Efficient management of diarrhea in the acquired immunodeficiency syndrome (AIDS). A medical decision analysis.
To compare the efficacy and cost effectiveness of alternative strategies for the evaluation and medical management of diarrhea in patients with the acquired immunodeficiency syndrome (AIDS). Medical decision analysis using a decision tree. Three management strategies were compared: full evaluation, which included stool culture, ova and parasite examination, stain for protozoa, blood cultures, esophagogastroduodenoscopy with biopsy, and colonoscopy with biopsy; limited evaluation, which included stool culture, ova and parasite examination, stool stain for protozoa, and blood cultures; and minimal evaluation, which included only a stool culture. Treatment was based on the outcome of the diagnostic workup. Patients without a specific diagnosis were treated symptomatically with diphenoxylate hydrochloride. Nonrespondents to initial symptomatic treatment and patients with recurrent diarrhea after specific therapy were given the full evaluation. Average probabilities of diagnostic and therapeutic success were calculated from previous reports. Costs were compiled based on diagnostic and therapeutic expenditures. Under baseline assumptions, the remission rates for diarrhea were 75.2%, 74.8%, and 74.8% in patients undergoing the full, limited, and minimal evaluations, respectively. The respective costs of the three strategies were $5419, $1997, and $1700 per patient in remission. A sensitivity analysis showed that the differences in efficacy and cost among the full, limited, and minimal strategies remained unchanged over a broad range of possible rates of diagnostic or therapeutic success. The minimal evaluation in all patients, with the full evaluation reserved only for nonrespondents to symptomatic treatment, is efficacious and is the most cost-effective strategy for managing AIDS-related diarrhea.


S,O-Ligand-Promoted Palladium-Catalyzed C-H Functionalization Reactions of Nondirected Arenes.
Pd(II)-catalyzed C-H functionalization of nondirected arenes has been realized using an inexpensive and easily accessible type of bidentate S,O-ligand. The catalytic system shows high efficiency in the C-H olefination reaction of electron-rich and electron-poor arenes. This methodology is operationally simple, scalable, and can be used in late-stage functionalization of complex molecules. The broad applicability of this catalyst has been showcased in other transformations such as Pd(II)-catalyzed C-H acetoxylation and allylation reactions.


Probing epitopes on human prorenin during its proteolytic and non-proteolytic activation.
The conformational changes of prorenin (PR) that are associated with its reversible non-proteolytic activation and irreversible proteolytic activation were monitored with immunoradiometric assays, using antibodies against epitopes belonging to the propeptide or the renin part of PR. Binding of PR to the renin inhibitor remikiren or protonation of PR resulted in the slowly progressive and simultaneous expression (t1/2 congruent with3.5-5.0 h at 4 degreesC) of epitopes of the N-terminal and C-terminal halves of the propeptide and an epitope that is manifest on renin but not on native non-activated PR. During reversible PR activation-inactivation, expression and disappearance of these epitopes coincided with the appearance and disappearance of enzyme activity. Cleavage of the propeptide from the renin part of PR by plasmin, as demonstrated by the failure of remikiren to unmask the N-terminal and C-terminal propeptide epitopes, was, with some time lag, followed by the simultaneous expression (t1/2 congruent with60 min at 4 degreesC) of the renin-specific epitope and enzymatic activity. Based on these findings we propose a model for the non-proteolytic activation of PR that involves the formation of an intermediary form of activated PR with the following properties: (1) the covalently bound propeptide has moved out of the active-site cleft, so that binding sites are exposed to active site ligands, (2) the propeptide is still not in the 'relaxed' conformation that is characteristic for fully, non-proteolytically, activated PR, and (3) the N-terminal part of the renin polypeptide chain has not yet attained the proper location that is required for enzymatic activity.


Surface area of dental enamel, bone, and hydroxyapatite: chemisorption from solution.
The surface areas of three different samples of hydroxyapatite, samples of deproteinized bone, and samples of whole and deproteinized enamel were determined by adsorption of an adduct (the diglycidyl ether of bisphenol A with N-phe-nylglycine) from methylene chloride solution. In all cases, the surface areas of these samples agree well with those obtained by the BET (N2) method.


Parvalbumin-immunoreactive structures of the adult human entorhinal and transentorhinal region.
Parvalbumin-immunoreactive structures in the entorhinal and transentorhinal region of the adult human brain were studied using the avidin-biotin-peroxidase technique. Parvalbumin-immunoreactive neurons and fibers (axons) were present in all layers (layer nomenclature according to Rose, 1927). The density of fibers was high in the islands of the superficial cell layer pre-alpha and in layer pre-beta and still heavier in pre-gamma. In the subjacent lamina dissecans it diminished abruptly and remained low in all layers of the internal principal stratum (layers pri-alpha, -beta, -gamma). This low density of fibers facilitated recognition of axon cartridges in layers pri-alpha and pri-gamma. Axon cartridges were also present within layers pre-beta and pre-gamma but were obscured by the dense fiber network there. Parvalbumin immunoreactivity was observed in the nerve cell soma and throughout the dendritic tree allowing the distinction of numerous nerve cell types. All parvalbumin-immunoreactive neurons belonged to the class of nonpyramidal neurons. Their lipofuscin pigment patterns differed distinctly from that of the pyramidal and modified pyramidal neurons. Based on their location, soma size, and dendritic arborization, they were grouped as large, medium-sized, and small neurons either of the multipolar or bipolar (vertical or horizontal) type. One type could be identified as an axo-axonic neuron, more specifically as a chandelier neuron generating axon cartridges. The dense fiber net within layer pre-gamma suggested the existence of another neuronal type, probably a neuron with an extended axonal ramification. The identified neurons were compared to neuronal types described in the literature from Golgi studies.


Association of stearoyl-CoA desaturase 1 activity with familial combined hyperlipidemia.
Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme involved in the synthesis of monounsaturated fatty acids, and in mice SCD1 activity is associated with plasma triglyceride levels. We used the fatty acid desaturation index (the plasma ratio of 18:1/18:0) as a marker of SCD1 activity to investigate the relationship of SCD1 to familial combined hyperlipidemia (FCHL). The fatty acid desaturation index was measured in 400 individuals from 18 extended FCHL pedigrees. FCHL-affected individuals exhibited increased SCD1 activity when compared to unrelated controls (P < 0.0001). The fatty acid desaturation index was found to be highly heritable (h(2) = 0.48, P = 2.2 x 10(-11)) in this study sample. QTL analysis in 346 sibling pairs from 18 FCHL families revealed suggestive linkage of the desaturation index to chromosomes 3p26.1 to 3p13 (z = 2.7, P = 0.003), containing the peroxisome proliferator-activated receptor gamma (PPARgamma) gene, and 20p11.21 to 20q13.32 (z = 1.7, P = 0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4alpha) gene. A specific haplotype of HNF4alpha was found to be associated with the desaturation index in these FCHL families (P = 0.002). Our results demonstrate that the fatty acid desaturation index is a highly heritable trait that is associated with the dyslipidemia observed in FCHL.


Social security status and mortality in Belgian and Spanish male workers.
To assess differences in mortality rates between social security statuses in two independent samples of Belgian and Spanish male workers. Study of two retrospective cohorts (Belgium, n=23,607; Spain, n=44,385) of 50-60 year old male employees with 4 years of follow-up. Mortality rate ratios (MRR) were estimated using Poisson regression models. Mortality for subjects with permanent disability was higher than for the employed, for both Belgium [MRR=4.56 (95% CI: 2.88-7.21)] and Spain [MRR=7.15 (95% CI: 5.37-9.51)]. For the unemployed/early retirees, mortality was higher in Spain [MRR=1.64 (95% CI: 1.24-2.17)] than in Belgium [MRR=0.88 (95% CI: 0.46-1.71)]. MRR differences between Belgium and Spain for unemployed workers could be partly explained because of differences between the two social security systems. Future studies should further explore mortality differences between countries with different social security systems.


Fine needle aspiration of breast carcinoma in a fibroadenoma.
A case of concurrent carcinoma of the breast with a fibroadenoma in a 59-year-old woman is described. The diagnosis was made on fine needle aspiration cytology. Despite the rarity of such a lesion, it is felt that a cytological diagnosis of this lesion from a fine needle aspirate specimen is possible.


Function of cloned T4 recombination genes, uvsX and uvsY, in cells of Escherichia coli.
Genes uvsX and uvsY of bacteriophage T4 both control genetic recombination and repair of damaged DNA, and their mutant phenotypes bear a striking resemblance to each other. It has been shown recently that the uvsX gene product is analogous to the recA gene product of Escherichia coli (Yonesaki et al. 1985; Yonesaki and Minagawa 1985; Formosa and Alberts 1986), but the function of the uvsY gene is unknown. To obtain further insight into the function of these genes we introduced plasmidborne copies of the two genes separately or together into E. coli. The uvsX gene rendered recA- cells more resistant to UV and raised the recombination frequency of lambda phage and E. coli, but hampered induction of the lambda prophage and the SOS function of E. coli. The uvsY gene had no detectable function when introduced alone into E. coli but significantly enhanced the function of the uvsX gene when the two plasmid-borne genes were introduced together.


A decline in perceived social status leads to post-traumatic stress disorder symptoms in adults half a year after the outbreak of the COVID-19 pandemic: consideration of the mediation effect of perceived vulnerability to disease.
In December 2019, Wuhan, Hubei, China firstly reported the existence of the COVID-19 virus. It is crucial to prioritize the psychological well-being of citizens in lockdown cities and make more strides in the academic field of post-traumatic stress disorder (PTSD) to prepare for the post-pandemic era. We took the cognitive-relational theory as our basis and collected Hubei province-level data (N = 3,465) to examine the impact of perceived social status decline on the prevalence of PTSD symptoms, and checked the mediating effect of perceived vulnerability to disease (PVD) during the period of psychological adjustment. Using propensity score matching, we estimate the average treatment effect of perceived social status decline on PTSD level, and we robustly regress the two with weight adjustment generated in matching. We found that more decline in perceived social status is associated with a worse degree of PTSD symptoms, and confirmed PVD's buffering role although the mediating effect was not as high as hypothesized. Our study confirmed the decisive role of subject social status in health prediction compared to traditional socioeconomic measures, which extends the cognitive-relational in examining socioeconomic status and contributes to the dialog on socioeconomic inequality. We also suggested providing more social support at the community level and enhancing individuals' positive understanding to protect mental health.


The cognitive enhancer SGS742 does not involve major known signaling cascades in OF1 mice.
In a previous study we have shown that SGS742, a cognitive enhancer acting by GABA(B) receptor antagonism improved spatial learning in OF1 mice. The aim of the study was therefore to screen representatives of several signaling cascades known to be involved in memory formation at the protein level. NaCl-, SGS742- treatment and yoked controls for NaCl and SGS742 were studied. Six hours following testing OF1 mice in the Morris water maze, hippocampal signaling proteins calmodulin kinase II (CaMKII) (phosphorylated (P) and non-phosphorylated (NP) form), CREB (P, NP), ERK (P, NP), BDNF, Egr-1, Trk-B and neuro-cytoskeleton elements drebrin and PSD-95 were determined by immunoblotting. Protein patterns were comparable between the control and SGS742 treated group revealing that these proteins may not be involved in the mechanisms underlying cognitive enhancement by SGS742 and this should be taken into account for interpretation and design of previous and future related neurochemical studies.


Cytoprotective and antioxidant effects of human lactoferrin against H2O2-induced oxidative stress in human umbilical vein endothelial cells.
Lactoferrin (LF) is an iron-binding glycoprotein with antioxidant, anti-inflammatory and nitric oxide-dependent vasodilatory properties. In the present study, we investigated the protective and antioxidant effects of LF on H2O2-induced oxidative stress in human umbilical vein endothelial cells (HUVECs). HUVECs were pretreated by (6.25-100 μg/ml) LF for 24 h and then exposed to 0.5 mM H2O2 for 2 h. Cell viability was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The intra- and extra-cellular hydroperoxides concentration and ferric reducing antioxidant power (FRAP) were determined in pretreated cells. Pretreatment of HUVECs with LF at the concentrations of 25-100 μg/ml significantly reduced the cytotoxicity of H2O2 in a concentration-dependent manner using MTT assay. LF pretreatment at different concentration ranges also decreased the hydroperoxides level and augmented the FRAP value in both intra-and extra-cellular assay. These findings revealed antioxidant and cytoprotective effects of LF against H2O2-induced oxidative stress in HUVECs. With regard to the beneficial vascular activity of LF, further investigations are suggested for understanding its clinical value in human endothelial dysfunction and prevention and/or treatment of CVDs.


Vasoparalysis associated with brain damage in asphyxiated term infants.
The relationship of cerebral blood flow to acute changes in arterial carbon dioxide and mean arterial blood pressure (MABP) was determined during the first day of life in 19 severely asphyxiated term infants supported by mechanical ventilation. For comparison, 12 infants without perinatal asphyxia were also investigated. Global cerebral blood flow (CBF infinity) was determined by xenon 133 clearance two or three times within approximately 2 hours. During the cerebral blood flow measurement, the amplitude-integrated electroencephalogram and visual-evoked potential were recorded. Changes in arterial carbon dioxide pressure followed adjustments of the ventilator settings, whereas MABP fluctuated spontaneously. Arterial oxygen pressure and blood glucose concentration were in the normal range. Five of the asphyxiated infants had isoelectric electroencephalograms and died subsequently with severe brain damage. They had a high CBF infinity (mean 30.6 ml/100 gm/min) and abolished carbon dioxide and MABP reactivity. Lower CBF infinity (mean 14.7 ml/100 gm/min) and abolished MABP reactivity were found in another five asphyxiated infants with burst-suppression electroencephalograms in whom computed tomographic or clinical signs of brain lesions developed. The carbon dioxide reactivity was preserved in these infants. In the remaining nine asphyxiated infants without signs of central nervous system abnormality, carbon dioxide and MABP reactivity were preserved, as was also the case in the control group. We conclude that abolished autoregulation is associated with cerebral damage in asphyxiated infants and that the combination of isoelectric electroencephalograms and cerebral hyperperfusion is an early indicator of very severe brain damage.


Evaluation of monoclonal antibodies to human plasma low density lipoproteins. A requirement for lipids to maintain antigenic structure.
Human plasma low density lipoproteins (LDL) are composed of approximately 25% apoproteins and 75% lipids (w/w). Immunochemical properties of LDL were studied using monoclonal antibodies. BALB/c mice were immunized with LDL and the spleen cells from these mice were then fused with a non-immunoglobulin secreting myeloma cell line (F0). The clones producing desirable antibodies were selected to study the antigenic properties of LDL by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay. First, it was found that the maximal binding of 125I-labeled LDL to polyvinyl chloride microtiter dishes was not temperature dependent. The binding affinity was high with a Ka value of approximately 1.9 X 10(10) M-1 while the monoclonal antibodies possessed an affinity to LDL of 5 X 10(8) M-1 which was 2 orders less than the affinity of LDL to the dishes. The former binding, once established, was irreversible as judged by a subsequent incubation with an excess of unlabeled LDL. The latter binding could be displaced by unlabeled LDL. Therefore, the ELISA technique offered a satisfactory approach to study the interaction between LDL and monoclonal antibodies. Removal of lipids from bound LDL by organic extraction resulted in a 50% loss of immunoreactivity, suggesting that the lipids of LDL are important in maintaining the antigenic structure of LDL. Since the apoprotein of LDL also constitutes approximately 40% of the mass (w/w) of very low density lipoproteins (VLDL), the immunoreactivity of VLDL assessed by LDL-monoclonal antibodies was also carried out. Removal of triglycerides from VLDL by lipoprotein lipase resulted in a substantial loss of immunoreactivity as determined by radioimmunoassay. These findings are consistent with the concept that lipids play a role in maintaining the integrity of the antigenic structure of LDL.


Untargeted metabolomics by high resolution mass spectrometry coupled to normal and reversed phase liquid chromatography as a tool to study the in vitro biotransformation of new psychoactive substances.
In 2016, several synthetic cathinones were seized by the State Bureau of Criminal Investigation Bavaria in Germany. Due to their previous appearances in other countries their metabolism was already investigated in human urine as well as different in vitro models. These investigations were conducted using ordinary metabolism studies for drugs of abuse by using general knowledge about drug metabolism and visual comparison of mass spectra. The present study aimed to use untargeted metabolomics to support and improve those methods that highly depend on the investigators experience. Incubations were conducted using pooled human liver microsomes (pHLM) and the two cathinones 1-phenyl-2-(1-pyrrolidinyl)-1-butanone and 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone. Samples were analyzed by LC-HRMS/MS using a metabolomics workflow consisting of a reversed phase or normal phase separation followed by electrospray ionization and full scan in positive or negative mode. LC-MS data was afterwards statistically evaluated using principal component analysis, t-distributed stochastic neighborhood embedding, and hierarchical clustering. Significant features were then identified using MS/MS. The workflow revealed 24 significant features after 1-phenyl-2-(1-pyrrolidinyl)-1-butanone and 39 after 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone incubation, consisting of adducts, artifacts, isomers, and metabolites. The applied untargeted metabolomics strategy was able to find almost all of the metabolites that were previously described for 1-phenyl-2-(1-pyrrolidinyl)-1-butanone in literature as well as three additional metabolites. Concerning 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone biotransformation in pHLM, merely four metabolites described in primary human hepatocytes and human urine were not found. This study revealed that untargeted metabolomics workflows are well suited to support biotransformation studies at least of the investigated compounds in pHLM.


Influential role of black carbon in the soil-air partitioning of polychlorinated biphenyls (PCBs) in the Indus River Basin, Pakistan.
Levels of polychlorinated biphenyls (PCBs) were assessed in surface soils and passive air samples from the Indus River Basin, and the influential role of black carbon (BC) in the soil-air partitioning process was examined. ∑26-PCBs ranged between 0.002-3.03 pg m(-3) and 0.26-1.89 ng g(-1) for passive air and soil samples, respectively. Lower chlorinated (tri- and tetra-) PCBs were abundant in both air (83.9%) and soil (92.1%) samples. Soil-air partitioning of PCBs was investigated through octanol-air partition coefficients (KOA) and black carbon-air partition coefficients (KBC-A). The results of the paired-t test revealed that both models showed statistically significant agreement between measured and predicted model values for the PCB congeners. Ratios of fBCKBC-AδOCT/fOMKOA>5 explicitly suggested the influential role of black carbon in the retention and soil-air partitioning of PCBs. Lower chlorinated PCBs were strongly adsorbed and retained by black carbon during soil-air partitioning because of their dominance at the sampling sites and planarity effect.


Human non-interferon macrophage activating factor: biological and biochemical characterization.
A HTLV-1 transformed T cell line has been demonstrated to constitutively produce and secrete a lymphokine with macrophage activating properties. This lymphokine was biologically and biochemically distinct from interferon gamma, the interleukins, the colony stimulating factors and lymphotoxin. In vitro treatment of human monocytes with the partially purified lymphokine resulted in the acquisition of microbicidal and tumoricidal activities. The activity was associated with a protein with an apparent molecular weight of 55,000 daltons and an isoelectric point of 5.5. The potential for the efficacy of such a lymphokine in activating macrophages in vivo provides aspirations for its use in the therapy/prevention of opportunistic infections in immunocompromised hosts.


Design, synthesis and biological evaluation of 3-substituted-2-thioxothiazolidin-4-one (rhodanine) derivatives as antitubercular agents against Mycobacterium tuberculosis protein tyrosine phosphatase B.
Mycobacterium tuberculosis infections still pose a serious threat to human health. Combination therapies are effective medical solutions to the problem. Mycobacterium tuberculosis is an intracellular pathogen that mainly depends on a virulence factor (Mycobacterium tuberculosis protein tyrosine phosphatase B, MptpB) for its survival in the host. Therefore, MptpB inhibitors are potential components of tuberculosis combination treatments. Herein, a new series of MptpB inhibitors bearing a rhodanine group were developed using a structure-based strategy based on the virtual screening hit. The new MptpB inhibitors displayed potent MptpB inhibitory activities and great improvements in cell membrane permeability. The optimal compounds reduced the bacterial burden in a dose-dependent manner in a macrophage infection model, especially, a combination of compound 20 and rifampicin led to a bacterial burden reduction of more than 95%, greater than the reductions achieved with compound 20 or rifampicin alone. This research provides new insights into the rational design of new MptpB inhibitors and verifies that the MptpB inhibitor has a promising potential as a component of tuberculosis treatment.


Novel aspects of the neuropathology of the vegetative state after blunt head injury.
A detailed neuropathological study was undertaken of the brains of patients who had been assessed clinically as vegetative after blunt head injury. There were 35 cases, (33 male; median age 38 years) with a survival of 6.5-19 months (median 9): 17 were injured in a road traffic accident, 9 after assault and 6 after a fall; 3 were recorded as having had a lucid interval. There was an intracranial hematoma in 9 and the median contusion index was 4; raised intracranial pressure was identified in 25, grades 2 and 3 diffuse traumatic axonal injury was present in 25, ischemic damage in 15 and hydrocephalus in 27. Thalamic and hippocampal damage was present in 28 and stereological studies revealed a differential loss of neurons in three principal nuclei of the thalamus and in different sectors of the hippocampus. Immunohistochemistry provided evidence of an inflammatory reaction and in situ DNA fragmentation, features that are strongly indicative of a continuing neuronal loss in subcortical gray matter. These findings provide evidence for the importance of diffuse brain damage to white matter as the structural basis of the vegetative state after blunt head injury with contributions from neuronal loss in the thalami and the hippocampus. Although amyloid plaques and tau inclusions were identified in some, their contribution did not seem important in the ultimate clinical outcome.


High performance force feedback mechanism for virtual reality training of endotracheal intubation.
A high-performance mechanism has been developed to provide force feedback during virtual reality simulations of endotracheal intubation for training purposes for the first time. The force feedback mechanism (FFM) prototype permits planar motion of the intubation tool with three degrees of freedom, each with force feedback. The FFM is computer controlled using a hybrid position-force feedback algorithm that includes a feedforward term to counterbalance the mechanism. This allows the intubation force profiles to be superimposed onto the FFM weight compensation to complete the overall force feedback effort. The development of a mechanism of this type introduces several theoretical and experimental design challenges that are addressed in this paper.


Bactericidal/permeability-increasing protein and group I and II phospholipase A2 during the induction phase of human acute pancreatitis.
Activated endogenous mediators of inflammation have important roles in the pathogenesis and complications of acute pancreatitis (AP). These mediators include bactericidal/ permeability-increasing protein (BPI) and phospholipase A2 (PLA2). The time course of their activation during human AP is not known. The aim of this study was to evaluate the kinetics of BPI, group I (pancreatic) and group II (synovial type) PLA2 during human AP with temporally defined onset, as being induced by endoscopic retrograde cholangiopancreatography (ERCP). Serum samples of 273 consecutive patients undergoing ERCP were collected before and at 3, 6, and 24 h after ERCP. Twenty-four (8.7%) patients developed ERCP-induced pancreatitis. Seven of them were graded to have a severe disease. Forty randomly selected patients undergoing ERCP without evidence of pancreatitis served as controls. The serum concentrations of BPI and groups I and II PLA2 were measured by specific immunoassays. The mean concentration of BPI increased from 14 to 26 microg/L at 24 h after ERCP in patients with AP. In the control group, BPI values remained unchanged, and the difference was statistically significant (p<0.001). The increase of BPI was seen in 22 of 28 patients with AP at 3 h after the onset of the disease. BPI values were higher in severe post-ERCP pancreatitis than in mild disease (p = 0.07; NS). The serum concentrations of group II PLA2 before ERCP were consistently higher in the control patients than in the patients with pancreatitis, 65.8 and 14.2 microg/L, respectively. High baseline values in the control group were associated with preexisting infectious diseases. Thereafter, the mean concentration decreased in the control group to 44 microg/L and increased in the pancreatitis group up to 27.5 microg/L. The difference was statistically significant (p = 0.007). Increased group II PLA2 values were seen in 10 of 17 patients with mild AP and in five of seven patients with severe disease. There were no significant differences in group I or II PLA2 values in patients with mild or severe AP. The serum concentration of group I PLA2 increased in the patients with post-ERCP pancreatitis from 5.4 to 37.5 microg/L at 24 h. The difference was statistically significant, (p< 0.001) as compared with controls. In conclusion, in acute pancreatitis, the increase of BPI in serum starts at 3 h after the onset of the disease, and the concentration seems to correlate with the severity of the disease. Increased group II PLA2 concentrations also were seen in patients with mild AP. The kinetics of group I PLA2 resembles that of other pancreatic enzymes.


Solution properties and taste behavior of lactose monohydrate in aqueous ascorbic acid solutions at different temperatures: Volumetric and rheological approach.
The densities and viscosities of lactose monohydrate in aqueous ascorbic acid solutions with several molal concentrations m=(0.00-0.08)molkg(-1) of ascorbic acid were determined at T=(298.15-318.15)K and pressure p=101kPa. Using experimental data apparent molar volume (ϕV), standard partial molar volume (ϕV(0)), the slope (SV(∗)), apparent specific volumes (ϕVsp), standard isobaric partial molar expansibility (ϕE(0)) and its temperature dependence [Formula: see text] the viscosity B-coefficient and solvation number (Sn) were determined. Viscosity B-coefficients were further employed to obtain the free energies of activation of viscous flow per mole of the solvents (Δμ1(0≠)) and of the solute (Δμ2(0≠)). Effects of molality, solute structure and temperature and taste behavior were analyzed in terms of solute-solute and solute-solvent interactions; results revealed that the solutions are characterized predominantly by solute-solvent interactions and lactose monohydrate behaves as a long-range structure maker.


Development of a stratum corneum and barrier function in an organotypic skin culture.
The stratum corneum of human skin is responsible for maintaining the epidermal permeability barrier. We have developed a bilayered skin culture (SC) which forms a corneum 35 +/- 1 cell layers thick 21 days after being raised to the air-liquid (A/L) interface. By the 7th day after raising to the A/L interface the corneocytes were irregularly shaped and had cross-sectional areas (CSA) of > or = 300 microns 2. By the 21st day the corneocytes had assumed polygonal shapes and had a CSA (100-250 microns 2) similar to that of human foreskin. The total lipid (TL) content of the corneum averaged 5-7% of the lyophilized weight. Ceramide content increased from 20% of TL at day 7 of A/L interface culture to 30% at day 21. Triglycerides decreased from 43% to 17% of TL during the same period. Free fatty acids comprised 5.5% of TL at day 21 of A/L interface culture. The intercorneocyte spaces contained stacks of lipid lamellae. However, the stacks lacked the Landmann unit repeat. Abnormal lamellar structures were observed in both the intra- and extracorneocyte spaces. Transepidermal water loss (TEWL) was > 4 mg/cm2 per h throughout the culture period. Lipid supplementation of the culture medium and culturing in a low humidity environment improved barrier function by 50%. However, the effects were not additive. The SC developed a near-normal corneum, but did not achieve barrier competence, due at least partially to abnormalities in lipid composition and organization.(ABSTRACT TRUNCATED AT 250 WORDS)


MicroRNA-449b-5p targets HMGB1 to attenuate hepatocyte injury in liver ischemia and reperfusion.
MicroRNAs (miRNAs) participate in the pathological process of liver ischemia/reperfusion (I/R) injury. MiR-449b-5p is the target miRNA of high mobility group box 1 (HMGB1). Its role and molecular mechanism in liver I/R injury remain unidentified. In this study, we found a protective effect of miR-449b-5p against hepatic I/R injury. HMGB1 expression significantly increased, whereas miR-449b-5p dramatically decreased in patients after liver transplant and in L02 cells exposed to hypoxia/reoxygenation (H/R). A dual-luciferase reporter assay confirmed the direct interaction between miR-449b-5p and the 3' untranslated region of HMGB1 messenger RNA. We also found that overexpression of miR-449b-5p significantly promoted cell viability and inhibited cell apoptosis of L02 cells exposed to H/R. Moreover, miR-449b-5p repressed HMGB1 protein expression and nuclear factor-κB (NF-κB) pathway activation in these L02 cells. In an in vivo rat model of hepatic I/R injury, overexpression of miR-449b-5p significantly decreased alanine aminotransferase and aspartate aminotransferase and inhibited the HMGB1/NF-κB pathway. Our study thus suggests that miR-449b-5p alleviated hepatic I/R injury by targeting HMGB1 and deactivating the NF-κB pathway, which may provide a novel and promising therapeutic target for hepatic I/R injury.


Nintendo Wii rehabilitation ("Wii-hab") provides benefits in Parkinson's disease.
Parkinson's disease (PD) impairs both activities of daily living (ADLs) and motor function and has adverse effects on mood in many patients. While dopaminergic medications are quite helpful for motor and ADLs impairments in PD, complementary therapies are also important in helping patients achieve maximum benefits and quality of life. We hypothesized that the Nintendo Wii (Wii) is a useful tool in improving motor and non-motor aspects in patients with PD, given its ability to drive functional movements and interactive nature. We enrolled twenty subjects with early to mid-stage PD in an open-label within-subjects study design where each subject was evaluated at baseline and then re-evaluated after playing the Wii three times per week for four weeks. Subjects were then re-evaluated one month later after not playing the Wii for a month to see if effects carried over. Subjects demonstrated significant improvements in the primary outcome measure (Nottingham Extended Activities of Daily Living Test (NEADL)), quality of life (PDQ-39) and motor function (UPDRS), and a trend toward improved mood (HAM-D) after four weeks of Wii therapy. Follow-up assessments one month later showed continued improvement for quality of life and UPDRS scores. The results demonstrate that Wii therapy provides short-term motor, non-motor, and quality of life benefits in PD. Further studies are needed to determine if there are long-term benefits of Wii therapy in PD.


A Novel Technique for Rejuvenation of Degenerated Caterpillar Medicinal Mushroom, Cordyceps militaris (Ascomycetes), a Valued Traditional Chinese Medicine.
Cordyceps militaris has been used in traditional Chinese medicine for many years, but its frequent degeneration during continuous maintenance in culture can lead to substantial commercial losses. In this study, a degenerated strain of C. militaris was obtained by subculturing a wild-type strain through 10 successive subcultures. The relative abundance of the 2 mating types seems to be out of balance in the degenerated strain. By cross-mating 4 single-ascospore isolates (2 for MAT 1-1 and 2 for MAT 1-2) from the degenerated strain, we were able to restore fruiting body production to wild-type levels. The rejuvenated strain not only produced well-developed fruiting bodies but also accumulated more cordycepin and adenosine than either the original wild-type strain or the degenerated strain. These new characteristics remained stable after 4 successive transfers, which indicates that the method used to rejuvenate the degenerated strain in this study is an effective approach.


Inhibition of cystathionine-gamma lyase dampens vasoconstriction in mouse and human intracerebral arterioles.
In extracerebral vascular beds cystathionine-gamma lyase (CSE) activity plays a vasodilatory role but the role of this hydrogen sulfide (H2 S) producing enzyme in the intracerebral arterioles remain poorly understood. We hypothesized a similar function in the intracerebral arterioles. Intracerebral arterioles were isolated from wild type C57BL/6J mouse (9-12 months old) brains and from human brain biopsies. The function (contractility and secondary dilatation) of the intracerebral arterioles was tested ex vivo by pressure myography using a perfusion set-up. Reverse transcription polymerase chain reaction was used for detecting CSE expression. CSE is expressed in human and mouse intracerebral arterioles. CSE inhibition with L-propargylglycine (PAG) significantly dampened the K+ -induced vasoconstriction in intracerebral arterioles of both species (% of maximum contraction: in human control: 45.4 ± 2.7 versus PAG: 27 ± 5.2 and in mouse control: 50 ± 1.5 versus PAG: 33 ± 5.2) but did not affect the secondary dilatation. This effect of PAG was significantly reversed by the H2 S donor sodium hydrosulfide (NaSH) in human (PAG + NaSH: 38.8 ± 7.2) and mouse (PAG + NaSH: 41.7 ± 3.1) arterioles, respectively. The endothelial NO synthase (eNOS) inhibitor, Nω-Nitro-l-arginine methyl ester (L-NAME), and the inhibitor of soluble guanylate cyclase (sGC), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reversed the effect of PAG on the K+ -induced vasoconstriction in the mouse arterioles and attenuated the K+ -induced secondary dilatation significantly. CSE contributes to the K+ -induced vasoconstriction via a mechanism involving H2 S, eNOS, and sGC whereas the secondary dilatation is regulated by eNOS and sGC but not by CSE.


Inflammation of rat molar pulp and periodontium causes increased calcitonin gene-related peptide and axonal sprouting.
We have studied the response of nerve fibers containing calcitonin gene-related peptide immunoreactivity (CGRP-IR) to inflammation using a rate dental experimental system. Inflammation was induced by drilling tooth cusps to create pulpal exposures; the induced pulpitis and subsequent periapical lesions were studied 1-35 days later using standard CGRP immunohistochemistry and the avidin-biotin peroxidase method. The injury and resulting inflammation caused a disruption of CGRP-IR nerve fiber location and arborization that varied depending on whether the initial injury was limited to the pulp tip or extended throughout the pulp horn. At shorter survival periods (24 hr, 3 days) nerve fibers were either decreased or bundled into the center of the pulp with sprouting along the wound border. At 6 days necrosis and acute inflammation had advanced to varying degrees, and CGRP-IR fibers were extensively sprouted in the surviving pulp; the pulp also stained specifically for CGRP within 1-2 mm of the inflamed tissue at 6 days. At 35 days, we found total pulp necrosis in most teeth and the development of periapical bone loss, granulomatous tissue, and periapical abscesses. There was also an extensive increase in CGRP-IR nerve fibers in the tissues surrounding sites of severe periodontal inflammation and necrosis. In some cases, macrophage-like cells staining specifically for CGRP were near the abscesses. The results show important interactions between peptidergic nerve fibers and inflammatory cells, and are discussed in terms of the role of nerve fibers containing CGRP in neurogenic inflammation, mechanisms for intensification of CGRP immunoreactivity in affected fibers or neighboring cells, and implications for chronic inflammatory conditions, dental pain, and anesthesia.


Co-immobilization of multiple enzymes by self-assembly and chemical crosslinking for cofactor regeneration and robust biocatalysis.
Artificial multienzyme biocatalysts have played a crucial role in biosynthesis because they allow for conducting complex reactions. Here, we reorted a facile approach to fabricate multienzyme nanodevices with high catalytic activity and stability based on protein assembly and chemical crosslinking. The self-assembled partner SpyCatcher and SpyTag were genetically fused with 2,3-butanediol hydrogenase and formate hydrogenase to produce KgBDH-SC (SpyCatcher-fused 2,3-butanediol hydrogenase) and FDH-ST (SpyTag-fused formate hydrogenase), respectively. After assembling the two fusion proteins, the complexes were then immobilized on the functionalized silicon dioxide nanoparticles by glutaraldehyde, forming KgBDH-SC-ST-FDH-SiO2 with the capability of reducing 2-hydroxyacetophenone to (R)-1-phenyl-1,2-ethanediol with cofactor regeneration. Under the optimal conditions, the created co-immobilized enzymes performed 49% activity recovery compared with the mixture of free enzymes as well as showed 2.9-fold higher catalytic activity than the traditional random co-immobilized enzymes. Moreover, KgBDH-SC-ST-FDH-SiO2 showed better pH stability and organic solvents stability than the free enzymes, and remained 52.5% overall catalytic activity after 8 cycles. Finally, the co-immobilized enzymes can reduce 60 mM HAP for fabrication of (R)-PED with cofactor regeneration in the phosphate buffer reaction system, affording 83.9% yield and above 99% optical purity.


Risk Factors for Invasive Pulmonary Aspergillosis in Critically Ill Patients With Coronavirus Disease 2019-Induced Acute Respiratory Distress Syndrome.
Severe coronavirus disease 2019 pneumonia can lead to acute respiratory distress syndrome. Recently, several publications reported on coronavirus disease 2019-associated pulmonary aspergillosis. However, risk factors remain unclear. We retrospectively collected all the cases of coronavirus disease 2019 acute respiratory distress syndrome patients (n = 46) admitted to our 34-bed ICU between March 24, 2020, and May 25, 2020, and identified six patients that met the diagnosis of invasive pulmonary aspergillosis according to previously established definitions. This population exhibited higher severity scores at admission and less hospital discharge compared with noninvasive pulmonary aspergillosis patients. Chronic obstructive pulmonary disease, malnutrition, and systemic corticosteroid use were identified as risk factors for invasive pulmonary aspergillosis in coronavirus disease 2019-induced acute respiratory distress syndrome patients. Coronavirus disease 2019-associated pulmonary aspergillosis may be a serious concern regarding corticosteroids use to control the inflammatory response of coronavirus disease 2019-induced acute respiratory distress syndrome.


The significance of transient left ventricular dilation during SPECT dipyridamole thallium-201 scintigraphy.
We assessed the significance of transient left ventricular dilation (TLVD) during single photon emission computed tomography (SPECT) dipyridamole thallium-201 scintigraphy (DTS) in 49 patients who underwent both DTS and diagnostic coronary arteriography. Quantitative analysis of DTS images and independent review by 3 experienced observers determined that 17 patients had TLVD and 32 patients had no TLVD. Patients with TLVD were similar to patients without TLVD with respect to age, history of myocardial infarction, coronary risk factors and occurrence of chest pain or electrocardiographic changes during DTS. The frequency of three-vessel coronary artery disease (3VD) was greater in patients with TLVD than in patients without TLVD (94% vs. 16%, p < 0.01). The sensitivity of TLVD was 76% and the specificity 96% for the detection of 3VD. Of the 16 patients with 3VD who manifested TLVD, standard SPECT DTS analysis demonstrated defect or perfusion abnormalities in 14 patients and no abnormalities in 2 patients. In conclusion, the finding of TLVD during SPECT DTS is a specific marker for severe coronary disease and can provide additive information to standard SPECT thallium-201 analysis.


CYP2D6 genotypes in revolving door patients with bipolar disorders: A case series.
In psychiatric disorders, interindividual differences in cytochrome P450 (CYP)2D6 (CYP2D6) enzymatic activity could be responsible of adverse drug reactions (ADRs) and therapeutic failures (TFs) for CYP2D6-metabolized drugs, contributing to the periodical hospital readmissions of the revolving door (RD) condition. We investigated CYP2D6 genotypes in a controlled series of 5 consecutive RD patients with Bipolar Disorder (BD). Psychiatric patients affected by Bipolar Disorder. We defined TFs as a difference at the Brief Psychiatric Rating Scale score ΔBPRS < 25% at each 1-week of stable treatment, and ADRs as the onset of extrapyramidal symptoms and/or metabolic impairment with weight gain. At 3 months, a mean number of 2.75 ± 1.26 ADR and a mean ΔBPRS score of 16.07 ± 0.05% were observed. At 6 months of follow-up, compared to the only patient without BD (ΔBPRS < 32.10%), BD patients (n = 4) showed TFs (ΔBPRS < 25%). CYP2D6 genotyping revealed intermediate metabolizer phenotypes for BD patients and an extensive metabolizer phenotype for the patient without BD. In BD patients, the ratio of drugs maintained/discontinued for TFs or ADRs was 1.75 for non-CYP2D6 versus 0.33 for CYP2D6 interacting drugs, while the proportion of ADR:TF was 0:4 versus 6:3. Our findings may suggest that CYP2D6 clinically relevant genotypes may be involved in the unwanted outcomes observed in RD patients with BD.


Primary and recurrent sporadic desmoids: Prognostic factors influencing recurrence-free survival after complete gross resection.
There is continuing controversy over the significance of prognostic factors in sporadic desmoid-type fibromatosis (DF). Further, only limited data is available in the literature concerning second recurrence in patients with recurrent DF. The purpose of this study was to identify prognostic factors influencing recurrence-free survival (RFS) and to determine rates of local recurrence (LR) in patients with primary and recurrent DF. Fifty-three consecutive patients with DF who underwent surgery at a single institution were identified. As a result of strict exclusion criteria, a homogeneous cohort of thirty-two patients who received macroscopically complete resection was included in this study and split into a primary (PG) and recurrent disease (RG) group. Clinicopathological parameters and immunohistochemical markers were retrospectively and independently analyzed in both groups. The local recurrence rate was 35% for the PG and 33% for the RG. The PG's calculated median time to relapse was 17 months, and the RG's was 29 months. The estimated 1-, 5-, and 8-year RFS rates for the PG were 75%, 64%, and 55% while the corresponding RFS rates for the RG were 69%, 69%, and 52%, respectively. In primary disease, extraabdominal tumor location was the only significant adverse prognostic factor associated with worse RFS (p = 0.008). Whereas in recurrent disease, age ≥40 yrs (p = 0.022) and R0 margin status (p = 0.049) correlated with a significantly better outcome. Recurrence in primary and recurrent DF is characterized by different predictive factors and benefits from distinct therapeutic strategies. Immunohistochemical markers are valuable tools in the diagnosis of DF, although have limited potential in predicting the outcome.


Make room for dynein.
Three classes of cytoskeletal motor protein have been identified--myosins, kinesins and dyneins. Together, these proteins are now thought to be responsible for the remarkable variety of movements that occur in eukaryotic cells and that are essential for reproduction and survival. Crystallographic analysis of the myosin and kinesin motor domains at atomic resolution has provided insight into their mechanism of force production. However, because of its relative intractability to molecular manipulation, definition of the dynein motor domain, let alone progress in understanding how it works, has been slower. Evidence now indicates that the microtubule-binding domain of dynein is spatially isolated from the ATPase domain at the tip of a projecting coiled coil. As proposed here, this curious arrangement might serve to accommodate multiple copies of the outsized and functionally complex motor heads on the microtubule surface.


Evaluation of Early Diabetic Kidney Disease Using Ultrasound Localization Microscopy: A Feasibility Study.
The purpose of this study is to detect the hemodynamic changes of microvessels in the early stage of diabetic kidney disease (DKD) and to test the feasibility of ultrasound localization microscopy (ULM) in early diagnosis of DKD. In this study, streptozotocin (STZ) induced DKD rat model was used. Normal rats served as the control group. Conventional ultrasound, contrast-enhanced ultrasound (CEUS), and ULM data were collected and analyzed. The kidney cortex was divided into four segments, which are 0.25-0.5 mm (Segment 1), 0.5-0.75 mm (Segment 2), 0.75-1 mm (Segment 3), and 1-1.25 mm (Segment 4) away from the renal capsule, respectively. The mean blood flow velocities of arteries and veins in each segment were separately calculated, and also the velocity gradients and overall mean velocities of arteries and veins. Mann-Whitney U test was used for comparison of the data. Quantitative results of microvessel velocity obtained by ULM show that the arterial velocity of Segments 2, 3, and 4, and the overall mean arterial velocity of the four segments in the DKD group are significantly lower than those in the normal group. The venous velocity of Segment 3 and the overall mean venous velocity of the four segments in the DKD group are higher than those in the normal group. The arterial velocity gradient in the DKD group is lower than that in the normal group. ULM can visualize and quantify the blood flow and may be used for early diagnosis of DKD.


Investigation of a nonsense mutation located in the complex KIV-2 copy number variation region of apolipoprotein(a) in 10,910 individuals.
The concentrations of the highly atherogenic lipoprotein(a) [Lp(a)] are mainly genetically determined by the LPA gene locus. However, up to 70% of the coding sequence is located in the complex so-called kringle IV type 2 (KIV-2) copy number variation, a region hardly accessible by common genotyping and sequencing technologies. Despite its size, little is known about genetic variants in this complex region. The R21X variant is a functional variant located in this region, but it has never been analyzed in large cohorts. We typed R21X in 10,910 individuals from three European populations using a newly developed high-throughput allele-specific qPCR assay. R21X allelic location was determined by separating the LPA alleles using pulsed-field gel electrophoresis (PFGE) and typing them separately. Using GWAS data, we identified a proxy SNP located outside of the KIV-2. Linkage disequilibrium was determined both statistically and by long-range haplotyping using PFGE. Worldwide frequencies were determined by reanalyzing the sequencing data of the 1000 Genomes Project with a dedicated pipeline. R21X carriers (frequency 0.016-0.021) showed significantly lower mean Lp(a) concentrations (- 11.7 mg/dL [- 15.5; - 7.82], p = 3.39e-32). The variant is located mostly on medium-sized LPA alleles. In the 1000 Genome data, R21X mostly occurs in Europeans and South Asians, is absent in Africans, and shows varying frequencies in South American populations (0 to 0.022). Of note, the best proxy SNP was another LPA null mutation (rs41272114, D' = 0.958, R2 = 0.281). D' was very high in all 1000G populations (0.986-0.996), although rs41272114 frequency varies considerably (0-0.182). Co-localization of both null mutations on the same allele was confirmed by PFGE-based long-range haplotyping. We performed the largest epidemiological study on an LPA KIV-2 variant so far, showing that it is possible to assess LPA KIV-2 mutations on a large scale. Surprisingly, in all analyzed populations, R21X was located on the same haplotype as the splice mutation rs41272114, creating "double-null" LPA alleles. Despite being a nonsense variant, the R21X status does not provide additional information beyond the rs41272114 genotype. This has important implications for studies using LPA loss-of-function mutations as genetic instruments and emphasizes the complexity of LPA genetics.


Non-coding RNAs participate in the ischemia-reperfusion injury.
Ischemia, being defined as blood supply deficiency is involved in the pathogenesis of a number of life-threatening conditions such as myocardial infarction and cerebral stroke. Assessment of the molecular pathology of these conditions has led to identification of the role of reperfusion in induction and aggravation of tissue injury and necrosis. Thus, the term "ischemia/ reperfusion (I/R) injury" has been introduced. This process involves aberrant regulation of the mitochondrial function, apoptotic and autophagic pathways and signal transducers. More recently, non-coding RNAs including long non-coding RNAs (lncRNAs) ad microRNAs (miRNAs) have been shown to influence I/R injury. Animal studies and clinical investigations have shown up-/down-regulation of tens of lncRNAs and miRNAs in this process. In the current study, we summarize the role of these transcripts in the pathophysiology of I/R injury and their potential as biomarkers for detection of extent of tissue injury.


Methylphenidate in a patient with depression and respiratory insufficiency.
We report a case of severe depression in an elderly and critically ill patient with multiple medical complications who was treated with a combination of methylphenidate and sertraline. The objective of this report is to outline the usefulness of methylphenidate as an antidepressant in a patient with respiratory insufficiency. Case description. The patient had a positive clinical response with initial mental confusion due to methylphenidate. An initial dose of 2.5 mg/day allowed antidepressant response and improvement of respiratory function permitting the removal of mechanical ventilation. Methylphenidate may be useful for patients with severe medical conditions including ventilatory insufficiency.


Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma.
Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thereby impacting individuals' risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case-control study, four polymorphisms in the Cox-2 gene (two in the promoter, -663 insertion/deletion, GT/(GT) and -798 A/G; one in intron 5-5229, T/G; one in 3'untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/(GT) at -663 in the promoter and the variant homozygous genotype G/G at intron 5-5229 appeared to have inverse associations (odds ratio (OR)=0.59, confidence interval (CI): 0.34-1.02 and OR=0.48, CI: 0.24-0.99, respectively), whereas the heterozygous genotype T/C at 3'UTR-8494 had a positive association (OR=1.31, CI: 1.01-1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3'UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males (OR=1.35, CI: 1.07-1.70), but the one with a risk allele at 3'UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development (OR=0.85, CI: 0.66-1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment.


Feasibility of a Mobile Application to Enhance Swallowing Therapy for Patients Undergoing Radiation-Based Treatment for Head and Neck Cancer.
Dysphagia following treatment for head and neck cancer is one of the most significant morbidities impacting quality of life. Despite the value of prophylactic exercises to mitigate the impact of radiation on long-term swallowing function, adherence to treatment is limited. The purpose of this investigation was to explore the feasibility of a mobile health application to support patient adherence to swallowing therapy during radiation-based treatment. 36 patients undergoing radiation therapy were provided with the Vibrent™ mobile application as an adjunct to standard swallowing therapy. The application included exercise videos, written instructions, reminders, exercise logging, and educational content. 80% of participants used the app during treatment and logged an average of 102 exercise sessions over the course of treatment. 25% of participants logged at least two exercise sessions per day over the 7-week treatment period, and 53% recorded at least one session per day. Exit interviews regarding the patient experience with the Vibrent™ mobile application were largely positive, but also provided actionable strategies to improve future versions of the application. The Vibrent™ mobile application appears to be a tool that can be feasibly integrated into existing patient care practices and may assist patients in adhering to treatment recommendations and facilitate communication between patients and providers between encounters.


[Hypertrophic cardiomyopathy: clinical picture and diagnosis in myocardial hypertrophy of various localizations].
Sixty-nine patients with hypertrophic cardiomyopathy (HCMP) were subjected to clinical, electrocardiographic and ultrasound cardiographic examinations. Two-dimensional ultrasound cardiography revealed 4 types of most frequently occurring localizations of myocardial hypertrophy. The relationship was found between obstruction of the outlet tract of the left ventricle and localization and thickness of myocardial hypertrophy. The clinical and electrocardiographic signs of the disease were established in patients with HCMP in different localizations of myocardial hypertrophy. Subject to examination were also 15 relatives of the 5 patients. In 7 of them, HCMP was diagnosed for the first time.


Experiences of professional rugby union players returning to competition following anterior cruciate ligament reconstruction.
The purpose of this study was to gain a greater understanding of the emotions and coping strategies utilized when returning to competition following anterior cruciate ligament (ACL) reconstruction. A qualitative approach, consisting of five semi-structured interviews and a pre-designed diary, was conducted concurrent with each 'player's return to competition, allowing each to record emotional responses experienced and identify coping strategies employed. Five professional male rugby union players, who had suffered an ACL injury that required surgical reconstruction, participated in the study. Each had spent between six to twelve months in rehabilitation. Content analysis was conducted on both pre- and post- return data, identifying 12 higher order themes. Confidence building; anticipation; anxiety; physical preparation; psychological preparation; and social support were prevalent pre-return to competition. Post-return higher order themes consisted of confidence building; positive performance emotions; performance anxieties; problem focused coping; social support; and dealing with fears. For the players in this study, gaining confidence in the injured knee joint appears to be influential, with increases in confidence provided by completing clinical and sport specific tests, and by performance accomplishments. Successful return can be enhanced further by the use of a specific goal setting program aimed at reintroducing the player to competition.


Gene promoter methylation and expression of Pin1 differ between patients with frontotemporal dementia and Alzheimer's disease.
Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD) share the accumulation of fibrillar aggregates of misfolded proteins. To better understand these neurodegenerative diseases and identify biomarkers in easily accessible cells, we investigated DNA methylation at Pin1 gene promoter and its expression in peripheral blood mononuclear cells of FTD patients. We found a lower gene expression of Pin1 with a higher DNA methylation in three CpG sites at Pin1 gene promoter analysed in FTD subjects, in contrast to a higher gene expression with a lower methylation in AD subjects and controls. These data suggest an important and distinct involvement of Pin1 in these two types of dementia.


Impact of the economic recession on companion animal relinquishment, adoption, and euthanasia: a Chicago animal shelter's experience.
This study investigated how the current economic recession (since December 2007) has affected dog and cat relinquishment, adoption, and euthanasia at the Anti-Cruelty Society animal shelter in Chicago, Illinois. The study compared temporal patterns of the investigated statistics before (2000-2007) the start of the current recession with the patterns after the start of the recession (2008-2010). The results showed that once the guardianship (ownership) of a nonhuman animal had been established, the recession did not greatly affect the owner's decision on relinquishment-except for the relinquishment of senior dogs, which may be associated with increased costs of care. However, an unfavorable economic environment may have reduced adoption of animals. The consequences of a decline in adoptions might be reflected in an increase in the proportion or number of sheltered animals euthanized. This study demonstrated how monitoring changes in temporal patterns in these shelter statistics can help guide animal shelters to better prepare for the current recession.


Cytokine storm induced by SARS-CoV-2 infection: The spectrum of its neurological manifestations.
The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger a hyperinflammatory state characterized by elevated cytokine levels known as hypercytokinemia or cytokine storm, observed most often in severe patients. Though COVID-19 is known to be a primarily respiratory disease, neurological complications affecting both the central and peripheral nervous systems have also been reported. This review discusses potential routes of SARS-CoV-2 neuroinvasion and pathogenesis, summarizes reported neurological sequelae of COVID-19, and examines how aberrant cytokine levels may precipitate these complications. Clarification of the pathogenic mechanisms of SARS-CoV-2 is needed to encourage prompt diagnosis and optimized care. In particular, identifying the presence of cytokine storm in patients with neurological COVID-19 manifestations will facilitate avenues for treatment. Future investigations into aberrant cytokine levels in COVID-19 patients with neurological symptoms as well as the efficacy of cytokine storm-targeting treatments will be critical in elucidating the pathogenic mechanisms and effective treatments of COVID-19.


Pathophysiology of the Serotonin System in the Nervous System and Beyond.
Serotonin (5-HT) is an attractive neurotransmitter system, in terms of physiology, physiopathology, and medicines [...].


Corona charged aerosol detector non-uniform response factors of purified alcohol ethoxylated homologues using liquid chromatography.
Surfactants are used in various applications: cosmetics, pharmaceuticals, petrochemicals, environmental, etc. Many of these compounds are polydisperse, and because of this intrinsic polydispersity, it is essential to have a universal detector with a uniform response to quantify them in a simple way. Indeed, Charged Aerosol Detector (CAD) was presented as a universal detector with a uniform response. Thus, in the present study, the CAD response, in a High-Performance Liquid Chromatography - CAD configuration (HPLCCAD), was evaluated using purified alcohol ethoxylated surfactants. A semi-preparative liquid chromatography step using a Hydrophilic interaction chromatography (HILIC) bare silica column (150 mm, 4.6 mm, 2.6 µm) was implemented to prepare eleven homologues of BrijC10, a nonionic surfactant. These homologues differed only by the number of ethylene oxide units. BrijC10 homologues were analyzed by HPLCCAD, using a HILIC bare silica column (150 mm, 2.1 mm, 2.6 µm) to determine the HPLCCAD response factors of purified homologues. From the calibration curves (from 100 to 500 mg.kg-1), their response factors were estimated: differences in response factors were observed and a maximum difference in response factors of 3.6 was obtained. Thus, it could be concluded that CAD hyphenated to HILIC separation did not present a uniform response for this homologue's distribution.


Aryl-indolyl maleimides as inhibitors of CaMKIIdelta. Part 3: Importance of the indole orientation.
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 10nM to >20microM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core of the inhibitors. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.


Experiences of occupational violence in Australian urban general practice: a cross-sectional study of GPs.
To establish the prevalence and characteristics of occupational violence in Australian urban general practice, and examine practitioner correlates of violence. Cross-sectional questionnaire survey mailed to all members (n = 1085) of three urban divisions of general practice in New South Wales in August and September 2004. The three divisions were chosen to provide a range of socioeconomic status (SES) demographics. Occupational violence towards general practitioners during the previous 12 months. 528 GPs returned questionnaires (49% response rate). Of these, 63.7% had experienced violence in the previous year. The most common forms of violence were "low level" violence - verbal abuse (42.1%), property damage/theft (28.6%) and threats (23.1%). A smaller proportion of GPs had experienced "high level" violence, such as sexual harassment (9.3%) and physical abuse (2.7%). On univariate analysis, violence was significantly more likely towards female GPs (P < 0.001), less experienced GPs (P = 0.003) and GPs working in a lower SES status area (P < 0.001), and among practice populations encompassing greater social disadvantage (P = 0.006), mental health problems (P < 0.001), and drug- and alcohol-related problems (P < 0.001). Experience of violence was greater for younger GPs (P = 0.005) and those providing after-hours care (P = 0.033 for after-hours home visits). On multivariate analysis, a significant association persisted between high level violence and lower SES area (odds ratio [OR], 2.86), being female (OR, 5.87), having practice populations with more drug-related problems (OR, 5.77), and providing home visits during business hours (OR, 4.76). More experienced GPs encountered less violence (OR, 0.77) for every additional 5 years of practice. Occupational violence is a considerable problem in Australian urban general practice. Formal education programs in preventing and managing violence would be appropriate for GPs and doctors-in-training.


Prognosis and factors associated with disseminated nocardiosis: a ten-year multicenter study.
Nocardiosis is a rare opportunistic infection that is frequently associated with dissemination (i.e. involvement of several body sites). Identifying the factors associated with Nocardia spp. dissemination may help improving the management of patients with nocardiosis. This 10-year (2010-2020) retrospective multicenter cohort study included adult patients with Nocardia-confirmed infections. The first objective was to determine the factors associated with disseminated nocardiosis. The secondary endpoints were to determine and compare the management and the 12-month overall mortality in patients with localized and disseminated nocardiosis. Univariate and multivariate logistic regression analyses were used. Nocardia spp. infection was confirmed in 110 patients, of whom 38 (34.5%) had disseminated nocardiosis. In univariate analysis, the factors associated with dissemination were immunosuppressive conditions: having an auto-immune disease and receiving high-dose corticosteroid (31.5% vs 8.3%, P = 0.003 and 52.6% vs 26.3%, P = 0.007, respectively). Absolute lymphocyte count <1 G/L at diagnosis was the only biomarker associated with dissemination (57.2% vs 26.3%, P = 0.007). Nocardia farcinica was not only the most frequent species identified in patient specimens (n = 22, 20%) but was also associated with a higher rate of dissemination (36.8% vs 11.1%, P = 0.002). Multivariate analysis confirmed the association between auto-immune diseases, lymphopenia, N. farcinica species and the higher rate of dissemination. Even though patients with disseminated nocardiosis were treated longer and more often with an antibiotic combination therapy, their 12-month overall mortality was significantly higher than that of patients with localized nocardiosis (36.8% vs 18%). Dissemination of Nocardia spp. is favoured by auto-immune diseases, lymphopenia, and infection with N. farcinica.


Pondering Higher-Risk Pediatric Heart Donors: Can We Use More?
Pediatric heart transplantation is challenged with long waiting list times and high waiting list mortality, mostly due to a continuing organ shortage and high rates of nonuse. This analysis was conducted to determine the outcomes associated with high-risk donors when recipient variability is neutralized. The United Network for Organ Sharing (UNOS) thoracic organ transplant database was searched for pediatric heart transplant recipients (≤17 years old at time of listing) between January 2006 and December 2015. High-risk donors were identified using 2 previously published methods based on donor utilization (DUB) and recipient survival (RSB). Within each of the populations, which were not mutually exclusive, low- and high-risk donor cohorts were propensity matched on recipient characteristics, and outcomes (graft survival) were analyzed using Kaplan-Meier methods. When recipient variability was harmonized, the DUB population (n = 3048) did not have different graft survival times between the high-risk graft recipients (n = 1016) and low-risk graft recipients (n = 2032; P = .713). Likewise, the RSB population (n = 1053) also did not have different graft survival times between the high-risk graft recipients (n = 351) and low-risk graft recipients (n = 702; P = .706). Cardiac allografts deemed high risk by use- and survival-based methods led to equivalent posttransplant survival as matched recipients with low-risk donors. This study demonstrates that traditionally high-risk donors may have been associated with worst posttransplant survival because of the recipients that used them. Therefore, accepting these "high-risk" donor grafts should be considered as a potential approach to reduce waiting list times and mortality while maintaining comparable posttransplant survival.


Implementation of a Brief Screening Tool to Identify Needs of Breast Cancer Survivors.
Innovation in health care delivery is needed to improve care for cancer survivors. We report our experience with adapting screening questions from the National Comprehensive Cancer Network (NCCN) guideline to evaluate the needs of breast cancer survivors. We adapted the NCCN-recommended screening questions into a plain language, self-administered 1-page intake questionnaire. The tool was administered to a convenience sample of female breast cancer survivors at follow-up oncology and primary care visits. Domains included symptoms, lifestyle concerns, and financial issues. Frequency of concerns was assessed as "never," "rarely," "sometimes," "very frequently," and "always." We evaluated feasibility and utility of administration and the prevalence and frequency of patient-reported concerns. The questionnaire was highly acceptable to patients and enhanced visits for clinicians. Clinicians reported that it led to discussion of issues that may not otherwise be addressed in the visit and did not find it burdensome. The most commonly endorsed patient concerns were desire to improve fitness or nutrition, worry about cancer recurrence, and insomnia. A majority also reported feeling anxiety and aches or pains in joints or extremities. Several issues known to be underreported in clinic visits were frequently endorsed, included sexual dissatisfaction and memory impairments. Clinicians suggested incorporating the tool into the electronic health record to increase utility and awareness. Screening for individual needs among breast cancer survivors is feasible, efficient, and may identify prevalent issues that otherwise can be missed in routine survivorship care.


Volatile Organic Compounds in the Early Diagnosis of Non-healing Surgical Wounds: A Systematic Review.
The normal healing of surgical wounds can be disrupted by infection and/or dehiscence, leading to development of chronic, non-healing wounds (NHW). Diagnosis of NHWs is via clinical acumen and analysis of microbiology wound swabs. Volatile organic compounds (VOCs) are emitted generally by human subjects and specifically as products of bacterial metabolism and are detected in the wound area. This systematic review will assess the potential use of VOCs released by surgical wounds as a non-invasive method for identifying bacterial species and the progression to NHW. A systematic search of studies, via PRISMA guidelines, was conducted. Of 220 papers screened, seven studies were included. Outcome data were extracted on methods for VOC analysis and wound/bacterial VOC profiles. The studies have shown that VOC profiles are identified by two methods: gas chromatography-mass spectrometry and electronic nose. There are VOC profiles associated with causative bacterial species, with early indications that they could be anatomically specific or could monitor treatment effects. VOC profiling of bacterial species within wounds is possible and could become a point of care test. More research is needed on specific VOC profiles to wound location and whether these profiles may predict progression to NHW.


Poor self-reported sleep is associated with risk factors for cardiovascular disease: A cross-sectional analysis in half a million adults.
Sleep is known to affect cardiovascular health, but some controversy exists on the independent association between different sleep characteristics (duration, restfulness, difficulties falling asleep) and specific risk factors for cardiovascular disease (CVD). We aimed to assess the association between self-reported sleep characteristics and the likelihood of major CVD risk factors. Totally, 521,364 Spanish workers (32% female, 44 ± 9 years [18-64]) insured by an occupational risk prevention company participated in this nationwide cross-sectional study. Participants' sleep was considered 'poor' if they reported having ≥1 of the following conditions: excessively short (<6 h/d) or long (>9 h/d) sleep, unrestful sleep, or difficulties to fall asleep. We assessed the independent association between aforementioned sleep characteristics and the prevalence of hypertension, diabetes, hypercholesterolaemia, obesity and physical inactivity. Poor sleep (reported by 33% of participants) was associated with a higher likelihood of presenting all CVD risk factors individually, particularly physical inactivity (which prevalence was ~3-fold higher in the poor sleep group compared with participants reporting no sleep abnormality). In separate analyses, all the different sleep characteristics were associated with the likelihood of ≥2 CVD risk factors. Participants with optimal sleep, normal sleep duration, no difficulties falling sleep and restful sleep showed a lower total CVD risk score than their peers with poor sleep, short sleep duration, difficulties falling sleep and unrestful sleep, respectively (all p < .001). Poor sleep was associated with a higher likelihood of presenting major CVD risk factors. These findings might support the importance of monitoring and improving sleep patterns for primary CVD prevention.


High prevalence of sulphadoxine-pyrimethamine resistance-associated mutations in Plasmodium falciparum field isolates from pregnant women in Brazzaville, Republic of Congo.
Intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) has not been evaluated in the Republic of Congo since its implementation in 2006 and there is no published data on molecular markers of SP resistance among Plasmodium falciparum isolates from pregnant women. This first study in this country aimed to describe the prevalence of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) point mutations and haplotypes in P. falciparum isolates collected from pregnant women with asymptomatic infection. From March 2012 to December 2013, pregnant women attending Madibou health centre (in Southern Brazzaville) for antenatal visits were enrolled in this study after obtaining their written informed consent. Blood samples were collected and P. falciparum infections were characterized using PCR. A total of 363 pregnant women were enrolled. P. falciparum infection was detected in 67 (18.4%) samples as their PCR amplification of dhfr and dhps genes yielded bands and all the PCR products were successfully digested. Out of these 67 isolates, 59 (88%), 57 (85%) and 53 (79.1%) carried 51I, 59R and 108N dhfr mutant alleles, respectively. The prevalence of dhps 436A, 437G and 540E mutations were 67.1% (45/67), 98.5% (66/67) and 55.2% (37/67), respectively. More than one-half of the isolates carried quintuple mutations, with highly resistant haplotype dhfr51I/59R/108N + dhps437G/540E detected in 33% (22/67) whereas 25% (17/67) were found to carry sextuple mutations. We observed significantly higher frequencies of triple dhps mutations 436A/437G/540E and quintuple mutations dhfr51I/59R/108N+dhps437G/540E in isolates from women who received IPTp-SP than those who did not. Overall, this study shows high prevalence rates of SP-associated resistance mutations in P. falciparum isolates collected from pregnant women. The presence of the dhps mutant allele 540E and the high prevalence of isolates carrying quintuple dhfr/dhps mutations are here reported for the first time in the Republic of Congo. The increasing prevalence of multiple mutant alleles observed in this study is alarming and may present a challenge for the future interventions including IPTp-SP in the country.


Visualisation and characterisation of oestrogen receptor α-positive neurons expressing green fluorescent protein under the control of the oestrogen receptor α promoter.
Oestrogen receptor (ER)α plays important roles in the development and function of various neuronal systems through activation by its ligands, oestrogens. To visualise ERα-positive neurons, we generated transgenic (tg) mice expressing green fluorescent protein (GFP) under the control of the ERα promoter. In three independent tg lines, GFP-positive neurons were observed in areas previously reported to express ERα mRNA, including the lateral septum, bed nucleus of the stria terminalis, medial preoptic nucleus (MPO), hypothalamus, and amygdala. In these areas, GFP signals mostly overlapped with ERα immunoreactivity. GFP fluorescence was seen in neurites and cell bodies of neurons. In addition, the network and detailed structure of neurites were visible in dissociated and slice cultures of hypothalamic neurons. We examined the effect of oestrogen deprivation by ovariectomy on the structure of the GFP-positive neurons. The area of ERα-positive cell bodies in the bed nucleus of the stria terminalis and MPO was measured by capturing the GFP signal and was found to be significantly smaller in ovariectomy mice than in control mice. When neurons in the MPO were infected with an adeno-associated virus that expressed small hairpin RNA targeting the ERα gene, an apparent induction of GFP was observed in this area, suggesting a negative feedback mechanism in which ERα controls expression of the ERα gene itself. Thus, the ERα promoter-GFP tg mice will be useful to analyse the development and plastic changes of the structure of ERα-expressing neurons and oestrogen and its receptor-mediated neuronal responses.


Evaluation of readability and reliability of online patient information for intracranial aneurysms.
Intracranial aneurysms are common. Receiving this diagnosis can have a profound impact on patients and their families and this is compounded by the nuanced complexities around their management. An overwhelming majority of patients research health information using the internet. Patient-centred care and informed consent requires patients to have access to information that is readable and reliable. The aim of this study was to assess the readability and reliability of online health information about intracranial aneurysms. A Google search was conducted using the terms 'brain aneurysm', 'cerebral aneurysm', and 'intracranial aneurysm' and the first 75 websites were screened for assessment. The readability of each website was assessed using the Flesch reading ease score (FRE), the Flesch-Kincaid grade level (FKGL), the gunning fog index (GFI) and the simple measure of gobbledygook (SMOG) indices. Reliability was assessed using the DISCERN instrument and the Journal of the American Medical Association benchmark criteria (JAMA). Following exclusion, 36 websites were analyzed. The websites collectively scored as 'difficult' readability and 'poor' reliability on average. Statistically significant differences in readability were observed between websites categorized as patient health information and commercial compared with academic and physician. Differences in readability were also observed between search results of 'brain aneurysm' compared with 'intracranial aneurysm'. The readability and reliability of online health information about intracranial aneurysms is suboptimal. Health professionals must ensure their patients are well informed which includes directing them to high quality resources which are readable and reliable and use layperson-oriented language during the consultation.


Radionuclide bone imaging findings in loose cemented joint prostheses appear to be normal postoperative findings in cementless joint prostheses. Preliminary case report.
Two cases exemplify that three point uptake on radionuclide bone scans within the first postsurgical year of press-fit cementless joint prostheses appear to be a normal physiomechanical finding.


Root production and root turnover in two dominant species of wet heathlands.
Root biomass production, root length production and root turnover of Erica tetralix and Molinia caerulea were estimated by sequential core sampling and by observations in permanent minirhizotrons in the field. Root biomass production, estimated by core sampling, was 370 (Erica) and 1080 (Molinia) g m-2 yr-1. This was for both species equal to aboveground production. Assuming steady-state conditions for the root system, root biomass turnover rates (yr-1), estimated by core sampling, were 1.72 (Erica) and 1.27 (Molinia). Root length production of both species, estimated by minirhizotron observations, varied significantly with observation depth. Root length turnover rate (yr-1) of both species did not vary significantly with observation depth and averaged 0.92 in Erica and 2.28 in Molinia. Reasons are given for the discrepancy between the results of the two types of turnover measurements. The data suggest that the replacement of Erica by Molinia in a wet heathland, which occurs when nutrient availability increases, leads to an increased flow of carbon and nutrients into the soil-system. Therefore, there may be a positive feedback between dominance of Molinia and nutrient availability.


Cross-sectional analysis of generational differences in pain attitudes and beliefs of patients receiving physical therapy care in outpatient clinics.
Musculoskeletal pain is a common reason to seek outpatient physical therapy care. Generational differences regarding attitudes and beliefs have been found in many areas, but it has not been explored regarding pain. This study aimed to examine generational differences in attitudes and beliefs regarding pain and the potential differences between beneficial and non-beneficial treatment options in patients receiving care in outpatient physical therapy clinics. Cross-sectional descriptive survey. A survey was developed to explore attitudes, beliefs, and treatment preferences. The survey was emailed out to past and current physical therapy patients as part of the customer satisfaction survey over a four-month period. 2260 surveys were completed during the collection period. Generational differences were found between the different generational groups. Younger generations were more in line with current pain neuroscience, understanding that pain is normal and part of the survival mechanism and less likely to believe that pain meant something wrong with one's tissues. Younger generations also reported more agreeance to the ability to cope without medication. However, significant variations existed in treatment choices that were most beneficial and least beneficial between respondents. Generational differences do exist in some areas of pain attitudes and beliefs. Less variation was noted in treatment options between generations, but there were significant variations within all patient respondents.


Sensitised locomotion does not predict conditioned locomotion in cocaine-treated mice: further evidence against the excitatory conditioning model of context-dependent sensitisation.
The excitatory conditioning model of contextual sensitisation proposes that the progressive emergence of the locomotion-activating effect of cocaine (or any other stimulant drug) characterising that phenomenon is due to a growing conditioned response (the test context cues) that mimics the unchanging unconditioned response (the drug effect). The present study aimed at verifying whether the relationship between the amplitude of sensitisation and the size of the conditioned response was positive, a direct implication of that view. Sensitisation to the locomotion-activating effect of cocaine (10 mg/kg, s.c.) was firstly generated over 10 daily sessions in 25 mice (strain C57Bl/6J), another lot of 25 mice receiving the same dose of cocaine outside of the testing context. Conditioned locomotion was assessed 24 h later. No significant linear correlations were found between the magnitude of the conditioned response and the magnitude of the sensitised response (delta scores), the rate of sensitisation (individual regression coefficients) or the magnitude of the initial unconditioned response to cocaine (scores in the first session of sensitisation treatment). Accordingly, there was no significant correlation between the magnitude of the initial unconditioned response and the magnitude of the sensitised response or that of the initial unconditioned response. Therefore, the conditioned response is neither necessary nor sufficient for the development of context-dependent sensitisation of the locomotion-activating effect of cocaine, a conclusion that refutes the excitatory conditioning model of that chronic effect.


Bioavailability of the imidazole antifungal agent clotrimazole and its effects on key biotransformation genes in the common carp (Cyprinus carpio).
Clotrimazole (CTZ) is a persistent imidazole antifungal agent which is frequently detected in the aquatic environment and predicted to bio-concentrate in fish. Common carp (Cyprinus carpio) were exposed to mean measured concentrations of either 1.02 or 14.63μgl(-1) CTZ for 4 and 10 days, followed by a depuration period of 4 days in a further group of animals. Following each exposure regimen, plasma and liver CTZ concentrations were measured. Mean measured plasma concentrations of CTZ in animals exposed to the lower concentration of CTZ were 30 and 44μgl(-1) on days 4 and 10, respectively, and in the higher concentration were 318 and 336μgl(-1). Mean measured liver levels in the same animals were 514, 1725, 2111 and 7017μgl(-1) suggesting progressive hepatic accumulation. Measurement of CTZ in plasma after depuration suggested efficient elimination within 4 days, but appreciable levels of CTZ remained in the liver after depuration suggesting a degree of persistence in this tissue. In addition we measured responses of a number of key hepatic detoxification gene targets in the liver associated with the transcription factor pregnane X receptor (PXR); namely cyp450s 2k and 3a, glutathione-S-transferases a and p (gsta and p), and drug transporters multidrug resistance protein1 (mdr1), and MDR-related protein2 (mrp2). CTZ is a potent ligand of the PXR in humans and there is some evidence of PXR activation following exposure to CTZ in fish. The highest concentration of CTZ was adopted to explore the potential for alterations to detoxification gene expression in fish at a pharmacologically relevant dose level, and the lower concentration is within the range reported in effluents from waste water treatment works (WWTW). The genes for all biotransformation enzymes were up-regulated after exposure to the higher concentration of CTZ for 10 days, and alterations in expression occurred for the drug transporter genes mdr1 and mrp2 following exposure to the lower concentration of 1.02μgl(-1) CTZ (mean measured concentration). These data support the potential for CTZ to induce alterations in biotransformation and drug transporter genes associated with PXR in fish at concentrations measured in some WWTW effluents.


Ten-year experience with pericardial xenograft valves.
Five hundred fifty-three pericardial xenografts were inserted in 520 patients during a 9-year period at the Fu Wai Hospital in Beijing. The bovine pericardial xenograft was modeled after a similar type of prosthesis manufactured by Shiley Inc. (Irvine, Calif.). The late mortality rate in this series was only 1.8% per annum and the actuarial survival rate was 73.0% +/- 12% at 10 years. There was a very acceptable low incidence of thromboembolism of 0.41% per annum without the need for permanent anticoagulation. This is similar to the clinical reports with other tissue valves. The main question is the durability of the tissue prosthesis or, in other words, the freedom from valve-related clinical complications. In this series, the expected actuarial valve durability rate was 75.0% +/- 8.8% at 10 years. Whether this will continue to hold up over the next follow-up period is unclear. Certainly other tissue prostheses have shown significant degeneration rates beginning after the sixth year that have risen progressively thereafter. In any case, given the relatively low probability of thromboembolic phenomenon without anticoagulation, the trade-off of a prosthesis that may not be as durable as the mechanical ones is certainly acceptable.


Resting energy expenditure in injured, septic, and malnourished adult patients on intravenous diets.
Energy expenditures of 237 adult patients and 37 normal subjects receiving all nutrition intravenously were analysed retrospectively. Patients were classified as nutritionally depleted (67), post-operative (96), injured (43), or septic/depleted (31). Groups were further divided into those receiving either: (1) only 5% dextrose (D5W); (2) hypocaloric regimens including glucose and amino-acids; and (3) eucaloric or hypercaloric total parenteral nutrition (TPN) which also included fat. Resting energy expenditures (REE) of normal subjects on D5W were only 85% of predicted basal values based on either the Aub-Du Bois or Harris-Benedict equations. During D5W infusions, increases for the patient groups, above these values for normal subjects, varied depending on whether they were based on absolute values or ratios to predicted values. They were: (1) 1-11% for depleted; 1-21% for post-operative; 28-30% for injured; and 18-30% for septic/depleted patients. The average increase in REE with TPN was 10%. Variability within the patient groups was high, reducing the utility of these values as a basis for estimating energy requirements of patients needing artificial nutrition. Coefficients of variation averaged 15% across patient groups when the data were expressed in kJ/kg, and were reduced only slightly, to 12%, when data were expressed as ratios to predicted values. Thus, 1 3 of the patients would differ by more than 12% from mean values, and 1 out of 20 by more than 24%. Properly performed measurements of individual energy expenditure are therefore superior to values predicted from equations or average values previously obtained from patient groups and should be used wherever possible, particularly in the very sick.


Targeting TRPV1 for Body Weight Control using TRPV1(-/-) Mice and Electroacupuncture.
Obesity is a global social medical problem resulting in morbidity as high as 20-30%. Here we investigated whether the manipulation of TRPV1 can control mice body weight through electroacupuncture (EA). The results demonstrated that body weight increased with time in the control group (108.19 ± 1.31%, n = 7). The increase of mice body weight was significantly less in the EA group (104.41 ± 0.76%, p < 0.05, compared with the control group, n = 7) but not in the sham EA group (109.1 ± 0.63%, p < 0.05, compared with EA group, n = 7). EA did not decrease the gain of body weight in TRPV1 knock mice (107.94 ± 0.41% and 107.79 ± 1.04% for TRPV1(-/-) and TRPV1(-/-) with EA, respectively, p > 0.05). The visceral white adipose tissue (WAT) weight was lower in the EA group at 4 weeks after manipulation. Moreover, the protein levels of TRPV1, pPKA, pPKC, and pERK were increased in the dorsal root ganglion (DRG) and spinal cord (SC) after EA treatment but not in the sham EA and TRPV1(-/-) mice. This study suggests that targeting TRPV1 is beneficial in controlling body weight and TRPV1-associated mechanisms in mice.


Early postoperative radiotherapy is associated with improved outcomes over late postoperative radiotherapy in the management of completely resected (R0) Stage IIIA-N2 non-small cell lung cancer.
The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC. Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy ("early PORT") or with PORT administered after two cycles of chemotherapy ("late PORT") at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan-Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS. Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS. Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.


Hyperprolactinaemia and impotence.
Clinical, laboratory and radiological findings were evaluated in twenty-nine men who had raised serum prolactin concentrations and pituitary tumours. Twenty-one had functionless pituitary tumours ('prolactinomas') and eight had acromegaly. Supraseller extension was detected in twenty of the twenty-six men who had lumbar airencephalography. Three patients were studied before, sixteen before and after and ten only after pituitary ablative therapy. Seventeen of these men complained of complete lack of libido and impotence and six had impaired libido and sexual potency; only six patients in this series denied reproductive symptoms. Thirteen of the impotent subjects had small soft testes, ten reduced facial and body hair and three had marked gynaecomastia. No features of hypogonadism were noted in the six patients without reproductive symptoms and none of the patients had galactorrhoea. Serum prolactin concentrations were higher and serum testosterone concentrations lower in the impotent men compared with those with normal sexual potency. Serum LH and FSH (both basal and in response to LHRH) oestradiol and oestrone concentrations were not different between the two groups and, except in those with post-operative hypopituitarism, were within the normal range. Following successful lowering of prolactin concentrations by surgery or bromocripitine or both, serum testosterone rose and potency returned; by contrast failure to lower prolactin concentrations was associated with persistent impotence and hypogonadism. The endocrine profile of low serum testosterone concentrations with gonadotrophins which had not risen into the range usually seen in primary hypogonadism (together with the parallel increase of LH and testosterone in one patient studied sequentially during treatment which suppressed prolactin levels to normal), suggested that the impaired gonadal function was caused by a prolactin-mediated disturbance of hypothalamic-pituitary function.