascade in cerebral ischemia/reperfusion (I/R) by activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in rat hippocampi, and the neuroprotective effect of selenite against ischemic injury after 15 min of transient brain ischemia. Transient global brain ischemia was induced by 4-vessel occlusion into adult male Sprague-Dawley rats weighing 250-300 g. The rats were pretreated only with selenite (0.3 mg/kg dissolved in 0.9% saline) every 24 h for 7 d by means of intravenous injection of the tail or combined with LY294002 from d 5 by left cerebral ventricle injection before surgery. Selenite significantly increased AKT1 activation and decreased the activation of ASK1/ JNK cascade via phosphorylating ASK1 at Ser-83 residue by AKT1 during early reperfusion after 15 min transient global brain ischemia. On the contrary, combined pretreatment of the rats with LY294002 (a specific PI3K inhibitor) and selenite significantly inhibited the effects solely with selenite. The activation of the pro-apoptotic ASK1/JNK cascade, which is closely associated with oxidative stress, could be suppressed by selenite through activating the antiapoptotic PI3K/AKT pathway during early reperfusion after cerebral ischemia in rat hippocampi.


Semiology and subtyping of panic disorders.
To date, the quantitative psychopathology of panic disorder (PD) has been less well studied than that of other psychiatric conditions such as schizophrenia or major depression. The aim of the present study was to assess the frequency and factorial grouping of symptoms in a naturalistic sample of PD patients. A total of 274 consecutive cases of PD who contacted an out-patient clinic in Barcelona, Spain were assessed by two experienced interviewers. The assessment instruments included the Structured Clinical Interview for DSM-III-R Upjohn version (SCID-UP-R) and an inventory of panic attack symptoms based on DSM-III-R. Of the patients who presented at the unit during the assessment period, 8.5% presented with PD. Palpitations, shortness of breath, fear of dying and dizziness were the most frequent and intense symptoms reported by the PD patients. Principal-component analysis revealed four factors which accounted for 57% of the variance, including 'cardiorespiratory' (26.1%) and 'vestibular' (15.1%) factors, and two additional factors with mixed symptoms. The frequency of presentation of symptoms was similar to that reported in other studies. However, some discrepancies were observed that may be attributed to transcultural differences as well as to terminological problems and the range of symptoms assessed. These factors may also explain some of the differences found in factor analysis groupings in previous studies. Our findings support the symptom subtyping of PD.


Two alphaherpesvirus latency-associated gene products influence calcitonin gene-related peptide levels in rat trigeminal neurons.
Herpes simplex virus type-1 (HSV-1) initially infects mucoepithelial tissues of the eye and the orofacial region. Subsequently, the virus is retrogradely transported through the axons of the trigeminal sensory neurons. HSV-1 establishes a life-long latent infection in these neurons, during which the transcription of the viral genome is silent, except for the sequences encoding the latency-associated transcript (LAT). To determine if HSV-1 latency might affect calcitonin gene-related peptide (CGRP) expression in trigeminal sensory neurons, we transfected primary neuronal cultures of trigeminal ganglia from rat embryos with plasmids expressing LAT. In the presence of Bone Morphogenetic Protein-7 (BMP7), CGRP was expressed in 49% of sensory neurons. However, this percentage was reduced to 19% in neurons transfected with LAT expressing plasmids. We also found that transfection of the IE63 gene of varicella-zoster virus (VZV) reduced the percentage of trigeminal neurons containing CGRP. However, the observed effect of IE63 in contrast to that of LAT was completely reversed by treatment of cultures with MgCl2, which indicates that the effect of IE63 was due to increased release of CGRP from trigeminal neurons. We provide here the first evidence that HSV-1 LAT decreases the level of CGRP in trigeminal neurons. These effects may be important for reducing the neuroinflammatory response, thus protecting host neuronal cells during HSV-1 latency in trigeminal neurons. In contrast, increased release of CGRP in the presence of IE63 protein may contribute to the neuralgias associated with VZV infection.


[Radiologic diagnosis of primary extranodal lymphoma manifestations].
Primary extranodal lymphoma manifestation in the narrow sense is the term used to define the primary organ manifestation of a malignant lymphoma, excluding the thymus, spleen, Waldeyer's tonsillar ring, the appendix and Peyer's patches. However, in the clinical routine the term is also used for the secondary organ manifestation of underlying lymphoproliferative disease. Primary extranodal lymphomas are mainly non-Hodgkin lymphomas; there is primary extranodal manifestation of Hodgkin's disease in only about 1% of the cases. Among the extranodal NHL, the highly malignant forms predominate. A major exception is MALT lymphomas, which mainly show low slow growth. In the past, they were considered to be pseudolymphomas because of their slow and localized tumor growth. They were included as an entity of their own for the first time in the Revised European American Lymphoma (REAL) classification of 1994. The incidence data vary between < 10% and 25% for primary extranodal manifestation. The major reason for this is the difference in extranodal regions because of classification. Secondary organ involvement of an NHL occurs in up to 40% of the cases in the long-term course of the disease in primary nodal lymphomas. Secondary organ involvement is frequently diagnosed in AIDS patients who develop an AIDS-related lymphoma (85% of cases). The following contribution reports on the radiological imaging of extranodal lymphoma manifestation in the thoracoabdominal region.


The credibility of dental pulp in human blood group identification.
The identification of unknown individual has always been of paramount importance to the society. Blood groups are excellent aids to these pursuits. Dental tissue acts beneficial because tooth is the hardest of all human tissues, and they can be preserved intact for a long period of time after the death of the individual. Hence, this study is conducted to evaluate the role of dental pulp in identification of human blood group. To determine the ABO blood grouping from the pulpal tissue of an extracted tooth and to correlate the same with blood group details obtained from the study subjects. This is a double-blinded randomized controlled trial conducted on a sample of thirty extracted teeth. The teeth were stored dry for 2 months. An attempt to establish the blood group from pulp was made by absorption-elution method. The collected data were coded, and statistical analysis was carried out using Statistical Package of Social Science (SPSS Version 20). Cronbach's alpha was applied to check the reliability of the absorption-elusion method in the detection of blood group from dental pulp. Blood groups obtained from the pulp were compared with those obtained from the study subjects. Blood group establishment from dental pulp using absorption-elusion method had a good internal consistency in comparison with the conventional Karl Landsteiner's blood typing method. This study showed that pulp tissue is a reliable method to detect blood groups of individuals. It can be concluded that dental pulp can be used to establish identity, where teeth happen to be the only remnants available for personal identification.


Near-Transform-Limited Single Photons from an Efficient Solid-State Quantum Emitter.
By pulsed s-shell resonant excitation of a single quantum dot-micropillar system, we generate long streams of 1000 near-transform-limited single photons with high mutual indistinguishability. The Hong-Ou-Mandel interference of two photons is measured as a function of their emission time separation varying from 13 ns to 14.7 μs, where the visibility slightly drops from 95.9(2)% to a plateau of 92.1(5)% through a slow dephasing process occurring at a time scale of 0.7 μs. A temporal and spectral analysis reveals the pulsed resonance fluorescence single photons are close to the transform limit, which are readily useful for multiphoton entanglement and interferometry experiments.


Contours of Positive Mental Health: An Exploratory Delphi Study from India.
The need to broaden attention from a narrow focus on mental illness and pathology to investing in understanding and enhancing positive mental health is well recognized. The bulk of research on positive mental health tends to be largely based onwestern developed nationconceptualizations. This highlights the need to examine the construct of positive mental health in diverse socio-cultural contexts. Present study aimed at exploring indicators and dimensions of positive mental health in Indian adults. A two-step Delphi technique, involving a vignette- based tool was used for facilitating a contextualised understanding of indicators of positive mental health. The sample consisted of a panel of 35 experts from different regions of India, majority of whom had >10 years of professional experience. Using a bottom-up approach, content analysis of the emergent data in terms of responses of experts to 10 vignettes resulted in identification and operationalisation of 33 indicators which could be grouped under 13 dimensions. Comparisons with popular well-being frameworks indicated that eight of these could be considered newer dimensions. Though the remaining dimensions significantly overlapped with existing dimensions of well-being in the western literature; finer differences in their meanings and constituents were observed. Finding have implications for further research.


Pulmonary artery catheter occlusion as an indication of pulmonary embolus.
Two patients with respiratory failure had consistently reproducible findings on insertion of flow directed pulmonary artery catheters which led to the subsequent diagnosis of pulmonary embolus. Occlusion of the catheter tip and development of a rising "overwedge" tracing on deflation of the balloon may mean the catheter tip has become embedded in clot. When combined with the inability to obtain a wedge tracing, the deflation "overwedge" tracing should alert the physician to the possibility of unsuspected pulmonary embolus.


Covalently Functionalized MoS2 Initiated Gelation of Hydrogels for Flexible Strain Sensing.
Transition metal dichalcogenides (TMDs), with superior mechanical and electrical conductivity, are one of the most promising two-dimensional materials for creating a generation of intelligent and flexible electronic devices. However, due to the high van der Waals and electrostatic attraction, TMD nanomaterials tend to aggregate in dispersants to achieve a stable state, thus severely limiting their further applications. Surface chemical modification is a common strategy for improving the dispersity of TMD nanomaterials; however, there are still constraints such as limited functionalization methods, low grafting rate, and difficult practice application. Thus, it is challenging to develop innovative surface modification systems. Herein, we covalently modify an olefin molecule on surface-inert MoS2, and the modified MoS2 can be used as not only a catalyst for hydrogel polymerization, but also a cross-linker in the hydrogel network. Specifically, allyl is covalently grafted onto chemically exfoliated MoS2, and this modified MoS2 can be uniformly dispersed in polar solvents (such as acetone, N,N-dimethylformamide, and ethanol), remaining stable for more than 2 weeks. The allyl-modified MoS2 can catalyze the polymerization of polyacrylamide hydrogel and then integrate in the network, which increases the tensile strength of the composite hydrogel. The flexible sensor based on the composite hydrogel exhibits an ideal operating range of 600% and a quick response time of 150 ms. At the same time, the flexible device can also track the massive axial stretching movements of human joints, making it a reliable option for the next wave of wearable sensing technology.


Keraphyton gen. nov., a new Late Devonian fern-like plant from Australia.
The first plants related to the ferns are represented by several extinct groups that emerged during the Devonian. Among them, the iridopterids are closely allied to the sphenopsids, a group represented today by the genus Equisetum. They have been documented in Middle to early Late Devonian deposits of Laurussia and the Kazakhstan plate. Their Gondwanan record is poor, with occurrences limited to Venezuela and Morocco. Here we describe a new genus from a late Late Devonian locality of New South Wales. It is represented by a single anatomically preserved large stem characterized by a star-shaped vascular system with protoxylem strands located at rib tips, and by a lack of secondary tissues. Within the first fern-like plants, this stem shares the largest number of characters with iridopterid axes but differs by the pattern of its vascular system. Keraphyton mawsoniae gen. et sp. nov. adds a new record of early fern-like plants in eastern Gondwana. It provides new insights into the anatomical diversity within this key group of plants and supports the distinctiveness of the Australian flora in the latest Devonian.


Selenium as an anticancerogenic agent.
Selenium is an essential component of the intracellular antioxidant system, which defends the cell and the whole organism against oxidative damage and so from oxidative disease, especially from cancer. Selenium may be considered as an anticancerogenic agent, and a higher concentration of selenium in plasma may be a protective factor against human malignancies. It is also interesting to note that higher doses of selenium, applied to patients simultaneously with chemotherapy, may lower the toxicity of antineoplasm drugs without weakening the therapeutic effect.


A System for the Detection of Persons in Intelligent Buildings Using Camera Systems-A Comparative Study.
This article deals with the design and implementation of a prototype of an efficient Low-Cost, Low-Power, Low Complexity-hereinafter (L-CPC) an image recognition system for person detection. The developed and presented methods for processing, analyzing and recognition are designed exactly for inbuilt devices (e.g., motion sensor, identification of property and other specific applications), which will comply with the requirements of intelligent building technologies. The paper describes detection methods using a static background, where, during the search for people, the background image field being compared does not change, and a dynamic background, where the background image field is continually adjusted or complemented by objects merging into the background. The results are compared with the output of the Horn-Schunck algorithm applied using the principle of optical flow. The possible objects detected are subsequently stored and evaluated in the actual algorithm described. The detection results, using the change detection methods, are then evaluated using the Saaty method in order to determine the most successful configuration of the entire detection system. Each of the configurations used was also tested on a video sequence divided into a total of 12 story sections, in which the normal activities of people inside the intelligent building were simulated.


The Effect of Non-Surgical Periodontal Treatment on Patients with Combined Refractory Arterial Hypertension and Stage III, Grade B Periodontitis: A Preliminary Prospective Clinical Study.
We sought to evaluate the effects of non-surgical periodontal treatment (NSPT) on periodontal clinical parameters, systemic blood pressure (BP), and plasma levels of systemic inflammation markers in patients with combined refractory arterial hypertension (RAH) and stage III grade B periodontitis. Twenty-seven participants with RAH and periodontitis received NSPT. The analyzed clinical parameters were probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and plaque index (PI). An assessment was performed for systemic BP, complete blood count, coagulogram, creatinine measurement, C-reactive protein (CRP), glycated hemoglobin, cholesterol, glutamic oxaloacetic transaminase, glutamate pyruvic transaminase, waist-hip ratio, and body mass index. In the follow-up period, twenty-two patients were evaluated at baseline and after 90 and 180 days. The data were submitted for statistical analysis (α = 0.05%). As expected, the clinical results showed a significant improvement in the percentages of PI, BOP, PD, and CAL, which were statistically significant at 90 and 180 days (p < 0.0001). Importantly, NSPT significantly reduced the blood level of CRP (p < 0.02). However, no significant reduction in BP parameters was noted in the evaluated follow-up periods. NSPT, despite the benefits in periodontal clinical parameters, reduced the plasma level of CRP but not the BP in patients with combined RAH and periodontitis.


Value of the capsular enhancement sign on dynamic contrast-enhanced prostate multiparametric MRI for the detection of extracapsular extension.
To retrospectively determine the prevalence and diagnostic performance of the capsular enhancement sign (CES) on multiparametric (mp) MRI for the detection of prostate cancer (PCa) extracapsular extension (ECE). This retrospective study included patients who underwent mpMRI prior to radical prostatectomy. CES was defined as an area of asymmetrical early hyperenhancement on DCE-MRI adjacent to a peripheral zone tumour, matched or exceeded the tumour circumferential diameter, and with persistent enhancement. Two uro-radiologists evaluated the presence of CES on mpMRI, independently and in consensus, with interobserver agreement calculated using bias and prevalence-adjusted kappa (PABAK). CES performance for predicting ECE was assessed using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The study included 146 patients, with 91/146 (62%) having ECE on surgical pathology. Following initial review, Reader 1 identified 12/146 (8%) CES-positive cases, while Reader 2 reported 14/146 (10%) CES-positive cases, with 15/146 (10%) lesions determined as demonstrating the CES sign on consensus reading. PABAK for CES between the two readers was high at 0.90. All consensus determined CES-positive lesions represented pathological stage ≥ T3a disease, with the overall prevalence of CES among tumours with confirmed ECE being 15/91 (17%). The sign showed high specificity (100%) and PPV (100%) for ECE detection, but with low sensitivity, NPV, and accuracy at 16.5%, 41.3%, and 47.4%, respectively. CES was demonstrated to be a rare but highly specific ECE predictor on mpMRI that may improve local staging in the patients in whom it is demonstrated.


Classification of neuropathic pain in cancer patients: A Delphi expert survey report and EAPC/IASP proposal of an algorithm for diagnostic criteria.
Neuropathic pain (NP) in cancer patients lacks standards for diagnosis. This study is aimed at reaching consensus on the application of the International Association for the Study of Pain (IASP) special interest group for neuropathic pain (NeuPSIG) criteria to the diagnosis of NP in cancer patients and on the relevance of patient-reported outcome (PRO) descriptors for the screening of NP in this population. An international group of 42 experts was invited to participate in a consensus process through a modified 2-round Internet-based Delphi survey. Relevant topics investigated were: peculiarities of NP in patients with cancer, IASP NeuPSIG diagnostic criteria adaptation and assessment, and standardized PRO assessment for NP screening. Median consensus scores (MED) and interquartile ranges (IQR) were calculated to measure expert consensus after both rounds. Twenty-nine experts answered, and good agreement was found on the statement "the pathophysiology of NP due to cancer can be different from non-cancer NP" (MED=9, IQR=2). Satisfactory consensus was reached for the first 3 NeuPSIG criteria (pain distribution, history, and sensory findings; MEDs⩾8, IQRs⩽3), but not for the fourth one (diagnostic test/imaging; MED=6, IQR=3). Agreement was also reached on clinical examination by soft brush or pin stimulation (MEDs⩾7 and IQRs⩽3) and on the use of PRO descriptors for NP screening (MED=8, IQR=3). Based on the study results, a clinical algorithm for NP diagnostic criteria in cancer patients with pain was proposed. Clinical research on PRO in the screening phase and on the application of the algorithm will be needed to examine their effectiveness in classifying NP in cancer patients.


Use of the Internal Transcribed Spacer (ITS) Regions to Examine Symbiont Divergence and as a Diagnostic Tool for Sodalis-Related Bacteria.
Bacteria excel in most ecological niches, including insect symbioses. A cluster of bacterial symbionts, established within a broad range of insects, share high 16S rRNA similarities with the secondary symbiont of the tsetse fly (Diptera: Glossinidae), Sodalis glossinidius. Although 16S rRNA has proven informative towards characterization of this clade, the gene is insufficient for examining recent divergence due to selective constraints. Here, we assess the application of the internal transcribed spacer (ITS) regions, specifically the ITS(glu) and ITS(ala,ile), used in conjunction with 16S rRNA to enhance the phylogenetic resolution of Sodalis-allied bacteria. The 16S rRNA + ITS regions of Sodalis and allied bacteria demonstrated significant divergence and were robust towards phylogenetic resolution. A monophyletic clade of Sodalis isolates from tsetse species, distinct from other Enterobacteriaceae, was consistently observed suggesting diversification due to host adaptation. In contrast, the phylogenetic distribution of symbionts isolated from hippoboscid flies and various Hemiptera and Coleoptera were intertwined suggesting either horizontal transfer or a recent establishment from an environmental source. Lineage splitting of Sodalis-allied bacteria into symbiotic and free-living sister groups was also observed. Additionally, we propose an ITS region as a diagnostic marker for the identification of additional Sodalis-allied symbionts in the field. These results expand our knowledge of informative genome regions to assess genetic divergence since splitting from the last common ancestor, of this versatile insect symbiont clade that have become increasingly recognized as valuable towards our understanding of the evolution of symbiosis. These facultative and recently associated symbionts may provide a novel source of traits adaptable to the dynamic ecologies encountered by diverse host backgrounds.


Using simulation to teach paediatric complex care.
Training paediatric residents regarding the care of children with medical complexity (CMC) remains an important challenge given how frequently these patients are treated by trainees and the lack of educational activities specific to these patients. Our goal was to develop and assess a novel simulation regarding the acute care of CMC to improve residents' perceived confidence in areas related to CMC care. We developed a case of a patient with multiple chronic medical conditions who presented with acute vital sign changes and worsening discomfort due to an occult femur fracture related to a recent transfer. Paediatric residents worked in teams to complete a full physical exam, create a differential diagnosis, evaluate laboratory and imaging results and create a management plan. Thirty-three residents out of a total possible sample of 97 (34%) participated in the simulation, which was evaluated using pre- and post-surveys immediately before and after the simulation assessing resident confidence completing tasks related to CMC care. Residents perceived significant improvement in confidence regarding evaluating a differential diagnosis of vital sign and exam changes in CMC (p = 0.023), managing vital sign and exam changes in CMC (p = 0.009) and communicating with team members of CMC (p = 0.049). An innovative high-fidelity and low-stakes simulation was effective in teaching trainees about acute management of concerns related to CMC. This simulation may be appropriate for implementation at other institutions, serving as a foundation for use in resident education regarding CMC.


Medical assessment for health advocacy and practical strategies for exercise initiation.
The universal caution to consult your family doctor before beginning an exercise program creates an image of exercise as potentially harmful. Moreover, insistence on extensive screening prior to exercise is both unrealistic and often inappropriate for the older adult. Recasting the role of the physician as a physical activity advocate rather than as a gatekeeper is recommended for incorporation into guidelines for exercise screening. A geriatric assessment focusing on identification of specific parameters predictive of disablement risk can be incorporated into the exercise prescription as a guide for initiating exercise. The purpose of this article is to: (1). review the role of the primary care physician in screening and advocating exercise; (2). examine objectively the risk of exercise among older adults and place these risks in context with current screening guidelines with a particular emphasis on the exercise test; and (3). examine how key concepts derived from epidemiologic studies of disability can be distilled into practical guidelines for exercise therapy. We provide an overview of relevant literature related to screening and initiating exercise. Key challenges are highlighted and discussed. Suggestions for changes in policy are recommended. Given the apparent discordance between screening guidelines for the older adult and risk of adverse events, and between existing recommendations for physical activity and epidemiologic studies of disability, an evidence-based approach is recommended to review and revise screening and prescribing practices.


Breast pathology practice: most common problems in a consultation service.
Considerable progress has been made in understanding breast lesions utilizing molecular methods, but conventional morphology, simple immunohistochemical stains and common sense still prevail in diagnosing the vast majority of breast disease. The focus of this review is to identify the most common breast lesions sent to our consultation practice, and to reiterate salient diagnostic features, differential diagnoses and common pitfalls in identifying these lesions. Separation of epithelial proliferative lesions and differentiation between usual epithelial hyperplasia (UEH) and atypical ductal hyperplasia (ADH) are the most common problems encountered in our Consultation practice. Differentiation between UEH and ADH is based on the assumption that ADH is a clonal process, recognized by a uniform phenotype and more recently described immunohistochemical markers such as differential cytokeratin and also hormone receptor expression. Difficulty in subtyping invasive carcinomas and exclusion of in situ and/or invasive carcinoma in a sclerosing lesion is also commonly noted. Finally, problems in distinguishing various papillary and fibroepithelial lesions are also encountered. The use of common immunohistochemical stains such as various cytokeratin and myoepithelial markers, E-cadherin and hormone receptors is helpful in solving most of these diagnostic dilemmas.


Informing patterns of health and social care utilisation in Irish older people according to the Clinical Frailty Scale.
Background: There is increasing policy interest in the consideration of frailty measures (rather than chronological age alone) to inform more equitable allocation of health and social care resources. In this study the Clinical Frailty Scale (CFS) classification tree was applied to data from The Irish Longitudinal Study on Ageing (TILDA) and correlated with health and social care utilisation. CFS transitions over time were also explored. Methods: Applying the CFS classification tree algorithm, secondary analyses of TILDA data were performed to examine distributions of health and social care by CFS categories using descriptive statistics weighted to the population of Ireland aged ≥65 years at Wave 5 (n=3,441; mean age 74.5 (SD ±7.0) years, 54.7% female). CFS transitions over 8 years and (Waves 1-5) were investigated using multi-state Markov models and alluvial charts. Results: The prevalence of CFS categories at Wave 5 were: 6% 'very fit', 36% 'fit', 31% 'managing well', 16% 'vulnerable', 6% 'mildly frail', 4% 'moderately frail' and 1% 'severely frail'. No participants were 'very severely frail' or 'terminally ill'. Increasing CFS categories were associated with increasing hospital and community health services use and increasing hours of formal and informal social care provision. The transitions analyses suggested CFS transitions are dynamic, with 2-year probability of transitioning from 'fit' (CFS1-3) to 'vulnerable' (CFS4), and 'fit' to 'frail' (CFS5+) at 34% and 6%, respectively. 'Vulnerable' and 'frail' had a 22% and 17% probability of reversal to 'fit' and 'vulnerable', respectively. Conclusions: Our results suggest that the CFS classification tree stratified the TILDA population aged ≥65 years into subgroups with increasing health and social care needs. The CFS could be used to aid the allocation of health and social care resources in older people in Ireland. We recommend that CFS status in individuals is reviewed at least every 2 years.


Transient hypopituitarism.
Spontaneous recovery of pituitary function in patients with hypopituitarism is rare. We report the case of a 30-year-old man in whom hypopituitarism and sudden onset of bilateral hearing loss developed after a viral infection. No evidence of a mass lesion was detected on computed tomography or magnetic resonance imaging of the pituitary gland. The patient received a 3-week course of treatment with a high dose of glucocorticoids; in a period of 6 weeks, he felt clinically well, and biochemical tests showed spontaneous return of normal anterior pituitary function. We speculate that an immune response triggered by the viral infection initiated an inflammatory process that involved the hypothalamus or pituitary gland and caused the hypopituitarism. The treatment with high-dose glucocorticoids could have prompted the resolution of the hypothalamic-pituitary inflammatory process and facilitated spontaneous recovery of pituitary function. This case shows that hypopituitarism may be transient an outcome that should be considered in patients with idiopathic hypopituitarism.


Distal spinal muscular atrophy.
Spinal muscular atrophies (SMA) are clinically heterogenous group of motor system disorders characterised by progressive pure lower motor neuron involvement. The distal form of SMA is an extremely rare disorder, which presents in the adults and has a relatively slow progression with almost no effect on the patients' life-span. Differential diagnosis of this syndrome include other forms of neuromuscular disorders with peroneal muscular atrophy like hereditary motor sensory neuropathy (HMSN) and distal myopathies, which need exclusion before confirming this rare entity. We present a young male with this disorder and briefly discuss the theoretical aspects.


[Evaluation of Malassezia furfur Biofilm Formation on Polypropylene Membrane].
The Malassezia yeast species colonize on the skin immediately after birth and could be found on the healthy skin flora for life. Although they are more frequently involved in the etiology of common skin infections in the community, particularly Malassezia furfur could cause life-threatening infections such as fungemia. Detection of biofilm during the colonization of these yeasts on the skin is an important criterion for its virulence. Since they are lipophilic yeasts, commonly used biofilm detection methods are not applicable to the Malassezia strains. The aim of the study was to describe the growth and measurement of M.furfur isolates on a polypropylene membrane to demonstrate their biofilm-forming capacities. Twenty-seven M.furfur strains colonized in the newborns were included in the study. Basically, sterile polypropylene membranes were placed on different polysorbates (tween 20, 40, and 80) which were spread on Sabouraud dextrose agar. Ten µl saline suspension of M.furfur was dropped on the polypropylene membrane and incubated in standard growth conditions for three days. Later, the visible colony was removed gently by washing with running water and the biofilm structure formed on the membrane was stained with safranin. The stained biofilm was photographed. Performing image analysis, the values obtained against background activity were digitized according to the specified protocol. Moreover, XTT reduction test was performed and the measured metabolic activity results were compared with the safranin-stained biofilm data. The safranin hydrolysis of the strains was measured spectrometrically. Twenty-five (92.6%) of the strains included in the study were stained with safranin, which indicated the presence of biofilm on the polypropylene membrane. The strains grown with tween 20 and tween 80 formed a higher biofilm layer density than those supplied with tween 40. Isolates with low and high biofilm-forming capacity were clearly separated by tween 20 (p< 0.05). XTT activity was detected in 26 (96.3%) isolates. No correlation was found between biofilm density obtained by the described method and XTT reduction. It was observed that hydrolysis of safranin did not affect the biofilm evaluation method. In this study, it was shown that as a result of sufficient diffusion through hydrophobic membranes, polysorbate-based growth factors could maintain measurement of the biofilm layer formed by lipophilic M.furfur strains. The best grouping properties for M.furfur were obtained with tween 20 which could determine low and high level of biofilm formation. Image analysis was used with high performance for this method. As conclusion, the utilization of different hydrophobic membranes and dyes would lead to the development of new techniques for the application in other lipophilic yeasts.


New Highly Sensitive Real-Time PCR Assay for HIV-2 Group A and Group B DNA Quantification.
HIV-2 infection is characterized by a very low replication rate in most cases and low progression. This necessitates an approach to patient monitoring that differs from that for HIV-1 infection. Here, a new highly specific and sensitive method for HIV-2 DNA quantification was developed. The new test is based on quantitative real-time PCR targeting the long terminal repeat (LTR) and gag regions and using an internal control. Analytical performance was determined in three laboratories, and clinical performance was determined on blood samples from 63 patients infected with HIV-2 group A (n = 35) or group B (n = 28). The specificity was 100%. The 95% limit of detection was three copies/PCR and the limit of quantification was six copies/PCR. The within-run coefficients of variation were between 1.03% at 3.78 log10 copies/PCR and 27.02% at 0.78 log10 copies/PCR. The between-run coefficient of variation was 5.10%. Both manual and automated nucleic acid extraction methods were validated. HIV-2 DNA loads were detectable in blood cells from all 63 patients. When HIV-2 DNA was quantifiable, median loads were significantly higher in antiretroviral-treated than in naive patients and were similar for groups A and B. HIV-2 DNA load was correlated with HIV-2 RNA load (r = 0.68; 95% confidence interval [CI], 0.4 to 0.8; P < 0.0001). Our data show that this new assay is highly sensitive and quantifies the two main HIV-2 groups, making it useful for the diagnosis of HIV-2 infection and for pathogenesis studies on HIV-2 reservoirs.


[Venous thrombosis in Behçet's disease].
Venous lesions in Behçet's disease (BD) were defined by Adamantiades and represent one of the most suggestive signs of the disease. They are occasionally the first sign of the disease and are frequently the basis for the diagnosis in a case of recurrent thrombosis in a young subject, the preferential context of BD. Involvement of superficial vessels is virtually constant. Venous vasculitis is responsible for non-specific hypersensitivity and erythema nodosa, which constitute some of the major diagnostic criteria. Ocular periphlebitis is one of the elements responsible for posterior uveitis. The originality of the venous involvement is due to the involvement of deep territories. Any vein may be affected, but the remarkable features are the size of the thrombosed vessels: superior and inferior vena cava, iliofemoral veins and the unusual site of the involvement: supra-hepatic veins, cerebral vessels, etc. Inferior vena cava thrombosis may be associated with aneurysms of the pulmonary arteries in the context of Hughes-Stovin syndrome. Cerebral phlebitis, which can now be identified more easily by means of digital angiography, is responsible for a typical picture: headaches, bilateral papilloedema and raised CSF pressure. The classical pictures of optic chiasmatic arachnoiditis and so-called benign intracranial hypertension actually correspond to unrecognised phlebitis. They may also be associated with other neurological lesions. In one half of cases, phlebitis cutaneous manifestations. However, they may precede the diagnostic signs or may occur very late in the course of the disease. They are recurrent and affect a number of different territories.(ABSTRACT TRUNCATED AT 250 WORDS)


Lateral pancreaticojejunostomy for chronic pancreatitis.
Chronic pancreatitis is a progressive fibrosis of the pancreas that leads to loss of endocrine and exocrine function. The most common symptom in this disease is intractable pain. The etiology of pain in chronic pancreatitis is not clearly understood. However, many of these patients have dilated ducts consisting of saccular dilations and intervening constructions referred to as the "chain of lakes" phenomenon. These patients can be diagnosed with either endoscopic retrograde cholangiopancreatography (ERCP) or computed tomography (CT). These patients are best treated by the Partington Rochelle modification of the Puestow Procedure otherwise known as lateral pancreaticojejunostomy. Overall pain relief in published studies occurs in 50-90% of patients. Another proposed advantage of the lateral pancreaticojejunostomy is preservation of endocrine and exocrine pancreatic function as long as the pancreas is not further damaged by alcohol.


Low level of exosomal long non-coding RNA HOTTIP is a prognostic biomarker in colorectal cancer.
Molecular risk stratification of colorectal cancer can improve patient outcome. A panel of lncRNAs (H19, HOTTIP, HULC and MALAT1) derived from serum exosomes of patients with non-metastatic CRC and healthy donors was analyzed. Exosomes from healthy donors carried significantly more H19, HULC and HOTTIP transcripts in comparison to CRC patients. Correlation analysis between lncRNAs and clinical data revealed a statistical significance between low levels of exosomal HOTTIP and poor overall survival. This was confirmed by multivariate analysis that HOTTIP is an independent prognostic marker for overall survival (HR: 4.5, CI: 1.69-11.98, p = 0.0027). Here, HOTTIP poses to be a valid biomarker for patients with a CRC to predict post-surgical survival time.


The 5'-AG5 CC-3' Fragment from the Human CPEB3 Ribozyme Forms an Ultrastable Parallel RNA G-Quadruplex.
An unusually thermostable G-quadruplex is formed by a sequence fragment of a naturally occurring ribozyme, the human CPEB3 ribozyme. Strong evidence is provided for the formation of a uniquely stable intermolecular G-quadruplex structure consisting of five tetrad layers, by using CD spectroscopy, UV melting curves, 2D NMR spectroscopy, and gel shift analysis. The cationic porphyrin TMPyP4 destabilizes the complex.


Arterial pressure and plasma vasopressin: regulation by neurons in the caudal ventrolateral medulla of the rabbit.
Experiments in the anesthetized rabbit have demonstrated that the caudal ventrolateral medulla oblongata contains tonically active vasodepressor neurons which are themselves inhibited by GABAergic and glycine-like inputs. Alteration of neuronal function in this region also elevates plasma vasopressin levels, contributing to, but not completely accounting for, the hypertension and pulmonary edema observed after destruction of neurons in the region.


Samarium Barbier reactions of alpha-iodomethyloxazoles and thiazoles with aliphatic aldehydes.
[reaction: see text] The reductive coupling of substituted alpha-iodomethyloxazoles and thiazoles with aliphatic aldehydes under Barbier conditions provides an effective method for the direct incorporation of intact heterocyclic systems.


Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation.
Islet amyloid polypeptide (IAPP), or 'amylin', is co-stored with insulin in secretory granules of pancreatic islet beta-cells. In Type 2 diabetes, IAPP converts into a beta-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop beta-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.


PD-L1 (SP142) expression in neoplastic cells predicts a poor prognosis for patients with intravascular large B-cell lymphoma treated with rituximab-based multi-agent chemotherapy.
Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse large B-cell lymphoma (DLBCL) arising in extranodal sites. PD-L1 expression of tumor cells has been reported in IVLBCL cells, but its clinicopathological relevance remains to be elucidated. This study was aimed to reveal the characteristics of PD-L1+ IVLBCL. Neoplastic PD-L1 expression was examined in 34 cases of IVLBCL and clinicopathological characteristics between patients with PD-L1+ and PD-L1- IVLBCL were compared. We assessed PD-L1 expression with SP142 antibody. Twelve (35%) of 34 cases showed positivity for PD-L1. The PD-L1+ group had significantly lower survival rates compared to the PD-L1- group. The PD-L1+ IVLBCL group also had a significantly lower age distribution and a lower frequency of patients older than 60 years compared to the PD-L1- group. Very recently, we speculate that there is possible link between PD-L1+ IVLBCL and PD-L1+ extranodal DLBCL-NOS (eDLBCL) because features of the two groups showed overlapping. Therefore, we compared the clinicopathological characteristics of the PD-L1+ IVLBCL and PD-L1+ eDLBCL. There were no significant differences in clinicopathological parameters and prognosis. The worse prognosis of the PD-L1+ group might be caused by immune evasion mechanisms, which are linked to PD-L1 expression. Therefore, PD-L1+ IVLBCL cases might be regarded as good candidates for targeted immunotherapy. We also highlighted the overlapping features of PD-L1+ IVLBCL and PD-L1+ eDLBCL. This result suggests that they should be regarded as one entity, immune evasion-related extranodal large B-cell lymphoma.


Biochemical insights into the mechanisms central to the response of mammalian cells to cold stress and subsequent rewarming.
Mammalian cells cultured in vitro are able to recover from cold stress. However, the mechanisms activated during cold stress and recovery are still being determined. We here report the effects of hypothermia on cellular architecture, cell cycle progression, mRNA stability, protein synthesis and degradation in three mammalian cell lines. The cellular structures examined were, in general, well maintained during mild hypothermia (27-32 degrees C) but became increasingly disrupted at low temperatures (4-10 degrees C). The degradation rates of all mRNAs and proteins examined were much reduced at 27 degrees C, and overall protein synthesis rates were gradually reduced with temperature down to 20 degrees C. Proteins involved in a range of cellular activities were either upregulated or downregulated at 32 and 27 degrees C during cold stress and recovery. Many of these proteins were molecular chaperones, but they did not include the inducible heat shock protein Hsp72. Further detailed investigation of specific proteins revealed that the responses to cold stress and recovery are at least partially controlled by modulation of p53, Grp75 and eIF3i levels. Furthermore, under conditions of severe cold stress (4 degrees C), lipid-containing structures were observed that appeared to be in the process of being secreted from the cell that were not observed at less severe cold stress temperatures. Our findings shed light on the mechanisms involved and activated in mammalian cells upon cold stress and recovery.


The cost of obesity in radical cystectomy.
The prevalence of obesity is on the rise in the Unites States, and obesity has been associated with increased complications and costs in a variety of complex surgeries. However, the contribution of obesity to the overall costs of radical cystectomy has not been studied in detail using contemporary data. Our objective is to assess the variation in healthcare costs due to obesity on the index hospitalization for radical cystectomy in the United States between 2003 and 2015. This was a retrospective cohort study, using the Premier Healthcare Database, of 1,242 patients who underwent radical cystectomy and were either overweight (25 ≤ body mass index [BMI] < 30), obese (30 ≤ BMI < 40), or morbidly obese (BMI ≥ 40). The primary outcome costs of the index hospitalization for each BMI category. Multivariable median regression was used to identify drivers of increased costs. The cost of the index hospitalization for cystectomy was $24,596 (95% confidence interval [CI], $22,599-$26,592) for overweight patients. The costs for obese and morbidly obese patients were $2,158 (95% CI, -$80 to $4,395, P = 0.059) and $5,308 (95% CI, $2,652-$7,964, P < 0.001) higher compared to overweight patients, respectively. After adjustment for operative time or length of stay in the multivariable models, there were no longer any differences in cost. Operative time was prolonged as BMI increased (median operative time for overweight, obese, and morbidly obese: 346, 391, and 420 minutes, respectively P = 0.0001). Median length of stay was 1 day shorter for overweight vs. morbidly obese patients (P = 0.0030), with each additional day costing $1,738 (95% CI, $1,654 to $1,821, P < 0.0001) on multivariable analysis. The cost of radical cystectomy is greater for obese and morbidly obese patients compared to overweight patients. The increased financial cost is driven by increased operative times and longer length of stay.


Augmented renal clearance in non-critically ill abdominal and trauma surgery patients is an underestimated phenomenon: A point prevalence study.
Augmented renal clearance refers to increased renal elimination of circulating solutes as compared with normal baseline and could lead to underexposure of frequently used renally eliminated antimicrobials. The primary objective was to assess the prevalence of augmented renal clearance in an adult non-critically ill surgery population. Besides, predictors for augmented renal clearance were investigated. A prospective observational single-center point prevalence study was conducted. The measured creatinine clearance based on an 8-hour urinary collection was used as primary method for determining kidney function. Augmented renal clearance was defined as measured creatinine clearance of 130 mL/min per 1.73m² or greater. A Poisson regression model was applied to identify predictors for augmented renal clearance. Augmented renal clearance prevalence was 30% and 35% in 103 abdominal and 129 trauma surgery patients, respectively. Younger age (abdominal cohort: relative risk, 0.963 (95% CI, 0.949-0.978); trauma cohort: relative risk, 0.971 [95% CI, 0.960-0.983]) and also for trauma surgery patients, male sex (relative risk, 1.808 [95% CI, 1.026-3.185]) were found to be independent predictors for augmented renal clearance. Augmented renal clearance is an underestimated phenomenon in adult non-critically ill surgery patients. Especially younger patients, and, in the subset of trauma surgery, males are prone to exhibit augmented renal clearance. Since augmented renal clearance is a risk factor for lower antimicrobial exposure, the impact of augmented renal clearance in relation to antimicrobial underexposure should be investigated in this population. Prognostic/epidemiological study, level III.


In vitro and in vivo evaluation of a novel oral insulin formulation.
To develop a stable self-emulsifying formulation for oral delivery of insulin. Caco-2 cell line and diabetic beagles were used as in vitro and in vivo models to study the absorption mechanism and the hypoglycemic efficacy of the formulation. In addition, various physicochemical parameters of the formulation such as droplet size, insulin encapsulation efficiency and stability were evaluated. This formulation enabled changes in barrier properties of Caco-2 monolayers, as referred by transepithelial electrical resistance (TEER) and apparent permeability coefficients (P(app)) of the paracellular marker ranitidine (20-fold greater than control) but not transcellular marker propranolol, suggesting that the opening of tight junctions was involved. In diabetic beagle dogs, the bioavailability of this formulation was up to 15.2% at a dose of 2.5 IU/kg in comparison with the hypoglycemic effect of native insulin (0.5 IU/kg) delivered by subcutaneous injection. This formulation, recently approved by the China State Food and Drug Administration to enter clinical trials, was stable, degradation-protected and absorption-enhanced, and provided a promising formulation for oral insulin delivery.


Engineering of Glarea lozoyensis for exclusive production of the pneumocandin B0 precursor of the antifungal drug caspofungin acetate.
Pneumocandins produced by the fungus Glarea lozoyensis are acylated cyclic hexapeptides of the echinocandin family. Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate. In the wild-type strain, pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization. The pneumocandin biosynthetic gene cluster was previously elucidated by a whole-genome sequencing approach. Knowledge of the biosynthetic cluster suggested an alternative way to produce exclusively pneumocandin B0. Disruption of GLOXY4, encoding a nonheme, α-ketoglutarate-dependent oxygenase, confirmed its involvement in l-leucine cyclization to form 4S-methyl-l-proline. The absence of 4S-methyl-l-proline abolishes pneumocandin A0 production, and 3S-hydroxyl-l-proline occupies the hexapeptide core's position 6, resulting in exclusive production of pneumocandin B0. Retrospective analysis of the GLOXY4 gene in a previously isolated pneumocandin B0-exclusive mutant (ATCC 74030) indicated that chemical mutagenesis disrupted the GLOXY4 gene function by introducing two amino acid mutations in GLOXY4. This one-step genetic manipulation can rationally engineer a high-yield production strain.


Immunochemical cross-reactivity between cyanogen bromide fragments of human serum albumin.
The antigenic structure of human albumin was investigated in order to establish whether or not there was any similarity between its antigenic sites. Using immunoadsorbent columns prepared with cyanogen bromide fragments of human serum albumin, antibodies directed against different portions of the albumin molecules were isolated. Measurement of the amount of the antibodies isolated and study of their specificity by inhibition techniques show that these subpopulations of antibodies reacted not only with the fragment used for their isolation (homologous) but also with the other fragments (heterologous). Heterologous fragments were inhibiting only at a very high concentration with regard to the homologous ones. These results show that there is a weak cross-reactivity between different portions of the albumin molecule. This reaction is most probably due to the homology existing in the sequence of the human albumin molecule which has arisen by gene duplication. The same type of behavior can be predicted to extent to other molecules which have evolved by similar mechanisms.


A Hypercalcemic Enigma: A Rare Case of Bone Marrow Sarcoidosis.
Sarcoidosis is a multisystem inflammatory disease involving granuloma formation. The exact etiology of the disease remains unknown. While the lungs are the most commonly involved organs in sarcoidosis, bone marrow-only involvement is quite rare. As bone marrow-only involvement can have a presentation that closely resembles multiple myeloma, a significant diagnostic dilemma can occur as the treatment for sarcoidosis is different compared to multiple myeloma. We present a case of a 62-year-old female who presented with worsening lower extremity weakness and fatigue. She was found to have new-onset hypercalcemia, normocytic anemia, and lytic bony lesions. Extensive laboratory workup for multiple myeloma was negative with bone marrow biopsy showing non-caseating granulomas, thus diagnosing the patient with sarcoidosis involving the bone marrow.