An updated safety review of the current drugs for managing ADHD in children.
Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent condition that causes persistent problems with attention and/or hyperactivity-impulsivity and often results in significant impairment when left untreated. Medications for this disorder continue to evolve and provide new treatment options. Ongoing review of related medication safety and tolerability remains an important task for prescribers. This manuscript provides an updated safety review of medications used to treat ADHD in children and adolescents. PubMed and OneSearch online databases were utilized to search for literature relevant to the topic of ADHD medications and safety. Clinical trials of medications used to treat ADHD, systematic reviews and meta-analyses, and articles covering specific safety issues (adverse or unfavorable events) such as cardiovascular effects, seizures, impact on growth, depression, suicidal ideation, substance use disorders, psychosis, and tics are described. Available pharmacologic treatments for ADHD have favorable efficacy, safety and tolerability and allow many patients to achieve significant improvement of their symptoms. Despite the availability of multiple stimulant and non-stimulant formulations, some individuals with ADHD may not tolerate available medications or attain satisfactory improvement. To satisfy unmet clinical needs, ADHD pharmaceutical research with stimulant and nonstimulant formulations targeting dopamine, norepinephrine, and novel receptors is ongoing.


Flavonols, alkaloids, and antioxidant capacity of edible wild berberis species from patagonia.
There are 20 species of the Berberidaceae family described in Chile, whose fruits are edible and show high anthocyanin and hydroxycinnamic acid levels. Berberis microphylla G. Forst, commonly known as calafate, is the most extensively distributed. Flavonols and alkaloids in seed, pulp, skin, and whole calafate berry extracts and other Berberis were studied using HPLC-DAD-ESI-MS/MS and HPLC with fluorescence detector. Berry samples from different locations in Chilean Patagonia, including different phenological stages, were systematically addressed. Results were compared with other organs of the plant and with other Berberis species. Total flavonol concentration in calafate (n = 65) was 1.33 ± 0.54 μmol/g. Glycosyl metabolites of quercetin and isorhamnetin were the most abundant. Similar profiles were observed in calafate from distinct locations, but important differences were observed for the other edible Berberis species. Calafate pulp and skin have higher flavonol concentrations than seeds, and the maturation process reduced its levels. TEACCUPRAC and TEACABTS of whole calafate extracts and fractions are also explored. Finally, only berberine was detected in the fruit (0.001%), mainly in seeds. Results contribute to the promotion of this berry as a superfruit from Patagonia.


Early psychological intervention following the 2014 Nepal snowstorm.
The following is a case study of the blizzard of October 2014, an Israeli rescue team, the Special Mental Health Team (SMHT) of the Israeli Defense Forces Medical Corps, was sent to the disaster area to rescue Israeli trekkers. The SMHT intervention was provided immediately following the traumatic events with the purpose of lowering stress-related symptoms, shortening recovery time and reducing post-traumatic stress disorder symptoms that could occur in the future. Forty Israeli trekkers were assessed by SMHT: 75 % (n = 30) had mild acute stress reaction (ASR) symptoms and 25 % (n = 10) had severe acute stress disorder (ASD) symptoms. All participating trekkers receiving the intervention as a way to alleviate symptoms reported no symptoms of ASR and ASD following the intervention. Trekkers with mild ASR reported full recovery after 1 week and trekkers with ASD reported full recovery after 3 months. This case study describes the psychological intervention conducted by SMHT for the surviving trekkers following the blizzard and aims to extend the knowledge base of mental health intervention at the early phases of disaster. A research study should be conducted to develop a measurement tool capable of evaluating the effect of a short-term intervention conducted in the field.


Hepatitis C virus non-structural protein 3 interacts with cytosolic 5'(3')-deoxyribonucleotidase and partially inhibits its activity.
Infection with hepatitis C virus (HCV) is etiologically involved in liver cirrhosis, hepatocellular carcinoma and B-cell lymphomas. It has been demonstrated previously that HCV non-structural protein 3 (NS3) is involved in cell transformation. In this study, a yeast two-hybrid screening experiment was conducted to identify cellular proteins interacting with HCV NS3 protein. Cytosolic 5'(3')-deoxyribonucleotidase (cdN, dNT-1) was found to interact with HCV NS3 protein. Binding domains of HCV NS3 and cellular cdN proteins were also determined using the yeast two-hybrid system. Interactions between HCV NS3 and cdN proteins were further demonstrated by co-immunoprecipitation and confocal analysis in cultured cells. The cellular cdN activity was partially repressed by NS3 protein in both the transiently-transfected and the stably-transfected systems. Furthermore, HCV partially repressed the cdN activity while had no effect on its protein expression in the systems of HCV sub-genomic replicons and infectious HCV virions. Deoxyribonucleotidases are present in most mammalian cells and involve in the regulation of intracellular deoxyribonucleotides pools by substrate cycles. Control of DNA precursor concentration is essential for the maintenance of genetic stability. Reduction of cdN activity would result in the imbalance of DNA precursor concentrations. Thus, our results suggested that HCV partially reduced the cdN activity via its NS3 protein and this may in turn cause diseases.


[Evaluation of the effects of electric and magnetic fields in humans].
During the twentieth century, environmental exposure to electromagnetic fields generated by human activity has increased regularly, at the same time as the quest for electrical energy. Therefore we are all exposed to a complex set of electric and magnetic fields of weak intensity. The levels of exposure of the general population range from 5 to 50 V/m for electric fields and from 0.01 to 0.2 micro T for magnetic fields. Fields in cause are essentially those associated to the use of the electric current (extremely low frequency, ELF: 50 Hz in France, 60 Hz in the United States) and those related to the use of cell phones (radio frequency: 900 and 1,800 MHz). The question of the possible risk on health by exposure to electric and/or magnetic fields became a concern to scientists and is now an important public debate. A number of expertises, led in particular by the WHO, leaning on the careful inspection of scientific publications from numerous countries, conclude that current data do not allow to assert the existence of sanitary effects; however our knowledge of the biologic effects of electromagnetic fields still contains certain gaps which should be filled. Indeed, the numerous epidemiological studies relative to the occurrence of cancer by exposure to electromagnetic fields are conflicting. In every case the increase of the risk, when described, is always weak. The measure of the Relative Risk (RR) which establishes the relation is approximately 2-3. At present, some data concerning the risk of childhood leukemia in the event of exposure of ELF generated in the home indicate that this risk can exist when children are chronically exposed to more than 0.4 micro T (the relative risk is in the order of 2). In the field of radio frequencies, the increasing use of cell phones (38 million users in France) and their antennae - basis are another subject of concern for the effects on health they are susceptible to produce. Large-scale studies, implying numerous countries, carried on at present within the framework of the WHO should bring elements of answer to the unresolved questions.


Nanoscale effects leading to non-Einstein-like decrease in viscosity.
Nanoparticles have been shown to influence mechanical properties; however, transport properties such as viscosity have not been adequately studied. This might be due to the common observation that particle addition to liquids produces an increase in viscosity, even in polymeric liquids, as predicted by Einstein nearly a century ago. But confinement and surface effects provided by nanoparticles have been shown to produce conformational changes to polymer molecules, so it is expected that nanoparticles will affect the macroscopic viscosity. To minimize extraneous enthalpic or other effects, we blended organic nanoparticles, synthesized by intramolecular crosslinking of single polystyrene chains, with linear polystyrene macromolecules. Remarkably, the blend viscosity was found to decrease and scale with the change in free volume introduced by the nanoparticles and not with the decrease in entanglement. Indeed, the entanglements did not seem to be affected at all, suggesting unusual polymer dynamics.


Theoretical study of the quantitative structure-activity relationships for the toxicity of dibenzo-p-dioxins.
Density functional theory calculations of polychlorinated dibenzo-p-dioxins (PCDDs) were carried out to obtain the electronic descriptors, polarizabilities, and traceless quadrupole moments of 76 PCDD congeners. No simple relationships were found for the electronic descriptors with the relevant aryl hydrocarbon receptor (AhR) binding affinities of PCDDs, which suggests that they alone may not be sufficient to explain the variation in toxicity. However, quantitative structure-activity relationships (QSARs) were developed with the polarizabilities and traceless quadrupole moments, explaining about 74% and 59% of variation in AhR binding affinities of PCDDs, respectively. To explain the nature of toxic interaction, a mathematical model based on the ligand-receptor binding and solute-solvent interaction was presented, and then a multiple regression analysis of all the above parameters was performed to evaluate the contributions of the parameters to the bonding affinities. Other data for PCDFs found in the literature were also included in the regression analysis to minimize data over-fitting. The results suggest that dispersion and electrostatic interactions are equally important for the interaction of PCDD/Fs with the AhR.


Synthetic mixed-signal computation in living cells.
Living cells implement complex computations on the continuous environmental signals that they encounter. These computations involve both analogue- and digital-like processing of signals to give rise to complex developmental programs, context-dependent behaviours and homeostatic activities. In contrast to natural biological systems, synthetic biological systems have largely focused on either digital or analogue computation separately. Here we integrate analogue and digital computation to implement complex hybrid synthetic genetic programs in living cells. We present a framework for building comparator gene circuits to digitize analogue inputs based on different thresholds. We then demonstrate that comparators can be predictably composed together to build band-pass filters, ternary logic systems and multi-level analogue-to-digital converters. In addition, we interface these analogue-to-digital circuits with other digital gene circuits to enable concentration-dependent logic. We expect that this hybrid computational paradigm will enable new industrial, diagnostic and therapeutic applications with engineered cells.


Hypercalciuric hypophosphatemic rickets, mineral balance, bone histomorphometry, and therapeutic implications of hypercalciuria.
A 14-year-old Turkish boy had severe rickets that had been clinically evident since he was 2 years of age. When he was 5 years of age, he had normal serum calcium and phosphorus levels and increased alkaline phosphatase activity. Treatment with modest dosages of vitamin D (5000 U/d for 3 weeks) resulted in hypercalcemia. At 10 years of age, high-dose vitamin D (40,000 U/d) plus phosphorus (1.1 g/d) therapy for 20 days resulted in symptomatic nephrolithiasis. When, 14 years of age, he had normocalcemia, hypophosphatemia, increased alkaline phosphatase activity, and normal circulating parathyroid hormone concentration. Levels of 25-hydroxyvitamin D were normal but those of 1,25-dihydroxyvitamin D were markedly increased. Rickets and osteopenia were evident on radiographs, and osteomalacia was present on trabecular bone obtained at biopsy. Balance study results showed increased intestinal absorption of calcium and phosphorus, hypercalciuria, and increased urinary phosphorus excretion. This patient manifests an unusual form of hypophosphatemic rickets in which hypercalciuria is a cardinal feature. In contrast with most varieties of hypophosphatemia, this disorder is characterized by appropriately increased production of 1,25-dihydroxyvitamin D in response to hypophosphatemia. It is recommended that urinary calcium excretion be assessed in all patients with hypophosphatemic rickets so that appropriate therapy will be instituted.


Diagnostic value of silver-stained interphasic nucleolar organizer regions in breast tumors.
Seventy-six specimens of normal breast tissue and benign and malignant breast lesions were studied to assess the mean area occupied by silver-stained proteins of the nucleolar organizer regions (MNORA) of the nucleolus. The assessment was performed with a computer-assisted image analyzer. The results indicate that only 30% of malignant lesions have a MNORA value greater than that of normal breast tissue or benign lesions. On the other hand, MNORA values of ductal carcinoma in situ were significantly greater than those of epitheliosis (papillomatosis). MNORA values were also significantly different in grade I and grade III invasive ductal carcinomas, the latter exhibiting the highest MNORA values of all the cases observed. Evaluation of MNORA values may therefore help in differentiating benign epithelial proliferations from ductal carcinomas in situ. Furthermore, because there is evidence that MNORA values are indicative of the cell duplication rate, MNORA values may ultimately be considered an objective prognostic parameter in addition to grading for invasive ductal carcinomas.


[The present and future of continuous ambulatory peritoneal dialysis (CAPD)].
In order to establish an idea of the future of continuous ambulatory peritoneal dialysis, it is necessary to know the present application of this method, which if it used for a greater number of patients each time, it is performed occasionally with deficient resources and on patients nor selected properly. A possible solution is a very well established peritoneal dialysis program which can "support" an active renal transplant program. It would be interesting to make a prospective and aleatory study between peritoneal dialysis and hemodialysis. It is required to improve: the disconnecting system to the peritoneal catheter, the subcutaneous implantation method, to use the adequacy of the dialysis concept, to design methods to favor the duration and durability of the human peritoneum and look deeply into the opportune and correct treatment of peritonitis and to increase the automatic peritoneal dialysis systems. In the future of peritoneal dialysis we cannot overlook looking deeply into the peritoneum cellular biology in order to use the peritoneum taking into consideration the biology of its cells. DPCA has a bright future and it should play a more important role in the treatment of uremia.


Genetic diversity in populations of African mahogany (Khaya grandioliola C. DC.) introduced in Brazil.
Given its high-valued wood, the African mahogany (Khaya grandifoliola) has been envisaged as a renewable source of tropical hardwoods in Brazil. However, there are concerns about the hypothesized low diversity among the few K. grandifoliola germplasm sources introduced in the country. Using eight microsatellite markers, we evaluated the genetic diversity and divergence among 53 superior trees selected from three provenances of K. grandifoliola located in the state of Para. These populations are among the oldest plantations (>15 years) in Brazil and, therefore, the country's main seed sources. The average number of alleles per locus was 5.9, expected heterozygosity was moderate (^=0.56) and lower than the high observed heterozygosity (HO=0.74). Therefore, the intrapopulation fixation index was negative (f=-0.31) indicating the possibility that selection of superior trees might have favored heterozygous plants with heterosis. No genetic structure was observed between provenances. The genetic diversity observed within selected trees, with an effective population size (Ne) of 30.4, is comparable to that of natural populations of African and Brazilian mahoganies. Therefore, our results contradict the idea that the genetic diversity of K. grandifoliola introduced in Brazil is low and show that our germplasm can be exploited for breeding purposes.


Morphological assessment of polycystic ovary using transvaginal ultrasound.
A total of 104 patients with bilateral polycystic ovaries (PCO) diagnosed by transvaginal ultrasound were classified into four groups (A < 5 cysts, B 5-10 cysts, C > 10 cysts located under ovarian capsule, D numerous cysts distributed all over the ovary) according to the number of microcysts. Ovarian volume, clinical features (menstrual disturbance, obesity and hirsutism), endocrine levels [luteinizing hormone (LH), LH/follicle stimulating hormone ratio, testosterone, androstenedione and dehydroepiandrosterone-sulphate] and response to clomiphene were compared for each group and 17 control subjects with normal ovulatory cycles. Ovarian volume in PCO subjects was significantly larger than that in control subjects. As the number of microcysts increased, the ovarian volume enlarged and the endocrine abnormality worsened. All endocrine parameters in PCO subjects with menstrual disturbances were significantly higher than those in PCO subjects without menstrual disturbances and controls. In PCO subjects without menstrual disturbances only androstenedione was significantly higher than in controls. Among PCO subjects, the frequency of menstrual disturbances, the percentage of response to clomiphene and the pregnancy rate in groups C and D were significantly higher than in groups A and B. Therefore, screening the ovaries in infertile patients by means of transvaginal ultrasound and subsequent assessment of morphology in PCO may suggest endocrine abnormality and help in selecting the proper treatment.


Brain structural and functional signatures of impulsive-compulsive behaviours in Parkinson's disease.
This study assessed brain structural and functional alterations in patients with Parkinson's disease and impulsive-compulsive behaviours (PD-ICB) compared with controls and PD no-ICB cases. Eighty-five PD patients (35 PD-ICB) and 50 controls were recruited. All subjects underwent three-dimensional T1-weighted, diffusion tensor (DT), and resting state functional magnetic resonance imaging (RS fMRI). We assessed cortical thickness with surface-based morphometry, subcortical volumes using FIRST, DT MRI metrics using region of interest and tractography approaches, and RS fMRI using a model free approach. Compared with controls, both PD groups showed a pattern of brain structural alterations in the basal ganglia (more evident in PD no-ICB patients), sensorimotor and associative systems. Compared with PD no-ICB, PD-ICB cases showed left precentral and superior frontal cortical thinning, and motor and extramotor white matter tract damage. Compared with controls, all patients had an increased functional connectivity within the visual network. Additionally, PD no-ICB showed increased functional connectivity of bilateral precentral and postcentral gyri within the sensorimotor network compared with controls and PD-ICB. Severity and duration of PD-ICB modulated the functional connectivity between sensorimotor, visual and cognitive networks. Relative to PD no-ICB, PD-ICB patients were characterised by a more severe involvement of frontal, meso-limbic and motor circuits. These data suggest ICB in PD as the result of a disconnection between sensorimotor, associative and cognitive networks with increasing motor impairment, psychiatric symptoms, and ICB duration. These findings may have important implications in understanding the neural substrates underlying ICB in PD.


cis-platinum, 5-fluorouracil, and hydroxyurea in the treatment of advanced non-small-cell lung cancer. A phase II study.
Sixteen patients with advanced non-small-cell lung cancer were treated with the combination of cis-platinum, 5-fluorouracil, and hydroxyurea. There were two complete responses (lasting 16 weeks each) and one partial response (lasting 12 weeks). Toxicity was manageable, but responders were unable to tolerate further therapy. Despite the obtaining of complete responses, the overall benefit of this particular combination requires further clinical investigation.


Amyloidogenic nature of spider silk.
In spiders soluble proteins are converted to form insoluble silk fibres, stronger than steel. The final fibre product has long been the subject of study; however, little is known about the conversion process in the silk-producing gland of the spider. Here we describe a study of the conversion of the soluble form of the major spider-silk protein, spidroin, directly extracted from the silk gland, to a beta-sheet enriched state using circular dichroism (CD) spectroscopy. Combined with electron microscopy (EM) data showing fibril formation in the beta-sheet rich region of the gland and amino-acid sequence analyses linking spidroin and amyloids, these results lead us to suggest that the refolding conversion is amyloid like. We also propose that spider silk could be a valuable model system for testing hypotheses concerning beta-sheet formation in other fibrilogenic systems, including amyloids.


Distribution of elastin in hamsters and the turnover rates of different elastin pools.
Desmosine (DES) and isodesmosine (IDES) concentration in the urine can be used as a noninvasive method of assessing degradation of mature elastin in normal and pathologic states. The present study was undertaken to determine the distribution of elastin among organs and tissues of normal hamsters, and to determine the turnover rates of two elastin-containing organs (lung, thoracic aorta) as a reflection of their contributions to DES and IDES excretion in the urine. Hamsters were metabolically labeled at 5 days of age with 14C-lysine and studied at 1.5, 4.5, 8, and 12 months of age. The aorta DES + IDES-associated radioactivity did not change significantly over the age span of 1.5-12 months. Lung DES + IDES-associated radioactivity decreased with a half-life of 420 days. Measurement of DES + IDES pools in other tissues, with relatively low concentrations of elastin, was carried out by the isotope dilution technique. At 12 months of age, the head and paws pool, skin, skeletal muscle, gastrointestinal tract, heart-liver-kidney-spleen pool, lungs, and thoracic aorta represented 37%, 28%, 13%, 11%, 6%, 4%, and 1%, respectively, of total body DES + IDES. The organs with the highest DES + IDES-specific radioactivity at 12 months were heart-liver-kidney-spleen, lung, and gastrointestinal tract, with 310, 217, and 217 dpm/nmol, respectively. Skin had the lowest specific radioactivity, with 90 dpm/nmol. The specific radioactivity of DES + IDES in urine was 62 dpm/nmol at 12 months, down from 251 dpm/nmol at 1.5 months. These data clearly indicate that non-lung tissues contain a high proportion of the total body DES + IDES and suggest that pathology in these other pools of DES + IDES could result in significant elevation of urinary DES + IDES. Nevertheless, the relatively high specific radioactivity of DES + IDES in lung elastin as compared with urine makes monitoring labeled urinary DES + IDES in this animal model a sensitive tool for assessing elastin degradation in experimental lung disease.


Adipose stem cells for soft tissue regeneration.
Adipose-derived stem cells (ASCs) can be isolated from human adipose tissue with the exceptional potential for differentiation into mature adipocytes. Utilization of this system is very promising in developing improved techniques to repair soft tissue defects. Current reconstructive procedures, especially after trauma and oncological surgery, transfer autologous soft tissue grafts having limitations. However, ASCs offer the ability to either generate soft tissue with no donor-site morbidity (with the exception of a minor loss of adipose tissue) or enhance the viability and durability of other grafts. This review will discuss the relevant properties of human adult adipose-derived stem cells for the regeneration of adipose tissue. Discussion will focus on the biology of ASCs, cell delivery vehicles/scaffolds useful in applying ASCs as a therapy, and suitable IN VIVO animal models for studying adipose tissue engineering. Also included is a description of the current clinical studies with ASCs in Europe and Asia.


6-C-methyl flavonoids isolated from Pinus densata inhibit the proliferation and promote the apoptosis of the HL-60 human promyelocytic leukaemia cell line.
Three structurally related 6-C-methyl flavonoids isolated from Pinus densata, including 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone (PD1), 5,7,4'-trihydroxy-3,8-dimethoxy-6-C-methylflavone (PD2), and 5,7,4'-trihydroxy-3-methoxy-6-C-methylflavone (PD3), were tested for their ability to inhibit the proliferation and promote the apoptosis of the HL-60 human leukaemia cell line. Cytotoxicity assays in the HL-60 human cancer cell line demonstrated that 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone exhibited the most potent cytotoxicity of the three structurally related 6-C-methyl flavonoids. 5,4'-Dihydroxy-3,7,8-trimethoxy-6-C-methylflavone inhibited the proliferation of HL-60 cells in a dose-dependent manner with an IC₅₀ of 7.91 µM (48 h treatment). Furthermore, 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone-induced apoptosis was associated with mitochondrial membrane disruption and cytochome c release. Flow cytometry analyses revealed an increase in the hypodiploid population in 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone-treated HL-60 cells. Treatment with a concentration of 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone that induced apoptosis activated caspase-3 but did not activate caspase-1. A caspase-3 inhibitor (Ac-DEVD-CHO), but not a caspase-1 inhibitor (Ac-YVAD-CHO), reversed the cytotoxic effects of 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone in HL-60 cells. These data demonstrated that 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone effectively induced the apoptosis of HL-60 cells and exhibited significant anticancer activity via the mitochondrial caspase-3-dependent apoptosis pathway.


Evaluation of CancerChatCanada: a program of online support for Canadians affected by cancer.
Professional-led cancer support groups can improve quality of life and address unmet needs, but most Canadians affected by cancer do not have access to or do not make use of cancer support groups. A collaborative interdisciplinary team developed, operated, and evaluated Internet-based, professional-led, live-chat support groups (osgs) for cancer patients, caregivers, and survivors across Canada. Our study aimed to report participant and participation characteristics in the pan-Canadian initiative known as CancerChatCanada, and to understand participant perspectives about the quality of communication and professional facilitation, overall satisfaction, and psychosocial benefits and outcomes. Participants in osgs provided informed consent. Participant and participation characteristics were gathered from program data collection tools and are described using frequencies, means, and chi-squares. Patient, survivor, and caregiver perspectives were derived from 102 telephone interviews conducted after osg completion and subjected to a directed qualitative content analysis. The 55 professional-led osgs enrolled 351 participants from 9 provinces. More than half the participants came from rural or semirural areas, and more than 84% had no received previous cancer support. The attendance rate was 75%, the dropout rate was 26%, and 80% of participants were satisfied or very satisfied. The convenience and privacy of osgs were benefits. Meaningful communication about important and difficult topics, kinship and bonding with others, and improved mood and self-care were perceived outcomes. Our results demonstrate that this collaborative initiative was successful in increasing reach and access, and that pan-Canadian, professional-led osgs provide psychosocial benefit to underserved and burdened cancer patients, survivors, and family caregivers.


Oligodendrocyte survival in Wallerian degeneration.
The long-term survival of oligodendrocytes in the absence of axons in adult animals was studied following Wallerian degeneration of the optic nerves of adult rats for periods up to 22 months. In contrast to the findings in development and in young animals, large numbers of oligodendrocytes survived during this time period even when deprived of axonal stimuli. The morphological phenotype of many of these cells differed from those of normal oligodendrocytes, and their oligodendrocytic nature was confirmed at a light microscopic level using antibodies to carbonic anhydrase, and at an electron microscopic level by using antibodies to myelin oligodendrocyte glycoprotein. Although there did appear to be some loss of oligodendrocytes over time, a large proportion appeared to remain intact. Many of the remaining cells and processes appeared to resemble resting or quiescent cells. The survival of these cells demonstrates the differential susceptibility of mature and developing oligodendrocytes to loss of axonal stimulus and also indicates a possible reserve capacity for repair following central nervous system injury.


Distinction of deep versus superficial clinical and nonclinical isolates of Trichosporon beigelii by isoenzymes and restriction fragment length polymorphisms of rDNA generated by polymerase chain reaction.
Fifteen clinical and environmental strains of Trichosporon beigelii were analyzed for similarities by using morphological features, biochemical profiles based on carbon compound assimilation and uric acid utilization, isoenzyme electrophoresis, and restriction fragment length polymorphisms of a segment of genes coding for rRNA expanded with the polymerase chain reaction. The findings suggest that strains that cause invasive disease are distinct from the superficial and the nonclinical isolates and that isolates from the skin and mucosae represent a number of different organisms, including some environmental forms. The study shows that T. beigelii is a complex of genetically distinct organisms and that more than one type is found in clinical samples.


Cardiac electrophysiological dynamics from the cellular level to the organ level.
Cardiac alternans describes contraction of the ventricles in a strong-weak-strong-weak sequence at a constant pacing frequency. Clinically, alternans manifests as alternation of the T-wave on the ECG and predisposes individuals to arrhythmia and sudden cardiac death. In this review, we focus on the fundamental dynamical mechanisms of alternans and show how alternans at the cellular level underlies alternans in the tissue and on the ECG. A clear picture of dynamical mechanisms underlying alternans is important to allow development of effective anti-arrhythmic strategies.


The Triticum aestivum non-specific lipid transfer protein (TaLtp) gene family: comparative promoter activity of six TaLtp genes in transgenic rice.
Plant non-specific lipid transfer proteins (nsLTPs) are encoded by a multigene family and support physiological functions, which remain unclear. We adapted an efficient ligation-mediated polymerase chain reaction (LM-PCR) procedure that enabled isolation of 22 novel Triticum aestivum nsLtp (TaLtp) genes encoding types 1 and 2 nsLTPs. A phylogenetic tree clustered the wheat nsLTPs into ten subfamilies comprising 1-7 members. We also studied the activity of four type 1 and two type 2 TaLtp gene promoters in transgenic rice using the 1-Glucuronidase reporter gene. The activities of the six promoters displayed both overlapping and distinct features in rice. In vegetative organs, these promoters were active in leaves and root vascular tissues while no beta-Glucuronidase (GUS) activity was detected in stems. In flowers, the GUS activity driven by the TaLtp7.2a, TaLtp9.1a, TaLtp9.2d, and TaLtp9.3e gene promoters was associated with vascular tissues in glumes and in the extremities of anther filaments whereas only the TaLtp9.4a gene promoter was active in anther epidermal cells. In developing grains, GUS activity and GUS immunolocalization data evidenced complex patterns of activity of the TaLtp7.1a, TaLtp9.2d, and TaLtp9.4a gene promoters in embryo scutellum and in the grain epicarp cell layer. In contrast, GUS activity driven by TaLtp7.2a, TaLtp9.1a, and TaLtp9.3e promoters was restricted to the vascular bundle of the embryo scutellum. This diversity of TaLtp gene promoter activity supports the hypothesis that the encoded TaLTPs possess distinct functions in planta.


Magnetohydrodynamic motion of a colloidal sphere with self-electrochemical surface reactions in a spherical cavity.
An analytical study is presented for the magnetic-field-induced motion of a colloidal sphere with spontaneous electrochemical reactions on its surface situated at the center of a spherical cavity filled with an electrolyte solution at the quasi-steady state. The zeta potential associated with the particle surface may have an arbitrary distribution, whereas the electric double layers adjoining the particle and cavity surfaces are taken to be thin relative to the particle size and the spacing between the solid surfaces. The electric current and magnetic flux density distributions are solved for the particle and fluid phases of arbitrary electric conductivities and magnetic permeabilities. Applying a generalized reciprocal theorem to the Stokes equations with a Lorentz force term resulting from these density distributions for the fluid motion, we obtain explicit formulas for the translational and angular velocities of the colloidal sphere valid for all values of the particle-to-cavity size ratio. The particle velocities decrease monotonically with an increase in this size ratio. For the limiting case of an infinitely large cavity, our result reduces to the relevant solution for an unconfined spherical particle. The boundary effect on the movement of the particle with interfacial self-electrochemical reactions induced by the magnetohydrodynamic force is equivalent to that in sedimentation and much stronger than that in general phoretic motions.


Age identification: a comparison between Finnish and North-American cultures.
This study examined perceptions of age among Finnish males and females in three age groups; twenty-five to thirty-nine-year-olds (n = 446), forty to fifty-four-year-olds (n = 482) and fifty-five to sixty-four-year-olds (n = 427). The age perceptions of the Finnish sample were further compared with those of a North-American sample with corresponding age groups (n = 169, n = 187, n = 222) reported by Barak, Stern, and Gould (1988). Four age concepts used were chronological age, subjective age, ideal age, and disparity age. As expected on the basis of previous studies in age identification, no difference was found between Finnish males and females in terms of subjective age. Ideal age, however, differentiated Finnish males and females; the age ideal of females was significantly higher when compared with males with respective chronological ages. The comparison between Finnish and North-Eastern U.S. sample indicated that the latter group had more youthful age identity while the Finns expressed a greater acceptance of their present age status. This was seen in higher subjective and ideal ages of Finns when compared with their North-American counterparts. Socio-cultural differences in terms of meanings associated with chronological age and aging are discussed.


Indications and case series of intentional replantation of teeth.
This case series aims to comprehensively introduce intentional replantation with a focus on its indications and case selection in endodontics. In all represented cases, calcium enriched mixture (CEM) cement is used for root-end filling. This case series demonstrates twenty cases of IR and extraoral root-end resection and filling with CEM cement. All the selected teeth had a failed endodontic treatment and required surgical/nonsurgical endodontic (re)treatment or extraction. Subsequent to gentle tooth extraction, an appropriate root-end cavity was prepared and filled with CEM cement. Then the tooth was replanted; maximun procedure time was 15 min. A total of 18 cases (90%) were successful over a mean follow-up period of 15.5 months. It can be concluded that intentional replantation with careful case selection can have a high success rate over 2 years. Intentional replantation may be a suitable treatment option for both trained general practitioners and specialists provided that the extraction is simple and straightforward.


Lithobezoar: A Case Report and Literature Review of an Infrequent Cause of Abdominal Pain.
A bezoar is the accumulation of indigestible substances in the gastrointestinal system. Presently described is the case of a 47-year-old male patient who was admitted to the clinic with nausea, vomiting, pain, and abdominal distension. He had a medical history of obsessive-compulsive disorder. He had begun eating soil in the previous 3 to 4 months. Gastroscopy revealed a large, solid, clay-like mass in the stomach. Surgery was successfully performed to remove the collected soil, but unfortunately, the patient died due to an acute myocardial infarction on the postoperative fourth day. Physicians should keep bezoars in mind in cases of unexplained abdominal symptoms, especially in females and patients with psychiatric disorders. Psychiatric disorders are often ignored by surgeons during examinations, which can lead to serious and life-threatening complications.


Long Acting Injectables and their Correlation with Subjectivity in Schizophrenia Spectrum Disorder.
Nowadays, mental illness can no longer be considered as a mere list of symptoms corresponding to localized brain dysfunctions but rather as a disturbance of the patient's subjectivity. Thus, a solid, qualitative study of patients' subjectivity could represent a useful tool in the complex evaluation of efficacy of pharmacotherapy in schizophrenic persons. In this perspective, authors performed a phenomenological oriented investigation on 49 patients, diagnosed with schizophrenia spectrum disorder, who were receiving long-acting injectable (LAI) antipsychotic therapy. From data analysis, authors found a positive correlation between general psychopathology and the use of LAI antipsychotic therapies. The present study highlighted the necessity of a careful investigation of patients' subjectivity in a phenomenological way as an irreducible part of both psychopathological and psychopharmacological matters.


Don't Sugar Coat It: Glycemic Control in the Intensive Care Unit.
Stress hyperglycemia is the transient increase in blood glucose as a result of complex hormonal changes that occur during critical illness. It has been described in the critically ill for nearly 200 years; patient harm, including increases in morbidity, mortality, and lengths of stay, has been associated with hyperglycemia, hypoglycemia, and glucose variability. However, there remains a contentious debate regarding the optimal glucose ranges for this population, most notably within the past 15 years. Recent landmark clinical trials have dramatically changed the treatment of stress hyperglycemia in the intensive care unit (ICU). Earlier studies suggested that tight glucose control improved both morbidity and mortality for ICU patients, but later studies have suggested potential harm related to the development of hypoglycemia. Multiple trials have tried to elucidate potential glucose target ranges for special patient populations, including those with diabetes, trauma, sepsis, cardiac surgery, and brain injuries, but there remains conflicting evidence for most of these subpopulations. Currently, most international organizations recommend targeting moderate blood glucose concentration to levels <180 mg/dL for all patients in the intensive care unit. In this review, the history of stress hyperglycemia and its treatment will be discussed including optimal glucose target ranges, devices for monitoring blood glucose, and current professional organizations' recommendations regarding glucose control in the ICU.


Analysis of cellular events using CellCard System in cell-based high-content multiplexed assays.
High-content screening technologies utilize assays that monitor and quantify multiple cellular events. These assays are typically performed on a single cell type with automated microscopy and image analysis. However, in order to better understand the selectivity of a compound across multiple cell lines, these types of assay must be run serially, which is time consuming. The CellCard System developed by Vitra Bioscience enables multiple cell types to be assayed within a single microtiter well, thereby enabling the simultaneous determination of cellular responses across ten cell types. This multiplexed approach could address the demand for assay capacity, increase the quality of the biologic data, reduce timelines, and improve cost-effectiveness in hit identification and lead evaluation. The authors have carried out an in-depth evaluation of this technology platform using ten cancer cell lines and a library of compounds that affect cellular growth through different mechanisms. Multiple assays were used to investigate the compound effects on membrane integrity, cell cycle progression and apoptosis. In this technology review, the authors discuss personal experience with assay validation, data analysis, results such as cell type-specific compound effects, and the potential application of the CellCard System in drug discovery.


Glycation as an atherogenic modification of LDL.
To highlight the potential importance of glycation as an atherogenic modification of LDL in both diabetic and nondiabetic people. Small dense LDL which is known to be most closely associated with atherogenesis is more susceptible to glycation than more buoyant LDL. Glycation and oxidation of LDL appear to be intimately associated. Glycation of LDL occurs chiefly due to the nonenzymatic reaction of glucose and its metabolites with the free amino groups of lysine in which LDL is rich. Higher concentrations of glycated LDL are present in diabetic than in nondiabetic individuals, but even in the latter, there is generally more circulating glycated LDL than oxidatively modified LDL. Probably, oxidation and glycation of LDL are at least partially interdependent, but both prevent LDL receptor-mediated uptake and promote macrophage scavenger receptor uptake. The recognition that LDL glycation is at least as important as oxidation in atherogenesis may lead to improvements in our understanding of its mechanism and how to prevent it.


Therapy of methicillin-resistant Staphylococcus epidermidis experimental endocarditis.
Antibiotic therapy of methicillin-resistant Staphylococcus epidermidis endocarditis was investigated with the rabbit endocarditis model. Time-kill studies in vitro demonstrated that gentamicin and rifampin had the most rapid early bactericidal rates. With rifampin alone, rifampin-resistant subpopulations emerged. Combinations of antibiotics with gentamicin or rifampin in vitro did not significantly alter the killing rate but prevented emergence of subpopulations resistant to the latter. In the rabbit endocarditis model, gentamicin and vancomycin were the most effective single antibiotic regimens in terms of ability to reduce the bacterial densities on cardiac valve vegetations. Five treatment regimens were equally effective, including vancomycin, gentamicin, vancomycin plus rifampin or gentamicin, and rifampin plus gentamicin. The three-drug combination of vancomycin, rifampin, and gentamicin did not significantly improve the results. Cephalothin therapy was significantly less effective than any of the regimens noted above. It was no more effective than no treatment at 2 days and was only slightly more effective at 4 days. This result with cephalothin treatment was not predicted by routine types of in vitro antibiotic susceptibility testing. Treatment of rabbits with methicillin or cephalothin was associated with an increase in the subpopulation of bacteria resistant to the respective drugs. A number of regimens show potential for therapy of these infections, including vancomycin plus rifampin or gentamicin, rifampin plus gentamicin, and vancomycin alone.


Microtubule destabilization is shared by genetic and idiopathic Parkinson's disease patient fibroblasts.
Data from both toxin-based and gene-based models suggest that dysfunction of the microtubule system contributes to the pathogenesis of Parkinson's disease, even if, at present, no evidence of alterations of microtubules in vivo or in patients is available. Here we analyze cytoskeleton organization in primary fibroblasts deriving from patients with idiopathic or genetic Parkinson's disease, focusing on mutations in parkin and leucine-rich repeat kinase 2. Our analyses reveal that genetic and likely idiopathic pathology affects cytoskeletal organization and stability, without any activation of autophagy or apoptosis. All parkinsonian fibroblasts have a reduced microtubule mass, represented by a higher fraction of unpolymerized tubulin in respect to control cells, and display significant changes in microtubule stability-related signaling pathways. Furthermore, we show that the reduction of microtubule mass is so closely related to the alteration of cell morphology and behavior that both pharmacological treatment with microtubule-targeted drugs, and genetic approaches, by transfecting the wild type parkin or leucine-rich repeat kinase 2, restore the proper microtubule stability and are able to rescue cell architecture. Taken together, our results suggest that microtubule destabilization is a point of convergence of genetic and idiopathic forms of parkinsonism and highlight, for the first time, that microtubule dysfunction occurs in patients and not only in experimental models of Parkinson's disease. Therefore, these data contribute to the knowledge on molecular and cellular events underlying Parkinson's disease and, revealing that correction of microtubule defects restores control phenotype, may offer a new therapeutic target for the management of the disease.


Cell proliferation during the maturation of natural killer cells.
The requirement for cell division during the maturation of natural killer (NK) cells was studied by following the appearance of donor-type NK cells in irradiated mice injected with bone marrow cells and by blocking the cell division at different times during this development. Irradiation (700 rad) or treatment with hydroxyurea (1 mg/g body weight, twice daily) of the recipient mice 7 days after the bone marrow cell inoculation inhibited the appearance of normal NK cell levels, suggesting that the NK cell progenitors are dividing cells. Blocking of the cell division in chimeras that had already developed high NK levels decreased the splenic NK activity, indicating the presence of a dividing NK cell population at this stage of maturation. These results are in accordance with the concept that mature NK cells are nondividing cells but are derived from actively proliferating progenitors in the bone marrow, and some of the first NK cells appearing in the spleen from the bone marrow can still be dividing.


The presence of blocking factors in Brugia malayi microfilaraemic patients.
Serum from microfilaraemic patients have been shown to be unable to promote the antibody-dependent, cell-mediated adherence reaction to infective larvae of Brugia malayi in vitro. In this study, it was found that peripheral leucocytes from microfilaraemic patients were also incapable of promoting the adherence reaction even when incubated with serum of tropical pulmonary eosinophilia (TPE) patients. The TPE sera would normally promote the most intense adherence reaction. It was further shown that preincubation of normal human peripheral leucocytes with sera of microfilaraemic patients would similarly render them incapable of adherence. Such preliminary studies suggest that blocking factors may be present in microfilaraemic patients.


Exclusive fluoride ion recognition and fluorescence "turn-on" response with a label-free DMN Schiff base.
A label-free DMN Schiff base (4) has been explored as a highly selective and sensitive fluoride ion receptor. Fluoride-induced deprotonation results in a charge transfer (CT) transition red shifted with a fluorescence 'turn-on'. Anion selectivity can be tuned by the electron push-pull property of substituents at the phenyl para-position. Selectivity for F(-) is attributed to the suitable acidity of -NH2.


Acute vision loss associated with retinal circulatory disturbances after intravitreal injection of bevacizumab.
Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), specifically binds to VEGF protein, and inhibits angiogenesis. Intravitreal/intracameral injection of bevacizumab has been reported as another treatment option for patients with various ocular ischemic conditions. However, we report 4 cases of acute vision loss after bevacizumab intravitreal injection. Intravitreal bevacizumab injections were administrated to 2 ocular ischemic syndrome (OIS) patients and 2 central retinal vein occlusion (CRVO) patients. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), funduscopic findings, and fluorescein angiography were evaluated before and after the treatments. All 4 cases presented with acute vision loss within 1 week after bevacizumab injection, before its clearance from the eye, and showed that microcirculatory disturbances occurred in the retina. We believe that intravitreal injection of bevacizumab should be undertaken with extreme caution in patients with a history of cerebral infarction, especially with OIS or nonischemic CRVO, and with diabetic retinopathy and vitrectomized eye with pseudophakia.


Expression of streptococcal M protein in mammalian cells.
The M protein encoded by group A streptococci is a cell-wall polypeptide that has the property of enabling these organisms to evade the phagocytic cells of the human host. Therefore, the M protein plays a major role in the pathogenesis of streptococcal diseases. As an initial step toward the use of this protein as a target antigen for the production of protective anti-streptococcal immunity, a live vaccinia virus recombinant containing the M-protein gene has been constructed (VV:M6 delta). The bacterial M-protein DNA sequence is stable within this genetic context and is actively transcribed by viral RNA polymerase. Furthermore, high levels of immunoreactive M protein were detected in vivo when the VV:M6 delta recombinant was used to infect mammalian cells in culture. Thus, in addition to providing a powerful approach for dissecting the immunodominant domains of the M protein, the VV:M6 delta recombinant appears to be an excellent candidate vaccine for animal trials.


Effect of pharmacokinetic profile on the pancreatic toxicity and efficacy of tacrolimus in rats.
The aim of this study is to investigate the effect of the pharmacokinetic profile of tacrolimus on its pancreatic toxicity and efficacy in rats. For toxicity evaluation, doses of 0.03, 0.1, or 0.3 mg/kg/day were given once daily for 8 days in the bolus intravenous injection groups. In the continuous intravenous infusion groups, tacrolimus was infused using an Alzet osmotic mini-pump for 9 days at the same doses. Pancreatic insulin content decreased dose-dependently in both the bolus intravenous injection and continuous intravenous infusion groups, and there was no significant difference between the decreases caused by the two dosing regimens. At 0.03 mg/kg, continuous intravenous infusion did not cause glucose intolerance, but bolus intravenous injection induced significant and dose-dependent glucose intolerance. The pharmacokinetic data indicated that continuous intravenous infusion resulted in a sustained blood drug concentration with an area under the curve (AUC) similar to that obtained with the bolus administration at the same dose. For efficacy evaluation, donor ear grafts were transplanted to the lateral thoraxes of recipients. Tacrolimus doses of 0.01, 0.1, or 1 mg/kg/day were administered from day 0 to day 13. Both bolus intramuscular administration and continuous intravenous infusion prolonged skin allograft survival dose-dependently, and there was no significant difference between the median survival times of groups given the same doses. To summarize, the sustained-release of tacrolimus resulted in a steady blood drug concentration with an AUC similar to that of the bolus administration. In rats, it was better tolerated and just as efficacious as the bolus administration without producing a higher maximal blood concentration (Cmax). These results indicate that the sustained-release formulation has the potential to improve the safety of tacrolimus.


A Comprehensive Study of Electronic, Optical, and Thermoelectric Characteristics of Cs2PbI2Br2 Inorganic Layered Ruddlesden-Popper Mixed Halide Perovskite through Systematic First-Principles Analysis.
In this research, we present a comprehensive study on the influence of layer-dependent structural, electronic, and optical properties in the two-dimensional (2D) Ruddlesden-Popper (RP) perovskite Cs2PbI2Br2. Employing first-principles computations within the density functional theory method, including spin orbit coupling contribution, we examine the impact of various factors on the material. Our results demonstrate that the predicted 2D-layered RP perovskite Cs2PbI2Br2 structures exhibit remarkable stability both structurally and energetically, making them promising candidates for experimental realization. Furthermore, we observe that the electronic band gap and optical absorption coefficients of Cs2PbI2Br2 strongly depend on the thickness variation of the layers. Interestingly, Cs2PbI2Br2 exhibits a notable absorption coefficient in the visible region. Using a combination of density functional theory and Boltzmann transport theory, the thermoelectric properties were forecasted. The calculation involved determining the Seebeck coefficient (S) and other associated thermoelectric characteristics, such as electronic and thermal conductivities, as they vary with the chemical potential at room temperature. These findings open up exciting opportunities for the application of this 2D RP perovskite in solar cells and thermoelectric devices, owing to its unique properties.


[Regulation of lipid and carbohydrate metabolism of the heart by carbocromen (author's transl)].
The influence of 3-(2-diethylaminoethyl)-4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen, Intensain) on lipid and carbohydrate metabolism of the heart was investigated. Carbocromen inhibits the incorporation of 14C-palmitate in heart slices of the rat. The degree of inhibition is dose-dependent and can reach a maximum of 30%. However, the relative concentrations of the various lipid components do not vary significantly. In the heart tissue of the mouse carbocromen increases the uptake of 14C-3-O-methyl-D-glucose by about 30% which might be due to an increased influx of glucose into the heart. The metabolic degradation of 14C-palmitate to 14CO2 decreases up to 40% in the presence of carbocromen with a parallel reduction in oxygen consumption.


Stereotype threat and performance: how self-stereotypes influence processing by inducing regulatory foci.
The authors hypothesized that activated self-stereotypes can influence the strategies of task solution by inducing regulatory foci. More specifically, positive self-stereotypes should induce a promotion focus state of eagerness, whereas negative stereotypes should induce a prevention focus state of vigilance. Study 1 showed that a negative ascribed stereotype with regard to task performance leads to better recall for avoidance-related statements whereas a positive stereotype leads to better recall for approach-related statements. In Studies 2 and 3, both an experimental manipulation of group performance expectation and the preexisting stereotype of better verbal skills in women than in men led to faster and less accurate performance in the positive as compared with the negative stereotype group. Studies 4 and 5 showed that positive in-group stereotypes led to more creative performance whereas negative stereotypes led to better analytical performance. These results point to a possible mechanism for stereotype-threat effects.


[Effects of cefotaxime single administration and of cefotaxime + fosfomycin administration against respiratory tract infections].
Subjects in a cefotaxime (CTX) single administration group and in a CTX + fosfomycin (FOM) administration group were randomly selected for a comparative study on the utility of each product against respiratory tract infections. Overall improvement rates were 81.3% in 32 cases of the CTX single administration group, and 75.6% in 41 cases of the CTX + FOM concomitant administration group. No statistical difference was observed. As for adverse reactions and abnormal laboratory test results, pyrexia, thrombocytopenia, increases in GOT and GPT, and increase in GPT were observed in 4 cases of the CTX single administration group, while angialgia, increases in GOT and GPT (3 cases), and increases in BUN, (totalling 5), were observed in the CTX + FOM group. However, all the symptoms were transient, and none was serious in nature.


Focusing on Mechanoregulation Axis in Fibrosis: Sensing, Transduction and Effecting.
Fibrosis, a pathologic process featured by the excessive deposition of connective tissue components, can affect virtually every organ and has no satisfactory therapy yet. Fibrotic diseases are often associated with organ dysfunction which leads to high morbidity and mortality. Biomechanical stmuli and the corresponding cellular response havebeen identified in fibrogenesis, as the fibrotic remodeling could be seen as the incapacity to reestablish mechanical homeostasis: along with extracellular matrix accumulating, the physical property became more "stiff" and could in turn induce fibrosis. In this review, we provide a comprehensive overview of mechanoregulation in fibrosis, from initialing cellular mechanosensing to intracellular mechanotransduction and processing, and ends up in mechanoeffecting. Our contents are not limited to the cellular mechanism, but further expand to the disorders involved and current clinical trials, providing an insight into the disease and hopefully inspiring new approaches for the treatment of tissue fibrosis.


Discovery of pentapeptide-inhibitor hits targeting FKBP51 by combining computational modeling and X-ray crystallography.
FKBP51 is well-known as a cochaperone of Hsp90 machinery and implicated in many human diseases including stress-related diseases, tau-mediated neurodegeneration and cancers, which makes FKBP51 an attractive drug target for the therapy of FKBP51-associated diseases. However, it has been reported that only nature product rapamycin, cyclosporine A, FK506 and its derivatives exhibit good binding affinities when bound to FKBP51 by now. Given the advantages of peptide-inhibitors, we designed and obtained 20 peptide-inhibitor hits through structure-based drug design. We further characterized the interaction modes of the peptide-inhibitor hits on the FK1 domain of FKBP51 by biochemical and structural biology methods. Structural analysis revealed that peptide-inhibitor hits form U-shaped conformations and occupy the FK506 binding pocket and share similar interaction modes with FK506. Using molecular dynamics simulations, we delved into the interaction dynamics and found that hits are anchored to the FK506 binding pocket in a quite stable conformation. Meanwhile, it was shown that interactions between FK1 and peptide-inhibitor hits are mainly attributed to the hydrogen bond networks comprising I87 and Y113 and FPF cores of peptide-inhibitors involved extensive hydrophobic interactions. We presumed that the peptide design strategy based on the small molecule structure probably shed new lights on the peptide-inhibitor discovery of other targets. The findings presented here could also serve as a structural basis and starting point facilitating the optimization and generation of FKBP51 peptide-inhibitors with better bio-activities.


Isoproterenol inhibits rod outer segment phagocytosis by both cAMP-dependent and independent pathways.
The authors studied the involvement of cAMP-dependent second messenger systems in the inhibition of rod outer segment (ROS) phagocytosis by isoproterenol (ISO) and forskolin (FSK) using two membrane-permeant analogs of cyclic adenosine monophosphate (cAMP), the Rp and Sp diastereoisomers of cyclic adenosine 3',5' monophosphothioate (cAMPS). Rp-cAMPS is a potent competitive inhibitor of cAMP-dependent protein kinase I and II (PKA I and II), whereas Sp-cAMPS is a potent activator of these enzymes. ROS phagocytosis was quantitated in cultured rat RPE cells using a previously described double immunofluorescence assay. Sp-cAMPS showed a dose-dependent inhibition of ROS phagocytosis, whereas 100 microM Rp-cAMPS had no effect on this process. Rp-cAMPS fully prevented the inhibitory effect of Sp-cAMPS and FSK but was able to prevent only partially the inhibition of ROS phagocytosis induced by ISO. Isoproterenol plus FSK showed an additive effect on the inhibition of phagocytosis, suggesting that they act at two independent sites. However, ISO plus Sp-cAMPS or FSK plus Sp-cAMPS showed no additivity. Results suggest that FSK inhibits ROS phagocytosis by RPE cells through a cAMP-dependent pathway, whereas ISO inhibits ROS phagocytosis by RPE cells through cAMP-dependent and cAMP-independent pathways.


[Cellular lymphatic tissue of the endometrium and uterine tube].
The presence of T-lymphocyte subsets in human endometrium and tubal mucosa in correlation to the menstrual cycle was investigated by the immunoperoxidase technique. The main cell populations were the pan T-cells (CD 3) and T-suppressor cells (CD 8). The T-helper cells (CD 4) and the B-lymphocytes (CD 22) were sparsely distributed. Significant differences between the phases of menstrual cycle could not be observed.


Cadmium in urine of children and adults from industrial areas.
Various human activities result in the release of significant quantity of cadmium to the environment. The study population included adults (230) and children (100) residing near the tobacco plant and a control group, unexposed to elevated cadmium concentrations, living in unpolluted area in the same city. Biomonitoring methods were used to assess the effects of contaminated air on the health of the public (urine samples). Ambient air samples were collected near the cadmium-related plant and in unpolluted area during the last ten years. Values of cadmium concentrations in urine found in polluted area were in range of 0.05-0.42 microg/g creatinine for children and 0.15-1.96 microg/g creatinine for adults. The results indicated statistical significant age-dependent differences in urine cadmium concentration between polluted and unpolluted area for adults. Boys and men had significantly higher urine cadmium levels than girls and women, but in children there were no significant gender-dependent differences in cadmium excretion found out. In conclusion, the results from the present study indicate that cadmium urine concentration in polluted area are very high, particularly in children.


Complete Genome Sequences of Three phi29-Like Bacillus cereus Group Podoviridae.
Three double-stranded DNA phi29-like Bacillus cereus group bacteriophages, BeachBum, Harambe, and SerPounce, were identified and characterized. BeachBum and Harambe are closely related but are remarkably different from previously identified phi29-like phages. SerPounce is substantially closer to other phi29-like phages, enabling the identification of its prohead RNA (pRNA) gene.


Measurement of DNA and antigen expression of live cells using three fluorochromes and two detectors.
In a multiparameter flow cytometric study, the fluorescence from the two different dyes fluorescein and dansyl-lysine were detected in the same spectral interval on the same photomultiplier tube, using two lasers to excite the fluorochromes at two separate laser foci. The two signals were split by a T-cable at the output of the photomultiplier tube and synchronized by delaying the first signal. Dansyl-lysine binds to the membrane of heat-inactivated cells and was used to distinguish between live and dead cells after a hyperthermic treatment. By gating on the dansyl-lysine signal, the DNA distribution and surface antigen expression of live and dead cells were obtained separately, using Hoechst 33342 and a monoclonal antibody conjugated to fluorescein.


Thromboembolic problems after the Fontan operation.
One of the major causes of morbidity and mortality after the Fontan operation is thromboembolic events (TE). To assess the current knowledge of TE after Fontan surgery, a comprehensive MEDLINE search of the English literature from 1971 to 2000 was conducted using the key words Fontan, univentricular heart, children, thrombosis, congenital heart disease, cavopulmonary, and palliation. Other relevant publications were identified from bibliographies of the literature retrieved. Fifty-one studies were identified and analyzed for incidence, potential morbidity and mortality, risk factors, prophylactic options, and risk/benefit ratio of prophylactic anticoagulation as relates to TE after Fontan surgery. There were 23 case reports, 13 retrospective cohort studies that included some details about TE among other reported outcomes after Fontan procedures, eight retrospective cohort studies in which TE was the primary outcome measure, and seven articles reporting cross-sectional point surveys, only three of which directly surveyed TE as an outcome. Based on an analysis of the current literature, there is insufficient evidence to make clear recommendations about optimal anticoagulant prophylaxis at this time. Multicenter randomized controlled trials comparing prophylactic antiplatelet with anticoagulation therapies are needed to provide rational scientific guidelines for future management of Fontan patients.


Caenorhabditis elegans pgp-5 is involved in resistance to bacterial infection and heavy metal and its regulation requires TIR-1 and a p38 map kinase cascade.
Animals and plants respond to bacterial infections and environmental stresses by inducing overlapping repertoires of defense genes. How the signals associated with infection and abiotic stresses are differentially integrated within a whole organism remains to be fully addressed. We show that the transcription of a Caenorhabditis elegans ABC transporter, pgp-5 is induced by both bacterial infection and heavy metal stress, but the magnitude and tissue distribution of its expression differs, depending on the type of stressor. PGP-5 contributes to resistance to bacterial infection and heavy metals. Using pgp-5 transcription as a read-out, we show that signals from both biotic and abiotic stresses are integrated by TIR-1, a TIR domain adaptor protein orthologous to human SARM, and a p38 MAP kinase signaling cassette. We further demonstrate that not all the TIR-1 isoforms are necessary for nematode resistance to infection, suggesting a molecular basis for the differential response to abiotic and biotic stress.


[Interventional methods in diagnostics of the breast -- a new vacuum biopsy system for the breast in routine clinical practice].
To evaluate the diagnostic potential of the new vacuum-assisted method VacuFlash (VF) in clinical routine of breast diagnostics. From april 2002 to march 2003, the new sonographically guided vacuum-assisted system VacuFlash was used in 75 patients with a BI-RADS 5 lesion (analogue). The patients were aged between 31-75 yrs (median: 51 yrs), the size of the lesions measured 8-33 mm (median: 14 mm). 5 specimens were taken from each lesion. In 69 of the 75 lesions (92 %, respectively), malignancy was confirmed. In 8 lesions (8 %, resp.), we found a benign histology, confirmed by consecutive surgery. The new vacuum-assisted device VacuFlash is a technically perfected and applicable diagnostic method. Especially in the view of the cost it has to be compared with high-speed core cut biopsy, the hand-held Mammotome system and open surgical biopsy. High-speed core cut biopsy seems to be the standard procedure in diagnostic percutaneous breast intervention to clarify sonographically detected breast lesions.


Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer.
Repeat positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and chest computed tomography (CT) are used to assess the effectiveness of chemoradiotherapy in patients with non-small cell lung cancer (NSCLC); however, the change in the standardized uptake values (SUV) has not been correlated with the pathologic change of the primary tumor. This is a retrospective cohort study of a prospective database of 56 patients who had NSCLC, FDG-PET, and chest CT scans both before and after neoadjuvant therapy, followed by complete resection of their cancer. Maximum SUVs (maxSUV) and tumor size were measured, and the percentage of change was compared with the percentage of nonviable tumor cells. The primary objective was to measure the degree of correlation between these values. The change in the maxSUV has a near linear relationship to the percent of nonviable tumor cells in the resected tumors. FDG-PET's maxSUV is better correlated to pathology than the change in size on CT scan (r2 = 0.75, r2 = 0.03, p < 0.001). When the maxSUV decreased by 80% or more, a complete pathologic response could be predicted with a sensitivity of 90%, specificity of 100%, and accuracy of 96%. The change in maxSUV on FDG-PET scan after neoadjuvant therapy holds a near linear relationship with pathologic response. It is a more accurate predictor than the change of size on CT scan. When the maxSUV decreases by 80% or more it is likely that the patient is a complete responder irrespective of cell type, neoadjuvant treatment, or the final absolute maxSUV. These findings may help guide treatment strategies.


Doxycycline-Dependent Self-Inactivation of CRISPR-Cas9 to Temporally Regulate On- and Off-Target Editing.
Exome and deep sequencing of cells treated with a panel of lentiviral guide RNA demonstrate that both on- and off-target editing proceed in a time-dependent manner. Thus, methods to temporally control Cas9 activity would be beneficial. To address this need, we describe a "self-inactivating CRISPR (SiC)" system consisting of a single guide RNA that deactivates the Streptococcus pyogenes Cas9 nuclease in a doxycycline-dependent manner. This enables defined, temporal control of Cas9 activity in any cell type and also in vivo. Results show that SiC may enable a reduction in off-target editing, with less effect on on-target editing rates. This tool facilitates diverse applications including (1) the timed regulation of genetic knockouts in hard-to-transfect cells using lentivirus, including human leukocytes for the identification of glycogenes regulating leukocyte-endothelial cell adhesion; (2) genome-wide lentiviral sgRNA (single guide RNA) library applications where Cas9 activity is ablated after allowing pre-determined editing times. Thus, stable knockout cell pools are created for functional screens; and (3) temporal control of Cas9-mediated editing of myeloid and lymphoid cells in vivo, both in mouse peripheral blood and bone marrow. Overall, SiC enables temporal control of gene editing and may be applied in diverse application including studies that aim to reduce off-target genome editing.


Haemophilus influenzae type b disease in Auckland children 1981-87.
Haemophilus influenzae type b invasive disease was reviewed in the Auckland paediatric population. A total of 205 episodes were confirmed by sterile cavity culture in 203 patients under 15 years of age over a seven year period. The incidence of invasive disease was 14/100,000/year in those under 15 years and 41/100,000/year in under 5 year olds. The age range was from 1 month to 11 years, with 91% under 5 years and 64% under 2 years. Most cases were due to meningitis (63%). Other diseases included epiglottitis, pneumonia, cellulitis, arthritis, and occult bacteraemia. There was only one fatality. Beta lactamase production was found in 9% of meningeal isolates. Recently a new conjugated haemophilus vaccine has been licensed in the United States for use in children 18 months and older. Consideration should be given to introducing this vaccine in New Zealand.


H4HBEDpa: Octadentate Chelate after A. E. Martell.
H4HBEDpa, a new octadentate chelator inspired by the 1960s ligand HBED of Arthur E. Martell, has been investigated for a selection of trivalent metal ions useful in diagnostic and therapeutic applications (Sc3+, Fe3+, Ga3+, In3+, and Lu3+). Complex formation equilibria were thoroughly investigated using combined potentiometric and UV-vis spectrophotometric titrations which revealed effective chelation and high metal-sequestering capacity, in particular for Fe3+, log KFeL = 36.62, [Fe(HBEDpa)]-. X-ray diffraction study of single crystals revealed that the ligand is preorganized and forms hexa-coordinated complexes with Fe3+ and Ga3+ at acidic pH. Density functional theory (DFT) calculations were applied to probe the geometries and energies of all the possible conformers of [M(HBEDpa)]- (M = Sc3+, Fe3+, Ga3+, In3+, and Lu3+). DFT calculations confirmed the experimental findings, indicating that [Fe(HBEDpa)]- is bound tightly in an asymmetric pattern as compared to the symmetrically bound and more open [Ga(HBEDpa)]-, prone to hydrolysis at higher pH. DFT calculations also showed that a large metal ion such as Lu3+ fully coordinates with HBEDpa4-, forming a binary octadentate complex in its lowest-energy form. Smaller metal ions form six or seven coordinate complexes with HBEDpa4-.


Mediation analyses of Internet-facilitated cognitive behavioral intervention for maternal depression.
This study evaluated the putative mediating mechanisms of an Internet-facilitated cognitive-behavioral therapy (CBT) intervention for depression tailored to economically disadvantaged mothers of preschool-age children. The CBT mediators were tested across two previously published randomized controlled trials which included the same measures of behavioral activation, negative thinking, and savoring of positive events. Trial 1 included 70 mothers with elevated depressive symptoms who were randomized to either the eight-session, Internet-facilitated intervention (Mom-Net) or to treatment as usual. Trial 2 included 266 mothers with elevated depressive symptoms who were randomized to either Mom-Net or to a motivational interviewing and referral to services condition. Simple mediation models tested each putative mediator independently followed by tests of multiple mediation that simultaneously included all three mediators in the model to assess the salient contributions of each mediator. The pattern of results for the mediating effects were systematically replicated across the two trials and suggest that behavioral activation and negative thinking are salient mediators of the Mom-Net intervention; significant mediating effects for savoring were obtained only in the simple mediation models and were not obtained in the multiple mediation models.


Endodontic implants.
Endodontic implants were introduced back in 1960. Endodontic implants enjoyed few successes and many failures. Various reasons for failures include improper case selection, improper use of materials and sealers and poor preparation for implants. Proper case selection had given remarkable long-term success. Two different cases are being presented here, which have been treated successfully with endodontic implants and mineral trioxide aggregate Fillapex (Andreaus, Brazil), an MTA based sealer. We suggest that carefully selected cases can give a higher success rate and this method should be considered as one of the treatment modalities.


Interpretation of the vibrational relaxation of H2 in H2 within the semiclassical effective mass approach.
The temperature dependence of the rate coefficients for vibrational relaxation of H2 in neat H2 is interpreted within the semiclassical effective mass approach. Across the temperature range of 80-3000 K, the experimental rate coefficients vary by five orders of magnitude and fall onto a strongly nonlinear Landau-Teller plot. This behavior is explained by the nonclassical nature of the energy release and by a substantial participation of rotation of the colliding partners in inducing the vibrational transition. A single fitting parameter, the optimal reduced mass, permits one to represent the temperature dependence of the rate coefficient within a factor of 2. This parameter is found to be close to that obtained from a simple model suggested by Sewell et al. [J. Chem. Phys. 99, 2567 (1993)].


Description of the egg of Hulecoeteomyia koreica (Edwards) (Diptera: Culicidae) using scanning electron microscopy.
The egg of Hulecoeteomyia koreica (Edwards) [=Aedes koreicus (Edwards)], an invasive mosquito in Europe, is described from material obtained in Italy. Eggs are cigar-shaped and tapered posteriorly. They are 667.5 ±47.27 µm in length, and the width posteriorly, in the middle and near the micropyle is, respectively, 113.18 ±10.07, 182.5 ±26.92 and 142.25 ±13.85µm. The outer chorion has groups of tubercles, 3 or 4 in an irregular row in the anterior region and 4-6 irregularly dispersed in cavities surrounded by a covering similar to a membrane. The micropyle is surrounded by an irregular collar, and groups of tubercles are less defined in this region. This pattern is different from the egg described for any other mosquito species.


Supportive care needs of men with prostate cancer after hospital discharge: multi-stakeholder perspectives.
This study explored the supportive care needs of men with prostate cancer (PCa) after hospital discharge based on the perceptions of multiple stakeholders. Eight semi-structured focus groups and three individual interviews were conducted between September 2019 and January 2020, with 34 participants representing men with PCa, primary and secondary healthcare professionals, and cancer organizations in western Norway. Data was analysed using systematic text condensation. Four categories emerged: 1) men with PCa have many information needs which should be optimally provided throughout the cancer care process; 2) various coordination efforts among stakeholders are needed to support men with PCa during follow-up; 3) supportive care resources supplement the healthcare services but knowledge about them is random; and 4) structured healthcare processes are needed to improve the services offered to men with PCa. Variations were described regarding priority, optimal mode and timeliness of supportive care needs, while alignment was concerned with establishing structures within and between stakeholders to improve patient care and coordination. Despite alignment among stakeholders' regarding the necessity for standardization of information and coordination practices, the mixed prioritization of supportive care needs of men with PCa indicate the need for additional individualized and adapted measures.


A retrospective comparative study of robotic distal pancreatectomy with or without splenic vessel and spleen preservation.
Robotic distal pancreatectomy has been accepted to be safe and effective for pancreatic tail lesion. Whether spleen preservation by preserving the splenic vessels with robot assistance is feasible and beneficial remains controversial. Here we would like to compare the operative outcomes of robotic distal pancreatectomy and splenectomy (DPS) with robotic spleen preserving distal pancreatectomy by means of splenic vessel preservation (SVP). Between March 2011 and September 2019, 56 consecutive patients undergoing robotic distal pancreatectomy were identified, with 28 patients in each group. Patient demographics, histopathology findings and operative outcomes were prospectively collected and compared between the two groups. A subgroup analysis was made after excluding malignant and pancreatic lesions >6 cm in the DPS group. The two groups had similar conversion rate, blood loss, morbidity and pancreatic fistula rate. There was no operative mortality. The SVP group had shorter median operative time (245 vs 303.5 min, P = 0.019) and shorter median hospital stay (5 vs 6 days, P = 0.019) than the DPS group. However, all malignant lesions occurred in the DPS group and lesion size in DPS group was significantly larger. After matching, there were 28 SVP and 15 DPS. The histopathology findings and lesion size became comparable. The SVP group still had shorter operative time (245 vs 290 min, P = 0.022) and shorter hospital stay (5 vs 7 days, P = 0.014) than the DPS group. Apart from avoiding risk of overwhelming postsplenectomy sepsis, robotic SVP had additional advantage of shorter operative time and shorter hospital stay than robotic DPS.


Decrease in the response to ADH of the rat kidney as a result of early postnatal treatment with cortisol.
Wistar rats were injected just once, intraperitoneally with cortisol (1 microgram/g) or saline at the age of 5 days. The cortisol-treated rats did not differ significantly in the (U/P)osm ratio from the saline-treated controls before 15 days of life. Their response to ADH was distinct but weaker than in the saline controls aged 30 days. This reduced response persisted to 60 days of life. In the collecting tubule fragments, (3H)AVP specific binding was lower in the cortisol-treated rats than in the controls at the age of 20 and 60 days. There was no (3H)AVP specific binding in the proximal convoluted tubules in the cortisol- and saline-injected rats of both ages. The ontogenetic patterns of cAMP specific binding in the papillary cytosolic fraction were different: the early increase in cAMP binding was protracted in the cortisol-treated rats, and no peak appeared at the age of 25 days. Cytosolic protein kinase activity was lower, no peak appeared at 30 days, no activation of protein kinase occurred to the end of weaning in the cortisol-treated rats. The difference between the cortisol and saline groups was abolished by day 30. The interference of cortisol with the ontogenetic changes in AVP binding capacity and cAMP-dependent protein kinase appears to be a plausible cause of the altered development of the response to ADH.


Two-brightness-amplifier imaging system for energetic-materials-combustion study.
This paper discusses a laser monitor with two channels for acquiring images synchronized in time and its use for visualizing the surface of metal nanopowders during combustion. Each channel is an independent optical system based on a copper bromide vapor brightness amplifier and a high-speed camera that allows visualizing a specified area of the sample. Thus, the laser monitor allows real-time imaging of the same sample area with different spatial resolutions and simultaneously two areas of the sample. In comparison with the "master oscillator-power amplifier" system and a bistatic laser monitor in the proposed system, the radiation pulses of the brightness amplifiers are synchronized in such a way that the inversion in the active media is formed at different time intervals. Such a system makes it possible to register processes in one area of the sample in the mode of double frames with a time shift of 35 ns. As an additional option in the proposed system, it is possible to implement a laser illumination mode in which an additional camera is used with a narrow-band filter installed on it for the emission wavelength of brightness amplifiers, and the same radiation from the brightness amplifier is used as an illuminating light source. The proposed technique was used to visualize the combustion of aluminum nanopowders without additives in real time in the area of laser initiation with different spatial resolutions and nanoAl + microAl + microFe powder mixtures in the laser ignition area and the adjacent area of the sample simultaneously as the combustion wave propagates.


Theta Coherence Asymmetry in the Dorsal Stream of Musicians Facilitates Word Learning.
Word learning constitutes a human faculty which is dependent upon two anatomically distinct processing streams projecting from posterior superior temporal (pST) and inferior parietal (IP) brain regions toward the prefrontal cortex (dorsal stream) and the temporal pole (ventral stream). The ventral stream is involved in mapping sensory and phonological information onto lexical-semantic representations, whereas the dorsal stream contributes to sound-to-motor mapping, articulation, complex sequencing in the verbal domain, and to how verbal information is encoded, stored, and rehearsed from memory. In the present source-based EEG study, we evaluated functional connectivity between the IP lobe and Broca's area while musicians and non-musicians learned pseudowords presented in the form of concatenated auditory streams. Behavioral results demonstrated that musicians outperformed non-musicians, as reflected by a higher sensitivity index (d'). This behavioral superiority was paralleled by increased left-hemispheric theta coherence in the dorsal stream, whereas non-musicians showed stronger functional connectivity in the right hemisphere. Since no between-group differences were observed in a passive listening control condition nor during rest, results point to a task-specific intertwining between musical expertise, functional connectivity, and word learning.


A potential molecular ferroelectric material: poly[[bis(1-aza-4-azoniabicyclo[2.2.2]octane)di-μ3-chlorido-tetra-μ2-chlorido-dichloridotricadmium(II)] dihydrate].
The title compound, {[Cd3(C6H13N2)2Cl8]·2H2O}n, consists of pendant protonated cationic diamine ligands bonded to an anionic one-dimensional coordination polymer chloridocadmate scaffold. Each coordination chain features two kinds of Cd(II) centre, each with distorted octahedral coordination geometry. One Cd(II) cation lies on a centre of inversion and is coordinated by six bridging chloride ligands, while the other is coordinated by four bridging chloride ligands, one terminal chloride ligand and a 1-aza-4-azoniabicyclo[2.2.2]octane aza N atom. This gives a reversible corner-sharing half-cubic linear polymer that lies along the crystallographic a direction. The chains interact through hydrogen bonding with solvent water, with each water molecule accepting one N-H...O interaction from a cation and donating to two O-H...Cl interactions with anionic chains, thus linking three separate chains and completing the packing structure.


Elevated numbers of PD-L1 expressing B cells are associated with the development of AIDS-NHL.
The risk for non-Hodgkin lymphoma (NHL) is markedly increased in persons living with human immunodeficiency virus (HIV) infection, and remains elevated in those on anti-retroviral therapy (cART). Both the loss of immunoregulation of Epstein-Barr virus (EBV) infected cells, as well as chronic B-cell activation, are believed to contribute to the genesis of AIDS-related NHL (AIDS-NHL). However, the mechanisms that lead to AIDS-NHL have not been completely defined. A subset of B cells that is characterized by the secretion of IL10, as well as the expression of the programmed cell death ligand-1 (PD-L1/CD274), was recently described. These PD-L1+ B cells can exert regulatory function, including the dampening of T-cell activation, by interacting with the program cell death protein (PD1) on target cells. The role of PD-L1+ B cells in the development of AIDS-NHL has not been explored. We assessed B cell PD-L1 expression on B cells preceding AIDS-NHL diagnosis in a nested case-control study of HIV+ subjects who went on to develop AIDS-NHL, as well as HIV+ subjects who did not, using multi-color flow cytometry. Archival frozen viable PBMC were obtained from the UCLA Multicenter AIDS Cohort Study (MACS). It was seen that the number of CD19+CD24++CD38++and CD19+PD-L1+cells was significantly elevated in cases 1-4 years prior to AIDS-NHL diagnosis, compared to controls, raising the possibility that these cells may play a role in the etiology of AIDS-NHL. Interestingly, most PD-L1+ expression on CD19+ cells was seen on CD19+CD24++CD38++ cells. In addition, we showed that HIV can directly induce PD-L1 expression on B cells through interaction of virion-associated CD40L with CD40 on B cells.


Th-1 cytokines gene polymorphism in human brucellosis.
Brucellosis is a worldwide zoonosis. Infection with Brucella species results in the activation of cell-mediated immune response. The interaction between Th1and Th2 cytokines determines the outcome of disease. Production of each cytokine is in turn affected by genetic factors. In this study, we investigated the possible association between Th1 cytokines gene polymorphism and brucellosis. Different genotypes of TNF-alpha, IFN-gamma and IL-2 were determined by polymerase chain reaction-sequence-specific primer in 47 patients with brucellosis and in 166 healthy controls. Allele frequencies of these genotypes were compared using the chi2 test. The results showed a significant difference in the TNF-alpha genotype GG/GG in patients in comparison with controls (76.7% vs. 21%) (P = 0.001, OR = 12.42, 95%CI 5.7-27.7). There was no significant difference in the frequency distribution of the IFN-gamma genotypes between two groups. IL-2 GG genotype at position -330 was about two times more common in cases than in controls, but the difference was not significant (10.6 vs. 4.6 P value = 0.09). This study shows that genetically low producers of TNF-alpha are possibly susceptible to brucellosis and raise doubt about the role of gene polymorphism of INF-gamma in brucellosis which was demonstrated in previous studies. It seems that patients with brucellosis did not have a defect in producing IL-2 with even a trend towards producing higher amounts of this cytokine.


Systemic lupus erythematosus: review of synthetic drugs.
Synthetic drugs are prescribed for nearly all patients with systemic lupus erythematosus (SLE), a multisystem autoimmune disease, to ameliorate symptoms and positively influence outcome. While only 2 biologic agents have been approved for the treatment of SLE, synthetic drugs are still the mainstay of therapy in SLE. The highly variable and unpredictable course of SLE poses a challenge for physicians as to what drug(s) should be prescribed for which patient. Previous and recent studies have evaluated several synthetic drugs in the treatment of SLE. This article reviews currently available evidence for the efficacy and safety of synthetic drugs in SLE and discusses future treatment perspectives. Hydroxychloroquine should be considered an anchor drug in SLE because of the multiple beneficial effects of this agent. When patients present with persistent disease activity despite hydroxychloroquine therapy or need higher dosages and/or prolonged use of glucocorticoids (GCs), additional immunosuppressants should be promptly prescribed. Based on available evidence, azathioprine and mycophenolate mofetil are the drugs of first choice. Determination of a 'safe' GC dose for chronic daily use is of major importance and should be subject of further studies in large patient populations.


Decentration of posterior chamber IOL: effects of loop material and fixation technique.
A prospective study was conducted on 90 eyes undergoing extracapsular cataract extraction and posterior chamber IOL implantation. Postoperative IOL decentration was evaluated with respect to the loop material, either polypropylene (prolene) or polymethylmethacrylate (PMMA), and the IOL fixation technique, either in the capsular sac (in-the-bag) after capsulorhexis, or in the ciliary sulcus after "can-opener" capsulotomy. More decentration was observed with IOL having polypropylene loops than with those having PMMA loops (0.80 +/- 0.735 mm versus 0.373 +/- 0.299 mm). IOL implanted in the bag showed greater decentration than those implanted in the sulcus, but the difference was not significant. Our findings confirm the recommendation to use an IOL with PMMA loops when placing the implant in the capsular sac.


Biologic efficacy optimization--a step towards personalized medicine.
This following is a review of the factors that influence the outcome of biologic agents in the treatment of adult RA and, when synthesized into the clinical decision-making process, enhance optimization. Adiposity can exacerbate inflammatory diseases; patients with high BMI have worse outcomes from RA, including TNF inhibitors (TNFis), whereas the efficacy of abatacept and tocilizumab is unaffected. Smoking adversely affects TNFi outcomes but has less or no effect on the efficacy of rituximab and tocilizumab, and the effect on abatacept is unknown. Patients who are positive for ACPA and RF have better efficacy with rituximab and abatacept than those who are seronegative, whereas the influence of serotype is less significant for tocilizumab and more complex for TNFis. All biologics seem to do better when co-prescribed with MTX, whereas in monotherapy, tocilizumab is superior to adalimumab and prescription of a non-MTX DMARD has advantages over no DMARD for rituximab and adalimumab. Monitoring of TNFi drug levels is an exciting new field, correlating closely with efficacy in RA and PsA, and is influenced by BMI, adherence, co-prescribed DMARDs and anti-drug antibodies. The measurement of trough levels provides a potential tool for patients who are not doing well to determine early whether to switch within the TNFi class (if levels are low) or to a biologic with an alternative mode of action (if levels are normal or high). Conversely, the finding of supratherapeutic levels has the potential to enable individual patient selection for dose reduction without the risk of flare.


The copper-iron connection in biology: structure of the metallo-oxidase Fet3p.
Fet3p is a multicopper-containing glycoprotein localized to the yeast plasma membrane that catalyzes the oxidation of Fe(II) to Fe(III). This ferrous iron oxidation is coupled to the reduction of O(2) to H(2)O and is termed the ferroxidase reaction. Fet3p-produced Fe(III) is transferred to the permease Ftr1p for import into the cytosol. The posttranslational insertion of four copper ions into Fet3p is essential for its activity, thus linking copper and iron homeostasis. The mammalian ferroxidases ceruloplasmin and hephaestin are homologs of Fet3p. Loss of the Fe(II) oxidation catalyzed by these proteins results in a spectrum of pathological states, including death. Here, we present the structure of the Fet3p extracellular ferroxidase domain and compare it with that of human ceruloplasmin and other multicopper oxidases that are devoid of ferroxidase activity. The Fet3p structure delineates features that underlie the unique reactivity of this and homologous multicopper oxidases that support the essential trafficking of iron in diverse eukaryotic organisms. The findings are correlated with biochemical and physiological data to cross-validate the elements of Fet3p that define it as both a ferroxidase and cuprous oxidase.


Protomers of the green and cyan fluorescent protein chromophores investigated using action spectroscopy.
The photophysics of biochromophore ions often depends on the isomeric or protomeric distribution, yet this distribution, and the individual isomer contributions to an action spectrum, can be difficult to quantify. Here, we use two separate photodissociation action spectroscopy instruments to record electronic spectra for protonated forms of the green (pHBDI+) and cyan (Cyan+) fluorescent protein chromophores. One instrument allows for cryogenic (T = 40 ± 10 K) cooling of the ions, while the other offers the ability to perform protomer-selective photodissociation spectroscopy. We show that both chromophores are generated as two protomers when using electrospray ionisation, and that the protomers have partially overlapping absorption profiles associated with the S1 ← S0 transition. The action spectra for both species span the 340-460 nm range, although the spectral onset for the pHBDI+ protomer with the proton residing on the carbonyl oxygen is red-shifted by ≈40 nm relative to the lower-energy imine protomer. Similarly, the imine and carbonyl protomers are the lowest energy forms of Cyan+, with the main band for the carbonyl protomer red-shifted by ≈60 nm relative to the lower-energy imine protomer. The present strategy for investigating protomers can be applied to a wide range of other biochromophore ions.