Development of polysaccharide gel-coated pellets for oral administration: swelling and release behavior of calcium pectinate gel.
The aim of this study was to examine the effect of pellet size, pectin type, pectin concentration, and dissolution medium on the swelling and drug release behavior of spherical pellets containing theophylline and coated with 2 different calcium pectinates, using a multi-level factorial design approach. The spherical pellets were prepared by an extrusion-spheronization method and then coated with calcium pectinate using the diffusion-controlled interfacial complexation technique, which provides a defect-free and uniform coating on solid cores. Theophylline release from the pellets was slowed by the application of the coatings. The time to release 50% of the payload (ie, T50) in an acidic medium was approximately 7 minutes from uncoated small pellets and was 55 minutes after an amidated calcium pectinate coat was applied; a comparable coat on large pellets showed a T50 of 93 minutes. Drug release profiles of dry coated pellets showed a lag time (all less than 20 minutes) when the gel coat hydrated and swelled, followed by a zero-order release. It was found that the release rate was controlled by the pellet size, pectin type, pectin concentration, and dissolution medium.


In vitro and in vivo gene-transferring characteristics of novel cationic lipids, DMKD (O,O'-dimyristyl-N-lysyl aspartate) and DMKE (O,O'-dimyristyl-N-lysyl glutamate).
We chemically synthesized two different cationic lipids consisting of a core of lysine, two C-14 hydrocarbon chains, and either aspartatic acid or glutamic acid. The lipids were assigned the acronyms, DMKD and DMKE. Cationic liposomes prepared with the two different lipids were tested for their gene-transferring capabilities in various cell lines compared with that of control DOTAP liposomes. Under the same experimental conditions, the order of in vitro gene transfection efficiency was DMKE>or=DMKD>DOTAP. To identify the parameters influencing transfection efficiency, the DNA-binding affinities of the liposomes were compared and changes in particle size and surface charge were examined after complex formation. Both the DNA-binding affinity of the liposomes and the cell surface-binding affinity of the liposome-pDNA complexes were crucial for gene transfection. In addition, intravenously administered DMKE and DMKD liposomes exhibited different biodistribution characteristics and intensity of in vivo organ transfection from the DOTAP liposomes. Compared to the DOTAP liposomes, they were more readily transferred to the liver. Interestingly, when they were directly injected into tumor tissues, the DMKE lipoplexes were able to induce more efficient transgene expression in these tissues than the DOTAP and DMKD lipoplexes. This study suggests that a small difference in the cationic lipid backbone structure significantly affects gene-transferring capabilities. DMKE and DMKD liposomes can be utilized as efficient gene-transferring vehicles for hepatic or intra-tumoral gene transfection.


A comparison of the effects of a 4% modified fluid gelatin and a 6% hydroxyethyl starch on haemodilution, colloid osmotic pressure, haemostasis and renal parameters in healthy ponies.
Adverse effects on renal health and haemostasis have been documented in human patients administered hydroxyethyl starches (HESs). Gelatins may represent useful substitutes should similar adverse effects be identified in horses. To compare the effects of a 4% modified fluid gelatin (MFG) with a 6% (130/0.4) HES on haemodilution, colloid osmotic pressure (COP), haemostasis and renal parameters in healthy ponies. Randomised crossover experiment. Three treatments (Treatment A: 10 ml/kg bwt HES; Treatment B: 10 ml/kg bwt MFG; Treatment C: 20 ml/kg bwt MFG) were administered to 6 healthy ponies with a 1 week washout period between treatments. Haematocrit, platelet count, total serum protein, COP, thromboelastography (TEG), prothrombin time (PT), activated partial thromboplastin time (aPTT) and fibrinogen concentration were measured at baseline and at multiple time points up to 24 h post-infusion. Serum creatinine concentration, urine specific gravity (USG), urine protein:creatinine ratio (UPC), urine γ-glutamyltransferase:creatinine ratio (UGC) and urine sediment examination (USE) were performed before and at 24 h after each treatment, as well as at 1 week after the final treatment. All treatments resulted in significant haemodilution and increases in COP. Treatment C had a significantly greater effect on haematocrit than the other treatments. The platelet count decreased with all treatments and was significantly lower following Treatment C compared with Treatment B. No clinically relevant differences were observed in any of the TEG parameters within or between treatments. No significant differences in PT, aPTT or fibrinogen concentration were observed among treatments. Serum creatinine concentration, UPC and UGC did not change significantly between pre- and post-study measurements. USG and USE remained within normal limits. Modified fluid gelatin could be considered as an alternative to HES for volume expansion and oncotic support. Neither MFG nor HES were associated with clinically significant adverse effects on haemostasis or renal parameters.


Changing trends of disease burden of stroke from 1990 to 2019 and its predictions among the Chinese population.
This study aimed to understand the temporal trends in the disease burden of stroke and its attributable risk factors in China, along with the future trends in the next 25 years, that is important for effective prevention strategies and improvement, and to provide new insights into the age- and sex-specific incidence, prevalence, mortality, disability-adjusted life-years (DALYs) and their trends from 1990 to 2019, and the prediction in the next 25 years. The Global Burden of Disease Study (2019) was used to extract the data on age- and sex-specific incidence, mortality, and disability-adjusted life-years (DALYs) of stroke in China, 1990-2019. We estimated the estimated annual percentage change (EAPC) to access the temporal trends of the disease burden of stroke. The R package called Nordpred was used to perform an age-period-cohort analysis to predict the prevalence of stroke. The number of incidence cases, deaths, and DALYs of stroke increased from 1990 to 2019. Overall downward trends were observed in the age-standardized incidence rate (ASIR) from 1990 to 2019. Significant temporal trends in mortality and DALYs of stroke were observed. High systolic blood pressure, smoking, and high-sodium diet were the main driving forces for stroke. The DALYs lost attributable to smoking were different for male and female patients. In the next 25 years, the number of new cases and deaths from stroke should continue to increase. The ASIR and age-standardized mortality rate (ASMR) should show a downward trend among male and female patients. Despite the overall rates of stroke declined over the period from 1990 to 2019, the absolute number of people affected by stroke has substantially increased. There has been a substantial increase in the burden of stroke due to risk factors and will continue to increase in the next 25 years.


Neuropeptide Y and neuropeptide Y 3-36: isolation from human pancreatic endocrine tumours.
Using an antiserum raised to the C-terminal region of neuropeptide Y (NPY) which does not cross-react with pancreatic polypeptide (PP), immunoreactivity has been detected in two different endocrine tumours of the human pancreas in concentrations permitting isolation and structural analysis. In a clinically-typical gastrinoma, resected from the head of pancreas, the concentration of NPY immunoreactivity was 3.4 nmol/g. Reverse phase HPLC analysis of extracts of this tumour resolved a single immunoreactive peptide coeluting with synthetic human NPY. The molecular mass of the isolated peptide, determined by mass spectroscopy, was 4270 Da, which was in close agreement with that derived from the deduced primary structure of human tumour NPY (4271.7 Da), obtained by gas-phase sequencing. A somatostatinoma, resected from the region of the ampulla of Vater, contained 3.8 nmol/g of NPY immunoreactivity and isolation of this immunoreactive peptide followed by structural analyses, indicated a molecular structure consistent with NPY 3-36. These data suggest that NPY immunoreactivity detected in human pancreatic endocrine tumours is molecularly heterogenous, a finding which may be of relevance in the symptomatology of such tumours as attenuation of the N-terminus of this peptide generates receptor selectivity.


Double-Strangeness Molecular-Type Pentaquarks from Coupled-Channel Dynamics.
The existence of pentaquarks with strangeness content zero and one are major discoveries of the latest years in hadron physics. Most of these states can be understood as hadronic molecules and were predicted prior to their discovery within a model based on unitarized meson-baryon amplitudes obtained from vector-meson exchange interactions. Contrary to earlier statements, we show this model to also predict the existence of pentaquarks with double strangeness, at about 4500 and 4600 MeV, which are generated in a very specific and unique mechanism, via an attraction induced by a strong coupling between the two heaviest meson-baryon states.


[Microbiological aspects of enteric dysbacteriosis in patients of different age groups, visiting outpatient clinics of Moscow].
The analysis of the intestinal microflora in 2,378 patients of different age revealed changes in the state of enteric microflora in all examined patients. In the maximum percent of cases a decrease in the amount of bifidobacteria was observed in children of up to 1 month old and in the amount of lactobacilli, in children aged 6 - 14 years. In patients of all age groups the representatives of such facultative microflora as Staphylococcus aureus or fungi of the genus Candida dominated. The highest proportion of isolated staphylococci was characteristic of children in the first year of life. In the highest percent of cases a decrease in the amount of Escherichia coli with typical properties was observed in persons over 65 years old. Other enterobacteria were most often isolated from adults aged 56 - 65, but the percentage of their isolation was 1.5 times lower than that of Candida. The conclusion was made that the treatment of patients with quantitative and qualitative disturbances of normal enteric microflora needed individual approach in each concrete case with due regard to the patient's age.


Potential anti-SARS-CoV-2 drug candidates identified through virtual screening of the ChEMBL database for compounds that target the main coronavirus protease.
A novel coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or 2019 novel coronavirus] has been identified as the pathogen of coronavirus disease 2019. The main protease (Mpro , also called 3-chymotrypsin-like protease) of SARS-CoV-2 is a potential target for treatment of COVID-19. A Mpro homodimer structure suitable for docking simulations was prepared using a crystal structure (PDB ID: 6Y2G; resolution 2.20 Å). Structural refinement was performed in the presence of peptidomimetic α-ketoamide inhibitors, which were previously disconnected from each Cys145 of the Mpro homodimer, and energy calculations were performed. Structure-based virtual screenings were performed using the ChEMBL database. Through a total of 1 485 144 screenings, 64 potential drugs (11 approved, 14 clinical, and 39 preclinical drugs) were predicted to show high binding affinity with Mpro . Additional docking simulations for predicted compounds with high binding affinity with Mpro suggested that 28 bioactive compounds may have potential as effective anti-SARS-CoV-2 drug candidates. The procedure used in this study is a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that may significantly shorten the clinical development period with regard to drug repositioning.


Protein deficiency impairs DNA vaccine-induced antigen-specific T cell but not B cell response in C57BL/6 mice.
DNA vaccination is a simple method to induce antigen (Ag)-specific immunoresponse and has many potential advantages over other vaccines. Although people who need to receive vaccines often suffer undernutrition, there has been no study on a how nutritional status affects the immunoresponse induced by DNA vaccination. The aim of this study was to determine the relationship between protein deficiency and DNA vaccine-induced immunoresponses. C57BL/6 mice were fed a 5% or 20% casein diet for 30 d. The mice were immunized with an ovalubumin (OVA)-expression plasmid by the gene gun-based method three times at 10-d intervals. Body weight and serum albumin concentration in protein-deficient mice were significantly lower than those in mice fed the 20% casein diet (p<0.01, p<0.05). The percentage of OVA-specific CD8+ T cells was significantly decreased in the 5% casein group compared to that in the 20% casein group (p<0.05). Furthermore, CD4+ T cells from mice fed the low-protein diet showed lower interleukin (IL)-2 production than did those from the 20% group. In contrast to the T-cell function, protein deficiency did not affect OVA-specific Ab responses (p>0.05). These results suggest that protein deficiency impairs the induction of Ag-specific T-cell but not B-cell response in DNA-immunized mice. Our observation indicates that, in addition to development of an effective of DNA vaccine, the management of nutritional state is important for the prevention of infectious disease by DNA vaccination.


Prevalence and Clinical Profile of Drug Eruptions among Antiretroviral Therapy-Exposed HIV Infected People in Yaoundé, Cameroon.
Prevalence and incidence of drug eruptions vary around the world and are influenced by some key factors including HIV infection. This study aimed to find the peculiarities of drug eruptions in people living with HIV (PLHIV) and on antiretroviral therapy (ART). This was a retrospective cross-sectional study including ART-taking PLHIV, aged 15+ years, followed up between January 2010 and December 2014 at the day-care unit of the Yaoundé Central Hospital, and who presented with drug eruptions after ART initiation. Of 6,829 ART-experiencing PLHIV, 41 presented with drug eruptions, giving a prevalence of 0.6%. The M/F sex ratio equaled 0.17. The mean age was 41.07 ± 11.36 years. Benign drug eruptions accounted for 83.3%. Milder forms were essentially maculopapular exanthema (36.6%), fixed pigmented erythema (7.3%), and urticaria (4.9%). Severe forms were represented by multiform erythema (4.9%), toxic epidermal necrolysis (2.4%), and drug hypersensitivity syndrome (2.4%). The Zidovudine + Lamivudine + Efavirenz ART-protocol was received by 48.8% of patients and 69% of patients were receiving Cotrimoxazole prophylaxis. Nevirapine, Efavirenz, Zidovudine, and Cotrimoxazole were suspected as the potential causes in 43.7%, 4.8%, 2.4%, and 26.8% of cases, respectively. Drug eruptions seem infrequent among ART-exposed HIV infected adult Cameroonians.


Concurrent administration of Docetaxel and Stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection.
The substantial augmentation of the radiation sequelae during chemo-radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo-radiotherapy scheme with Stealth liposomal doxorubicin (Caelyx and Docetaxel (Taxotere in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere was 20 mg m(-2) week and of Caelyx was 15 mg m(-2) every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere/Caelyx was, thereafter, increased to 20/25 (five patients) and 30/25 mg m(-2) (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The 'in-field' radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere/Caelyx chemo-radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the 'in-field' toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer.


Economic evaluation of uterine artery embolization versus hysterectomy in the treatment of symptomatic uterine fibroids: results from the randomized EMMY trial.
To investigate whether uterine artery embolization (UAE) is a cost-effective alternative to hysterectomy for patients with symptomatic uterine fibroids, the authors performed an economic evaluation alongside the multicenter randomized EMMY (EMbolization versus hysterectoMY) trial. Between February 2002 and February 2004, 177 patients were randomized to undergo UAE (n = 88) or hysterectomy (n = 89) and followed up until 24 months after initial treatment allocation. Conditional on the equivalence of clinical outcome, a cost minimization analysis was performed according to the intention to treat principle. Costs included health care costs inside and outside the hospital as well as costs related to absence from work (societal perspective). Cumulative standardized costs were estimated as volumes multiplied with prices. The nonparametric bootstrap method was used to quantify differences in mean (95% confidence interval [CI]) costs between the strategies. In total, 81 patients underwent UAE and 75 underwent hysterectomy. In the UAE group, 19 patients (23%) underwent secondary hysterectomies. The mean total costs per patient in the UAE group were significantly lower than those in the hysterectomy group ($11,626 vs $18,563; mean difference, -$6,936 [-37%], 95% CI: -$9,548, $4,281). The direct medical in-hospital costs were significantly lower in the UAE group: $6,688 vs $8,313 (mean difference, -$1,624 [-20%], 95% CI: -$2,605, -$586). Direct medical out-of-hospital and direct nonmedical costs were low in both groups (mean cost difference, $156 in favor of hysterectomy). The costs related to absence from work differed significantly between the treatment strategies in favor of UAE (mean difference, -$5,453; 95% CI: -$7,718, -$3,107). The costs of absence from work accounted for 79% of the difference in total costs. The 24-month cumulative cost of UAE is lower than that of hysterectomy. From a societal economic perspective, UAE is the superior treatment strategy in women with symptomatic uterine fibroids.


Synthesis of Prebiotic Caramels Catalyzed by Ion-Exchange Resin Particles: Kinetic Model for the Formation of Di-d-fructose Dianhydrides.
Caramel enriched in di-d-fructose dianhydrides (DFAs, a family of prebiotic cyclic fructodisaccharides) is a functional food with beneficial properties for health. The aim of this work was to study the conversion of fructose into DFAs catalyzed by acid ion-exchange resin, in order to establish a simplified mechanism of the caramelization reaction and a kinetic model for DFA formation. Batch reactor experiments were carried out in a 250 mL spherical glass flask and afforded up to 50% DFA yields. The mechanism proposed entails order 2 reactions that describe fructose conversion on DFAs or formation of byproducts such as HMF or melanoidines. A third order 1 reaction defines DFA transformation into fructosyl-DFAs or fructo-oligosaccharides. The influence of fructose concentration, resin loading and temperature was studied to calculate the kinetic parameters necessary to scale up the process.


Infrared spectra of protonated neurotransmitters: dopamine.
The infrared (IR) spectrum of the isolated protonated neurotransmitter dopamine was recorded in the fingerprint range (570-1880 cm(-1)) by means of IR multiple photon dissociation (IRMPD) spectroscopy. The spectrum was obtained in a Fourier transform ion cyclotron resonance mass spectrometer equipped with an electrospray ionization source, which was coupled to a free electron laser (FEL). The spectroscopic studies are complemented by quantum chemical calculations at the B3LYP and MP2 levels of theory using the cc-pVDZ basis set. Several low-energy isomers with protonation occurring at the amino group are predicted in the energy range 0-50 kJ mol(-1). Good agreement between the measured IRMPD spectrum and the calculated linear absorption spectra is observed for the two gauche conformers lowest in energy (ΔE) and free energy (ΔG) at both levels of theory, denoted g-1 and g+1. Minor contributions of higher lying gauche isomers cannot be ruled out spectroscopically but their calculated energies suggest only minor population in the sampled ion cloud. In all these gauche structures, one of the three protons of the ammonium group is pointing toward the catechol subunit, thereby maximizing the intramolecular NH-π interaction of the positive charge with the aromatic ring. In total, 16 distinct vibrational bands are observed in the IRMPD spectrum and assigned to individual normal modes of the energetically most stable g-1 conformer, with deviations of less than 24 cm(-1) (average 11 cm(-1)) between measured and calculated frequencies. Comparison with neutral dopamine reveals the effects of protonation on the geometric and electronic structure.


[Influence of electroacupuncture with penetration needling method on comprehensive pain score in patients with cervical spondylotic radiculopathy].
To compare the efficacy differences among electroacupuncture with penetration needling method, Jiaji electroacupuncture and Jing fukang granule for cervical spondylotic radiculopathy (CSR) and to explore the best therapeutic method. One hundred and sixty patients with CSR were randomly divided into 3 groups. Sixty patients in electroacupuncture with penetration needling method group (group A) were treated by electroacupuncture with penetration needling method, and C4 Jiaji-to-C7 Jiaji, Jianwaishu (SI 14)-to-Quyuan (SI 13), Tianzong (SI 11)-to-Naoshu (SI 10), Shousanli (LI 10)-to-Xialian (LI 8) were selected, once a day. Sixty patients in Jiaji electroacupuncture group (group B) were treated by Jiaji electroacupuncture at C4 Jiaji-to-C7 Jiaji, once a day. Fourty patients in Jing fukang granule group (group C) were treated by oral administration of Jing fukang granule, 1 bag each time, twice each day. Six days as a course, the 3 groups were all treated for two courses. The simplified MPQ (SF-MPQ) scale which was internationally accepted was adopt to evaluate the improving situations in pain. After treatment, pain rating idex (PRI), visual analogue scale (VAS), present pain intensity (PPI) and the total pain score were significantly improved in the group A and B compared with those before treatment (all P < 0.01), which was also improved in the group C (all P < 0.05). Compared with the group C, all the scores were significantly improved in the group A (all P < 0.01), the improvement of PRI, VAS, PPI and total pain score in the group B was superior to those in the group C (all P < 0.05), and all the improvements in the group A were superior to those in the group B (P < 0.05, P < 0.01). Electroacupuncture with penetration needling method can relive pain rapaidly in patients with CSR, which is superior to Jiaji electroacupuncture and Jing fukang granule in improving the comprehensive pain scores.


Computational study of radial particle migration and stresslet distributions in particle-laden turbulent pipe flow.
Particle-laden turbulent flows occur in a variety of industrial applications as well as in naturally occurring flows. While the numerical simulation of such flows has seen significant advances in recent years, it still remains a challenging problem. Many studies investigated the rheology of dense suspensions in laminar flows as well as the dynamics of point-particles in turbulence. Here we employ a fully-resolved numerical simulation based on a lattice Boltzmann scheme, to investigate turbulent flow with large neutrally buoyant particles in a pipe flow at low Reynolds number and in dilute regimes. The energy input is kept fixed resulting in a Reynolds number based on the friction velocity around 250. Two different particle radii were used giving a particle-pipe diameter ratio of 0.05 and 0.075. The number of particles is kept constant resulting in a volume fraction of 0.54% and 1.83%, respectively. We investigated Eulerian and Lagrangian statistics along with the stresslet exerted by the fluid on the spherical particles. It was observed that the high particle-to-fluid slip velocity close to the wall corresponds locally to events of high energy dissipation, which are not present in the single-phase flow. The migration of particles from the inner to the outer region of the pipe, the dependence of the stresslet on the particle radial positions and a proxy for the fragmentation rate of the particles computed using the stresslet have been investigated.


Dissociation of Subjective and Objective Alertness During Prolonged Wakefulness.
Although the deterioration of subjective and objective alertness during prolonged wakefulness has been investigated rigorously, whether perceived sleepiness and fatigue are consistent with actual decrements in behavioral performance in the time course is still disputed. The present study examined the dissociation between decrements of subjective alertness and performance deficits during prolonged wakefulness of one night and explored the relationship between body temperature and the impairments of subjective and objective alertness. Thirty-eight participants (27 females; age: 21.76 ± 2.37 years old) underwent prolonged wakefulness for one night at habitual bedtime (0:00-6:00 am). Participants completed a 10-min PVT to assess objective alertness, fatigue, and sleepiness ratings to assess subjective alertness every 2 hours, and body temperature was measured every hour during scheduled wakefulness. Subjective alertness reflected a linear decline with time, but the magnitudes of objective performance deterioration increased significantly between 4:00 and 6:00 am. The increasing magnitudes of performance deficits were associated with the change of body temperature between 4:00 and 6:00 am. These results indicate that the perceived degree of decline in alertness is temporally dissociated with the actual decline in objective vigilance with increased duration of wakefulness. The dissociation of magnitudes of subjective and objective alertness decrements mainly occurs between 4:00 and 6:00 am, and the changes of performance deficits have a relationship with body temperature.


Peanut allergen Ara h 1 interacts with proanthocyanidins into higher molecular weight complexes.
Mildly extracted peanut allergen Ara h 1 was previously reported to occur as an oligomeric complex. In this paper we describe how the protein in this oligomeric complex interacts noncovalently with phenolic compounds of the proanthocyanidin type. These interactions are being disrupted during anion exchange chromatography, resulting in the dissociation of the oligomeric Ara h 1 complex into protein trimers. By use of the known three-dimensional structure of beta-conglycinin, a soy protein homologous to Ara h 1, proline-rich regions were observed in silico on both faces of its trimeric structure, which are conserved in Ara h 1. These proline-rich regions could explain the binding of proanthocyanidins to Ara h 1 and the formation of multiple Ara h 1 trimer complexes. This was supported by the observation that the addition of peanut proanthocyanidins to trimeric Ara h 1 and to beta-conglycinin resulted in the formation of soluble oligomeric protein complexes. The structurally related legumin proteins do not contain such proline-rich regions on both sides of the protein, and proanthocyanidins were shown to have a lower affinity for legumin proteins from peanuts and soybeans (peanut allergen Ara h 3 and soy glycinin, respectively). Ara h 1 present as the oligomeric complex is assumed to be the representative form of the allergen in which it is consumed by humans.


Curcumin loaded solid lipid nanoparticles: an efficient formulation approach for cerebral ischemic reperfusion injury in rats.
To evaluate curcumin loaded solid lipid nanoparticles (C-SLNs) in the experimental paradigm of cerebral ischemia (BCCAO model) in rats. Oral administration of free curcumin and C-SLNs (25 and 50 mg/kg) was started 5 days prior and continued for 3 days after BCCAO. Alleviation in behavioral, oxidative and nitrosative stress, acetylcholinesterase, mitochondrial enzyme complexes, and physiological parameters were assessed. Confirmation of effective brain delivery of C-SLNs (p.o) was done using biodistribution studies in mice and confocal microscopy of rat brain section. There was an improvement of 90% in cognition and 52% inhibition of acetylcholinesterase versus cerebral ischemic group (I/R). Neurological scoring improved by 79%. Levels of superoxide dismutase, catalase, glutathione, and mitochondrial complex enzyme activities were significantly increased, while lipid peroxidation, nitrite, and acetylcholinesterase levels decreased (p<0.05) after C-SLNs administration. It is noteworthy to report the restoration of SOD, GSH, catalase, and mitochondrial complex enzyme levels equivalent to sham control values. Gamma-scintigraphic studies show 16.4 and 30 times improvement in brain bioavailability (AUC) upon oral and i.v administration of C-SLNs versus solubilized curcumin (C-S). Study indicates protective role of curcumin against cerebral ischemic insult; provided it is packaged suitably for improved brain delivery.


Invasive Cryptococcus laurentii disease in a nine-year-old boy with X-linked hyper-immunoglobulin M syndrome.
We report a 9-year-old boy with X-linked hyper-immunoglobulin M syndrome and invasive Cryptococcus laurentii infection identified on the basis of morphologic and biochemical characteristics and serologic tests. Fluconazole treatment resulted in complete recovery. We believe that C. laurentii should be included in the differential diagnosis of opportunistic fungal infections in patients with primary T cell immunodeficiencies.


Rehabilitation and quality of life in patients undergoing surgery for esophageal cancer.
The impact of esophageal cancer surgery, postoperatively as well as on quality of life (QoL) is still largely unknown. Clinical experience and the scarce existing literature concur that these patients show difficulty in returning to their original lifestyles and previous social activities, not just due to the difficulties common to all tumor pathologies but also for the specific dietary and digestive disturbances which characterize esophageal cancer therapy. As specific rehabilitation protocols are nonexistent in the literature, in this study a rehabilitation planning program, is proposed based on evaluation of postoperative and long-term problems which can be tackled with rehabilitation.


Studies on human epidermal Langerhans' cells: II. Activation of human T lymphocytes to herpes simplex virus.
Epidermis from patients suffering from recurrent herpes labialis was separated from dermis by means of a suction blister device and dissociated with trypsin. The epidermal cell suspensions obtained were 80--95% viable and contained 3--5% Langerhans' cells, as judged by immunofluorescence staining of the cells with a rabbit anti-DR antiserum. T lymphocytes from the same patients were co-cultured with herpes simplex virus antigen (HSV-Ag) or live virus (HSV), with or without epidermal cells or macrophages. A strong proliferative T cell response to HSV-Ag and HSV was obtained, provided that the cultures also contained epidermal cells or macrophages. Pretreatment of the epidermal cells with a rabbit anti-DR antiserum plus complement abolished the responses, while pretreatment with normal rabbit serum plus complement did not. These data therefore indicate that HLA--DR positive Langerhans' cells are able to present herpes simplex virus in an immunogenic way to T lymphocytes.


Highly selective recognition of carbenicillin via concerted interactions in 100% aqueous solution.
A fluorescent probe (QA) based on quinine bearing two quaternary ammonium groups and a long hydrophobic chain was synthesized, and it showed highly selective recognition of carbenicillin (a typical beta-lactam antibiotic) in 100% aqueous solution via concerted interactions.


Hypertension and Diabetes Mellitus Program evaluation on user's view.
to evaluate the program proposed by the Reorganization Care Plan for Hypertension and Diabetes Mellitus on user's view, and describe aspects of the trajectory of the participants correlating with the program's evaluation. evaluative study with a qualitative approach conducted in health units with the Family Health Strategy, in a city of the metropolitan region of Curitiba, in the period from September to March, 2012. A total of 30 adults with hypertension and/or Diabetes mellitus were interviewed. Data were analyzed through content analysis. Four categories were identified: Disease diagnosis; Reasons for the program need; Knowledge of the program, and program evaluation. there was the recognition of the orientations, and the monitoring of activities developed, with emphasis in cost reduction for users.


Certolizumab pegol in the treatment of Crohn's disease.
The introduction of antibodies directed against tumour necrosis factor (anti-TNF) has dramatically changed the concept of treating patients with Crohn's disease (CD). Unfortunately, the long-term efficacy of anti-TNF agents may be hampered by immunogenicity. The availability of more anti-TNF agents in the therapeutic armamentarium would therefore be of great benefit in patients loosing response to another anti-TNF. In this review, the authors will focus on the efficacy of certolizumab pegol (CZP). A literature search to January 2013 was performed to identify all trials studying CZP in patients with CD. The authors first focused on the mechanism of action of CZP. Second, they evaluated the efficacy of an induction and maintenance therapy with CZP and the impact of CZP on mucosal healing and fistula closure. Next, they explored the influence of previous anti-TNF exposure and baseline C-reactive protein levels. Finally, they analysed the safety data on CZP, including the development of antibodies against CZP and the use of CZP during pregnancy. Based on the provided literature, CZP could be a good alternative in patients with moderate-to-severe CD failing another anti-TNF agent. More data are required to conclude on its impact on the long-term outcome of CD.


A Wide Dynamic Range CMOS Image Sensor with a Charge Splitting Gate and Two Storage Diodes.
In this paper, a wide dynamic range (WDR) CMOS image sensor (CIS) with a charge splitting gate (SG) and two storage diodes (SDs) is presented. By using single-gate on/off control with the SG, photocurrent path to the first (SD1) or second storage diodes (SD2) is switched alternatively and periodically during exposure and signal electrons generated in a photodiode (PD) are transferred to and accumulated in the SD1 or SD2. By setting a large ratio of the off-time to on-time of the SG, two different sensitivity signals, which are originated by the same photodiode, are generated and a WDR image signal is obtained. This technique has a distinct advantage on mitigating the problem of motion artifact in WDR imaging with high and low sensitivity signals and flexible dynamic control of the dynamic range. An experimental WDR CMOS image sensor with 280 (H) × 406 (V)-pixel array consisting of 14 sub-arrays, each of which have 20 (H) × 406 (V) pixels, was implemented and tested. For the SG on/off-time ratio of 30 and 279, the DR of 93 dB and 104 dB, respectively, was demonstrated. The effect of the proposed WDR imaging operation on the reduced motion artifact was experimentally confirmed.


Excretory/secretory products from the gastrointestinal nematode Trichuris muris.
To better control gastrointestinal nematode infections in humans and animals, it is important to understand the strategies used by these parasites to modulate the host immune system. In this regard, molecules released by parasites have been attributed crucially important roles in host-parasite negotiations. We characterized the excretory/secretory (E/S) microRNA (miRNA) and protein profiles from the mouse gastrointestinal nematode parasite Trichuris muris. Released miRNAs were subjected to miRNA sequencing and E/S proteins were analysed by mass spectrometry. Fourteen miRNAs were identified in T. muris exosome-like vesicles, as well as 73 proteins of nematode origin, 11 of which were unique to this study. Comparison with published nematode protein secretomes revealed high conservation at the functional level.


[Efficiency of computer-based documentation in long-term care--preliminary project].
In Germany the documentation of processes in long-term care is mainly paper-based. Planning, realization and evaluation are not supported in an optimal way. In a preliminary study we evaluated the consequences of the introduction of a computer-based documentation system using handheld devices. We interviewed 16 persons before and after introducing the computer-based documentation and assessed costs for the documentation process and administration. The results show that reducing costs is likely. The job satisfaction of the personnel increased, more time could be spent for caring for the residents. We suggest further research to reach conclusive results.


Contribution and performance of female Community-Directed Distributors in the treatment of onchocerciasis with Ivermectin in Sub-Saharan Africa: a systematic review.
The African Program for Onchocerciasis Control (APOC) was launched in 1995 with the main goal being to boost the fight against onchocerciasis in Africa. In 2011, over 80 million people benefited from this intervention thanks to the contribution of 268.718 Community-Directed Distributors (CDD). These significant results obscure the role of women CDD in this fight. Indeed, the insufficient involvement of female CDD has been identified as a concern by the APOC partners early in the program. The present study aims to assess the contribution and performance of women involved in a strategy to control onchocerciasis by community-directed treatment with ivermectin in sub Saharan Africa. We searched the following electronic databases from January 1995 to July 2013: Medline, Embase (Excerpta Medica Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), LILAS (Latin American and Caribbean Literature on Health Sciences), International Bibliography of Social Sciences, Social Services Abstracts, and Sociological Abstracts. Two research team members independently conducted data extraction from the final sample of articles by using a pre-established data extraction sheet. The primary outcome was the contribution of female CDD in the control of onchocerciasis by community-directed treatment with Ivermectin. Of 25 hits, 7 papers met the inclusion criteria. For the management of onchocerciasis, female CDDs are elected by the health committee from the communities they will serve. The significant proportion of those treated (about 61%) were women, although only 24% of CDDs were women. Many community members reported that women were more committed, persuasive and more patient than men in the distribution of ivermectin. Some studies have identified underutilization of female CDD as one reason for the limited effectiveness or, in some cases, pure failure related to the distribution of Ivermectin interventions in the fight against onchocerciasis in sub-Saharan Africa. Evidence from this review suggests that female CDD contribute to the treatment of onchocerciasis with Ivermectin in sub-Saharan Africa. Large-scale rigorous studies including Randomized controlled trials (RCTs) are needed to compare Community-Directed intervention involving men and women CDDs.


Interferon regulatory factors: A key to tumour immunity.
Interferon regulatory factors (IRFs), which have 10 members, belong to the transcription factor family and were named because of the regulation of interferon expression. They play important roles in the immune regulation, cell differentiation, cell apoptosis, and cell cycle regulation. This article will review the functional characteristics and immune activity of the family members, especially in the role of cell differentiation and autoimmune diseases. Intensive studies will help uncover the pathogenesis of the disease in a more comprehensive view, and provide novel targets for disease treatment. But the most important problems yet to solve is IRFs function in the development processes of tumour, and whether IRFs can be an important regulator in tumour immune treatment.


Facile Construction of Functionalized GO Nanocomposites with Enhanced Antibacterial Activity.
The development of antimicrobial materials with sustained drug release performance is of great importance. Graphene oxide (GO) is considered to be an ideal drug carrier. In this study, tetracycline hydrochloride (TC) was loaded onto polyethyleneimine-functionalized GO (PG) to fabricate TC/PG nanocomposites. The success of the fabrication was confirmed by zeta potential, TEM, FTIR, and Raman analyses. The TC/PG nanocomposites showed a controlled and sustained drug release behavior, and a pseudo second order kinetic model was employed to illustrate the release mechanism. The antibacterial activity was studied using the disk diffusion method against Escherichia coli and Staphylococcus aureus. The TC/PG nanocomposites exhibited great bacterial inhibition performance. The results indicate that the fabricated TC/PG nanocomposites with effective antibacterial activity have great potential in antibacterial applications.


A cross-sectional study of nutritional status in healthy, young, physically-active German omnivores, vegetarians and vegans reveals adequate vitamin B12 status in supplemented vegans.
Plant-based diets reduce the risk of cardiovascular disease but also increase the risk of certain micronutrient deficiencies, particularly, of vitamin B12 (B12). The extent to which the unsupervised use of oral nutrient supplements is sufficient to prevent these deficiencies is not well established. We analyzed nutrient intake, laboratory biomarkers, supplementation behavior, and B12 status adequacy amongst young, healthy, physically active omnivores, lacto-ovo-vegetarians and vegans from Germany. We recruited 115 participants (n = 40 omnivores; n = 37 lacto-ovo-vegetarians, and n = 38 vegans) with comparable age, sex, marital status, physical activity and educational levels through online advertisements and local newspapers in Freiburg, Germany. Energy intake and macronutrient distribution were comparable across diets. Major differences included intake of fiber, cholesterol, and several vitamins. Vegans had the lowest intake of B12 from foods (0.43 (0.58) µg/d), compared to omnivores (2.14 (2.29) µg/d) and lacto-ovo-vegetarians (0.98 (1.34) µg/day). Multivariate analysis of 36 blood biomarkers revealed that three major classes of biomarkers contributed the most to the clustering of individuals by dietary group, namely, biomarkers of B12 status (B12, holoTC, Hcy), iron (iron, ferritin, transferrin) and lipid metabolism (vitamin A, HDL, LDL, total cholesterol, TAG). This suggests that nutrients that modify the metabolic pathways represented by these biomarkers have the most penetrating effect on health status across diets. Analysis of B12 status (including 4cB12) revealed adequacy in omnivores and vegans, and a poorer B12 status amongst lacto-ovo-vegetarians. Fewer lacto-ovo-vegetarians used B12 supplements compared to vegans (51% versus 90%). Even amongst homogeneously healthy Germans, each diet manifested with measurable differences in dietary intakes and biomarkers of health. Plant-based diets, in particular the vegan diet, exhibited the most favorable patterns of lipid metabolism and glycemic control, but the lowest food intake of B12. Supplementation of healthy vegans with B12 (median 250 µg B12/day, over 2 years) secured an adequate B12 status that was comparable to that of healthy omnivores.Clinical Trial Registry: German Clinical Trial register number: DRKS00027425.


[The classification and surgical treatment of the terminal phalanx of congenital thumb duplication ].
To study the classification and individualized treatment of the terminal phalanx of thumb duplication. From Apr. 2003 to Dec. 2012, 76 patients with 77 involved thumbs duplication at the level which is distal to the interphalangeal joint were retrospectively studied. Based on the morphology (the nail width and the thumb circumference) and the deviation of the thumb, we classified the terminal phalanx of thumb duplication into 5 types as Type A (no bony connection called floating thumb), Type B(asymmetry and no deviation), Type C(asymmetry and deviation), Type D (symmetry and no deviation) and Type E(symmetry and deviation). Different surgical procedures were selected according to different types. Simple excision of the smaller thumb was adopted for Type A case. Removement of the smaller thumb (usually the radial) and of the collateral ligament of the interphalangeal joint were selected for Type B. Removement of the smaller thumb (usually the radial) and reconstruction of the collateral ligament of the interphalangeal joint, as well as corrective osteotomies at the neck of the proximal phalanx were performed for Type C. The modified Bilhaut-Cloquet procedure with reconstruction of the collateral ligament of the interphalangeal joint were adopted in Type D. The classical Bilhaut-Cloquet procedure, or the modified Bilhaut-Cloquet procedure with reconstruction of the collateral ligament of the interphalangeal joint and corrective osteotomies at the neck of the proximal phalanx were performed in Type E. The results were assessed by an evaluation form for thumb duplication by the Japanese Society for Surgery of the Hand. According to our new classification standard, there were 3 cases with Type A duplicated thumbs, 36 with Type B, 13 with Type C, 15 with Type D, 10 with Type E. All the 76 patients underwent the individualized surgical treatment. The patients were followed up for 6-60 months. According to the evaluation form, excellent results were achieved in 66 thumbs, good in 9 thumbs and fair in 2 thumbs. The new classification could comprehensively describe the clinical features of the terminal phalanx of congenital thumb duplication. Individualized therapy, including basic and repeated surgical procedure could be adopted for each type with satisfactory results.


FluMob: Enabling Surveillance of Acute Respiratory Infections in Health-care Workers via Mobile Phones.
Singapore is a hotspot for emerging infectious diseases and faces a constant risk of pandemic outbreaks as a major travel and health hub for Southeast Asia. With an increasing penetration of smart phone usage in this region, Singapore's pandemic preparedness framework can be strengthened by applying a mobile-based approach to health surveillance and control, and improving upon existing ideas by addressing gaps, such as a lack of health communication. FluMob is a digitally integrated syndromic surveillance system designed to assist health authorities in obtaining real-time epidemiological and surveillance data from health-care workers (HCWs) within Singapore, by allowing them to report influenza incidence using smartphones. The system, integrating a fully responsive web-based interface and a mobile interface, is made available to HCW using various types of mobile devices and web browsers. Real-time data generated from FluMob will be complementary to current health-care- and laboratory-based systems. This paper describes the development of FluMob, as well as challenges faced in the creation of the system.


[Fatal anaphylactic shock in a patient treated with beta-blockers].
The occurrence of an anaphylactoid shock in a patient treated with beta-adrenergic blocking agents during a long time prior to surgery constitutes a high risk because beta-receptors are refractory to adrenergic substances and compensatory mechanisms are obtunded. The shock is characterized by severe hypotension and bradycardia, both resistant to adrenaline. These signs were observed in a patient treated with metoprolol for hypertension several months prior to surgery. The intravenous injection of an iodine containing contrast medium during general anaesthesia was followed by a lethal anaphylactoid shock resistant to adrenaline, atropine and isoprenaline. The treatment of the shock needs, besides adrenaline, massive vascular filling, high doses of beta-agonists and glucagon.


Profiling analysis of long non-coding RNAs in early postnatal mouse hearts.
Mammalian cardiomyocytes undergo a critical hyperplastic-to-hypertrophic growth transition at early postnatal age, which is important in establishing normal physiological function of postnatal hearts. In the current study, we intended to explore the role of long non-coding (lnc) RNAs in this transitional stage. We analyzed lncRNA expression profiles in mouse hearts at postnatal day (P) 1, P7 and P28 via microarray. We identified 1,146 differentially expressed lncRNAs with more than 2.0-fold change when compared the expression profiles of P1 to P7, P1 to P28, and P7 to P28. The neighboring genes of these differentially expressed lncRNAs were mainly involved in DNA replication-associated biological processes. We were particularly interested in one novel cardiac-enriched lncRNA, ENSMUST00000117266, whose expression was dramatically down-regulated from P1 to P28 and was also sensitive to hypoxia, paraquat, and myocardial infarction. Knockdown ENSMUST00000117266 led to a significant increase of neonatal mouse cardiomyocytes in G0/G1 phase and reduction in G2/M phase, suggesting that ENSMUST00000117266 is involved in regulating cardiomyocyte proliferative activity and is likely associated with hyperplastic-to-hypertrophic growth transition. In conclusion, our data have identified a large group of lncRNAs presented in the early postnatal mouse heart. Some of these lncRNAs may have important functions in cardiac hyperplastic-to-hypertrophic growth transition.


Precision and accuracy of fluconazole susceptibility testing by broth microdilution, Etest, and disk diffusion methods.
Interpretive agreements among the results of fluconazole broth microdilution tests, Etests, and disk diffusion tests were documented by evaluating 495 Candida spp. Microdilution reference test results were in agreement with 96% of the Etest results; most discrepancies were minor differences. Fluconazole resistance of Candida krusei strains often required a full 48 h of incubation in order to be observed by the standard method. For the disk diffusion tests that were performed on Mueller-Hinton agar with glucose and methylene blue, 97% of results were in agreement with those of the reference test, especially when zones of inhibition were measured after the first 24 h of incubation. Some Candida glabrata isolates failed to grow satisfactorily until a full 48 h of incubation was completed. Precision was determined by testing 50 selected isolates in triplicate in each of three laboratories. The reproducibility of results of disk diffusion tests was comparable to that of the reference method. With all procedures, determination of test results was particularly challenging with some strains, and new methods are needed in order to improve endpoint definition.


Quality of life, life satisfaction, and spirituality: comparing outcomes between rehabilitation and cancer patients.
To determine differences in quality of life, life satisfaction, and spirituality across different patient groups and to determine what factors may relate to these three outcomes across rehabilitation and cancer patients. Subjects were first stratified by five diagnostic groupings. Patient data were then regrouped for additional analytic purposes into two large cohorts. All subjects completed questionnaires once. Differences in scores and correlations were computed, and regression models were specified. Group differences were found across the quality of life measures used in the study. There were also differences in life satisfaction and spiritual well-being. Spirituality was found to be associated with both quality of life and life satisfaction, although it was not a significant predictor in a multivariate context. In general, subjects with prostate cancer reported higher scores across all measures. Spirituality showed a strong association with both life satisfaction and quality of life, and it was a significant predictor of life satisfaction among rehabilitation subjects. Factors such as age, marital status, and work status, in addition to specific dimensions of quality of life, such as social functioning and functional well-being, were found to be associated with total quality of life.


Lumbosacral plexopathy.
This article provides an up-to-date review of the clinical features and pathogenesis of different types of lumbosacral plexopathy and a clinical approach to their evaluation and management. Often, the pathologic involvement is not limited to the plexus and also involves the root and nerve levels. These conditions are called lumbosacral radiculoplexus neuropathies. The pathophysiology of diabetic and nondiabetic lumbosacral radiculoplexus neuropathy has been elucidated; it is ischemic injury due to a perivascular inflammatory process and microvasculitis. The clinical and neurophysiologic features of these two entities have been found to be similar, consisting of acute or subacute onset of pain and paresthesia followed by profound motor weakness asymmetrically involving the lower limbs and associated with weight loss. A lower limb and motor predominant neuropathy without pain also occurs in diabetes mellitus and has been shown to be a form of diabetic lumbosacral radiculoplexus neuropathy and not diabetic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The pathophysiology of some cases of postsurgical lumbosacral plexopathies has recently been shown also to be inflammatory from microvasculitis, and treatment with immunotherapy in a timely fashion may be desirable. Many pathophysiologic processes, such as neoplastic, traumatic, infectious, radiation, and inflammatory/microvasculitic processes, can affect the lumbosacral plexus causing lumbosacral plexopathy. The clinical symptoms and signs depend on the part of the plexus involved and the temporal course. Management depends on the cause of the lumbosacral plexopathy. Many cases of lumbosacral plexopathy previously thought to be idiopathic have been shown to be caused by ischemic injury from microvasculitis; despite lack of evidence for efficacy in improving neurologic deficits, the authors of this article include immunotherapy in their management of patients with this condition.


Understanding fragile X syndrome: insights from animal models.
The fragile X mental retardation syndrome is caused by large methylated expansions of a CGG repeat in the FMR1 gene leading to the loss of expression of FMRP, an RNA-binding protein. FMRP is proposed to act as a regulator of mRNA transport or translation that plays a role in synaptic maturation and function. To study the physiological function of the FMR1 protein, mouse and Drosophila models have been developed. The loss-of-function mouse model shows slightly enlarged testes, a subtle behavioral phenotype, and discrete anomalies of dendrite spines similar to those observed in brains of patients. Studies in Drosophila indicate that FXMR plays an important role in synaptogenesis and axonal arborization, which may underlie the observed deficits in flight ability and circadian behavior of FXR mutant flies. The relevance of these studies to our understanding of fragile X syndrome is discussed.


Effect of rat developmental stage at initiation on the expression of biochemical markers during liver tumor promotion.
The phenotypic response of rat liver to a carcinogenic protocol involving initiation/selection and promotion with and without phenobarbital (PB) feeding was studied in pubertal and adult male rats. Considering the early presence of preneoplastic nodular areas, it appeared that pubertal rats, initiated at 6-7 weeks, presented a higher susceptibility to the protocol than adult rats initiated at 9-10 weeks. Altered liver phenotype was characterized by: (1) gamma-glutamyl-transpeptidase (GGT) and glutathione S-transferase (GST) activities; (2) the expression of two forms of cytochrome P-450; de novo PB-inducible P-450 II B 1,2 and P-450 II C 7 normally expressed in 45-day-old rats and PB-inducible, and (3) the expression of albumin and alpha-fetoprotein cDNAs. In the absence of PB, the susceptibility of pubertal rat liver to hepatocarcinogenesis was related to a special metabolic phenotype enriched in GGT and GST activities by comparison with the quasi-normal expression of both P-450s. Adult rat liver presented a less altered pattern closer to that of noninitiated rat liver. During PB promotion, the loss of PB inducibility of P-450 II C 7 in pubertal rat liver suggested that the hormonal status of the animals could interact with initiation to modulate specific gene expression. The late phase of PB promotion revealed the loss of highly differentiated functions (P-450s, albumin), whereas enzymatic markers associated with preneoplastic foci showed a persistent high expression.


Very low birth weight increases risk for sleep-disordered breathing in young adulthood: the Helsinki Study of Very Low Birth Weight Adults.
We investigated whether very low birth weight (<1500 g) is associated with the risk of sleep-disordered breathing in young adulthood. The study was a retrospective longitudinal study of 158 young adults born with very low birth weight and 169 term-born control subjects (aged 18.5-27.1 years). The principal outcome variable was sleep-disordered breathing defined as chronic snoring. The crude prevalence of chronic snoring was similar in both groups: 15.8% for the very low birth weight group versus 13.6% for the control group. However, after controlling for the confounding variables in multivariate logistic regression models (age, gender, current smoking, parental education, height, BMI, and depression), chronic snoring was 2.2 times more likely in the very low birth weight group compared with the control group. In addition, maternal smoking during pregnancy was significantly and independently of very low birth weight related to risk of sleep-disordered breathing. Maternal preeclampsia, standardized birth weight, and, for very low birth weight infants, small-for-gestational-age status were not related to sleep-disordered breathing. Premature infants with very low birth weight have a twofold risk of sleep-disordered breathing as young adults. In addition, maternal smoking during pregnancy increases the risk of sleep-disordered breathing by more than twofold.


Integrative genomic analysis of phosphatidylinositol 3'-kinase family identifies PIK3R3 as a potential therapeutic target in epithelial ovarian cancer.
The phosphatidylinositol 3'-kinase (PI3K) family plays a key regulatory role in various cancer-associated signal transduction pathways. Here, we investigated the genomic alterations and gene expression of most known PI3K family members in human epithelial ovarian cancer. The DNA copy number of PI3K family genes was screened by a high-resolution array comparative genomic hybridization in 89 human ovarian cancer specimens. The mRNA expression level of PI3K genes was analyzed by microarray retrieval approach, and further validated by real-time reverse transcription-PCR. The expression of p55gamma protein in ovarian cancer was analyzed on tissue arrays. Small interfering RNA was used to study the function of PIK3R3 in ovarian cancer. In ovarian cancer, 6 of 12 PI3K genes exhibited significant DNA copy number gains (>20%), including PIK3CA (23.6%), PIK3CB (27.0%), PIK3CG (25.8%), PIK3R2 (29.2%), PIK3R3 (21.3%), and PIK3C2B (40.4%). Among those, only PIK3R3 had significantly up-regulated mRNA expression level in ovarian cancer compared with normal ovary. Up-regulated PIK3R3 mRNA expression was also observed in liver, prostate, and breast cancers. The PIK3R3 mRNA expression level was significantly higher in ovarian cancer cell lines (n = 18) than in human ovarian surface epithelial cells (n = 6, P = 0.002). Overexpression of p55gamma protein in ovarian cancer was confirmed by tissue array analysis. In addition, we found that knockdown of PIK3R3 expression by small interfering RNA significantly increased the apoptosis in cultured ovarian cancer cell lines. We propose that PIK3R3 may serve as a potential therapeutic target in human ovarian cancer.


Male sterility in the domestic fowl (Gallus domesticus) after 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitroso-trans-urea (NSC-95441) treatment of chicks.
Of 11 male baby chicks treated twice with 3 mg of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitroso-trans-urea (once on the day of hatching and once on the day after), 9 showed absolute lack of spermatogenesis and 2 showed severe inhibition when examined at the age of 6 months. Plasma testosterone level was not altered, however, and histologic examination revealed well-organized testicular interstitial tissue with an abundance of Leydig's cells. In the lining of the seminiferous tubules only Sertoli's cells were present. The weight of the testes from treated animals was only about 10% of control weight. These findings emphasized the possibility that the nitrosoureas cause severe damage to the reproductive system in man.


ROC analysis for assessment of lesion detection performance in 3D PET: influence of reconstruction algorithms.
Image quality in positron emission tomography (PET) can be assessed with physical parameters, as spatial resolution and signal-to-noise ratio, or using psychophysical approaches, which include the observer performance and the considered task (ROC analysis). For PET in oncology, such a task is the detection of hot lesions. The aim of the present study was to assess the lesion detection performance due to adequate modeling of the scanner and the measurement process in the image reconstruction process. We compared the standard OSEM software of the manufacturer with a sophisticated fully 3D iterative reconstruction technique (USC MAP). A rectangular phantom with 6 oblique line sources in a homogeneous background (2.6 kBq/ml 18F) was imaged dynamically with an ECAT EXACT HR+ scanner in 3D mode. Reconstructed activity contrasts varied between 15 and 0, as the line sources were filled with 11C (3.2 MBq/ml). Measured attenuation and standard randoms, dead time, and scatter corrections of the manufacturer were employed. For the ROC analysis, a software tool presented a cut-out of the phantom (15 x 15 pixels) to two observers. These cut-outs were rated (5 classes) and the area Az under the ROC curve was determined as a measure of detection performance. The improvement for Az with USC MAP compared to the OSEM reconstructions ranged between 0.02 and 0.23 for signal-to-noise ratios of the background between 2.8 and 3.1 and lesion contrast between 2.1 and 4.2. This study demonstrates that adequate modeling of the measurement process in the reconstruction algorithm improves the detection of small hot lesions markedly.


Platelet factor-4 excretion in myeloproliferative disease: implications for the aetiology of myelofibrosis.
Experimental evidence suggests that the fibroblastic proliferation often associated with the myeloproliferative disorders is not part of the neoplastic process, but is secondary to an unknown stimulus. This stimulus may be a factor derived from platelets which promotes the proliferation of fibroblasts in vitro (PDGF). Platelet-derived growth factor is localized to platelet alpha-granules together with PF4 and beta-TG. As an indicator of alpha-granule release, we have measured PF4 levels in plasma, platelets and urine in 46 normal subjects and 49 patients with myeloproliferative disorders, secondary thrombocytosis and miscellaneous malignancies. All 11 patients with elevated urinary PF4 excretion exhibited myelofibrosis, whereas 11 of 22 patients with documented myelofibrosis had urinary PF4 excretion in the normal range. No correlation was seen between marrow fibrosis and plasma levels or the platelet content of PF4. The data are consistent with the possibility that release of mitogen(s) from platelet or megakaryocyte alpha-granules in some patients with myeloproliferative disorders is pathogenetically related to the development of marrow fibrosis.


180-Nucleotide Duplication in the G Gene of Human metapneumovirus A2b Subgroup Strains Circulating in Yokohama City, Japan, since 2014.
Human metapneumovirus (HMPV), a member of the family Paramyxoviridae, was first isolated in 2001. Seroepidemiological studies have shown that HMPV has been a major etiological agent of acute respiratory infections in humans for more than 50 years. Molecular epidemiological, genetic, and antigenetic evolutionary studies of HMPV will strengthen our understanding of the epidemic behavior of the virus and provide valuable insight for the control of HMPV and the development of vaccines and antiviral drugs against HMPV infection. In this study, the nucleotide sequence of and genetic variations in the G gene were analyzed in HMPV strains prevalent in Yokohama City, in the Kanto area, Japan, between January 2013 and June 2016. As a part of the National Epidemiological Surveillance of Infectious Diseases, Japan, 1308 clinical specimens (throat swabs, nasal swabs, nasal secretions, and nasal aspirate fluids) collected at 24 hospitals or clinics in Yokohama City were screened for 15 major respiratory viruses with a multiplex reverse transcription-PCR assay. HMPV was detected in 91 specimens, accounting for 7.0% of the total specimens, and the nucleotide sequences of the G genes of 84 HMPV strains were determined. Among these 84 strains, 6, 43, 10, and 25 strains were classified into subgroups A2a, A2b, B1, and B2, respectively. Approximately half the HMPV A2b subgroup strains detected since 2014 had a 180-nucleotide duplication (180nt-dup) in the G gene and clustered on a phylogenic tree with four classical 180nt-dup-lacking HMPV A2b strains prevalent between 2014 and 2015. The 180nt-dup causes a 60-amino-acid duplication (60aa-dup) in the G protein, creating 23-25 additional potential acceptor sites for O-linked sugars. Our data suggest that 180nt-dup occurred between 2011 and 2013 and that HMPV A2b strains with 180nt-dup (A2b180nt-dup HMPV) became major epidemic strains within 3 years. The detailed mechanism by which the A2b180nt-dup HMPV strains gained an advantage that allowed their efficient spread in the community and the effects of 60aa-dup on HMPV virulence must be clarified.


In planta expression of oomycete and fungal genes.
Large-scale genome sequencing projects have generated a wealth of sequence information for plant pathogenic microbes such as oomycetes and fungi. Functional genomic approaches are essential to exploit the sequence information to identify pathogen effector genes that trigger cellular and molecular responses in plant cells. This chapter describes two functional assays, agroinfiltration and agroinfection. These assays allow rapid functional expression of pathogen genes in plants and can be used in high-throughput screens.


Hydrolyzed caseinomacropeptide conjugated galactooligosaccharides support the growth and enhance the bile tolerance in Lactobacillus strains.
In this study bioactive caseinomacropeptide was conjugated with prebiotic galactooligosaccharides (hCMP:GOS) by Maillard reaction to synthesize value added prebiotic compounds to Lactobacillus strains. Growth study showed the ability of hCMP:GOS to serve as a sole carbon source for Lactobacillus strains. A significant amount of acetate and lactate was detected in cell free culture supernatant by HPLC. It demonstrated the ability of Lactobacillus strains to ferment the hCMP:GOS as a carbon source. In addition, hCMP:GOS grown Lactobacillus cells exhibited enhanced bile tolerance and retained 90% viability. Overall results of this study indicate that the hCMP conjugated GOS can be potential multipurpose prebiotic substrates to enhance the growth and bile tolerance in Lactobacillus strains and serve as a fermentable substrate to produce beneficial metabolites in the host.


Identification of Major Bioactive Anti-inflammatory Compounds of Derris scandens Stem Using RAW 264.7 Cells and HPLC-UV Analysis.
Derris scandens (DS) is widely recognized for its therapeutic properties, specifically its analgesic effects, which significantly alleviate muscle pain. The chemical constituents of DS stem include various isoflavone derivatives. However, there is currently a lack of specified anti-inflammatory chemical markers and analytical methods for quality control. The present study aimed to evaluate the anti-inflammatory activity of DS and its constituents using the RAW 264.7 cell model. The expression of inflammatory genes such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and 5-lipoxygenase (5-LOX) was examined using quantitative RT-PCR. An high-performance liquid chromatography with a UV detection method was developed to quantitatively analyze genistein-7-O-[α-rhamnopyranosyl-(1 → 6)]-β-glucopyranoside, genistein, derrisisoflavone A, lupalbigenin, and 6,8-diprenylgenistein in DS stem. The developed HPLC-UV method demonstrated high sensitivity with limits of detection and quantification ranging from 0.01 to 0.06 µg/mL and 0.03 to 0.18 µg/mL, respectively. The accuracy of the method ranged from 93.3 to 109.6%. Furthermore, the repeatability and reproducibility of the method were suitable, as indicated by the relative standard deviations of ≤ 3.02% and ≤ 6.22%, respectively. The DS extract notably inhibited NO production, exhibiting effects comparable to those of 500 µM diclofenac, and substantially suppressed the expression of iNOS, COX-2, IL-6, and 5-LOX of lipopolysaccharide (LPS)-induced genes. As to the pure isoflavone derivatives, the order of NO production inhibition was found to be genistein > lupalbigenin > derrisisoflavone A > 6,8-diprenylgenistein > genistein-7-O-[α-rhamnopyranosyl-(1 → 6)]-β-glucopyranoside. Genistein, derrisisoflavone A, and 6,8-diprenylgenistein significantly suppressed the upregulation of all LPS-induced genes. Consequently, these compounds are recommended as anti-inflammatory markers for the quantitative chemical analysis of DS.


Expression of mouse Gal beta 1,4GlcNAc alpha 2,6-sialyltransferase in an insoluble form in Escherichia coli and partial renaturation.
Mouse Gal beta 1,4GlcNAc alpha 2,6-sialyltransferase was produced in an insoluble form in Escherichia coli cells harboring expression plasmids. The insoluble protein was solubilized with 8 M urea and diluted for renaturation of the enzyme. The substrate specificity and kinetic parameters, except for the specific activity, of the renatured enzyme were similar to those of the enzyme obtained from rat liver. These results suggest that a bacterial expression system is a potentially powerful tool for the large scale production of sialyltransferases and for elucidating the molecular mechanisms of sialyltransferases.


Mutational analysis of the ST7 gene in human myeloid tumor cell lines.
The recently described ST7 (for suppression of tumorigenicity 7) gene has been suggested to be a major target gene on chromosome 7q31 for inactivation in a variety of human neoplasias. Loss of heterozygosity (LOH) in chromosome 7q31 is frequently observed in a variety of human neoplasias including malignant myeloid tumors. We, therefore, sought to examine a total of 22 human malignant myeloid tumor cell lines comprising 17 of acute myelogenous leukemia (AML) cell lines and 5 chronic myelogenous leukemia (CML) cell lines for somatic mutations of the ST7 gene by means of bidirectional direct DNA sequencing analysis. As a result, no mutations were detected in any of these cell lines examined. In addition, our analysis of two breast tumor cell lines, which had been reported to harbour ST7 mutations, provided no evidence for such mutations. Thus, our results strongly suggest that somatic mutations of ST7 do not commonly contribute to the molecular pathogenesis of human malignant myeloid tumors and further raise questions regarding the pathological role of ST7 as a tumor suppressor gene (TSG) in a variety of human neoplasias.


Comprehensive investigation of novel serum markers of pulmonary fibrosis associated with systemic sclerosis and dermato/polymyositis.
To investigate the association between serum levels and clinical signs of lung fibrosis in patients with systemic sclerosis and inflammatory myopathies. ELISA tests for a mucin-like glycoprotein KL-6, von Willebrandt factor (vWF), soluble E-selectin (sES) and surfactant protein D (SP-D) were performed in sera of 104 patients with systemic sclerosis, 31 patients with poly/dermatomyositis) and 24 patients with Raynaud's phenomenon as controls. The clinical and laboratory data were evaluated by a simple standard protocol including chest x-ray, lung function tests, echocardiography and, in selected cases, high resolution computer tomography (HRCT). Clinically significant pulmonary fibrosis (PF) defined as a simultaneous presence of radiological sign of pulmonary fibrosis and restrictive impairment. Severe PF was established if HRCT scans showed diffuse interstitial lung disease with low diffusing capacity. End stage PF was determined as severe PF with very low diffusing capacity. Patients with pulmonary fibrosis on chest x-ray showed significantly elevated serum levels of KL-6, SP-D and vWF. Inverse correlation was found between serum levels of KL-6/SP-D and lung function parameters, such as DLCO% and FVC. With regard to HRCT findings, patients with elevated serum level of KL-6 showed significantly more frequently ground glass opacity, diffuse and honeycombing fibrosis than patients with normal level of KL-6. The sensitivity of KL-6 for PF in SSc is increased with the severity of PF (PF on chest x-ray < severe PF < end stage of PF). Lung fibrosis occurred more frequently in patients with simultaneously elevated KL-6 and sES compared to cases with a single positivity of either KL-6 or sES. KL-6, SP-D, vWF and ES are good surrogate factors of pulmonary fibrosis but can not replace conventional diagnostic procedures. However, these markers are suitable for the assessment of progression and severity of pulmonary fibrosis in systemic autoimmune disorders once the diagnosis is established.


Use of social stories to improve self-regulation in children with autism spectrum disorders.
A multiple baseline across participants design was used to evaluate the effects of Social Stories to help preschool-aged children with characteristics of Autism Spectrum Disorders (ASD) increase their engagement in functional behaviors and use sensory integrative-based strategies to promote self-regulation. Three children, 3-5 years old, from a self-contained preschool classroom were selected to participate in the study. The intervention package included reading individualized Social Stories that discussed desired behaviors and self-regulation strategies. The researchers measured the percentage of intervals in which participants engaged in desired behaviors. The frequency of desired behaviors increased for all participants. The use of self-regulation strategies varied across participants. These findings suggest that the intervention was successful in increasing desired behaviors of the three children. Further research is recommended on the effectiveness of embedding sensory integrative strategies into Social Stories. Practitioners may consider the use of Social Stories as a tool to increase independence and encourage self-regulated behaviors in children with characteristics of ASD.


Sex-Related Differences in Self-Paced All Out High-Intensity Intermittent Cycling: Mechanical and Physiological Responses.
The purpose of this study was to compare sex-related responses to a self-paced all out high-intensity intermittent exercise (HIIE). 9 women and 10 men were submitted to a maximal incremental test (to determine maximum aerobic power - MAP and VO2peak), and an HIIE cycling (60x8s:12s, effort:pause). During the protocol the mean value of V̇O2 and heart rate for the entire exercise (VO2total and HRtotal) as well as the values only in the effort or pause (V̇O2effort, VO2pause and HReffort and HRpause) relative to VO2peak were measured. Anaerobic power reserve (APR), blood lactate [La] and the respiratory exchange ratio (RER) were also measured. These variables were compared between men and women using the unpaired t test. Men used greater APR (109 ± 12%MAP vs 92 ± 6%MAP) with similar V̇O2total (74 ± 7 vs 78 ± 8% VO2peak), however, when effort and pause were analysed separately, V̇O2effort (80 ± 9 vs 80 ± 5%VO2peak) was similar between sexes, while V̇O2pause was lower in men (69 ± 6% vs 77 ± 11% VO2peak, respectively). Women presented lower power decrement (30 ± 11 vs 11 ± 3%), RER (1.04 ± 0.03 vs 1.00 ± 0.02) and [La]peak (8.6 ± 0.9 vs 5.9 ± 2.3 mmol.L(-1)). Thus, we can conclude that men self-paced HIIE at higher APR but with the same cardiovascular/aerobic solicitation as women. Key pointsMen self-paced high-intensity intermittent exercise at higher intensities than women.Men utilized greater anaerobic power reserve than women.Men and women had same cardiovascular solicitation.


The impact of contact lens care solutions on the thickness of the tear film and contact lens.
To determine the impact of compositional differences in contact lens care solutions on the thickness of the tear film during contact lens wear. A randomized, crossover, investigator-masked clinical trial was conducted to compare AMO's Complete MoisturePlus to Alcon's Opti-Free Express in 31 subjects. The primary outcome of this study was a comparison of prelens tear film (PLTF) and postlens tear film (PoLTF) thickness values obtained during the first 2 hours of etafilcon A hydrogel lens wear. Each solution was used by each participant for a period of 7 days, separated by a washout period of 1 day. Alternative outcomes studied included prelens tear film thinning rates, solution preference, and dry eye-related symptom scores. Tear film thickness measurements were made using a noninvasive wavelength-dependent interferometric system. The average overall PLTF thickness over the 120-minute time period after using Complete MoisturePlus was 3.02 +/- 1.07 microm, whereas the average overall PLTF thickness in this same time interval after using Opti-Free Express was 2.72 +/- 0.86 (P = 0.003). For both solutions, the PLTF could be fitted by the sum of an exponential decay plus a constant. The PLTF decay amplitudes did not statistically differ when the solutions were compared (P = 0.11). There was no difference in overall PoLTF thicknesses when the average values after using each solution were compared (P = 0.57), although there was a difference immediately after the lens was applied to the eye (Complete MoisturePlus average = 4.10 versus Opti-Free Express average = 3.48, P = 0.02). The PoLTF also demonstrated an exponential decay for both solutions. The PoLTF decay amplitudes did not statistically differ (P = 0.14). Twenty subjects (64.5%) preferred Complete MoisturePlus to Opti-Free Express (35.5%) (P = 0.11), and nearly every subject (90.3%) suggested "comfort" as their reason for preference. Complete MoisturePlus is associated with a thicker PLTF when compared with Opti-Free Express in contact lens wearers without dry eye symptoms, especially during the first 5 minutes following lens insertion.


Ultrasonography of the medial palmar intercarpal ligament in the Thoroughbred: technique and normal appearance.
Tearing of the medial palmar intercarpal ligament (MPICL) has been recognised as a cause of lameness in the Thoroughbred, but diagnosis is difficult due to the nonspecific clinical signs, and can be achieved only by performing arthroscopy on the mid carpal joint (MCJ). It would be beneficial to be able to image the MPICL using ultrasonography to determine whether pathology is present in the ligament in order to aid diagnosis and prognosis. To determine whether the MPICL could be imaged using ultrasound from the dorsal aspect of the MCJ, and to describe the technique and normal ultrasonographic appearance of the ligament. A pilot study was performed using 2 cadaver carpi. Each carpus in turn had the MPICL imaged simultaneously using arthroscopy and ultrasound, with a metallic probe positioned on the dorsal aspect of the ligament to highlight the position of the MPICL. Six further pairs of carpi had the MPICL imaged ultrasonographically followed by dissection of the carpus to evaluate the ligament and relate its anatomy to the ultrasound images. Finally, 15 Thoroughbreds with no history of lameness isolated to the carpus had their MPICLs assessed and measured ultrasonographically. The MPICL could be imaged via the dorsal aspect of the MCJ using standard ultrasound equipment. The body and division into medial and lateral branches could be seen as a distinct, moderately dense granular echogenic structure in the palmar aspect of the joint, with clearly defined margins. The normal MPICL can be imaged reliably using ultrasound in the Thoroughbred from the dorsal aspect of the MCJ. There is a wide range in the normal width of the lateral aspect of the MPICL, but there is good symmetry between contralateral limbs. This report of the normal ultrasonographic appearance of the ligament will be beneficial in acting as a reference for the detection of pathology using ultrasound.


[A case of renal cell carcinoma in tuberous sclerosis].
A 43-year-old woman with mental retardation, epilepsy, and urinary stone disease had a right renal tumor. Acne-like anthema around the nose and dental pits of the nine teeth were typical signs of tuberous sclerosis (TSC), and the biopsy finding of the facial anthema was consistant with TSC. The pathological diagnosis of laparoscopic nephrectomy was renal cell carcinoma in the hemorrhagic cyst. The TSC-related renal cell carcinoma tends to develop bilaterally in younger individuals compared with the sporadic RCC. This case is the 27th case of TSC-related RCC in Japan.


Ex vivo multiphoton analysis of rabbit corneal wound healing following conductive keratoplasty.
Ex vivo multiphoton imaging is used to characterize rabbit corneal wound healing after conductive keratoplasty (CK) procedures. CK is performed on the right eyes from eight New Zealand albino rabbits while the left eyes are punctured by a keratoplast tip without energy application. Rabbits are humanely sacrificed 1 day, 1, 2, and 4 weeks after the CK procedure. Eye balls are enucleated and placed on the microscope for multiphoton imaging. Multiphoton imaging reveals damage of corneal epithelium and stroma caused by the CK procedure and the subsequent wound healing process can be followed without histological procedures. Multiphoton excited autofluorescence images demonstrate that re-epithelilialization is accomplished within 1 week in both CK and control groups. However, epithelial hyperplasia is observed in CK corneas. In addition, stromal wounds in the control group become inconspicuous within 1 week while obvious wounds still exist in CK corneas for at least 4 weeks. Postconductive keratoplasty corneal damage and wound healing can be characterized by multiphoton microscopy without histological procedures. Our results suggest that multiphoton microscopy has potential in the clinical evaluation of corneal damage due to refractive surgery, and can be used to study and reduce the unwanted side effects of these procedures.


Epicardial cells of human adults can undergo an epithelial-to-mesenchymal transition and obtain characteristics of smooth muscle cells in vitro.
Myocardial and coronary development are both critically dependent on epicardial cells. During cardiomorphogenesis, a subset of epicardial cells undergoes an epithelial-to-mesenchymal transition (EMT) and invades the myocardium to differentiate into various cell types, including coronary smooth muscle cells and perivascular and cardiac interstitial fibroblasts. Our current knowledge of epicardial EMT and the ensuing epicardium-derived cells (EPDCs) comes primarily from studies of chick and mouse embryonic development. Due to the absence of an in vitro culture system, very little is known about human EPDCs. Here, we report for the first time the establishment of cultures of primary epicardial cells from human adults and describe their immunophenotype, transcriptome, transducibility, and differentiation potential in vitro. Changes in morphology and beta-catenin staining pattern indicated that human epicardial cells spontaneously undergo EMT early during ex vivo culture. The surface antigen profile of the cells after EMT closely resembles that of subepithelial fibroblasts; however, only EPDCs express the cardiac marker genes GATA4 and cardiac troponin T. After infection with an adenovirus vector encoding the transcription factor myocardin or after treatment with transforming growth factor-beta1 or bone morphogenetic protein-2, EPDCs obtain characteristics of smooth muscle cells. Moreover, EPDCs can undergo osteogenesis but fail to form adipocytes or endothelial cells in vitro. Cultured epicardial cells from human adults recapitulate at least part of the differentiation potential of their embryonic counterparts and represent an excellent model system to explore the biological properties and therapeutic potential of these cells.


The molecular and cellular action properties of artemisinins: what has yeast told us?
Artemisinin (ART) or Qinghaosu is a natural compound possessing superior anti-malarial activity. Although intensive studies have been done in the medicinal chemistry field to understand the structure-effect relationship, the biological actions of artemisinin are poorly understood and controversial. Due to the current lack of a genetic amiable model to address this question, and an accidental finding made more than a decade ago during our initial exploratory efforts that yeast Saccharomyces cerevisiae can be inhibited by artemisinin, we have since been using the baker's yeast as a model to probe the molecular and cellular properties of artemisinin and its derivatives (ARTs) in living cells. ARTs were found to possess potent and specific anti-mitochondrial properties and, to a lesser extent, the ability to generate a relatively general oxidative damage. The anti-mitochondrial effects of artemisinin were later confirmed with purified mitochondria from malaria parasites. Inside some cells heme appears to be a primary reducing agent and reduction of ARTs by heme can induce a relatively nonspecific cellular damage. The molecular basis of the anti-mitochondrial properties of ARTs remains not well elucidated yet. We propose that the anti-mitochondrial and heme-mediated ROS-generating properties constitute two cellcidal actions of ARTs. This review summarizes what we have learned from yeast about the basic biological properties of ARTs, as well as some key unanswered questions. We believe yeast could serve as a window through which to peek at some of the biological action secrets of ARTs that might be difficult for us to learn otherwise.


Blood glucose concentration control for type 1 diabetic patients: a non-linear suboptimal approach.
In this study, a closed-loop treatment strategy is proposed for the control of blood glucose levels in type 1 diabetic patients. Toward this end, a non-linear technique for designing suboptimal tracking controllers, called the state-dependent Riccati equation tracker, is used based on a mathematical model of the glucose-insulin regulatory system. Since two state variables of the utilised model are not available to the controller, a non-linear filter is also designed to estimate these variables using the measured blood glucose concentration. Effects of unannounced meals and regular exercise are investigated for a nominal patient and nine diabetic patients with unknown parameters. Numerical simulations are given to show the effectiveness of the proposed treatment strategy even in the presence of parametric uncertainties and the observation noise.


The complex dynamics of antimicrobial activity in the human gastrointestinal tract.
The human gastrointestinal tract is a complex environment of mutualistic associations. As bacteria form a major component of fecal content, the natural balance of the colon can be significantly altered by exposure to antimicrobial agents. However, the effects of antimicrobial therapy on fecal content are difficult to predict and can at times be quite surprising. The emergence and spread of vancomycin-resistant enterococci are cases in point. Resistance to the glycopeptide vancomycin emerged in enterococci (primarily in Enterococcus faecium) in the late 1980s in both Europe and the United States. In Europe, this emergence was tied to the use of the glycopeptide antibiotic avoparcin to promote growth in food animals and had little actual impact on hospital infections. In the United States, where avoparcin has never been licensed, vancomycin-resistant enterococci (VRE) emerged as a major hospital pathogen. Paradoxically, while the initial entry of the vancomycin resistance determinants into enterococci was almost certainly driven by high fecal concentrations of vancomycin associated with treatment for Clostridium difficile colitis, clinical infection and outbreaks were more frequently tied to use of extended-spectrum cephalosporins and agents with potent activity against anaerobic bacteria. Animal studies suggest that cephalosporins promote initial VRE colonization because of the frequent concomitant high-level resistance to β-lactam antibiotics expressed by these strains. Anti-anaerobic agents appear to increase the output of VRE in the feces, presumably by reducing the number of competitive flora in the colon. Intravenously administered vancomycin appears to have little impact because it achieves negligible concentrations in the feces after short courses. Thus, the spread of glycopeptide resistance in enterococci is promoted in a large measure by the administration of non-glycopeptide antibiotics.


Congenital mesoblastic nephroma: Clinical analysis of eight cases and a review of the literature.
Congenital mesoblastic nephroma (CMN) is a mesenchymal renal tumor. The aim of the present study was to review the clinical characteristics and outcome of CMN in infants. A retrospective file review was conducted of eight cases of CMN treated at the Children's Hospital of Fudan University between 2004 and 2012. Ultrasound and computerized tomography scans had been performed on all eight patients. Two cases presented with a solid tumor and exhibited pathological features consistent with those of classic CMN, five cases exhibited cystic, hemorrhagic and necrotic characteristics, with calcification and pathology consistent with the cellular variant of CMN and one case presented with a solid tumor, which exhibited pathological features consistent with ceullular CMN. Histology confirmed classic CMN in two patients and cellular CMN in six patients. For surgical intervention, four cases had radical nephrectomy, one case had a half nephrectomy and three cases had tumor enucleation performed. Two cases had received pre-operative chemotherapy, but exhibited no response, and three cases received post-operative chemotherapy. Two patients were lost to follow-up, but the remaining six patients survived to the end of follow-up without further complications. The mean follow-up time was 24.6 months. In conclusion, the differential diagnosis between CMN and Wilms' tumor is critical. Imaging characteristics are partially correlated with pathological characteristics. Surgery is the main treatment for CMN, but pre-operative chemotherapy is not particularly effective. The efficacy of post-operative chemotherapy requires further investigation, but the prognosis is positive.


Black client, white therapist: working with race in psychoanalytic psychotherapy in South Africa.
In post-apartheid South Africa we speak about race extensively. It permeates our workplace, weaves a thread through the fabric of our professional and personal lives, as well as our private conversations and public interactions with others. From within psychoanalytic theory, the thread weaves through the unknown content of our racialized unconscious. When there is a focus on race in the South African psychoanalytic context it largely takes the form of the struggle to articulate the complexities of working with difference, as Swartz notes, or the struggle to map out issues of race. Such struggles are not localized in South Africa, but strongly reflect a much broader struggle within the global psychoanalytic community, as mirrored in the expanding focus on race. Although the consulting rooms seem far removed from the ongoing political tensions that have recently emerged in South Africa, psychoanalytic psychotherapy remains a space of meaningful engagement with the other, and where the therapeutic dyad is one of racial difference it permits an encounter with our racialized unconscious. This article seeks to document the experience of my black client and my white response to her racial pain and struggle; in doing so, I describe the racial 'contact' between us and within us that triggers a racialized transference and countertransference dynamic, which contains the space for racial healing for both of us.


MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma.
MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients.


[Expression of BMP2/Smad1/Runx2 Signal Pathway in Renal Artery of Rat with Vascular Calcification].
To investigate the activation and its role of bone morphogenetic protein 2 (BMP2)/Smad1/Runt-related transcription factor 2 (Runx2) signal pathway in renal artery of rat models with vascular calcification. Twenty four male SD rats were randomly divided into control group and calcification group. Rat vascular calcification model was constructed by administration of vitamin D3 plus nicotine. Vascular calcification was confirmed by Von Kossa staining and calcium content was detected by calcium assay. Real time-PCR was applied to detect the expression of BMP2, Smad1, Runx2 mRNA, and immunohistochemistry was used to measure the protein levels of BMP2, Smad1, Runx2, α-smooth muscle actin (α-SMA). Von Kossa staining showed a large number of black granules deposited in renal artery. Calcium content in calcification group was significantly higher than that in normal group. Compared with the control group, the expressions of BMP2, Smad1 and Runx2 mRNA in renal artery were increased in calcification group. The protein levels of BMP2, Smad1 and Runx2 were higher while the expression of α-SMA was lower in calcification group than those in control group. The correlation analysis was found a positivie correlation between the calcium content and BMP2 mRNA (r = 0.655, P < 0.05), Smad1 mRNA (r = 0.735, P < 0.05), Runx2 mRNA (r = 0.734, P < 0.05). The expression of BMP2/Smad1/Runx2 signal pathway was strongly correlated with the severity of vascular calcification, which may be involved in the occurrence and development of vascular calcification.


Diurnal variation in QT dispersion in patients with chronic heart failure.
QT dispersion is defined as the difference in QT interval among the different leads of the standard 12-lead electrocardiogram and reflects inhomogeneity of myocardial repolarization. Dispersion of repolarization is an important electrophysiologic feature that is considered fundamental for the initiation of ventricular fibrillation. However, no data exist regarding the diurnal variation of QT dispersion measured from simultaneous 12-lead recording in chronic heart failure patients. The aim of this study was to identify diurnal variation in QT dispersion in patients with chronic heart failure. QT dispersion was measured in the 12-lead standard electrocardiogram in 11 patients with chronic heart failure. QT dispersion in these patients was increased in the afternoon compared to the morning. It is concluded that QT dispersion has a clear diurnal variation in patients with chronic heart failure. These findings have potentially significant implications for therapy and prevention of sudden cardiac death in patients with chronic heart failure.