Analyzing the Psychological and Social Contents of Evidence-Experimental Comparison between Guessing, Naturalistic Observation, and Systematic Analysis.
To improve inferences about psychological and social evidence contained in pictures and texts, a five-step algorithm-Systematic Analysis (SA)-was devised. It combines basic principles of interpretation in forensic science, providing a comprehensive record of signs of evidence. Criminal justice professionals evaluated the usefulness of SA. Effects of applying SA were tested experimentally with 41 subjects, compared to 39 subjects observing naturally (naturalistic observation) and 47 subjects guessing intuitively intuitive guessing group. After being trained in SA, prosecutors and police detectives (N = 217) attributed it a good usefulness for criminal investigation. Subjects (graduate students) using SA found significantly more details about four test cases than those observing naturally (Cohen's d = 0.58). Subjects who learned SA well abducted significantly better hypotheses than those who observed naturally or who guessed intuitively. Internal validity of SA was α = 0.74. Applying SA improved observation significantly and reduced confirmation bias.


Fluoxetine alone in the treatment of first episode anxious-depression: an open clinical trial.
Many studies have reported the effectiveness of antidepressants in patients with so-called "anxious depression". This is the first report aimed at studying the beneficial therapeutic effects of fluoxetine alone on anxiety dimension in first episode drug naive patients suffering from DSM-IV major depression (MDD) and double depression (DD). Twenty-two outpatients (11 women and 11 men) were recruited in a University clinic for the treatment of a first episode pure MDD (n = 13) or DD (n = 9). All of the patients were drug naive, had Hamilton Rating Scale for Depression (HRSD) and Anxiety (HRSA) scores > or = 15, and were interviewed using the Structured Clinical Interview for DSM-IV-Patient edition. Fluoxetine alone (20 mg daily) was used in an attempt to treat depression with comorbid anxiety symptoms. A series of clinical- and self-rating scales (i.e., HRSD, HRSA, Beck Depression Inventory, and Stait Trait Anxiety Inventory) were used to measure the psychopathology at day 0, and every 10 days until day 50. In the whole group, there were statistically significant changes, starting from the baseline, in depression and anxiety symptoms after 10 days of treatment. Self evaluated anxiety, however, improved after 20 days. Furthermore, at day 50, the patients with comorbid DD experienced a major improvement (diminished anxiety symptoms) compared to pure MDD patients. This open study suggests that depression and anxiety symptoms in first-episode drug-naive patients with anxious depression diminished very quickly with fluoxetine.


In vitro reversal of the fasting state of liver metabolism in the rat. Reevaluation of the roles of insulin and glucose.
Studies were conducted to determine whether the direction of hepatic carbohydrate and lipid metabolism in the rat could be switched simultaneously from a "fasted" to a "fed" profile in vitro. When incubated for 2 h under appropriate conditions hepatocytes from fasted animals could be induced to synthesize glycogen at in vivo rates. There was concomitant marked elevation of the tissue malonyl-coenzyme A level, acceleration of fatty acid synthesis, and suppression of fatty acid oxidation and ketogenesis. In agreement with reports from some laboratories, but contrary to popular belief, glucose was not taken up efficiently by the cells and was thus a poor substrate for eigher glycogen synthesis or lipogenesis. The best precursor for glycogen formation was fructose, whereas lactate (pyruvate) was most efficient in lipogenesis. In both case the addition of glucose to the gluconeogenic substrates was stimulatory, the highest rates being obtained with the further inclusion of glutamine. Insulin was neither necessary for, nor did it stimulate, glycogen deposition or fatty acid synthesis under favorable substrate conditions. Glucagon at physiological concentrations inhibited both glycogen formation and fatty acid synthesis. Insulin readily reversed the effects of glucagon in the submaximal range of its concentration curve. The following conclusions were drawn. First, the fasted-to-fed transition of hepatic carbohydrate and lipid metabolism can be accomplished in vitro over a time frame similar to that operative in vivo. Second, reversal appears to be a substrate-driven phenomenon, in that insulin is not required. Third, unless an unidentified factor (present in protal blood during feeding) facilitates the uptake of glucose by liver it seems unlikely that glucose is the immediate precursor for liver glycogen or fat synthesis in vivo. A likely candidate for the primary substrate in both processes is lactate, which is rapidly formed from glucose by the small intestine and peripheral tissues. Fructose and amino acids may also contribute. Fourth, the requirement for insulin in the reversal of the fasting state of liver metabolism in vivo can best be explained by its ability to offset the catabolic actions of glucagon.


The impact of sporotrichosis in HIV-infected patients: a systematic review.
Sporotrichosis is a fungal infection of man and animals caused by Sporothrix complex. It usually presents as a lymphocutaneous form, but disseminated disease may occur. Given the paucity of data about HIV/AIDS and sporotrichosis co-infection, a systematic review of reported cases of HIV-associated sporotrichosis found via Pubmed (1984-2013) was done. A total of 39 papers were included, and 58 patients' data analyzed. Thirty-three (56.9 %) cases were from Brazil and 18 (31 %) from the USA. Patients' mean age was 37.8 ± 10.4 years; males predominated (84.5 %). The median CD4(+) cell count was 97 cells/mm(3). The most common clinical forms were disseminated and disseminated cutaneous with 33 (56.9 %) and 10 (17.5 %) patients, respectively. There was a correlation between CD4(+) count and clinical categories (p = 0.002). Mortality was 30 % and there was a correlation between central nervous system involvement and death (p < 0.001).


Inebriety, doctors, and the state. Alcoholism treatment institutions before 1940.
This chapter recounts what is known about the international development of treatment institutions for inebriates in the century before 1940. It begins with the origins of treatment in the self-help temperance movement of the 1830s and 1840s and the founding of the first inebriate homes, tracing in the United States the transformation of these small, private, spiritually inclined programs into the medically dominated, quasipublic inebriate asylums of the late 19th century. A similar institutional development occurred in other English-speaking countries. Both in the United States and Britain, these institutions almost disappeared by the end of the First World War. In Germany and Switzerland, a three-tier system of community advice bureaus, inpatient sanatoria, and work camps developed at the turn of the century; an analogous system, with temperance boards at the community level, developed in Nordic countries between 1912 and 1940. The societal emphasis on the problem of impoverished inebriates often turned inebriate treatment efforts in the direction of coercive and custodial handling.


CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease.
C3H/HeJBir mice are a new substrain that spontaneously develop colitis early in life. This study was done to determine the T cell reactivity of C3H/HeJBir mice to candidate antigens that might be involved in their disease. C3H/HeJBir CD4+ T cells were strongly reactive to antigens of the enteric bacterial flora, but not to epithelial or food antigens. The stimulatory material in the enteric bacteria was trypsin sensitive and restricted by class II major histocompatibility complex molecules, but did not have the properties of a superantigen. The precursor frequency of interleuken (IL)-2-producing, bacterial-reactive CD4+ T cells in colitic mice was 1 out of 2,000 compared to 1 out of 20,000-25,000 in noncolitic control mice. These T cells produced predominately IL-2 and interferon gamma, consistent with a T helper type 1 cell response and were present at 3-4 wk, the age of onset of the colitis. Adoptive transfer of bacterial-antigen-activated CD4+ T cells from colitic C3H/HeJBir but not from control C3H/HeJ mice into C3H/HeSnJ scid/scid recipients induced colitis. These data represent a direct demonstration that T cells reactive with conventional antigens of the enteric bacterial flora can mediate chronic inflammatory bowel disease.


[What I learned interacting with orphan children].
The Author reports her experience with orphan children during her field work in an orphange as a nursing student, emphasizing some significant aspects for her learning. She concludes that there must be someone willing to receive all the love the orphan children have to give.


Neural mechanisms and potential treatment of epilepsy and its complications.
The factors underlying epilepsy are multifaceted, but recent research suggests that the brain's neural circuits, which play a key role in controlling the balance between epileptic and antiepileptic factors, may lie at the heart of epilepsy. This article provides a comprehensive review of the neural mechanisms and potential treatment of intractable epilepsy from neural inflammatory responses, melanocortin circuits in brain and pedunculopontine tegmental nucleus. Further studies should be undertaken to elucidate the nature of neural circuits so that we may more effectively apply these new preventive and symptomatic therapies to the patient suffering from medically refractory seizures and its complications.


Conditionally Immortal Slc4a11-/- Mouse Corneal Endothelial Cell Line Recapitulates Disrupted Glutaminolysis Seen in Slc4a11-/- Mouse Model.
To establish conditionally immortal mouse corneal endothelial cell lines with genetically matched Slc4a11+/+ and Slc4a11-/- mice as a model for investigating pathology and therapies for SLC4A11 associated congenital hereditary endothelial dystrophy (CHED) and Fuchs' endothelial corneal dystrophy. We intercrossed H-2Kb-tsA58 mice (Immortomouse) expressing an IFN-γ dependent and temperature-sensitive mutant of the SV40 large T antigen (tsTAg) with Slc4a11+/+ and Slc4a11-/- C57BL/6 mice. The growth characteristics of the cell lines was assessed by doubling time. Ion transport activities (Na+/H+ exchange, bicarbonate, lactate, and Slc4a11 ammonia transport) were analyzed by intracellular pH measurement. The metabolic status of the cell lines was assessed by analyzing TCA cycle intermediates via gas chromatography mass spectrometry (GC-MS). The immortalized Slc4a11+/+ and Slc4a11-/- mouse corneal endothelial cells (MCECs) remained proliferative through passage 49 and maintained similar active ion transport activity. As expected, proliferation was temperature sensitive and IFN-γ dependent. Slc4a11-/- MCECs exhibited decreased proliferative capacity, reduced NH3:H+ transport, altered expression of glutaminolysis enzymes similar to the Slc4a11-/- mouse, and reduced proportion of TCA cycle intermediates derived from glutamine with compensatory increases in glucose flux compared with Slc4a11+/+ MCECs. This is the first report of the immortalization of MCECs. Ion transport of the immortalized endothelial cells remains active, except for NH3:H+ transporter activity in Slc4a11-/- MCECs. Furthermore, Slc4a11-/- MCECs recapitulate the glutaminolysis defects observed in Slc4a11-/- mouse corneal endothelium, providing an excellent tool to study the pathogenesis of SLC4A11 mutations associated with corneal endothelial dystrophies and to screen potential therapeutic agents.


Corrective valgus osteotomy after free vascularized fibula transfer for the treatment of osteomyelitis at the neck of the femur: case report.
Reconstruction using a free vascularized fibula was performed on a long bony defect after osteomyelitis of the proximal femur. For this type of bone defect, a double-barrel fibular graft is recommended. The authors used this procedure for a 58-year-old male who had osteomyelitis of the left proximal femur. As osteotomy through a transplanted fibula can be safely performed, abduction osteotomy should be considered when coxa vara remains after reconstruction with a free vascularized fibula transfer.


Evaluation of Acquired Antibiotic Resistance in Escherichia coli Exposed to Long-Term Low-Shear Modeled Microgravity and Background Antibiotic Exposure.
The long-term response of microbial communities to the microgravity environment of space is not yet fully understood. Of special interest is the possibility that members of these communities may acquire antibiotic resistance. In this study, Escherichia coli cells were grown under low-shear modeled microgravity (LSMMG) conditions for over 1,000 generations (1000G) using chloramphenicol treatment between cycles to prevent contamination. The results were compared with data from an earlier control study done under identical conditions using steam sterilization between cycles rather than chloramphenicol. The sensitivity of the final 1000G-adapted strain to a variety of antibiotics was determined using Vitek analysis. In addition to resistance to chloramphenicol, the adapted strain acquired resistance to cefalotin, cefuroxime, cefuroxime axetil, cefoxitin, and tetracycline. In fact, the resistance to chloramphenicol and cefalotin persisted for over 110 generations despite the removal of both LSMMG conditions and trace antibiotic exposure. Genome sequencing of the adapted strain revealed 22 major changes, including 3 transposon-mediated rearrangements (TMRs). Two TMRs disrupted coding genes (involved in bacterial adhesion), while the third resulted in the deletion of an entire segment (14,314 bp) of the genome, which includes 14 genes involved with motility and chemotaxis. These results are in stark contrast with data from our earlier control study in which cells grown under the identical conditions without antibiotic exposure never acquired antibiotic resistance. Overall, LSMMG does not appear to alter the antibiotic stress resistance seen in microbial ecosystems not exposed to microgravity.IMPORTANCE Stress factors experienced during space include microgravity, sleep deprivation, radiation, isolation, and microbial contamination, all of which can promote immune suppression (1, 2). Under these conditions, the risk of infection from opportunistic pathogens increases significantly, particularly during long-term missions (3). If infection occurs, it is important that the infectious agent should not be antibiotic resistant. Minimizing the occurrence of antibiotic resistance is, therefore, highly desirable. To facilitate this, it is important to better understand the long-term response of bacteria to the microgravity environment. This study demonstrated that the use of antibiotics as a preventive measure could be counterproductive and would likely result in persistent resistance to that antibiotic. In addition, unintended resistance to other antimicrobials might also occur as well as permanent genome changes that might have other unanticipated and undesirable consequences.


[Dynamics of the symptoms of chronic ischemia during the treatment with cytoflavin].
Sixty patients with chronic brain ischemia (discirculatory encephalopathy, I and II stages) were enrolled in the study. Patients of the first group (n=30) were treated with cytoflavin and patients of the second group (n=30) received piracetam prescribed first as injections and then in pills. The treatment duration was 35 days. Standard neurological examination and psychometric assessment of patients and dopplerography of cerebral vessels were carried out. Cytoflavin was shown to have a positive effect on the neurological status. It decreases asthenic, cephalgia and vestibulo-cerebellar syndromes as well as neurological and emotional disturbances reducing the symptoms of depression and anxiety and improving cognitive functions and memory as well as quality of life of patients. The changes were significant compared to those in the group of patients treated with piracetam.


[Clinical effectiveness of cytoflavin inclusion in intensive care of patients with combined traumatic brain injury].
Autors determine the clinical effectiveness of including cytoflavin in intensive care of patients with severe combined traumatic brain injury. A prospective blind randomized controlled study was conducted on two groups involving 101 participants. In group I (58 patients), the intensive care was standard. In group II (43 patients), the intensive care included cytoflavin which was added beginning with the second day of the post-traumatic period. For this purpose, 10 ml of cytoflavin was dissolved in 200 ml of 10% aqueous solution of glucose and was administered intravenously at a speed of 140 drops (7 ml) per minute within 7 days. The use of cytoflavin in complex intensive care of severe combined traumatic brain injury within two days after injury (with the proper correction of blood circulation and respiration) reduced the number of multiple organ dysfunctions, the number is purulent-septic complications, the time of regress in multiple organ dysfunctions, and the reanimation period in intensive care department on the average by a factor of 1.4 - 1.6 (p < 0.005).


Enhancement of Programmed Death Ligand 2 on Hepatitis C Virus Infected Hepatocytes by Calcineurin Inhibitors.
Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2. The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines. The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity. The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.


Endo-SPONGE pulley system for the treatment of chronic anastomotic leakage after rectal resection. A case report.
Anastomotic leakage (AL) after anterior rectal resection unresponsive to diverting ileostomy is difficult to manage. Endoscopic vacuum-assisted (E-VAC) wound closure system is a new approach based on co-axial sponge positioning under endoscopic control. If the abscess is not co-axial, however, endoscopic positioning is not feasible. Aim is to report an original method of sponge positioning. A 62-year-old woman with chronic AL after anterior rectal resection for cancer was referred. AL had been treated with diverting ileostomy without healing. Due to the peri-rectal abscess anatomy, standard E-VAC positioning was not possible. A combined endoscopic-interventional radiology procedure for Endo-SPONGE® (B. Braun Aesculap AG, Germany) positioning was thus employed. Under general anesthesia, a guidewire was passed after small counter-incision on the left gluteus and through the left levator muscle, reaching the anastomotic dehiscence and rectal lumen through the chronic abscess. The guidewire was retrieved through the anus and connected to a long silk thread. By retracting the trans-gluteal guidewire, the silk thread was pulled through the abscess to exit from the gluteal skin incision. A tailored Endo-SPONGE® was then connected to the trans-anal silk thread. By pulling on the gluteal silk thread, the sponge was positioned inside the abscess. The silk thread remained in place under a medication for sponge replacements. Twelve Endo-SPONGE replacements under sedation were required until AL completely resolved after 35 days. When traditional endoscopic sponge insertion into AL is not possible, this original "pulley system" proved effective for sponge introduction and replacement. Anastomotic leakage (AL), Anterior rectal resection, Endo-SPONGE, Endoscopic-Interventional radiology, Pulley system.


Special hospitals. About the size of it.
Special hospitals are facing their third major upheaval in a decade with their proposed assimilation into mental health trusts. Their size is likely to continue to decrease. But the need for them remains. Patients' needs would be best served by smaller hospitals offering more specialised care, closely integrated with other forensic services.


Mixed Lichenoid and Follicular T- and B-Cell Lymphoid Reaction to Red Tattoos With Monoclonal T Cells.
Pseudolymphomatous reactions have been described to occur in tattoos. Most cases have exhibited T-cell predominance and polyclonal T-cell receptor gene rearrangements. One case with monoclonal IgH gene rearrangements progressed into B-cell lymphoma. Lichenoid infiltrates are commonly described but lymphoid follicles much less frequently. We report a case with mixed lichenoid and follicular T- and B-cell reaction to red tattoos. The histopathology and the immunohistochemical studies were constant with a mixed T- and B-cell pseudolymphoma, the IgH gene rearrangement study was polyclonal, but the T-cell receptor gene rearrangement study was monoclonal. The patient who responded to intralesional corticosteroid injections remains under close scrutiny.


Direct Respiration of Lipids During Heat Production in the Inflorescence of Philodendron selloum.
Respiration in the heat-generating, sterile florets of Philodendron selloum was examined by electron microscopy and carbon isotopic analysis of respired carbon dioxide. After the spathe unfolded, the florets switched from carbohydrate oxidation to lipid oxidation, which persisted during heating and for at least 2 days thereafter. The scarcity of glyoxysome-like organelles and the low catalase activity in this tissue indicate that the lipid was respired directly and not after conversion to carbohydrate by the glyoxylate shunt. Thus, lipid metabolism in this heat-generating plant tissue appears to mimic aspects of the biochemistry and physiology of heat production in some animal tissues.


The evaluation of anosognosia in stroke patients.
Anosognosia in stroke patients showed a relevant detrimental effect on the rehabilitation course and patients' quality of life, especially in those with brain injury. Although a number of reliable scales for the assessment of anosognosia in stroke and traumatic brain injury have been developed, at present no single measure fully explores the multifaceted nature of the phenomenon. A PubMed search with appropriate terms was carried out in order to critically review the issue. The main dimensions to consider in the investigation of anosognosia in brain-injured patients are (a) awareness of deficit and related functional implications, (b) modality specificity, (c) causal attribution, (d) expectations of recovery, (e) implicit knowledge and (f) differential diagnosis with psychological denial. Time elapsed from stroke, aetiology, laterality, aphasia and clinical complications may influence all these characteristics and must be taken into consideration. Finally, an adequate association of the anosognosia evaluation with other neuropsychological and behavioural aspects is relevant for a modern holistic approach to the patient. This review is meant to stimulate the development of a new comprehensive assessment procedure for anosognosia in brain injury and particularly in stroke, in order to catch the multidimensionality of the phenomenon and to shape rehabilitation programmes suitable to the specific clinical features of every single patient.


Analysis of medical resources for allocation equity using traditional Chinese medicine resource as a model.
This study is designed to analyse current allocation equity of medical resources in China for a better distribution of medical resources. Descriptive statistical methods were used to analyse the overall allocation of Traditional Chinese medicine (TCM) resources between 2012 and 2018. Lorentz curve and Gini coefficient were used to quantitatively analyse the fairness of the allocation from the population and geography two dimensions. This study revealed an increase of TCM resources for the 6-year period, but the fair allocation of these resources was subjected to the methods used. The Gini coefficients were <0.3 based on population distribution but >0.5 basing on the geography allocation. Population based analysis for the equity of the TCM resource allocation is superior, more attention for health resource planning is needed to focus on geographical fairness in the future, especially for the less populated rural regions.


Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats.
Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.


Role of soybean oil fat emulsion in the prevention of hepatic xenobiotic transporter mRNA up- and down-regulation induced by overdose of fat-free total parenteral nutrition in infant rats.
Total parenteral nutrition (TPN) is associated with cholestasis and hepatic steatosis in human infants. The present study focused on the changes in hepatic xenobiotic transporters associated with overdose of fat-free or fat-containing TPN in infant rats. Three-week-old male Sprague-Dawley rats were divided into three groups: group 1 received an oral diet, group 2 received TPN without fat, and group 3 received TPN with 20% of its calories from fat (soybean oil emulsion). After TPN administration for 4 days, both serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, which are indicators of hepatic dysfunction, in group 2 were significantly higher (p<0.001) than those in the other groups, whereas there were no differences between groups 1 and 3 in either serum AST or ALT levels. The serum bilirubin concentration in group 2 was also markedly higher than that in the other groups. Mdr2, Bsep, Mrp2, Mrp6, Oct1, and Oat2 mRNA levels were decreased in group 2 (fat-free TPN) compared with those in group 1 (oral diet), whereas Mdr1b, Mrp1, and Mrp5 mRNA levels were increased. Specifically, the level of Mdr1b mRNA in group 2 was 16 times higher (p<0.001) than that in group 1. On the other hand, the changes in these mRNA expression levels in group 3 (fat-containing TPN) were smaller than those in group 2, and specifically, the expression levels of Mdr1b, Mrp1, Mrp5, Mrp6, and Oat2 mRNA in group 3 were not significantly different from those in group 1. The results of the present study indicate that including fat in the TPN regimen is very important in preventing the mRNA up- and down-regulation of xenobiotic transporters, which is considered to be the main factor responsible for the abnormal hepatic changes such as cholestasis associated with the excessive administration of fat-free TPN.


Effect of lithium on function and growth of thyroid cells in vitro.
Lithium has been reported to alter thyroid function and cause goiter in some patients. To explain the mechanism of lithium action in the thyroid gland, we studied the effect of lithium on thyroid function and cell growth in FRTL-5 rat thyroid cells and on de novo thyroid hormone formation in primary cultures of porcine thyroid follicles. TSH-induced iodide uptake was suppressed at 2 mM lithium in both FRTL-5 cells and porcine follicles. In porcine thyroid follicles, iodide uptake stimulated by 8-bromo-cAMP, iodine organification, and de novo thyroid hormone formation were also reduced by lithium; however, 2 mM lithium did not inhibit TSH-induced cAMP production. In FRTL-5 cells, lithium also inhibited forskolin-stimulated iodide uptake. These results suggested that lithium exerts its effect at a step involving cAMP signal transduction rather than inhibiting cAMP production. In both FRTL-5 thyroid cells and porcine follicles, lithium enhanced cell growth in basal states (lacking TSH) and with TSH treatment. In porcine thyroid cells, the protein kinase C activator, tetradecanoyl phorbol-13-acetate, increased cell growth, and lithium had an additive effect with tetradecanoyl phorbol-13-acetate on cell growth. To examine the possibility that the action of lithium was mediated by the protein kinase C pathway, porcine cells were incubated with lithium and H7, a selective protein kinase C inhibitor. Lithium-induced cell growth was suppressed to the basal level by H7. These results suggest that lithium exerts its growth-promoting effect through the protein kinase C system.


In vivo expression of an interferon-alpha gene by intramuscular injection of naked DNA.
Acid-stable type I interferons belong to a multigene family. The biologic relevance of each subtype in vivo remains unknown. We have developed an experimental model in which muscles were transfected in situ with naked DNA plasmids encoding an IFN transgene to assess the roles of individual IFN subtypes in vivo. Murine IFN-alpha 9 gene was subcloned into several mammalian expression vectors. Adult C57BL/6 mice were injected bilaterally in regenerating tibialis anterior muscles with naked DNA 5 days after muscle injury to enhance DNA uptake and expression. In the muscles of mice given the IFN-alpha 9 plasmid constructs, acid-stable IFNs were detected by bioassay using reduction in cytopathic effect of encephalomyocarditis virus-infected L929 cells. In these same muscles, IFN-alpha 9 transcripts were identified by RT-PCR, indicating that transcription had occurred. Acid-stable IFNs were detected from days 7 to 28 post-DNA inoculation. Furthermore, these proteins were found in the sera of DNA-inoculated mice. Control groups of mice given the blank expression vectors did not produce detectable IFNs in muscle or sera as determined by bioassay, nor were transcripts detected by RT-PCR. This approach now allows investigation of the effector function of individual subtypes in various murine disease models.


A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection.
Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.


closo-borane conjugated regulatory peptides retain high biological affinity: synthesis of closo-borane conjugated Tyr(3)-octreotate derivatives for BNCT.
Despite the improvements in cancer therapy during the past years, high-grade gliomas and many other types of cancer are still extremely resistant to current forms of therapy. Boron neutron capture therapy (BNCT) provides a promising way to destroy cancer cells without damaging healthy tissue. However, BNCT in practice is still limited due to the lack of boron-containing compounds that selectively deliver boron to cancer cells. Since many neuroendocrine tumors show an overexpression of the somatostatin receptor, it was our aim to synthesize compounds that contain a large number of boron atoms and still show high affinity toward this transmembrane receptor. The synthetic peptide Tyr (3)-octreotate (TATE) was chosen as a high-affinity and internalizing tumor targeting vector (TTV). Novel boron cluster compounds, containing 10 or 20 boron atoms, were coupled to the N-terminus of TATE. The obtained affinity data demonstrate that the use of a spacer between TATE and the closo-borane moiety is the option to avoid a loss of biological affinity of closo-borane conjugated TATE. For the first time, it was shown that closo-borane conjugated regulatory peptides retain high biological affinity and selectivity toward their transmembrane tumor receptors. The results obtained and the improvement of spacer and boron building block chemistry may stimulate new directions for BNCT.


The cargo of CRPPR-conjugated liposomes crosses the intact murine cardiac endothelium.
Ligand-conjugated liposomes and other nano-sized constructs are attractive drug carriers due to their extended plasma circulation; however, limited data are available as to whether their cargo can traverse the endothelium of solid organs. To determine whether the cargo of endothelially targeted liposomes is internalized by endothelial cells and transported into tissue, and to evaluate whether such liposomes can accumulate in models of cardiovascular disease, we tracked the fate of the cargo (a hydrophilic fluorescent dye) and shell (conjugated with a radioisotope) of a heart-homing liposome (CRPPR-conjugated). The ex vivo heart was imaged with confocal microscopy and the in vivo heart with positron emission tomography in sham-treated mice and models of ischemia/reperfusion (I/R) and myocardial infarction (MI). Within 30 min of injection of 20mg/kg CRPPR liposomes, fluorescence increased by 47 fold in the tissue surrounding the vascular lumen, as compared with non-targeted liposomes. Both the accumulation on the endothelium and the interstitial fluorescence saturated at an injected dose of 20mg/kg. In both I/R and MI models, CRPPR liposomes accumulated in diseased sites, although less than in surrounding healthy tissue. The accumulation in the diseased sites increased with time post-injury: the ratio of accumulated radioactivity in the diseased and healthy cardiac tissue increased from 0.20±0.04, to 0.58±0.12 and 0.61±0.19 for 1, 7, and 99 days post-MI, indicating the potential for adequate delivery and therapeutic efficacy if the targeted particles are injected at 7 or more days post-MI. In summary, CRPPR- liposomes accumulated in normal and diseased hearts, and the cargo accumulated in the tissue within minutes and remained detectable after 24 h.


Clinical course in corticobasal syndrome and corticobasal degeneration: implications for diagnosis and management.
This scientific commentary relates to 'Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome', by Aiba et al. (https://doi.org/10.1093/braincomms/fcad296).


Sampling and repeatability in the evaluation of hepatitis C virus genetic variability.
Among the experimental techniques available to study the genetic variability of RNA virus populations, the most informative involve reverse transcription (RT), amplification, cloning and sequencing. The effects of several aspects of these techniques on the estimation of genetic variability in a virus population were analysed. Hepatitis C virus populations from four patients were examined. For each patient, ten series of data derived from independent PCR amplifications of a single RT reaction were obtained. The sample size of each data set was 10 sequences (in nine series) and 100 sequences (in one series). An additional data set derived from an independent RT reaction (about 10 sequences) performed on RNA extracted from the same serum sample was also analysed. The availability of data sets of different sample sizes allowed the effect of sample size on the amount and nature of the genetic variability recovered to be examined. The repeatability of the data obtained in different amplification experiments as well as from different RT reactions was also determined, together with the best strategy to obtain a given number of sequences by comparing the set of 100 sequences obtained from a single amplification with those obtained by pooling the nine sets of 10 sequences. In all cases, these results confirm the high repeatability of the conclusions and parameters derived from the sets of 10 sequences. These results validate the use of relatively small sample sets for the evaluation of genetic variability and for the estimation of phylogenetic relationships of RNA viruses in population and epidemiological studies.


The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable Nuclear-Cytosolic Shuttling in Response to Inflammation.
Inactivation of DNA mismatch repair propels colorectal cancer (CRC) tumorigenesis. CRCs exhibiting elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) show reduced nuclear MutS homolog 3 (MSH3) expression with surrounding inflammation and portend poor patient outcomes. MSH3 reversibly exits from the nucleus to the cytosol in response to the proinflammatory cytokine interleukin-6 (IL-6), suggesting that MSH3 may be a shuttling protein. In this study, we manipulated three putative nuclear localization (NLS1 to -3) and two potential nuclear export signals (NES1 and -2) within MSH3. We found that both NLS1 and NLS2 possess nuclear import function, with NLS1 responsible for nuclear localization within full-length MSH3. We also found that NES1 and NES2 work synergistically to maximize nuclear export, with both being required for IL-6-induced MSH3 export. We examined a 27-bp deletion (Δ27bp) within the polymorphic exon 1 that occurs frequently in human CRC cells and neighbors NLS1. With oxidative stress, MSH3 with this deletion (Δ27bp MSH3) localizes to the cytoplasm, suggesting that NLS1 function in Δ27bp MSH3 is compromised. Overall, MSH3's shuttling in response to inflammation enables accumulation in the cytoplasm; reduced nuclear MSH3 increases EMAST and DNA damage. We suggest that polymorphic sequences adjacent to NLS1 may enhance cytosolic retention, which has clinical implications for inflammation-associated neoplastic processes.


Measurements of single molecules in solution and live cells over longer observation times than those currently possible: the meaningful time.
Monitoring translational diffusion of single molecules in solution or in a living cell, particularly DNA and proteins brings valuable information unperturbed by interaction with an artificial surface. The article derives theoretical relationships for time intervals during which just one molecule in the effective probe region can be studied, the time we call meaningful time. This time is greater than the transit time of the molecule through the detection volume, as a single molecule will likely reenter the detection volume several times during measurement. From the infinitely stretched molecular Poisson distribution of single molecules or particles, we select the contribution of the selfsame molecule or particle by applying rules for choosing appropriate statistics for the single-molecule trajectories. The results point to a useful and sensitive predictive power of the derived relationships. The meaningful time relationships are the criteria to check the experimental single molecule data measured under conditions of normal and anomalous Brownian diffusion of the molecules of interest. At femtomolar bulk concentration, it would be possible to observe an individual molecule over a second time interval or longer during which biological processes - and not conformational biophysical changes - are just starting.


A case imitating Panayiotopoulos syndrome.
Panayiotopoulos syndrome is one of the most common childhood-specific epileptic disorders. It is characterized by autonomic symptoms; the most common being emesis. However, the presence of emetic symptoms may cause misdiagnosis, for example with some organic disorders which have similar autonomic features. On the other hand, since this syndrome has been recently well documented, the tendency for early recognition may lead to overdiagnosis. Here, we present a case which could be mistaken for Panayiotopoulos syndrome based on anamnesis, however, with the aid of ictal video-EEG monitoring, the patient was shown to present with a non-epileptic psychogenic seizure. This report is an example of careful evaluation in order to avoid over- or underdiagnosis of this benign disorder. [Published with video sequences].


Intratympanic Dexamethasone in the Treatment of Ménière's Disease: A Comparison of Two Techniques.
To assess the efficacy and safety of two different intratympanic dexamethasone (IT Dex) injection protocols for intractable unilateral Ménière's disease. Prospective case series. Tertiary neurotology clinic. One hundred six consecutive adult patients with definite unilateral Ménière's disease who had failed medical management were studied for an average of 1,061 days. None had previous oral steroid, IT steroid, or ablative treatment. Two different IT Dex regimes, either a single injection or a series of four injections, that were subsequently repeated as indicated. Requirement for subsequent ablative therapy in the form of intratympanic gentamicin, vestibular nerve section, or labyrinthectomy. Hearing outcomes were measured using pure-tone average of 0.5, 1, 2, and 3 kHz on standard audiometry. The number of intratympanic dexamethasone injections per patient ranged from 1 to 29 (median = 4). Using the Kaplan-Meier method, predicted survival (patients not requiring ablative therapy) at 2 and 4 years after initial treatment was 83.9 and 79.3%, respectively. The injection series protocol ultimately yielded 5% better survival than the single injection protocol, but this was not statistically significant. Injections did not protect against hearing loss, and the most recent pure-tone averages declined compared with pretreatment values by an average of 8.27 dB (p < 0.05). The treatments did not result in any acute hearing losses, permanent tympanic membrane perforations, or other significant adverse events. Intratympanic dexamethasone injections were successful in controlling vertigo insofar as they were able to obviate ablative therapy in the majority of Ménière's disease patients in this study. The injection series protocol may have been more beneficial compared with the single injection, although the difference between the two protocols was nonsignificant. Hearing mildly declined over the treatment course, which likely represents natural disease progression. The lack of adverse events suggests that IT Dex may be a nonablative option for patients with bilateral disease or only hearing/vestibular ears.


Skeletal implications of prostate cancer.
This manuscript reviews the theories behind the propensity of prostate cancer to cause bone metastases and skeletal implications of the prostate cancer biology and treatment modalities. The escape of tumor cells from the primary tumor in the prostate to secondary tumor sites in the axial skeleton probably occurs before the primary tumor is detected. Several theories offer explanations for the observed proclivity of prostate tumors to selectively colonize the axial skeleton. The interaction between the tumor cells and cells that populate bone marrow, in particular osteoblasts and osteoclasts, is important for creating a 'fertile' environment where tumor cells can establish and grow. Prostate cancer cells are capable of producing growth factors that can affect both osteoblasts, resulting in osteoblastic bone formation, and osteoclasts, resulting in excessive bone resorption. In addition to the capability to progress from testosterone-dependent to testosterone-independent phenotype, the hallmark of metastatic prostate cancer is osteosclerosis similar to one induced experimentally in nude rats using CWR22 human prostate cancer cell line. Metastatic bone disease caused by excessive bone formation and bone resorption is the major cause of morbidity in patients with prostate cancer. The most common symptoms include pain, pathological fractures, spinal cord compression, cranial nerve palsies, bone marrow suppression and hypercalcemia. The introduction of prostate-specific antigen in clinical practice created a shift to where more prostate cancer patients with early disease receive androgen ablation treatment, which in return causes more bone loss and cancer-associated osteoporosis. Introduction of third generation bisphosphonates to treat skeletal consequences of malignancy further stressed the important interaction between the bone marrow stroma and cancer cells. Nevertheless, animal models and human prostate tumor cell lines that mimic all aspects of skeletal conditions in prostate cancer patients including osteoblastic bone response are needed to develop and screen for novel therapeutic and diagnostic modalities.


How mothers allocate support among adult children: evidence from a multiactor survey.
Using a within-family perspective, we examine how mothers allocate support among their adult children, and we test alternative theories about support exchange. We use a large-scale multiactor survey from the Netherlands in which mothers and children were interviewed independently. We analyze sibling pairs (aged 36 on average) who were connected to 604 mothers (aged 63 on average). Fixed effects regression models and instrumental variable models are used to examine effects of child characteristics on received support. Mothers give more support to the child who lives without a partner, has children, has health problems, and is lower educated than to the child who does not have these characteristics. Children who more strongly support filial norms also receive more support. Support given to one child has a small positive effect on the support that the mother gives to the other child. The analyses provide new and supportive evidence for the notion that parents are altruistically motivated. At the same time, older parents are motivated by exchange because they invest more in children who are more likely to reciprocate. Some evidence exists for the norm of equality.


Ligation of patent ductus arteriosus in very low birthweight premature neonates.
The results of ligation of a patent ductus arteriosus in 30 premature neonates with a very low birth weight were analysed. The mean gestational age at birth was 27 weeks and the mean weight 811 g. Attempted closure of the ductus with indomethacin in 19 infants failed, though there was temporary closure in nine. Congestive heart failure was present in 29 and respiratory distress in 22 patients. Endotracheal intubation with assisted ventilation was necessary in all cases. The mean age at operation was 13.5 days and ductal ligation was performed in the intensive care unit under local anaesthesia supplemented with pancuronium and pethidine. There were no intraoperative deaths, but five infants died in hospital. There were seven late deaths. Eighteen survivors have been followed for a mean of 26.5 months. Early ligation of a patent ductus arteriosus in premature infants with a very low birth weight improved the cardiorespiratory state. Long term follow up showed good clinical progress in two thirds of the surviving group.


Outside stenting of the vein graft decreases VEGF-A expression and induces significant down-regulation of VEGFR-1 in the intimal and medial layers after the re-endothelialization period.
Neointimal hyperplasia (NIH) in vein grafts implanted into the arterial system develops after re-endothelialization and is considered a significant risk factor of occlusion. Evidence suggests that VEGF-A expression with VEGFR-2 activation and/or VEGFR-1 down-regulation might be involved in inhibiting NIH formation. The aim was to assess whether a stented vein graft (SV) has an impact on VEGF-A and VEGFR-1 expression compared with non-stented vein grafts. Twelve sheep received a radial vein with an outside stent (SV) and a radial vein (RV) transplanted into their carotid arteries. The covering of the luminal surface of the SV and RV grafts by endothelium was 98.3% and 96.3%, respectively, at 6 weeks. From the 6th to 12th weeks after transplantation, the time course of total VEGF-A expression and VEGFR-1 expression were evaluated separately for the intima and media. VEGF-A and VEGFR-1 expression were significantly lower in the SV than in the RV group in the intima. In the media the SV grafts were associated with higher VEGF-A and VEGFR-1 expression at 6 and 8 weeks, but lower values were observed at weeks 10 and 12 compared with the RV grafts. Comparing the time courses of VEGF-A and VEGFR-1 expression in the intima and media with intimal/medial thickening in the SV and RV groups, negative correlations for the SV grafts were found. These findings indicate that outside stenting of the vein graft decreases VEGF-A expression and induces significant down-regulation of VEGFR-1 in the intima and media after the re-endothelialization.


Imprinting of female offspring with testosterone results in insulin resistance and changes in body fat distribution at adult age in rats.
In women, a relative hyperandrogenicity is statistically associated with insulin resistance and centralization of body fat, which are predictors for the development of non-insulin-dependent diabetes mellitus. The aim of this study was to evaluate the effect of androgenization of newborn female rats on insulin sensitivity at adult age. To mimic the neonatal androgen peak normally observed in male rats, female pups were administered one high dose of testosterone (T) subcutaneously within 3 h after birth. They were then given back to their mothers and followed to adult age. At the end of the week 9, tail samples were taken, showing no differences in fasting plasma concentrations of glucose, lactate, insulin, or free fatty acids between T-treated rats and controls. Plasma concentrations of T and progesterone were significantly lower in the T-treated rats, whereas no differences were found in the levels of corticosterone, estradiol, insulin-like growth factor I, or ACTH. After 10 wk, insulin sensitivity was studied with hyperglycemic and euglycemic hyperinsulinemic (5 mU insulin/kg/min) clamp techniques. The T-treated rats showed insulin resistance with both techniques, which was overcome with time and increasing insulin concentrations during the clamp measurements. The T-treated rats were also heavier and had increased relative weights of skeletal muscles and the spleen. Parametrial, retroperitoneal, and inguinal adipose tissues decreased in weight while mesenteric adipose tissue tended to increase, resulting in an approximately 30-50% larger mesenteric than other adipose tissues. It is concluded that neonatal T imprinting of female rats is followed by insulin resistance, changes in adipose tissue distribution, and an enlarged lean mass, without elevation of circulating T. Similar changes are seen in adult female rats or women receiving T.


Activating transcription factor 4 regulates osteoclast differentiation in mice.
Activating transcription factor 4 (ATF4) is a critical transcription factor for osteoblast (OBL) function and bone formation; however, a direct role in osteoclasts (OCLs) has not been established. Here, we targeted expression of ATF4 to the OCL lineage using the Trap promoter or through deletion of Atf4 in mice. OCL differentiation was drastically decreased in Atf4-/- bone marrow monocyte (BMM) cultures and bones. Coculture of Atf4-/- BMMs with WT OBLs or a high concentration of RANKL failed to restore the OCL differentiation defect. Conversely, Trap-Atf4-tg mice displayed severe osteopenia with dramatically increased osteoclastogenesis and bone resorption. We further showed that ATF4 was an upstream activator of the critical transcription factor Nfatc1 and was critical for RANKL activation of multiple MAPK pathways in OCL progenitors. Furthermore, ATF4 was crucial for M-CSF induction of RANK expression on BMMs, and lack of ATF4 caused a shift in OCL precursors to macrophages. Finally, ATF4 was largely modulated by M-CSF signaling and the PI3K/AKT pathways in BMMs. These results demonstrate that ATF4 plays a direct role in regulating OCL differentiation and suggest that it may be a therapeutic target for treating bone diseases associated with increased OCL activity.


Clinical competence of biopsychosocially trained physicians and controls.
To assess and compare clinical observations and interpretations by physicians trained in biopsychosocial internal medicine (group A) and a control group (C) of physicians with no such special training. A verbatim first-interview of a 36-year old woman, seen for consultation by RHA, was presented to both groups (A, trained physicians: n = 30, and C, controls: n = 29). The patient's symptoms included: shaky knees, strange sensations in the abdomen and chest, insecurity and dizziness. The symptoms had begun before her final nursing- exam and exacerbated on her mother's 60th birthday two months later. The patient's mother is the sole caretaker for the patient's sister, who also attended the birthday party. The patient's sister is 19 and had been diagnosed with storage disease and is wheelchair-bound. The doctors were asked to record their observations and interpretations while reviewing the case report. Group A-physicians mentioned and interpreted the physician-patient relationship and the patient's body language as described in the case report more often (p = 0.002, Wilcoxon-Mann-Whitney rank sum test (RS)), mentioned physical symptoms more often (p = 0.0099, Fisher's exact test (FE)) and more often interpreted illness settings with respect to the patient's fear and guilt (Fisher's exact test, p = 0.007 and p = 0.015). A precise integrative diagnosis (life events leading to stress, the latter evoking fear and guilt, leading to symptoms of the fight-flight reaction) was suggested by 7 of group A and 4 of group C. Extensive laboratory work-up and requests for consultations were more frequently asked for by the C group (p = 0.048, RS). Residency training in biopsychosocial medicine in an Internal Medicine Department increased sensitivity to and interpretation of biological and psychosocial data many years after the training and decreased the extent of work-up and consultation costs. However it only tended to enhance psychosomatic conceptualisation with respect to anxiety/guilt/hyperventilation and conversion symptoms.


Robust face tracking via collaboration of generic and specific models.
Significant appearance changes of objects under different orientations could cause loss of tracking, "drifting." In this paper, we present a collaborative tracking framework to robustly track faces under large pose and expression changes and to learn their appearance models online. The collaborative tracking framework probabilistically combines measurements from an offline-trained generic face model with measurements from online-learned specific face appearance models in a dynamic Bayesian network. In this framework, generic face models provide the knowledge of the whole face class, while specific face models provide information on individual faces being tracked. Their combination, therefore, provides robust measurements for multiview face tracking. We introduce a mixture of probabilistic principal component analysis (MPPCA) model to represent the appearance of a specific face under multiple views, and we also present an online EM algorithm to incrementally update the MPPCA model using tracking results. Experimental results demonstrate that the collaborative tracking and online learning methods can handle large pose changes and are robust to distractions from the background.


The Expression of Matryoshka Gene Encoding a Homologue of Kunitz Peptidase Inhibitor Is Regulated Both at the Level of Transcription and Translation.
The gene for Kunitz peptidase inhibitor-like protein (KPILP) contains nested alternative open reading frame (aORF) that controls expression of the maternal mRNA. The content of NbKPILP mRNA in intact leaves of Nicotiana benthamiana plant is low but increases significantly upon extended dark exposure or when foreign nucleic acid is overexpressed in the cells. The NbKPILP gene promoter along with the expressed nested aORF are likely to play an important role in maintaining the levels of NbKPILP mRNA. To elucidate the role of NbKPILP promoter, we isolated a fragment of N. benthamiana chromosomal DNA upstream of the NbKPILP transcription start, sequenced it, and created constructs in which reporter E. coli uidA gene coding for β-D-glucuronidase (GUS) was placed under control of the NbKPILP promoter. By assessing the efficacy of uidA mRNA synthesis directed by the NbKPILP promoter and 35S promoter of the cauliflower mosaic virus in a transient expression system, we showed that the levels of GUS accumulation were comparable for both promoters. Prolonged incubation of the agroinjected plants in the darkness stimulated accumulation of the uidA mRNA directed by the NbKPILP promoter. Our experiments indicate that along with regulation at the transcriptional level, expression of NbKPILP mRNA can be affected by expression of the nested aORF controlled by the polypurine block (PPB) located upstream of its start codon, since introduction of mutations in the PPB resulted in significant accumulation of the NbKPILP mRNA. Nucleotide replacement in the aORF start codon led to the drastic increase in the amounts of NbKPILP mRNA and its protein product.


Analysis of sub-wavelength light propagation through long double-chain nanowires with funnel feeding.
The surface integral equation (SIE) method is utilized to characterize plasmonic waveguide made of two parallel chains of silver nanowires with radius of 25nm fed by a V-shaped funnel at a working wavelength of 600nm. The efficiency of energy transport along the waveguide due to surface plasmonic coupling is investigated for different dimensions and shapes. The opening angle of the V-shaped funnel region for optimum light capturing is included in the investigation as well. A long plasmonic double-chain waveguide of length ~3.3mum has been analyzed and optimized.


Segregation analysis of abdominal visceral fat: the HERITAGE Family Study.
A major gene hypothesis for abdominal visceral fat (AVF) level, both before and after adjustment for total body fat mass, was investigated in 86 white families who participated in the HERITAGE Family Study. In this study, sedentary families were tested for a battery of measures (baseline), endurance exercise trained for 20 weeks, and then remeasured again. The baseline measures reported here are unique in that the variance due to a potentially important environmental factor (activity level) was limited. AVF area was assessed at L4 to L5 by the use of computerized tomography scan, and total body fat mass was assessed with underwater weighing. For fat mass, a putative locus accounted for 64% of the variance, but there was no evidence of a multifactorial component (i.e., no polygenic and/or common familial environmental effects). For AVF area, both a major gene effect accounting for 54% of the variance and a multifactorial component accounting for 17% of the variance were significant. However, after AVF area was adjusted for the effects of total level of body fat, the support for a major gene was reduced. In particular, there was a major effect for fat mass-adjusted AVF area, but it was not transmitted from parents to offspring (i.e., the three transmission probabilities were equal). The importance of this study is twofold. First, these results confirm a previous study that suggested that there is a putative major locus for AVF and for total body fat mass. Second, the findings from the HERITAGE Family Study suggest that the factors underlying AVF area in sedentary families may be similar to those in the population at large, which includes both sedentary and active families. Whether the gene(s) responsible for the high levels of AVF area is the same as that which influences total body fat content remains to be further investigated.


Structural and functional characterization of MppR, an enduracididine biosynthetic enzyme from streptomyces hygroscopicus: functional diversity in the acetoacetate decarboxylase-like superfamily.
The nonproteinogenic amino acid enduracididine is a critical component of the mannopeptimycins, cyclic glycopeptide antibiotics with activity against drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus. Enduracididine is produced in Streptomyces hygroscopicus by three enzymes, MppP, MppQ, and MppR. On the basis of primary sequence analysis, MppP and MppQ are pyridoxal 5'-phosphate-dependent aminotransferases; MppR shares a low, but significant, level of sequence identity with acetoacetate decarboxylase. The exact reactions catalyzed by each enzyme and the intermediates involved in the route to enduracididine are currently unknown. Herein, we present biochemical and structural characterization of MppR that demonstrates a catalytic activity for this enzyme and provides clues about its role in enduracididine biosynthesis. Bioinformatic analysis shows that MppR belongs to a previously uncharacterized family within the acetoacetate decarboxylase-like superfamily (ADCSF) and suggests that MppR-like enzymes may catalyze reactions diverging from the well-characterized, prototypical ADCSF decarboxylase activity. MppR shares a high degree of structural similarity with acetoacetate decarboxylase, though the respective quaternary structures differ markedly and structural differences in the active site explain the observed loss of decarboxylase activity. The crystal structure of MppR in the presence of a mixture of pyruvate and 4-imidazolecarboxaldehyde shows that MppR catalyzes the aldol condensation of these compounds and subsequent dehydration. Surprisingly, the structure of MppR in the presence of "4-hydroxy-2-ketoarginine" shows the correct 4R enantiomer of "2-ketoenduracididine" bound to the enzyme. These data, together with bioinformatic analysis of MppR homologues, identify a novel family within the acetoacetate decarboxylase-like superfamily with divergent active site structure and, consequently, biochemical function.


A Critical Review on Pulsed Electric Field: A Novel Technology for the Extraction of Phytoconstituents.
Different parts of a plant (seeds, fruits, flower, leaves, stem, and roots) contain numerous biologically active compounds called "phytoconstituents" that consist of phenolics, minerals, amino acids, and vitamins. The conventional techniques applied to extract these phytoconstituents have several drawbacks including poor performance, low yields, more solvent use, long processing time, and thermally degrading by-products. In contrast, modern and advanced extraction nonthermal technologies such as pulsed electric field (PEF) assist in easier and efficient identification, characterization, and analysis of bioactive ingredients. Other advantages of PEF include cost-efficacy, less time, and solvent consumption with improved yields. This review covers the applications of PEF to obtain bioactive components, essential oils, proteins, pectin, and other important materials from various parts of the plant. Numerous studies compiled in the current evaluation concluded PEF as the best solution to extract phytoconstituents used in the food and pharmaceutical industries. PEF-assisted extraction leads to a higher yield, utilizes less solvents and energy, and it saves a lot of time compared to traditional extraction methods. PEF extraction design should be safe and efficient enough to prevent the degradation of phytoconstituents and oils.


Drift-diffusion simulation of the ephaptic effect in the triad synapse of the retina.
Experimental evidence suggests the existence of a negative feedback pathway between horizontal cells and cone photoreceptors in the outer plexiform layer of the retina that modulates the flow of calcium ions into the synaptic terminals of cones. However, the underlying mechanism for this feedback is controversial and there are currently three competing hypotheses: the ephaptic hypothesis, the pH hypothesis, and the GABA hypothesis. The goal of this investigation is to demonstrate the ephaptic hypothesis by means of detailed numerical simulations. The drift-diffusion (Poisson-Nernst-Planck) model with membrane boundary current equations is applied to a realistic two-dimensional cross-section of the triad synapse in the goldfish retina to verify the existence of strictly electrical feedback, as predicted by the ephaptic hypothesis. The effect on electrical feedback from the behavior of the bipolar cell membrane potential is also explored. The computed steady-state cone calcium transmembrane current-voltage curves for several cases are presented and compared with experimental data on goldfish. The results provide convincing evidence that an ephaptic mechanism can produce the feedback effect seen in experiments. The model and numerical methods presented here can be applied to any neuronal circuit where dendritic spines are invaginated in presynaptic terminals or boutons.


Probiotics, prebiotics, and the host microbiome: the science of translation.
Recent advances in our understanding of the community structure and function of the human microbiome have implications for the potential role of probiotics and prebiotics in promoting human health. A group of experts recently met to review the latest advances in microbiota/microbiome research and discuss the implications for development of probiotics and prebiotics, primarily as they relate to effects mediated via the intestine. The goals of the meeting were to share recent advances in research on the microbiota, microbiome, probiotics, and prebiotics, and to discuss these findings in the contexts of regulatory barriers, evolving healthcare environments, and potential effects on a variety of health topics, including the development of obesity and diabetes; the long-term consequences of exposure to antibiotics early in life to the gastrointestinal (GI) microbiota; lactose intolerance; and the relationship between the GI microbiota and the central nervous system, with implications for depression, cognition, satiety, and mental health for people living in developed and developing countries. This report provides an overview of these discussions.


Borreliacidal activity of Borrelia metal transporter A (BmtA) binding small molecules by manganese transport inhibition.
Borrelia burgdorferi, the causative agent of Lyme disease, utilizes manganese (Mn) for its various metabolic needs. We hypothesized that blocking Mn transporter could be a possible approach to inhibit metabolic activity of this pathogen and eliminate the infection. We used a combination of in silico protein structure prediction together with molecular docking to target the Borrelia metal transporter A (BmtA), a single known Mn transporter in Borrelia and screened libraries of FDA approved compounds that could potentially bind to the predicted BmtA structure with high affinity. Tricyclic antihistamines such as loratadine, desloratadine, and 3-hydroxydesloratadine as well as yohimbine and tadalafil demonstrated a tight binding to the in silico folded BmtA transporter. We, then, tested borreliacidal activity and dose response of the shortlisted compounds from this screen using a series of in vitro assays. Amongst the probed compounds, desloratadine exhibited potent borreliacidal activity in vitro at and above 78 μg/mL (250 μM). Borrelia treated with lethal doses of desloratadine exhibited a significant loss of intracellular Mn specifically and a severe structural damage to the bacterial cell wall. Our results support the possibility of developing a novel, targeted therapy to treat Lyme disease by targeting specific metabolic needs of Borrelia.


[Growth dynamics of transplantable murine tumors in the course of dicarbamin-protected chemotherapy].
Dicarbamin-assisted mono- and combination chemotherapy (cyclophosphamide + carboplatin + cisplatin) for transplantable tumors born by linear or hybrid mice of both sexes was investigated. It was shown that long-term oral administration contributed to the effect of a range of cytostatic therapeutic dosage rather than adversely affected it. Our findings were used to make a case for clinical studies of dicarbamin for its potential of lowering hematological toxicity of antitumor therapy.


Hydrodynamic regime determines the feeding success of larval fish through the modulation of strike kinematics.
Larval fishes experience extreme mortality rates, with 99% of a cohort perishing within days after starting to actively feed. While recent evidence suggests that hydrodynamic factors contribute to constraining larval feeding during early ontogeny, feeding is a complex process that involves numerous interacting behavioural and biomechanical components. How these components change throughout ontogeny and how they contribute to feeding remain unclear. Using 339 observations of larval feeding attempts, we quantified the effects of morphological and behavioural traits on feeding success of Sparus aurata larvae during early ontogeny. Feeding success was determined using high-speed videography, under both natural and increased water viscosity treatments. Successful strikes were characterized by Reynolds numbers that were an order of magnitude higher than those of failed strikes. The pattern of increasing strike success with increasing age was driven by the ontogeny of traits that facilitate the transition to higher Reynolds numbers. Hence, the physical growth of a larva plays an important role in its transition to a hydrodynamic regime of higher Reynolds numbers, in which suction feeding is more effective.


Psychosomatic symptoms associated with traumatic events experienced in medical students.
Many facts indicate the important role of psychosomatic symptoms that occur due to traumatic events. This study is an analysis of the coexistence of psychosomatic symptoms and traumatic events. Though not every person taking part in these events develops a fully symptomatic post-traumatic stress disorder (PTSD), psychosomatic symptoms with a strong psychological component are observed in many. This study focuses on a comparison of the intensity of somatization, anxiety, depression, and distress of medical university students, who encountered a traumatic event and those who have not experienced trauma. The data was collected from 594 students of different academic majors at the Poznan University of Medical Sciences, Poland. The participants were asked if they had experienced situations that caused psychological trauma as well as about the intensity of their psychosomatic symptoms. The data was collected with 2 questionnaires: Post-traumatic Stress Diagnostic Scale and Four-Dimensional Symptom Questionnaire. The study reveals that 78% of students experienced a traumatic event, in 15% moderate and severe symptoms of PTSD are observed, 45% presents average and high stress levels, 23% experiences symptoms of depression, whereas 30% has anxiety and 26% somatic symptoms. Studies show that experiencing traumatic events in life is linked to the higher intensity of an/the entire range of psychosomatic symptoms. Int J Occup Med Environ Health. 2023;36(5):606-17.


Isoproterenol directly stimulates the Na+-K+ pump in isolated cardiac myocytes.
It has been suggested that catecholamines directly stimulate Na+-K+ pump activity in heart; however, these studies on multicellular preparations are confounded by possible alterations of extracellular K+ concentrations ([K+]o). We reinvestigated this problem by studying the effect of the beta-agonist isoproterenol (Iso) on intracellular Na+ activity (aiNa) in ventricular myocytes enzymatically isolated from rabbit heart. In 5 mM [K+]o, 0.1 microM Iso caused a 24.6 +/- 2.0% decrease of aiNa. Exposure to 1 microM Iso only caused a small additional decrease (27.8 +/- 2.4%), while a diminution of aiNa could already be noticed with only 10 nM Iso (12.8 +/- 1.9% diminution). Myocytes superfused with 15 mM [K+]o also exhibited a significant decrease of aiNa (22.9 +/- 3.6%) when exposed to 0.1 microM Iso. These data argue that accumulation of external K+ does not account for the effect of Iso on steady-state aiNa as postulated by Gadsby (Nature Lond. 306: 691-693, 1983). Furthermore, aiNa in myocytes superfused with 1.5 mM [K+]o decreased by only 8.7% on addition of 0.1 microM Iso. The latter observation suggests that the beta-agonist effect on aiNa regulation is directly or indirectly dependent on membrane potential and/or aiNa. Finally, kinetic analysis of the effect of 1 microM Iso on the decrease in aiNa on changing [K+]o from 1.5 to 5 mM demonstrated that the time course of aiNa recovery was accelerated by a factor of 1.9. This readily suggests that active Na+ transport is directly stimulated by Iso. The much greater relative effect of Iso on the time constant than on steady-state aiNa further indicates that Iso may also increase passive Na+ influx.


Comparison of anteroposterior and posteroanterior screw fixation techniques for posterior malleolar fractures: a retrospective and clinical study.
The posterior malleolus is an important component of the distal tibiofibular complex and plays a crucial role in maintaining ankle joint stability. This study aimed to compare the clinical and radiological outcomes of fixation with anteroposterior (AP) and posteroanterior (PA) compression screws in patients with Haraguchi Type 1 PMFs. Data from 306 patients who underwent surgery for trimalleolar fractures between January 2018 and March 2022 were retrospectively reviewed, and 60 patients meeting the criteria were included in the study. Thirty-one patients with AP screw fixation and 29 patients with PA screw fixation were compared clinically and radiologically. Radiological parameters such as fracture healing time, step-off amount, displacement amount, and development of arthritis were evaluated. Clinical outcomes including ankle joint range of motion at final follow-up, American Orthopedic Foot and Ankle Society (AOFAS) score, Visual Analog Scale (VAS), and Olerud-Molander Score were compared. There were no statistically significant differences between the groups in terms of average age, gender distribution, smoking history, fracture etiology, time from injury to surgery, operation time, fracture healing time, and follow-up duration. Step-off and displacement amounts were lower in the PA screw group (P<0.001, P=0.004, respectively). When comparing the development of arthritis, according to the Kellgren-Lawrence Classification, no signs of arthritis were observed in 62.1% of the PA screw group, while this rate was 22.6% in the AP screw group. Ankle dorsiflexion, plantar flexion range of motion, AOFAS score, Olerud-Molander Score, and VAS results were statistically better in the PA screw group (P=0.002, P=0.001, P=0.002, P=0.001, P=0.002, respectively). There were no significant differences between the groups regarding complications. Two different screw fixation techniques used in the treatment of trimalleolar fracture patients with Haraguchi Type 1 PMF were compared. In conclusion; percutaneous PA screw fixation is more advantageous than the AP screw fixation method because it provides less step-off in the fracture line, less arthrosis in the ankle, and better functional scores.


The context of collecting family health history: examining definitions of family and family communication about health among African American women.
Public health initiatives encourage the public to discuss and record family health history information, which can inform prevention and screening for a variety of conditions. Most research on family health history discussion and collection, however, has predominantly involved White participants and has not considered lay definitions of family or family communication patterns about health. This qualitative study of 32 African American women-16 with a history of cancer-analyzed participants' definitions of family, family communication about health, and collection of family health history information. Family was defined by biological relatedness, social ties, interactions, and proximity. Several participants noted using different definitions of family for different purposes (e.g., biomedical vs. social). Health discussions took place between and within generations and were influenced by structural relationships (e.g., sister) and characteristics of family members (e.g., trustworthiness). Participants described managing tensions between sharing health information and protecting privacy, especially related to generational differences in sharing information, fear of familial conflict or gossip, and denial (sometimes described as refusal to "own" or "claim" a disease). Few participants reported that anyone in their family kept formal family health history records. Results suggest family health history initiatives should address family tensions and communication patterns that affect discussion and collection of family health history information.


Influence of chronic diseases on societal participation in paid work, volunteering and informal caregiving in Europe: a 12-year follow-up study.
This study aims to provide insight into (1) the associations between having a chronic disease and participation in paid work, volunteer activities or informal care, (2) the associations between the onset of a chronic disease and these forms of societal participation, and (3) whether these associations differ across educational level and gender. The study population consisted of n=21 875 respondents of the Survey of Health, Ageing and Retirement in Europe aged between 50 years and the country-specific retirement age. The influence of having and the onset of a chronic disease on societal participation was analysed using a hybrid Poisson regression model, combining fixed and random effects, and presented by relative risks (RRs). Individuals with a chronic disease were less likely to participate in paid work (RR: 0.69; 95% CI 0.67 to 0.71) and volunteer activities (RR: 0.92; 95% CI 0.88 to 0.97), but more likely to give informal care (RR: 1.05; 95% CI 1.01 to 1.08). Onset of a chronic disease was associated with a higher likelihood to quit paid work (RR: 0.91; 95% CI 0.86 to 0.97) and to give informal care (RR: 1.08; 95% CI 1.01 to 1.16). Lower educated individuals with a chronic disease or with the onset of a chronic disease were less likely to have paid work than higher educated individuals. Individuals with a chronic disease were less likely to participate in paid work and volunteer activities, and more likely to provide informal care. Educational inequalities were present for paid work. More insight into which factors hinder societal participation among individuals with a chronic disease is needed.


Adolescent Δ9-Tetrahydrocannabinol Exposure Selectively Impairs Working Memory but Not Several Other mPFC-Mediated Behaviors.
As the frequency of cannabis use by 14-16-year-olds increases, it becomes increasingly important to understand the effect of cannabis on the developing central nervous system. Using mice as a model system, we treated adolescent (28 day old) C57BL6/J mice of both sexes for 3 weeks with 3 mg/kg tetrahydrocannabinol (THC). Starting a week after the last treatment, several cognitive behaviors were analyzed. Mice treated with THC as adolescents acquired proficiency in a working memory task more slowly than vehicle-treated mice. Working memory recall in both sexes of THC-treated mice was also deficient during increasing cognitive load compared to vehicle-treated mice. Our adolescent THC treatment did not strongly affect social preference, anxiety behaviors, or decision-making behaviors on the elevated T maze task. In summary, under the conditions of this study, adolescent THC treatment of mice markedly affected the establishment, and persistence of working memory, while having little effect on decision-making, social preference or anxiety behaviors. This study provides further support that adolescent THC affects specific behavioral domains.


A Novel Hazard for an Endangered Fox in a Novel Environment.
Animals colonizing novel environments can encounter novel hazards. Endangered San Joaquin kit foxes (Vulpes macrotis mutica) are found in the cities of Bakersfield and Taft in central California. We documented 66 incidents of kit foxes becoming entangled in sports netting (e.g., soccer nets, batting-cage nets) occurring from the 1980s through 2022. Overall, 25 of the foxes died. Adults were more likely to get entangled in soccer nets, whereas pups (<1 yr) were more likely to get entangled in batting-cage nets. Pups are more likely to die while entangled, probably due to smaller body mass and lower energy reserves. The reasons that kit foxes get entangled in netting were unclear, although incidents involving batting-cage netting and pups may be due to natal dens being located under or near batting cages. At current rates, this hazard is unlikely to limit urban kit fox populations. However, losses of this endangered species should be minimized and the incidents are easily mitigated by dropping or lifting nets when not in use.


Proteins expressed by the c-myc oncogene in lymphomas of human and avian origin.
We have prepared antisera against synthetic peptides corresponding to the C-terminal region of the avian and human myc oncogene coding sequences. Immunoprecipitates from avian and human cells show two major proteins which, by the criteria of hybrid-selected translation, transfection, and peptide-blocking assays, are the c-myc protein products. These proteins are phosphorylated nuclear proteins which are tightly bound to the nuclear matrix-lamin and which have a short half-life. Analysis of avian and human lymphoma cell lines containing rearranged c-myc alleles show significant changes in the ratio of the two proteins although only the avian lymphomas have increased quantities of c-myc protein.


Boswellia frereana (frankincense) suppresses cytokine-induced matrix metalloproteinase expression and production of pro-inflammatory molecules in articular cartilage.
The aim of this study was to assess the anti-inflammatory efficacy of Boswellia frereana extracts in an in vitro model of cartilage degeneration and determine its potential as a therapy for treating osteoarthritis. Cartilage degradation was induced in vitro by treating explants with 5 ng/ml interleukin1alpha (IL-1alpha) and 10 ng/ml oncostatin M (OSM) over a 28-day period, in the presence or absence of 100 microg/ml B. frereana. Treatment of IL-1alpha/OSM stimulated cartilage explants with B. frereana inhibited the breakdown of the collagenous matrix. B. frereana reduced MMP9 and MMP13 mRNA levels, inhibited MMP9 expression and activation, and significantly reduced the production of nitrite (stable end product of nitric oxide), prostaglandin E2 and cycloxygenase-2. Epi-lupeol was identified as the principal constituent of B. frereana. This is the first report on the novel anti-inflammatory properties of Boswellia frereana in an in vitro model of cartilage degradation. We have demonstrated that B. frereana prevents collagen degradation, and inhibits the production of pro-inflammatory mediators and MMPs. Due to its efficacy we propose that B. frereana should be examined further as a potential therapeutic agent for treating inflammatory symptoms associated with arthritis.


Association between Macronutrient Intake and Excessive Daytime Sleepiness: An Iso-Caloric Substitution Analysis from the North West Adelaide Health Study.
Epidemiological evidence on the association between macronutrient intake and excessive daytime sleepiness (EDS) is scarce. Using data from the North West Adelaide Health Study, we aimed to determine the association between iso-caloric substitution of macronutrients and EDS. Data from 1997 adults aged ≥ 24 years were analyzed. Daytime sleepiness was measured using the Epworth Sleepiness Scale, a score ≥ 11 was considered EDS. Dietary intake data were collected using a food frequency questionnaire. We determined absolute and relative energy intake based on consumption of saturated and unsaturated fats, protein, and carbohydrate. Odds ratios (ORs) were used to determine the associations using log-binomial logistic regression with and without iso-caloric substitution methods, and models were adjusted for confounders. The prevalence of EDS in the sample was 10.6%. After adjusting for potential confounders, substituting 5% energy intake from protein with an equal amount of saturated fat (OR = 1.57; 95% CI: 1.00-2.45) and carbohydrate (OR = 1.23; 95% CI: 0.92-1.65) increased the odds of EDS. When carbohydrate was substituted with saturated fat (OR = 1.27; 95% CI: 0.93-1.59), the odds of EDS were increased. The odds of EDS were lower when saturated fat was substituted with unsaturated fat (OR = 0.74; 95% CI: 0.51-1.06), protein (OR = 0.63; 95% CI: 0.41-0.99) or carbohydrate (OR = 0.79; 95% CI: 0.57-1.08). While these results were consistent over different iso-caloric substitution methods, inconsistent results were found with standard regression. While substitution of fat and carbohydrate with protein was inversely associated with EDS, substitution of protein with fat and carbohydrate was positively associated with EDS. Randomized trials are needed to confirm if dietary interventions can be used to improve daytime alertness in those with EDS.


Image texture analysis of sonograms in chronic inflammations of thyroid gland.
The current practice in assessing sonographic findings of chronic inflamed thyroid tissue is mainly qualitative, based just on a physician's experience. This study shows that inflamed and healthy tissues can be differentiated by automatic texture analysis of B-mode sonographic images. Feature selection is the most important part of this procedure. We employed two selection schemes for finding recognition-optimal features: one based on compactness and separability and the other based on classification error. The full feature set included Muzzolini's spatial features and Haralick's co-occurrence features. These features were selected on a set of 2430 sonograms of 81 subjects, and the classifier performance was evaluated on a test set of 540 sonograms of 18 independent subjects. A classification success rate of 100% was achieved with as few as one optimal feature among the 129 texture characteristics tested. Both selection schemes agreed on the best features. The results were confirmed on the independent test set. The stability of the results with respect to sonograph setting, thyroid gland segmentation and scanning direction was tested.


Varicella Zoster vaccination in hemodialysis patients: The state of the art.
Varicella Zoster Virus (VZV) infection is a common childhood exanthematous disease, which in adults and immunocompromised people may result in severe neurologic complications. Up to one-third of infected subjects may have VZV clinical reactivation particularly if immunocompromised. Patients affected by end-stage renal disease on hemodialysis present immunodepression that contributes to their higher incidence of VZV infections and reactivation. While antiviral treatment in these patients shows low efficacy, the prevention of VZV through vaccination avoids the primary infection and the risk of reactivation. Two VZV vaccines are currently available: the live attenuate Zoster Vaccine (LZV) and a Recombinant Zoster Vaccine (RZV), with the latter appearing to provide greater efficacy. Given the higher incidence of VZV infection and reactivation, the lesser response to antivirals and the lower impact of VZ vaccine in hemodialysis patients in terms of side effects, a higher diffusion of VZV vaccination should be promoted by nephrologists in these patients in particular in those with future transplant opportunities.


Non-enzymic glycation of human extracellular superoxide dismutase.
The secretory enzyme extracellular superoxide dismutase (EC-SOD) is in plasma heterogenous with regard to heparin-affinity and can be divided into three fractions, A that lacks affinity, B with intermediate affinity and C with high affinity. The C fraction forms an equilibrium between the plasma phase and heparan sulphate proteoglycan on the surface of the endothelium. In vitro EC-SOD C could be time-dependently glycated. The enzymic activity was not affected in glycated EC-SOD, but the high heparin-affinity was lost in about half of the studied glycated fraction. Addition of heparin decreased the glycation in vitro, and EC-SOD C modified with the lysine-specific reagent trinitrobenzenesulphonic acid could not be glycated in vitro. The findings suggest that the glycation sites are localized rather far away from the active site and may occur on lysine residues in the heparin-binding domain in the C-terminal end of the enzyme. The proportion of glycated EC-SOD in serum of diabetic patients was considerably higher than in normal subjects. Of the subfractions, EC-SOD B was by far the most highly glycated, followed by EC-SOD A. EC-SOD C was glycated only to be a minor extent. The findings suggest that glycation is one of the factors that contribute to the heterogeneity in heparin-affinity of plasma EC-SOD. Since this phenomenon is increased in diabetes, the cell-surface-associated EC-SOD may be decreased in this disease, increasing the susceptibility of cells to superoxide radicals produced in the extracellular space.


Structural analysis of WbpE from Pseudomonas aeruginosa PAO1: a nucleotide sugar aminotransferase involved in O-antigen assembly.
In recent years, the opportunistic pathogen Pseudomonas aeruginosa has emerged as a major source of hospital-acquired infections. Effective treatment has proven increasingly difficult due to the spread of multidrug resistant strains and thus requires a deeper understanding of the biochemical mechanisms of pathogenicity. The central carbohydrate of the P. aeruginosa PAO1 (O5) B-band O-antigen, ManNAc(3NAc)A, has been shown to be critical for virulence and is produced in a stepwise manner by five enzymes in the Wbp pathway (WbpA, WbpB, WbpE, WbpD, and WbpI). Herein, we present the crystal structure of the aminotransferase WbpE from P. aeruginosa PAO1 in complex with the cofactor pyridoxal 5'-phosphate (PLP) and product UDP-GlcNAc(3NH(2))A as the external aldimine at 1.9 A resolution. We also report the structures of WbpE in complex with PMP alone as well as the PLP internal aldimine and show that the dimeric structure of WbpE observed in the crystal structure is confirmed by analytical ultracentrifugation. Analysis of these structures reveals that the active site of the enzyme is composed of residues from both subunits. In particular, we show that a key residue (Arg229), which has previously been implicated in direct interactions with the alpha-carboxylate moiety of alpha-ketoglutarate, is also uniquely positioned to bestow specificity for the 6''-carboxyl group of GlcNAc(3NH(2))A through a salt bridge. This finding is intriguing because while an analogous basic residue is present in WbpE homologues that do not process 6''-carboxyl-modified saccharides, recent structural studies reveal that this side chain is retracted to accommodate a neutral C6'' atom. This work represents the first structural analysis of a nucleotide sugar aminotransferase with a bound product modified at the C2'', C3'', and C6'' positions and provides insight into a novel target for treatment of P. aeruginosa infection.


Coupled mixed model for joint genetic analysis of complex disorders with two independently collected data sets.
In the last decade, Genome-wide Association studies (GWASs) have contributed to decoding the human genome by uncovering many genetic variations associated with various diseases. Many follow-up investigations involve joint analysis of multiple independently generated GWAS data sets. While most of the computational approaches developed for joint analysis are based on summary statistics, the joint analysis based on individual-level data with consideration of confounding factors remains to be a challenge. In this study, we propose a method, called Coupled Mixed Model (CMM), that enables a joint GWAS analysis on two independently collected sets of GWAS data with different phenotypes. The CMM method does not require the data sets to have the same phenotypes as it aims to infer the unknown phenotypes using a set of multivariate sparse mixed models. Moreover, CMM addresses the confounding variables due to population stratification, family structures, and cryptic relatedness, as well as those arising during data collection such as batch effects that frequently appear in joint genetic studies. We evaluate the performance of CMM using simulation experiments. In real data analysis, we illustrate the utility of CMM by an application to evaluating common genetic associations for Alzheimer's disease and substance use disorder using datasets independently collected for the two complex human disorders. Comparison of the results with those from previous experiments and analyses supports the utility of our method and provides new insights into the diseases. The software is available at https://github.com/HaohanWang/CMM .


HCN ice in Titan's high-altitude southern polar cloud.
Titan's middle atmosphere is currently experiencing a rapid change of season after northern spring arrived in 2009 (refs 1, 2). A large cloud was observed for the first time above Titan's southern pole in May 2012, at an altitude of 300 kilometres. A temperature maximum was previously observed there, and condensation was not expected for any of Titan's atmospheric gases. Here we report that this cloud is composed of micrometre-sized particles of frozen hydrogen cyanide (HCN ice). The presence of HCN particles at this altitude, together with temperature determinations from mid-infrared observations, indicate a dramatic cooling of Titan's atmosphere inside the winter polar vortex in early 2012. Such cooling is in contrast to previously measured high-altitude warming in the polar vortex, and temperatures are a hundred degrees colder than predicted by circulation models. These results show that post-equinox cooling at the winter pole of Titan is much more efficient than previously thought.


[Study of the antitumor activity of carminomycin in malignant tumors in children (a preliminary report)].
Side reactions and therapeutic effect of carminomycin were studied in 21 children with various malignant tumors. Carminomycin was administered intravenously in doses of 0.15-0.2 mg/kg twice a week for 2-3 weeks. The treatment courses were repeated in a month. The drug was better tolerated by children than by adults. After the treatment course leucopenia may develop. When used alone or in combination with vincristin or cyclophosphan carminomycin proved to be effective in treatment of sarcoma of the soft tissues (liposarcoma, synovial sarcoma), chondrosarcoma and reticulosarcoma.