Characterization of ibuproxam binary and ternary dispersions with hydrophilic carriers.
This work investigates the possibility of increasing the dissolution properties of ibuproxam (a poorly water-soluble anti-inflammatory drug) using hydrophilic carriers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or urea, alone or in combination. Phase-solubility studies showed that the carrier solubilizing power was in the order PEG>PVP>urea and evidenced a synergistic effect in drug solubility improvement when using carrier combinations. Binary and ternary systems, at 20/80 or 20/40/40 (w/w) drug/carrier(s) ratios, prepared by coevaporation of their ethanolic solutions or by cogrinding physical mixtures in a high-energy vibrational micromill, were characterized by differential scanning calorimetry (DSC), hot stage microscopy (HSM), and scanning electron microscopy (SEM) analyses. The results of dissolution tests (USP paddle method), in terms of Dissolution Efficiency, indicated that ternary systems were up to 35% more effective than the corresponding binary preparations and coevaporated products were up to 45% more efficacious than the corresponding coground ones. The IBUX-PEG-PVP coevaporated was the best product, allowing a more than three-times increase in Dissolution Efficiency with respect to drug alone; moreover, t50% (> 60 min for pure ibuproxam) was < 10 min, and 90% dissolution was achieved after 30 min, whereas only 40% was obtained after 60 min for pure drug. The best performance of this system was attributed to a joined effect of the strong amorphizing power of PVP (as demonstrated by solid state analyses) with the high solubilizing efficacy of PEG (as emerged from phase-solubility studies). The drug dissolution rate from solid dispersions remained practically unchanged after one-year storage at room temperature in closed containers.


Whole Brain Radiotherapy Combined with Stereotactic Radiosurgery versus Stereotactic Radiosurgery Alone for Brain Metastases.
The aim of this study was to evaluate the effect of whole brain radiotherapy (WBRT) combined with streotactic radiosurgery versus stereotactic radiosurgery (SRS) alone for patients with brain metastases. This was a retrospective study that evaluated the results of 46 patients treated for brain metastases at Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Radiation Oncology Department, between January 2012 and January 2015. Twenty-four patients were treated with WBRT+SRS while 22 patients were treated with only SRS. Time to local recurrence was 9.7 months in the WBRT+SRS arm and 8.3 months in SRS arm, the difference not being statistically significant (p= 0.7). Local recurrence rate was higher in the SRS alone arm but again without significance (p=0,06). In selected patient group with limited number (one to four) of brain metastases SRS alone can be considered as a treatment option and WBRT may be omitted in the initial treatment.


The deubiquitinating enzyme PSMD14 facilitates tumor growth and chemoresistance through stabilizing the ALK2 receptor in the initiation of BMP6 signaling pathway.
Although bone morphogenetic protein 6 (BMP6) signaling pathway has been implicated in many types of cancer, its role of tumorigenesis seems to be controversial and its ubiquitin-modifying mechanisms have not been fully addressed. Our study was designed to investigate how BMP6 signaling pathway is regulated by ubiquitin-modifying systems and to address molecular and clinical significance in colorectal cancers. Human deubiquitnase (DUB) siRNA library was used to screen the specific DUB, named PSMD14, involved in BMP6 signaling pathway. Immunoblot, immunoprecipitation and ubiquitination assays were used to analyze targets of the PSMD14. A role of PSMD14-mediated BMP6 signaling pathway for malignant cancer progression was investigated using in vitro and in vivo model of colorectal cancers as well as clinical samples of colorectal cancer patients. The deubiquitinase PSMD14 acts as a positive regulator for the initiation of the BMP6 signaling pathway through deubiquitinating K48-linked ALK2 type I receptor ubiquitination mediated by Smurf1 E3 ligase, resulting in increased stability of the ALK2. This role of PSMD14 is independent of its intrinsic role in the 26S proteasome system. Furthermore, either PSMD14 or ALK2 depletion significantly decreases tumorigenesis of HCT116 colorectal cancer cells in a xenograft model as well as cancer stemness/chemoresistance, and expression of the PSMD14 and ALK2 gene are correlated with malignant progression and the survival of colorectal cancer patients. These findings suggest that the PSMD14-ALK2 axis plays an essential role in initiation of the BMP6 signaling pathway and contributes to tumorigenesis and chemoresistance of colorectal cancers.


Role of CC-chemokine ligand 2 in gynecological cancer.
Gynecological cancer is one of the most severe diseases that threaten the lives and health of women worldwide. Its incidence rate increases with each passing year and becomes more prevalent among young people. The prognosis of gynecological cancer remains poor despite significant advances in surgical removal and systemic chemotherapy. Several chemokines play a role in the progression of gynecologic cancers. CCL2 (CC-chemokine ligand 2), also termed MCP-1 (monocyte chemotactic protein 1), plays a significant physiological role in monocyte cell migration and the inflammatory response. Recent studies have demonstrated that CCL2 plays a pro-tumorigenic function in the tumor microenvironment. According to previous studies, CCL2 plays a significant role in the occurrence and development of gynecological cancers. Furthermore, recent studies noted that CCL2 could be a potential diagnostic biomarker and prognostic predictor. The purpose of this paper is to review the role of CCL2 in the occurrence and development of gynecological cancers and to discuss the potential therapeutic strategy of CCL2 for gynecological cancers, with a primary focus on breast cancer, ovarian cancer, cervical cancer, and endometrial cancer.


Trp-Trp Cross-Linking: A Structure-Reactivity Relationship in the Formation and Design of Hyperstable Peptide β-Hairpin and α-Helix Scaffolds.
Using model peptide β-hairpin scaffolds, the facile formation of a remarkably stable covalently cross-linked modification is reported in the tryptophan side chain, which confers hyperstability to the scaffold and displays a unique structure-reactivity relationship. This strategy is also validated to obtain a thermostable α-helix. Such imposition of conformational constraints can have versatile applications in peptide-based drug discovery, and this strategy may improve peptide bioavailability.


Acupuncture for reducing pruritus induced by intrathecal morphine at elective cesarean delivery: a placebo-controlled, randomized, double-blind trial.
Intrathecal morphine is a standard postoperative analgesic administered after cesarean delivery, but frequently causes pruritus. Acupuncture reportedly resolves refractory pruritus in certain patients. The aim of the study was to investigate the effectiveness of acupuncture in preventing pruritus induced by intrathecal morphine. Thirty parturients received intrathecal hyperbaric bupivacaine (12 mg), fentanyl (10 µg), and morphine (150 µg) for spinal anesthesia at elective cesarean delivery at term. Patients were randomly divided into the acupuncture group (n=15) and the control group (n=15). In the acupuncture and control groups, certified acupuncturists inserted either indwelling press needles or sham needles, into Hegu (LI4), Neiguan (PC6), Quchi (LI11), and Zhigou (SJ6) on both arms the day before surgery. Needles were removed 48 hours postoperatively. The primary outcome was the incidence of postoperative pruritus. Adverse effects including nausea and vomiting were also investigated. There were no significant differences between the acupuncture group and the control group in the incidence of pruritus (67% vs. 67%, P=1.000, RR 1.0 [95% CI 0.60 to 1.66]) or the requirement for antipruritic therapy (6.7% vs. 20.0%, P=0.283, RR 0.33 [95% CI 0.04 to 2.85]). The incidence of postoperative nausea in the acupuncture group versus control group was 40.0% vs. 13.3%, P=0.099, RR 3.0 [95% CI 0.72 to 12.6]). The postoperative analgesic effect was comparable. Preoperatively administered acupuncture using press needles did not decrease intrathecal morphine-induced pruritus or the requirement for treatment.


Mixed phospholipid-cardiotoxin monomolecular films studied by intrinsic polarized surface fluorescence.
Surface fluorescence spectroscopy was used to study mixed phospholipid-cardiotoxin monomolecular films. Using polarized incident light we were able to detect the intrinsic fluorescence emission at a wavelength of 339 nm of the single Trp11 in the cardiotoxin molecule. Its fluorescence intensity increased continuously upon film compression up to a maximal value reached at 42 mN x m-1 in surface pressure. A relative polarization index can be used as an indication of the orientation of the indole ring. A transition at around 25 +/- 5 mN x m-1 in the orientation of the Trp11 relative to the plane of the interface was clearly evidenced during film compression, in agreement with our independent data showing a flipping of the whole toxin molecule (Bougis et al., (1981), Biochemistry 20, 4915-4920).


Risk Factors Associated With a Noncontact Anterior Cruciate Ligament Injury to the Contralateral Knee After Unilateral Anterior Cruciate Ligament Injury in High School and College Female Athletes: A Prospective Study.
The incidence of contralateral anterior cruciate ligament (CACL) injuries after recovery from a first-time anterior cruciate ligament (ACL) disruption is high in women; however, little is known about the risk factors associated with this trauma. Patient characteristics, strength, anatomic alignment, and neuromuscular characteristics of the contralateral uninjured leg at the time of the first ACL trauma are associated with risk of subsequent CACL injury, and these risk factors are distinct from those for a first-time ACL injury. Case-control study; Level of evidence, 3. Sixty-one women who suffered a first-time noncontact ACL injury while participating in high school or college sports and underwent measurement of potential risk factors on their contralateral limb soon after the initial ACL injury and before reconstruction were followed until either a CACL injury or an ACL graft injury occurred, or until the last date of contact. Follow-up information was available for 55 (90.0%) of the 61 athletes and 11 (20.0%) suffered a CACL injury. Younger age, decreased participation in sport before the first ACL disruption, decreased anterior stiffness of the contralateral knee, and increased hip anteversion were associated with increases in the risk of suffering a CACL injury. A portion of CACL injury risk factors were modifiable (time spent participating in sport and increasing anterior knee stiffness with bracing), while others were nonmodifiable (younger age and increased hip anteversion). The relationship between younger age at the time of an initial ACL injury and increased risk of subsequent CACL trauma may be explained by younger athletes having more years available to be exposed to at-risk activities compared with older athletes. A decrease of anterior stiffness of the knee is linked to decreased material properties and width of the ACL, and this may explain why some women are predisposed to bilateral ACL trauma while others only suffer the index injury. The risk factors for CACL injury are unique to women who suffer bilateral ACL trauma compared with those who suffer unilateral ACL trauma. This information is important for the identification of athletes who may benefit from risk reduction interventions.


Impaired peripheral circulation in lower-leg arteries caused by higher arterial stiffness and greater vascular resistance associates with nephropathy in type 2 diabetic patients with normal ankle-brachial indices.
Diabetic nephropathy is a major cause of lower-limb amputation. We enrolled 250 type 2 diabetic patients without apparent occlusive peripheral arterial disease (ankle-brachial indices >0.9) and 40 age-matched nondiabetic subjects consecutively admitted to our hospital. Flow volume and resistive index (RI), an index of vascular resistance, at the popliteal artery were evaluated using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial distensibility. Flow volume was negatively correlated with both baPWV (p=0.0009) and RI (p<0.0001) among the patients. When the patients were grouped into four subgroups with or without albuminuria and renal insufficiency according to the levels of urinary albumin excretion rate (>or=20 or <20microg/min) and estimated glomerular filtration rate (eGFR) (<60 or >or=60ml/min/1.73m(2)), albuminuric patients with renal insufficiency (n=30) showed the lowest flow volume (p=0.0078) and the highest baPWV (p=0.0006) and RI (p=0.0274) among the groups. Simple linear regression analyses demonstrated that eGFR correlated positively with flow volume (p=0.0020) and negatively with baPWV (p=0.0258) and RI (p=0.0029) in patients with albuminuria (n=92), but not with normoalbuminuria (n=158). Impaired peripheral circulation in lower-leg arteries associates with nephropathy in diabetic patients even though they have normal ankle-brachial indices.


Small-Molecule Regulators of MicroRNAs in Biomedicine.
Preclinical Research MicroRNAs (miRNAs) can regulate gene expression at the post-transcriptional level and have been implicated in the development of various human diseases, including cancer. The regulatory networks of miRNAs play a vital role not only in normal physiology but also in pathology and may represent novel targets for drug discovery. Regulation of miRNAs and the elucidation of miRNA networks will advance miRNA-targeted research but are challenging due to a shortage of appropriate tools. Using different assay systems, diverse small molecules with unique miRNA regulatory activity have been identified. These bioactive small molecules not only showed regulation on different miRNAs but revealed previously unknown miRNA networks. Treatment of cancer both in vitro and in vivo with small-molecule regulators of miRNAs has demonstrated their therapeutic potential. In this review, we discuss assay systems for the identification of small-molecule regulators of miRNAs and reported small molecules, and discuss their applications as probes and candidate drug leads.


Design of novel electron transfer mediators based on indophenol derivatives for lactate sensor.
Novel indophenol derivatives which have limited solubility in water solution functioned as excellent electron-transfer mediators for lactate oxidase and a lactate sensor, showing good sensor performance, including a high sensitivity and good durability. These less water-soluble mediators were prepared by the O-alkylation or acylation of indophenols in order to prevent the mediator being leached from the sensor. Consequently the characteristic substituent effects of indophenol derivatives were found to be follows, (1) modification of the phenolic OH group improved sensor durability; (2) the presence of chloride groups at the 2,6-positions of the phenol ring improved the sensitivity of the sensor; (3) the introduction of substituents at the quinoide moiety led to a deterioration in durability. A mediator based lactate sensor using these derivatives was found to be nearly independent of oxygen concentration, showed a low level of interference effect, and a quite long durability.


Selective hepatic vascular exclusion versus Pringle manoeuvre in liver resection for tumours encroaching on major hepatic veins.
Control of bleeding is crucial during liver resection, and several techniques have been developed to achieve this. This study compared the safety and efficacy of selective hepatic vascular exclusion (SHVE) and Pringle manoeuvre in partial hepatectomy for liver tumours compressing or involving major hepatic veins. All patients undergoing liver resection between January 2003 and December 2010 for liver tumours compressing or involving one or more major hepatic veins were identified retrospectively from a prospective institutional database. Either SHVE or Pringle manoeuvre was used to minimize blood loss during hepatectomy. Data on demographics and the intraoperative and postoperative course were analysed. From the database of 3900 patients, 1420 were identified who underwent liver resection for tumours encroaching on major hepatic veins using either SHVE (550) or the Pringle manoeuvre (870). Intraoperative blood loss (mean(s.d.) 480(210) versus 830(340) ml; P = 0·007) and transfusion requirements (mean(s.d.) 1·3(0·6) versus 2·9(1·4) units; P = 0·008) were significantly less in the SHVE group. In the Pringle group, hepatic vein injury resulted in major intraoperative bleeding of over 1000 ml in 65 patients (7·5 per cent) and air embolism in 14 (1·6 per cent), and three patients (0·3 per cent) died during surgery, whereas there was no major bleeding, air embolism or intraoperative death in the SHVE group. Postoperative liver failure, multiple organ failure and in-hospital death were significantly more common in the Pringle group (P = 0·019, P = 0·032 and P = 0·004 respectively). SHVE was more efficacious than the Pringle manoeuvre in minimizing intraoperative bleeding and air embolism during partial hepatectomy for tumours encroaching on major hepatic veins, and decreased the postoperative liver failure rate.


Coherence and phase locking in the scalp EEG and between LORETA model sources, and microstates as putative mechanisms of brain temporo-spatial functional organization.
Brain electric mechanisms of temporary, functional binding between brain regions are studied using computation of scalp EEG coherence and phase locking, sensitive to time differences of few milliseconds. However, such results if computed from scalp data are ambiguous since electric sources are spatially oriented. Non-ambiguous results can be obtained using calculated time series of strength of intracerebral model sources. This is illustrated applying LORETA modeling to EEG during resting and meditation. During meditation, time series of LORETA model sources revealed a tendency to decreased left-right intracerebral coherence in the delta band, and to increased anterior-posterior intracerebral coherence in the theta band. An alternate conceptualization of functional binding is based on the observation that brain electric activity is discontinuous, i.e., that it occurs in chunks of up to about 100 ms duration that are detectable as quasi-stable scalp field configurations of brain electric activity, called microstates. Their functional significance is illustrated in spontaneous and event-related paradigms, where microstates associated with imagery- versus abstract-type mentation, or while reading positive versus negative emotion words showed clearly different regions of cortical activation in LORETA tomography. These data support the concept that complete brain functions of higher order such as a momentary thought might be incorporated in temporal chunks of processing in the range of tens to about 100 ms as quasi-stable brain states; during these time windows, subprocesses would be accepted as members of the ongoing chunk of processing.


Anosmia and olfactory tract neuropathy in a case of COVID-19.
Coronavirus Disease-19 (COVID-19) has been in a global pandemic currently and relating symptoms were reported variously around the world. We reported a previously healthy man of COVID-19 presenting with anosmia as the obvious symptom with relevant radiological findings on brain magnetic resonance imaging.


Effects of extracts and fractions of Gynura procumbens on rat atrial contraction.
There is currently a great deal of research interest in utilizing plant compounds against human diseases, including hypertension. The present study investigated the effects of different extracts and fractions from leaves of Gynura procumbens Merr. on rat atrial contraction in vitro. Isolated left and right atria, mounted in a 20-ml organ bath, were allowed to equilibrate for 15 min before the application of the extracts or fractions. The extracts (petroleum-ether extract (PE) and methanol extract (ME)) and the fractions (chloroform fraction (CHL), ethyl-acetate fraction (EA), n-butanol fraction (NB) and water fraction (WA) of the methanol extract) were tested at three concentrations (0.25, 0.5 and 1.0 mg/ml), with a β-adrenergic agonist (isoprenaline) as a control. All data on contraction responses were log-transformed and analyzed. When exposed to the different extracts, both atria tended to exhibit greater contractive responses with the NB whereas cardiac contractions had a tendency to be reduced with most other extracts. For a given extract, the contraction responses were particularly greater at 0.5 mg/ml for the right atrium and at 1 mg/ml for the left atrium. Further analysis focusing on the NB fraction revealed that positive inotropism was greater in left atria exposed to highly-concentrated F2 and F3 sub-fractions. Taken together, our results suggest that NB extracts and fractions from the G. procumbens-leaf methanol extract have positive inotropic activities and, hence, can be considered as an alternative/traditional medicine against increased blood pressure in humans or can be used in strategies aimed at finding antihypertensive biomolecules from an accessible source.


Targeted Luminescent Europium Peptide Conjugates: Comparative Analysis Using Maleimide and para-Nitropyridyl Linkages for Organelle Staining.
The syntheses and photophysical behavior of nine strongly luminescent nonadentate Eu(III) complexes are reported. Each complex is based on N-functionalized 1,4,7-triazacyclononane, and linkage to other groups or targeting vectors can occur either via amide bond formation to a coordinated pyridine p-aminopropyl group or via a nucleophilic substitution reaction involving thiol attack on a metal coordinated p-nitropyridyl moiety. Evidence is presented in favor of the latter conjugation strategy, as parallel work with maleimide conjugates was complicated or compromised by the propensity to undergo post-conjugation thiol exchange or succinimide ring hydrolysis reactions. Confocal microscopy and spectral imaging studies revealed that the peptide conjugate of AcCFFKDEL was found to localize selectively in the endoplasmic reticulum of mouse fibroblast cells, whereas the related maleimide conjugate was only observed in cellular lysosomes.


Immunofluorescence Microscopy.
Visualizing fluorescence-tagged molecules is a powerful strategy that can reveal the complex dynamics of the cell. One robust and broadly applicable method is immunofluorescence microscopy, in which a fluorescence-labeled antibody binds the molecule of interest and then the location of the antibody is determined by fluorescence microscopy. The effective application of this technique includes several considerations, such as the nature of the antigen, specificity of the antibody, permeabilization and fixation of the specimen, and fluorescence imaging of the cell. Although each protocol will require fine-tuning depending on the cell type, antibody, and antigen, there are steps common to nearly all applications. This article provides protocols for staining the cytoskeleton and organelles in two very different kinds of cells: flat, adherent fibroblasts and thick, free-swimming Tetrahymena cells. Additional protocols enable visualization with widefield, laser scanning confocal, and eSRRF super-resolution fluorescence microscopy. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Immunofluorescence staining of adherent cells such as fibroblasts Basic Protocol 2: Immunofluorescence of suspension cells such as Tetrahymena Basic Protocol 3: Visualizing samples with a widefield fluorescence microscope Alternate Protocol 1: Staining suspension cells adhered to poly-l-lysine-coated coverslips Alternate Protocol 2: Visualizing samples with a laser scanning confocal microscope Alternate Protocol 3: Generating super-resolution images with SRRF microscopy.


Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria.
Antibiotics are a modifiable iatrogenic risk factor for the most common human nosocomial fungal infection, invasive candidiasis, yet the underlying mechanisms remain elusive. We found that antibiotics enhanced the susceptibility to murine invasive candidiasis due to impaired lymphocyte-dependent IL-17A- and GM-CSF-mediated antifungal immunity within the gut. This led to non-inflammatory bacterial escape and systemic bacterial co-infection, which could be ameliorated by IL-17A or GM-CSF immunotherapy. Vancomycin alone similarly enhanced the susceptibility to invasive fungal infection and systemic bacterial co-infection. Mechanistically, vancomycin reduced the frequency of gut Th17 cells associated with impaired proliferation and RORγt expression. Vancomycin's effects on Th17 cells were indirect, manifesting only in vivo in the presence of dysbiosis. In humans, antibiotics were associated with an increased risk of invasive candidiasis and death after invasive candidiasis. Our work highlights the importance of antibiotic stewardship in protecting vulnerable patients from life-threatening infections and provides mechanistic insights into a controllable iatrogenic risk factor for invasive candidiasis.


Protein phosphatase role in adenosine A1 receptor-induced AMPA receptor trafficking and rat hippocampal neuronal damage in hypoxia/reperfusion injury.
Adenosine signaling via A1 receptor (A1R) and A2A receptor (A2AR) has shown promise in revealing potential targets for neuroprotection in cerebral ischemia. We recently showed a novel mechanism by which A1R activation with N(6)-cyclopentyl adenosine (CPA) induced GluA1 and GluA2 AMPA receptor (AMPAR) endocytosis and adenosine-induced persistent synaptic depression (APSD) in rat hippocampus. This study further investigates the mechanism of A1R-mediated AMPAR internalization and hippocampal slice neuronal damage through activation of protein phosphatase 1 (PP1), 2A (PP2A), and 2B (PP2B) using electrophysiological, biochemical and imaging techniques. Following prolonged A1R activation, GluA2 internalization was selectively blocked by PP2A inhibitors (okadaic acid and fostriecin), whereas inhibitors of PP2A, PP1 (tautomycetin), and PP2B (FK506) all prevented GluA1 internalization. Additionally, GluA1 phosphorylation at Ser831 and Ser845 was reduced after prolonged A1R activation in hippocampal slices. PP2A inhibitors nullified A1R-mediated downregulation of pSer845-GluA1, while PP1 and PP2B inhibitors prevented pSer831-GluA1 downregulation. Each protein phosphatase inhibitor also blunted CPA-induced synaptic depression and APSD. We then tested whether A1R-mediated changes in AMPAR trafficking and APSD contribute to hypoxia-induced neuronal injury. Hypoxia (20 min) induced A1R-mediated internalization of both AMPAR subunits, and subsequent normoxic reperfusion (45 min) increased GluA1 but persistently reduced GluA2 surface expression. Neuronal damage after hypoxia-reperfusion injury was significantly blunted by pre-incubation with the above protein phosphatase inhibitors. Together, these data suggest that A1R-mediated protein phosphatase activation causes persistent synaptic depression by downregulating GluA2-containing AMPARs; this previously undefined role of A1R stimulation in hippocampal neuronal damage represents a novel therapeutic target in cerebral ischemic damage.


Multiple karyotypic rearrangements, including t(X;18)(p11;q11), in a fibrosarcoma.
The tumor stem line of a soft tissue fibrosarcoma, histologic malignancy grade III, had 43 chromosomes with several clonal chromosome aberrations, including the three balanced translocations t(X;18)(p11;q11), t(2;15)(p23;q26), and t(7;22)(q11;q13), two partly identifiable marker chromosomes, der(3)dic(3;?)(p11;?) and der(5), one small marker of unknown origin, and loss of one chromosome #11, #18, #19, and #21.


The diagnosis of organophosphorus fatal intoxication by the AChE activity in CSF.
A preliminary test for the diagnosis of intoxications with organophosphorous pesticides in fatal cases is described, based on the fact that these compounds inhibit AChE activity. For this purpose we measured AChE activity in CSF in 30 samples from fresh bodies autopsied after traffic accidents and in six after poisoning with organophosphorous insecticides. In order to exclude any other effect on the postmortem inactivation of the enzyme e.g. putrefaction we determined the AChE activity under different conditions. Thus we confirmed that in the reference samples, regardless the conditions, the activity of the enzyme was detectable at least 48 h after death, while in cases of poisoning the detection of AChE was inevitable early after death.


Localization of DJ-1 protein in the murine brain.
Mutations in the DJ-1 gene have been identified to cause Parkinson's disease. In humans, nonmutated DJ-1 is expressed in specific brain areas but seems to be expressed by astrocytes rather than by neurons. In contrast, DJ-1 mRNA is mainly found in neurons in the mouse brain. We have investigated the distribution of DJ-1 protein in the mouse brain and found that DJ-1 protein is predominantly expressed by neurons but can also be detected in astrocytes. Consistent with a global role of DJ-1 in the brain, we found immunoreactivity, for example, in cortical areas, hippocampus, basolateral amygdala, the reticular nucleus of the thalamus, zona incerta, and locus coeruleus. Within the substantia nigra, however, DJ-1 is localized in both neuronal and nonneuronal cells, suggesting a distinct role in this area.


An inhibition study of beauvericin on human and rat cytochrome P450 enzymes and its pharmacokinetics in rats.
Beauvericin is a secondary metabolite natural product from microorganisms and has been shown to have a new potential antifungal activity. In this study, the metabolism and inhibition of beauvericin in human liver microsomes (HLM) and rat liver microsomes (RLM) were investigated. The apparent K(m) and V(max) of beauvericin in HLM were determined by substrate depletion approach and its inhibitory effects on cytochromes P450 (CYP) activities were evaluated using probe substrates, with IC(50) and the (K(i)) values were 1.2 microM (0.5 microM) and 1.3 microM (1.9 microM), respectively for CYP3A4/5 (midazolam) and CYP2C19 (mephenytoin). Similarly, beauvericin was also a potent inhibitor for CYP3A1/2 (IC(50): 1.3 microM) in RLM. Furthermore, the pharmacokinetics of beauvericin in the rat were studied after p.o administration alone and co-administration with ketoconazole, which indicated a pharmacodynamic function may play a role in the synergistic effect on antifungal activity.


Nonlinearity in protein assays by the Coomassie blue dye-binding method.
The Coomassie brilliant blue (CBB) method for protein determination takes advantage of the fact that a low-pH red form of CBB reverts to a blue form when CBB binds to protein. The increase in absorbance at 595 nm of a protein-dye mixture compared to a blank containing only the dye reagent has been used to estimate the total amount of protein present in the sample mixture. A disadvantage of this method of protein determination is that the assay plot of absorbance at 595 nm versus total protein is not linear.


Direct determination of chromium in infant formulas employing high-resolution continuum source electrothermal atomic absorption spectrometry and solid sample analysis.
The present work proposed an analytical method for the direct determination of chromium in infant formulas employing the high-resolution continuum source electrothermal atomic absorption spectrometry combined with the solid sample analysis (SS-HR-CS ET AAS). Sample masses up to 2.0mg were directly weighted on a solid sampling platform and introduced into the graphite tube. In order to minimize the formation of carbonaceous residues and to improve the contact of the modifier solution with the solid sample, a volume of 10 µL of a solution containing 6% (v/v) H2O2, 20% (v/v) ethanol and 1% (v/v) HNO3 was added. The pyrolysis and atomization temperatures established were 1600 and 2400 °C, respectively, using magnesium as chemical modifier. The calibration technique was evaluated by comparing the slopes of calibration curves established using aqueous and solid standards. This test revealed that chromium can be determined employing the external calibration technique using aqueous standards. Under these conditions, the method developed allows the direct determination of chromium with limit of quantification of 11.5 ng g(-1), precision expressed as relative standard deviation (RSD) in the range of 4.0-17.9% (n=3) and a characteristic mass of 1.2 pg of chromium. The accuracy was confirmed by analysis of a certified reference material of tomato leaves furnished by National Institute of Standards and Technology. The method proposed was applied for the determination of chromium in five different infant formula samples. The chromium content found varied in the range of 33.9-58.1 ng g(-1) (n=3). These samples were also analyzed employing ICP-MS. A statistical test demonstrated that there is no significant difference between the results found by two methods. The chromium concentrations achieved are lower than the maximum limit permissible for chromium in foods by Brazilian Legislation.


Sexual and reproductive health and rights in the United Kingdom at ICPD+10.
At the mid-point of the Programme of Action of the 1994 International Conference on Population and Development, we reviewed the situation in the UK in key areas. In recent years, greater attention has been paid to sexual health at a national policy level, including strategies on teenage pregnancy and sexual health, but there is still a long way to go. The law against female genital mutilation has been strengthened, twice as many men attend family planning clinics as ten years ago, access to abortion services funded by the National Health Service has improved substantially, up to 80% of contraceptive advice and care is accessed through general practice, a national screening programme for chlamydia is being rolled out, the age of consent has been equalised for men and women and for heterosexuals and homosexuals, and new recommended standards for sexual health and HIV services have been developed. However, many family planning services do not involve young men, waiting times for an abortion are too long, the abortion law has never been extended to Northern Ireland, and there are rising rates of STIs and HIV. Rapid improvements in sexuality education, training and improved resources for family planning and abortion providers and the re-introduction of national public information campaigns about all aspects of sexual health are all required.


Externally sensitized deprotection of PPG-masked carbonyls as a spatial proximity probe in photoamplified detection of binding events.
Externally sensitized electron-transfer fragmentation in dithiane PPG (photoremovable protecting group)-protected carbonyls is adopted for detection and amplification of molecular recognition events. The new methodology allows for detection of as low as 50 attomoles of avidin utilizing an imager based on a low sensitivity mass-produced consumer CCD camera. Numeric modelling is carried out to demonstrate the intrinsic limitations of 2D amplification on surfaces and the advantages of unconstrained amplification in a compartmentalized volume of spatially addressable 3D solutions.


Abamectin at environmentally-realistic concentrations cause oxidative stress and genotoxic damage in juvenile fish (Schizothorax prenanti).
Abamectin (ABM) has been extensively used in Chinese aquaculture systems for parasite control, but no information is available regarding its effects on the important freshwater commercial fish species Schizothorax prenanti. We performed an acute toxicity test to determine the effects of ABM on S. prenanti, and the 48- and 96-h median lethal concentration values were 33.32 and 15.98 μg/L, respectively. In a second test, animals were exposed to sublethal concentrations of ABM (0.5, 2 or 8 μg/L) for 8 days, and various cytological and biochemical parameters were measured. ABM caused DNA damage in hepatocytes, with significant increases in Olive Tail Moment values and 8-hydroxy-2'-deoxyguanosine levels. Hepatocytic apoptosis occurred following all treatments, and was accompanied by an increase in reactive oxygen species (ROS) generation and caspase activity in a dose- and time-dependent manner. In addition, there were significant decreases in glutathione peroxidase levels and superoxide dismutase and catalase activity and increases in malonaldehyde levels. ABM-induced hepatocytic apoptosis in S. prenanti was probably triggered by ROS generation following a cascade reaction of caspases in mitochondrial or death receptor pathways, which caused antioxidant inhibition, oxidative product accumulation, and DNA damage in the liver.


Role of calcium in the inotropic effects of caffeine in cardiac Purkinje fibers.
The inotropic effects of caffeine (1-3 mM) were studied in the presence and absence of strophanthidin in canine Purkinje fibers perfused in vitro. Caffeine (1 mM) induced a similar initial increase in contractile force in different calcium solutions (+22, +23 and +24% in 0.54, 2.7 and 8.1 mM calcium, respectively) and when propranolol (3.4 X 10(-6) M) was present. Also, caffeine increased contractile force in high potassium (16.2 mM) at a time when the slow action potentials were unaltered. After the increase, 1 mM caffeine decreased force by about 50%, and the decrease was larger when caffeine (3 mM) or [Ca]0 (8.1 mM) was higher. In the presence of caffeine, strophanthidin (3 X 10(-7)-1 X 10(-6) M) increased force (+302%) if caffeine (0.3 mM) and Ca concentrations (0.54 mM) were low. If either caffeine or calcium was increased, strophanthidin had no effect or decreased force. Strophanthidin alone increased force and then decreased it; caffeine increased force in the first stage and decreased it during the second stage. The positive inotropic effect (+224%) of low sodium (78.4 mM versus 149.4 mM in Tyrode solution) was also abolished by caffeine (-24%). In ventricular muscle fibers, caffeine increased force more (+59%) and reduced force less in the presence of strophanthidin. The results indicate that caffeine increases force initially by releasing calcium from intracellular stores. The caffeine-induced decline in force is modulated by calcium in that it is exaggerated by agents or procedures which increase cellular calcium (strophanthidin, high calcium, low sodium solutions) and is reversed in a low calcium solution.


New and emerging drugs for the treatment of advanced cutaneous squamous cell carcinoma.
Cutaneous squamous cell carcinoma (CSCC) is the second most common form of human cancer. Treatment of locally advanced and/or recurrent CSCC is often challenging. A subset of patients are not candidates for curative-intent therapies due to extent of loco-regional disease, refractoriness to prior local therapy, or presence of distant metastasis. Traditionally, CSCC has been treated with surgery and/or radiotherapy, but in some instances, local therapies can lead to significant functional morbidity or are no longer feasible. Until 2018, systemic therapy options to treat patients with advanced CSCC were limited. Recently, clinical studies have shown activity of Immune Checkpoint Inhibitors (ICI) in patients with advanced CSCC. This article reviews the current systemic therapy options for CSCC with a focus on ICI and emerging promising therapies in the treatment of this challenging disease. ICI is currently the most effective and tolerable systemic therapy in the treatment of non-immunosuppressed advanced CSCC and can lead to cure in a subset of patients. Combinatorial therapies to overcome resistance to ICI may further increase the proportion of patients who will benefit from ICI and may help improve the quantity and quality of life of patients affected by this disease.


Continuity of health care: measurement and application in two rural counties of Guangxi Province, China.
Continuity of care (COC) is highly regarded in health promotion and health system strengthening. However, there is a lack of multidimensional quantitative assessment of continuity, making it challenging to evaluate and compare. Our objective was to create a novel measurement for COC and apply it in two rural counties in China to assess its validity and feasibility in evaluating health system reform. This study conducted a scoping literature review on COC, examining existing frameworks and indicators. Following an online expert poll, a composite indicator was developed using the analytical hierarchy process (AHP). The measurement tool was then applied to assess the current state of COC in two rural counties in China. In addition to descriptive analysis, demographic and economic characteristics were analyzed for their association with COC scores using t-tests and multiple linear regression models. The final COC measurement encompasses three dimensions, six sub-dimensions, and ten individual indicators, which integrated and improved the current frameworks and indicators. Relational continuity, informational continuity, and management continuity were identified as the primary dimensions of COC measurement. The COC score is 0.49 in County A and 0.41 in County B, with information continuity being the highest-scoring dimension. Notably, the disparity in continuity scores is most pronounced among individuals with varying attitudes towards health, demonstrating a positive correlation. The construction of the composite indicator in this study offers a scientific and effective metric for comprehensively measuring continuity of care. The empirical data analysis conducted in Western China serves as an illustrative application of the indicator, demonstrating its efficiency. The results obtained from this analysis provide a solid foundation and valuable reference for strengthening the health system.


The multilevel society of a small-brained bird.
Animal societies can be organised in multiple hierarchical tiers [1]. Such multilevel societies, where stable groups move together through the landscape, overlapping and associating preferentially with specific other groups, are thought to represent one of the most complex forms of social structure in vertebrates. For example, hamadryas baboons (Papio hamadryas) live in units consisting of one male and one or several females, or of several solitary males, that group into clans. These clans then come together with solitary bachelor males to form larger bands [2]. This social structure means that individuals have to track many different types of relationships at the same time [1,3]. Here, we provide detailed quantitative evidence for the presence of a multilevel society in a small-brained bird, the vulturine guineafowl (Acryllium vulturinum). We demonstrate that this species lives in large, multi-male, multi-female groups that associate preferentially with specific other groups, both during the day and at night-time communal roosts.


AIM2ACT: Randomized controlled trial protocol for a mobile health intervention for early adolescents with asthma.
Early adolescents diagnosed with asthma have difficulties consistently performing disease self-management behaviors, placing them at-risk for poor asthma control, morbidity, and reduced quality of life. Helpful caregiver support is pivotal in determining whether early adolescents develop and master asthma self-management behaviors. We developed Applying Interactive Mobile health to Asthma Care in Teens (AIM2ACT), a mobile health intervention to facilitate helpful caregiver support in early adolescents (12-15 year-olds) with poorly controlled asthma. AIM2ACT is a dyadic smartphone intervention that contains three components: 1) ecological momentary assessment to identify personalized strengths and weaknesses in asthma self-management behaviors; 2) collaborative identification and tracking of goals that help early adolescents to become increasingly independent in managing their asthma; and 3) a suite of skills training videos. This paper describes our plans to test the efficacy of AIM2ACT and evaluate long-term maintenance of treatment effects in a fully powered randomized controlled trial with 160 early adolescents with poorly controlled persistent asthma, ages 12-15 years, and a caregiver. Families will be randomly assigned to receive AIM2ACT (n = 80) or a mHealth attention control condition (n = 80) that accounts for attention and novelty of a technology-based intervention for 6 months. Assessments will occur at baseline, post-intervention, and 3-, 6-, and 12-month follow-up time points. We will collect patient-reported and objectively monitored (e.g., spirometry, adherence) outcomes. Given the timing of the trial, a secondary exploratory goal is to evaluate the perceived impact of COVID-19 on family functioning and parental control of their adolescent's asthma in the context of our intervention.


A WRKY transcription factor, PyWRKY75, enhanced cadmium accumulation and tolerance in poplar.
Cadmium (Cd) pollution has detrimental effects on the ecological environment and human health. Currently, phytoremediation is considered an environmentally friendly way to remediate Cd pollution. The application of transgenic plants to remediate soil pollution is a new technology that has emerged in recent years. In this study, PyWRKY75 was isolated and cloned from Populus yunnanensis, and the functionality of PyWRKY75 in woody plants (poplar) under Cd stress was verified. The increase in plant height of the OE-41 line (overexpression poplar) was 33.2% higher than that of the wild type (WT). Moreover, PyWRKY75 significantly promoted the absorption and accumulation of Cd in poplar, which increased by 51.32% in the OE-41 line when compared with the WT. The chlorophyll content of transgenic poplar leaves was higher than that of the WT, which reflected a protective mechanism of PyWRKY75. Other antioxidants, such as POD, SOD, CAT, APX, AsA, GSH and PCs, also made the transgenic poplars more tolerant to Cd, and they behaved differently in roots, stems and leaves. In general, PyWRKY75 played a potential role in regulating plant tolerance to Cd stress. This study provides a scientific basis and a new type of modified poplar for Cd pollution remediation.


Prevalence of childhood exanthematic disease antibodies in paramedical students: need of vaccination.
The immunity to common childhood exanthematic diseases such as varicella, rubella, mumps and measles was evaluated in 1024 students of the degree courses of health professions at Padua University Medical School. Subjects were subdivided according to gender and age (25 years old or less, and older than 25 years). Results showed that the prevalence of positive antibodies (IgG) to varicella and rubella (94.1 and 94.5%, respectively) was significantly higher (p<0.001) than mumps (78.6%) and measles (86.3%). In addition, measles showed a significant higher prevalence than mumps (p<0.001). Prevalence of positive antibodies to rubella in females (97.4%) was significantly higher (p<0.001) than males (87.5%), but only if aged 25 years or less. Furthermore, males older than 25 years were significantly more immune (p<0.001) to measles (93.0%) than younger ones (84.3%). A vaccination strategy was applied but compliance was less than 50%; in addition, about 40.0% of vaccinated subjects eluded control after vaccination. Seroconversion after vaccine appeared high for rubella, mumps and measles (92.3, 88.9 and 88.1%, respectively), but low for varicella (43.8%).


A systematic capillary electrophoresis study on the effect of the buffer composition on the reactivity of the anticancer drug cisplatin to the DNA model 2'-deoxyguanosine 5'-monophosphate (dGMP).
The development of DNA-targeted next-generation platinum-based anticancer chemotherapeutics is often accompanied by studies on the reactivity to DNA models. However, the incubation conditions used in literature vary widely, and some of the buffer/salts used are known to form complexes with Pt. Such coordination can influence the binding process and also the adducts formed. In a systematic approach, studies on the binding of cisplatin (1 mM) to dGMP (2 mM) in a series of different incubation solutions of relevance to biological systems are reported, employing capillary zone electrophoresis (CZE) with UV/vis and electrospray ionization-mass spectrometric (ESI-MS) detectors. Kinetic experiments performed with CZE-UV showed a high reactivity of dGMP to cisplatin in pure water (τ(1/2) = 4.1 ± 0.7 h) but a significantly slowed down in a solution containing a carbonate/phosphate buffer supplemented with NaCl, resulting in a half-life of dGMP of 25 ± 3 h. Especially carbonate had a major impact on the binding, though no coordination to the metal center was detectable with the methods used. The only adducts containing buffer components were (phosphate)Pt and tris(ammine)Pt species, as identified by means of CZE-ESI-MS, in addition to the main adduct [Pt(NH3)2(dGMP)2 - 4H(+)](2-) and other less abundant Pt-containing species.


Design and delivery of home-based telehealth pulmonary rehabilitation programs in COPD: A systematic review and meta-analysis.
Home-based telehealth pulmonary rehabilitation (HTPR) for chronic obstructive pulmonary disease (COPD) is increasingly common partly due to the COVID-19 pandemic. However, optimal HTPR programming has not been described. This review provides a comprehensive overview of the design, delivery, and effects of HTPR for people with COPD. Relevant databases were searched to July 2021 for studies on adults with COPD utilizing information or communication technology to monitor or deliver HTPR. A meta-analysis was performed on a subset of randomized controlled trials. Of 3124 records retrieved, 38 studies evaluating 1993 individuals with stable COPD (age 54-75 and FEV1 31-92% predicted) were included. Program components included exercise and education (n = 17) or exercise alone (n = 15) with in-clinic baseline assessments commonly conducted (n = 26). Few trials (n = 7) featured synchronous virtual exercise supervision. Aerobic exercise commonly involved walking (n = 14) and cycling (n = 11) and most programs included resistance training (n = 25). Exercise progressions and emergency action plans were inconsistently reported. Meta-analysis demonstrated HTPR was comparable to outpatient PR and had a greater effect than usual care for the modified Medical Research Council dyspnea scale (mean difference [95 %CI]: -0.49 [-0.77, -0.22], p < 0.01) and COPD Assessment Test score (-4.90 [-7.13, -2.67], p < 0.01). Neither HTPR nor outpatient PR impacted sedentary time or step count. Only 6% of studies reported race and no studies reported participant ethnicity. This review revealed the heterogeneity of HTPR program designs in COPD. HTPR programs had similar effects to outpatient PR programs and greater effects than usual care for people with COPD.


Type D personality and depressive symptoms are independent predictors of impaired health status in chronic heart failure.
To examine whether Type D personality exerts a stable, independent effect on health status in CHF over time, adjusted for depressive symptoms. CHF outpatients (n = 166; 75% men; mean age 66 years) completed the Type D Scale and Beck Depression Inventory (baseline) and the Minnesota Living with Heart Failure Questionnaire and Short-Form Health Survey (baseline and 12 months). There was a general improvement in disease-specific physical (p = .029) and mental (p < .001) health over time, but Type D patients scored significantly lower on both outcomes (p < or = .001). The interaction effects Type D x time were not significant, indicating stability of the personality effect. Type D patients also scored significantly lower on all generic physical (p values between .001 and .04) and mental (all p values < or = .01) health status subdomains; these effects were also stable over time. Type D was an independent predictor of disease-specific mental health (p < .001), social functioning (p = .04), role emotional functioning (p < .001), bodily pain (p = .05), and general health (p = .04), adjusted for depressive symptoms, baseline health status and clinical characteristics. Depressive symptoms was an independent predictor of role physical functioning and bodily pain. Type D personality and depressive symptoms were independent predictors of impaired health status in CHF.


Variants of the SCD gene and their association with fatty acid composition in Awassi sheep.
Genetic factors affect the variability of fatty acid composition in ruminant products. Thus, this study aimed to investigate the association between the variations of the SCD gene and fatty acid composition in Awassi sheep. A total of 100 Awassi rams between the ages of one and two and a half years old were used in this study. Blood samples were taken at abattoirs in Babylon, and from each animal, longissimus dorsi (LD) muscle samples were taken to measure the fatty acid composition. DNA samples were isolated from each blood sample, then PCR-single strand conformation polymorphism (PCR-SSCP) experiments were conducted for genotyping followed by sequencing reactions. The study identified two genotypes (TT and TA) of the SCD gene (exon 3). Several novel variants were discovered in the amplified fragments of the SCD gene. The TA genotype resulted in increased intramuscular fat and monounsaturated fatty acids compared to the TT genotype. Breeding for the TA genotype could be used for producing meat containing less saturated fatty acids and more monounsaturated fatty acids, making meat more favorable for human consumption.


Prebiotics: actual and potential effects in inflammatory and malignant colonic diseases.
This paper will summarize the most recent clinical and experimental data on the effects of prebiotics in inflammatory and cancerous diseases of the large intestine. Animal studies, as well as data obtained in in-vitro cell culture systems, have underlined the potential of certain prebiotics to protect against inflammatory and cancerous processes in the large intestine. Clinical trials are now in progress to assess the relevance of these promising results. The biochemical mechanisms are still incompletely deciphered, but both the promotion of lactic acid-producing bacteria and the production of short-chain fatty acids, particularly butyrate, during the fermentation of prebiotics could be key factors. Enteric resident bacteria are involved in inflammatory bowel diseases and may contribute to colonic carcinogenesis. Dietary manipulation of the flora may thus represent a useful aid to prevent or to treat these diseases, and this could be a place for prebiotics. Inulin-like prebiotics have shown encouraging results in animal models, but clinical and epidemiological trials are necessary to define their efficacy in humans. In the next few years, important advances are expected in understanding the interactions between prebiotics, intestinal flora and the colonic mucosa in health and diseases, enabling the improvement of therapy as well as better nutritional handling of susceptible individuals.


Stress-inducing effect of hypoxia of different origin and its correction with Inula Helenium L. tincture.
In order to evaluate the severity of stress, the effects of single and repeated exposure to hypoxia of different origin (hemic, tissue, and circulatory) on the classical parameters of the Selye triad, cytological characteristics of lymphoid organs, and karyometric parameters (nucleus diameters) were studied in all adrenal zones, and analysis of correlations was carried out. The corrective effect of Inula helenium L. tincture manifested in prolongation of the life-span and normalization of somatic and morphological parameters.


Posterior Stabilized Polyethylene Inserts in Total Knee Arthroplasty: A Retrieval Study Comparing Conventional to High-Flexion Designs.
High-flex (HF) total knee arthroplasties are modified posterior-stabilized (PS) implants designed to accommodate greater flexion. We examined differences between HF and PS retrieved tibial inserts with regard to polyethylene surface damage. Twenty HF inserts from each of 3 manufacturers were matched using patient demographics with 20 PS inserts from the same manufacturers. Ranges of motion between matched patients were not different. Based on subjective damage scores, no differences were detected between HF and PS groups. Differences were found, however, among manufacturers, consistent with design approaches taken for PS and HF implants. In our series, high flexion did not influence damage, although this was likely influenced by the fact that few HF patients in our study had larger range of motions than their PS counterparts.


Colletotrichum gloeosporioides can overgrow Colletotrichum kahawae on green coffee berries first inoculated with C. kahawae.
Colletotrichum gloeosporioides is a weak pathogen of coffee that infects ripe berries at dark red stage causing necrotic lesions, but only penetrates up to the second superficial layers of the pericarp at the rose and pink stages. C. kahawae, the causal agent of coffee berry disease (CBD) and responsible for 70-80% of crop loss, infects berries at any stage of development. When green berries are first inoculated with C. kahawae and then at 2, 72 or 96 h later with C. gloeosporioides, the necrotic lesions were significantly larger than in the controls, and were much more evident when the berries were incubated at the optimum growth temperature of 28 degrees C for C. gloeosporioides. Isolations from the lesions induced by the first inoculations with C. kahawae followed by inoculation with C. gloeosporioides revealed that all or most of the time the recovered isolates of the latter. Thus, C. gloeosporioides can overwhelm C. kahawae under conditions of higher environmental temperature and humidity and may enhance the CBD infection process under field conditions.


Myocardial Na+,K(+)-ATPase in tachycardia induced cardiomyopathy.
Na+,K(+)-ATPase is a major determinant of myocyte homeostasis and excitation-contraction. Cardiac glycosides such as digitalis and ouabain increase the inotropic state of the heart through the inhibition of Na+,K(+)-ATPase. While cardiac glycosides are commonly used in the setting of congestive heart failure, optimal therapy would depend upon an intact Na+,K(+)-ATPase system. Changes in Na+,K(+)-ATPase activity and glycoside receptor density with the development of cardiomyopathy have not been well defined. Accordingly, left ventricular (LV) function and Na+,K(+)-ATPase activity and glycoside binding were examined in 7 pigs with dilated cardiomyopathy and in 7 controls. Dilated cardiomyopathy was produced by pacing induced supraventricular tachycardia (SVT) for 3 weeks at 240 bpm. Left ventricular function was examined by simultaneous echocardiography and catheterization. Left ventricular fractional shortening significantly decreased with SVT (34 +/- 2 vs. 10 +/- 2%, P less than 0.05) and LV diastolic dimension and pressure significantly increased (3.8 +/- 0.3 vs. 5.1 +/- 0.4 cm, and 8 +/- 2 vs. 27 +/- 2 mmHg, respectively, P less than 0.05) as compared to controls. Na+,K(+)-ATPase activity was assayed as potassium dependent p-nitrophenol-phosphatase activity. Glycoside receptor density (Bmax) and affinity (KD) was determined using [3H]-ouabain binding assays. Na+,K(+)-ATPase activity, Bmax, and KD all significantly fell from control values with SVT induced cardiomyopathy (0.64 +/- 0.06 vs. 0.45 +/- 0.12 micrograms pNP/mg/h, 5.5 +/- 0.4 vs. 1.9 +/- 0.4 pmol/mg, and 15 +/- 3 vs. 9 +/- 3 nM, respectively, P less than 0.05). The distribution of Na+,K(+)-ATPase in LV sections taken from control and SVT hearts were examined using immunohistochemical techniques. A patchy distribution of Na+,K(+)-ATPase along the sarcolemma in SVT sections was observed as opposed to a more uniform distribution in control myocytes. There was no observable change in the relative content and distribution of the Na+,K(+)-ATPase isoforms alpha 2 and alpha 3 in the SVT sections as compared to controls. In an additional set of experiments, changes in LV as well as isolated myocyte responsiveness to ouabain were examined. Left ventricular fractional shortening and peak dP/dt were measured following administration of 20-60 micrograms/Kg of ouabain in control (n = 3) and SVT (n = 3) pigs. In the control group, 40 micrograms/Kg caused a 25% in LV fractional shortening and a 60% increase in peak dP/dt from baseline. Cumulative doses of 60 micrograms/Kg in the control pigs resulted in over a 75% increase in peak dP/dt from baseline values.(ABSTRACT TRUNCATED AT 400 WORDS)


Migration background and patient satisfaction in a pediatric nephrology outpatient clinic.
We examined the association of a migration background and patient satisfaction in a pediatric nephrology outpatient clinic in Germany. This was a cross-sectional study of 348 families presenting at the Pediatric Nephrology Outpatient Department of Charité University Children's Hospital in Berlin during 2008. Parents were asked to complete a questionnaire containing basic sociodemographic information, a subjective categorical rating of disease severity and communication with the medical team, and a validated patient satisfaction score (ZUF-8) derived from a customer satisfaction score used by industry and modified for healthcare providers. Of the 348 families included in the study, 131 patients (38 %) had a migration background (20 different nationalities, 22 different native languages). Patient satisfaction (rated on a scale from 8 to 40) was significantly higher in families without (32.9 ± 4.6) than in those with a migration background (30.8 ± 4.7; p < 0.0001). A multivariate linear regression analysis revealed that trust in doctors, friendliness of the doctor, severity of the child's disease, number of medications prescribed, and a migration background were significantly and independently correlated with patient satisfaction. Migrant families were less satisfied with the provision of the outpatient care provided by our department than non-migrants.


Antihypertensive and vasodilator actions of antioxidants in spontaneously hypertensive rats.
This study was designed to determine whether the antioxidants ascorbic acid, aminotriazole, and glutathione acutely reduce blood pressure (BP) by endothelium-independent or -dependent vasorelaxation in spontaneously hypertensive rats. Blood pressure of male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) was measured before and 4 h after administration of antioxidants. Thoracic aortic rings with and without endothelium were suspended in organ chambers for isometric tension recordings. Each of the antioxidants, administered in vivo, significantly decreased blood pressure in SHR but had no significant effect on BP in WKY rats. The endothelium-dependent impaired relaxation of SHR aortic rings to acetylcholine (ACh) was improved by prior in vivo administration of each antioxidant. ACh-induced relaxations of aortic rings from WKY was not affected by prior antioxidant treatment. Addition of each antioxidant directly to the organ chamber containing SHR or WKY aortas produced dose- and endothelium-dependent relaxations. Moreover, antioxidant pretreatment of SHR aortic rings significantly potentiated ACh-induced relaxations in these aortas, suggesting that this effect was endothelium dependent. Relaxations induced by the antioxidants alone or by ACh in the presence of antioxidants were inhibited by addition of either xanthine plus xanthine oxidase or nitro-L-arginine. These findings suggest that either excess production of oxidants or a deficiency of antioxidant systems may contribute to the high blood pressure and the endothelium-dependent impairment of vascular relaxation in SHR.


A RNA-Targeted Two-Photon Bioprobe with High Selective Permeability into Nuclear Pore Complexes for Dynamically Tracking the Autophagy Process among Multi-Organelles.
Dynamic tracking of the spatiotemporal coordination among various organelles to in-depth understanding of the mechanism of autophagy have attracted considerable attention. However, the monitor of nucleoli participation in autophagy was somehow neglected. Herein, we report a RNA-targeted bioprobe (ADAP) with high selective permeability into nuclear pore complexes, which induced a two-photon (TP) fluorescence "off-on" response by groove combination with RNA, dynamically monitoring the autophagy process among multiorganelles (nucleoli, mitochondria, and mitochondria-containing lysosomes). This work provides a simple and convenient way to observe the dynamic behavior of multiorganelles during the autophagy process, which benefits the understanding of cellular metabolism.


Corneal changes following short-term rigid contact lens wear.
The aim of this cross-over study was to investigate the changes in corneal thickness, anterior and posterior corneal topography, corneal refractive power and ocular wavefront aberrations, following the short term use of rigid contact lenses. Fourteen participants wore 4 different types of contact lenses (RGP lenses of 9.5mm and 10.5mm diameter, and for comparison a PMMA lens of 9.5mm diameter and a soft silicone hydrogel lens) on 4 different days for a period of 8h on each day. Measures were collected before and after contact lens wear and additionally on a baseline day. Anterior corneal curvature generally showed a flattening with both of the RGP lenses and a steepening with the PMMA lens. A significant negative correlation was found between the change in corneal swelling and central and peripheral posterior corneal curvature (all p ≤ 0.001). RGP contact lenses caused a significant decrease in corneal refractive power (hyperopic shift) of approximately 0.5D. The PMMA contact lenses caused the greatest corneal swelling in both the central (27.92 ± 15.49 μm, p<0.001) and peripheral (17.78 ± 12.11 μm, p=0.001) corneal regions, a significant flattening of the posterior cornea and an increase in ocular aberrations (all p ≤ 0.05). The corneal swelling associated with RGP lenses was relatively minor, but there was slight central corneal flattening and a clinically significant hyperopic change in corneal refractive power after the first day of lens wear. The PMMA contact lenses resulted in significant corneal swelling and reduced optical performance of the cornea.


Spatial and temporal distribution characteristics of typical pollution loads based on SWAT model across Tuojiang River watershed located in Sichuan Province, Southwest of China.
Tuojiang River watershed is an economically developed and densely populated area in Sichuan Province (southwest of China), which is also an important tributary of the Yangtze River. Nitrogen (N) and phosphorus (P) are the main pollutants affecting water quality, but there is still lack of study on the spatial and temporal distribution characteristics of these two pollutants. In this study, the typical non-point source pollution loads in the Tuojiang River watershed are simulated by Soil and Water Assessment Tool (SWAT) model, and the spatial autocorrelation method is used to reveal the spatial and temporal distribution characteristics of the pollution loads from the annual average and water periods. Combined with redundancy analysis (RDA) and geographically weighted regression (GWR) analysis, the main driving factors affecting the typical non-point source pollution loads in the Tuojiang River watershed are discussed from the global and local perspectives. The results show that (1) from different water periods, the pollution loads of total nitrogen (TN) and total phosphorus (TP) in three water periods show obviously different, is the highest in the abundant water period, with 323.4 kg/ha and 47.9 kg/ha, followed by the normal water period, with 95.7 kg/ha and 14.1 kg/ha, and the lowest in the dry water period, with 28.4 kg/ha and 4.2 kg/ha. The annual average value of TN pollution load is higher than that of TP, with 447.5 kg/ha and 66.1 kg/ha, respectively; (2) the TN and TP pollution loads are stable on the whole, and the overall level in the middle reaches is higher. The pollution loads of Shifang City and Mianzhu City are higher in all three water periods. (3) Elevation and slope are two main driving factors affecting the TN and TP pollution loads in the Tuojiang River watershed. Therefore, the visualization and quantification of temporal and spatial distribution characteristics of typical non-point source pollution loads in the Tuojiang River watershed are helpful to provide the basis for scientific prevention and control of pollution in the Tuojiang River watershed and are of great significance to promote the sustainable, coordinated, and healthy development of water environment and economy in the watershed.


Disease assessment indices: activity, damage and severity.
The methodology for developing and assessing disease status measures is now well-advanced. For some diseases, in particular SLE and RA, these methods have been applied and instruments either are being or have been validated. For other conditions, such as ankylosing spondylitis and Behçet's disease, there is still a need for reliable measures to be proposed and evaluated.


Novel Niosome-Encapsulated 2,5-Diketopiperazine (BHPPD): Synthesis, Formulation, and Anti-breast Cancer Activity.
In the course of this investigation, a brand-new noisome-encapsulated 2,5-diketopiperazine (BHPPD) was developed, synthesized, and assessed. Utilizing CCK-8, invasion screens, MTT test, flow cytometry, and cell cycle analysis, we evaluated the anti-breast cancer properties of niosome-encapsulated BHPPD. Apoptosis-related gene expression and cytotoxicity was measured using quantitative real-time PCR and MTT assays. This meta-analysis showed a significant drug-binding affinity for intestinal protease. The spherical mean diameters of the free BHPPD, the F1 niosomal-BHPPD, and the F2 niosomal-BHPPD were all determined to be108.91 ± 4.2, 129.13 ± 7.2 nm, and 149.43 ± 3.2 nm, respectively. Also, it was found that the entrapment efficiency (EE%) of the F1 formulations of BHPPD that was niosome-encapsulated was 81.01 0.09% and that it was 70.22 0.13%, respectively. Early, late, necrotic, and viable MCF-7 cells were present in the cells with F1 formulation in proportions of 38.24%, 34.34%, 4.02%, and 23.40%, respectively. Compared to the control group, the treatment group's expression of the genes P57, Prkca, MDM4, Map2k6, and FADD was considerably greater (P < 0.001). Furthermore, compared to control cells, cells in the treatment group expressed less BCL2 and survival genes (P < 0.001). Moreover, formulations of BHPPD encapsulated in niosomes showed a biocompatible nanoscale delivery method and exhibited little cytotoxicity against the HEK-293 standard cell line. According to the findings, formulations of BHPPD with niosome-encapsulation might be viable for boosting anticancer activity.


Molecular cloning and sequencing of cDNA for rat cathepsin L.
A near full-length cDNA for rat cathepsin L was isolated. The deduced protein comprises 334 amino acid residues (Mr 37,685) containing a typical signal sequence (N-terminal 17 residues), pro-peptide (96 residues), and the sequence for mature cathepsin L (221 residues). Rat cathepsin L shows 94% amino acid identity with mouse cysteine proteinase. Amino acid sequence homologies of rat cathepsin L with rat cathepsins H and B are 45 and 25%, respectively. These facts indicate that mouse cysteine proteinase is probably mouse cathepsin L and that cathepsin L is more closely related to cathepsin H than cathepsin B.


An efficient stereoselective synthesis of 4,5-trans-1,5-cis-3-oxabicyclo[3.1.0]hexan-2-ones via the iodolactonization of alkylidenecyclopropyl esters.
[reaction: see text] A highly stereoselective iodolactonization of alkylidenecyclopropyl esters with iodine or N-iodosuccinimide (NIS) in aqueous CH3CN to afford 4,5-trans-1,5-cis-3-oxabicyclo-[3.1.0]hexane-2-ones is described. The reaction is very general, accommodating a wide range of substituents. A plausible mechanism that explains the essential role of water in this reaction is proposed.


UCP1 and AOX1a contribute to regulation of carbon and nitrogen metabolism and yield in Arabidopsis under low nitrogen stress.
Nitrogen (N) availability is a critical factor for plant development and crop yield, and it closely correlates to carbon (C) metabolism. Uncoupling protein (UCP) and alternative oxidase (AOX) exhibit a strong correlation with N and C metabolism. Here, we investigated the functions of UCP1 and AOX1a using their mutants and complementation lines in Arabidopsis adaptation to low N. Low N markedly increased AOX1a and UCP1 expression, alternative pathway capacity and UCP activity. Eight-day-old aox1a/ucp1 seedlings were more sensitive to low N than Col-0 and single mutants, exhibiting lower primary root length and higher anthocyanin accumulation. The net photosynthetic rate, electron transport rate, PSII actual photochemical efficiency, stomatal conductance and carboxylation efficiency were markedly decreased in ucp1 and aox1a/ucp1 compared to those in Col-0 and aox1a under low N stress; comparatively, chlorophyll content and non-photochemical quenching coefficient were the lowest and highest in aox1a/ucp1, respectively. Nitrate acquisition rate was accelerated in aox1a/ucp1, but its transport activity was decreased, which resulted in low nitrate content and nitrate reductase activity under low N condition. The C/N ratio in seeds, but not in leaves, is higher in aox1a/ucp1 than that in Col-0, aox1a and ucp1 under low N condition. RNA-seq analysis revealed that many genes involved in photosynthesis and C/N metabolism were markedly down-regulated in aox1a/ucp1 under low N stress. These results highlight the key roles of UCP1 and AOX1a in modulating photosynthetic capacity, C/N assimilation and distribution under low N stress.


Novel thermostable endo-xylanase cloned and expressed from bacterium Geobacillus sp. WSUCF1.
A gene encoding a GH10 endo-xylanase from Geobacillus sp. WSUCF1 was cloned and expressed in Escherichia coli. Recombinant endo-xylanase (37kDa) exhibited high specific activity of 461.0U/mg of protein. Endo-xylanase was optimally active on birchwood xylan at 70°C and pH 6.5. The endo-xylanase was found to be highly thermostable at 50 and 60°C, retaining 82% and 50% of its original activity, respectively, after 60h. High xylan conversions (92%) were obtained with oat-spelt xylan hydrolysis. Higher glucan and xylan conversions were obtained on AFEX-treated corn stover with an enzyme cocktail containing WSUCF1 endo-xylanase (71% and 47%) as compared to enzyme cocktail containing commercial fungal endo-xylanase (64% and 41%). High specific activity, active at high pH's, wide substrate specificity, and higher hydrolytic activity on recalcitrant lignocellulose, make this endo-xylanase a suitable candidate for biofuel and bioprocess industries.


Supine sleep and obstructive sleep apnea syndrome in Parkinson's disease.
Supine sleep is associated with increased obstructive sleep apnea. People with Parkinson's disease (PD) complain about difficulties turning around in bed. The relationship between supine sleep and sleep-disordered breathing has never been explored in people with Parkinson's disease. Fifteen consecutive people with PD with severe Obstructive Sleep Apnea Syndrome (OSAS) were compared to: (1) 15 age-matched, gender-matched, body mass index-matched and Unified Parkinson's Disease Rating Scale-III score-matched people with PD without sleep-disordered breathing; (2) 11 age-matched and gender-matched people with severe obstructive sleep apnea syndrome (OSAS) alone; and (3) 11 age-matched and gender-matched healthy controls. Outcomes were: number of position changes during the night and per hour of sleep, and the percentage of sleep time spent in supine. People with PD and severe OSAS spent most of their sleep time in the supine position (93 ± 11%); while people with PD without OSAS (61 ± 24%, p <0.001), people with isolated, severe OSAS (50 ± 28%, p <0.001), and the controls (40 ± 21, p <0.001) spent significantly less time on their back. People with PD and severe OSAS changed their position in bed per hour of sleep (0.4 ± 0.5) less frequently than those with PD without OSAS (1.1 ± 0.8, p = 0.002), those with isolated OSAS (1.2 ± 1.0, p = 0.006) and the controls (1.5 ± 0.5, p <0.001). PD and severe OSAS are associated with a major reduction in the number of position changes and an increased supine sleep position during the night. For people with PD, alleviating the difficulties of turning around in bed might reduce the supine sleep position and improve sleep-disordered breathing.


The group of primitive Pythagorean triples over Gaussian integers.
A group structure of the set of primitive Pythagorean triples over Gaussian integers is investigated. In addition, we show that it is a free abelian group. Base on the study, the construction and enumeration of the primitive Pythagorean triples having the same hypotenuse are established.


The hand in the Pierre Robin syndrome.
In reviewing eight cases of children with the Pierre Robin syndrome, we found three cases to have abnormalities of the extremities such as syndactyly, hypoplastic digits, and a Poland syndrome. These hand abnormalities have not been previously emphasized in patients with the Pierre Robin syndrome.


Elevation of intratesticular and scrotal skin surface temperature in men with varicocele.
A possible mechanism of varicocele-induced infertility is believed to be elevation of testicular temperature. Sensitive needle thermistors were used to measure directly intratesticular and bilateral scrotal surface temperatures simultaneously in anesthetized infertile men with varicocele and control subjects. We found that intratesticular temperature is elevated significantly in humans with varicocele. In addition, we have shown that scrotal skin surface temperature is elevated in men with varicocele. Furthermore, we demonstrate that unilateral varicocele is associated with bilateral elevation of scrotal surface temperature. These findings confirm the results of animal studies revealing elevation of intratesticular temperature associated with varicocele and suggest bilateral elevation in unilateral varicocele.


Macrophage migration inhibitory factor regulates innate γδ T-cell responses via IL-17 expression.
T cells expressing invariant γδ antigen receptors (γδ T cells) bridge innate and adaptive immunity and facilitate barrier responses to pathogens. Macrophage migration inhibitory factor (MIF) is an upstream mediator of host defense that up-regulates the expression of pattern recognition receptors and sustains inflammatory responses by inhibiting activation-induced apoptosis in monocytes and macrophages. Surprisingly, Mif-/- γδ T cells, when compared with wild type, were observed to produce >10-fold higher levels of the proinflammatory cytokine IL-17 after stimulation with gram-positive exotoxins. High-IL-17 expression was associated with the characteristic features of IL-17-producing γδ T (γδ17) cells, including expression of IL-23R, IL-1R1, and the transcription factors RORγt and Sox13. In the gram-positive model of shock mediated by toxic shock syndrome toxin (TSST-1), Mif-/- mice succumbed to death more quickly with increased pulmonary neutrophil accumulation and higher production of cytokines, including IL-1β and IL-23. Mif-/- γδ T cells also produced high levels of IL-17 in response to Mycobacterium lipomannan, and depletion of γδ T cells improved survival from acutely lethal Mycobacterium infection or TSST-1 administration. These data indicate that MIF deficiency is associated with a compensatory amplification of γδ17 cell responses, with implications for innate immunity and IL-17-mediated pathology in situations such as gram-positive toxic shock or Mycobacterium infection.-Kim, H. K., Garcia, A. B., Siu, E., Tilstam, P., Das, R., Roberts, S., Leng, L., Bucala, R. Macrophage migration inhibitory factor regulates innate γδ T-cell responses via IL-17 expression.


High galectin-1 expression correlates with poor prognosis and is involved in epithelial ovarian cancer proliferation and invasion.
Galectin-1 (Gal-1) is a 14-kDa laminin-binding galectin involved in several biological events including regulation of tumour proliferation and metastasis. In this study, we investigated the clinical significance of Gal-1 expression and its functional role in cell proliferation and invasion in epithelial ovarian cancer (EOC). We evaluated the expression of Gal-1 in 52 serous, 11 endometrioid, and 3 mucinous type EOC tumour samples from 66 patients by immunohistochemistry. In vitro experiments were performed to determine the function of Gal-1 in cell survival, proliferation, and invasion in EOC cells using siRNA and anginex, a Gal-1 inhibitor, as well as recombinant Gal-1 protein. Patients with strong Gal-1 peritumoural staining had poorer progression-free survival (PFS) than patients with weak peritumoural staining (p=0.03). Inhibition of Gal-1 by siRNA or anginex resulted in the inhibition of cell growth and proliferation of HeyA8 and SKOV3ip1 cells. Moreover, the ability of cells to migrate was significantly reduced by treatment of cells with Gal-1 siRNA but was increased by treatment of cells with recombinant Gal-1. When we evaluated the interaction between fibroblasts (T HESCs) and cancer cells (A2780-CP20), we found that MMP-2 expression in cancer cells was affected by Gal-1 secreted by fibroblast cells, which suggests that Gal-1 in human fibroblasts might affect the invasive abilities of tumour cells. Our results suggest that Gal-1 expression is a potential prognostic factor for PFS and that Gal-1 could be a novel treatment target in EOC patients.


Preparation and luminescent properties of YVO4:Eu3+ nanofibers by electrospinning.
This paper describes a procedure based on electrospinning for generating europium-doped yttrium vanadate (YVO4:Eu3+) nanofibers with diameters ranging from 30 to 50 nm. The YVO4:Eu3+ nanofibers were obtained through calcining precursory nanofibers, which were prepared through the electrospinning method. Suitable electrospinning parameters, such as concentration of PVP in solution, spinneret tip-to-collector plate distance (TCD), and applied voltage between spinneret and collector plate, are used to obtain thinner and more uniform precursory nanofibers of YVO4:Eu3+, which is important for preparing smaller diameter pure YVO4:Eu3+ nanofibers. The luminescent properties of the YVO4:Eu3+ nanofibers including excitation and emission spectra and fluorescence lifetime were studied. The excitation spectrum shows a broad band extending from 200 to 350 nm, which corresponds to the strong vanadate absorption in YVO4:Eu3+. The emission spectrum is dominated by the red 5D0 --> 7F2 hypersensitive transition of Eu3+. The fluorescence lifetime of Eu3+ 5D0 --> 7F2 (619 nm) is determined to be 493 micros at room temperature, which is basically in accordance with that in the bulk (521 micros).


Identification of MLL partner genes in 27 patients with acute leukemia from a single cytogenetic laboratory.
Chromosomal rearrangements involving the MLL gene have been associated with many different types of hematological malignancies. Fluorescent in situ hybridization with a panel of probes coupled with long distance inverse-PCR was used to identify chromosomal rearrangements involving the MLL gene. Between 1995 and 2010, 27 patients with an acute leukemia were found to have a fusion gene involving MLL. All seven ALL patients with B cell acute lymphoblastic leukemia were characterized by the MLL/AFF1 fusion gene resulting from a translocation (5 patients) or an insertion (2 patients). In the 19 AML patients with acute myeloblastic leukemia, 31.6% of all characterized MLL fusion genes were MLL/MLLT3, 21.1% MLL/ELL, 10.5% MLL/MLLT6 and 10.5% MLL/EPS15. Two patients had rare or undescribed fusion genes, MLL/KIAA0284 and MLL/FLNA. Seven patients (26%) had a complex chromosomal rearrangement (three-way translocations, insertions, deletions) involving the MLL gene. Splicing fusion genes were found in three patients, leading to a MLL/EPS15 fusion in two and a MLL/ELL fusion in a third patient. This study showed that fusion involving the MLL gene can be generated through various chromosomal rearrangements such as translocations, insertions and deletions, some being complex or cryptic. A systematic approach should be used in all cases of acute leukemia starting with FISH analyses using a commercially available MLL split signal probe. Then, the analysis has to be completed, if necessary, by further molecular cytogenetic and genomic PCR methods.


Two-year general and neurodevelopmental outcome after neonatal complex cardiac surgery in patients with deletion 22q11.2: a comparative study.
Neonatal complex cardiac surgery carries a significant risk for adverse neurodevelopmental outcome. We hypothesized this risk to be higher in patients with deletion 22q11.2. From 1996 to 2004, neonates who had complex cardiac surgery at age 6 weeks or less had multisite, multidisciplinary health and neurodevelopmental outcomes (Bayley Scales of Infant Development II; mental and psychomotor developmental indices [MDI, PDI] as mean [SD] and delay [<70]) assessed at 18 to 24 months of age. All 16 patients with deletion 22q11.2 (group 1) were compared with 16 patients without deletion 22q11.2 (group 2) having undergone neonatal complex cardiac surgery at the same center and matched for cardiac lesion, socioeconomic status, and year of operation. Outcomes were compared by univariate and multivariate analyses. Heart lesions in each group consisted of 6 (37.5%) cases of interrupted aortic arch, 6 (37.5%) cases of truncus arteriosus, and 4 (25%) cases of tetralogy of Fallot. Outcomes were available for all survivors. Mortality was 3 (19%) and 1 (6%) in groups 1 and 2, respectively (P = .6). MDI and PDI scores were 66.1 (10.6) and 55.0 (9.4) for group 1 and 86.3 (14.6) and 82.3 (14.3) for group 2 (P < .001). Only deletion 22q11.2 was significant in stepwise multiple regression to predict MDI and PDI scores. Mental delay occurred in 8 (61.5%) of 13 in group 1 and 2 (13.8%) of 15 in group 2 (P = .016). Psychomotor delay occurred in 11 (84.6%) of 13 in group 1 and 1 (6.7%) of 15 in group 2 (P < .001). Neonates affected by deletion 22q11.2 and having neonatal complex cardiac surgery have significantly worse neurodevelopmental outcome than do those without deletion 22q11.2.


Cognition and driving ability in isolated and symptomatic REM sleep behavior disorder.
To analyze cognitive deficits leading to unsafe driving in patients with REM Sleep Behavior Disorder (RBD), strongly associated with cognitive impairment and synucleinopathy-related neurodegeneration. Twenty isolated RBD (iRBD), 10 symptomatic RBD (sRBD), and 20 age- and education-matched controls participated in a prospective case-control driving simulation study. Group mean differences were compared with correlations between cognitive and driving safety measures. iRBD and sRBD patients were more cognitively impaired than controls in global neurocognitive functioning, processing speeds, visuospatial attention, and distractibility (p < .05). sRBD patients drove slower with more collisions than iRBD patients and controls (p < .05), required more warnings, and had greater difficulty following and matching speed of a lead car during simulated car-following tasks (p < .05). Driving safety measures were similar between iRBD patients and controls. Slower psychomotor speed correlated with more off-road accidents (r = 0.65) while processing speed (-0.88), executive function (-0.90), and visuospatial impairment (0.74) correlated with safety warnings in sRBD patients. Slower stimulus recognition was associated with more signal-light (0.64) and stop-sign (0.56) infractions in iRBD patients. iRBD and sRBD patients have greater selective cognitive impairments than controls, particularly visuospatial abilities and processing speed. sRBD patients exhibited unsafe driving behaviors, associated with processing speed, visuospatial awareness, and attentional impairments. Our results suggest that iRBD patients have similar driving-simulator performance as healthy controls but that driving capabilities regress as RBD progresses to symptomatic RBD with overt signs of cognitive, autonomic, and motor impairment. Longitudinal studies with serial driving simulator evaluations and objective on-road driving performance are needed.


Utility of histopathological revision in the management of gastro-entero-pancreatic neuroendocrine neoplasia.
Histological evaluation and grading assessment are key points in the diagnostic work-up of gastroentero-pancreatic neuroendocrine neoplasms (GEP-NENs). To analyze the impact of histopathological revision on the clinical management of patients with GEP-NEN. Patients referred to our Center of Excellence between 2015 and 2021 were included in this study. Immunohistochemical slides at the time of initial diagnosis were reviewed to assess tumor morphology, diagnostic immunohistochemistry, and Ki67. 101 patients were evaluated, with 65 (64.4%) gastrointestinal, 25 (24.7%) pancreatic, and 11 (10.9%) occult neoplastic lesions suspected to be of GEP origin. The main changes resulting from the revision were: first Ki-67 assessment in 15.8% of patients, Ki-67 change in 59.2% of patients and grading modification in 23.5% of patients. An additional immunohistochemical evaluation was performed in 78 (77.2%) patients, leading to a confirmation of GEP origin in 10 of 11 (90.9%) of unknown primary site neoplastic lesions and an exclusion of NEN diagnosis in 2 (2%) patients. After histopathological revision, a significant modification in clinical management was proposed in 42 (41.6%) patients. Histopathological revision in a referral NEN center is strongly advised in newly diagnosed GEP-NENs to properly plan prognostic stratification and therapeutic choice.


Evaluation of a testicular sperm head counting technique using rats exposed to dimethoxyethyl phthalate (DMEP), glycerol alpha-monochlorohydrin (GMCH), epichlorohydrin (ECH), formaldehyde (FA), or methyl methanesulphonate (MMS).
Single dosages of DMEP (1,000-2,000 mg/kg), GMCH (50 mg/kg), ECH (25 and 50 mg/kg), FA (100 and 200 mg/kg), and MMS (100-400 mg/kg) were administered orally to 10 week old male Wistar rats. The rats were necropsied on the 11th day following dosing. The testes were weighed, homogenised and sonicated; numbers of sperm heads (total and abnormal) were counted and percentage sperm head abnormalities were calculated. Testes weights were significantly reduced only in rats exposed to 1,500 and 2,000 mg DMEP/kg. Compared with controls, there were significant increases in the incidence of abnormal sperm at all dose levels of MMS and the higher dose levels of DMEP (1,500 and 2,000 mg/kg), ECH and FA. No toxicologically significant effects upon total sperm counts were seen following the oral administration of any of the five chemicals tested. However, an additional group of rats given 100 mg MMS/kg intraperitoneally (i.p.) showed significant reductions in testes weight and total sperm head counts compared with control animals. It is concluded that this testicular sperm head counting technique is a useful tool in the detection of selective adverse effects of chemicals upon testicular sperm but requires further evaluation.


European experience with the antiarrhythmic efficacy of propafenone for supraventricular and ventricular arrhythmias.
Seventy-one patients (mean age 53 years) were treated with oral propafenone, 900 mg/day, for a mean of 6.6 months. A large spectrum of arrhythmias was encountered, and particular attention was paid to their relation with the autonomic nervous system. Drug efficacy was graded from 1 (no effect) to 5 (complete control) according to the clinical result and Holter recording. This method permitted comparisons to be made between propafenone and 3 other antiarrhythmic agents: quinidine, beta-blockers and amiodarone. Among the 32 patients with supraventricular arrhythmias, 9 cases of vagally dependent atrial flutter and fibrillation were less sensitive to propafenone (mean effect 1.4) than to quinidine (mean effect 2.0) or amiodarone (mean effect 2.3). However, 8 cases of adrenergically dependent atrial tachycardia and fibrillation were more sensitive to propafenone (mean effect 4.1) than to beta blockers (3.0) or amiodarone (mean effect 3.5). In 12 cases of miscellaneous atrial arrhythmias the response to propafenone was intermediate. However, 3 patients with resistant junctional tachycardia were improved with propafenone. Among 42 ventricular arrhythmias, 5 patients with extrasystole who were responsive to quinidine (mean effect 3.8) were also improved with propafenone (mean effect 4.6). Propafenone (mean effect 4.1) was much more effective than quinidine (mean effect 2.4) in treating 8 cases of idiopathic benign ventricular tachycardia and even more successful in treating 13 cases of more severe arrhythmias in diseased hearts (propafenone's mean effect 4.1, quinidine's mean effect 1.9 and amiodarone's mean effect 1.9). Propafenone was less effective (mean effect 3.3) than amiodarone (mean effect 4.0) in 4 cases of severe, adrenergically dependent idiopathic ventricular tachycardia (VT).(ABSTRACT TRUNCATED AT 250 WORDS)


Management of severe cleft maxillary deficiency with distraction osteogenesis: procedure and results.
Distraction osteogenesis has become an important technique to treat craniofacial skeletal dysplasia. In this study, the technique of maxillary distraction with a rigid external distraction device is presented. Cephalometric results in the first 14 consecutive patients are analyzed. The study sample consisted of 14 patients with various cleft types and maxillary hypoplasia treated with the rigid external distraction technique. Analysis of the predistraction and postdistraction cephalometric radiographs revealed significant skeletal maxillary advancement. All patients had correction of the maxillary hypoplasia with positive skeletal convexity and dental overjet after maxillary distraction. The morbidity for the procedure was minimal. Surgical and orthodontic procedures are thoroughly described.


17β-Estradiol stimulates the translocation of endogenous estrogen receptor α at the plasma membrane of normal anterior pituitary cells.
In the present work we aimed at identifying ERα in the plasma membrane of normal anterior pituitary cells and investigated if 17β-estradiol was able to induce their subcellular redistribution. Our results show that about 8% of anterior pituitary cells expressed ERα in the plasma membrane, with the geometrical mean fluorescence intensity being increased after steroid hormone treatment. 17β-Estradiol and the selective ERα agonist PPT induced an increase of ERα expression in the plasma membrane and activated the PKCα/ERK 1/2 pathway in a time-course not compatible with genomic actions, thus supporting the notion of membrane-initiated effects. These findings suggest that 17β-estradiol stimulates the translocation of endogenous ERα to the plasma membrane, consequently modulating this ER pool and leading to cellular biological effects in normal anterior pituitary gland.


Characteristics of patients who visited emergency departments for headache in South Korea: A descriptive cross-sectional study.
This study aimed to describe the characteristics of adult patients who visit emergency departments (EDs) for non-traumatic headache in South Korea. Little is known about East Asian patients who visit EDs for headache. This observational, descriptive, cross-sectional study retrospectively analyzed 2019 National Emergency Department Information System data, including age, sex, co-occurring fever, symptom duration, insurance type, transportation mode, ED level, triage level, ED visit time, specialist consultations at the ED, disposition from the ED, and outcomes. The proportion of patients with a life-threatening secondary headache and the diagnostic codes were investigated. A total of 227,288 patients were observed in this study, accounting for 2.2% (227,288/10,238,360) of all ED visits. Females (63.1%; 143,493/227,288) visited EDs more than males, and patients aged 50-60 years (21.0%; 47,637/227,288) visited most frequently. A total of 61.5% (93,789/151,494) of ED visits were within 24 h after headache onset, and 57.6% (131,056/227,288) of visits were assigned to non-urgent triage levels. The most frequent discharge codes were "R51: Headache (not better specified)" from the ED and ward, and "I60: Subarachnoid hemorrhage" from the intensive care unit. The rate of migraine diagnosis was 7.2% (16,471/227,288). A total of 3.1% (7153/227,288) of patients were diagnosed with life-threatening secondary headaches, most commonly subarachnoid hemorrhage (1.2%; 2744/227,288) and cerebral infarction (0.6%; 1341/227,288). In South Korea, the characteristics of patients who visited the ED for non-traumatic headache were not very different from those in existing studies; however, patients tended to visit EDs early and be classified as non-urgent, and emergency physicians tended to enter the diagnosis code "R51: Headache (not better specified)", resulting in a much lower rate of migraine diagnoses. Non-urgent early visitors coded with "R51" may include those who have not yet been diagnosed with primary headache and have not been treated, but who need further research. Not applicable.


The absence of hemolytic disease in the newborn rhesus monkey (Macaca mulatta).
Hemolytic disease of the newborn has not been observed in rhesus monkeys even though the newborn's erythrocytes may be coated with maternal antibodies. Using a 51chromium-erythrocyte survival assay, we found that maternal antibodies do not mediate immune elimination of newborn's red blood cells. However, certain allogeneic or xenogeneic antibodies mediate clearance via sequestration by the reticuloendothelial system, or by intravascular hemolysis, or by a combination of these. The class of antibody plays a major role in elimination since red cells coated with IgG but not with IgM were rapidly cleared. In addition, the quantity of antibody controls the rate and extent of clearance. A comparison of rhesus alloantisera suggests that coating of multiple antigenic sites is necessary for clearance. Passive immunization with selected high-titered anti-erythrocyte alloantisera can induce some hematologic signs of erythrocyte destruction in newborn monkeys.