Comprehensive comparative analysis of the prognostic impact of systemic inflammation biomarkers for patients underwent cardiac surgery.
Inflammation plays an integral role in the development of cardiovascular disease, and few studies have identified different biomarkers to predict the prognosis of cardiac surgery. But there is a lack of reliable and valid evidence to determine the optimal systemic inflammatory biomarkers to predict prognosis. From December 2015 and March 2021, we collected 10 systemic inflammation biomarkers among 820 patients who underwent cardiac surgery. Time-dependent receiver operating characteristic curves (ROC) curve at different time points and C-index was compared at different time points. Kaplan-Meier method was performed to analyze overall survival (OS). Cox proportional hazard regression analyses were used to assess independent risk factors for OS. A random internal validation was conducted to confirm the effectiveness of the biomarkers. The area under the ROC of lymphocyte-to-C-reactive protein ratio (LCR) was 0.655, 0.620 and 0.613 at 1-, 2- and 3-year respectively, and C-index of LCR for OS after cardiac surgery was 0.611, suggesting that LCR may serve as a favorable indicator for predicting the prognosis of cardiac surgery. Patients with low LCR had a higher risk of postoperative complications. Besides, Cox proportional hazard regression analyses indicated that LCR was considered as an independent risk factor of OS after cardiac surgery. LCR shows promise as a noteworthy representative among the systemic inflammation biomarkers in predicting the prognosis of cardiac surgery. Screening for low LCR levels may help surgeons identify high-risk patients and guide perioperative management strategies.


Marked difference in membrane-protein-binding properties of the two isoforms of protein 4.1R expressed at early and late stages of erythroid differentiation.
Two major isoforms of protein 4.1R, a 135 kDa isoform (4.1R(135)) and an 80 kDa isoform (4.1R(80)), are expressed at distinct stages of terminal erythroid differentiation. The 4.1R(135) isoform is exclusively expressed in early erythroblasts and is not present in mature erythrocytes, whereas the 4.1R(80) isoform is expressed at late stages of erythroid differentiation and is the principal component of mature erythrocytes. These two isoforms differ in that the 4.1R(135) isoform includes an additional 209 amino acids designated as the HP (head-piece) at the N-terminus of 4.1R(80). In the present study, we performed detailed characterization of the interactions of the two 4.1R isoforms with various membrane-binding partners and identified several isoform-specific differences. Although both 4.1R(135) and 4.1R(80) bound to cytoplasmic domains of GPC (glycophorin C) and band 3, there is an order of magnitude difference in the binding affinities. Furthermore, although both isoforms bound CaM (calmodulin), the binding of 4.1R(80) was Ca2+-independent, whereas the binding of 4.1R(135) was strongly Ca2+-dependent. The HP of 4.1R(135) mediates this Ca2+-dependent binding. Ca2+-saturated CaM completely inhibited the binding of 4.1R(135) to GPC, whereas it strongly reduced the affinity of its binding to band 3. Interestingly, in spite of the absence of spectrin-binding activity, the 4.1R(135) isoform was able to assemble on to the membrane of early erythroblasts suggesting that its ability to bind to membrane proteins is sufficient for its membrane localization. These findings enable us to offer potential new insights into the differential contribution of 4.1R isoforms to membrane assembly during terminal erythroid differentiation.


Adiponectin and metformin additively attenuate IL1β-induced malignant potential of colon cancer.
Both adiponectin (AD) and metformin (Met) have been proposed to downregulate cell proliferation of colon cancer cells, but whether their effect might be additive has not been studied to date. Genetic studies in humans have suggested an important role for interleukin 1β (IL1β) in cancer pathogenesis. Direct evidence that IL1β contributes to the development of colon cancer has not yet been fully confirmed and no previous studies have evaluated how IL1β may interact with AD and/or Met to regulate malignant potential and intracellular signaling pathways in human and mouse colon cancer cells. We conducted in vitro studies using human (LoVo) and mouse (MCA38) colon cancer cell lines to evaluate whether AD and Met alone or in combination may antagonize IL1β-regulated malignant potential in human and mouse colon cancer cell lines. IL1β increased malignant potential and regulated the expression of tumor suppressor (p53) and cell cycle regulatory genes (p21, p27, and cyclin E2) in human and mouse colon cancer cell lines. These effects were reversed by co-administration of AD and/or Met and were additively altered by AD and Met in combination in a STAT3- and AMPK/LKB1-dependent manner. We also observed using fluorescence activated cell sorter analysis that IL1β-regulated cell cycle progression is altered by AD and Met alone or in combination. Our novel mechanistic studies provide evidence for an important role for IL1β in colon cancer and suggest that AD and/or Met might be useful agents in the management or chemoprevention of IL1β-induced colon carcinogenesis.


Postgraduate research training: the PhD and MD thesis.
Higher research degrees, such as the PhD, MPhil and MD, have existed within universities for 80 years or more, although the differences between the MD and PhD remain confused. A higher research degree training provides individuals with greater research knowledge and skills, and benefits the specialty. Concern exists about the levels of supervision sometimes provided, failure to complete degrees, and the variable levels of research knowledge and skills attained. We propose that higher research degrees in palliative care have four functions: extending personal scholarship, generating knowledge, training for the individual and contributing to the growth of the specialty. Such an approach may include: a formalised first year with taught components such as in research MSc programmes, formal supervision and progress assessment. In palliative care, clinical and academic approaches need greater integration. Multiprofessional learning is essential. To allow individuals to undertake higher research degree programmes, fellowships or specific funding are needed.


Platelet-activating factor and the release of a platelet-derived coronary artery vasodilator substance in the canine.
Platelet-activating factor (acetyl-glyceryl-ether-phosphorylcholine; 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine), which is released by stimulated neutrophils and platelets, possesses the ability to alter vascular tone and permeability and to activate various formed blood elements. We have characterized the hemodynamic effects of intracoronary injections of platelet-activating factor and the influences of pharmacological blockade and platelet depletion on its activity. Intracoronary injections of platelet-activating factor produced maximum increases in left circumflex coronary artery blood flow of 55 +/- 8, 52 +/- 8, and 52 +/- 7 ml/min at 0.5, 1.0, and 2.0 nM, respectively. Only modest changes in systemic arterial blood pressure and regional developed isometric contractile force were associated with the intracoronary artery administration of platelet-activating factor over the range of doses studied. The increase in left circumflex coronary artery blood flow in response to platelet-activating factor was attenuated (44%), but not prevented, by pretreatment with diphenhydramine, (4 mg/kg, iv), and was not affected by pretreatment with aspirin (20 mg/kg, iv) or the systemic administration of the serotonin receptor antagonist, methysergide. The coronary vasodilator response to platelet-activating factor was reduced significantly by the induction of thrombocytopenia (95 +/- 3% platelet depletion) through the administration of sheep-derived canine platelet antiserum. The intracoronary artery injection of platelet-rich plasma activated with platelet-activating factor into thrombocytopenic dogs produced a significantly greater increase in coronary artery blood flow than the injection of either non-activated platelet-rich plasma or platelet-depleted plasma to which platelet-activating factor was added. Similar changes in coronary artery blood flow could be obtained with the intracoronary artery injection of cell-free supernates from washed platelets activated with platelet-activating factor. The observed results suggest that circulating platelets, when exposed to platelet-activating factor, can release a coronary dilator substance, and that the coronary artery dilation is not prevented by pharmacological receptor antagonists for histamine, serotonin, or inhibitors of cyclooxygenase.


Influence of Hindfoot Malalignment on Hallux Valgus Operative Outcomes.
Hindfoot deformity has been described as a risk factor for poor hallux valgus (HV) surgery outcomes. However, there has been no study that demonstrates it. The purpose of this investigation was to evaluate the influence of hindfoot misalignment in HV surgery results. All patients operated on for HV during 2010 and 2011 at 3 university hospitals were included. The preoperative and 2-year postoperative radiologic data included the HV and the intermetatarsal (IM) angles, the naviculocuboid overlap (NC), the talonavicular coverage (TN) angle, the talus-first metatarsal (T-1MT) angle, as well as the calcaneal pitch (CP) angle. Additionally, the Short Form-36 questionnaire version 2.0 (SF-36) and the American Orthopaedic Foot & Ankle Society (AOFAS) score, satisfaction and recurrence were also analyzed. A total of 207 met the inclusion criteria. There were 26 patients (12.6%) who could not be assessed at the 2-year follow-up. Patients were allocated to a varus, normal, or a valgus hindfoot tertile using the values for the CP, NC, TN, and T-1MT angles. No significant differences (P > .05) were found between the groups when the HV or IM angles, AOFAS, SF-36 Mental Composite Scale, SF-36 Physical Composite Scale, or satisfaction were compared. Similarly, no significant and strong correlations were observed (P > .05, ρ < 0.3) between any of the mentioned hindfoot measures and the outcomes scales. No influence of hindfoot misalignment on HV surgery outcomes was found in the present study in terms of correction, pain, function, satisfaction, or quality of life. Patients with hindfoot misalignment did not obtain worse outcomes in HV surgery. Level II, prognostic, comparative study.


Superprotonic Conductivity of a Functionalized Metal-Organic Framework at Ambient Conditions.
Seeking fast proton transport pathways at ambient conditions is desirable but challenging. Here, we report a strategy to synthesize a composite material with a polyoxometalate (POM) and an ionic liquid (IL) confined in stable metal-organic framework (MOF) channels through electrostatic interaction. The obtained SO3H-IL-PMo12@MIL-101 possesses fast proton transfer, and its proton conductivity can reach 1.33 × 10-2 S cm-1 at ambient conditions (30 °C, 70% relative humidity (RH)), which is the highest value among the MOF-based proton conductors operated in an ambient environment. Therefore, it has the potential of becoming a room-temperature proton conductor without a humidifier. Importantly, the composite material is further fabricated into a composite membrane for proton-exchange membrane fuel cells (PEMFCs), which can deliver a power density of 0.93 mW cm-2 at 30 °C and 98% RH. This result can lay a fundamental basis for the application of MOF-based proton conductors in the area of electrochemical energy conversion.


Using Hemolysis as a Novel Method for Assessment of Cytotoxicity and Blood Compatibility of Decellularized Heart Tissues.
Developing patient-specific transplantable organs is a promising response to the increasing need of more effective therapies for patients with organ failure. Advances in tissue engineering strategies have demonstrated favorable results, including the use of decellularized hearts as scaffolds for cardiac engineering; however, there is a need to establish methods to characterize the cytotoxicity and blood compatibility of cardiac extracellular matrix (cECM) scaffolds created by decellularization. In this study, porcine hearts were decellularized in an automated perfusion apparatus utilizing sodium dodecyl sulfate (SDS) detergent. Residual SDS was measured by a colorimetric assay. Phosphate-buffered saline, distilled water (DW), and Triton X-100 washes were used to remove SDS. The efficiency of detergent removal was measured as a function of time. It was observed that using Triton-X 100 can nearly double the rate of SDS removal. An assay based on human blood hemolysis was developed to measure the remaining cytotoxicity of the cECM. The results from the hemolysis cytotoxicity assay were consistent with a standard live/dead assay using MS1 endothelial cells incubated with the cECM. This study demonstrated an effective, reliable, and relatively inexpensive method for determining the cytotoxicity and blood compatibility of decellularized cECM scaffolds.


[Population movement within small areas].
Internal migration trends in Hungary between 1962 and 1982 are analyzed. The socioeconomic causes and consequences of migration are first reviewed. Changes in the distribution of migration among counties over time are then examined. "In order to measure these changes, four-dimensional row vectors, based on standardized data, are elaborated and used for demonstrating the structure of movement. Finally, an attempt is made to forecast the movement of the population, based on the structure described in this way." (SUMMARY IN ENG AND RUS)


Transcutaneous continuous carbon dioxide tension monitoring reduced incidence, degree and duration of hypercapnia during combined regional anaesthesia and monitored anaesthesia care in shoulder surgery patients.
We studied the impact of transcutaneous continuous carbon dioxide tension (PtcCO2) monitoring on ventilation and oxygenation during monitored anaesthesia care (MAC) in patients scheduled for shoulder surgery with continuous interscalene block. 50 patients were randomised either to the intervention (I-group) or the control (C-group) group. In both groups MAC was performed using target controlled infusion of propofol and remifentanil. MAC regimen was adapted to PtcCO2 values in the I-group, whereas the C-group was blinded for these values. Primary outcome was the incidence, degree and duration of hypoventilation stages. In the I-group and the C-group the mean ± SD [range] of PtcCO2 and PaCO2 was 5.79 ± 0.84 [4.37] and 5.44 ± 0.59 [2.78] kPa, as well as 6.41 ± 1.17 [6.29] and 6.01 ± 0.96 [7.15] kPa. Periods of PtcCO2/PaCO2 > 6.5 kPa were 21.0 ± 35.7/1.2 ± 4.2 min in the I-group and 45.6 ± 40.0/18.6 ± 26.8 min in the C-group. Severe hypercapnia (PtcCO2 and/or PaCO2 > 7.5 kPa) was dected in 3/0 patients of the I-group and in 10/3 patients of the C-group. PtcCO2 and PaCO2 showed a strong correlation (r = 0.78), but only moderate agreement with a mean bias (LOA) of -0.37 (-1.69; +0.95) kPa showing an overestimation of the PaCO2. Sensitivity and specificity of PtcCO2 to detect changes of PaCO2 was 0.94 and 0.56, respectively. In no patient SpO2 or SaO2 values lower than 90% were measured. Despite a moderate agreement between PaCO2 and PtcCO2 the PtcCO2 monitoring significantly reduced incidence, degree and duration of hypercapnia in shoulder surgery patients with MAC.


Molecular Insights into the Potential Insecticidal Interaction of β-Dihydroagarofuran Derivatives with the H Subunit of V-ATPase.
Celangulin V (CV), one of dihydroagarofuran sesquiterpene polyesters isolated from Chinese bittersweet (Celastrus angulatus Maxim), is famous natural botanical insecticide. Decades of research suggests that is displays excellent insecticidal activity against some insects, such as Mythimna separata Walker. Recently, it has been validated that the H subunit of V-ATPase is one of the target proteins of the insecticidal dihydroagarofuran sesquiterpene polyesters. As a continuation of the development of new pesticides from these natural products, a series of β-dihydroagarofuran derivatives have been designed and synthesized. The compound JW-3, an insecticidal derivative of CV with a p-fluorobenzyl group, exhibits higher insecticidal activity than CV. In this study, the potential inhibitory effect aused by the interaction of JW-3 with the H subunit of V-ATPase c was verified by confirmatory experiments at the molecular level. Both spectroscopic techniques and isothermal titration calorimetry measurements showed the binding of JW-3 to the subunit H of V-ATPase was specific and spontaneous. In addition, the possible mechanism of action of the compound was discussed. Docking results indicated compound JW-3 could bind well in 'the interdomain cleft' of the V-ATPase subunit H by the hydrogen bonding and make conformation of the ligand-protein complex become more stable. All results are the further validations of the hypothesis, that the target protein of insecticidal dihydroagarofuran sesquiterpene polyesters and their β-dihydroagarofuran derivatives is the subunit H of V-ATPase. The results also provide new ideas for developing pesticides acting on V-ATPase of insects.


Grommets in HBOT patients: GA vs LA, unanswered questions.
We read with interest the article on grommet procedures for patients undergoing hyperbaric oxygen therapy (HBOT), and have a number of comments. It appears the authors may have missed a number of cases. In a previous paper from The Townsville Hospital Hyperbaric Unit (TTH HMU), Commons et al presented 14 of 106 patients (13%) who required grommets over the period between June 2009 and May 2010. These patients are included in the Lamprell et al data set. Figure 1 shows an apparent spike in their cases in 2010 (n = 13, part of the period covered in the previous paper) when compared to the remaining four years of their study (mean number of cases 4.5 per year, for an incidence of 3%). This difference in incidence is statistically significant (chi square = 8.336, df = 1, P = 0.004). We suspect the difference may be the result of missed cases rather than a true spike; however, it is not possible to determine this from the paper. Lamprell et al describe identifying cases using the TTH HMU patient database. Did the authors also consider using the operating theatre database and/or ENT clinic records to ensure all cases were captured? We also have concerns regarding Lamprell's primary outcome measure: time from ENT referral to date of re/commencement of HBOT. These data are presented as median values with the associated ranges, rather than an interquartile range (IQR), the traditional measure of dispersion in non-parametric data. We believe the data sets contain a number of outliers that should be excluded, e.g., 98 days. We ask to see the IQRs and box-and-whisker plots for both data sets, and suspect the statistically significant difference in medians might not remain with outliers excluded from the analysis. There is also no discussion about the clinical relevance of this difference of seven days. Based on the most common indications for HBOT listed, most patients would have received at least 30 daily sessions of HBOT. What impact does a delay of seven days have on their treatment? As doctors who have worked at this HMU, we know patients preferentially received their grommets under GA prior to 2012 at the request of the ENT surgeon, who believed that insertion under LA was poorly tolerated. The authors do not describe whether the insertion of grommets under LA was associated with patient discomfort; a limitation of this retrospective paper, but a clinically relevant factor in the decision-making process of which form of anaesthesia to use. The paper by Lamprell et al has shown us that patients may experience a more rapid insertion of grommets and return to HBOT, if inserted under LA versus GA, but this difference may not be important clinically. We believe the authors may have failed to collect all cases and exclude outliers and this, coupled with the lack of documentation about patient satisfaction with insertion under LA, leaves us with more questions than answers.


New insights into structure and function of mitochondria and their role in aging and disease.
This review covers some novel findings on mitochondrial biochemistry and discusses diseases due to mitochondrial DNA mutations as a model of the changes occurring during physiological aging. The random collision model of organization of the mitochondrial respiratory chain has been recently challenged on the basis of findings of supramolecular organization of respiratory chain complexes. The source of superoxide in Complex I is discussed on the basis of laboratory experiments using a series of specific inhibitors and is presumably iron sulfur center N2. Maternally inherited diseases due to mutations of structural genes in mitochondrial DNA are surveyed as a model of alterations mimicking those occurring during normal aging. The molecular defects in senescence are surveyed on the basis of the "Mitochondrial Theory of Aging", establishing mitochondrial DNA somatic mutations, caused by accumulation of oxygen radical damage, to be at the basis of cellular senescence. Mitochondrial production of reactive oxygen species increases with aging and mitochondrial DNA mutations and deletions accumulate and may be responsible for oxidative phosphorylation defects. Evidence is presented favoring the mitochondrial theory, with primary mitochondrial alterations, although the problem is made more complex by changes in the cross-talk between nuclear and mitochondrial DNA.


Metaplastic breast cancer: an old histotype but a current therapeutic problem.
Metaplastic breast cancer (MPBC) is a rare and aggressive tumor type in great need of satisfactory therapies. Although most cases of MPBC are 'triple negative', they are nonetheless related to worse outcomes compared with other triple-negative invasive tumors. MPBC presents high levels of genetic and molecular heterogeneity, suggesting that novel targeted therapies can be exploited. Overexpression of PD-L1 and high levels of tumor-infiltrating lymphocytes have also been observed in these tumors, suggesting a role for immunotherapy. We present an updated literature revision on clinical, histopathological and molecular features of MPBC and their significance to prognosis and therapy options. We discuss emerging efforts to improve and personalize prognostic and therapeutic approaches, exploiting the molecular signature of MPBC with targeted therapies and immunotherapies.


Gender-Related Differences in Semiology of Psychogenic Non-Epileptic Seizures.
The aim of the study is to detect possible gender-related differences in the semiology of psychogenic non-epileptic seizures (PNES). One hundred fifty-five patients (male: female=63:92) aged 13 to 67 years, who were diagnosed with PNES by video-monitoring electroencephalogram (EEG) between 2010 and 2017, were included in this retrospective study. Patients were grouped according to their gender. The primary semiological characteristics of PNES for each case were defined, standardized, and categorized by an epileptologist during video-monitoring EEG. The chi-square test and the Fisher exact test were used statistically. An age histogram showed peaks at ages 20 to 23 and at ages 40 to 43, which were more prominent in the female gender. Whereas major motor activity (p=0.032), lateralizing motor activity (p=0.017), and opisthotonic posture and pelvic thrust motion (p=0.017) were significantly related to the male gender, weeping (p<0.001) was significantly related to the female gender. Our study showed that there are some semiological differences between the genders in PNES. In male patients, lateralized motor findings are more prominent and not accompanied by ictal crying in seizures, which may lead to further confusion with epileptic seizures. It is important to know the semiological characteristics for early and accurate diagnosis.


Stabilization of alpha-helical structures in short peptides via end capping.
The alpha-helix-stabilizing effect of different amino acid residues at the helical termini of short peptides in aqueous solution has been determined. Several dodecapeptides containing alanine, asparagine, aspartate, glutamine, glutamate, and serine at the amino terminus and arginine, lysine, and alanine at the carboxyl terminus were synthesized, and the alpha-helical content of each peptide was measured by using circular dichroism spectroscopy. The trend in alpha-helix-inducing ability of these amino acids was found to be as follows: aspartate > asparagine > serine > glutamate > glutamine > alanine at the amino terminus and arginine > lysine > alanine at the carboxyl terminus. Our results agree with the Presta and Rose hypothesis [Presta, L. G. & Rose, G. D. (1988) Science 240, 1632-1641] on the role of end capping in helix stabilization.


Induction of Hydrolytic Enzymes in Brassica campestris in Response to Pathovars of Xanthomonas campestris.
Inoculation of mature leaves of turnip (Brassica campestris) with the incompatible Xanthomonas campestris pv vitians resulted in the induction of beta-1,3-glucanase and chitinase/lysozyme (CHL) activity. No increase in the basal activity of beta-1,3-glucanase was observed after inoculation of leaves with heat- or rifampicin-killed X. c. vitians, Escherichia coli, or sterile water. Inoculation with the compatible X. campestris pv campestris resulted in a slower induction of glucanase than that seen with X. c. vitians. In contrast, all bacteria caused an induction of CHL activity. One major beta-1,3-glucanase (molecular mass 36.5 kilodaltons, isoelectric point [pl] ~8.5) was purified from both inoculated and untreated leaves by ion-exchange chromatography. The enzyme degraded laminarin by an endo-glycolytic mechanism. Two major CHL isozymes (CHL 1 and CHL 2, molecular mass 30 kilodaltons and pl 9.4 and 10.2, respectively) were purified from X. c. vitians inoculated leaves by affinity chromatography on a chitin column followed by ion-exchange chromatography. Both enzymes degraded chitin by an endo-glycolytic mechanism although the ratio of lysozyme to chitinase specific activities for CHL 1 and CHL2 were different. The induction of CHL 1 was associated with the hypersensitive reaction caused by X. c. vitians whereas all other treatments induced largely CHL 2.


High-resolution structure and conformational dynamics of rigid, cofacially aligned porphyrin-bridge-quinone systems as determined by NMR spectroscopy and ab initio simulated annealing calculations.
The high-resolution solution structure and dynamics of a cofacially aligned porphyrin--phenylene--quinone compound have been determined using (1)H NMR spectroscopy and simulated annealing calculations. Members of this class of pi-stacked assemblies feature a 1,8-naphthyl pillaring motif that enforces sub van der Waals interplanar separations between juxtaposed porphyryl, aromatic bridge, and quinonyl components of the donor--spacer--acceptor compound; this structural motif gives rise to a comprehensive set of structurally significant NOE signatures that can be used as constraints in quantitative structural calculations. Examination of such data using ab initio simulated annealing analytical methods shows that 5-[8'-(4' '-[8' "-(2' " ',5' "-benzoquinonyl)-1' "-naphthyl]-1' '-phenyl)-1'-naphthyl]-10,20-diphenylporphyrin displays an unusual degree of conformational homogeneity in the condensed phase, and represents a rare example where such an analysis determines unequivocally a single unique structure in solution.


Properties and structure-function relationship of HGF-SF.
HGF-SF is a cytokine independently isolated and characterized for its activities as a mitogen for liver cells in culture (hepatocyte growth factor, HGF) and as a factor which enhances the movement and induces the dissociation of epithelial colonies (scatter factor, SF). The factor is composed of two subunits (A and B) with a M(r) of approximately 57 K and approximately 30 K produced by proteolytic cleavage of a polypeptide precursor. Based on the complete conservation of critical cysteine residues, the domain structure of HGF-SF appears to be remarkably similar to the domain structures of plasminogen, (a blood protease involved in fibrinolysis) and the HGF-like protein (the translation product of a gene recently isolated and which shares extensive sequence identity with HGF-SF). The A subunit of HGF-SF consists of an N-terminal domain, homologous to plasminogen preactivation peptide (PAP), followed by four kringle domains. The B subunit has the basic structure of a serine protease domain although HGF-SF has no protease activity due to replacement substitutions in two of the three residues of the catalytic site. Experiments with a truncated form of HGF-SF generated by alternative splicing and with a series of deletion and point mutants generated by site-directed mutagenesis, have established that both the N-terminal and the kringle domains of the A chain and the B chain are all required for biological activity. Loss of mitogenic activity in the HGF-SF mutants is always associated with loss of motogenic activity and vice versa. Thus, the protein engineering experiments confirm the hypothesis that the mitogenic and motogenic responses to HGF-SF diverge at the post-receptor level.


A bis-Pyrazolate Pincer on Reduced Cr Deoxygenates CO2 : Selective Capture of the Derived Oxide by CrII.
Reduction of the bis-(pyrazolyl)pyridine complex [LCr]2 with stoichiometric KC8 in THF produces a species that is reactive with CO2 to produce an aggregate composed of paramagnetic K2 L2 Cr2 (CO3 ) linked by KCl into a product of formula [K2 L2 Cr2 (CO3 )]4 ⋅2KCl. X-ray diffraction reveals a pincer hydrocarbon exterior and an inorganic interior composed of K+ , Cl- and carbonate oxygens. Every Cr is five coordinate and square pyramidal, with the axial N donor weakly bonded to Cr due to the Jahn-Teller effect of a high spin d4 configuration. Reaction with 13 CO2 confirms that carbonate here is derived from CO2 , that oxide is derived from CO2 , and that CO is indeed released, since it is not a competent ligand to CrII . Guiding principles for selectivity in CO2 reduction are deduced from the diverse successful molecular constructs to date.


Restoration of 3D vestibular sensation in rhesus monkeys using a multichannel vestibular prosthesis.
Profound bilateral loss of vestibular hair cell function can cause chronically disabling loss of balance and inability to maintain stable vision during head and body movements. We have previously shown that chinchillas rendered bilaterally vestibular-deficient via intratympanic administration of the ototoxic antibiotic gentamicin regain a more nearly normal 3-dimensional vestibulo-ocular reflex (3D VOR) when head motion information sensed by a head-mounted multichannel vestibular prosthesis (MVP) is encoded via rate-modulated pulsatile stimulation of vestibular nerve branches. Despite significant improvement versus the unaided condition, animals still exhibited some 3D VOR misalignment (i.e., the 3D axis of eye movement responses did not precisely align with the axis of head rotation), presumably due to current spread between a given ampullary nerve's stimulating electrode(s) and afferent fibers in non-targeted branches of the vestibular nerve. Assuming that effects of current spread depend on relative orientation and separation between nerve branches, anatomic differences between chinchilla and human labyrinths may limit the extent to which results in chinchillas accurately predict MVP performance in humans. In this report, we describe the MVP-evoked 3D VOR measured in alert rhesus monkeys, which have labyrinths that are larger than chinchillas and temporal bone anatomy more similar to humans. Electrodes were implanted in five monkeys treated with intratympanic gentamicin to bilaterally ablate vestibular hair cell mechanosensitivity. Eye movements mediated by the 3D VOR were recorded during passive sinusoidal (0.2-5 Hz, peak 50°/s) and acceleration-step (1000°/s(2) to 150°/s) whole-body rotations in darkness about each semicircular canal axis. During constant 100 pulse/s stimulation (i.e., MVP powered ON but set to stimulate each ampullary nerve at a constant mean baseline rate not modulated by head motion), 3D VOR responses to head rotation exhibited profoundly low gain [(mean eye velocity amplitude)/(mean head velocity amplitude) < 0.1] and large misalignment between ideal and actual eye movements. In contrast, motion-modulated sinusoidal MVP stimuli elicited a 3D VOR with gain 0.4-0.7 and axis misalignment of 21-38°, and responses to high-acceleration transient head rotations exhibited gain and asymmetry closer to those of unilaterally gentamicin-treated animals (i.e., with one intact labyrinth) than to bilaterally gentamicin-treated animals without MVP stimulation. In comparison to responses observed under similar conditions in chinchillas, acute responses to MVP stimulation in rhesus macaque monkeys were slightly better aligned to the desired rotation axis. Responses during combined rotation and prosthetic stimulation were greater than when either stimulus was presented alone, suggesting that the central nervous system uses MVP input in the context of multisensory integration. Considering the similarity in temporal bone anatomy and VOR performance between rhesus monkeys and humans, these observations suggest that an MVP will likely restore a useful level of vestibular sensation and gaze stabilization in humans.


Diagnostic dilemmas and clinical correlates of mixed states in bipolar disorder.
Patients with bipolar disorder frequently have varying degrees of mixed states rather than pure episodic manic and depressive episodes. However, DSM-IV-TR and ICD-10 criteria do not fully account for patients' varying presentations; currently, there is no consensus on whether mixed states is a distinct, categorically different type of mania or whether it is a transitional state between depression and mania. Inconsistent diagnostic criteria can be problematic for clinicians when treating patients.


Direct vasodilator effect of hyperventilation-induced hypocarbia in autonomic failure patients.
Hyperventilation produces small decreases in blood pressure in normal subjects and larger decreases in patients with autonomic failure. The authors studied the mechanism for this observation by measuring mean arterial pressure (MAP) and arterial blood gas (ABG) changes in eight patients with severe primary autonomic failure after various maneuvers designed to alter PaCO2, PaO2, and pH. Maneuvers included voluntary hyperventilation, breathing a 5% CO2/95% O2 mixture, breathing 12% O2, breathing through a 1 meter tube to increase dead space, breathing 100% O2, and infusion of 120 mEq NaHCO3 over 30 minutes. All maneuvers led to expected changes in ABGs. Voluntary hyperventilation lowered MAP by 23 +/- 4 (p less than 0.01) mmHg but MAP was raised 11 +/- 3 and 7 +/- 1 mmHg by hyperventilation resulting from increasing breathing dead space or from breathing 5% CO2, respectively. Breathing 100% O2 or 12% O2 had no significant effect on MAP, and NaHCO3 infusion raised MAP by 8 +/- 4 (p less than 0.05) mmHg. With all maneuvers, change in MAP correlated with change in PaCO2 (r = 0.72, p less than 0.001) and change in pH (r = -0.57, p less than 0.01) but not with PaO2. Multiple regression analysis showed that only changes in PaCO2 predicted the change in MAP for all maneuvers. The authors conclude that a decrease in PaCO2 causes the observed decreases in MAP with hyperventilation. This most likely represents a direct peripheral vasodilator effect of hypocarbia rather than a reflex or centrally-mediated mechanism since our patient population is characterized by inadequate or absent autonomic cardiovascular reflex responses.


Ultra-processed food targets bone quality via endochondral ossification.
Ultra-processed foods have known negative implications for health; however, their effect on skeletal development has never been explored. Here, we show that young rats fed ultra-processed food rich in fat and sugar suffer from growth retardation due to lesions in their tibial growth plates. The bone mineral density decreases significantly, and the structural parameters of the bone deteriorate, presenting a sieve-like appearance in the cortices and poor trabecular parameters in long bones and vertebrae. This results in inferior mechanical performance of the entire bone with a high fracture risk. RNA sequence analysis of the growth plates demonstrated an imbalance in extracellular matrix formation and degradation and impairment of proliferation, differentiation and mineralization processes. Our findings highlight, for the first time, the severe impact of consuming ultra-processed foods on the growing skeleton. This pathology extends far beyond that explained by the known metabolic effects, highlighting bone as a new target for studies of modern diets.


Rare testicular tumor discovered by assault: an unusual presentation of a primary testicular neuroendocrine tumor grade 2.
Testicular neuroendocrine tumors (NET) or carcinoid tumors are rare neoplasms which represent 1% of all testicular tumors and can be divided into 3 subgroups: pure primary testicular NET, primary testicular NET associated with a teratoma, and NET metastases to the testis. We report an unusual presentation of a primary testicular neuroendocrine tumor in a 39-year-old male who presented after a physical altercation during a soccer game. Histology showed a diffuse infiltrating tumor with extensive involvement of the tunica albuginea and tunica vaginalis. Immunohistochemical expression of CD56, synaptophysin, and chromogranin A was strongly positive in the tumor cells. Foci of tumor cell necrosis and occasional mitotic figures as well as extensive lymph-vascular invasion were also identified. A review of the literature reveals differing opinions on the prognostic significance of primary tumor size, mitotic index, tumor necrosis, and nuclear atypia. In our patient, the increased mitotic rate (3-5 mitotic figures per 10 hpf and a Ki-67 index of 5%), foci of necrosis, and mild to moderate nuclear atypia warranted a diagnosis of neuroendocrine tumor grade 2, formerly atypical carcinoid. Long term surveillance in these patients is essential as metastasis occurs in up to 15% of cases. At the 6-month followup, the patient remains symptom free.


Acute hepatitis C treatment in advanced renal failure using 8 weeks of pan-genotypic daclatasvir and reduced-dose sofosbuvir.
Sofosbuvir is not recommended in persons with estimated glomerular filtration rate (eGFR) <30 mL/min. We report the results of treatment with an off-label 8-week regimen of daclatasvir and half-dose sofosbuvir in patients with acute infection with hepatitis C virus ( HCV) and eGFR <30 mL/min. Clinic records were searched to identify treatment-naïve, noncirrhotic adults with acute hepatitis C (HCV viremia and a ≥10-fold elevation of serum alanine aminotransferase activity) and eGFR <30 mL/min, who had been treated with a sofosbuvir-based regimen. Treatment response was assessed using serum HCV RNA testing at 4 weeks of treatment, end of the 8-week treatment and 12 weeks after stopping treatment. Of the 31 patients with acute hepatitis C, 27 [median age (range): 36 (18-74) years; 20 (74%) male] were started on treatment with 200 mg sofosbuvir and 60 mg daclatasvir daily for 8 weeks, irrespective of HCV genotype. All the 27 completed the planned 8-week treatment. One patient died 10 weeks after completing the treatment of an unrelated cause. All the 27 patients had undetectable HCV RNA after 4 weeks of and at the end of treatment. At 12 weeks after completion of treatment, only one tested HCV RNA positive and 25 were negative, with sustained virological response rate of 25/27 (92.6%) and 25/26 (96.2%) on intention-to-treat and per-protocol basis, respectively. Eight-week course of daclatasvir and half-dose sofosbuvir is effective for acute hepatitis C in patients with eGFR <30 mL/min and could be a useful alternative to costly, kidney-safe anti-HCV oral drugs in resource-constrained settings.


Pericardial tamponade caused by massive fluid resuscitation in a patient with pericardial effusion and end-stage renal disease -A case report-.
Pericardial tamponade can lead to significant hemodynamic derangement including cardiac arrest. We experienced a case of pericardial tamponade in a patient with end-stage renal disease. Hemodynamic changes occurred by unexpectedly aggravated pericardial effusion during surgery for iatrogenic hemothorax. We quickly administered a large amount of fluids and blood products for massive bleeding and fluid deficit due to hemothorax. Pericardial effusion was worsened by massive fluid resuscitation, and thereby resulted in pericardial tamponade. Hemodynamic parameters improved just after pericardiocentesis, and the patient was transferred to the intensive care unit.


The concept of an organic dissociative syndrome: what is the evidence?
The question of whether organic conditions, such as complex partial seizures, can cause dissociative symptoms is controversial. Although a diagnostic category for organic dissociation is included in the tenth edition of International Classification of Disease, it has never been identified in the Diagnostic and Statistical Manual. Its inclusion in the upcoming DSM-IV is currently under debate. This article surveys representative literature regarding the role of organic factors in the causation of dissociative symptoms and considers the differential diagnosis of organic dissociation from current and historic perspectives. Dissociative symptoms and disorders (including amnesia, fugue, depersonalization, multiple personality, automatisms, and certain furors) can be induced by a variety of medications, drugs of abuse, and medical illnesses or conditions affecting cerebral function. Organic dissociation can be distinguished from intoxication, amnestic disorder, and delirium. Psychiatric nosology and our conceptualization of altered mental states and functions would benefit from use of the concept of an organic dissociative syndrome, which has clinical, neurophysiologic, and medicolegal significance. Such a category should be included in DSM-IV.


Experience with the routine use of an abbreviated crossmatch.
Three years' experience with the routine use of an abbreviated crossmatch procedure is reported. If a patient had no known history of and/or no currently demonstrable unexpected antibodies, ABO and Rh type specific blood was crossmatched at the time of need by using an immediate spin saline abbreviated crossmatch. Once blood was issued, both a 37 degrees C incubation and an antiglobulin crossmatch were done using the same tube employed for the abbreviated crossmatch. This served as a check that clinically significant antibodies were not overlooked. None of the 19,818 patients transfused following an abbreviated crossmatch suffered an acute hemolytic transfusion reaction as a result of this strategy; however, two patients may have manifested asymptomatic hemolysis. This approach to compatibility testing might be appealing to hospitals faced with fiscal limitations and new regulations affecting hospital reimbursement.


In vivo skin penetration of quantum dot nanoparticles in the murine model: the effect of UVR.
Ultraviolet radiation (UVR) has widespread effects on the biology and integrity of the skin barrier. Research on the mechanisms that drive these changes, as well as their effect on skin barrier function, has been ongoing since the 1980s. However, no studies have examined the impact of UVR on nanoparticle skin penetration. Nanoparticles (NP) are commonly used in sunscreens and other cosmetics, and since consumer use of sunscreen is often applied to sun damaged skin, the effect of UVR on NP skin penetration is a concern due to potential toxicity. In this study, we investigate NP skin penetration by employing an in vivo semiconductor quantum dot nanoparticle (QD) model system. This model system improves NP imaging capabilities and provides additional primary interest due to widespread and expanding use of QD in research applications and manufacturing. In our experiments, carboxylated QD were applied to the skin of SKH-1 mice in a glycerol vehicle with and without UVR exposure. The skin collection and penetration patterns were evaluated 8 and 24 h after QD application using tissue histology, confocal microscopy, and transmission electron microscopy (TEM) with EDAX analysis. Low levels of penetration were seen in both the non-UVR exposed mice and the UVR exposed mice. Qualitatively higher levels of penetration were observable in the UVR exposed mice. These results are the first for in vivo QD skin penetration, and provide important insight into the ability of QD to penetrate intact and UVR compromised skin barrier. Our findings raise concern that NP of similar size and surface chemistry, such as metal oxide NP found in sunscreens, may also penetrate UV damaged skin.


Erythrocyte-derived ectosomes have immunosuppressive properties.
Several clinical studies have suggested that blood transfusions are immunosuppressive. Whereas there have been reports describing immunosuppression induced by leukocytes or fragments thereof, the possibility that microparticles, released by erythrocytes during storage, are also involved was not investigated. We present evidence here that such microparticles have all the properties of ectosomes including size, the presence of a lipid membrane, and the specific sorting of proteins. These erythrocyte-derived ectosomes (E-ecto) fixed C1q, which was followed by activation of the classical pathway of complement with binding of C3 fragments. Similarly to ectosomes released by PMN, they express phosphatidylserine on their surface membrane, suggesting that they may react with and down-regulate cells of the immune system. In vitro, they were taken up by macrophages, and they significantly inhibited the activation of these macrophages by zymosan A and LPS, as shown by a significant drop in TNF-alpha and IL-8 release (respectively, 80% and 76% inhibitions). In addition, the effect of E-ecto was not transient but lasted for at least 24 h. In sum, E-ecto may interfere with the innate immune system/inflammatory reaction. Therefore, E-ecto transfused with erythrocytes may account for some of the immunosuppressive properties attributed to blood transfusions.


High efficiency solid state dye sensitized solar cells with graphene-polyethylene oxide composite electrolytes.
Novel and highly effective composite electrolytes were prepared by combining the two dimensional graphene (Gra) and polyethylene oxide (PEO) for the solid electrolyte of dye sensitized solar cells (DSSCs). Gra sheets were uniformly coated by the polymer layer through the ester carboxylate bonding between oxygenated species on Gra sheets and PEO. The Gra-PEO composite electrolyte showed the large scale generation of iodide ions in a redox couple. From rheological analysis, the decrease in viscosity after the addition of LiI and I2 in the Gra-PEO electrolyte might be explained by the dipolar interactions being severely disrupted by the ionic interactions of Li(+), I(-), and I3(-) ions. A composite electrolyte with 0.5 wt% Gra presented a higher ionic conductivity (3.32 mS cm(-1)) than those of PEO and other composite electrolytes at room temperature. A high overall conversion efficiency (∼5.23%) with a very high short circuit current (JSC) of 18.32 mA cm(-2), open circuit voltage (VOC) of 0.592 V and fill factor (FF) of 0.48 was achieved in DSSCs fabricated with the 0.5 wt% Gra-PEO composite electrolyte. This enhanced photovoltaic performance might be attributed to the large scale formation of iodide ions in the redox electrolyte and the relatively high ionic conductivity.


Inequalities in multimorbidity among elderly: a population-based study in a city in Southern Brazil.
Lower socioeconomic level is positively related to multimorbidity and it is possible that the clustering of health conditions carries the same association. The aim of this study was to identify prevalence of multimorbidity and clusters of health conditions among elderly, as well the underlying socioeconomic inequalities. This was a cross-sectional population-based study carried out with 60-year-old individuals. Multimorbidity was defined as the presence of 2+, 3+, 4+ or 5+ health conditions in the same individual. Schooling levels and the National Economic Index were used to investigate inequalities in the prevalence of multimorbidities among elderly. Slope and concentration indexes of inequality were used to evaluate absolute and relative differences. A factorial analysis was performed to identify disease clusters. In every ten older adults, about nine, eight, seven and six presented, respectvely, 2+, 3+, 4+ and 5+ health conditions. Three clusters of health conditions were found, involving musculoskeletal/mental/functional disorders, cardiometabolic, and respiratory factors. Higher inequalities were found the higher amount of health conditions (5+), when considering economic level, and for 3+, 4+ and 5+, when considering educational level. These findings show high multimorbidity prevalence among elderly, highlighting the persistence of health inequalities in Southern Brazil. Strategies by the health services need to focus on elderly at lower socioeconomic levels.


MCMI-III Scores on Substance Abusers With and Without Histories of Suicide Attempts.
Sixty-eight patients with a history of suicide attempt were compared to 340 patients without a history of suicide attempt using the MCMI-III, a frequently used test for measuring personality disorders. Patients with a suicide attempt history scored higher on Schizoid, Avoidant, Depression, Dependent, Passive-Aggressive (Negativistic), Self-Defeating, and Paranoid and significantly lower on Histrionic and Compulsive and scored higher on all clinical syndrome scales except for Drug Dependence and Delusional Disorder. Logistic regression correctly predicted the no-suicide-history group with 97% accuracy, but only accurately predicted 16% of the patients with a suicide attempt history. A discriminant function analysis correctly predicted 90% of the patients with a suicidal attempt history and 63% of the patients with no history of suicide attempt. Results suggest that MCMI-III scores may be able to detect patients with a history of suicide attempt, using multivariate statistics.


Lymphoma presenting as an abdominal mass involving an ectopic spleen.
We recently evaluated a patient with a huge asymptomatic abdominal mass which eventually proved to be an ectopic spleen. Pathology revealed a well-differentiated lymphoma involving the entire spleen and hilar nodes. Before her operation, a series of radiographic procedures was carried out which demonstrated the nature of the mass. The radiographic findings and diagnostic modalities used to establish the diagnosis form the basis of this report.


Initial table treatment of decompression sickness and arterial gas embolism.
This descriptive, nonrandomized, multicenter-based study compares the treatment outcomes of two major categories of recompression treatment tables for recreational sport SCUBA divers suffering from decompression sickness and/or arterial gas embolism. Stratified and logistic regression analyses were used to compare the enhanced tables, which use pressures of 165 fsw (feet of salt water) or 60 fsw with extended recompression time, to the regular tables, which use pressures of 60 fsw or less without extended recompression time. A total of 113 cases were treated with enhanced tables, 54 being successes. A total of 214 cases were treated with regular tables, 135 being successes. The final logistic statistical model after adjusting for confounding factors found a significant improvement in successful treatment outcomes for divers treated with tables that use pressures of 60 fsw or less without extended recompression time (OR = 0.47, 95% CI = 0.28-0.78).


Comparisons of Photosynthetic Responses of Xanthium strumarium and Helianthus annuus to Chronic and Acute Water Stress in Sun and Shade.
We have examined the effects of mild, chronic water stress and acute water stress on two water stress sensitive plants, Xanthium strumarium and Helianthus annuus. Using a combination of the leaf disc O(2) electrode to measure the light responses of photosynthesis and 77 K fluorescence to monitor damage to the primary photochemistry, we have found the following: (a) The CO(2) saturated rate of photosynthesis at high light is the most water stress sensitive parameter measured. (b) The apparent quantum yield (moles O(2) per mole photons) was slightly, if at all, affected by mild water stress (>-1.5 megapascals). (c) Severe water stress (<-1.5 megapascals) reduced the quantum yield of photosynthesis regardless of whether the stress was applied in sun or shade. The light independent reduction of quantum yield was not associated with a reduction in 77 K fluorescence (F(v)/F(m)) indicating that the quantum yield reduction was not the result of damage to primary photochemistry. (d) The diel fluctuation in 77 K fluorescence seen in sun-exposed control leaves was greatly exaggerated in water stressed leaves because of enhanced decline in 77 K fluorescence in the morning. The rate of recovery was similar in both control and water stressed leaves. Shaded leaves showed no change in 77 K fluorescence regardless of whether water stress was imposed or not. (e) The water stress sensitive plants used in these experiments did not recover from acute water stress severe enough to reduce the quantum yield or chronic water stress which lasted long enough that light dependent damage to primary photochemistry occurred.


A decade of molecular studies of fragile X syndrome.
Fragile X syndrome is one of the most common forms of inherited mental retardation. In most cases the disease is caused by the methylation-induced transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene that occurs as a result of the expansion of a CGG repeat in the gene's 5'UTR and leads to the loss of protein product fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein that associates with translating polyribosomes as part of a large messenger ribonucleoprotein (mRNP) and modulates the translation of its RNA ligands. Pathological studies from the brains of patients and from Fmr1 knockout mice show abnormal dendritic spines implicating FMRP in synapse formation and function. Evidence from both in vitro and in vivo neuronal studies indicates that FMRP is located at the synapse and the loss of FMRP alters synaptic plasticity. As synaptic plasticity has been implicated in learning and memory, analysis of synapse abnormalities in patients and Fmr1 knockout mice should prove useful in studying the pathogenesis of fragile X syndrome and understanding learning and cognition in general. If an appreciable portion of the total variance (in IQ) is due to sex linked genes, it is of more importance that a boy should have a clever mother than a clever father. Hogben 1932 (quoted in Lehrke 1974)


Estimating the effect of nonresponse bias in a survey of hospital organizations.
Nonresponse bias in survey research can result in misleading or inaccurate findings and assessment of nonresponse bias is advocated to determine response sample representativeness. Four methods of assessing nonresponse bias (analysis of known characteristics of a population, subsampling of nonresponders, wave analysis, and linear extrapolation) were applied to the results of a postal survey of U.K. hospital organizations. The purpose was to establish whether validated methods for assessing nonresponse bias at the individual level can be successfully applied to an organizational level survey. The aim of the initial survey was to investigate trends in the implementation of radiographer abnormality detection schemes, and a response rate of 63.7% (325/510) was achieved. This study identified conflicting trends in the outcomes of analysis of nonresponse bias between the different methods applied and we were unable to validate the continuum of resistance theory as applied to organizational survey data. Further work is required to ensure established nonresponse bias analysis approaches can be successfully applied to organizational survey data. Until then, it is suggested that a combination of methods should be used to enhance the rigor of survey analysis.


[Preliminary study on DHAP regimen for patients with relapsed and refractory non-Hodgkin's lymphoma].
The treatment of the patients with relapsed and refractory non-Hodgkin's lymphoma(NHL) remains difficult. It was reported that DHAP regimen(cisplatin + Ara-C + dexamthsone) was an effective salvage therapy, but there was no report about it in China. The current study was designed to observe the efficacy and toxicity of DHAP regimen for the patients with relapsed and refractory NHL. Seventeen patients with relapsed and 10 with refractory intermediate or high grade NHL was involved in this study. These patients were treated with cytarabine 1 g/m2 intravenous(i.v.) every 12 hours on day 1 to 2, cisplatin 20 mg/m2 i.v. on day 1 to 4, dexamethone 40 mg i.v. on day 1 to 4. Four patients with CR after DHAP were followed by autologous peripheral blood stem cell transplantation(APBPCT). Overt responses to DHAP were seen in 12 patients (44.4%) including 8 complete responses(CR) (29.6%) and 4 partial responses (PR) (14.8%). The effective release time lasted a median of 4.8 months. Median survival time was 8.3 months. 1-year and 2-year survival rate were 30.8% and 19.3%, respectively. Myelosuppression was the major toxicity; 15 patients(57.7%) had grade III-IV neutropenia and 21 patients (80.8%) had grade III-IV thromcytopenia, but there was no treatment-related death. The authors conclude that DHAP regimen is an effective salvage therapy for the patients with relapsed and refractory NHL, but the remission duration time is short and long-term prognosis remains poor. High dose chemotherapy supported by APBPCT is necessary for improvement in long-term survival.


Are cholinergic pathways involved in the anesthetic response to alpha2 agonists.
1. We investigated whether change in neuronal activity in cholinergic pathways mediates the anesthetic effect of the alpha2 agonist, dexmedetomidine, by determining whether physostigmine, a cholinesterase inhibitor, could antagonize the hypnotic response to dexmedetomidine in the rat and whether dexmedetomidine decreases the release of acetylcholine (ACh) in the thalamus in vivo. 2. Physostigmine did not significantly change the duration of the hypnotic response to dexmedetomidine. There was no significant change in thalamic ACh release after administration of dexmedetomidine. Therefore, alpha2-adrenergic agonists produce their anesthetic effect through mechanisms which do not involve alteration of the activity of the brainstem cholinergic nuclei.


Gut microbiota analysis of juvenile genetically improved farmed tilapia (Oreochromis niloticus) by dietary supplementation of different resveratrol concentrations.
The genetically improved farmed tilapia (GIFT, Oreochromis niloticus) is cultured widely for production of freshwater fish in China, while streptococcosis, likely related to pathogenic infections, occurs frequently in juvenile, mother, and operated GIFT. The gut microbiota plays an important role in nutrient digestibility in animals, and resveratrol (RES) has been used in feed for different freshwater fish species. Therefore, understanding changes in the tilapia gut microbiota across different concentrations of dietary RES supplementation is extremely important. The gut microbiota population in tilapia at 45 d after supplementation with different concentrations (0, 0.025, 0.05, 0.1 g/kg) of dietary RES was assessed by 16S rDNA gene sequencing. A total of 5445 operational taxonomic units were identified from all samples, and 14 phyla and 81 families were identified from all fecal samples. The bacteria of the phylum Firmicutes were significantly enriched in the 0.025 g/kg RES group when compared with the controls. Proteobacteria, Firmicutes and Cyanobacteria were the most dominant three phyla in all samples. With the increasing concentrations, the proportion of beneficial microbial taxa (Acetobacteraceae and Methylobacteriaceae) increased, whereas the proportion of harmful microbial taxa decreased, eg. Streptococcaceae except for 0.1 g/kg RES groups. RES did not affect the richness and diversity in tilapia gut microbiota. These findings provide information on the diversity and differences in GIFT gut microbiota database, and may contribute to developing strategies for management of diseases and long-term sustainability of O. niloticus culture.


A rapid assay for affinity and kinetics of molecular interactions with nucleic acids.
The Differential Radial Capillary Action of Ligand Assay (DRaCALA) allows detection of protein interactions with low-molecular weight ligands based on separation of the protein-ligand complex by differential capillary action. Here, we present an application of DRaCALA to the study of nucleic acid-protein interactions using the Escherichia coli cyclic AMP receptor protein (CRP). CRP bound in DRaCALA specifically to (32)P-labeled oligonucleotides containing the consensus CRP binding site, but not to oligonucleotides with point mutations known to abrogate binding. Affinity and kinetic studies using DRaCALA yielded a dissociation constant and dissociation rate similar to previously reported values. Because DRaCALA is not subject to ligand size restrictions, whole plasmids with a single CRP-binding site were used as probes, yielding similar results. DNA can also function as an easily labeled carrier molecule for a conjugated ligand. Sequestration of biotinylated nucleic acids by streptavidin allowed nucleic acids to take the place of the protein as the immobile binding partner. Therefore, any molecular interactions involving nucleic acids can be tested. We demonstrate this principle utilizing a bacterial riboswitch that binds cyclic-di-guanosine monophosphate. DRaCALA is a flexible and complementary approach to other biochemical methods for rapid and accurate measurements of affinity and kinetics at near-equilibrium conditions.


Reel syndrome-not a twiddler variant.
We report three cases of an unusual form of "reel syndrome" characterized by isolated, reeling dislodgement of a single lead in patients with dual-chamber or biventricular devices. One of these patients presented with worsening heart failure due to loss of left ventricular pacing and the others were detected incidentally during scheduled device checks. We suspect that a ratchet mechanism was probably responsible for this and that this type of dislodgement is not a twiddler variant. We propose a simple solution for prevention.


Efficient path routing strategy for flows with multiple priorities on scale-free networks.
In real networks, traffic flows are different in amount as well as their priorities. However, the latter priority has rarely been examined in routing strategy studies. In this paper, a novel routing algorithm, which is based on the efficient path routing strategy (EP), is proposed to overcome network congestion problem caused by large amount of traffic flows with different priorities. In this scheme, traffic flows with different priorities are transmitted through different routing paths, which are based on EP with different parameters. Simulation results show that the traffic capacity for flows with different priorities can be enhanced by 12% with this method, compared with EP. In addition, the new method contributes to more balanced network traffic load distribution and reduces average transmission jump and delay of packets.


Comparing the measurement properties and relationship to gait speed recovery of the Mini-Balance Evaluation Systems Test and the Berg Balance Scale in ambulatory individuals with subacute stroke.
Although the Mini-Balance Evaluation Systems Test (Mini-BESTest) is known to be a reliable and valid measure of balance in individuals with stroke, the utility of this tool in relation to subacute stroke walking speed and the recovery of gait ability has not been explored. Here, we compared the measurement properties and their relationship to gait speed on the Mini-BESTest and the Berg Balance Scale (BBS) in middle and older ambulatory individuals with subacute stroke, and we investigated which balance assessment tool is more likely to capture the status of the recovery of gait speed. We retrospectively analyzed the cases of 88 individuals 50 years or older with stroke who had been evaluated using the Mini-BESTest by using the BBS and by assessing their comfortable walking speed (CWS). The proportion of subjects who showed improvement was calculated for 34 stroke survivors from data obtained at admission to and discharge from the hospital. Compared with the BBS, the Mini-BESTest showed a better distribution of total scores without a ceiling effect. The two scales showed correlations with gait speed (Mini-BESTest: r=0.702; BBS: r=0.592) and discrimination between fast and slow walkers. The responsiveness of the Mini-BESTest was excellent, with an area under the curve of 0.894, thus discriminating between gait speed improvement versus non-improvement. These results indicate that the Mini-BESTest is more useful than the BBS in terms of its measurement properties and ability to measure gait recovery in middle and older ambulatory individuals with subacute stroke.


Total hip arthroplasty in ankylosing spondylitis: an analysis of 181 hips.
The results of cemented total hip arthroplasty (THA) in patients with ankylosing spondylitis were studied to determine the utility of THA for these patients. A total of 103 patients with ankylosing spondylitis underwent 181 THAs; 72 patients (69.9%) had bilateral surgery. The mean follow-up was 10.3 years. The mean age of patients at surgery was 47 years. Before surgery, 42 hips (23.2%) were ankylosed. Revision surgery was carried out in 25 hips (13.8%). Heterotopic ossification was present in 21 hips (11.6%); however, no patients had functional impairment or reankylosis. At final follow-up examination, 173 hips (96%) had an excellent (low) pain score, and 53 hips had a normal or near-normal function score (29.2%). The probability of survival of the implant was 71% at 27 years. THA provides long-term improvement in hip function for patients with ankylosing spondylitis.


Protection of ischemic hearts by high glucose is mediated, in part, by GLUT-4.
Metabolic interventions that promote glucose use during ischemia have been shown to protect ischemic myocardium and improve functional recovery on reperfusion. We evaluated whether the cardioprotection afforded by high glucose during low-flow ischemia is associated with changes in the sarcolemmal content of glucose transporters, specifically GLUT-4. Isolated rat hearts were paced at 300 beats/min and perfused under normal glucose (5 mM) or high glucose (10 mM) conditions in buffer containing 0.4 mM albumin, 0.4 mM palmitate, and 70 mU/l insulin and subjected to 50 min of low-flow ischemia and 60 min of reperfusion. To determine the importance of insulin-sensitive glucose transporters in mediating cardioprotection, a separate group of hearts were perfused in the presence of cytochalasin B (10 microM), a preferential inhibitor of insulin-sensitive glucose transporters. Ischemic contracture during low-flow ischemia and creatine kinase release on reperfusion was decreased, and the percent recovery of left ventricular function with reperfusion was enhanced in hearts perfused with high glucose (P < 0.03). Hearts perfused with high glucose exhibited increased GLUT-4 protein expression in the sarcolemmal membrane compared with control hearts under baseline conditions, and these changes were additive with low-flow ischemia. In addition, high glucose did not affect the baseline distribution of sarcolemmal GLUT-1 and blunted any changes with low-flow ischemia. These salutary effects were abolished when glucose transporters are blocked with cytochalasin B. These data demonstrate that protection of ischemic myocardium by high glucose is associated with increased sarcolemmal content of the insulin-sensitive GLUT-4 and suggest a target for the protection of jeopardized myocardium.


Giant basal cell carcinoma associated with vitiligo.
We report a woman with two giant Basal cell carcinomas (BCCs) on the back, the largest with 12 cm in diameter, inside a vitiligo plaque. They were metatypical subtype BCC associated with a nodular subtype area. Thinking of BCC in vitiligo lesion is extremely important. Giant BCC and vitiligo are rare association.


[N-acetylcysteine-induced reduction in susceptibility of transformed and embryonic cells to lytic activity of natural killer cells].
We studied N-acetylcysteine (NAC) ability to change the phenotype properties of several transformed and embryonic cells. We examined human epidermoid carcinoma A431 cells, murine hepatoma MH22a cells, and murine embryonic fibroblasts (MEFs) in terms of the sensitivity to natural killer (NK) recognition and abolishment. We have demonstrated that treatment with NAC (10 mM) results in a loss of susceptibility to NK cell activity by transformed A431 and MH22a cells similar to 3T3-SV40 transformed cells whose partial reversion caused by NAC was revealed by us before. We have shown that MEFs are also sensitive to NK activity and abolished by NK cells as well as transformed cells. MEFs pretreated with 10 mM NAC as well as transformed cells lose their susceptibility to NK cell activity. The loss of cell sensitivity to NK cytolytic activity was accompanied by a reorganization of the actin cytoskeleton and the appearance of well-pronounced stress-fibers.


The impact of consumer affordability on access to assisted reproductive technologies and embryo transfer practices: an international analysis.
To systematically quantify the impact of consumer cost on assisted reproduction technology (ART) utilization and numbers of embryos transferred. Ordinary least squared (OLS) regression models were constructed to measure the independent impact of ART affordability-measured as consumer cost relative to average disposable income-on ART utilization and embryo transfer practices. Not applicable. Women undergoing ART treatment. None. OLS regression coefficient for ART affordability, which estimates the independent effect of consumer cost relative to income on utilization and number of embryos transferred. ART affordability was independently and positively associated with ART utilization with a mean OLS coefficient of 0.032. This indicates that, on average, a decrease in the cost of a cycle of 1 percentage point of disposable income predicts a 3.2% increase in utilization. ART affordability was independently and negatively associated with the number of embryos transferred, indicating that a decrease in the cost of a cycle of 10 percentage points of disposable income predicts a 5.1% increase in single-embryo transfer cycles. The relative cost that consumers pay for ART treatment predicts the level of access and number of embryos transferred. Policies that affect ART funding should be informed by these findings to ensure equitable access to treatment and clinically responsible embryo transfer practices.


Effects of benidipine on glomerular hemodynamics and proteinuria in patients with nondiabetic nephropathy.
Experimental studies suggest that some long-acting calcium antagonists decrease glomerular hypertension and suppress the progression of nephropathy, but clinical evidence is lacking. To investigate clinically whether a long-acting calcium antagonist, benidipine, lowers glomerular capillary hydraulic pressure via a decrease in efferent arteriolar resistance and decreases proteinuria, we examined hypertensive patients with nondiabetic nephropathy. The subjects were 7 patients with chronic glomerulonephritis or glomerulosclerosis. Before and during the administration of benidipine (4 mg/day), systemic pressure, glomerular hemodynamics, the sodium sensitivity index (reciprocal of the pressure-natriuresis curve), and urinary excretion of proteins (total protein, albumin, and immunoglobulin G) were investigated. The glomerular hemodynamics in terms of glomerular capillary hydraulic pressure and resistance of afferent and efferent arterioles were calculated from the renal clearance, plasma total protein concentration, and pressure-natriuresis relationship. Benidipine lowered the mean arterial pressure from 105 +/-5 to 99 +/- 4 mm Hg (p = 0.002; mean +/- SD) and glomerular pressure from 48 +/- 8 to 39 +/- 5 mmHg (p = 0.006) by decreasing the resistance of efferent arterioles. Benidipine made the pressure-natriuresis curve steeper and decreased the median sodium sensitivity index from 0.099 (0.084 and 0.117; 25th and 75th percentiles) to 0.048 (0.017 and 0.058; p = 0.018). Urinary excretion of proteins did not change. Our clinical study showed that benidipine lowered the glomerular pressure by decreasing the resistance of efferent arterioles and decreased the sodium sensitivity of blood pressure, but did not affect proteinuria in patients with nondiabetic nephropathy.


[A multicenter retrospective study on the efficacy of different anti-reflux reconstruction methods after proximal gastrectomy for gastric cancer].
Objective: To examine the clinical efficacy of 3 anti-reflux methods of digestive tract reconstruction after proximal gastrectomy for gastric cancer. Methods: The clinical data and follow-up data of gastric cancer patients who underwent anti-reflux reconstruction after proximal gastrectomy in 11 medical centers of China from September 2016 to August 2021 were retrospectively collected, including 273 males and 65 females, aging of (63±10) years (range: 28 to 91 years). Among them, 159 cases were performed with gastric tube anastomosis (GTA), 107 cases with double tract reconstruction (DTR), and 72 cases with double-flap technique (DFT), respectively. The duration of operation, length of postoperative hospital stay and early postoperative complications (referring to Clavien-Dindo classification) of different anti-reflux reconstruction methods were assessed. Body mass index, hemoglobin and albumin were used to reflect postoperative nutritional status. Reflux esophagitis was graded according to Los Angeles criteria based on the routinely gastroscopy within 12 months after surgery. The postoperative quality of life (QoL) was evaluated by Visick score system. The ANOVA analysis, Kruskal-Wallis rank sum test, χ2 test and Fisher's exact test were used for comparison between multiple groups, and further comparison among groups were performed with LSD, Tamhane's test or Bonferroni corrected χ2 test. The mixed effect model was used to compare the trends of Body mass index, hemoglobin and albumin over time among different groups. Results: The operation time of DFT was significantly longer than that of GTA and DTR ((352±63) minutes vs. (221±66) minutes, (352±63) minutes vs. (234±61) minutes, both P<0.01). The incidence of early complications with Clavien-Dindo grade Ⅱ to Ⅴ in GTA, DFT and DTR groups was 17.0% (27/159), 9.7% (7/72) and 10.3% (11/107), respectively, without significant difference among these three groups (χ2=3.51, P=0.173). Body mass index decreased more significantly in GTA than DFT group at 6 and 12 months after surgery (mean difference=1.721 kg/m2, P<0.01; mean difference=2.429 kg/m2, P<0.01). body mass index decreased significantly in DTR compared with DFT at 12 months after surgery (mean difference=1.319 kg/m2, P=0.027). There was no significant difference in hemoglobin or albumin fluctuation between different reconstruction methods perioperative. The incidence of reflux esophagitis one year after surgery in DTR group was 12.9% (4/31), which was lower than that in DFT (45.9% (17/37), χ2=8.63, P=0.003). Follow-up of postoperative quality of life showed the incidence of Visick grade 2 to 4 in DFT group was lower than that in GTA group (10.4% (7/67) vs. 34.6% (27/78), χ2=11.70, P=0.018), while there was no significant difference between DFT and DTR group (10.4% (7/67) vs. 22.2% (8/36, P>0.05). Conclusions: Compared with GTA and DTR, DFT is more time-consuming, but there is no significant difference in early complications among three methods. DFT reconstruction is more conducive to maintain postoperative nutritional status and improve QoL, especially compared with GTA. The risk of reflux esophagitis after DTR reconstruction is lower than that of DFT.


The Self-Absorptive Trait of Dissociative Experience and Problematic Internet Use: A National Birth Cohort Study.
Functional and excessive use of internet are hard to distinguish from each other, and internet use can affect adolescents' development of self-identity. The aim of our study was to investigate the associated relationships between the risk and protective factors for internet use, including parental monitoring, the absorptive dissociative trait, having been bullied, exercise, self-perceived depressive mood, and happiness of 12-year-old adolescents. The Taiwan Birth Cohort Study dataset, which used a national household probability sampling method and included 17,694 12-year-old adolescents, was used for this study. Our results showed that 5.3% of adolescents reported spending more than five hours online during school days. Additionally, adolescents that spent more than five hours online during school days tended to have a higher absorptive trait, perceived less care from mothers, were more likely to have been bullied, and expressed a higher level of depressed mood, which led to a lower level of perceived happiness. Adolescents that spent more than five hours online during school days, compared to those that spent less than an hour online, were more likely to have been bullied, which effected their level of happiness, showing that they may be a group of higher concern. Therefore, spending more than five hours per day online maybe a clinical prevention indicator for problematic internet use.


Alanine scanning mutagenesis of the switch I region in the ATPase site of Dictyostelium discoideum myosin II.
In order to determine the functional roles of the conserved sequence (NXNSSRFG) of the "switch I" loop (residues 233-240 in Dictyostelium myosin II), alanine scanning mutagenesis was performed on Dictyostelium myosin II. N233A and S237A mutant myosins did not bind a fluorescent analog of ADP, mant-deoxyADP, at the low concentration range (micromolar and had low level of ATPase activities. They were nonmotile when examined by the in vitro motility assay. Dictyostelium cells expressing these myosins showed worse phenotypes than that of myosin-null cells. In contrast to these mutant myosins, R238A myosin tightly bound mant-deoxyADP. However, the mutant had a defect in the ATP hydrolysis step and exhibited the lowest ATPase activities among the mutants examined here. The R238A myosin was nonmotile. R238C or R238H mutations, which mimic the Usher syndrome mutations, generated myosins with similar functional defects to those of the R238A mutation. Cells expressing the R238A myosin exhibited the phenotype similar to that of the myosin-null cells. N235A, S236A, F239A, and G240A myosins retained moderate levels of ATPase activities and could drive sliding of actin filaments at various speeds. Phenotypes of cells expressing them were very similar to that of the wild-type cells. Taken together, these results suggest that side chains of N233 and S237 may play essential roles in holding a nucleotide in the ATPase pocket and that R238 may play crucial roles in the ATP hydrolysis step, while those of the other residues in the switch I loop are not essential for the process.


[Beta-blockers in the treatment of chronic heart failure].
The authors discuss in the submitted review the problem of therapeutic use of beta-blockers in the treatment of cardiac failure. n the introduction they emphasize the medical and societal consequences of this disease with emphasis on necessary prevention. In the subsequent part they present a review of the most important clinical studies (completed and under way) focused on the mentioned problem. In the discussion they analyze the role of the sympathetic nervous system in the pathogenesis of cardiac failure and the theoretical basis of the use of beta-blockers in its treatment. In the conclusion they present a summary of practical principles for the use of beta-blockers in this indication.


[Respiratory allergies].
A respiratory allergy corresponds to an inflammation of the airways linked to an immunological reaction of an allergic origin. Asthma is a common manifestation of such an allergy. A global approach involving the patient, and taking into account the allergen and the environment determines the effectiveness of the care.


Therapeutic drug monitoring of voriconazole in Japanese patients: analysis based on clinical practice data.
The aim of this study was to investigate whether routine therapeutic drug monitoring (TDM) of voriconazole (VRCZ) reduced discontinuation due to hepatotoxicity. Hepatotoxicity was observed in 15 (51.7%) out of 29 patients. The percentages of patients who developed hepatotoxicity within 4 days and 1 week were 26.7 and 46.7%, respectively. The drug trough concentrations in patients with and without hepatotoxicity were 5.55 ± 2.73 and 2.36 ± 1.67 μg/ml (P < 0.01, the two-sided Student's t-test), respectively. Trough concentrations reached the target of 1-5 μg/ml in patients with gradual dose reductions based on TDM, and, consequently, liver enzyme levels returned to the original levels before the VRCZ treatment. All patients eventually continued effective VRCZ therapy despite its hepatotoxicity. Thus, dose adjustments by TDM to achieve the target trough concentrations is useful in order to avoid hepatotoxicity and enable continued effective VRCZ therapy for Japanese patients with invasive fungal infections.


Dosing Heat: Expected Core Temperature Change with Warmed or Cooled Intravenous Fluids.
Emergent modification of a patient's body temperature is crucial in certain disease or injury states. Advanced targeted temperature management techniques such as central venous catheter devices are not universally available, however, virtually all medical centers have access to intravenous fluids. This study approximates the change in body temperature for a given volume of room temperature, chilled, or heated isotonic crystalloid bolus. Using thermodynamic principles, a mathematical model was created to approximate change in body core temperature in response to a given volume and temperature of intravenous fluid. The model assumes rapid fluid infusion and the previously published specific heat capacity of the human body of 3.47 J/kg · °C. Values were calculated under conditions of varying body temperatures from profound hypothermia to hyperthermia (18°C-45°C). Various crystalloid temperatures representing iced, room temperature, and warmed (4°C, 20°C, 42°C) were used in the calculations. Each 30 mL/kg dose of 20°C crystalloid is expected to cool a hyperthermic (38°C-45°C) patient by 0.6°C-0.9°C. Each 30 mL/kg dose of 4°C crystalloid is expected to cool a hyperthermic (38°C-45°C) patient by 1.2°C-1.4°C. Each dose of 42°C crystalloid is expected to warm a hypothermic patient by 0.2°C-0.8°C. Using the results in this study, clinicians may roughly estimate the effect of temperature management with varying doses of intravenous fluids and thus assess the benefits of this technique. Risk should be evaluated based on inevitable coadministered volume and electrolytes. Individuals with volume-sensitive conditions such as heart, liver, or kidney failure deserve particular attention. Based on a mathematical model, typical expected core temperature change is about 0.2°C-1.4°C per 30 mL/kg crystalloid bolus, depending on patient and fluid temperature.


Analytical characterization of movements of the spinal column and risk assessment due to repeated movements of the upper limbs of building painters.
Manual activities of construction workers may induce musculoskeletal disorders. This study on a group of painters aimed to analytically characterize movements of the spinal column by both lumbar motion monitor and television cameras and to determine, using the Occupational Repetitive Actions (OCRA) Index method, the risk exerted by repeated movements of the upper limbs. The main results are: painting with a roller generally exposes workers to a lesser risk for upper limbs than painting with a brush; a roller-stick fixed at the wrong length can lead to stretching of the back at lumbar and cervical levels; to remain within the range of 'acceptable risk' (OCRA Index evaluation), a worker should not paint a vertical wall for over 3 h if using a roller and 2.5 h if painting with a brush; and, on average, a painter who paints for 5 h in a day lifts the bucket about 120,140 times.


Biochemical basis of angioedema associated with recombinant tissue plasminogen activator treatment: an in vitro experimental approach.
Angioedema has been reported during recombinant tissue plasminogen activator (rtPA) treatment of acute ischemic stroke, often with concomitant use of angiotensin I-converting enzyme inhibitor treatment. Angioedema has been partly attributed to the nonapeptide bradykinin (BK), although its precise role has been poorly documented until now. The purposes of this report are 2-fold. First, we sought to define and characterize the in vitro kinin-forming capacity of rtPA when incubated with human plasma at a concentration within the therapeutic concentration range of rtPA attained in blood in vivo during fibrinolysis. Second, we sought to define the mechanism by which rtPA liberates BK from purified human single-chain high-molecular-weight kininogen, a key constituent of the contact system of plasma and the precursor of BK. When incubated with human plasma, in the presence of an angiotensin I-converting enzyme inhibitor, rtPA generates BK, which is further metabolized to des-Arg9-BK. The quantity of kinins generated by rtPA is similar to that observed during the activation of the contact system of plasma with a negatively charged surface, suggesting that it is physiologically relevant. The total amount of des-Arg9-BK liberated during the incubation period depends on the aminopeptidase P activity, its main degrading peptidase. Additionally, incubations using purified proteins of the fibrinolytic and the contact system pathways show that the rtPA kinin-forming capacity is mediated by plasmin. We conclude that rtPA used in vitro at a therapeutic concentration has the capacity to generate significant quantities of kinins from human plasma. This kinin-forming activity depends on the activation of the fibrinolytic pathway. These data suggest that angioedema associated with rtPA treatment of ischemic stroke results directly from plasmin-mediated release of BK.


New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD.
Calcium mishandling in Duchenne muscular dystrophy (DMD) suggested that dystrophin, a membrane-associated cytoskeleton protein, may regulate calcium-signalling cascades such as calcium entries. Calcium overload in human DMD myotubes is dependent on their contractile activity suggesting the involvement of channels being activated during contraction and/or calcium release. Forced expression of mini-dystrophin in dystrophin-deficient myotubes, reactivates appropriate sarcolemmal expression of dystrophin-associated proteins and restores normal calcium handling in the cytosol. Furthermore, the recombinant mini-dystrophin reduced the store-operated calcium influx across the sarcolemma, and the mitochondrial calcium uptake during this influx. A slow component of calcium release dependent on IP3R, as well as the production of IP3, were also reduced to normal levels by expression of mini-dystrophin. Our studies provide a new model for the convergent regulation of transmembrane calcium influx and IP3-dependent calcium release by the dystrophin-based cytoskeleton (DBC). We also suggest molecular association of such channels with DBC which may provide the scaffold for assembling a multiprotein-signalling complex that modulates the channel activity. This suggests that the loss of this molecular association could participate in the alteration of calcium homeostasis observed in DMD muscle cells.


Why Practices Should Screen Against Every State Exclusion List.
Many physician practices believe it is enough to screen their employees against the Office of Inspector General's (OIG's) List of Excluded Individuals and Entities upon employment, and perhaps annually thereafter. Although this may have been an acceptable practice in years past, the OIG's Updated Advisory Bulletin on the Effect of Exclusions, the Centers for Medicare & Medicaid Services mandates to state Medicaid programs on screening, and the rules and regulations issued by the states themselves in response to these initiatives have broadly and significantly increased providers' exclusion screening obligations. This article discusses the nature of the expanded screening requirements for providers, and why the risks of noncompliance are too great to ignore.


The Impact of Initial Postoperative Destination on Unplanned Critical Care Admissions After Lung Resection.
Despite an increasing proportion of patients undergoing lung resection being managed postoperatively in a ward-based environment, studies analyzing the impact of initial postoperative destination (IPD) on perioperative outcomes and unplanned critical care admission (UCCA) are lacking. A single-center retrospective review. A cardiothoracic surgery center in the Northwest of England. A total of 3,841 patients between 2012 and 2018. All patients underwent lung resection. Patients were classified as either IPD ward or IPD critical care. Outcomes assessed included in-hospital and 90-day mortality and UCCA. Differences in mortality rates between groups were assessed using the chi-square test. Multivariate logistic regression analyses were performed to identify variables independently associated with 90-day mortality and UCCA. In total, 23.8% (n = 913) of patients went to critical care as their IPD. Overall in-hospital mortality was 1.6% (n = 62), and 90-day mortality was 2.9% (n = 112). The rate of UCCA was 10.5% (n = 404) and was significantly higher for IPD ward patients compared to IPD critical care patients (11.9% v 6.2%, p < 0.001). The 90-day mortality rates after UCCA were 5.2% (IPD ward) and 19.3% (IPD critical care) (p < 0.001). Advanced age, worse pulmonary function, IPD ward, and timing of surgery were all independently associated with UCCA. Most patients undergoing lung resection can be managed safely postoperatively in a ward-based environment. Short-term mortality is higher after UCCA, with patients who experience readmission to critical care at the highest risk of death. Patients should receive additional monitoring immediately following discharge from critical care.


Molecules specific to pigment epithelial cells: expression during in situ development and in vitro lens transdifferentiation of chick embryo pigment epithelium.
The retinal pigment epithelium (PE) is a monolayer of cells and plays a vital role in the regulation of the neural retina. We prepared monoclonal antibodies directed against retinal PE cells to analyze the specificity and differentiation of these cells. Spleen cells from BALB/c mice immunized with chick embryo retinal PE cells were fused with myeloma cells. Seven independent monoclonal antibodies were obtained which specifically recognized PE cells but did not react with any other tissues examined. None of the monoclonal antibodies reacted with the choroid and skin of pigmented chicks, suggesting that these antigens were unrelated to melanogenesis. Two of the 7 antibodies reacted with the PE cells in the retina, ciliary body and iris; the remaining 5 antibodies were specific to the PE cells in the retina. In the process of in vitro lens transdifferentiation from PE cells, the distribution of an antigen detected by one monoclonal antibody changed from the cytoplasmic granules to the actin fibers and then its immunoreactivity declined. The other monoclonal antibodies did not react with the differentiated PE cells and transdifferentiated lens cells, suggesting that the antibodies might be specific to the PE cells in the differentiated state, both in vivo and in vitro. During the in situ developmental process, each monoclonal antibody began to be immunoreactive to future PE cells in the optic eye cup at various stages from 72 to 120 h. The molecules common to all types of PE cells were expressed earlier than those specific to PE cells of the retina. Future ciliary and iridial PE cells appeared to transiently express the molecules specific to the retinal PE cells before the tip of eye cup contacted the lens vesicle. These data suggest that the monoclonal antibodies established in this study are powerful probes for exploring the functions and differentiation of PE cells.


Evolution of Prodromal Multiple System Atrophy from REM Sleep Behavior Disorder: A Descriptive Study.
Prodromal multiple system atrophy (MSA) has been characterized mainly by retrospective chart reviews. Direct observation and tracking of prodromal markers in MSA have been very limitedObjective:To report the baseline characteristics and evolution of prodromal markers of MSA as they were prospectively measured in patients with idiopathic/isolated REM sleep behavior disorder (iRBD)Methods:Patients with iRBD were evaluated as part of a comprehensive protocol repeated annually. The protocol included assessment of motor, sleep, psychiatric, and autonomic symptoms supplemented by motor examination, quantitative motor testing, neuropsychological examination, orthostatic blood pressure measurement, and tests of olfaction and color vision. Patients who eventually developed MSA were described and compared with those who phenoconverted to Lewy body disease (Parkinson's disease and dementia with Lewy bodies). Of 67 phenocoverters, 4 developed MSA-P and 63 developed Lewy body disease. An additional 2 MSA-C patients were seen at baseline, already with cerebellar signs. Compared to those with Lewy body disease, those with MSA-P were younger, had less severe loss of tonic REM sleep atonia, more insomnia symptoms, and better olfaction. Clinically-evident autonomic dysfunction was not invariable in prodromal stages, often developing proximate to or after motor phenoconversion. Of the autonomic symptoms, genitourinary dysfunction was the first to develop in all cases. Olfaction and cognition remained normal throughout the prodromal and clinical disease course, in clear contrast to patients with Lewy body disease. Prodromal MSA progresses rapidly, often without substantial autonomic dysfunction, and with preserved olfaction and cognition throughout its prodromal course.


Analytical curve or standard addition method: how to elect and design--a strategy applied to copper determination in sugarcane spirits using AAS.
In most instrumental analysis, the analyte concentration is usually obtained the by Analytical Curve Method (ACM) or Standard Addition Method (SAM). Thus, it is important for the analyst to select the most appropriate method, to seek the best conditions of analysis, and to provide parameters of analytical performance. A strategy to do so is proposed in this paper in conjunction with MATLAB software to implement it. The proposed strategy was applied to copper determination by atomic absorption spectrometry in Brazilian sugarcane spirits termed 'Cachaça' and SAM was chosen as the most appropriate method. To select the best experimental design for SAM, the influence of some factors, such as the number of standard additions and concentration levels, the location of the levels and the average concentration of the standard additions were demonstrated. The design with six standard additions, four concentration levels located near the inferior and superior levels and the average concentration of the standard additions closer to zero yielded SAM with an adequate compromise between precision, cost and time of analysis. The uniform distribution of concentration levels, usually used in routine analysis, is not a good design regarding precision. On the other hand, it is adequate when the linear range is unknown. Generally, the proposed strategy can be applied to different instrumental techniques and samples, which aim to improve their analytical performance.


Individual density-elasticity relationships improve accuracy of subject-specific finite element models of human femurs.
In a previous study on subject-specific finite-element-models, we found that appropriate density-elasticity relationships to compute the mechanical behavior of femurs seem to be subject-specific. The purpose of this study was to test the hypothesis that the predictive error of a cohort of subject-specific finite element-models is lower with subject-specific density-elasticity relationships than with a cohort-specific density-elasticity relationship. Finite-element-analysis and inverse optimization based on response surface methodology were employed to test the hypothesis. Subject-specific FE-models of 17 human femurs and corresponding experimental data from biomechanical tests were taken from a previous study. A power function for the relation between radiological bone density and elastic modulus was set up with the optimization variables a and b: E(MPa)=aρqCT(b)(gK2HPO4/cm(3)). The goal of the optimization was to minimize the root-mean-square error in percent (RMSE%) between computational and experimental results. A Wilcoxon test (p=0.05) was performed on all absolute relative errors between the two groups (subject-specific functions vs. cohort-specific function). The subject-specific functions resulted in a 6% lower overall prediction error and a 6% lower RMSE% than the cohort-specific function (p<0.001). The determined subject-specific relations were mostly linear, with variable a ranging from 9307 to 15673 and variable b ranging from 0.68 to 1.40. For the cohort-specific relation, the following power law was obtained: E(MPa)=12486ρqCT(1.16)(gK2HPO4/cm(3)). We conclude that individual density-elasticity relationships improve the accuracy of subject-specific finite element models. Future subject-specific finite-element-analyses of bones should include the individuality of the elastic properties by a stochastic density-elasticity relationship with mean and standard deviation of a and b.