Aerotaxis by the freshwater oligochaete Tubifex sp.
1. The influence of oxygen on the direction of movement (aerotaxis) by the freshwater oligochaete, Tubifex sp., was investigated by monitoring the behaviour of adult animals in different oxygen gradients. 2. The results show that Tubifex expresses negative aerotaxis, i.e. moves away from oxygen, with preference for anoxia. 3. The time course of Tubifex movements in oxygen gradients shows that the mechanism of aerotaxis is both sensitive and fast. This suggests that Tubifex possesses some kind of oxygen sensor by means of which it is able to recognize even small oxygen gradients.


Comparison of extended esophagectomy through mini-thoracotomy/laparotomy with conventional thoracotomy/laparotomy for esophageal cancer.
In order to assess the usefulness of esophagectomy through mini-thoracotomy/laparotomy as a minimally invasive surgical procedure for esophageal cancer, we compared the results to those of conventional right thoracotomy/laparotomy. From 1998 to 2002, 40 patients with thoracic esophageal cancer were prospectively assigned to two groups. Twenty patients underwent esophagectomy through mini-thoracotomy/laparotomy (M-group), while the other 20 had conventional thoracotomy/laparotomy (C-group). Surgical complications, the duration of the systemic inflammatory response syndrome (SIRS), postoperative pain, cytokine responses, and respiratory function were compared between the two groups. There was no difference of morbidity between the M- and C-groups after surgery. There were also no differences between the two groups with respect to the operating time, bleeding, and number of dissected lymph nodes. The duration of SIRS was shorter in the M-group than in the C-group (p = 0.055). Use of morphine was lower in the M-group than in the C-group with patient-controlled anesthesia (p = 0.002). The interleukin-6 level of the M-group was lower than that of the C-group at 3, 6 hours, and 3 days after the operation. Recovery of vital capacity by the M-group was better than by the C-group after the operation. Postoperative hospital stay of the M-group was significantly shorter than that of the C-group (p = 0.014). Long-term survival was not different in the two groups. Mini-thoracotomy/laparotomy reduces invasiveness and pain compared with conventional thoracotomy/laparotomy for esophagectomy without causing any differences of morbidity or long-term survival.


An unusual cause of blocked reduction of the Galeazzi injury.
Two cases of the Galeazzi lesion are described, in which a mechanical block to closed reduction of the dislocated inferior radio-ulnar joint was encountered. This does not seem to have been described before.


Approach to Immunization for the Traveling Child.
Children are traveling to regions of the world that could pose a risk of acquiring diseases such as malaria, dermatosis, and infectious diarrhea. Most of these can be prevented by modifying high-risk behaviors or through the use of medications. Many of these same regions are endemic with diseases that are preventable through vaccination. Clinicians must be able to effectively prepare their pediatric-age travelers for international travel. Preventive education, prophylactic and self-treating medications, and vaccinations are all important components of this preparation. Familiarity with the use of travel vaccines is imperative.


Surgical ampullectomy with resection of the common bile duct for biliary papillomatosis.
Intraductal papillary neoplasm of the bile duct (IPNB) or biliary papillomatosis is a precursor lesion of papillary cholangiocarcinoma.1 IPNB is recognized as a biliary counterpart of IPMN (pancreatic intraductal papillary mucinous neoplasm). IPNB is a rare disease involving entire (diffuse type) or one part (localized type) of biliary tree. Patients without distant metastasis are considered for surgical resection. For patients with distal bile duct papillomatosis, pancreaticoduodenectomy (PD) is recommended for patients with invasive distal bile duct IPNB. PD is a high complex procedure associated with the deterioration of endocrine and exocrine functions leading to a significant impact on quality of life.2 Some authors have reported a new surgical approach leading to a complete resection of the common bile duct without pancreatectomy.3 METHODS: We report the case of a 71-year-old female presented to our department with jaundice. At endoscopic ultrasound with cholangioscopy and CT scan, 2-cm distal bile duct mass tumor with villous component was seen. All needle biopsies were benign, and no distant disease was found. According to the risk of degeneration of this tumor, a surgical resection was decided. Intraoperative frozen section assessed the benignity of peripancreatic lymph nodes. We performed surgical ampullectomy with resection of the common bile duct. The intrapancreatic common bile duct was completely mobilized between the ampullectomy area and the upper edge of the pancreas. Frozen sections on distal and proximal margins of common bile duct were performed to discard malignancy. Finally, reconstruction consisted on the main pancreatic duct reimplantation to the duodenum and choledochoduodenostomy. The histological analysis confirmed the diagnosis of biliary papillomatosis with low-grade dysplasia. This procedure allows complete resection of benign tumors with endobiliary extension and preserve intestinal continuity and pancreatic parenchyma.


Autologous chondrocyte transplantation of the ankle.
Autologous chondrocyte transplantation has been used in the treatment of chondral and osteochondral lesions in a limited number of patients. The results are promising over a medium-length follow-up (2-6 years). Deeper involvement of the subchondral bone may need autologous bone grafting along with ACT. Future long-term, comparative studies are needed to evaluate the efficacy and safety of the treatment.


The genotoxicity and systemic toxicity of a pharmaceutical effluent in Wistar rats may involve oxidative stress induction.
There is scarcity of information on the possible mechanisms of pharmaceutical effluent induced genotoxicity and systemic toxicity. This study investigated the genotoxicity and systemic toxicity of a pharmaceutical effluent in Wistar rats. Rats were orally treated with 5-50% concentrations of the effluent for 28 days. At post-exposure, blood, liver, kidney and bone marrow cells were examined for alterations in serum biochemical parameters and hematological indices, histopathological lesions and micronucleated polychromatic erythrocytes formation (MNPCE). The effluent caused concentration independent significant (p < 0.05) alterations in aspartate (AST) and alanine (ALT) aminotransferases, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), total and direct bilirubin and creatinine. There was reduction in red blood count (RBC), hemoglobin concentration (HGB), platelets, percentage hematocrit (HCT), white blood count (WBC) and mean corpuscle hemoglobin (MCH) except mean corpuscle hemoglobin concentration (MCHC), which increased in the treated rats. Histopathological lesions observed in the liver and kidney of the effluent treated rats were thinning of the hepatic cord, kuffer cell hyperplasia, vacuolation of the hepatocytes and renal cells, multifocal inflammatory changes, necrosis and congestion of the renal blood vessels and central vein. MNPCE significantly increase in the bone marrow of the treated rats compared to the negative control. The concentration of some toxic metals and anions in the effluent were above standard permissible limits. These findings showed that the pharmaceutical effluent caused somatic DNA damage and systemic toxicity in rats may involve induction of oxidative stress, suggesting environmental contamination and health risks in wildlife and humans.


Instrumented Versus Uninstrumented Posterolateral Fusion for Lumbar Spondylolisthesis: A Randomized Controlled Trial.
In Scandinavia, spinal fusion is frequently performed without instrumentation, as use of instrumentation in the elderly can be complicated by poor bone quality and the risk of screw pull-out. However, uninstrumented fusion carries the risk of nonunion. We performed a randomized controlled trial in an attempt to determine if use of instrumentation leads to better outcomes and fusion rates when spinal fusion is performed for degenerative spondylolisthesis in the elderly. This was a randomized, single-center, open-label trial of patients with symptomatic single-level degenerative spondylolisthesis who were assigned 1:1 to decompression and fusion with or without instrumentation after at least 12 weeks of nonoperative treatment had failed. The primary outcome was the change in the Oswestry Disability Index (ODI), and secondary outcomes included fusion rates within 1 year, reoperation rates within 2 years, and changes in the EuroQol-5 Dimension-3 Level (EQ-5D) score. Fifty-four subjects were randomized to each of the 2 groups, which had similar preoperative demographic and surgical characteristics. We found similar improvements in the ODI (p = 0.791), back pain, leg pain, and quality of life between groups at 1 and 2 years of follow-up. Solid fusion on computed tomography (CT) scans was noted in 94% of the patients in the instrumented group and 31% in the uninstrumented group (p < 0.001). One patient (2%) in the instrumented group and 7 (13%) in the uninstrumented group (p = 0.031) had a reoperation within 2 years after the index surgery. We found no difference in patient-reported outcomes when we compared instrumented with uninstrumented fusion in patients with degenerative spondylolisthesis. The uninstrumented group had a significantly higher rate of nonunion and reoperations at 2 years. Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.


Realization and potential advantages of gradient separations performed under steady state temperature regime.
This paper describes a new method designed to perform gradient separations while keeping constant the distribution of temperature throughout the column during the three phases of a gradient run (the ramp up of the strong eluent concentration, the column wash, and the re-equilibration steps) in high pressure liquid chromatography (vHPLC). The method is based on the solution of the integrated heat balance equation along the column knowing the variations of the eluent specific heat, its thermal expansion coefficient, and its viscosity with the concentration of the strong eluent. This new method is called gradient under constant wall heat (cWH). Its value is demonstrated by the stability of the eluent temperature at the column outlet during a series of consecutive gradient runs. The potential advantages of cWH gradients over classical gradients execution mode at constant flow rate (cF) are illustrated in the example of two such gradients run in the same time. They include (1) a diminution by a factor 8 of the largest temperature variation during the sequence of injections (0.4°C versus 3.2°C); (2) a reduction of the baseline noise by a factor two (0.05mAU versus 0.10mAU); and (3) the achievement of an excellent injection-to-injection repeatability of the vHPLC system used to measure the first (average RSDs, 0.04%) and the second central (average RSDs≃0.75%) moments of the peaks of an eight-compounds mix, baseline separated, from the first to the last injection.


Pigmentation abnormalities in Coffin-Siris syndrome.
Pigmentary abnormalities in Coffin-Siris Syndrome should be considered as part of the wide phenotypical spectrum of this patients.


A device-based stretch training for office workers resulted in increased range of motion especially at limited baseline flexibility.
It is unclear whether and under which conditions stretch training programs lead to gains in flexibility when applied in work health promotion for office workers in order to reduce musculoskeletal disorders (MSD). The aim of this study was to analyze whether the stretch training "five-Business" leads to gains in range of motion (ROM). Furthermore, the influence of baseline flexibility and socio-demographic factors (sex, age, weight, height and body mass index (BMI)) on trainability was assessed. 161 office workers (n = 45 female; n = 116 male) without major MSD were recruited. Over three months, a standardized static stretch training ("five-Business") was executed on a device, supervised twice per week for 10 min. ROM was assessed using a digital inclinometer (shoulder, hip and trunk extension) and a tape measure (fingertip-to-floor and lateral inclination). ROM gains (p≤0.001) were present in all tests, except for the hip extension. ROM changes correlated moderately (0.24-0.62) with the baseline flexibility (p≤0.001). Subjects with limited flexibility reached the largest gains (1.41-25.33%). Regarding the socio-demographic factors only one low correlation occurred (weight - retroflexion; -0.177). The "five-Business" stretch training effectively increases ROM in office workers, especially when baseline flexibility is limited.


Comparison of varying operating parameters on heavy metals ecological risk during anaerobic co-digestion of chicken manure and corn stover.
In this study, the potential ecological risk of heavy metals (Mn, Zn, Cu, Ni, As, Cd, Pb, Cr) accumulation from anaerobic co-digestion of chicken manure (CM) and corn stover (CS) was evaluated by comparing different initial substrate concentrations, digestion temperatures, and mixture ratios. Results showed that the highest volumetric methane yield of 20.3±1.4L/L reactor was achieved with a CS:CM ratio of 3:1 (on volatile solid basis) in mesophilic solid state anaerobic digestion (SS-AD). Although co-digestion increased the concentrations of all tested heavy metals and the direct toxicity of some heavy metals, the potential ecological risk index indicated that the digestates were all classified as low ecological risk. The biogasification and risk variation of heavy metals were affected by the operating parameters. These results are significant and should be taken into consideration when optimizing co-digestion of animal manure and crop residues during full-scale projects.


Serum electrolyte abnormalities in pediatric patients presenting to an emergency department with various diseases: Age-related differences.
This study evaluated the prevalence and frequency of serum electrolyte abnormalities (SEAs) in children presenting to a pediatric emergency department (PED) with various diseases. Pediatric patients (≤18 years) with blood electrolyte panels obtained in the PED of Lin-Kou Chang Gung Memorial Hospital, Taiwan, in the 5 years from January 1, 2016, to August 31, 2021, were enrolled in this retrospective observational study. Patients were divided into three age groups: Group A, < 4 years; Group B, 4-11 years; and Group C, 12-18 years. The associations between SEAs and clinical diseases in children and age-related differences were assessed. This study included 182,058 pediatric patients visiting our PED over a 5-year period. A total of 250 (0.14%) patients with SEAs were included in the analysis. The study population consisted of 127 boys and 123 girls with a median (IQR) age of 9.0 (3.2-14.1) years. Hospital admission was required in 86.4% (n = 216) of the patients, and 32.4% (n = 81) of them were admitted to the pediatric intensive care unit (PICU). The median (IQR) hospital stay and PICU stay was 6.5 (4.0-11.0) and 4.0 (3.0-8.0) days, respectively. The PICU stay was longer in Group A (p < 0.05) and shorter in group C (p < 0.05). Hyponatremia was the most common SEA in group A (46.3%, n = 31), while hypokalemia was common in groups B (54.2%, n = 52) and C (32.2%, n = 28). Gastrointestinal, renal, and endocrine diseases were common clinical conditions associated with SEAs in pediatric patients in our PED. The detection rate of SEAs in patients in the PED was 0.14%. Hyponatremia was a common SEA in pediatric patients aged <4 years, while the most common electrolyte disorder in those >4 years old was hypokalemia. In infants and young children, SEAs were associated with a longer PICU stay.


In vitro inhibition of feline leukaemia virus infection by synthetic peptides derived from the transmembrane domain.
The feline leukaemia virus (FeLV) is a gammaretrovirus commonly affecting cats. Infection with this virus often leads to fatal outcomes and, so far, no cure is available for this disease. Synthetic peptides with structures mimicking the transmembrane protein of the viral surface proteins hold the potential to effectively interfere with viral entry by hampering the fusion of viral and host cell membranes and constitute a novel approach for the treatment of infections with retroviruses. We identified and synthetically produced 11 FeLV peptides and evaluated their potential to block FeLV infection in vitro. Cell cultures were exposed to FeLV subgroup A prior to the addition of the peptides. The inhibitory effect of the peptides was assessed by measuring FeLV gag protein in the supernatant of peptide versus mock-treated cell cultures using an ELISA. A peptide (EPK364) of 37 amino acids in length, with sequence homology to the HIV fusion inhibitor T-20, significantly suppressed viral replication by 88%, whereas no effects were found for shorter peptides. Two structurally modified variants of EPK364 also inhibited viral replication by up to 58% (EPK397) and 27% (EPK398). Our data support the identification of synthetic FeLV peptides that have the potential for a curative short-term therapy of viraemic cats. In addition, these peptides might become an important tool in xenotransplantation, where endogenous gammaretroviruses of the donor species might be able to infect the host.


Pleiotropic effects of BDNF on the cerebellum and hippocampus: Implications for neurodevelopmental disorders.
Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the mammalian brain, essential not only to the development of the central nervous system but also to synaptic plasticity. BDNF is present in various brain areas, but highest levels of expression are seen in the cerebellum and hippocampus. After birth, BDNF acts in the cerebellum as a mitogenic and chemotactic factor, stimulating the cerebellar granule cell precursors to proliferate, migrate and maturate, while in the hippocampus BDNF plays a fundamental role in synaptic transmission and plasticity, representing a key regulator for the long-term potentiation, learning and memory. Furthermore, the expression of BDNF is highly regulated and changes of its expression are associated with both physiological and pathological conditions. The purpose of this review is to provide an overview of the current state of knowledge on the BDNF biology and its neurotrophic role in the proper development and functioning of neurons and synapses in two important brain areas of postnatal neurogenesis, the cerebellum and hippocampus. Dysregulation of BDNF expression and signaling, resulting in alterations in neuronal maturation and plasticity in both systems, is a common hallmark of several neurodevelopmental diseases, such as autism spectrum disorder, suggesting that neuronal malfunction present in these disorders is the result of excessive or reduced of BDNF support. We believe that the more the relevance of the pathophysiological actions of BDNF, and its downstream signals, in early postnatal development will be highlighted, the more likely it is that new neuroprotective therapeutic strategies will be identified in the treatment of various neurodevelopmental disorders.


Plasma electrolyte concentration in food-deprived goats orally supplemented with potassium chloride.
The aim of the present study was to investigate whether oral potassium supplementation during food deprivation could stimulate rumen electrolyte absorption and maintain plasma electrolyte concentration. Eight goats were subjected to food deprivation in combination with intrarumen loads of potassium chloride or, as a control, mannitol in a change-over design. In addition, four KCl- and four mannitol-treated goats were given an extra KCl load towards the end of the experiment. Food-deprived goats which were given KCl maintained their plasma concentration of Na and Cl, while plasma K concentration increased from 3.6 mM to 4.4 mM. In control goats receiving mannitol during food deprivation, the plasma concentration (mM) decreased from 144 to 140 for Na, 105 to 100 for Cl and from 3.8 to 3.6 for K, but concentrations were restored when these goats were given a load of KCl. The plasma renin activity was suppressed in food-deprived goats receiving KCl, while those given mannitol showed increased activity. It is suggested that the hyponatraemia which occurs in food-deprived ruminants is mainly caused by diminished K intake.


Hydrogen-deuterium exchange studies on guanidinated pig heart lactate dehydrogenase.
Pig heart lactate dehydrogenase becomes more thermostable on increasing the degree of guanidination (conversion of lysine to homoarginine) (Minotani, N., Sekiguchi, T., Bautista, J.G. and Nosoh, Y. (1979) Biochim. Biophys. Acta 581, 334-341). The conformational change of the protein on guanidination was then examined by hydrogen-deuterium (H-2H) exchange reactions. It ws found that (i) the fluctuation degrees of peptides and tyrosine and tryptophan residues in the protein decrease in that order, (ii) two H-2H exchangeable tryptophan residues per subunit are freely accessible to solvent and the fluctuation degrees of the residues does not change on guanidination, (iii) the H-2H exchange detectable tyrosine residues are not freely accessible to solvent and become less fluctuating when 15 lysine residues per subunit are guanidinated, and (iv) the peptides become much less fluctuating on increasing the degree of guanidination. The specific activity of the enzyme decreased on guanidination. The increased thermostability of the protein on guanidination may be related to the decrease in flexibility of the molecular structure by sacrificing the enzyme activity.


The efficacy of guanfacine in reducing perioperative hemodynamic changes and volatile anesthetic requirement.
To evaluate the efficacy of guanfacine, an alpha 2-adrenergic agonist, for attenuating hemodynamic changes associated with tracheal intubation or extubation, providing intraoperative hemodynamic stability, and reducing inhalation anesthetic requirement in patients undergoing gynecologic surgery. Randomized, double-blind, placebo-controlled study. Inpatient gynecology at a university hospital. 45 women (ASA I) undergoing elective abdominal hysterectomy. Guanfacine and placebo supplementation. Oral guanfacine at 0.5 or 1 mg or a placebo (control) 3 hours before induction of anesthesia. Anesthesia was induced with thiamylal 5 mg/kg and vecuronium 0.2 mg/kg, and maintained with isoflurane and 50% nitrous oxide (N2O) in oxygen. The inspired isoflurane concentration was maintained at 1% during the first 5 minutes following induction of anesthesia and titrated to the concentration required to maintain hemodynamic stability [defined as +/- 10% of systolic blood pressure (SBP)]. The end-tidal concentration of isoflurane was monitored throughout anesthesia. On completion of surgery, N2O and isoflurane were discontinued. Following confirmation of recovery from anesthesia and muscle relaxation, the endotracheal tube was removed. Patients in the control group showed significant increases in SBP and diastolic blood pressure (DBP) and heart rate (HR) associated with tracheal intubation 50 +/- 5, 57 +/- 6.3, and 45 +/- 4.6 (%, mean +/- SEM, p < 0.05 for any variables), respectively. Plasma norepinephrine and epinephrine concentrations increased to 382 +/- 40 pg/ml and 49 +/- 4.2 pg/ml, respectively (p < 0.05 compared with basal values). These changes were attenuated in patients receiving 1 mg of guanfacine (29 +/- 4.2, 33 +/- 4.5, 25 +/- 3.2, 210 +/- 32, and 22 +/- 3.5, respectively (p < 0.05 for any variables compared with placebo group). Higher inspired concentrations of isoflurane (%) were required in the control and 0.5 mg guanfacine-treated groups (1.2 +/- 0.05 and 1.0 +/- 0.04, respectively) than in the 1 mg guanfacine-treated group (0.62 +/- 0.03) for hemodynamic stability (p < 0.05). Coefficient of variation in HR changes during surgery was 17.2, 13.9, and 8.8 in the placebo, guanfacine 0.5 mg, and guanfacine 1 mg treated groups, respectively. Compared with placebo, guanfacine 1 mg reduced the maximum changes (mean +/- SEM) in SBP (7 +/- 1.2 vs. 18 +/- 2.2) and in HR (23 +/- 2.1 vs. 44 +/- 3.6) occurring during tracheal extubation. The incidence of perioperative complications was similar among the three groups. Guanfacine 1 mg administered orally proved to be an effective premedicant for providing intraoperative hemodynamic stability, attenuating the increase in BP and HR associated with tracheal intubation and extubation, and reducing anesthetic requirements without increasing the incidence of perioperative complications.


Low-level laser therapy for treatment of temporomandibular joint pain: a double-blind and placebo-controlled trial.
The objective of this study was to assess the effectiveness of low-level laser therapy (LLLT) in the management of temporomandibular joint (TMJ) pain in a random and double-blind research design. TMJ pain patients, randomly assigned, received 2 to 3 treatments per week for 8 weeks of active LLLT (Helium Neon, 632.8 nm, 30 mW) (n = 26) or sham LLLT (n = 26). Measures of TMJ pain during function were evaluated at baseline and weeks 2, 4, and 8 after the first laser therapy. At the 8-week point, within-group improvements were present for TMJ pain during function, for both the active and sham LLLT groups (P = .000). Between-group differences were not highly evident (P > .05). The study suggests that LLLT is not better than placebo at reducing TMJ pain during function.


Effect of 10% cerium chloride on artificial caries lesions of human enamel evaluated using quantitative light-induced fluorescence: an in vitro study.
To evaluate the effect of 10% cerium chloride intervention on pre-demineralised human enamel subjected to cycles of de- and remineralisation. This was an in vitro, comparative type study of 60 human enamel samples that were randomly divided into control and test groups. The samples were then subjected to a cycle of demineralisation followed by intervention with respective treatment solutions (control group: placebo solution; test: 10% cerium chloride) for 30 s under constant agitation and then to a 2nd cycle of demineralisation followed by remineralisation using artificial saliva. After the first and second cycles of demineralisation (4th and 8th day) and a cycle of remineralisation (22nd day), the samples were evaluated for fluorescence values using a quantitative light-induced fluorescence camera. The data was analysed using paired t test and ANOVA. Comparing the fluorescence values and mean difference of lesion area between the first cycle of demineralisation to the cycle of remineralisation and the second cycle of demineralisation to the cycle of remineralisation, the test group showed a statistically significant reduction in loss of fluorescence values and lesion area compared to the control group (p < 0.001). Mean fluorescence values and lesion area comparison between cycles of de- and remineralisation for control and test groups (inter-group comparison) showed a statistically significant difference (p < 0.001). Cerium chloride alone reduced demineralisation and improved remineralisation of artificial caries lesions in human enamel when subjected to pH cycling in vitro.


The chromodomain helicase Chd4 is required for Polycomb-mediated inhibition of astroglial differentiation.
Polycomb group (PcG) proteins form transcriptional repressor complexes with well-established functions during cell-fate determination. Yet, the mechanisms underlying their regulation remain poorly understood. Here, we extend the role of Polycomb complexes in the temporal control of neural progenitor cell (NPC) commitment by demonstrating that the PcG protein Ezh2 is necessary to prevent the premature onset of gliogenesis. In addition, we identify the chromodomain helicase DNA-binding protein 4 (Chd4) as a critical interaction partner of Ezh2 required specifically for PcG-mediated suppression of the key astrogenic marker gene GFAP. Accordingly, in vivo depletion of Chd4 in the developing neocortex promotes astrogenesis. Collectively, these results demonstrate that PcG proteins operate in a highly dynamic, developmental stage-dependent fashion during neural differentiation and suggest that target gene-specific mechanisms regulate Polycomb function during sequential cell-fate decisions.


Cell-mediated defense against Yersinia pestis infection.
Yersinia pestis (Yp)--one of the world's most deadly human pathogens--is the gram-negative bacterium that causes pneumonic plague. Virulent antibiotic-resistant Yp strains exist and Cold War scientists devised means to effectively aerosolize Yp. These facts raise grave concern that Yp will be exploited as a bioweapon. To counter that possibility, it is essential that we develop a safe and effective pneumonic plague vaccine. Recent studies suggest that the leading vaccine candidate, which primarily stimulates antibody-mediated humoral immunity, may not suffice. T cell-dependent cellular immunity comprises a second means by which vaccines prime long-lived protection against virulent bacterial pathogens. However, a plasmid carried by virulent Yp encodes factors that dampen inflammation and debilitate phagocytes, thereby compromising cellular defense mechanisms. As such, plague vaccine researchers have devoted relatively little attention to cellular immunity. Here we review our recent work demonstrating that the passive transfer of primed T cells can suffice to protect mice against lethal intranasal Yp infection, a model of pneumonic plague. We also demonstrate that key elements of cellular immunity even play critical roles during antibody-mediated defense against plague. We conclude that next-generation plague vaccines should strive to prime both cellular and humoral immunity.


Fusion proteins and select lipids cooperate as membrane receptors for the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vam7p.
Vam7p, the vacuolar soluble Qc-SNARE, is essential for yeast vacuole fusion. The large tethering complex, homotypic fusion and vacuole protein sorting complex (HOPS), and phosphoinositides, which interact with the Vam7p PX domain, have each been proposed to serve as its membrane receptors. Studies with the isolated organelle cannot determine whether these receptor elements suffice and whether ligands or mutations act directly or indirectly on Vam7p binding to the membrane. Using pure components that are active in reconstituted vacuolar fusion, we now find that Vam7p binds to membranes through its combined affinities for several vacuolar membrane constituents: HOPS, phosphatidylinositol 3-phosphate, SNAREs, and acidic phospholipids. Acidic lipids allow low concentrations of Vam7p to suffice for fusion; without acidic lipids, the block to fusion is partially bypassed by high concentrations of Vam7p.


Exit time of turbulent signals: a way to detect the intermediate dissipative range.
The exit-time statistics of experimental turbulent data is analyzed. By looking at the exit-time moments (inverse structure functions) it is possible to have a direct measurement of scaling properties of the laminar statistics. It turns out that the inverse structure functions show a much more extended intermediate dissipative range than the structure functions, leading to the first clear evidence of the existence of such a range of scales.


Association of fine particulate matter and its constituents with hypertension: the modifying effect of dietary patterns.
Studies have shown that nutritional supplements could reduce the adverse effects induced by air pollution. However, whether dietary patterns can modify the association of long-term exposure to fine particulate matter (PM2.5) and its constituents with hypertension defined by the 2017 ACC/AHA guideline has not been evaluated. We included 47,501 Chinese adults from a nationwide cross-sectional study. PM2.5 and five constituents were estimated by satellite-based random forest models. Dietary approaches to stop hypertension (DASH) and alternative Mediterranean diet (AMED) scores were calculated for each participant. Interactions between dietary patterns and air pollution were examined by adding a multiplicative interaction term to logistic models. Long-term exposure to PM2.5 and its constituents was associated with an increased risk of hypertension and stage 1-2 hypertension. The DASH and AMED scores significantly modified these associations, as individuals with higher scores had a significantly lower risk of air pollution-related hypertension and stage 1-2 hypertension (P-interaction < 0.05), except for interaction between PM2.5, sulfate, nitrate, ammonium, and AMED score on stage 1 hypertension. For each IQR increase in PM2.5, participants with the lowest DASH and AMED quintiles had hypertension risk with ORs (95%CI) of 1.20 (1.10, 1.30) and 1.19 (1.09, 1.29), whereas those with the highest DASH and AMED quintiles had lower risks with 0.98 (0.91, 1.05) and 1.04 (0.97, 1.11). The stratified analysis found modification effect was more prominent in the < 65 years age group. Consuming more fresh vegetables, fruits, whole grains, and dairy would reduce the risk of hypertension caused by PM2.5 and its constituents. Dietary patterns rich in antioxidants can reduce long-term exposure to PM2.5 and its constituents-induced hypertension defined by the 2017 ACC/AHA guideline, especially in young and middle-aged individuals. Compared to the Mediterranean diet, the DASH diet offers superior dietary guidance to prevent stage 1 hypertension caused by air pollution.


Floristic composition and plant community distribution along environmental gradients in Guard dry Afromontane forest of Northwestern Ethiopia.
Dry evergreen montane forests of Ethiopia provide economic and ecological services for the community but it is under several threats of natural and anthropogenic disturbances. The study aimed to investigate the floristic composition, species diversity, and plant community distribution of Guard forest along environmental gradients. A systematic sampling technique was used to collect vegetation and environmental data. Fifty eight plots each with 400 m2 (20 m X 20 m) were established for trees and shrubs and 2 m x2m (4 m2) for herbs along eleven transect lines. Shannon Weiner diversity index and evenness were used to assess the species diversity and richness. The similarities among plant communities were computed using Sorenson's similarity index. The plant community types and vegetation-environment relationships were analyzed using hierarchical cluster analysis and Canonical correspondence analysis (CCA) in R software, respectively. A total of 137 plant species belonging to 111 genera and 55 families were identified. The most dominant families in the study area were Fabaceae and Asteraceae. Among the total plant species documented in the forest, 42(30.65%) were trees, 36 (26.28%) were shrubs, 48(35.04%) were herbs, and 11 (8.03%) were climbers. Of the total species, 14(10.22%) species are endemic to Ethiopia and Eritrea. Three plant community types were identified by cluster analysis. The Shannon-Weiner Diversity Index was 3.39 and evenness was 0.87 for the forest. The pattern of plant species distribution was significantly influenced by altitude, pH, BD, slope, and charcoal (P < 0.05). Guard forest has good species diversity and richness, and supports different endemic plant species that show the potential of the area to support useful but some of the characteristics species are not found in the forest and others are rare in their existence due to the presence of disturbances and need immediate conservation to ensure sustainable use and management of the forest.


Critical nucleotides in the upstream region of the XylS-dependent TOL meta-cleavage pathway operon promoter as deduced from analysis of mutants.
The Pm promoter, dependent on TOL plasmid XylS regulator, which is activated by benzoate effectors, drives transcription of the meta-cleavage pathway for the metabolism of alkylbenzoates. This promoter is unique in that in vivo transcription is mediated by RNA-polymerase with different sigma factors. In vivo footprinting analysis shows that XylS interacted with nucleotides in the -40 to -70 region. In vivo and in vitro methylation of Pm shows extensive methylation of T at position -42 in the bottom strand, suggesting that it represents a key distortion point that may favor XylS/RNA polymerase interactions. Methylation of T-42 was highest in cells bearing XylS and in the presence of an effector. Gs in the -47 to -61 region appeared to be more protected in cells harboring XylS in the presence than in the absence of the effector. Almost 100 mutants in the Pm region between -41 and -78 were generated; transcriptional analysis of these mutants defined the XylS target as two direct repeats with the sequence TGCAN6GGNCA. These motifs cover the -70 to -56 and the -49 to -35 regions. Single point mutations revealed that nucleotides located at -49 to -46 and at -59, -60, -62, and -70 are the most critical for appropriate XylS-Pm interactions.


[Phalloidin counteracts the destructive effects of osmic acid and potassium permanganate on F-actin (author's transl)].
Osmium tetroxide and potassium permanganate destroy F-actin filaments in vitro, and split actin molecules into smaller peptides. It is shown by viscometry, spectrophotometry, electrophoresis and electron microscopy that the destruction of F-actin by these agents is inhibited by phalloidin. Other proteins are unprotected.


Immunoenzymatic method for detection of terminal deoxynucleotidyl transferase by light and electron microscopy.
Methods for using rabbit polyclonal and mouse monoclonal antibodies to detect terminal deoxynucleotidyl transferase (TdT) in human leukemia lines were developed. Use of 1% paraformaldehyde in 0.1 M Na cacodylate buffer, pH 7.6, as a fixative provides a procedure that can be used for immunofluorescence, immunoalkaline phosphatase (APAAP), or horseradish peroxidase conjugate detection procedures in these cell lines. The peroxidase procedure can also be used for electron microscopy, clearly demonstrating nuclear localization of TdT in interphase nuclei of TdT-positive cells.


Association between kharra chewing and periodontal health status in oral submucous fibrosis patients of Central India, Nagpur.
Kharra is a mixture of areca nut and tobacco. Arecoline, an areca nut extract, disrupts the harmony of the periodontal cells and thus leads to destruction of the periodontium. Oral submucous fibrosis (OSMF) is a premalignant condition that arises due to the consumption of kharra. The aim of this study was to evaluate and compare the effects of kharra chewing on periodontal status in patients with OSMF. Forty-five patients were divided into Group I: healthy periodontium (n = 15), Group II: chronic periodontitis without OSMF group (n = 15), and Group III: chronic periodontitis with OSMF group (n = 15). The clinical parameters assessed for patients with chronic periodontitis were gingival index (GI), plaque index (PI), probing pocket depth (PPD; overall and regional) ≥3 mm, and clinical attachment level (CAL; overall and regional) ≥3 mm. For patients in Group III, the OSMF diagnosis and staging were based on Khanna's classification. The level of significance was set at P < 0.05. The sample with a mean age of 35 years had a frequency of chewing kharra >6 times per day for at least 3 years. PI, PPD and CAL in Group III were 2.1 ± 0.4, 3.2 ± 0.6, and 4.8 ± 0.6 mm, respectively. the results of the clinical parameters in Group III and Group II were higher than Group I. GI was higher in Group II as compared to the other groups. The habit of chewing kharra is found to be associated with poor periodontal health in patients with OSMF.


Higher treatment effect after total knee arthroplasty is associated with higher patient satisfaction.
The aim of this study was to investigate what influence the treatment effect after total knee arthroplasty (TKA) had on patient satisfaction. Prospective registry data of a University-based arthroplasty centre were used. 582 patients with unilateral bicondylar TKA were analyzed. Treatment effect (TE) was deduced from Oxford Knee Score (OKS) before and one year after surgery. Positive values correspond to improved symptoms (maximum 1.0 reflect no symptoms at all) and negative values correspond to deterioration of symptoms. Satisfaction on a visual-analogue scale from 0 to 10 and the willingness to undergo TKA surgery again was assessed one year after surgery. The mean OKS improved from 22.1 before to 36.7 one year after TKA. Treatment effects ranged from 1.0 to -0.62 with a mean TE of 0.56. Taking an individual treatment effect of 0.2 as a cut-off between responder and non-responder, a total of 85.8% would be classified as responder after TKA. The mean satisfaction score with the TKA was 8.1. There was a significant correlation between the individual treatment effect and satisfaction after TKA (p < 0.001). The majority of patients (84.5%) would undergo surgery again. Patients not willing to undergo surgery again or those uncertain about this had lower satisfaction scores, a lower treatment effect and were more often female compared to patients who would undergo surgery again. Higher individual treatment effects resulted in higher patient satisfaction and willingness to undergo surgery again. However, some patients with a relatively low treatment effect were highly satisfied, which indicates the need for both information. II.


Epstein-Barr virus (EBV) antibody in patients treated by radical radiotherapy for head and neck cancer.
Antibody against Epstein Barr Viral capsid (EBV-VCA) was measured in 65 patients with primary head and neck cancer referred for radical radiotherapy. Sixty-three percent had locally advanced cancer and 37% had early disease. Forty-eight percent had detectable antibody in their sera. Thirty-three percent had elevated titers (above 1:20 dilution). Only 19% of cases with early cancer had increased titers. Almost 50% of those with locally advanced cancer or recurrence following treatment had titers above 1:20. A rise in titer within six months following radiotherapy was associated with a significant incidence of recurrence. There was no correlation between delayed hypersensitivity skin reaction to 2--4 dinitrochlorobenzene (DNCB) and titer values. EBV-VCA may be an additional parameter which can be used to determine host defenses in patients with malignancies.


Seed bank versus seed rain in the regeneration of a tropical pioneer tree.
We used the tropical pioneer tree, Cecropia obtusifolia to evaluate the relative importance of different sources of seeds in the regeneration of species that depend on ephemeral sites. We studied seed production in a population established in a 5 ha plot, and dispersal, dormancy and seed predation in two recent treefall gaps (<1 year-old), two building or successional forest patches (10-15 since disturbed), and two mature forest patches (>35 years since disturbed) for a one year period at Los Tuxtlas (Mexico). Flowers and fruits were counted at monthly intervals. Annual fecundity per tree ranged from 1.4×104 to 1.4×107 seeds. Seeds were continuously available on the trees and on the ground. Average annual seed rain per m2 (as measured by 0.5×0.5 m seed traps) varied from 184 to 1925 among the six sites. Distance to nearest seed source and patch type explained more than 60% of the seed rain variation among sites. Soil seed density, estimated by counting seeds from ten samples (78.5 cm2×10 cm deep) collected from each site in October and January, ranged among the six sites from 269 to 4485 seeds per m2 in January and from 204 to 5073 in October. Soil seed viabilities were much lower (17.1% in October and 5.1% in January) than those of rain seeds (48.26%). Annual survivorships of 2.2% were estimated for seeds artificially sown on the soil surface of a gap and a mature patch, and 3.75% in a building patch. In two other experiments seed removal rates ranged from 27% to 98% in 4 days. Removal rates were significantly higher in gap and mature patches than in building patches. Ants (Paratrechina vividula) and grasshopper nymphs (Hygronemobius. sp.) were the main predators. We draw three main conclusions from our data: (1) Pathogens and predators determine low survivorship of C. obtusifolia's seeds in the soil and a rapid turnover rate (1.07 to 1.02 years) of its seed bank; (2) a continuous and copious seed production and an abundant and extensive seed rain replenish the soil seed pool in patches with different disturbance ages at least up to 86 m from nearest source; (3) more than 90% of the seeds contributing to C. obtusifolia seedling recruitment in gaps are less than one year-old. We discuss our results in the context of previous similar studies for tropical forests.


Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma.
We as well as others have recently shown that Hsp90 is overexpressed in multiple myeloma (MM) and critically contributes to tumour cell survival. Pharmacologic blockade of Hsp90 has consistently been found to induce MM cell death. However, most data have been obtained with MM cell lines whereas knowledge about the molecular effects of pharmacologic Hsp90 blockade in primary tumour cells is limited. Furthermore, these investigations have so far focused on geldanamycin derivatives. We analysed the biochemical effects of a novel diarylisoxazole-based Hsp90 inhibitor (NVP-AUY922) on signalling pathways and cell death in a large set of primary MM tumour samples and in MM cell lines. Treated cells displayed the molecular signature and pharmacodynamic properties for abrogation of Hsp90 function, such as downregulation of multiple survival pathways and strong upregulation of Hsp70. NVP-AUY922 treatment efficiently induced MM cell apoptosis and revealed both sensitive and resistant subgroups. Sensitivity was not correlated with TP53 mutation or Hsp70 induction levels and stromal cells from the bone marrow microenvironment were unable to abrogate NVP-AUY922-induced apoptosis of MM cells. Thus, NVP-AUY922 may be a promising drug for treatment of MM and clinical studies are warranted.


Studies on the positive-ion mass spectra from atmospheric pressure chemical ionization of gases and solvents used in liquid chromatography and direct liquid injection.
Detailed studies have been made using different source gases and solvents in a Micromass Quattro mass spectrometer under positive ion atmospheric pressure chemical ionization conditions. The major background ions from nitrogen, air, or carbon dioxide were investigated by tandem mass spectrometry, followed by similar studies on solvents commonly employed in normal- and reversed-phase high-performance liquid chromatography, namely, water-acetonitrile, acetonitrile, and dichloromethane, with nitrogen, air, or carbon dioxide; hydrocarbon solvents were studied using nitrogen. Spectra were interpreted in terms of the gases, solvents, and their impurities. The acetonitrile spectra provided clear evidence for both charge exchange and proton transfer, the former being facilitated by the introduction of some air into a flow of nitrogen. Radical cations of acetonitrile dimers, trimers, and tetramers were observed, as were protonated dimer and trimer species. Examination of the analytical response of four polycyclic aromatic hydrocarbons in various hydrocarbon solvents, with nitrogen gas, showed that the sensitivity of detection for an analyte and its ionization mechanism are dependent on both the analyte structure and the solvent, with pyrene showing the highest sensitivity, phenanthrene and fluorene being intermediate, and naphthalene having the lowest sensitivity. The degree of protonation followed the same trend. Signal intensity and degree of protonation were dependent on the alkane solvent used, with isooctane providing the best overall sensitivity for the sum of protonated molecules and molecular ions. The ions observed in these studies appeared to be the most stable ions formed under equilibrium conditions in the source.


Variation in the Prescription of Androgen Deprivation Therapy in Intermediate- and High-risk Prostate Cancer Patients Treated with Radiotherapy in the Netherlands, and Adherence to European Association of Urology Guidelines: A Population-based Study.
According to (inter-)national guidelines, (neo-)adjuvant and concurrent androgen deprivation therapy (ADT) in combination with external beam radiotherapy (EBRT) is optional for intermediate-risk prostate cancer (PCa) patients and is the recommended standard treatment for high-risk PCa patients. The aim of this study is to provide insight into the prescription of ADT in intermediate- and high-risk PCa patients treated with EBRT in the Netherlands, and to evaluate adherence to European Association of Urology guidelines and factors affecting prescription. All intermediate- and high-risk PCa patients between October 2015 and April 2016 were identified through the population-based Netherlands Cancer Registry. Variation in the prescription of ADT in patients with EBRT was evaluated. Multivariable multilevel logistic regression analyses were performed to determine the probability of ADT and to examine the role of patient-, tumour-, and hospital-related factors. Overall, 29% of patients with intermediate-risk PCa received ADT varying from 3% to 73% between institutions. From the multivariable regression analysis, higher Gleason grade, magnetic resonance imaging, and computed tomography (CT)-positron-emission tomography/CT prior to radiotherapy appeared to be associated with increased prescription of ADT. Among high-risk patients, 83% received ADT, varying from 57% to 100% between departments. A higher prostate-specific antigen level, more advanced tumour stage, and a higher Gleason grade were associated with increased prescription. Less than one-third of intermediate-risk PCa patients treated with EBRT receive ADT. The variation in the prescription of ADT between different institutions is substantial. This suggests that the prescription is largely dependent on different institutional policies. The guideline adherence in high-risk PCa is fairly good, as the vast majority of patients received ADT as recommended. However, given the clear recommendations in the guidelines, adherence could be improved. In this review, we looked at the variation of hormonal treatment in intermediate- and high-risk prostate cancer patients. We found substantial variation between institutions.


[Predictors of institutionalization of elderly persons in dependency situation in Andalusia].
Identifying preferences regarding type of care and risk factors for institutionalization of elderly persons in dependency situations in Andalusia. The data on 200,039 persons registered in the System for Autonomy and Dependency Care over the period 2007-2012 were analysed. The study population was described in terms of: age, dependency situation, preferences, support network and clinical factors at the time of inclusion in the study. Separate analysis was made for men and women. A logistic regression model was designed to determine the risk factors for institutionalization for each sex. 87,4% of women and 85,9% of men expressed their wish to receive care in their own home. The risk of institutionalization is three times higher among men than among women. Among women, the risks of institutionalization are: level of dependency, wishing to move into a residential care home, medium consistency and fragility of support network and being diagnosed with dementia. Among men, the risks are: wishing to move into a residential care home and low or medium consistency of support network. Care in the home is the preferred alternative for elderly persons in dependency situations. The risk of institutionalization is conditioned more by the preferences of the person and their family and the characteristics of the support network than by individual's clinical condition.


[Metric index and blood pressure values in 15-year-old students].
This longitudinal study of blood pressure in adolescents contains the mean and regression of systolic and diastolic blood pressure according to the metric index as the body mass index. The results show higher levels of blood pressure in pyknopyknomorphs than in mesomorphs and lepto-leptomorphs.


The influence of age and drugs on the thermoregulatory behaviour of rats.
A method is described which allows to measure thermoregulatory effective conditioned behaviour in rats. This method makes it possible to vary the preset ambient temperature (Ta) in a wide range. The results only deal with subnormal Ta (normal housing temperature 23 degrees C). Rats are able to acquire a conditioned behaviour additional to inborn behaviour which is adequate to contribute to thermal homoeostasis. Exposed to -4 degrees C adult animals adjusted their mean Ta to +4 degrees C, old animals to +8 degrees C. A dose of 40 micromol/kg Phentolamine caused adult rats to adjust mean temperature to +9 degrees C, old rats to +13.5 degrees C. But even this increased behavioural activity did not prevent the hypothermic effect of the drug totally. Core temperature in adult animals dropped by 0.8 degrees C, in old animals by 1.4 degrees C.


[Contribution of socioeconomic status to smoking behavior of parents of 4th grade elementary school students in Japan].
The present study was performed to elucidate the effects of individual and social factors on smoking behavior of parents of fourth grade elementary school students in Japan. A self-administered questionnaire was sent to a total of 4,179 households of fourth grade elementary school students. A total of 3,522 responses including actual numbers of children, smoking behavior of parents, and marital status were available for the analysis. Current smoking rate in mothers was 21.2%. In mothers, "smoking of spouse" "single mother", "under the age of 34", "not taking child-care leave;", "mother's parents not alive", "mothers from Chiba", "nursery use", "not use parenting circles", "unvaccinated measles or inoculation unknown" and "life dissatisfaction" were statistically associated with smoking behavior. The current smoking rate in fathers was 51.4%. Four factors of "smoking of spouse", "under the age of 34", "non-skilled labor, sales work" and "employees of private companies of less than 1,000 employees" were statistically associated with smoking behavior. The present study demonstrated a close link between smoking behavior and individual socioeconomic status in Japanese parents. Especially, smoking of spouse and being a single female parent were important factors for smoking.


Automated electrical source imaging with scalp EEG to define the insular irritative zone: Comparison with simultaneous intracranial EEG.
To evaluate the accuracy of automatedinterictallow-density electrical source imaging (LD-ESI) to define the insular irritative zone (IZ) by comparing the simultaneous interictal ESI localization with the SEEG interictal activity. Long-term simultaneous scalp electroencephalography (EEG) and stereo-EEG (SEEG) with at least one depth electrode exploring the operculo-insular region(s) were analyzed. Automated interictal ESI was performed on the scalp EEG using standardized low-resolution brain electromagnetic tomography (sLORETA) and individual head models. A two-step analysis was performed: i) sublobar concordance betweencluster-based ESI localization and SEEG-based IZ; ii) time-locked ESI-/SEEG analysis. Diagnostic accuracy values were calculated using SEEG as reference standard. Subgroup analysis wascarried out, based onthe involvement of insular contacts in the seizure onset and patterns of insular interictal activity. Thirty patients were included in the study. ESI showed an overall accuracy of 53% (C.I. 29-76%). Sensitivity and specificity were calculated as 53% (C.I. 29-76%), 55% (C.I. 23-83%) respectively. Higher accuracy was found in patients with frequent and dominant interictal insular spikes. LD-ESI defines with good accuracy the insular implication in the IZ, which is not possible with classical interictalscalpEEG interpretation. Automated LD-ESI may be a valuable additional tool to characterize the epileptogenic zone in epilepsies with suspected insular involvement.


TGFβ-2 signaling is essential for osteoblast migration and differentiation during fracture healing in medaka fish.
TGFβ is known as a canonical coupling factor based on its effects on bone formation and bone resorption. There are 3 different isoforms of it related to bone metabolism in mammals. TGFβ function in vivo is complicated, and each isoform shows a different function. Since TGFβs are secreted during inflammation accompanied by the release of latent TGFβ from inside of the bones where they are stored in the extracellular matrix, TGFβ function is potentially related to fracture healing. Although a few reports examined the TGFβ expression during fracture healing, the function of TGFβ in this process is poorly understood. To investigate TGFβ function during fracture healing in vivo, we used the fracture healing model of the medaka fish, which enabled us to observe the behavior and function of living cells in response to a bone-specific injury. RNA in-situ hybridization analysis showed that only tgfβ-2 of the 4 TGFβ isoforms in medaka was expressed in the bone-forming region. To examine the TGFβ-2 function for bone formation by osteoblasts, we used a medaka transgenic line, Tg (type X collagen: GFP); and the results revealed that type X collagen-positive immature osteoblasts migrated to the fracture site and differentiated to osterix-positive osteoblasts. However, only a few type X collagen-positive osteoblasts exhibited BrdU incorporation after the fracture. Then we inhibited TGFβ signaling by using a chemical TGFβ receptor kinase inhibitor (SB431542), and demonstrated that inhibition of TGFβ strongly impaired osteoblast migration and differentiation. In addition, this TGFβ inhibitor reduced the RANKL expression and caused a delay of osteoclast differentiation. Our findings thus demonstrated that TGFβ-2 functioned specifically during fracture healing to stimulate the migration of osteoblasts as well as the differentiation of osteoblasts and osteoclasts.


The antifungal and antibiofilm activity of Cymbopogon nardus essential oil and citronellal on clinical strains of Candida albicans.
This study investigated the antifungal and antibiofilm activity of Cymbopogon nardus essential oil (EO) and its major compound, citronellal, in association with miconazole and chlorhexidine on clinical strains of Candida albicans. The likely mechanism(s) of action of C. nardus EO and citronellal was further determined. The EO was chemically characterized by gas chromatography coupled with mass spectrometry (GC-MS). The antifungal activity (MIC/MFC) and antibiofilm effects of C. nardus EO and citronellal were determined by the microdilution method, and their likely mechanism(s) of action was determined by the sorbitol and ergosterol assays. Then, the samples were tested for a potential association with standard drugs through the checkerboard technique. Miconazole and chlorhexidine were used as positive controls and the assays were performed in triplicate. The GC-MS analysis tentatively identified citronellal as the major compound in C. nardus EO. Both samples showed antifungal activity, with MIC of 256 µg/mL, as compared to 128 µg/mL and 8 µg/mL of miconazole and chlorhexidine, respectively. C. nardus EO and citronellal effectively inhibited biofilm formation (p < 0.05) and disrupted preformed biofilms (p < 0.0001). They most likely interact with the cell membrane, but not the cell wall, and did not present any synergistic activity when associated with standard drugs. C. nardus EO and citronellal showed strong in vitro antifungal and antibiofilm activity on C. albicans. Natural products have been historically bioprospected for novel solutions to control fungal biofilms. Our data provide relevant insights into the potential of C. nardus EO and citronellal for further clinical testing. However, additional bioavailability and toxicity studies must be carried out before these products can be used for the chemical control of oral biofilms.


The analog of Ginkgo biloba extract 761 is a protective factor of cognitive impairment induced by chronic fluorosis.
Ginkgo biloba extract EGb761 is widely used to treat patients with learning and memory impairment in Alzheimer's disease and Parkinson's disease in China. However, it is not yet clear whether the analog of EGb761 (EGb) has a protective effect on the learning and memory damage induced by chronic fluorosis. In this study, 30 Wistar rats were randomly divided into three groups: a control group, a sodium fluoride (NaF) + EGb group, and a NaF group. The rats were administered 0.5 ml water containing NaF (100 mg/l) and EGb (120 mg/kg) per day via gavage. After 3 months, the rats' capacity for learning and memory was tested using a Y-maze. Damage to hippocampal neurons was evaluated by histological examination of the CA3 area. Superoxide dismutase (SOD) activity and the levels of glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured. Furthermore, the expression levels of Bcl-2 and Bax and the levels of cleaved Caspase3 in the hippocampus were evaluated by RT-PCR and Western blotting. The results showed that EGb could improve learning and memory abilities, enhance the activities of SOD and GSH-Px, attenuate the level of MDA, upregulate the ratio of Bcl-2/Bax, and downregulate the level of cleaved Caspase3.


Archaea inhibition: Strategies for the enhancement of volatile fatty acids production from microalgae.
In the present study, anaerobic sludge was subjected to thermal and chemical pretreatments to favour VFAs production from a protein-rich waste (i.e. microalgae biomass). Sludge pretreatments have been previously used in hydrogen production; however, information about how they can affect VFAs production from microalgae is still lacking. Thermal pretreatment was studied at: (i) 80 °C for 10 and 30 min; (ii) 120 °C for 10 and 30 min; and (iii) 100 °C for 20 min. 2-bromoethanesulfonate (BES) at 10 mM and 30 mM was used as chemical pretreatment. Besides, a combination of both pretreatment methods (80 °C and 120 °C at 10 mM and 30 mM BES) was also tested. Thermal pretreatment increased organic matter conversions into VFAs (up to 71% COD-VFAs/CODin) when compared to control values (40% in the untreated anaerobic sludge). Acetic acid was the most abundant VFAs at high temperatures (120 °C) and when BES was employed (up to 60% and 40%, respectively, in terms of COD). On the other hand, propionic acid was the most abundant product at low temperatures and in the untreated anaerobic sludge (up to 60% in terms of COD). This research work might set guidelines in order to choose a suitable sludge pretreatment for VFAs production from microalgae.


Unleashing the potential of cell biomimetic nanoparticles: Strategies and challenges in their design and fabrication for therapeutic applications.
In this contribution to the Orations - New Horizons of the Journal of Controlled Release, I present design strategies for the two main biomimetic nanoparticles (BNP) groups: BNP composed of isolated cell membrane proteins, and BNP composed of the native cell membrane. I furthermore describe BNP fabrication methods and analyze their advantages and challenges. Finally, I suggest future therapeutic applications of each BNP group and propose a new revolutionary concept for their use.


Patterns of metastasis and recurrence in thymic epithelial tumours: longitudinal imaging review in correlation with histological subtypes.
To determine the patterns of metastasis and recurrence in thymic epithelial tumours based on longitudinal imaging studies, and to correlate the patterns with World Health Organization (WHO) histological classifications. Seventy-seven patients with histopathologically confirmed thymomas (n=62) and thymic carcinomas (n=15) who were followed with cross-sectional follow-up imaging after surgery were retrospectively studied. All cross-sectional imaging studies during the disease course were reviewed to identify metastasis or recurrence. The sites of involvement and the time of involvement measured from surgery were recorded. Metastasis or recurrence was noted in 24 (31%) of the 77 patients. Patients with metastasis or recurrence were significantly younger than those without (median age: 46 versus 60, respectively; p=0.0005), and more commonly had thymic carcinomas than thymomas (p=0.002). The most common site of involvement was the pleura (17/24), followed by the lung (9/24), and thoracic nodes (9/24). Abdominopelvic involvement was noted in 12 patients, most frequently in the liver (n=8). Lung metastasis was more common in thymic carcinomas than thymomas (p=0.0005). Time from surgery to the development of metastasis or recurrence was shortest in thymic carcinoma, followed by high-risk thymomas, and was longest in low-risk thymoma (median time in months: 25.1, 68.8, and not reached, respectively; p=0.0015). The patterns of metastasis and recurrence of thymic epithelial tumours differ significantly across histological subgroups, with thymic carcinomas more commonly having metastasis with shorter length of time after surgery. The knowledge of different patterns of tumour spread may contribute to further understanding of the biological and clinical behaviours of these tumours.


Difficulties in retrieval multiplication facts: The case of interference to reconsolidation.
Many students have difficulties in retrieving multiplication facts from memory. The aim of the present study was to test the difficulty in retrieval of multiplication facts from the perspective of the reconsolidation of long-term memory phase, which has been found to be sensitive to interferences. Students learned multiplication facts and then received a reminder, which led to reactivation and reconsolidation. After the reminder, additional multiplication facts (interference) were learned and memory was tested. Students who received both a reminder and interference during reconsolidation showed no significant improvement in retrieving multiplication facts from memory, whereas Students who received either a reminder or additional multiplication facts (interference) exhibited a better performance in retrieval. These results indicate, for the first time, that the reconsolidation phase is sensitive to interferences in mathematical declarative memory content. The findings indicate additional possible causes for difficulties in retrieval of multiplication facts in class.


Use of progestogen therapy.
Estrogen therapy for postmenopausal women has received adverse publicity since the mid-1970s because several reports implicated estrogens with an increased risk of endometrial cancer. Other studies indicated that the risk of endometrial malignancy is reduced when a progestogen is added to the estrogen. Not all postmenopausal women need estrogen replacement, since many are symptom free because they continue to produce endogenous estrogens. Within this group may be the women at greatest risk for adenocarcinoma of the endometrium. The progestogen challenge test was devised to identify women at greatest risk for endometrial cancer. The number of endometrial malignancies declined at Wilford Hall U.S. Air Force Medical Center with increasing use of this test from 1975 through 1983. The lowest incidence of endometrial cancer was observed in the estrogen-progestogen users (49.0 per 100,000) and was significantly lower than that found in either the unopposed estrogen users (390.6 per 100,000; p less than or equal to 0.0001) or in the untreated women (245.5 per 100,000; p less than or equal to 0.005). The incidence of breast cancer was also significantly lower in the estrogen-progestogen users (66.8 per 100,000) than in the untreated group (343.5 per 100,000) and lower than that expected from two national cancer surveys (188.3 and 229.2 per 100,000; p less than or equal to 0.01). Progestogens should be added to estrogen replacement therapy in women who have undergone a hysterectomy, as well as in those with an intact uterus.


Targeting Natriuretic Peptide Levels in Heart Failure with Therapy: Does "X" Really Mark the Spot?
Explore controversial biomarker-guided management of patients with heart failure (HF) with reduced ejection fraction. Natriuretic peptides (e.g., BNP, NT-proBNP) are elevated in HF as a result of end-diastolic stress and are used in the diagnosis and prognosis of heart failure. Natriuretic peptide levels decrease with guideline-directed medical therapy (GDMT). Multiple small studies examined whether the use of biomarker-guided therapy would be beneficial to guide HF care and potentially improve outcomes. Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT), the largest randomized control study seeking to answer that question, did not find biomarker guided therapy to be more effective than usual care in improving the primary endpoints of HF hospitalization or cardiovascular mortality in HF patients. Natriuretic peptides are important for diagnosis and prognosis in HF. GUIDE-IT showed that patients with HF and reduced ejection did not benefit from biomarker-guided strategy in terms of clinical outcomes. Future studies could focus on additional routine clinical care settings and take into account other HF phenotypes including preserved ejection fraction.


"Frailty Indices Outperform Historic Risk Proxies as Predictors of Post-Abdominoplasty Complications: An Analysis of a National Database".
While age, BMI, and major comorbidities were historically used as predictors of surgical risk, recent literature supports patient frailty as a more accurate predictor. Database studies and chart reviews support the modified Charlson Comorbidity Index (mCCI) and the Modified 5-Item Frailty Index (mFI-5) as predictors of postsurgical complications in plastic surgery. The authors hypothesized that the mFI-5 and mCCI are more predictive of abdominoplasty complications than historic risk proxies. A retrospective review of the NSQIP database was performed, for abdominoplasty patients from 2013 to 2019. Demographics, comorbidities, and complications were gathered. The mFI-5 and mCCI scores were calculated per patient. Age, BMI, major comorbidities, ASA class, mFI-5 score, and mCCI score were compared as predictors of all-cause 30-day complications, 30-day surgical site complications, length of stay, and aggregate Clavien-Dindo complication severity score. Of 421 patients, the strongest predictors for all-cause complications and complication severity were mCCI score ≥ 3 and mFI-5 score ≥2. mFI-5 score was the strongest predictor of unplanned reoperation. Length of stay was best predicted by age ≥ 65. The only predictor of surgical site complications was BMI ≥ 30.0. Smoking was predictive of complication severity, but not any other outcome. The mFI-5 and mCCI are stronger outcome predictors than historically-used factors, which showed little predictive value in this cohort. While the mCCI is a stronger predictor than the mFI-5, the mFI-5 is easily calculated during an initial consultation. Surgeons can apply these tools to aid in risk stratification for abdominoplasty.


Impact of Resident Training Level on Radiation Exposure During Fixation of Proximal Femur Fractures.
To identify whether residents are at greater risk of radiation exposure from intraoperative fluoroscopy while earlier in their training and during more complex procedures. We analyzed 852 extracapsular proximal femur fracture fixation cases. We compared fluoroscopy times by various levels of resident training, fracture type, and implant used. Attending-only cases were used as a control group. Fluoroscopy times during subtrochanteric fracture fixation (176.1 ± 11.27 seconds) were longer than intertrochanteric (111.4 ± 2.44 seconds) and basicervical fractures (91.49 ± 5.77 seconds). Long nail (150.2 ± 3.75 seconds) times were longer than short (92.3 ± 3.15 seconds) and intermediate (76.45 ± 3.01 seconds) nails. Significantly, more fluoroscopy was used in junior (115.9 ± 4.24 seconds), senior (123.0 ± 6.08 seconds), junior combo (130.6 ± 7.74 seconds), and senior combo cases (131.8 ± 6.11 seconds) compared with the control (94.91 ± 3.91). Orthopaedic surgery residents and attendings must remain aware of radiation exposure secondary to intraoperative fluoroscopy. Appropriate personal protective equipment should be worn, and more experienced surgeons should take a more active role in the complex cases to decrease exposure risk. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Electrospun poly (vinyl alcohol) nanofibers incorporating caffeic acid/cyclodextrins through the supramolecular assembly for antibacterial activity.
Here, we prepared the solid inclusion complexes between Caffeic acid (CA) and Cyclodextrins (β- and γ-CDs) (CA/CDs) that were effectively embedded into Poly (vinyl alcohol) (PVA) electrospun nanofibers via electrospinning technique to enhanced solubility and antibacterial activity. In tested Cyclodextrins are β-and γ-CDs with CA in the ratio of 1:1 resulting in the formation of CA/CDs by co-precipitation method. The physical properties of CA/CDs were examined by FT-IR, UV, and Raman Spectroscopy. The phase solubility test showed a much higher solubility of CA due to inclusion complexes (ICs). Furthermore, CA/β-CD and CA/γ-CD perfected achieved 0.70:1 and 0.80:1 the molar ratio of ICs, confirmed by NMR studies. The fiber size distribution, average diameter, and morphology features were evaluated by SEM analysis. The dissolution profile of PVA/CA and PVA/CA/CDs were tested within 150 min, resulting in CA dissolved in PVA/CA/CDs slightly higher than PVA/CA nanofibers due to enhanced solubility of ICs. Moreover, PVA/CA/CDs exhibit high antibacterial activity against gram-positive bacteria of E-Coli and gram-negative bacteria of S. aureus. Finally, these results suggest that PVA/CA/CDs may be promising materials for active food packaging applications.


Anatomy-guided injections of botulinum neurotoxin in neck muscles: how accurate is needle placement?
In cervical dystonia, the accuracy of botulinum neurotoxin (BoNT) injections may influence the response to the treatment. We used ultrasound to evaluate the accuracy of anatomy-guided injections of BoNT in the neck muscles. A total of 56 consecutive patients and 332 injections were evaluated. The overall accuracy was 76.6%. The lowest accuracy (67.9%) was observed for the splenius capitis muscle. Anatomic guidance of BoNT injections in the neck muscles is often inaccurate. Imaging guidance may improve the accuracy of BoNT injections in cervical dystonia.


Lactic acid bacteria alleviate di-(2-ethylhexyl) phthalate-induced liver and testis toxicity via their bio-binding capacity, antioxidant capacity and regulation of the gut microbiota.
Di-(2-ethylhexyl) phthalate (DEHP) is a plasticiser that, if absorbed into the human body, can cause various adverse effects including reproductive toxicity, liver toxicity and gut microbiota dysbiosis. So far, some studies have proved that the toxicity of DEHP can be reduced by using antioxidants. However, these candidates all show potential side effects and cannot prevent the accumulation of DEHP in the body, making them unable to be used as a daily dietary supplement to relieve the toxic effects of DEHP. Lactic acid bacteria (LAB) have antioxidant capacity and the ability to adsorb harmful substances. Herein, we investigated the protective effects of five strains of LAB, selected based on our in vitro assessments on antioxidant capacities or bio-binding capacities, against the adverse effects of DEHP exposure in rats. Our results showed that LAB strains with outstanding DEHP/MEHP binding capacities, Lactococcus lactis subsp. lactis CCFM1018 and Lactobacillus plantarum CCFM1019, possess the ability to facilitate the elimination of DEHP and its metabolite mono-(2-ethylhexyl) phthalate (MEHP) with the faeces, decrease DEHP and MEHP level in serum further. Meanwhile, DEHP-induced liver and testicular injuries were effectively alleviated by CCFM1018 and CCFM1019. In addition, CCFM1018 effectively alleviated the DEHP-induced oxidative stress with its strong antioxidant ability. Furthermore, both CCFM1018 and CCFM1019 modulated the gut microbiota, which in turn increased the concentrations of faecal propionate and butyrate and regulated the pathways related to host metabolism. Correlation analysis indicate that DEHP/MEHP bio-binding capacity of LAB plays a crucial role in protecting the body from DEHP exposure, and its antioxidant capacity and the ability to alleviate the gut microbiota dysbiosis are also involved in the alleviation of damage. Thus, LAB with powerful bio-binding capacity of DEHP and MEHP can be considered as a potential therapeutic dietary strategy against DEHP exposure.


Blood oxygenation level-dependent (BOLD) MRI of human skeletal muscle at 1.5 and 3 T.
To evaluate the dependence of skeletal muscle blood oxygenation level-dependent (BOLD) effect and time course characteristics on magnetic field strength in healthy volunteers using an ischemia/reactive hyperemia paradigm. Two consecutive skeletal muscle BOLD magnetic resonance imaging (MRI) measurements in eight healthy volunteers were performed on 1.5 T and 3.0 T whole-body MRI scanners. For both measurements a fat-saturated multi-shot multiecho gradient-echo EPI sequence was applied. Temporary vascular occlusion was induced by suprasystolic cuff compression of the thigh. T2 time courses were obtained from two different calf muscles and characterized by typical curve parameters. Ischemia- and hyperemia-induced changes in R2 (ΔR2) were calculated for both muscles in each volunteer at the two field strengths. Skeletal muscle BOLD changes are dependent on magnetic field strength as the ratio ΔR2(3.0 T)/ΔR2(1.5 T) was found to range between 1.6 and 2.2. Regarding time course characteristics, significantly higher relative T2 changes were found in both muscles at 3.0 T. The present study shows an approximately linear field strength dependence of ΔR2 in the skeletal muscle in response to ischemia and reactive hyperemia. Using higher magnetic fields is advisable for future BOLD imaging studies of peripheral limb pathologies.


Association of dental fluorosis with polymorphisms of estrogen receptor gene in Chinese children.
Dental fluorosis (DF) is one of the important performances of endemic fluorosis. Some studies indicated that estrogen receptor (ESR) gene polymorphisms were associated with bone metabolism-related diseases. Therefore, it is possible that the variation in ESR genotypes will be associated with DF status. A case-control study was conducted among children aged 8-12 years with (n = 75) or without (n = 165) DF in China to investigate the relationship between ESR gene polymorphisms and DF. Gene polymorphisms were genotyped using the PCR-RFLP procedure. Children carrying R allele of ER RsaI had significantly increased risk of DF (Odds ratio (OR) = 1.821; 95% confidence interval (CI), 1.013-3.274) compared to children carrying r allele of ER RsaI in endemic fluorosis villages. For children with high-loaded fluoride status, carrying X allele of ESRα XbaI had a significantly decreased risk of DF (OR = 0.542; 95% CI, 0.314-0.936) compared to carrying x allele. This study provides the first evidence of an association between polymorphisms in the ESR gene with DF in high-fluoride-exposed populations. Further studies are needed to confirm the association.


Post-embolization syndrome as an early predictor of overall survival after transarterial chemoembolization for hepatocellular carcinoma.
Transarterial chemoembolization (TACE) is the most common treatment for patients with unresectable hepatocellular carcinoma (HCC). Post-embolization syndrome (PES) is a common post-TACE complication. The goal of this study was to evaluate PES as an early predictor of the long-term outcome. A retrospective cohort study of HCC patients treated with TACE at a tertiary referral centre was performed (2008-2014). Patients were categorized on the basis of PES, defined as fever with or without abdominal pain within 14 days of TACE. The primary outcome was overall survival (OS). Multivariate Cox regression was done to examine the association between PES and OS. Among 144 patients, 52 (36.1%) experienced PES. The median follow-up for the cohort was 11.4 months. The median and 3-year OS rates were 16 months and 18% in the PES group versus 25 months and 41% in the non-PES group (log rank, P = 0.027). After multivariate analysis, patients with PES had a significantly increased risk of death [hazard ratio 2.0 (95%CI 1.2-3.3), P = 0.011]. PES is a common complication after TACE and is associated with a two-fold increased risk of death. Future studies should incorporate PES as a relevant early predictor of OS and examine the biological basis of this association.


Primary versus revision arthroscopically-assisted acromio- and coracoclavicular stabilization of chronic AC-joint instability.
A gracilis tendon autograft with TightRope-augmentation can be used for arthroscopically-assisted acromioclavicular (AC)- and coracoclavicular (CC-)stabilization of chronic bidirectional AC-joint instability after failed primary treatment. The impact of failed initial treatment on postoperative outcome is unclear. Hence, the purpose of this study was to evaluate it. Twenty-seven of 38 patients suffering from chronic AC-joint instability after either failed conservative (group 1) or surgical treatment (group 2) treated in the above-mentioned technique were finally included in this study. The Subjective Shoulder Value, the Constant Score, the Taft Score and the Acromioclavicular Joint Instability Score were used for clinical evaluation. Bilateral anteroposterior stress radiographs and bilateral Alexander views were obtained for radiological evaluation. 14 patients of group 1 [3f/11m; median age 47.6 (range 20.9-57.4) years] could be evaluated after a median follow-up of 24.3 (range 20-31.2) months and 13 patients of group 2 [6f/7m; median age 44.9 (range 24.9-61.0) years] were available after a median follow-up of 28.8 (range 20-33) months. Comparison of clinical score results revealed no significant differences between both groups. The median CC-difference showed no significant difference between the groups [group 1 0.8 (0-10.5) mm, group 2 0.9 (0-4.3) mm]. AC- and CC-stabilization of chronic bidirectional AC-joint instability using a gracilis tendon autograft with TightRope-augmentation can be recommended after failed conservative and surgical treatment. Retrospective cohort study; Level of evidence III.


Endoscopic skull base surgery and its impact on sinonasal-related quality of life.
Endoscopic skull base surgery (ESBS) is considered a minimally-invasive surgical modality with less morbidity and patient discomfort. Quality-of-life (QOL) assessments provide a patient-reported estimate of well-being that may be clinically relevant. Although the sinonasal tract is integral to ESBS, the change in sinonasal-related QOL with ESBS has not been well studied. The aim of this study was to prospectively assess QOL before and after ESBS using validated outcome measures. Consecutive adult patients undergoing ESBS for anterior skull base lesions were prospectively enrolled from a tertiary referral center. Each patient was asked to complete the 22-item Sinonasal Outcome Test (SNOT-22) and the Anterior Skull Base Questionnaire (ASBQ) preoperatively, and again at 3 weeks, 6 weeks, 12 weeks, 6 months, and 1 year postoperatively. Eighty-five patients were included for study, 44.7% of whom underwent ESBS for nonpituitary pathology. Mean SNOT-22 scores transiently worsened in the early postoperative period, and significantly improved at 1 year after surgery (p < 0.01). Gross-total tumor resection and use of autologous grafting materials were associated with improved SNOT-22 scores at later time points (p < 0.05). Type of reconstruction, tumor pathology, and functionality did not affect QOL scores. Correlation between SNOT-22 and ASBQ scores was good at all time points (r < -0.50). Cerebrospinal fluid leak and other complications were uncommon. ESBS does not have a detrimental long-term effect and is associated with ultimate improvement in sinonasal-related QOL. Short-term impairments of sinonasal-related QOL are predictable and self-limited. Prospective assessment using sinonasal-related and site-specific QOL instruments provide complementary information about ESBS outcomes.


Does the cerebellum initiate movement?
Opinion is divided on what the exact function of the cerebellum is. Experiments are summarized that support the following views: (1) the cerebellum is a combiner of multiple movement factors; (2) it contains anatomically fixed permanent focal representation of individual body parts (muscles and segments) and movement modes (e.g., vestibular driven vs. cognitive driven); (3) it contains flexible changing representations/memory of physical properties of the body parts including muscle strength, segment inertia, joint viscosity, and segmental interaction torques (dynamics); (4) it contains mechanisms for learning and storage of the properties in item no. 3 through trial-and-error practice; (5) it provides for linkage of body parts, motor modes, and motordynamics via the parallel fiber system; (6) it combines and integrates the many factors so as to initiate coordinated movements of the many body parts; (7) it is thus enabled to play the unique role of initiating coordinated movements; and (8) this unique causative role is evidenced by the fact that: (a) electrical stimulation of the cerebellum can initiate compound coordinated movements; (b) in naturally initiated compound movements, cerebellar discharge precedes that in downstream target structures such as motor cerebral cortex; and (c) cerebellar ablation abolishes the natural production of compound movements in the awake alert individuals.


45 years German Society of Biological Psychiatry (DGBP).
The foundation of a German Society of Biological Psychiatry (DGBP) was initiated at the Second World Congress of Biological Psychiatry of the WFSBP in Barcelona in 1978. Its mission was and is to promote interdisciplinary research on the biology of mental disorders and to translate results of biological research into clinical practice. During the presidency of Peter Falkai, its tasks were defined to improve the quality and support of biologically oriented research in Germany by the DFG (Deutsche Forschungsgemeinschaft; German Research Foundation), BMBF (Bundesministerium für Bildung und Forschung) and EU (European Union), to promote young researchers doing biologically oriented research, to improve on the diagnosis and therapy of mental disorders and to advise policy makers by taking part in legal processes. The DGBP has been a corporate member of the WFSBP from its beginning, became a cooperative member of the DGPPN (Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde), later of the German Brain Council, and fostered relationships with other scientific societies. Over the past 45 years, more than twenty congresses were held in Germany and neighboring countries. Emerging from the pandemic, the DGBP is ready to continue its mission to promote interdisciplinary research on the biology of mental disorders with a focus on the development of young scientists and to translate results of biological research into clinical practice, with regard to pharmacotherapy in close cooperation with the Arbeitsgemeinschaft Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). In this sense, this article also aims to stimulate the cooperation of the society with other national and international partners and to foster new relationships with young scientists and professionals interested in the aims and goals of the DGBP.


Vigilance impairment after a single dose of benzodiazepines.
While outpatients or other users of therapeutic drugs have to be informed about the risk of impaired functioning during driving or work, the prescribing physician needs to be familiar with the side effects of alternative drugs in order to select the most suitable treatment. With this aim, several types of benzodiazepine anxiolytics in low anxiolytic doses (diazepam 5 mg or 10 mg, nitrazepam 5 mg, oxazepam 10 mg, medazepam 10 mg, and alprazolam 0.2 or 0.5 mg-per 2m2 body surface) were tested under laboratory conditions for their effects on vigilance performance. In a double-blind design, 145 healthy volunteers performed a 60 min vigilance test (composed of discriminatory reactions to acoustic stimuli and a secondary visual tracking task) and four short psychomotor tests (lasting 1-7 min each) before and after a single dose of drug or placebo. Subjects described their perception of the drug effect with the help of a mood check list, and fatigue, sleepiness, and effort scales. Only diazepam 5 mg and 10 mg, alprazolam 0.5 mg, and nitrazepam 5 mg caused significant deterioration in vigilance performance along with perceived sleepiness and the need for a greater effort to overcome it. The onset of diazepam effect was quicker, whereas alprazolam effect lasted longer. No effect was noted in the short psychomotor tests except for the Bourdon Cancellation Test, where the first phase of diazepam effect was registered.


Whole genome re-sequencing identifies a mutation in an ABC transporter (mdr2) in a Plasmodium chabaudi clone with altered susceptibility to antifolate drugs.
In malaria parasites, mutations in two genes of folate biosynthesis encoding dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) modify responses to antifolate therapies which target these enzymes. However, the involvement of other genes which modify the availability of exogenous folate, for example, has been proposed. Here, we used short-read whole-genome re-sequencing to determine the mutations in a clone of the rodent malaria parasite, Plasmodium chabaudi, which has altered susceptibility to both sulphadoxine and pyrimethamine. This clone bears a previously identified S106N mutation in dhfr and no mutation in dhps. Instead, three additional point mutations in genes on chromosomes 2, 13 and 14 were identified. The mutated gene on chromosome 13 (mdr2 K392Q) encodes an ABC transporter. Because Quantitative Trait Locus analysis previously indicated an association of genetic markers on chromosome 13 with responses to individual and combined antifolates, MDR2 is proposed to modulate antifolate responses, possibly mediated by the transport of folate intermediates.


The once-daily formulation of tacrolimus: a step forward in kidney transplantation?
Nonadherence is a critical issue in transplantation. Recently, Astellas designed a once-daily-extended release formulation of tacrolimus (Tac). Despite initial reports showing bioequivalence of Tac once-daily (Advagraf) with the original formulation requiring twice-daily intake (Tac twice-daily, Prograf), several groups have now shown a sustained decrease in Tac exposure upon conversion from Prograf to Advagraf. Here, we discuss the possible reasons for this observation and how it could affect the expected benefits of Advagraf, and we comment on the fact that a similar lack of bioequivalence might prevail with generic immunosuppressive drugs.


Prevalence and determinants of virological failure, genetic diversity and drug resistance among people living with HIV in a minority area in China: a population-based study.
Liangshan Yi Autonomous Prefecture is one of the areas that most severely affected by human immunodeficiency virus (HIV) in China, and virological failure on antiretroviral therapy (ART) is serious in this area. Analyses of prevalence and determinants of ART failure, the genetic diversity and drug resistance among people living with HIV (PLWH) helps improve HIV treatment efficiency and prevent HIV transmission. A total of 5157 PLWH were recruited from 2016 to 2017. The venous blood samples were subjected to RT-PCR, followed by sequencing of the HIV-1 pol gene, targeting the protease and reverse transcriptase fragments. HIV-1 diversity was analyzed using the DNAStar software and drug resistance mutations were analyzed using the Stanford University HIV Drug Resistance Database. A total of 2156 (41.81%) PLWH showed virological failure on ART. Males (ORm = 1.25), heterosexual behaviors and drug injection (ORm = 1.44) and mother to child transmission routes (ORm = 1.58), the clinical stage of AIDS (ORm = 1.35), having used illicit drugs and shared the needles (1-4 times: ORm = 1.34; more than 5 times: ORm = 1.52), having ever replaced ART regimen (ORm = 1.48) increased the risk of virological failure among PLWH, while higher education lever (ORm = 0.77) and ≥ 12 months on ART (12 ~ 36 months: ORm = 0.72; ≥36 months: ORm = 0.66) was associated with lower likelihood of virological failure. The data revealed that CRF07_BC (1508, 95.62%) were the most common strains, and the drug-resistant rate was 32.10% among PLWH with virological failure in this area. The high frequencies of drug resistance were found in EFV and NVP of NNRTIs, ABC, FTC and 3TC of NRTIs, and TPV/r in PIs. The most common mutations in NNRTIs, NRTIs and PIs were K103N/KN (64.69%), M184V/MV/I (36.29%) and Q58E/QE (4.93%), respectively. We concluded that surveillance of virological failure, HIV-1 subtypes, and drug resistance to understand HIV-1 epidemiology and guide modification of ART guidelines, and target prevention and control strategies should be formatted to reduce the virological failure and drug resistance to promote viral suppression and prevent HIV-1 transmission.


Anodic titania nanotubes decorated with gold nanoparticles produced by laser-induced dewetting of thin metallic films.
Herein, we combine titania layers with gold species in a laser-supported process and report a substantial change of properties of the resulting heterostructures depending on the major processing parameters. Electrodes were fabricated via an anodisation process complemented with calcination to ensure a crystalline phase, and followed by magnetron sputtering of metallic films. The obtained TiO2 nanotubes with deposited thin (5, 10 nm) Au films were treated with a UV laser (355 nm) to form Au nanoparticles on top of the nanotubes. It was proven that selected laser working parameters ensure not only the formation of Au nanoparticles, but also simultaneously provide preservation of the initial tubular architecture, while above-threshold laser fluences result in partial destruction (melting) of the top layer of the nanotubes. For almost all of the samples, the crystalline phase of the nanotubes observed in Raman spectra was maintained independently of the laser processing parameters. Enhanced photoresponse up to ca 6 mA/cm2 was demonstrated by photoelectrochemical measurements on samples obtained by laser annealing of the 10 nm Au coating on a titania support. Moreover, a Mott-Schottky analysis indicated the dramatically increased (two orders of magnitude) concentration of donor density in the case of a laser-treated Au-TiO2 heterojunction compared to reference electrodes.


Injectable gelatin/glucosamine cryogel microbeads as scaffolds for chondrocyte delivery in cartilage tissue engineering.
In this study, we fabricate squeezable cryogel microbeads as injectable scaffolds for minimum invasive delivery of chondrocytes for cartilage tissue engineering applications. The microbeads with different glucosamine concentrations were prepared by combining the water-in-oil emulsion and cryogelation through crosslinking of gelatin with glutaraldehyde in the presence of glucosamine. The physicochemical characterization results show the successful preparation of cryogel microbeads with uniform shape and size, high porosity, large pore size, high water uptake capacity, and good injectability. In vitro analysis indicates proliferation, migration, and differentiated phenotype of rabbit chondrocytes in the cryogel scaffolds. The seeded chondrocytes in the cryogel scaffold can be delivered by injecting through an 18G needle to fully retain the cell viability. Furthermore, the incorporation of glucosamine in the cryogel promoted the differentiated phenotype of chondrocytes in a dose-dependent manner, from cartilage-specific gene expression and protein production. The in vivo study by injecting the cryogel microbeads into the subcutaneous pockets of nude mice indicates good retention ability as well as good biocompatibility and suitable biodegradability of the cryogel scaffold. Furthermore, the injected chondrocyte/cryogel microbead constructs can form ectopic functional neocartilage tissues following subcutaneous implantation in 21 days, as evidenced by histological and immunohistochemical analysis.


Secondary aortoduodenal fistula identified by ultrasonography.
A 73-year-old man underwent coronary artery bypass grafting, abdominal aortic aneurysm resection, and prosthetic implantation as a single procedure in 2002. His progress was favorable until April 2008, when he was admitted to our hospital with melena. B-mode ultrasonography revealed a 5-mm defect in the abdominal aorta at the graft anastomosis, and an umbilicated lesion was seen projecting between the posterior wall of the third part of the duodenum and the abdominal aorta. A color signal was noticed at this site on color Doppler ultrasonography, leading to the diagnosis of a secondary aortoduodenal fistula (ADF). We resected the inflammatory mass comprising the graft and the third part of the duodenum, and performed prosthetic re-implantation, omentopexy, and duodenojejunostomy. We could not find any previous reports of successful identification of secondary ADF using ultrasonography. When a patient with gastrointestinal hemorrhage following reconstructive aortic surgery is encountered in the emergency department, ultrasonography may be considered to be a useful modality in the diagnosis of secondary ADF.