Induction of CD4+CD25+ T cells and control of cardiac allograft rejection by CD40/CD40L costimulatory pathway blockade in mice.
Rejection is a major problem in organ transplantation. We speculated that dendritic cells (DCs) with low expression of CD40 may inhibit T-cell responses providing protective effects on organ transplantions. RNA interference (RNAi) is an effective approach to degrade RNA levels of a target gene. We used RNAi to reduce CD40 levels in mouse bone marrow-derived DCs. Allogeneic T-lymphocyte proliferation stimulated by DCs was assessed in mixed lymphocyte reactions. A mouse model of heterotopic abdominal heart transplantation was performed to evaluate survival times and histologic grade of acute rejection at 7 days after transplantation. CD4(+)CD25(+) regulatory T cells (Tregs) in peripheral blood were quantified by flow cytometry. Mouse DCs with reduced CD40 expression lowered the proliferation of recipient T cells. More DCs with silenced CD40 delayed cardiac allograft rejection. Reduction of CD40 in DCs induced peripheral Tregs and delayed cardiac allograft rejection.


Age dependent influence of external temperature on the pathogenesis of idiopathic lower extremity deep vein thrombosis.
The aim of the present study was to investigate the relationship between the incidence of idiopathic lower extremity deep vein thrombosis (DVT), age, location of the thrombus, and changes of temperature. During the two year period between May 2009 and April 2011, inclusive, 124 consecutive patients were diagnosed as having idiopathic lower extremity DVT at the Vascular Surgery Clinic, Clinical Center of Nis, Serbia. In patients younger than 45 years, the increase in average daily temperature with 1 degree C 7 days before the event took place was associated (p 0.05) with a decrease of the risk of occurrence of idiopathic DVT of the lower limbs of 3.6% (0.4 6.7%) as well as DVT above the knees (p 0.01) of 4.7 % (1.3 8.0%). In patients of the age of 45 years and over the age of 45 years the increase of average daily temperature with 1 degree C 7 days before the event took place was associated (p 0.01) with the increase of the risk of occurrence of DVT below the knees of 9.4% (3.3 15.9%). According to the results of this study, one can conclude that the influence of external temperature change on DVT incidence and location is based on age.


Systematics, biogeography, and evolution of Hemidactylus geckos (Reptilia: Gekkonidae) elucidated using mitochondrial DNA sequences.
With more than 80 species inhabiting all warm continental land masses and hundreds of intervening continental and oceanic islands, Hemidactylus geckos are one of the most species-rich and widely distributed of all reptile genera. They consequently represent an excellent model for biogeographic, ecological, and evolutionary studies. A molecular phylogeny for Hemidactylus is presented here, based on 702 bp of mtDNA (303 bp cytochrome b and 399 bp 12S rRNA) from 166 individuals of 30 species of Hemidactylus plus Briba brasiliana, Cosymbotus platyurus, and several outgroups. The phylogeny indicates that Hemidactylus may have initially undergone rapid radiation, and long-distance dispersal is more extensive than in any other reptilian genus. In the last 15 My, African lineages have naturally crossed the Atlantic Ocean at least twice. They also colonized the Gulf of Guinea, Cape Verde and Socotra islands, again sometimes on more than one occasion. Many extensive range extensions have occurred much more recently, sometimes with devastating consequences for other geckos. These colonizations are likely to be largely anthropogenic, involving the 'weedy' commensal species, H. brookii s. lat, H. mabouia, H. turcicus, H. garnotii, and H. frenatus. These species collectively have colonized the Mediterranean region, tropical Africa, much of the Americas and hundreds of islands in the Pacific, Indian, and Atlantic oceans. Five well-supported clades are discernable in Hemidactylus, with the African H. fasciatus unallocated. 1. Tropical Asian clade: (Cosymbotus platyurus (H. bowringii, H. karenorum, H. garnotii)) (H. flaviviridis (Asian H. brookii, H. frenatus)). 2. African H. angulatus and Caribbean H. haitianus. 3. Arid clade, of NE Africa, SW Asia, etc.: (H. modestus (H. citernii, H. foudai)) (H. pumilio (H. granti, H. dracaenacolus) (H. persicus, H. macropholis, H. robustus, H. turcicus (H. oxyrhinus (H. homoeolepis, H. forbesii))). 4. H. mabouia clade (H. yerburii, H. mabouia). 5. African-Atlantic clade: H. platycephalus ((H. agrius, H. palaichthus) (H. longicephalus, H. greeffi, H. bouvieri, Briba brasiliana))). Cosymbotus and Briba are synonymized with Hemidactylus, and African populations of H. brookii separated as H. angulatus, with which H. haitianus may be conspecific. Some comparatively well-sampled widespread species show high genetic variability (10-15% divergence) and need revision, including Cosymbotus platyurus, H. bowringii, Asian H. brookii, H. frenatus, H. angulatus, and H. macropholis. In contrast, most populations of H. mabouia and H. turcicus are very uniform (1-2% divergence). Plasticity of some of the morphological features of Hemidactylus is confirmed, although retention of primitive morphologies also occurs.


Rectal microbicide development.
The last few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis, vaginal microbicides, and treatment as prevention as effective strategies for reducing the risk of acquiring or transmitting HIV infection. There has also been significant progress in the development of rectal microbicides. Preclinical non-human primate studies have demonstrated that antiretroviral microbicides can provide significant protection from rectal challenge with SIV or SHIV. Recent Phase 1 rectal microbicide studies have characterized the safety, acceptability, compartmental pharmacokinetics (PK), and pharmacodynamics (PD) of both UC781 and tenofovir gels. The tenofovir gel formulation used in vaginal studies was not well tolerated in the rectum and newer rectal-specific formulations have been developed and evaluated in Phase 1 studies. The PK/PD data generated in these Phase 1 studies may reduce the risk of advancing ineffective candidate rectal microbicides into late stage development. Tenofovir gel is currently poised to move into Phase 2 evaluation and it is possible that a Phase 2B/3 effectiveness study with this product could be initiated in the next 2-3 years.


Prevention and suppression of experimental allergic encephalomyelitis by an orally active leukocyte recruitment inhibitor, NPC 16570.
An orally active leukocyte recruitment inhibitor, NPC 16570 (N-[9H-fluoren-9-ylethoxycarbonyl]-4-aminobenzoic acid), was evaluated in experimental allergic encephalomyelitis (EAE) in rats. The mean time of disease onset in control animals was 12 +/- 1 days, with peak average clinical scores of 2.5 +/- 0.2, accompanied by perivascular infiltration of inflammatory cells into the CNS. Daily administration (p.o.) of NPC 16570 reduced the clinical severity (by 70%) at 10 and 30 mg/kg, and at 100 mg/kg, no clinical symptoms were detected. When NPC 16570 (100 mg/kg) treatment was initiated 7 days after EAE induction, the severity (75% inhibition) and duration of the disease were attenuated; 2 out of 6 animals showed no overt clinical symptoms and perivascular cell infiltration was prevented, suggesting potential utility in autoimmune diseases.


An unbiased correction factor for cell counts in histological sections.
It is common procedure to correct raw counts of cells (or nuclei or other such particles) in histological sections by multiplying them by a 'correction factor', to allow for sectioned particles being counted more than once. However, the derivation of the standard formulae assumes that the particles to be counted are of uniform size. Therefore, these formulae may be biased in practical situations. Here, a more general correction factor (C) not depending on this restrictive assumption is derived: C = sigma i = 1 m T/(T - h(i))/sigma i = 1 m (T - R - S + h(i))/(T - h(i)) where T is section thickness, h(i) is the height of particle i measured perpendicular to the section plane, R and S are the heights, assumed constant, of the upper and lower 'lost caps', and the summation is performed over m (about 20) particles sampled randomly from among those lying wholly within individual sections. It is proposed that h(i) be measured by a differential focusing method; the formula will then be valid for particles of variable shape as well as size.


Inpatient cardiac rehabilitation and changes in self-reported health related quality of life--a pilot study.
To assess changes in self-reported health related quality of life (HRQoL) among cardiac patients who participated in an inpatient rehabilitation programme. Medical Outcomes Study Short Form 36 (SF-36) and the MacNew Heart Disease Health-related Quality of Life Questionnaire (MacNew) was used to assess HRQoL at baseline (T1), after rehabilitation (T2) and 5 months after discharge (T3). The rehabilitation programme consisted of physical exercise, theoretical education, group discussions and individual consultations. Friedman's test with Wilcoxon post-hoc test was used to analyse changes between T1, T2 and T3. Effect size (ES) were calculated. Eighty-nine participants were included (79% male) with mean age of 60.0 ± 8.6 years. All SF-36 and MacNew domains showed significant improvement from T1 to T2 (P < 0.05), and all except the SF-36 domain for emotional role with a moderate to large ES. At T3, change and ES are diminished in all domains, except for the physical and social domains of the MacNew. These findings indicate an improvement in HRQoL over time among cardiac patients attending the rehabilitation programme, particularly so in the domains of physical role and physical function, vitality, bodily pain and emotional-, physical- and social-well-being, all which are important domains for maintaining an active life. Future randomised studies comparing inpatient- and outpatient-programmes with longer follow-up are necessary to ascertain if such improvements persist and if patients are able to change life-style in line with the stated goals of cardiac rehabilitation (CR).


Diagnosis and surgical treatment of progressive pseudorheumatoid dysplasia in an adult with severe spinal disorders and polyarthropathy.
Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal-recessive disorder. The polyarthritis of PPD has been detailed before. However, the spinal disorder and surgical treatment been rarely mentioned. A 44-year-old patient who has been misdiagnosed as juvenile rheumatoid arthritis (JRA) and given unilateral total hip replacement yet, suffers mainly from severe spinal disorder this time. The platyspondyly, Scheuermann-like lesions of the spine and JRA-like features of the peripheral joints were found on radiographic films, combining negative inflammatory and rheumatoid factors, which most suggested the diagnosis of PPD. As the homozygous nucleotide deletion was found in WISP3 gene, diagnosis of PPD was definite. Neurological examination and further imaging examination indicated severe compression of thoracic and lumbar spinal cord which might lead to his conspicuous spinal disorder. Decompressive laminectomy, posterior fusion and fixation were performed. And an excellent clinical outcome was achieved 1 year after the decompression and fusion: leg pain and hypoesthesia resolved and osseous fusion performed. This is the first reported decompression in the adult spine of PPD. Surgical treatment could receive satisfactory result in PPD, however, it is a palliative therapy which has less help to prevent the development of this disease. Early diagnosis and rehabilitation interventions remain the most important. Clinical, radiographic and genetic features in PPD are crucial in the differential diagnosis.


Monoclonal antibodies against human urinary bladder carcinomas: selectivity and utilization for gamma scintigraphy.
Mouse monoclonal antibodies to human urinary bladder carcinoma cells have been examined by indirect membrane immunofluorescence using a panel of 27 human cell lines. Two of the monoclonal antibodies, 7E9 (IgG3) and S2C6 (IgGl), were found to distinguish between urinary bladder carcinoma cells and normal urothelium. The third monoclonal antibody, T24.06.5(IgGl), discriminated among cell lines of urothelial and non-urothelial origin but did not distinguish between urinary bladder carcinoma and normal urothelial cells. None of the of the antibodies was found to be strictly selective, and occasional cross-reactions with unrelated cell types were observed. The monoclonal antibody 7E9, showing the highest degree of selectivity, was further examined by an indirect immunoperoxidase technique on frozen tissue sections from 19 patients. The antibody reacted with all (7/7) bladder carcinomas examined and gave negative results with control normal bladder mucosa (0/8) and unrelated tumor tissue (0/4) sections. The 7E9 antibody was purified by protein A affinity chromatography, labeled with 131I and used for gamma-scintigraphy in nude mice xenografted with human urinary bladder carcinoma T24. The 7E9 antibody was capable of locating the T24 xenografts in nude mice; it localized preferentially in the T24 tissue compared to normal mouse tissues. The T24 xenografts could not be detected by gamma-scintigraphy with 131I-labeled monoclonal antibody against human mammary carcinoma cells and two other control antibodies. Likewise the 131I-labeled 7E9 antibody was not capable of locating human mammary carcinoma xenografts in nude mice.


Application of ultrasound-guided percutaneous intrahepatic portal vein catheterization with antibiotic injection for treating unliquefied bacterial liver abscess.
To investigate whether ultrasound-guided percutaneous portal vein catheterization can be successfully carried out in the intrahepatic region of patients with unliquefied bacterial liver abscess (UBLA), who are subsequently treated with an injection of antibiotics. Thirty-two UBLA patients were enrolled in this study. Among them, 13 patients were included in the experimental group; an ultrasound-guided percutaneous portal vein catheterization was undertaken in the intrahepatic region of these patients, and they also received an injection of antibiotics. The remaining 19 patients were retrospectively included in the control group; these patients only received systemic antibiotic therapy. The efficacy of intervention was compared with that of systemic treatment. The catheterization procedures were successful in all the patients of the experimental group. However, two cases (15.4%) developed complications postoperatively. Compared to the control group, the following parameters of the experimental group were significantly shorter/lower: (i) duration for regaining normal body temperature; (ii) time period for achieving normal white blood cell count; (iii) length of hospitalization; (iv) cases of liquefied liver abscess during follow-up; and (v) cost of hospitalization (P < 0.05). Ultrasound-guided percutaneous portal vein catheterization is a simple, minimally invasive, and effective treatment for UBLA. It must be carried out in the intrahepatic region and a subsequent injection of antibiotics must be given.


The prevalence of diffuse idiopathic skeletal hyperostosis in Japan - the first report of measurement by CT and review of the literature.
Diffuse idiopathic skeletal hyperostosis (DISH) is prone to be accompanied by a spinal column fracture which is resistant to conservative therapy. This major characteristic of DISH is not recognized adequately by physicians, because the disease's detailed pathological condition has not yet been investigated. Therefore, the purposes of this study were to investigate the prevalence of DISH using computed tomography (CT), and to validate the reliability of CT interpretation. Subjects were 558 patients (300 male and 258 female) who underwent both CT of chest to pelvis and x-ray of chest and abdomen from August 2011 to July 2012 at any department other than orthopedic surgery in our institution. The definition of DISH based on x-ray as well as CT was the presence of consecutive fused vertebral bodies according to Resnick's criteria. The prevalence of DISH based on both modalities was calculated in all subjects. For 107 subjects extracted at random, intra- (Cohen kappa) and inter-observer error (Fleiss kappa) were calculated and the levels of fused segments were investigated. Ninety-eight of 558 subjects (17.6%) were diagnosed as DISH by x-ray, and 152 (27.2%) by CT. Among males, 70 of 300 subjects (23.3%) were diagnosed by x-ray, and 116 (38.7%) by CT. Among females, 28 of 258 subjects (10.9%) were diagnosed by x-ray and 36 (14.0%) by CT. The levels of fused segments were presented from thoracic spine to lumbar spine, especially the middle and lower thoracic spine. Cohen kappa of x-ray was 0.587, and that of CT was 0.825. Fleiss kappa of x-ray was 0.552, and that of CT was 0.643. The prevalence of DISH based on CT was 27.1%, which was higher than that of x-ray. In addition, intra- and inter-observer error by review of CT was less than that of x-ray. CT evaluation would be a better method for precise understanding of the state of DISH.


Biology of monoclonal antibodies in tumor therapy.
This paper gives an overview of the biology of monoclonal antibodies in tumor therapy. The complexity of the monoclonal antibody concept is discussed with functional aspects on tumor antigen, antigen binding, Ig isotypes and effector mechanisms involved.


How to Measure Pain.
Pain is a multi-faceted symptom. Effective pain assessment involves properly defining the pain syndrome, utilizing various assessment tools, and recognizing different conditions which may affect the expression and the management of pain. Pain results from multiple physical and psychosocial etiological interplay. It has traditionally been categorized as acute or chronic with chronic pain having been categorized further into 6 categories in ICD 11. At the same time, the opioid epidemic and the recent surge in cannabis popularity further complicates pain assessment and effective pain management. Adequate management of pain begins with proper assessment including conducting extensive medical and psychosocial history and physical examination, and utilizing various pain and substance risk assessment tools. An interdisciplinary team approach may be more effective in managing complex pain behaviors compared to a solo approach.


Analysis of Circulating Endostatin and Vascular Endothelial Growth Factor in Patients with Pituitary Adenoma Treated by Stereotactic Radiosurgery: A Preliminary Study.
The purpose of this study was to investigate plasma levels of endostatin and vascular endothelial growth factor (VEGF) in normal subjects and in patients with pituitary adenoma and to evaluate change in these levels following stereotactic radiosurgery (SRS) for pituitary adenoma. Peripheral venous blood was collected from five patients with pituitary adenoma before SRS using Gamma Knife and at the 1 week and 1 month follow-up visits. Plasma endostatin and VEGF levels were measured using commercially available enzyme-linked immunosorbent assay kits. Peripheral blood samples were obtained from 10 healthy volunteers as controls. Mean baseline plasma endostatin level (105.3 ng/mL, range, 97.0-120.2 ng/mL) in patients with pituitary adenoma was higher than that of the healthy controls (86.6 ng/mL, range, 71.3-98.2 ng/mL) (p=0.001). Mean plasma VEGF level was 89.5 pg/mL (range, 24.1-171.8 pg/mL) in patients with pituitary adenoma at baseline and 29.3 pg/mL (range, 9.2-64.3 pg/mL) in the control group (p=0.050). Plasma endostatin level changed to 106.6 ng/mL 1 week after SRS and decreased to 95.9 ng/mL after 1 month. Plasma VEGF level following SRS decreased to 74.1 pg/mL after 1 week and 79.0 pg/mL after 1 month. There was a trend toward decreased plasma endostatin and VEGF concentrations 1 month after SRS compared to baseline levels (p=0.195, p=0.812, respectively). Plasma endostatin and VEGF levels in patients with pituitary adenoma were significantly elevated over controls at baseline, which decreased from baseline to 1 month after SRS for pituitary adenomas.


Yeast mitochondrial biogenesis: a model system for humans?
Recently, our knowledge of yeast mitochondrial biogenesis has considerably progressed. This concerns the import machinery that guides preproteins synthesized on the cytoplasmic ribosomes through the mitochondrial outer and inner membranes, as well as the inner membrane insertion machinery of mitochondrially encoded polypeptides, or the proteins participating in the assembly and quality control of the respiratory complexes and ATP synthase. More recently, two new fields have emerged, biosynthesis of the iron-sulfur clusters and dynamics of the mitochondrion. Many of the newly discovered yeast proteins have homologues in human mitochondria. Thus, Saccharomyces cerevisiae has proven a particularly suitable simple organism for approaching the molecular bases of a growing number of human mitochondrial diseases caused by mutations in nuclear genes identified by positional cloning.


Diagnosis and treatment of ectopic renal papilla.
Although ectopic renal papilla has been reported only recently, there is indication that it is more common than these few experiences would suggest. Awareness of this entity and its radiographic features should direct the urologist toward a conservative approach confirming the diagnosis by operative nephroscopy, thereby obviating nephrectomy.


Subclinical levels of maternal depression and infant sensitivity to social contingency.
The aim of the study was to investigate how young infants respond to contingent and non-contingent interaction in relation to maternal level of depressive symptoms in a non-clinical sample of mothers and infants. Two groups of three-month-olds interacted with their mother who was assessed as either non-depressed or sub-clinically depressed, based on self-reported scores on the Edinburgh Postnatal Depression Scale (EPDS). The infants were presented with a continuous image and voice of their mother in a closed circuit computer system, using the double video procedure. The experiment comprised five sequences, alternating between contingent (Live) and non-contingent (Replay) maternal behaviur in a fixed Live1-Replay1-Live2-Replay2-Live3 sequence. The infants of the sub-clinically depressed mothers showed a high gaze focus at their mother independently of the quality of interaction, while the infants of the non-depressed mothers showed a preference for looking at the mother only when the interaction with their mother was contingent. Further, the infants of the sub-clinically depressed mothers showed no differentiation in affective expression between contingent and non-contingent interactions, while the infants of the non-depressed mothers expressed more positive affect than negative affect only when the interaction with their mother was contingent. Finally, there was a significant relation between the infant's preference for looking at the mother and the infant's amount of positive affect, but this was only found for the infants of the non-depressed. These results indicate that young infants' sensitivity to social contingency is related to maternal level of depression, even in a non-clinical sample. This expands the implications of earlier findings on the impact of maternal depression on infant sensitivity to social contingency, demonstrating that even sub-clinical levels of maternal depression may effect early interaction and child development.


Nectar extraction by hummingbirds: response to different floral characters.
Handling times of hummingbirds (Amazilia rutila and Cynanthus latirostris) visiting artificial flowers were a positive function of corolla length, nectar volume and nectar concentration. Corolla angle had no consistent effects on handling times. A multiple regression model explained 83% of the variation in handling times for these two species. The model also closely fit independent data from another hummingbird, Archilochus colubris, suggesting that it is general enough to apply to other medium-sized, short-billed hummingbird species. When examined across the range of variation normally encountered by hummingbirds in nature, corolla length and nectar volume had the largest effect on nectar extraction rates. At corolla lengths longer than a hummingbird's bill handling time increases markedly. Hummingbirds maximize their net rate of energy intake by selecting flowers with the shortest corolla, the highest nectar concentrations and the highest nectar volume. Since there is a positive relation between bill length and nectar extraction rate, it is surprising that most hummingbirds have relatively short bills.


Highly-stable cobalt metal organic framework with sheet-like structure for ultra-efficient water oxidation at high current density.
The development of efficient and robust non-precious electrocatalysts for water oxidation at a mild condition is extremely desirable for industrial water splitting. Herein we developed a facile solvothermal strategy to synthesize cobalt metal organic frameworks (Co-MOFs) with sheet-like structure, which showed highly promising performance for electrocatalytic oxygen evolution. The best Co-MOF sample afforded an ultra-high oxygen evolution current density of 63.4 mA cm-2 at 1.75 V in 1 M KOH with a catalyst loading of only 0.21 mg cm-2. Notably, its electrochemical performance remained unchanged after 10,000 cyclic voltammograms indicating very promising long-term stability. Detailed study of the mechanism of the oxygen evolution by density functional theory (DFT) indicated that the strong π-conjugation formed between the central cobalt ion and adjacent aromatic rings favored the high electrocatalytic performance. The solvothermally synthesized MOFs proposed in this paper are expected to inspire the rational design of high-performance electrocatalysts for water oxidation with atomic and molecular level structural control and the exploration of structure-performance relationships to understand the electrocatalytic origin.


Monitor of tray error rates for quality control.
Accuracy of tray assembly is essential for providing appropriate nutrition care to patients and maintaining patient satisfaction. A monitoring system of tray assembly error rates was designed to evaluate patient tray accuracy and to identify types of assembly errors. Data were collected during two morning, five noon, and five evening meals. Errors were classified according to type: omission, addition, or substitution. They were also classified by severity: error of convenience (not critical with respect to diet) or error of compliance (contradictory to diet order). Error rates were determined and compared by meal, weekday vs. weekend, and first half of assembly period vs. second half. An average error rate of 12.9% was calculated from the 6,553 trays studied, with error rates of 12.5%, 10.9%, and 15.1% for breakfast, lunch, and dinner, respectively. Evaluation of data revealed no significant difference in error rate as sorted by type of error, among meals, or between weekday and weekend. Only 2.7% of the trays had errors contradictory to the diet order. The error rate was significantly higher during the second half of the assembly period, and the highest error rates were observed for the evening meal. The methodology used in this study serves as the basis for quality control monitoring and as a motivational tool to stimulate improved performance by trayline employees.


APOE ε2 allele is associated with larger regional cortical thicknesses and volumes.
The protective effect of the apolipoprotein E (APOE) ε2 allele against Alzheimer's disease (AD) is controversial. Our purpose was to clarify if the ε2 allele affects regional cortical thicknesses and volumes. Regional cortical thicknesses and volumes were measured with an automated pipeline in 109 subjects with mild cognitive impairment, 114 AD patients and 105 age-matched healthy controls. In the mild cognitive impairment group, the ε2 carriers had thicker regional cortices at the transverse temporal cortex and parahippocampal gyrus than the subjects with ε3/ε3, and a larger cerebral gray matter and smaller lateral ventricles than the ε3/ε3 and ε4 carriers. In the AD group, the ε2 carriers had significantly thicker entorhinal and transverse temporal cortices, a larger whole cerebral gray matter, and smaller lateral ventricles than the subjects with the ε3/ε3 genotype, and a significantly thicker entorhinal cortex and larger cerebral gray matter than ε4 carriers. No APOE2 effect was found in the control group. The APOE ε2 allele is associated with larger regional cortical thicknesses and volumes in mild cognitive impairment and AD.


Up-regulation of astroglial heme oxygenase-1 by a synthetic (S)-verbenone derivative LMT-335 ameliorates oxygen-glucose deprivation-evoked injury in cortical neurons.
Excessive generation of free radicals is regarded as a major detrimental factor in cerebral ischemic insults. Neurons are particularly vulnerable to oxidative stress due to their limited anti-oxidant capacity. As an important source of antioxidants in the brain, astroglia are now thought to be attractive targets for pharmacological interventions to reduce neuronal oxidative stress in ischemic stroke. In the present study, we synthesized a novel antioxidant, the (1S)-(-)-verbenone derivative LMT-335, and investigated its anti-ischemic activities. In rat cortical neuronal/glial co-cultures, LMT-335 significantly reduced oxygen-glucose deprivation (OGD)/reoxygenation (R)-induced neuronal injury. Although it did not inhibit N-methyl-d-aspartate-induced excitotoxicity, LMT-335 significantly reduced OGD/R-evoked intracellular oxidative stress. However, the oxygen radical absorbance capacity assay and 1,1-diphenyl-2-picrylhydrazyl assay showed that the free radical scavenging activities of LMT-335 were lower than those of trolox. Instead, LMT-335 significantly increased the astroglial expression of heme oxygenase-1 (HO-1), a well-known anti-oxidant stress protein, as evidenced by immunocytochemistry and immunoblot analyses. Moreover, a selective HO-1 inhibitor, tin protoporphyrin IX (SnPP), significantly blocked the anti-ischemic effect of LMT-335. The present findings indicate that LMT-335 exerts neuroprotective effects against OGD/R by up-regulation of HO-1 in astroglial cells. Our data suggest that astroglial HO-1 represents a potential therapeutic target for the treatment of ischemic stroke.


A systematic review of traditional uses, phytochemistry, pharmacology and toxicity of Epimedium koreanum Nakai.
Epimedium koreanum Nakai (E. koreanum), a member of the genus Epimedium in the family Berberidaceae, is a well-known and well-liked traditional herb used as a "kidney tonic". For thousands of years, it has been utilized for renal yang deficiency, impotence, spermatorrhea, impotence, weakness of tendons and bones, rheumatic paralysis and discomfort, numbness, and constriction. The paper aims to comprehensively in-depth, and methodically review the most recent research on the traditional uses, phytochemistry, pharmacology, and toxicity of E. koreanum. Scientific databases including Web of Science, PubMed, Google Scholar, Elsevier, Springer, ScienceDirect, Baidu Scholar, and CNKI and medicine books in China were searched for relevant information on E. koreanum. In traditional uses, E. koreanum is frequently used to treat various diseases like erectile dysfunction, infertility, rheumatoid arthritis, osteoporosis, asthma, kidney-yang deficiency syndrome, etc. To date, more than 379 compounds have been discovered from various parts of E. koreanum, including flavonoids, lignans, organic acids, terpenoids, hydrocarbons, dihydrophenanthrene derivatives, alkaloids, and others. Research has revealed that the compounds and crude extracts have a wide range of pharmacological effects on the reproductive, cardiovascular, and nervous systems, as well as anti-osteoporosis, anti-tumor, antioxidant, anti-inflammatory, immunomodulatory, hepatoprotective, and antiviral properties. Besides, the crude extracts show potential hepatotoxicity. Based on recent domestic and international research investigations, E. koreanum contains a wealth of chemical components with pronounced pharmacological activities. Its traditional uses are numerous, and the majority of these traditional uses have been supported by contemporary pharmacological investigations. Crude extracts, on the other hand, can result in hepatotoxicity. Therefore, additional in vivo and in vitro experimental research on the pharmacology and toxicology of E. koreanum are required in the future to assess its safety and efficacy. This will give a firmer scientific foundation for its safe application and the development of new drugs in the future.


Three-dimensional electron cryo-microscopy as a powerful structural tool in molecular medicine.
Electron cryo-microscopy has established itself as a valuable method for the structure determination of protein molecules, protein complexes, and cell organelles. This contribution presents an introduction to the various aspects of three-dimensional electron cryomicroscopy. This includes the need for sample preservation in the microscope vacuum, strategies for minimizing radiation damage, methods of improving the poor signal-to-noise ratio in electron micrographs of unstained specimens, and the various methods of three-dimensional image reconstruction from projections. The various specimen types (e.g., flat and tubular two-dimensional crystals, protein filaments, individual protein molecules, and large complexes) require different means of three-dimensional reconstruction, and we review the five major reconstruction techniques (electron crystallography, helical reconstruction, icosahedral reconstruction, single-particle reconstruction, and electron tomography), with an emphasis on electron crystallography. Several medically relevant three-dimensional protein structures are chosen to illustrate the potential of electron cryo-microscopy and image reconstruction techniques. Among the structural methods, electron cryo-microscopy is the only tool for studying objects that range in size from small proteins over macromolecular complexes to cell organelles or even cells.


[Use of UV radiation for the disinfection of water. IV. Microbiological studies of the UV sensitivity of different aged cells of E. faecium, E. coli and P. aeruginosa].
With a flow-through u.v. light treatment apparatus the u.v.-susceptibility of E. faecium, E. coli and P. aeruginosa in drinking water was tested. The investigations were done with cells harvested in the exponential phase of growth. One part of the suspensions was used immediately (= 0 days old cells), two other parts were stored for 5 and 7 days in sterilised drinking water in the dark at room temperature (= 5 and 7 days old cells). In either case--0 or 5 and 7 days old cells--reductions of at least 99.999% were obtained by a dosage of 25 mWs/cm2. No difference concerning the u.v.-susceptibility could be noticed between the different kind of cells of E. faecium, E. coli, and P. aeruginosa.


Genotyping of Porphyromonas gingivalis in Relationship to Virulence.
Porphyromonas gingivalis, a significant periodontal pathogen, is known to possess genetic variations in relation to its virulence. Furthermore, fimbriae encoded by the fimA gene are involved in bacterial adherence to and invasion of host cells, and a known virulence factor of the bacterium. The fimA gene is classified into six variants (types I-V and Ib) and has been shown to be related to microbial virulence. Polymerase chain reaction (PCR) assay results are helpful to differentiate the genotypes, with fimA type-specific primer sets used for that have been developed by several researchers. Although room for improvement remains, fimA genotyping is expected to become a useful technique for periodontal examinations and diagnosis. In this chapter, currently available PCR methods to classify fimA genotypic variations of P. gingivalis are described.


Identification of key genes involved in the biosynthesis of triterpenic acids in the mint family.
Triterpenic acids (TAs), a large group of natural compounds with diverse biological activity, are produced by several plant taxa. Betulinic, oleanolic, and ursolic acids are the most medicinally important TAs and are mainly found in plants of the mint family. Metabolic engineering is strongly dependent on identifying the key genes in biosynthetic pathways toward the products of interest. In this study, gene expression tracking was performed by transcriptome mining, co-expression network analysis, and tissue-specific metabolite-expression analysis in order to identify possible key genes involved in TAs biosynthetic pathways. To this end, taxa-specific degenerate primers of six important genes were designed using an effective method based on the MEME algorithm in a phylogenetically related group of sequences and successfully applied in three members of the Lamiaceae (Rosmarinus officinalis, Salvia officinalis, and Thymus persicus). Based on the results of in-depth data analysis, genes encoding squalene epoxidase and oxido squalene cyclases are proposed as targets for boosting triterpene production. The results emphasize the importance of identifying key genes in triterpene biosynthesis, which may facilitate genetic manipulation or overexpression of target genes.


Cytogenetic and DNA analysis of two neuroectodermal tumors without a simple t(11;22).
Cytogenetic analysis was conducted on tumor biopsy material from two pediatric, small, round, blue-cell tumors whose histology failed to give a clearcut diagnosis. The first case showed a complex composite karyotype within which there were two normal chromosomes 11 and one abnormal chromosome 22 present. The composite karyotype in the second case was similarly complex but this time included an abnormal chromosome 11 but no corresponding abnormal chromosome 22. Analysis of tumor mRNA from both cases using a Reverse Transcriptase PCR test with primers derived from a Ewing's sarcoma t(11;22)(q24;q12) breakpoint sequence showed both to have abnormal, chimeric transcribed messengers, each of different lengths. Further analysis of case 2 using chromosome painting and centromeric probing confirmed the abnormal chromosome 11 to be a der(11)t(11;22)(q24;q12) and also revealed two additional minor clones containing a der(22), which may be the karyotypic locations of the t(11;22) fusion sequences. Taken into consideration with clinical and histologic information, the results of these investigations indicated that both were neuroectodermal tumors (Ewing sarcomas of the chest wall/Askin tumors). The comparative values of both cytogenetic and molecular analysis in the diagnosis of neuroectodermal tumors and the detection of covert chromosome rearrangements are discussed.


[Fungi at the beach].
Fungi responsible for dermatomycoses survive in a resting phase inside diverse parts of the environment. Sand in the wet, partly wet and dry portions of the beaches frequently contains dermatophytes, yeasts and moulds. These microorganisms possibly infect skin and nails during summertime.


The regulation of lipid and carbohydrate storage by the splicing factor gene snRNP-U1-70K in the Drosophila fat body.
Excess triglycerides from the diet are stored in structures called lipid droplets in adipose tissue. Genome-wide RNAi screens have identified mRNA splicing factors as important for lipid droplet formation; however, the full complement of splicing factors that regulate lipid storage is not known. Here, we characterize the role of snRNP-U1-70K , the gene encoding for a splicing protein involved in recognizing the 5' splice site in introns, in regulating lipid and carbohydrate storage in the Drosophila fat body. Decreasing snRNP-U1-70K specifically in the fly fat body resulted in less triglyceride, glycogen, and glucose in each fat body cell. Consistent with these decreased nutrient storage phenotypes, snRNP-U1-70K-RNAi flies ate less, providing a potential cause for less lipid and carbohydrate storage in these flies. These data further support the role of mRNA processing in regulating metabolic homeostasis in Drosophila .


Iron Measured in Nasal Exudate Samples as a New and Useful Biomarker in the Differential Diagnosis of Patients with Acute Stroke.
Differential diagnosis between ischemic and hemorrhagic strokes in the acute stage is one of the major challenges of neurovascular research. Several biomarkers have been studied, but attempts to date have focused on determining their blood levels. Recently, cerebral lymphatic drainage toward the nostrils has been discovered, giving us the chance to study nasal exudate looking for biomarkers of neural damage. We sought to confirm whether iron levels in nasal exudate could identify the hemorrhagic nature of acute stroke. We studied iron nasal exudate levels in 32 ischemic and 43 hemorrhagic stroke patients. All patients underwent neurological examination assessed by the National Institutes of Health Stroke Scale (NIHSS), brain computed tomography to the differential diagnosis of stroke subtype, laboratory tests, and measurement of iron levels in nasal exudate. The iron levels in nasal exudate were higher in hemorrhagic stroke patients. The area under the receiver operating characteristic curve for ischemic/hemorrhagic stroke discrimination was 0.896 (95% confidence interval 0.823-0.970) and cutoff point of 0.078 nmol/mg (sensitivity 93%, specificity 73%). Our findings suggest that iron levels in nasal exudate may be useful in the acute stage for the differential diagnosis between ischemic and hemorrhagic damage in acute stroke patients. They also open a potential field to study other biomarkers in nasal exudate in several neurological disorders. Clinical studies must be performed to confirm our results.


Assessment of Hazard Ratios in Oncology Clinical Trials Terminated Early for Superiority: A Systematic Review.
Group sequential designs allow potential early trial termination at the interim analysis, before study completion. Traditional maximum likelihood estimate is commonly used to quantify the treatment effect in group sequential design trials; however, in published clinical trials, a bias-adjusted estimator has rarely been reported. To emphasize the need for considering overestimation of treatment effect by applying 2 bias-adjusted estimators to previously published, early-terminated oncology clinical trials. Trials published from 2013 to 2017 were identified by searching MEDLINE and Embase on February 23, 2018. This review was restricted to oncology clinical trials using group sequential designs with a single preplanned interim analysis as well as 2-arm randomized clinical trials that were subsequently stopped for efficacy reasons. Each article was independently reviewed by 3 biostatisticians during text screening, and differences in opinion were resolved by discussion. This report presents the unadjusted hazard ratio (HR) of an experimental arm to a reference arm and 2 bias-adjusted HRs calculated by using the conditional mean-adjusted estimator (CMAE) and weighted CMAE (WCMAE). In total, 198 abstracts were screened for eligibility, of which, 19 eligible clinical trials were identified as applicable to the bias-adjusted estimators. Unadjusted HRs ranged from 0.203 (95% CI, 0.150-0.276) to 0.71 (95% CI, 0.60-0.84), number of events at the interim analysis from 58 to 540, and information time from 48% to 82%. In each study, the HRs adjusted by CMAE and WCMAE were higher than the unadjusted HR. Bias-adjusted estimates in large trials (243 and 414 events at the interim analysis) were similar to the unadjusted HR. However, in small trials (eg, with 58 events at the interim analysis), bias-adjusted estimates were highly disparate from the unadjusted HR. In trials with large treatment effects (eg, HRs of 0.20 and 0.22), the difference between unadjusted and bias-adjusted HRs was small even though the number of events at the interim analysis was small; larger differences were observed when the unadjusted HR was greater than 0.5. In this systematic review of oncology clinical trials that were stopped for efficacy at the interim analysis, relatively large differences were noted between the unadjusted and adjusted HRs when the number of events at the interim analysis was small or when the unadjusted HR was close to the boundaries. These findings suggest presenting the 2 bias-adjusted HRs along with the unadjusted HR in the data monitoring committee meeting.


Change in healthcare during Covid-19 pandemic was assessed through observational designs.
Methodological challenges for investigating the changes in healthcare utilization during COVID-19 pandemic must be considered for obtaining unbiased estimates. A population-based study in the Lombardy region (Italy) measured the association between the level of epidemic restrictions (increasing exposure during pre-epidemic, post-lockdown, and lockdown periods) and the recommended healthcare (outcome) for patients with schizophrenia, heart failure, chronic obstructive pulmonary disease, breast cancer, and pregnancy women. Two designs are applied: the self-controlled case series (SCCS) and the usual cohort design. Adjustments for between-patients unmeasured confounders and seasonality of medical services delivering were performed. Compared with pre-epidemic, reductions in delivering recommended healthcare during lockdown up to 73% (95% confidence interval: 63%-80%) for timeliness of breast cancer surgery, and up to 20% (16%-23%) for appropriated gynecologic visit during pregnancy were obtained from SCCS and cohort design, respectively. Healthcare provision came back to pre-epidemic levels during the post-lockdown, with the exception of schizophrenic patients for whom the SCCS showed a reduction in continuity of care of 11% (11%-12%). Strategies for investigating the changes in healthcare utilization during pandemic must be implemented. Recommendations for taking into account sources of systematic uncertainty are discussed and illustrated by using motivating examples.


The mitotic regulator Hec1 is a critical modulator of prostate cancer through the long non-coding RNA BX647187 in vitro.
Hec1 (highly expressed in cancer) is a member of a conserved Ndc80 (nuclear division cycle 80) complex that regulates mitotic processes. Its overexpression is seen in various tumours and is associated with cancer progression. However, its expression pattern and role inhuman prostate cancer (PCa) still not clear. The aim of our study is to investigate the expression and functional role of Hec1 in human PCa. Hec1 expression was measured in 10 pairs of PCa cancerous and non-cancerous tissue samples by quantitative real-time (qRT)-PCR. The effects of Hec1 on PCa cells were studied by RNAi approach. Apoptosis and cell cycle were analysed by flow cytometry. Cells viability was evaluated using cell counting Kit-8. Cyclin B1-Cdc2 (cell division cycle 2) activity was measured by ELISA assay. Long non-coding (Lnc)RNAs regulated by Hec1 were gained from bioinformatics analysis. The role of LncRNA BX647187, regulated by Hec1, was finally characterized in PCa cells by siRNA. Our results showed that Hec1 mRNA and protein were significantly overexpressed in Human PCa tissues and several PCa cell lines. Silencing Hec1 markedly suppressed proliferation, promoted apoptosis and induced cell-cycle arrest in G2/M-phase in PCa cells. Through bioinformatics analysis and knockdown Hec1 in PCa cells, we found LncRNA BX647187 was positively regulated by Hec1. We further demonstrated that suppression of BX647187 in PCa cells significantly reduced cell proliferation and promoted apoptosis. Thus, we conclude that Hec1 is consistently overexpressed in human PCa and Hec1 is closely linked with human PCa progression through the meditator LncRNA BX647187. Our studies may contribute to understand the molecular mechanism of PCa pathogenesis and clinical therapy.


Final steps of the maturation of Omp F, a major protein from the outer membrane of Escherichia coli.
Pulse-labelling experiments with E. coli cells allowed us to follow the incorporation of de novo proteins into the outer membrane of the cell envelope. Labelled membrane samples containing increasingly different levels of newly synthesized Omp F protein were subjected to chemical cross-linking with a bifunctional cleavable reagent in order to investigate the process of trimer formation of the protein. From the results obtained, we conclude that the formation of functional Omp F trimers is substantially delayed to, and can be distinguished from, the incorporation of Omp F monomers to the outer membrane.


Testing the accuracy and reliability of palmar friction ridge comparisons - A black box study.
Critics and commentators have been calling for some time for black box studies in the forensic science disciplines to establish the foundational validity of those fields-that is, to establish a discipline-wide, base-rate estimate of the error rates that may be expected in each field. While the well-known FBI/Noblis black box study has answered that call for fingerprints, no research to establish similar error rates for palmar impressions has been previously undertaken. We report the results of the first large-scale black box study to establish a discipline-wide error rate estimate for palmar comparisons. The 226 latent print examiner participants returned 12,279 decisions over a dataset of 526 known ground-truth pairings. There were 12 false identification decisions made yielding a false positive error rate of 0.7%. There were also 552 false exclusion decisions made yielding a false negative error rate of 9.5%. Given their larger number, false negative error rates were further stratified by size, comparison difficulty, and area of the palm from which the mark originated. The notion of "questionable conclusions," in which the ground truth response may not be the most appropriate, is introduced and discussed in light of the data obtained in the study. Measures of examiner consistency in analysis and comparison decisions are presented along with statistical analysis of the ability of many variables, such as demographics or image quality, to predict outcomes. Two online apps are introduced that will allow the reader to fully explore the results on their own, or to explore the notions of frequentist confidence intervals and Bayesian credible intervals.


Temporal lobe and inferior frontal gyrus dysfunction in patients with schizophrenia during face-to-face conversation: a near-infrared spectroscopy study.
Schizophrenia (SC) is marked by poor social-role performance and social-skill deficits that are well reflected in daily conversation. Although the mechanism underlying these impairments has been investigated by functional neuroimaging, technical limitations have prevented the investigation of brain activation during conversation in typical clinical situations. To fill this research gap, this study investigated and compared frontal and temporal lobe activation in patients with SC during face-to-face conversation. Frontal and temporal lobe activation in 29 patients and 31 normal controls (NC) (n = 60) were measured during 180-s conversation periods by using near-infrared spectroscopy (NIRS). The grand average values of oxyhemoglobin concentration ([oxy-Hb]) changes during task performance were analyzed to determine their correlation with clinical variables and Positive and Negative Syndrome Scale (PANSS) subscores. Compared to NCs, patients with SC exhibited decreased performance in the conversation task and decreased activation in both the temporal lobes and the right inferior frontal gyrus (IFG) during task performance, as indicated by the grand average of [oxy-Hb] changes. The decreased activation in the left temporal lobe was negatively correlated with the PANSS disorganization and negative symptoms subscores and that in the right IFG was negatively correlated with illness duration, PANSS disorganization, and negative symptom subscores. These findings indicate that brain dysfunction in SC during conversation is related to functional deficits in both the temporal lobes and the right IFG and manifests primarily in the form of disorganized thinking and negative symptomatology.


Zika Virus affects neurobehavioral development, and causes oxidative stress associated to blood-brain barrier disruption in a rat model of congenital infection.
Zika virus (ZIKV) is a mosquito-borne flavivirus associated with several neurodevelopmental outcomes after in utero infection. Here, we studied a congenital ZIKV infection model with immunocompetent Wistar rats, able to predict disabilities and that could pave the way for proposing new effective therapies. We identified neurodevelopmental milestones disabilities in congenital ZIKV animals. Also, on 22nd postnatal day (PND), blood-brain barrier (BBB) proteins disturbances were detected in the hippocampus with immunocontent reduction of β_Catenin, Occludin and Conexin-43. Besides, oxidative stress imbalance on hippocampus and cortex were identified, without neuronal reduction in these structures. In conclusion, even without pups' microcephaly-like phenotype, congenital ZIKV infection resulted in neurobehavioral dysfunction associated with BBB and oxidative stress disturbances in young rats. Therefore, our findings highlighted the multiple impact of the congenital ZIKV infection on the neurodevelopment, which reinforces the continuity of studies to understand the spectrum of this impairment and to provide support to future treatment development for patients affected by congenital ZIKV.


Identification and characterization of C1orf36, a transcript highly expressed in photoreceptor cells, and mutation analysis in retinitis pigmentosa.
By means of computational methods, we identified an uncharacterized human transcript, Chromosome 1 open reading frame 36 (C1orf36), that is expressed in the retina and that maps to 1q32.3. The cDNA contains an open reading frame of 585bp that encodes a 195-aminoacid protein with a predicted mass of 22.7kDa. An alternatively spliced transcript in a retinoblastoma cell line, encoding for a truncated peptide, was also identified. PCR experiments performed using human cDNA from several sources indicate that C1orf36 has a preferential expression in the retina. Accordingly, in situ hybridization experiments, performed using as probe a murine C1orf36 cDNA fragment, detected a hybridization signal on mouse retinal adult sections. The C1orf36 protein shares homology with putative proteins in Mus musculus and Fugu rubripes, suggesting evolutionary conservation of its function. Additional sequence analysis of the C1orf36 gene product predicts its subcellular mitochondrial localization and the presence of both evolutionary conserved phosphorylation sites and regions adopting a coiled-coil conformation. We also defined the genomic structure of the gene. This enabled us to perform a mutational analysis of the C1orf36 coding region of about 300 patients affected by retinitis pigmentosa. No pathological mutations were detected in this analysis.


Daily tobacco consumption and associated socioeconomic factors in the Portuguese population: National Health Interview Survey data 1987-2014.
Smoking patterns inform tobacco control policies. This study aimed to assess trends in smoking prevalence and associated socioeconomic factors in Portugal between 1987 and 2014. We used data from National Health Interview Surveys (NHIS) conducted in 1987, 1995/96, 1998/99, 2005/06 and 2014/15. For each NHIS, we estimated gender-specific and age-standardized smoking prevalences, stratified by education, occupation, marital status and region. We constructed NHIS- and gender-specific logistic regression models, adjusting for the above-mentioned variables. We describe changes in smoking prevalence and inequalities in associated socioeconomic factors between 1987 and 2014. In men, smoking prevalence (32.2% and 26.7%, respectively) and inequalities for all factors except for education decreased between 1987 and 2014. For women, inequalities decreased for region, age and occupation, and these changes occurred through increasing smoking prevalence in all groups. For marital status and education, inequalities were stable but smoking prevalence increased for all groups within these variables. In both sexes, the unemployed (adjusted odds ratio [aOR] 2014: men 2.33, women 2.76) and divorced (aOR 2014: men 2.12, women 3.18) consistently had the highest prevalences and aORs of smoking. For the first three NHIS higher aORs of smoking were observed among less-educated men and highly-educated women, while for the last two the higher odds were for the less-educated in both sexes. Smoking trends among men showed decreasing prevalences and diminishing inequalities. For women, inequalities were stable but there was an overall increase in prevalence. The unemployed and divorced had the highest smoking prevalences in both sexes. Smoking prevention and cessation policies in Portugal should take into consideration inequalities, particularly among men, and increasing consumption among women.


Changes to culture pH and dissolved oxygen can enhance chimeric antigen receptor T-cell generation and differentiation.
Chimeric antigen receptor (CAR) T-cell therapy is growing clinically and commercially as a powerful new approach to treat cancer. Understanding how key culture conditions such as pH and dissolved oxygen (DO) affect CAR T-cell generation and function is important in developing better CAR-T manufacturing processes and CAR T-cell therapies for patients. We used the automated mini-bioreactor (AMBR) 15 platform to assess how differences in pH and DO affect CAR T-cell transduction, proliferation, and differentiation. We found that higher pH can significantly improve CAR T-cell transduction and proliferation, and also biases CAR T-cells away from an effector memory and toward a more central memory phenotype. Both high and low DO negatively affect CAR T-cell generation, with both hypoxic and hyperoxic conditions reducing T-cell transduction into CAR T-cells. Collectively, this data underscores how pH and DO can significantly affect CAR T-cell expansion and differentiation, and provides insight into the optimal culture conditions to enhance CAR T-cell yield and phenotype in clinical and commercial processes.


Wide pH range enantioseparation of cyclodextrin silica-based hybrid spheres for high performance liquid chromatography.
pH plays an important role in the enantiomeric separation process by changing the polarity of the mobile phase and the conformation and ionization state of the enantiomers. Herein, β-cyclodextrin-silica hybrid spheres with n-propyl groups as hydrophobic linkers and ethyl-silica as a support were prepared using a one-pot approach, and then the hydroxyl group was further modified with 3,5-dimethylphenyl isocyanate. The new β-cyclodextrin-silica hybrid chiral stationary phase (CD-HCSP) was prepared and characterized using techniques including scanning electron microscopy and transmission electron microscopy. The enantioseparation properties of CD-HCSP were evaluated with different solvents over a wide pH range (1-10) in reversed phase. 14 enantiomers were successfully resolved, and favorable chiral resolution and high stability was demonstrated for multiple types of enantiomer under different pH conditions. Compared with commercial columns, CD-HCSP showed better chiral resolution and, more importantly, could be used for chiral resolution over a wide pH range. This work combines the high pH tolerance of the hybrid material and excellent chiral recognition of cyclodextrin for enantioseparation of chiral drugs, which could lead to the development of a new type of chiral separation material.


Analysis of vascularization in thyroid gland nodes with superb microvascular imaging (SMI) and CD34 expression histology: a pilot study.
The Doppler sonography technique known as "superb microvascular imaging" (SMI) is advancing sonographic micro vascularization imaging in various disciplines. In this study, we aimed to determine whether SMI could reliably reproduce the blood flow in thyroid nodes and whether malignancy could be diagnosed, based on vascularization properties. Immunhistochemical staining by CD34 and SMI where used to determine the vascularization of nodes in terms of quantified vascularization parameters gained by computational evaluation. We used image analysis programs to investigate whether the quantitative value for vascularization strength in the thyroid node, measured with SMI, was correlated with the actual degree of vascularization, determined microscopically. We included 16 patients that underwent thyroid resections. We prepared thyroid gland tissue slices for immunohistochemistry and labelled endothelial cells with CD34 to visualize blood vessels microscopically. We used image analysis programs, ImageJ, to quantify SMI Doppler sonographic measurements and CellProfiler to quantify CD34 expression in histological sections. We evaluated the numeric values for diagnostic value in node differentiation. Furthermore, we compared these values to check for correlations. Among the 16 nodes studied, three harboured malignant tumours (18.75%): two papillary and one follicular carcinoma. Among the 13 benign lesions (81.25%), four harboured follicular adenomas. Malignant and benign nodes were not significantly different in sonographic (0.88 ± 0.89 vs. 1.13 ± 0.19; p = 0.2790) or immunohistochemical measurements of vascularization strength (0.05 ± 0.05 vs. 0.08 ± 0.06; p = 0.2260). We found a positive, significant correlation (r = 0.55588; p = 0.0254) between SMI (quantitative values for vascularization strength) and immunohistochemistry (CD34 staining) evaluations of thyroid nodes.


The incubation of a social movement? Preterm babies, parent activists, and neonatal productions in the US context.
This article explores health-based activism on the part of the US 'parents of preemies' movement, a mutual-help network mobilized around babies born precariously early and acutely dependent upon life-support incubators. The movement articulates two meta-agendas for parental empowerment: (1) the quest to access/exercise greater participatory inclusivity vis-à-vis the preterm baby within the biomedical domain; and, (2) the quest to secure/command greater representational authority over the preterm baby within the public domain. Seen in terms of the erosion of the status quo, it can be argued that the movement's tangible and intangible aims to chip away at these traditions have been softly revolutionary: heralding new working partnerships between medical practitioners and patients' families; radical shifts in the technological consciousness and competences of preemie parents; and cyborg changes in conventional categories of the person. Yet, seen in terms of a normative order of things, it can be argued that the movement has largely and willingly been "co/operated": meaning that it has been "cooperative," but equally "co-opted" and "operated into" the disciplinary trajectory of neonatal medicine as well as the historical march of biopolitics with its governance of the collective body populous. From this critical perspective, the movement qua social movement thus itself might be considered incubated--cocooned, gestated, disciplined--and brought into existence by the very powers and hegemonic (patriarchal) machinery that viable resistance might struggle to govern instead of serve.


Fine structure of microgametogenesis of Eimeria ferrisi Levine and Ivens 1965 in Mus musculus.
The microgamogony of Eimeria ferrisi from experimentally infected mice was investigated with the electron microscope. Microgamonts were recognizable by the presence of peripherally arranged nuclei and the presence of single or paired centrioles between each nucleus and the limiting membrane of the parasite. Often an intranuclear centrocone directed toward the centriole was present. Differentiation of the microgamete began when elevations of the limiting membrane, which indicated the commencement of flagellar development, appeared above the centrioles. This event was accompanied by the segregation of nuclear content into a dense osmiophilic portion and an electron-pale portion. Then followed a gradual protrusion of the dense portion of the nucleus and developing flagella into the parasitophorous vacuole. A dense ring developed at the base of the differentiating microgamete, resulting in the formation of a stalk which was occupied by the residual portion of the nucleus. Fully developed microgametes became detached and occupied the parasitophorous vacuole along with residual cytoplasm. Microgametes had an anterior perforatorium, a dense elongate nucleus, with an anteriorly positioned mitochondrion in a small groove of the nucleus. Usually two flagella were present but one microgamete appeared to have three. Polysaccharide first appeared when differentiation was in progress and increased until large numbers of granules were present in the microgamont cytoplasm.


Unrelated donor allogeneic transplantation for adult acute lymphoblastic leukemia: a review.
Acute lymphoblastic leukemia is highly sensitive to induction chemotherapy; however, long-term survival in adults has been less than 35%, primarily as a result of high relapse rate. Treatment for relapsed disease is even less successful. The optimal post-remission therapy in the first complete remission offers the best opportunity for leukemia-free survival. Allogeneic donor stem cell transplantation can offer a unique anti-leukemia effect and a potential for extended survival. We will discuss advances in unrelated donor (URD) stem cells transplantation, improvements in transplantation process and supportive care along with growing experience with umbilical cord blood (UCB) allografts.


Suppression of spontaneous LH surges in estrogen-treated ovariectomized rats by microimplants of antiestrogens into the preoptic brain.
Studies by others have shown that parenteral administration of antiestrogens blocks the positive feedback effect of estrogen on the luteinizing hormone (LH) surge mechanism. Since all estrogen-accumulating cells could be affected by this treatment, it is difficult to identify the site(s) at which this steroid acts to affect LH surges. In the present study we attempted to deprive specific hypothalamic neurons of estrogen by stereotaxically implanting antiestrogen-containing microcannulae into the brains of ovariectomized (OVX) rats which, otherwise, were completely estrogenized. The animal model used in these studies was the 14-day OVX rat into which 2 estradiol-containing Silastic capsules were inserted s.c. on day 14 (day 0). Microcannulae were placed into either the medial or lateral preoptic nuclei (MPN, LPN) on day 0 and the effects on LH release were examined 2 days later (day 2). When empty cannulae were placed into the MPN or LPN, 6 of 7 and 8 of 8 rats, respectively, had normal spontaneous LH surges. In contrast, when cannulae containing either CI-628, LY 10074 or Keoxifene were implanted into MPN only 33.3, 0, and 14.3% of the rats, respectively, had LH surges by 16.00 h on day 2 (time of LH peak). When antiestrogen-containing cannulae were placed into the LPN, all rats displayed normal LH patterns of release and concentrations. The antiestrogens did not prevent estrogen from suppressing elevated high post-ovariectomy plasma LH concentrations (negative feedback). To evaluate whether Keoxifene affected releasable luteinizing hormone-releasing hormone (LH-RH), we examined the effects of MPN-Keoxifene implants on LH secretion evoked by electrochemical stimulation (ECS) of the MPN or the medial basal hypothalamus (MBH). In ketamine-anesthetized rats with empty cannulae, plasma LH increased significantly to reach peak concentrations 30-45 min after ECS. Similar LH concentrations and release patterns occurred in rats with the antiestrogen implant. Other studies examined the effects of MPN-Keoxifene implants on norepinephrine (NE) concentrations and rate constants following administration of alpha-methyl-p-tyrosine. NE concentrations and rate constants in the MPN and median eminence did not differ significantly in rats which had received empty versus Keoxifene-containing microcannulae. In the final series of studies we examined the response of LH-RH neurons to an intracerebroventricular (i.c.v.) infusion of norepinephrine (20 micrograms). Plasma LH peaked within 10 min after i.c.v. NE and, thereafter, declined towards baseline. Keoxifene did not affect LH-RH neuronal responsiveness to i.c.v. NE.(ABSTRACT TRUNCATED AT 400 WORDS)


Identification of gastric cyclic AMP binding proteins.
The photoaffinity ligand 8-azidoadenosine 3',5-monophosphate was employed to label cAMP binding proteins in both fractionated and freeze-thawed rabbit gastric glands. Fractionated glands incorporated the azido-cAMP label primarily into two cytosolic proteins with apparent molecular weights of 58 000 and 48 000. No enrichment of label was found in fractions containing basolateral or apical membranes. DEAE-cellulose chromatography of the cytosolic proteins resulted in the separation of two cAMP-dependent protein kinase peaks. Azido cAMP labelling of each peak suggested the initial peak contained type I cAMP-dependent protein kinase while the second peak contained the type II kinase. Labelling of 'resting' gastric glands resulted in radioactive proteins of apparent molecular weights of 58 000 and 48 000. When gastric glands were stimulated to produce acid by the addition of 10(-4) M histamine or 1 mM dibutyryl cAMP there was 32-44% dimunition of ligand incorporation compared to control glands. The results strongly suggest that histamine-mediated stimulus-secretion coupling in gastric glands involves activation of parietal cell cAMP-dependent protein kinases.


A high affinity and specificity anti-HER2 single-domain antibody (VHH) that targets trastuzumab's epitope with versatile biochemical, biological, and medical applications.
In the past decade, various single-domain antibodies from llamas, also known as VHH or nanobody, have been discovered with applications in tumor imaging and cancer therapy. However, the potential application of anti-HER2 VHHs as a diagnostic tool suitable for ELISA, flow cytometry, cell imaging, bispecific antibody engineering, and immunohistochemistry has not been fully elucidated. To investigate this potential, HER2 antigen was expressed in HEK293 F cells, purified, and used to immunize llama. Using phage display, anti-HER2 VHHs with high affinity and specificity were isolated, sequenced, and constructed with a Histag and c-Myc tag. The constructed anti-HER2 VHHs were then expressed in E. coli, purified, and evaluated for their use in ELISA, flow cytometry, cell imaging, and immunohistochemistry. The affinities of the anti-HER2 VHHs toward the HER2 antigen were determined using biolayer interferometry. Furthermore, the binding sites of the anti-HER2 VHHs were evaluated by epitope mapping and in silico modeling and docking. Here, we report the sequence of an anti-HER2 VHH with high affinity (sub-nanomolar), specificity, and selectivity. This VHH binds to the same epitope as trastuzumab and can be utilized to generate bispecific antibodies or used as a diagnostic tool to differentiate HER2+ from HER2- antigens on plates, cells, and tissues. This discovery has broad applications in biochemical, biological, and medical sciences.


[Preparing student nurses for critical care placements, a quasi-experimental mixed study].
Weaving a link between the academic pathway in nursing schools and health care facilities. To co-create a new and adaptive training for nursing students called to do a placement in an intensive care unit. To facilitate their integration and reduce their apprehension in a highly technical clinical environment. These are the goals of the Préparéa workshops implemented within the regional teaching and training center for health professions at the Toulouse University Hospital.


Quality of life in patients with advanced ovarian cancer after primary debulking surgery versus neoadjuvant chemotherapy: Results from the randomised SCORPION trial (NCT01461850).
To investigate the effect of treatment with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), versus primary debulking surgery (PDS), on quality of life (QoL) in patients with advanced epithelial ovarian cancer (EOC). Randomised trial conducted in a single institution. Division of Gynaecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Patients with stage-IIIC/IV EOC and high tumour load. Patients were randomised (1:1) to undergo either PDS (PDS group) or NACT followed by IDS (NACT/IDS group). Quality-of-life (QoL) data, assessed using the European Organization for Research and Treatment of Cancer core QoL questionnaire (QLQ-C30) and ovarian cancer module (OV28); co-primary outcomes were the QLQ-C30 global health score at 12 months (cross-sectional analysis) and the difference in mean QLQ-C30 global health score over time between treatment groups (longitudinal analysis). From October 2011 to May 2016, 171 patients were enrolled (PDS = 84; NACT/IDS = 87). We observed no clinical or statistically significant difference between treatment groups in any of the QoL functioning scales at 12 months, including QLQ-C30 global health score (NACT/IDS group vs PDS group, mean difference 4.7, 95% CI -4.99 to 14.4, p = 0.340). Over time, we found lower global health scores for those undergoing PDS than for those receiving NACT (difference in mean score 6.27, 95% CI 0.440-12.11, p = 0.035), albeit this was not clinically relevant. We found no difference in global QoL related to treatment approach at 12 months, even though patients in the NACT/IDS group reported better global health scores across the 12-month period compared with the PDS group; these findings further confirm that NACT/IDS might be a feasible option for patients unsuitable for PDS.


Conazole fungicides inhibit Leydig cell testosterone secretion and androgen receptor activation in vitro.
Conazole fungicides are widely used in agriculture despite their suspected endocrine disrupting properties. In this study, the potential (anti-)androgenic effects of ten conazoles were assessed and mutually compared with existing data. Effects of cyproconazole (CYPRO), fluconazole (FLUC), flusilazole (FLUS), hexaconazole (HEXA), myconazole (MYC), penconazole (PEN), prochloraz (PRO), tebuconazole (TEBU), triadimefon (TRIA), and triticonazole (TRIT) were examined using murine Leydig (MA-10) cells and human T47D-ARE cells stably transfected with an androgen responsive element and a firefly luciferase reporter gene. Six conazoles caused a decrease in basal testosterone (T) secretion by MA-10 cells varying from 61% up to 12% compared to vehicle-treated control. T secretion was concentration-dependently inhibited after exposure of MA-10 cells to several concentrations of FLUS (IC50 = 12.4 μM) or TEBU (IC50 = 2.4 μM) in combination with LH. The expression of steroidogenic and cholesterol biosynthesis genes was not changed by conazole exposure. Also, there were no changes in reactive oxygen species (ROS) formation that could explain the altered T secretion after exposure to conazoles. Nine conazoles decreased T-induced AR activation (IC50s ranging from 10.7 to 71.5 μM) and effect potencies (REPs) were calculated relative to the known AR antagonist flutamide (FLUT). FLUC had no effect on AR activation by T. FLUS was the most potent (REP = 3.61) and MYC the least potent (REP = 0.03) AR antagonist. All other conazoles had a comparable REP from 0.12 to 0.38. Our results show distinct in vitro anti-androgenic effects of several conazole fungicides arising from two mechanisms: inhibition of T secretion and AR antagonism, suggesting potential testicular toxic effects. These effects warrant further mechanistic investigation and clearly show the need for accurate exposure data in order to perform proper (human) risk assessment of this class of compounds.


Precision of time-resolved near-infrared spectroscopy-based measurements of cerebral oxygenation in preterm infants.
Significance: Time-resolved near-infrared spectroscopy (t-NIRS) is a new technology; at the moment, data on its precision in preterm infants are rare. Aim: Therefore, the aim of this study was to analyze the precision of t-NIRS-based measurements of the cerebral oxygenation in preterm infants. Approach: In 70 neonates [age: 4.7 ± 2.0 days, sex (f/m): 33/37], cerebral oxygenation ( t - rSO 2 ) was measured with an optode placed over the left frontotemporal lobe on the head, measurement duration was 1 min, and a reapplication was done for four further times (five applications). Results: Overall mean for t - rSO 2 values was 62.2 % ± 4.1 % . We found a within-patient variation for t - rSO 2 of 2.6%. Furthermore, 95% of all observed values were within a range of ± 5 % from the mean when looking on several reapplications and ± 2 % when looking within one application. Most of the variation in t - rSO 2 (60.4%) contributed to differences between patients. The remaining 39.6% of the variation was due to measurement errors and real changes of the measured signal within the neonates. Conclusions: Since within-patient variation of t - rSO 2 measures were below a clinical meaningful threshold of 5%, the measurement can be denoted as precise.


Separation of chlorogenic acid from honeysuckle crude extracts by macroporous resins.
Chlorogenic acid, one of the most bioactive compounds rich in the Chinese medicinal herb honeysuckle, is a natural antioxidant and serves as anti-inflammatory, anti-tumor, anti-mutagenic and anti-carcinogenic agent. An efficient preparative separation process of chlorogenic acid from honeysuckle crude extracts has been developed in the present study. HPD-850 resin offers the best adsorption capacity, and adsorption and desorption ratios for chlorogenic acid among the nine macroporous resins tested, and its adsorption rate at 25 degrees C fit best to the Langmuir isotherm. The adsorption capacity of HPD-850 resin was found to depend strongly on the pH value of the initial adsorption solution. The dynamic adsorption and desorption experiments have been carried out on a HPD-850 resin packed column to optimize the separation process of chlorogenic acid from honeysuckle crude extracts. After one run treatment with HPD-850 resin, the chlorogenic acid content in the final product was increased 4.46-fold from 11.2% to 50.0%, with a recovery yield of 87.9%. The preparative separation of chlorogenic acid can be easily and efficiently achieved via adsorption and desorption on HPD-850 resin, and the method developed will provide a potential approach for large-scale separation and purification of chlorogenic acid for its wide pharmaceutical use.


Atypical insufficiency fractures confused with Looser zones of osteomalacia.
Six women, aged 24-67 years, had osteopenia and insufficiency fractures, which suggested a diagnosis of osteomalacia. The insufficiency fractures occurred at traditional sites for Looser zones, were multiple in number, were symmetrically distributed in three patients, and did not heal promptly. Bone mass was low, as assessed by single-energy photon absorptiometry at the midshaft of the radius. Two postmenopausal women had vertebral compression fractures. Biochemical indices and bone histomorphometric analysis excluded osteomalacia, and in vivo double tetracycline labeling in five patients revealed both high and low bone turnover states. We propose more stringent radiographic criteria for the designation of the term "Looser zone" that retains the customary association between the radiologic event and osteomalacia. This paper also outlines a diagnostic strategy for future cases of atypical insufficiency fractures and proposes reasons for their resemblance to true Looser zones.


Anterior chamber lenses. Part II: A laboratory study.
An analysis of 606 surgically removed anterior chamber intraocular lens (IOL) specimens revealed that 351 or 58% of these were small-diameter, round loop, closed-loop styles. Because of the extremely high percentage of IOLs with this design received in our laboratory and the correlation of clinical histories with our histopathologic findings, we have concluded that such IOLs do not provide the safety and efficacy achieved by other anterior chamber lens designs. The finely polished, one-piece, all-PMMA styles fared well in our study. Although these one-piece styles comprise well over 50% of the American market share of anterior chamber IOLs, they comprise only 14% of all anterior chamber IOLs accessioned in our laboratory, compared to 58% for closed-loop designs. We believe that implantation of anterior chamber lenses with small-diameter, round, closed loops is no longer warranted. Patients in whom these IOLs have already been implanted should be carefully followed. It is our opinion that the FDA should recall or closely monitor all IOLs of this design and that implantation of closed-loop lenses should be discontinued in the United States. Furthermore, we believe that an IOL deemed to be not medically sound or worthy of implantation in the United States should not be marketed or donated outside of this country.


[Effects of Feiji decoction for soothing the liver combined with psychotherapy on quality of life in primary lung cancer patients].
Primary lung cancer is one of the most common malignant tumors. It causes great pain and mood disorders to patients, and significantly reduces their quality of life. The aim of the current study is to evaluate the effect of Feiji Decoction for soothing the liver combined with psychotherapy on quality of life (QoL) and physical status of patients with primary lung cancer. A total of 118 patients with primary non-small cell lung cancer were randomly divided into two groups. The 57 patients in the combined therapy group were treated with Feiji Decoction for soothing the liver and psychotherapy combined with chemotherapy, whereas the 61 patients in the control group were treated with chemotherapy only. Both groups were observed for the two treatment courses. The European Organization for Research and Treatment of Cancer QoL Questionnaire LC-43 (EORTC QLQ-LC43) was used to assess the QoL of every patient in both groups before and after treatment scales. At the same time, physical status was assessed using the Karnofsky performance status (KPS) and East Cooperative Oncology Group performance status (ECOG). The scores of physiology function, role function, emotion function, cognize function, society function, and general health in the therapy group were higher than that of the control group. The therapy group also showed better QoL results than the contol group. Significant differences were observed between the two groups (P<0.01). Meanwhile, the scores of fatigue, vomit, pain, polypnea, insomnia, anorexia, constipation, and specific manifestation of lung cancer in the therapy group were obviously lower than that of the control group; more patients were observed to be relieved. Significant differences between the two groups were observed (P<0.01). The KPS and ECOG scores of the patients were observed to have improved and stabilized in the therapy group than that of the control group; the differences were statistically significant (P<0.01). Feiji Decoction for soothing the liver combined with psychotherapy can alleviate the clinical symptoms, elevate the physical status, and improve the QOL of patients with primary lung cancer. Thus, this therapy has a good clinical therapeutic effect.


Two gel states of cerebrosides. Calorimetric and Raman spectroscopic evidence.
The enthalpy of the gel-to-liquid crystalline phase transition for kerasin (15.8 kcal/mol) is found to be markedly higher than that for phrenosin and unfractionated bovine brain cerebrosides (about 7 kcal/mol). Evidence for a higher degree of order in the hydrocarbon chains and a different configuration in the polar region of kerasin is supplied by Raman spectroscopic parameters for these gel phases. The high transition enthalpy for kerasin is ascribed to a lesser accommodation of gauche conformers in the hydrocarbon chains just below the transition temperature. The thermodynamic behavior of these cerebroside fractions, including hysteresis in kerasin gels, is compared to that previously reported for sphingomyelins.


Intrathoracic omental herniation through the esophageal hiatus in a young patient.
We herein present a case of intrathoracic omental herniation through the esophageal hiatus in a young patient. A 21-year-old obese man was asymptomatic, and his chest X-ray demonstrated a large, sharply defined mass. A computed tomography scan of the thorax indicated a large retrocardial mediastinal mass in which the density indicated the presence of fatty tissue judging from the Hounsfield unit range. A thoracotomy was performed under a diagnosis of either mediastinal lipoma or liposarcoma with an encapsulated fatty mass, measuring 17 x 12 x 8 cm in size. The mass, however, proved to be an omental herniation through the esophageal hiatus. It is generally assumed that the major contributing factors leading an individual to develop an omental herniation through the esophageal hiatus include aging and obesity. This is the first report of omental herniation through the esophageal hiatus in a patient still in his twenties.


Genital tract tumors in Proteus syndrome: report of a case of bilateral paraovarian endometrioid cystic tumors of borderline malignancy and review of the literature.
Proteus syndrome is a rare, sporadic disorder that causes postnatal overgrowth of multiple tissues in a mosaic pattern. Characteristic manifestations include: overgrowth and hypertrophy of limbs and digits, connective tissue nevus, epidermal nevus and hyperostoses. Various benign and malignant tumors and hamartomas may complicate the clinical course of patients with the syndrome. Commonly encountered tumors include hemangiomas, lymphangiomas and lipomas. Tumors of the genital tract occur less often. Bilateral ovarian cystadenomas are regarded as having diagnostic value in Proteus syndrome when occurring within the first two decades of life. We describe a 3-year-old girl with Proteus syndrome who developed bilateral paraovarian villoglandular endometrioid cystadenomatous tumors of borderline malignancy (low malignant potential) of the broad ligament. Desmoplastic tumor implants, presumably noninvasive, were present in biopsies from the pelvic floor, cul-de-sac and omentum. This is the first recognized example of a cystic borderline epithelial tumor of the female genital tract and the first paraovarian tumor reported in a patient with Proteus syndrome. Previously reported tumors and cystic lesions involving the female genital tract and the male genital tract in patients with Proteus syndrome are reviewed. We suspect that specific testicular and paratesticular tumors may prove to have the same diagnostic value in Proteus syndrome as do bilateral cystic ovarian and paraovarian tumors.


Management of psoriasis and psoriatic arthritis in a combined dermatology and rheumatology clinic.
Psoriasis and psoriatic arthritis (PsA) are chronic systemic inflammatory disorders with wide spectrums of cutaneous and musculoskeletal presentations. Management of joint disease in this population can be challenging and often requires the expertise of rheumatology in conjunction with dermatology. A multidisciplinary clinic setting may benefit these patients, and in this study we sought to evaluate the experience of such a model. We performed a retrospective chart review of patients evaluated between October 2003 and October 2009 in the Center for Skin and Related Musculoskeletal Diseases (SARM) at Brigham and Women's Hospital, Boston, MA, USA, where patients are seen by both an attending rheumatologist and dermatologist. Main outcomes included the presence of comorbidities, accuracy of the initial diagnosis, and escalation of treatment modalities. Over the 6-year period, 510 patients were evaluated. Two hundred sixty-eight patients had psoriasis and/or PsA. The prevalence of comorbidities was high (45% hypertension, 46% hyperlipidemia, 19% diabetes, and 36% history of the past or current smoking). Visit in SARM resulted in a revised diagnosis that differed from the previous diagnosis at outside clinics in 46% of cases. Patients were more likely to receive a systemic medication after the evaluation in SARM as compared to before, 25 versus 15%, respectively, with an odds ratio of 5.1. Patients were also more likely to be treated with a biologic agent after the evaluation in SARM as compared to before, 37 versus 16%, respectively. Multidisciplinary care may facilitate the diagnosis of joint disease and offers a more comprehensive treatment approach for patients with both psoriasis and PsA. Our data can be used to support the efforts to provide integrated rheumatologic and dermatologic care for this population.


[Community life for all: mental health, participation and autonomy. SESPAS Report 2020].
The objective of this article is to critically reflect on the participation in community of people with a diagnosis of mental disorder from a human rights and community health perspective. Firstly, we review basic concepts such as community mental health and the meaning of participation, which is understood as an end and not as a mean. It is important to increase the participation of people with a diagnosis in community spaces beyond the classic circuit of mental health care. This implies to create and share knowledge in a collective, horizontal and consensual way among all the people involved, especially the diagnosed people themselves. Secondly, the experience of the group of women of Radio Nikosia is narrated in first person by the participants themselves. The main highlights of the group are its horizontality, flexibility, and that is a self-organized space outside the health system where it is possible to express oneself without fear of being judged. Processes of trust, recognition, joy, social support and health are generated. Members of the group meet fortnightly and discuss on different topics chosen by them, and take part in political actions for women's own rights such as participation in the media, in feminist calls, in training and talks. We exemplify that other ways of doing community mental health are possible. The challenges are to make them visible, to systemize them and to be able to assess the impact they have on the health not only of the participants, but also the community.


Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma.
MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC-overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS-010759. In a B-lymphoid cell line, ectopic MYC activity and treatment with IACS-010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro-oxidant at high doses. In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, complex I inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and potentially other MYC-driven cancers.


Immunosuppression prior to marrow transplantation for sensitized aplastic anemia patients: comparison of TLI with TBI.
From May 1980 through July 1986, 26 patients with severe aplastic anemia, sensitized with multiple transfusions of blood products, were treated on either of two immunosuppressive regimens in preparation for bone marrow transplantation from a matched donor. There were 10 patients treated with total body irradiation (TBI), 200 cGy/fraction X 4 daily fractions (800 cGy total dose), followed by cyclophosphamide, 60 mg/kg/d X 2 d. An additional 16 patients were treated with total lymphoid irradiation (TLI) [or, if they were infants, a modified TLI or thoracoabdominal irradiation (TAI)], 100 cGy/fraction, 3 fractions/d X 2 d (600 cGy total dose), followed by cyclophosphamide, 40 mg/kg/d X 4 d. The extent of immunosuppression was similar in both groups as measured by peripheral blood lymphocyte depression at the completion of the course of irradiation (5% of initial concentration for TBI and 24% for TLI), neutrophil engraftment (10/10 for TBI and 15/16 for TLI), and time to neutrophil engraftment (median of 22 d for TBI and 17 d for TLI). Marrow and peripheral blood cytogenetic analysis for assessment of percent donor cells was also compared in those patients in whom it was available. 2/2 patients studied with TBI had 100% donor cells, whereas 6/11 with TLI had 100% donor cells. Of the five who did not, three were stable mixed chimeras with greater than or equal to 70% donor cells, one became a mixed chimera with about 50% donor cells, but became aplastic again after Cyclosporine A cessation 5 mo post-transplant, and the fifth reverted to all host cells by d. 18 post-transplant. Overall actuarial survival at 2 years was 56% in the TLI group compared with 30% in the TBI group although this was not statistically significant. No survival decrement has been seen after 2 years in either group. There was less long-term morbidity in the TLI group compared with TBI although the numbers of surviving patients are small. With no difference in engraftment or survival, it is suggested that, for sensitized severe aplastic anemia patients, who are to receive a non-T cell-depleted marrow from a matched donor, prudent cytoreduction should include a fractionated, moderate dose irradiation regimen with maximum organ sparing, that is either TLI or TAI.


Incidence and characteristics of early childhood wheezing, Dhaka, Bangladesh, 2004-2010.
Early childhood wheezing substantially impacts quality of life in high-income countries, but data are sparse on early childhood wheezing in low-income countries. We estimate wheezing incidence, describe wheezing phenotypes, and explore the contribution of respiratory viral illnesses among children aged <5 years in urban Bangladesh. During 2004-2010, respiratory illness surveillance was conducted through weekly home visits. Children with fever or respiratory illness were referred for examination by study physicians including lung auscultation. During 2005-2007, every fifth referred child had nasal washes tested for human metapneumovirus, respiratory syncytial viruses, and influenza and parainfluenza viruses. During April 2004-July 2010, 23,609 children were enrolled in surveillance. Of these, 11,912 (50%) were male, median age at enrollment was 20 months (IQR 5-38), and 4,711 (20%) had ≥1 wheezing episode accounting for 8,901 episodes (733 [8%] associated with hospitalization); 25% wheezed at <1 year of age. Among children aged <5 years, incidences of wheezing and wheezing hospitalizations were 2,335/10,000 and 192/10,000 child-years. Twenty-eight percent had recurrent wheezing. Recurrent versus non-recurrent wheezing episodes were more likely to be associated with oxygen saturation <93% (OR 6.9, 95%CI 2.8-17.3), increased work of breathing (OR 1.6, 95%CI 1.4-1.8), and hospitalization (OR 2.0, 95%CI 1.6-2.4). Respiratory viruses were detected in 66% (578/873) of episodes with testing. In urban Bangladesh, early childhood wheezing is common and largely associated with respiratory virus infections. Recurrent wheezing is associated with more severe illness and may predict children who would benefit most from closer follow-up and targeted interventions. Pediatr Pulmonol. 2016;51:588-595. © 2015 Wiley Periodicals, Inc.


Self-assembled multienzyme complex facilitates synthesis of glucosylglycerol from maltodextrin and glycerol.
Compound 2-O-α-d-glucosylglycerol (2αGG) naturally serves as a compatible osmolyte in acclimation to environmental stresses, such as high osmolarity, dryness, and extreme temperature. It presents several bioactivities and has been used in the food, agriculture, and cosmetics areas. In the present study, we attempted to synthesize the 2αGG from low-cost maltodextrin and glycerol by constructing an in vitro multi-enzyme system. The system contained two core enzymes, namely glucan phosphorylases (GPs) and glucosylglycerol phosphorylases (GGPs), and two auxiliary enzymes, namely isoamylase and 4-α-glucanotransferase. Several new GGPs from different organisms were characterized with the function of converting α-G1P and glycerol to sole stereo-configuration product 2αGG. Then, polypeptide SpyTag-SpyCatcher was employed to construct a self-assembled multienzyme complex, and different combinations between enzymes and peptides were constructed and tested. The best self-assembled multienzyme complex exhibited three-fold higher productivity compared to that of free enzyme. This reaction system also produced 240 mm (61 g L-1 ) 2αGG under high substrate concentration, with a conversion yield of 86%. The present study provides an efficient approach for producing 2αGG. It also demonstrates that the SpyTag-SpyCatcher system could be applied to construct other multienzyme complexes for increased productivity and product titer. © 2023 Society of Chemical Industry.