Mutant mouse lysozyme carrying a minimal T cell epitope of hen egg lysozyme evokes high autoantibody response.
Self proteins including foreign T cell epitope induce autoantibodies. We evaluated the relationship between the size of foreign Ag introduced into self protein and the magnitude of autoantibody production. Mouse lysozyme (ML) was used as a model self protein, and we prepared three different ML derivatives carrying T cell epitope of hen egg white lysozyme (HEL) 107-116, i.e, heterodimer of ML and HEL (ML-HEL), chimeric lysozyme that has residue 1-82 of ML and residue 83-130 of HEL in its sequence (chiMH), and mutant ML that has triple mutations rendering the most potent T cell epitope of HEL (sequence 107-116). Immunization of BALB/c mice with these three ML derivatives induced anti-ML autoantibody responses, whereas native ML induced no detectable response. In particular, mutML generated a 10(4) times higher autoantibody titer than did ML-HEL. Anti-HEL107-116 T cell-priming activities were almost similar among the ML derivatives. The heterodimerization of mutant ML and HEL led to significant reduction of the autoantibody response, whereas the mixture did not. These results show that size of the nonself region in modified self Ag has an important role in determining the magnitude of the autoantibody response, and that decrease in the foreign region in a modified self protein may cause high-titered autoantibody response.


A Stroke Alert With Unexpected Outcome.
Observational studies have suggested that intravenous (IV) thrombolysis may be unfavorable in patients with high-grade gliomas. However, current literature on thrombolysis outcomes in patients with primary brain tumors is largely limited to case reports and may be influenced by publication bias. A 69-year-old male presented with acute left hemiplegia, left hemisensory loss, neglect, dysarthria and right gaze preference (National Institutes of Health Stroke Scale 22). An emergent noncontrast head computerized tomography showed hypoattenuation in the right parietal lobe of unclear chronicity and IV thrombolysis with tissue plasminogen activator was administered within the 4.5 hour window. Following IV thrombolysis, a computerized tomography angiogram of the head and neck revealed no large vessel occlusion. However, a marginally enhancing, and centrally nonenhancing mass within the right parietal lobe associated with vasogenic edema was elucidated. Subsequently, the patient developed abnormal left hemibody tonic-clonic motor activity, left gaze preference and left-beating nystagmus concerning for focal motor status epilepticus. An emergent electroencephalogram, following administration of IV levetiracetam, showed right hemispheric electrographic seizures and right hemispheric periodic lateralized epileptiform discharges. Brain magnetic resonance imaging with gadolinium revealed 2.5 cm ring-enhancing mass in the right parietal lobe. The patient underwent right sided craniotomy with resection of the mass and pathology revealed Glioblastoma. We report a case of thrombolysis administered in a patient with high-grade glioma with no apparent complications.


Alistipes communis sp. nov., Alistipes dispar sp. nov. and Alistipes onderdonkii subsp. vulgaris subsp. nov., isolated from human faeces, and creation of Alistipes onderdonkii subsp. onderdonkii subsp. nov.
Three groups of Gram-stain-negative, obligately anaerobic, rod or coccoid-shaped bacteria, which were phylogenetically assigned in the genus Alistipes belonging to the family Rikenellaceae in the phylum Bacteroidetes, were isolated from the faecal samples of healthy Japanese humans. Group I (strains 5CBH24T and 6CPBBH3) showed highest 16S rRNA gene sequence similarity to 'Alistipes obesi' ph8T (99.73 %). Group II (strain 5CPEGH6T) was related to Alistipes shahii WAL 8301T (96.82 %). Ten strains of group III (3BBH6T, 5CPYCFAH4, 5NYCFAH2 and others) were related to Alistipes onderdonkii DSM 19147T (98.96 %). Group I could be differentiated from other strains by the ability to hydrolyse aesculin and the lack of catalase activity. Strain 5CPEGH6T could be differentiated from A. shahii JCM 16773T by the inability to hydrolyse aesculin and the lack of catalase activity, and so on. Phenotypic characteristics of group III were similar to those of A. onderdonkii JCM 16771T. Strains 5CBH24T, 6CPBBH3 and 'A. obesi' ph8T shared 98.8-98.9 % average nucleotide identity (ANI) with each other. In addition, the in silico DNA-DNA hybridization (DDH) values among three strains were 86.7-89.4 %. Strain 5CPEGH6T showed relatively low values (≤ 84.4 % for ANI ; ≤26.2 % for DDH) with other strains. Three strains in the group III (3BBH6T, 5CPYCFAH4 and 5NYCFAH2) shared 97.9-99.9% ANI with each other. These three strains showed 96.9-97.3 % ANI with A. onderdonkii DSM 19147T. The DDH values of strains 3BBH6T, 5CPYCFAH4 and 5NYCFAH2 among themselves were 80.5-99.8 %, while those compared to A. onderdonkii DSM 19147T were 71.0-73.4 %. On the basis of the collected data, three novel species, Alistipes communis sp. nov. (5CBH24T=JCM 32850T=DSM 108979T), Alistipes dispar sp. nov. (5CPEGH6T=JCM 32848T=DSM 108978T) and Alistipes onderdonkii subsp. vulgaris subsp. nov. (3BBH6T=JCM 32839T=DSM 108977T), are proposed.


High-grade glioma in infants and young children is histologically, molecularly, and clinically diverse-Results from the SJYC07 trial and institutional experience.
High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking. A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with non-protocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and pre-operative imaging were analyzed. Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (n=22), occurred in the youngest patients (median age=0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI:35.52 -79.47) and 90.91% (95%CI:79.66-100.00) vs. 0.0% and 16.67% (95%CI:2.78-99.74%) for HGG (p=0.0043, p=0.00013). EFS and OS were not different between IHG and LGG (p=0.95, p=0.43). Imaging review showed IHGs are associated with circumscribed margins (p=0.0047), hemispheric location (p=0.0010), and intratumoral hemorrhage (p=0.0149). HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.


Epigenetics and depressive disorders: a review of current progress and future directions.
Several broad lines of evidence support the involvement of epigenetic processes in neurodevelopment and psychiatric disorders. Epigenetic disruption also provides a potential mechanism to account for the numerous gene-environment interactions that have been reported in association with neuropsychiatric phenotypes. A review of the literature was performed with keywords 'depression', 'depressive disorder' or 'antidepressants' and 'DNA methylation', or 'epigenetics' in humans. Citations were limited to those written in English and published prior to July 2014. We present a summary of results to date. Most studies have focused on DNA methylation in various CNS or peripheral tissue, with almost universally small sample sizes. Although seven epigenome-wide association studies have now been reported, the majority of studies have used a candidate-gene approach. Three genes (SLC6A4, BDNF, NR3C1) have been investigated in more than one study, but replication of findings is generally lacking. Recent evidence provides insights to epigenetic processes in psychiatric disorders; however, replication is lacking and care must be taken in the interpretation of current findings. This applies to epigenetic epidemiology generally, which is subject to various limitations that no single approach can address in isolation. Due to limited focus of most depression studies to date, placing the findings within the broader context of mood disorder pathophysiology may prove challenging. However, identifying peripheral biomarkers for depressive disorder remains a tantalising possibility, especially given the potential for carefully-designed longitudinal studies with multiple biospecimens and ongoing advances in epigenetic technologies.


Intensive Farming: Evolutionary Implications for Parasites and Pathogens.
An increasing number of scientists have recently raised concerns about the threat posed by human intervention on the evolution of parasites and disease agents. New parasites (including pathogens) keep emerging and parasites which previously were considered to be 'under control' are re-emerging, sometimes in highly virulent forms. This re-emergence may be parasite evolution, driven by human activity, including ecological changes related to modern agricultural practices. Intensive farming creates conditions for parasite growth and transmission drastically different from what parasites experience in wild host populations and may therefore alter selection on various traits, such as life-history traits and virulence. Although recent epidemic outbreaks highlight the risks associated with intensive farming practices, most work has focused on reducing the short-term economic losses imposed by parasites, such as application of chemotherapy. Most of the research on parasite evolution has been conducted using laboratory model systems, often unrelated to economically important systems. Here, we review the possible evolutionary consequences of intensive farming by relating current knowledge of the evolution of parasite life-history and virulence with specific conditions experienced by parasites on farms. We show that intensive farming practices are likely to select for fast-growing, early-transmitted, and hence probably more virulent parasites. As an illustration, we consider the case of the fish farming industry, a branch of intensive farming which has dramatically expanded recently and present evidence that supports the idea that intensive farming conditions increase parasite virulence. We suggest that more studies should focus on the impact of intensive farming on parasite evolution in order to build currently lacking, but necessary bridges between academia and decision-makers.


Effectiveness of genetic counselling. Retinoblastoma.
The authors studied 32 families with 36 RB patients. Among them 24 were sporadic cases; four had recurrence of RB; two had RB plus bone tumour in relatives and two were RB propositi. Two evaluations with an interval from four to 13 years were made. In the first the recurrence risk was informed as high or low. The patients' decisions were evaluated at the second consultation. The authors considered that counselling was negative in more than 50% of cases. For normal parents, prognosis of RB was severe, whereas for RB patients it was mild.


Detection of hepatitis C virus sequences in liver tissue by the polymerase chain reaction.
Although sensitive assays for serum antibodies to hepatitis C virus (HCV/anti-HCV) have been developed recently, the relation of anti-HCV to HCV infection of the liver has not been clarified. Therefore, we determined the presence of HCV RNA by the reverse transcription-polymerase chain reaction (PCR) in liver biopsy specimens of 21 patients with chronic liver disease and 5 control patients. RNA was extracted from frozen liver tissues by the guanidinium method, HCV cDNA was synthesized by reverse transcription, and core region and NS3 region sequences were amplified by PCR. The sensitivity and specificity of the reaction was significantly enhanced by double PCR with nested primers followed by Southern blotting with an HCV specific oligomer probe. NS3 region sequences were detected in the liver specimens of 12 out of 15 anti-HCV positive patients. Core region sequences were detected in 9 patients, all of whom were also positive for NS3 region sequences. HCV sequences were not detected in 11 anti-HCV negative patients. In all cases, the integrity of the extracted RNA was demonstrated by successful amplification of albumin mRNA as internal control. Our findings demonstrate the feasibility of the reverse transcription-double PCR method followed by Southern blotting for the detection of HCV sequences in liver tissues. In this system, the detection rate of NS3 region sequences is higher than that of core region sequences. There is a statistically significant correlation between high titer anti-HCV antibodies in serum and NS3 region sequences in liver tissue. However, not all anti-HCV positive patients had HCV positive hepatitis. The reverse transcription-polymerase chain reaction for HCV sequences on liver tissue extracts may reveal valuable information on the diagnosis of HCV infection and the pathogenesis of chronic hepatitis C.


Mortality and morbidity of hepatectomy, radiofrequency ablation, and embolization for hepatocellular carcinoma: a national survey of 54,145 patients.
Reported mortalities and morbidities of therapeutic procedures for liver tumors vary between studies, because of different designs and small sample sizes. We investigated the mortalities and complication rates for hepatectomy, radiofrequency ablation (RFA), and trans-catheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) in a large sample, using a nationwide Japanese database (the Diagnosis Procedure Combination database). Data from the Diagnosis Procedure Combination database were analyzed for July 1 to December 31, 2007 and the same period in 2008. We identified 54,145 patients with HCC who underwent hepatectomy (n = 5,270), RFA (n = 11,688), or TAE (n = 37,187). In-hospital mortality and morbidity were analyzed for each procedure. The relationships between mortality and factors including patient characteristics and procedural backgrounds were assessed. In-hospital mortalities associated with hepatectomy, RFA, and TAE were 2.6 % [95 % confidence interval (CI) 2.2-3.1], 0.3 % (0.2-0.4), and 1.0 % (0.9-1.1), and post-procedural complication rates were 14.5 % (13.5-15.5), 4.5 % (4.2-4.9), and 4.5 % (4.3-4.7), respectively. Increased mortality following hepatectomy was significantly associated with older age, extended lobectomy (vs. partial hepatectomy; odds ratio [OR] 3.80, p < 0.001), lower hospital volume (OR 2.74, p < 0.001), and renal comorbidity (OR 3.01, p = 0.02). Older age and cardiac comorbidity (OR 5.14, p = 0.001) were significantly associated with RFA-related mortality, and lower hospital volume was significantly associated with TAE-related mortality (OR 1.60, p < 0.001). Mortalities and morbidities associated with therapeutic procedures for liver tumors were acceptably low in Japan, but were affected by patient and institutional characteristics.


Gel-based mass spectrometric analysis of recombinant GABA(A) receptor subunits representing strongly hydrophobic transmembrane proteins.
GABA(A) receptors are the major inhibitory transmitter receptors in mammalian brain and are composed of several protein subunits that can belong to different subunit classes, leading to enormous heterogeneity. To establish techniques for the analysis of GABA(A) receptors in complex mixtures such as brain tissue, recombinant receptors composed of alpha1 and His-tagged beta3 subunits expressed in insect cells were purified by affinity chromatography and run on blue native gels. After denaturing, receptors were subjected to one- or two-dimensional electrophoresis in SDS-gels. Proteins were cleaved by multienzyme proteolysis and subjected to nano-ESI-LC-MS/MS. Both GABA(A) receptor subunits were well-separated and unambiguously identified by sequence coverage of 99.1% (alpha1) and 92.9% (beta3).


Loss of AF6/afadin, a marker of poor outcome in breast cancer, induces cell migration, invasiveness and tumor growth.
Afadin/AF6, an F-actin-binding protein, is ubiquitously expressed in epithelia and has a key role during development, through its regulatory role in cell-cell junction organization. Afadin loss of expression in 15% of breast carcinoma is associated with adverse prognosis and increased risk of metastatic relapse. To determine the role of afadin in breast cancer, we studied the functional consequences of afadin protein extinction using in vitro and in vivo models. Three different breast cancer cell lines representative of the major molecular subtypes were stably repressed for afadin expression (knockdown of afadin (afadin KD)) using RNA interference. Collective and individual migrations as well as Matrigel invasion were markedly increased in afadin KD cells. Heregulin-β1 (HRG-β1)-induced migration and invasion were increased by twofold in afadin KD cells. Conversely, ectopic expression of afadin in the afadin-negative T47D cell line inhibited spontaneous and HRG-β1-induced migrations. RAS/MAPK and SRC kinase pathways were activated in afadin KD cells. Activation levels positively correlated with migration and invasion strength. Use of MEK1/2 (U0126) and SRC kinases (SU6656) inhibitors reduced afadin-dependent migration and invasion. Afadin extinction in the SK-BR-3 cell line markedly accelerated tumor growth development in mouse mammary gland and lung metastasis formation. These results may explain why the loss of afadin expression in tumors correlates with high tumor size and poor metastasis-free survival in patients.


A National Memory Clinic Survey to Assess Provision for People from Diverse Ethnic Backgrounds in England and Wales.
English national guidelines regarding dementia assessment and management recommend consideration of cultural and linguistic diversity when assessing people with cognitive complaints. To date there has been no assessment of adherence to these guidelines. We aimed to assess whether current services provided in memory assessment services (MAS) adhere to national policy, in their approach to the assessment and management of individuals with memory problems from minority ethnic backgrounds. We sent a survey to 213 memory services in England and Wales. Twenty MAS from seven regions responded to the survey. We found that 80% (16) provided translated resources, 70% (14) used cognitive assessment tools that are culturally sensitive and appropriate, and 65% (13) showed good use of sufficiently skilled and knowledgeable interpreters. Communication barriers, particularly language, were raised as a potential obstacle to diagnosing minority ethnic patients. Memory clinics appear to reflect national policy for the assessment and management of memory problems in minority ethnic patients. However, only a minority of services responded and they may be more engaged in considering these populations. We need wider knowledge of practice to explore how guidelines support healthcare professional's assessment of patients from minority ethnic groups in memory service diagnostic procedures.


Characterizing highly dynamic conformational states: The transcription bubble in RNAP-promoter open complex as an example.
Bio-macromolecules carry out complicated functions through structural changes. To understand their mechanism of action, the structure of each step has to be characterized. While classical structural biology techniques allow the characterization of a few "structural snapshots" along the enzymatic cycle (usually of stable conformations), they do not cover all (and often fast interconverting) structures in the ensemble, where each may play an important functional role. Recently, several groups have demonstrated that structures of different conformations in solution could be solved by measuring multiple distances between different pairs of residues using single-molecule Förster resonance energy transfer (smFRET) and using them as constrains for hybrid/integrative structural modeling. However, this approach is limited in cases where the conformational dynamics is faster than the technique's temporal resolution. In this study, we combine existing tools that elucidate sub-millisecond conformational dynamics together with hybrid/integrative structural modeling to study the conformational states of the transcription bubble in the bacterial RNA polymerase-promoter open complex (RPo). We measured microsecond alternating laser excitation-smFRET of differently labeled lacCONS promoter dsDNA constructs. We used a combination of burst variance analysis, photon-by-photon hidden Markov modeling, and the FRET-restrained positioning and screening approach to identify two conformational states for RPo. The experimentally derived distances of one conformational state match the known crystal structure of bacterial RPo. The experimentally derived distances of the other conformational state have characteristics of a scrunched RPo. These findings support the hypothesis that sub-millisecond dynamics in the transcription bubble are responsible for transcription start site selection.


Functional analysis of a human homologue of the Drosophila actin binding protein anillin suggests a role in cytokinesis.
We have characterized a human homologue of anillin, a Drosophila actin binding protein. Like Drosophila anillin, the human protein localizes to the nucleus during interphase, the cortex following nuclear envelope breakdown, and the cleavage furrow during cytokinesis. Anillin also localizes to ectopic cleavage furrows generated between two spindles in fused PtK(1) cells. Microinjection of antianillin antibodies slows cleavage, leading to furrow regression and the generation of multinucleate cells. GFP fusions that contain the COOH-terminal 197 amino acids of anillin, which includes a pleckstrin homology (PH) domain, form ectopic cortical foci during interphase. The septin Hcdc10 localizes to these ectopic foci, whereas myosin II and actin do not, suggesting that anillin interacts with the septins at the cortex. Robust cleavage furrow localization requires both this COOH-terminal domain and additional NH(2)-terminal sequences corresponding to an actin binding domain defined by in vitro cosedimentation assays. Endogenous anillin and Hcdc10 colocalize to punctate foci associated with actin cables throughout mitosis and the accumulation of both proteins at the cell equator requires filamentous actin. These results indicate that anillin is a conserved cleavage furrow component important for cytokinesis. Interactions with at least two other furrow proteins, actin and the septins, likely contribute to anillin function.


Missed opportunities for interval empathy in lung cancer communication.
Empathy is important in patient-physician communication and is associated with improved patient satisfaction and adherence to physicians' recommendations. To evaluate empathic opportunities and physician responses, we conducted a qualitative thematic analysis of 20 audiorecorded, transcribed consultations between patients with lung cancer and their thoracic surgeons or oncologists, from a larger observational study of 137 patients in a Veterans Affairs hospital in the southern United States. Using qualitative analysis, we collaboratively developed themes and subthemes until saturation. Then, each transcript was coded, using grounded theory methods, until consensus was achieved, counting and sequentially analyzing patient empathic opportunities and physician responses. Subthemes regarding patients' statements about lung cancer included (1) morbidity or mortality concerns, (2) cancer-related symptoms, (3) relationship to smoking, (4) decisions about treatment, (5) beliefs about or mistrust of medical care, (6) factors limiting ability to treat cancer, and (7) confusion regarding cancer status and treatment. We identified 384 empathic opportunities and found that physicians had responded empathically to 39 (10%) of them. Otherwise, physicians provided little emotional support, often shifting to biomedical questions and statements. We defined this phenomenon as missed opportunities for "interval empathy." When empathy was provided, 50% of these statements occurred in the last one-third of the encounter, whereas patients' concerns were evenly raised throughout the encounter. Physicians rarely responded empathically to the concerns raised by patients with lung cancer, and empathic responses that did occur were more frequently in the last third of the encounter. Our results may provide a typologic approach to help physicians recognize empathic opportunities and with further development may aid in improving physicians' communication skills.


N-acetyl- beta -D-glucosaminidase activity in the endometrial epithelium of the cow's uterus during the oestrous cycle and pregnancy.
The levels of N-acetyl-beta-D-glucosaminidase (NAGase) were measured in the endometrial epithelial tissue of the bovine uterus during the oestrous cycle and during pregnancy. NAGase levels were significantly (P<0.001) higher in the epithelial tissue of the cow's uterus during the luteal phase of the cycle and during pregnancy than during the non-luteal phase. There were significantly (P<0.001) higher mean NAGase values in the epithelial than the subepithelial layers of the uterus in the two cycle phases and in pregnancy. Leucocyte numbers were significantly (P<0.05 and P<0.001) higher in the cows' uteri during the non-luteal phase than during the luteal phase and pregnancy, respectively. It is concluded that the endometrial epithelial layer is significantly active in terms of NAGase release and that this may be related to increased progesterone concentrations. In addition, the epithelial tissue (not leucocytes) appears to be the main contributor to the total NAGase activity in uterine tissue.


[Philosophic basis of the general pathology theory].
The general human pathology is the theoretic basis of practical medicine. However the general theoretical comprehension of pathological process is in growing stage. The number of important problems remain unsolved. In this article a version of construction of the deductive theory of general pathology is presented. The principle of tissue adaptive regeneration is the optimal principle of general theory of pathology.


Nanostructured TaON/Ta3N5 as a highly efficient type-II heterojunction photoanode for photoelectrochemical water splitting.
Enhancing the charge separation by a semiconductor heterojunction is greatly promising and challenging for photoelectrochemical (PEC) water splitting. Here, we report for the first time the design and fabrication of a TaON/Ta3N5 heterojunction photoanode, in which the electrode Ta3N5 is the primary light absorber and TaON acts as an electron conductor. By combining the merits of the substantial light harvesting of Ta3N5 with the excellent charge transport capability of TaON, the TaON/Ta3N5 heterojunction photoanode, without any co-catalysts, shows a 350 mV negative shift of photocurrent onset potential to 0.65 V versus the reversible hydrogen electrode (RHE) compared to that of the Ta3N5 photoanode. The design and fabrication scheme can be readily extended to other (oxy)nitride semiconductors for heterojunction construction.


A mechanics comparison between landing from a countermovement jump and landing from stepping off a box.
It is common practice to study jump landing mechanics by having subjects step off a box set at a certain height instead of landing from a jump. This practice assumes that the landing mechanics are similar between stepping off a box and a countermovement jump as long as the heights can be matched. The mechanics of the two methods had never been compared when landing from identical heights. Thus, the purpose of this study was to compare the mechanics of landing from a countermovement jump to landing from a step-off. Participants performed three maximal countermovement jumps. The mechanics of one countermovement jump was compared with a center of mass fall height matched step-off landing. The step-off landing showed a more rapid time to peak ground reaction force (GRF) in both genders and greater GRF peak and loading rate in males only. No difference was observed between joint angles at initial contact; however, the countermovement jump showed significantly greater joint flexion angles at peak GRF for both genders. EMG showed greater muscle activity during the countermovement jump condition in all subjects. It was concluded that countermovement jump landings are different from step-off landings; thus, results from analyses involving step-off landings should be taken with caution if the aim is to relate them to landing from a jump.


Alcohol and gastrointestinal oncology.
Results from several large epidemiological studies have firmly established that alcohol is associated with elevated cancer incidence and mortality. Recently the International Agency for Cancer Research stated that acetaldehyde associated with alcoholic beverages is carcinogenic to humans and confirmed the Group 1 classification of alcohol consumption and of ethanol in alcoholic beverages. Alcohol consumption causes cancers of the oral cavity, pharynx, larynx, oesophagus, colorectum, liver, pancreas and female breast. The frequency of most alcohol-induced diseases increases in a linear fashion as intake increases: oral, oesophagus and colon cancer fall into this pattern. Very little is known about safe margins of alcohol consumption. US Department of Health and Human Services suggest a maximum of 28 g of alcohol a day in man and half of this in women.


Thymostimulin treatment of hepatocellular carcinoma on liver cirrhosis.
Hepatocellular carcinoma (HCC) on liver cirrhosis (LC) is a neoplasm with a poor prognosis. Only 10-36% of patients have resectable tumors at presentation, systemic chemotherapy is seldom useful and loco-regional treatments are feasible only in selected cases. On the basis of the possible role of depression of immune function in the pathogenesis of HCC on LC, we employed thymostimulin in the treatment of patients with unresectable HCC on LC, with the aim of influencing the course of the disease. Forty-six consecutive patients with HCC were enrolled from January 1987 to December 1993. All patients, 36 males and 10 females, with a median age of 67 years (range 58-82) had coexisting LC. All patients were treated with thymostimulin (TP-1 Serono) at doses of 70 mg/day i.m. five times a week until disease progression. Eleven patients achieved an objective response, with an overall response rate of 24%. Six patients obtained a CR (13.0%) with a median duration of 19+ months (range 5+/-23). Five patients (11%) achieved PR with a median duration of 10 months (range 7+/-22). Six patients (13.0%) presented MR (median duration: 12.5 months) and 12 (26.0%) had SD (median duration: 8 months). In 17 patients (36.9%) the disease progressed. Thymostimulin treatment was well tolerated and no major side effect was observed. Thymostimulin treatment can be considered a new promising therapy for advanced HCC.


pSLIP: SVM based protein subcellular localization prediction using multiple physicochemical properties.
Protein subcellular localization is an important determinant of protein function and hence, reliable methods for prediction of localization are needed. A number of prediction algorithms have been developed based on amino acid compositions or on the N-terminal characteristics (signal peptides) of proteins. However, such approaches lead to a loss of contextual information. Moreover, where information about the physicochemical properties of amino acids has been used, the methods employed to exploit that information are less than optimal and could use the information more effectively. In this paper, we propose a new algorithm called pSLIP which uses Support Vector Machines (SVMs) in conjunction with multiple physicochemical properties of amino acids to predict protein subcellular localization in eukaryotes across six different locations, namely, chloroplast, cytoplasmic, extracellular, mitochondrial, nuclear and plasma membrane. The algorithm was applied to the dataset provided by Park and Kanehisa and we obtained prediction accuracies for the different classes ranging from 87.7%-97.0% with an overall accuracy of 93.1%. This study presents a physicochemical property based protein localization prediction algorithm. Unlike other algorithms, contextual information is preserved by dividing the protein sequences into clusters. The prediction accuracy shows an improvement over other algorithms based on various types of amino acid composition (single, pair and gapped pair). We have also implemented a web server to predict protein localization across the six classes (available at http://pslip.bii.a-star.edu.sg/).


Characterisation of the legume SERK-NIK gene superfamily including splice variants: implications for development and defence.
SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) genes are part of the regulation of diverse signalling events in plants. Current evidence shows SERK proteins function both in developmental and defence signalling pathways, which occur in response to both peptide and steroid ligands. SERKs are generally present as small gene families in plants, with five SERK genes in Arabidopsis. Knowledge gained primarily through work on Arabidopsis SERKs indicates that these proteins probably interact with a wide range of other receptor kinases and form a fundamental part of many essential signalling pathways. The SERK1 gene of the model legume, Medicago truncatula functions in somatic and zygotic embryogenesis, and during many phases of plant development, including nodule and lateral root formation. However, other SERK genes in M. truncatula and other legumes are largely unidentified and their functions unknown. To aid the understanding of signalling pathways in M. truncatula, we have identified and annotated the SERK genes in this species. Using degenerate PCR and database mining, eight more SERK-like genes have been identified and these have been shown to be expressed. The amplification and sequencing of several different PCR products from one of these genes is consistent with the presence of splice variants. Four of the eight additional genes identified are upregulated in cultured leaf tissue grown on embryogenic medium. The sequence information obtained from M. truncatula was used to identify SERK family genes in the recently sequenced soybean (Glycine max) genome. A total of nine SERK or SERK-like genes have been identified in M. truncatula and potentially 17 in soybean. Five M. truncatula SERK genes arose from duplication events not evident in soybean and Lotus. The presence of splice variants has not been previously reported in a SERK gene. Upregulation of four newly identified SERK genes (in addition to the previously described MtSERK1) in embryogenic tissue cultures suggests these genes also play a role in the process of somatic embryogenesis. The phylogenetic relationship of members of the SERK gene family to closely related genes, and to development and defence function is discussed.


Synthesis of bis(amino alcohol)oxalamides and their usage for the preconcentration of trace metals by cloud point extraction.
C(2)-Symmetric two bis(amino alcohol)oxalamides (diamidediols) were synthesized and fully characterized. A new method was developed and successfully applied for the simultaneous preconcentration of both trace and toxic metals in water, by using C(2)-symmetric compounds. Under the optimum experimental conditions (i.e. pH = 10.0 +/- 0.2, 2.75 x 10(-3) mol L(-1) N,N'-bis[(1R)-1-ethyl-2-hydroxyethyl]ethanediamide (DAD1), 1.75 x 10(-3) mol L(-1) N,N'-bis[(1S)-1-benzyl-2-hydroxyethyl]-ethanediamide (DAD2), 0.10% w/v octylphenoxy-polyethoxyethanol (Triton X-114)), calibration graphs were linear in the range of 2.5 - 25.0 ng mL(-1) for Cu and Cd, 5.0 - 25.0 ng mL(-1) for Co and Ni. The enrichment factors were 18, 23, 18 and 20 for Cd, Cu, Co and Ni in the case of DAD1, respectively; 20, 22, 17 and 20 for Cd, Cu, Co and Ni in the case of DAD2. The limits of detection for DAD1 were found to be 0.45, 0.50, 1.25 and 0.60 ng mL(-1) for Cd, Cu, Co and Ni, respectively, and for DAD2 were found to be 0.44, 0.25, 0.60 and 1.55 ng mL(-1) for Cd, Cu, Co and Ni, respectively. The developed method was applied to the determination of Cu, Cd, Co and Ni in water samples and certified reference materials with satisfactory results.


Marmoricola korecus sp. nov.
A novel actinomycete, designated strain Sco-A36(T), was isolated from volcanic ash. Cells were aerobic, Gram-stain-positive, oxidase-negative, catalase-positive, non-motile cocci; colonies were yellow-coloured, smooth, entire and convex. Phylogenetic analysis showed that the organism formed a distinct phyletic line within the radiation of the genus Marmoricola. Its closest phylogenetic neighbours were Marmoricola aurantiacus DSM 12652(T) (97.9 % 16S rRNA gene sequence similarity), Marmoricola scoriae Sco-D01(T) (97.9 %), Marmoricola aequoreus SST-45(T) (97.4 %) and Marmoricola bigeumensis MSL-05(T) (96.3 %). The diagnostic diamino acid in the cell walls was ll-diaminopimelic acid. The predominant menaquinone was MK-8(H(4)). The polar lipids contained phosphatidylinositol, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine and an unknown phospholipid. The predominant fatty acids were C(16 : 0), C(17 : 1)ω8c, C(18 : 1)ω9c and C(16 : 1)ω7c and/or iso-C(15 : 0) 2-OH. The DNA G+C content of strain Sco-A36(T) was 71.0 mol%. Levels of DNA-DNA relatedness between the new isolate and the type strains of recognized species of the genus Marmoricola were 4.9-29.2 %. The phenotypic and DNA-DNA hybridization data presented here strongly suggest that strain Sco-A36(T) represents a novel species of the genus Marmoricola, for which the name Marmoricola korecus sp. nov. is proposed. The type strain is Sco-A36(T) ( = KCTC 19596(T) = DSM 22128(T)).


Unlocking the power of cross-species genomic analyses: identification of evolutionarily conserved breast cancer networks and validation of preclinical models.
The application of high-throughput genomic technologies has revealed that individual breast tumors display a variety of molecular features that require more personalized approaches to treatment. Several recent studies have demonstrated that a cross-species analytic approach provides a powerful means to filter through genetic complexity by identifying evolutionarily conserved genetic networks that are fundamental to the oncogenic process. Mouse-human tumor comparisons will provide insights into cellular origins of tumor subtypes, define interactive oncogenetic networks, identify potential novel therapeutic targets, and further validate as well as guide the selection of genetically engineered mouse models for preclinical testing.


Effectiveness of antilock braking systems in reducing motorcycle fatal crash rates.
Overbraking and underbraking have been shown to be common factors in motorcycle crashes. Antilock braking systems (ABS) prevent wheels from locking during braking and may make riders less reluctant to apply full braking force. The objective of this study was to evaluate the effect of ABS in fatal motorcycle crashes. Motorcycle drivers involved in fatal crashes per 10,000 registered vehicle years were compared for 13 motorcycle models with optional ABS and those same models without the option during 2003-2008. Motorcycles with optional ABS were included only if the presence of the option could be identified from the vehicle identification number. The rate of fatal motorcycle crashes per 10,000 registered vehicle years was 37 percent lower for ABS models than for their non-ABS versions. ABS appears to be highly effective in preventing fatal motorcycle crashes based on some early adopters of motorcycle ABS technology.


Role of Radiation Therapy in Adult Extraskeletal Ewing's Sarcoma Patients Treated with Chemotherapy and Surgery.
Radiation therapy (RT) is advocated in the multimodal treatment of high-grade soft tissue sarcoma (STS), but its role may be less clear in chemotherapy-sensitive STS such as extraskeletal Ewing sarcoma (EES). The purpose of this study was to determine the role of RT on overall survival (OS) in localized EES adult patients treated with chemotherapy and surgery. Adult patients diagnosed with EES and reported to the National Cancer Database from 2004 to 2014 were evaluated. All patients were treated with surgical resection. Patient demographics, tumor characteristics, treatments received, resection margins, and survival were examined for the 232 patients identified. Using multivariate analysis and Cox proportional hazard analysis, predictors of OS were determined. In the overall cohort, 40 percent of patients received RT and 78 percent received chemotherapy, with 31 percent receiving both. The addition of RT to the patients receiving surgery + chemotherapy did not improve OS (p < 0.05). Twenty-four percent of patients who achieved R0 resection after surgery still received RT without any improvement in OS. Patients treated at community cancer centers were more likely to receive additional RT compared with Comprehensive Cancer Centers (p < 0.05). In adult EES patients with localized disease treated with chemotherapy and surgery, the addition of RT does not improve overall survival.


Large-scale detection and analysis of RNA editing in grape mtDNA by RNA deep-sequencing.
RNA editing is a widespread post-transcriptional molecular phenomenon that can increase proteomic diversity, by modifying the sequence of completely or partially non-functional primary transcripts, through a variety of mechanistically and evolutionarily unrelated pathways. Editing by base substitution has been investigated in both animals and plants. However, conventional strategies based on directed Sanger sequencing are time-consuming and effectively preclude genome wide identification of RNA editing and assessment of partial and tissue-specific editing sites. In contrast, the high-throughput RNA-Seq approach allows the generation of a comprehensive landscape of RNA editing at the genome level. Short reads from Solexa/Illumina GA and ABI SOLiD platforms have been used to investigate the editing pattern in mitochondria of Vitis vinifera providing significant support for 401 C-to-U conversions in coding regions and an additional 44 modifications in non-coding RNAs. Moreover, 76% of all C-to-U conversions in coding genes represent partial RNA editing events and 28% of them were shown to be significantly tissue specific. Solexa/Illumina and SOLiD platforms showed different characteristics with respect to the specific issue of large-scale editing analysis, and the combined approach presented here reduces the false positive rate of discovery of editing events.


Risk for mental illness and family composition after migration to Sweden.
The aim of the present study is to determine how marital status and certain post-migration family structures are associated with the risk of mental illness among recently arrived Arabic- speaking refugees in Sweden. A cross-sectional study was conducted during 2015 and 2016. The study population was recruited by inviting all adult refugees who participated in the mandatory public integration support programme. All refugees that participated had received refugee status. A total of 681 of the invited participants returned the GHQ-12 questionnaires, through which the risk for mental illness was measured and only Arabic- speaking refugees (N = 638) were included in the analyses. Marital status per se was not associated with a risk for mental illness. However, for the whole study sample there was a statistical significant odds ratio of 1.72 (95% CI 1.03-2.86). For male Arabic-speaking refugees with a spouse or child left behind in the home country there was a borderline significant increased risk for mental illness, odds ratio = 1. 87 (95% CI 0.99-3.56). The risk for female Arabic-speaking refugees was non-significant, odds ratio = 1.35 (95% CI 0.55-3.33). Arabic- speaking refugees who were separated from family members reported an increased risk for mental illness after arriving in the host country. Actions to facilitate family reunion after arriving as a refugee (in Sweden) seems to be an important factor to promote mental health among refugees.


Tetraphenolate niobium and tantalum complexes for the ring opening polymerization of ε-caprolactone.
Reaction of the pro-ligand α,α,α',α'-tetra(3,5-di-tert-butyl-2-hydroxyphenyl-p-)xylene-para-tetraphenol (p-L(1)H4) with two equivalents of [NbCl5] in refluxing toluene afforded, after work-up, the complex {[NbCl3(NCMe)]2(μ-p-L(1))}·6MeCN (1·6MeCN). When the reaction was conducted in the presence of excess ethanol, the orange complex {[NbCl2(OEt)(NCMe)]2(μ-p-L(1))}·3½MeCN·0.614toluene (2·3½MeCN·0.614toluene) was formed. A similar reaction using [TaCl5] afforded the yellow complex {[TaCl2(OEt)(NCMe)]2(μ-p-L(1))}·5MeCN (3·5MeCN). In the case of the meta pro-ligand, namely α,α,α',α'tetra(3,5-di-tert-butyl-2-hydroxyphenyl-m-)xylene-meta-tetraphenol (m-L(2)H4) only the use of [Nb(O)Cl3(NCMe)2] led to the isolation of crystalline material, namely the orange bis-chelate complex {[Nb(NCMe)Cl(m-L(2)H2)2]}·3½MeCN (4·3½MeCN) or {[Nb(NCMe)Cl(m-L(2)H2)2]}·5MeCN (4·5MeCN). The molecular structures of 1-4 and the tetraphenols L(1)H4 and m-L(2)H4·2MeCN have been determined. Complexes 1-4 have been screened as pre-catalysts for the ring opening polymerization of ε-caprolactone, both with and without benzyl alcohol or solvent present, and at various temperatures; conversion rates were mostly excellent (>96%) with good control either at >100 °C over 20 h (in toluene) or 1 h (neat).


Pseudorabies virus glycoprotein gI: in vitro and in vivo analysis of immunorelevant epitopes.
Overlapping fragments of the gene encoding glycoprotein gI of pseudorabies virus (PRV; herpesvirus suis 1) were expressed in bacteria. Using the fusion proteins and a panel of monoclonal antibodies (MAbs) against gI as well as swine sera we found that the N-terminal part of gI (residues 33 to approximately 100) contains a highly antigenic and immunogenic domain. Transfer of antibodies binding to this region as well as vaccination with fusion proteins containing the N terminus of gI are able to confer protection to mice against a lethal challenge of virus. The results show that gI, which is non-essential for virus replication in tissue culture, can induce neutralizing and protective antibodies. The potential suitability of fusion proteins encompassing N-terminal parts of gI as diagnostic tools is demonstrated.


Tracking the CAR-T Revolution: Analysis of Clinical Trials of CAR-T and TCR-T Therapies for the Treatment of Cancer (1997-2020).
Chimeric antigen receptor and T-cell receptor (CAR-T/TCR-T) cellular immunotherapies have shown remarkable success in the treatment of some refractory B-cell malignancies, with potential to provide durable clinical response for other types of cancer. In this paper, we look at all available FDA CAR-T/TCR-T clinical trials for the treatment of cancer, and analyze them with respect to different disease tissues, targeted antigens, products, and originator locations. We found that 627 of 1007 registered are currently active and of those 273 (44%) originated in China and 280 (45%) in the US. Our analysis suggests that the rapid increase in the number of clinical trials is driven by the development of different CAR-T products that use a similar therapeutic approach. We coin the term bioparallels to describe such products. Our results suggest that one feature of the CAR-T/TCR-T industry may be a robust response to success and failure of competitor products.


Expression of CD10 by human T cells that undergo apoptosis both in vitro and in vivo.
This study shows that human postthymic T cells express CD10 when undergoing apoptosis, irrespective of the signal responsible for initiating the apoptotic process. Cells from continuous T-cell lines did not normally express CD10, but became CD10(+) when induced into apoptosis by human immunodeficiency virus (HIV) infection and exposure to CD95 monoclonal antibody, etoposide, or staurosporin. Inhibitors of caspases blocked apoptosis and CD10 expression. Both CD4(+) and CD8(+) T cells purified from normal peripheral blood expressed CD10 on apoptotic induction. CD10 was newly synthesized by the apoptosing cells because its expression was inhibited by exposure to cycloheximide and CD10 mRNA became detectable by reverse transcription-polymerase chain reaction in T cells cultured under conditions favoring apoptosis. To show CD10 on T cells apoptosing in vivo, lymph node and peripheral blood T cells from HIV(+) subjects were used. These suspensions were composed of a substantial, although variable, proportion of apoptosing T cells that consistently expressed CD10. In contrast, CD10(+) as well as spontaneously apoptosing T cells were virtually absent in peripheral blood from normal individuals. Collectively, these observations indicate that CD10 may represent a reliable marker for identifying and isolating apoptosing T cells in vitro and ex vivo and possibly suggest novel functions for surface CD10 in the apoptotic process of lymphoid cells.


A Strategy To Exploit Surrogate Sire Technology in Livestock Breeding Programs.
In this work, we performed simulations to develop and test a strategy for exploiting surrogate sire technology in animal breeding programs. Surrogate sire technology allows the creation of males that lack their own germline cells, but have transplanted spermatogonial stem cells from donor males. With this technology, a single elite male donor could give rise to huge numbers of progeny, potentially as much as all the production animals in a particular time period. One hundred replicates of various scenarios were performed. Scenarios followed a common overall structure but differed in the strategy used to identify elite donors and how these donors were used in the product development part. The results of this study showed that using surrogate sire technology would significantly increase the genetic merit of commercial sires, by as much as 6.5 to 9.2 years' worth of genetic gain compared to a conventional breeding program. The simulations suggested that a strategy involving three stages (an initial genomic test followed by two subsequent progeny tests) was the most effective of all the strategies tested. The use of one or a handful of elite donors to generate the production animals would be very different to current practice. While the results demonstrate the great potential of surrogate sire technology there are considerable risks but also other opportunities. Practical implementation of surrogate sire technology would need to account for these.


Effects of d-amphetamine and diazepam on fixed-interval, fixed-ratio responding in humans.
Human operant responding, maintained under a multiple fixed-ratio (FR) 30 fixed-interval (FI) 5 min schedule of point presentation was shown to be differentially sensitive to the effects of d-amphetamine and diazepam. d-Amphetamine (5-20 mg) increased rates of FR responding, whereas 10 and 20 mg of diazepam generally decreased FR rates. FI rates, in general, were unaffected by d-amphetamine, with consistent increases occurring in only one of four subjects. Diazepam decreased FI rates. The number of reinforcers obtained in the FR and the FI was increased by d-amphetamine and decreased by diazepam for two of the four subjects and was unaffected by either drug in the other two subjects. In addition, physiological measures, including heart rate and blood pressure, and verbal reports of drug effects as measured by the Profile of Mood Scales and the Addiction Research Center Inventory were generally differentially affected by the two drugs. These results suggest that a multiple FR 30 FI 5 min schedule of point presentation is capable of distinguishing behavioral effects of two different classes of drugs, the psychomotor stimulants and the minor tranquilizers. In addition, the results extend previously reported effects of diazepam on responding maintained under similar schedules from nonhuman subjects to humans. The effect of d-amphetamine in increasing rates of FR 30 responding, however, was unexpected in that amphetamine is generally reported to produce decreases in the high rates of responding generated by FR schedules in nonhuman subjects.


Steroid receptors and endometrial cancer.
Like breast carcinomas, endometrial carcinomas are derived from sex steroid target tissue. Progress and research directed into the clinicopathologic relationship of steroid receptors and endometrial carcinomas have been hampered by many factors, including: limited numbers of patients with advanced-stage disease compared to the number with breast carcinoma; contamination of specimens with surrounding benign endometrial components which may contribute to total steroid binding; and amount of tissue required for standard biochemical assays. Nevertheless, several clinicopathological associations have been made for steroid receptor content of endometrial carcinomas. Receptor content appears to correlate with histological differentiation in that well-differentiated lesions have higher mean levels of receptor and more receptor 'positive' lesions than do poorly differentiated lesions. Furthermore, receptor levels and status appear to correlate with prognosis of primary endometrial carcinomas and response to hormonal therapy of advanced endometrial carcinoma. Newer techniques utilizing monoclonal antibodies to directly localize receptor in tissue specimens may lead to a greater understanding of the dynamics of receptor physiology in endometrial carcinomas, and may make possible more accurate predictions of clinical behavior by allowing the direct analysis of the receptor content of the malignant component within a tissue specimen.


Using Infodemiology Metrics to Assess Public Interest in Liver Transplantation: Google Trends Analysis.
Liver transplantation (LT) is the only curative treatment for end-stage liver disease. Less than 10% of global transplantation needs are met worldwide, and the need for LT is still increasing. The death rates on the waiting list remain too high. It is, therefore, critical to raise awareness among the public and health care providers and in turn increasingly acquire donors. We performed a Google Trends search using the search terms liver transplantation and liver transplant on October 15, 2020. On the basis of the resulting monthly data, the annual average Google Trends indices were calculated for the years 2004 to 2018. We not only investigated the trend worldwide but also used data from the United Network for Organ Sharing (UNOS), Spain, and Eurotransplant. Using pairwise Spearman correlations, Google Trends indices were examined over time and compared with the total number of liver transplants retrieved from the respective official websites of UNOS, the Organización Nacional de Trasplantes, and Eurotransplant. From 2004 to 2018, there was a significant decrease in the worldwide Google Trends index from 78.2 in 2004 to 20.5 in 2018 (-71.2%). This trend was more evident in UNOS than in the Eurotransplant group. In the same period, the number of transplanted livers increased worldwide. The waiting list mortality rate was 31% for Eurotransplant and 29% for UNOS. However, in Spain, where there are excellent awareness programs, the Google Trends index remained stable over the years with comparable, increasing LT numbers but a significantly lower waiting list mortality (15%). Public awareness in LT has decreased significantly over the past two decades. Therefore, novel awareness programs should be initialized.


Pursuing sustainable productivity with millions of smallholder farmers.
Sustainably feeding a growing population is a grand challenge, and one that is particularly difficult in regions that are dominated by smallholder farming. Despite local successes, mobilizing vast smallholder communities with science- and evidence-based management practices to simultaneously address production and pollution problems has been infeasible. Here we report the outcome of concerted efforts in engaging millions of Chinese smallholder farmers to adopt enhanced management practices for greater yield and environmental performance. First, we conducted field trials across China's major agroecological zones to develop locally applicable recommendations using a comprehensive decision-support program. Engaging farmers to adopt those recommendations involved the collaboration of a core network of 1,152 researchers with numerous extension agents and agribusiness personnel. From 2005 to 2015, about 20.9 million farmers in 452 counties adopted enhanced management practices in fields with a total of 37.7 million cumulative hectares over the years. Average yields (maize, rice and wheat) increased by 10.8-11.5%, generating a net grain output of 33 million tonnes (Mt). At the same time, application of nitrogen decreased by 14.7-18.1%, saving 1.2 Mt of nitrogen fertilizers. The increased grain output and decreased nitrogen fertilizer use were equivalent to US$12.2 billion. Estimated reactive nitrogen losses averaged 4.5-4.7 kg nitrogen per Megagram (Mg) with the intervention compared to 6.0-6.4 kg nitrogen per Mg without. Greenhouse gas emissions were 328 kg, 812 kg and 434 kg CO2 equivalent per Mg of maize, rice and wheat produced, respectively, compared to 422 kg, 941 kg and 549 kg CO2 equivalent per Mg without the intervention. On the basis of a large-scale survey (8.6 million farmer participants) and scenario analyses, we further demonstrate the potential impacts of implementing the enhanced management practices on China's food security and sustainability outlook.


Chronic oral methylphenidate treatment increases microglial activation in rats.
Methylphenidate (MP) is a widely prescribed psychostimulant used to treat attention deficit hyperactivity disorder. Previously, we established a drinking paradigm to deliver MP to rats at doses that result in pharmacokinetic profiles similar to treated patients. In the present study, adolescent male rats were assigned to one of three groups: control (water), low-dose MP (LD; 4/10 mg/kg), and high dose MP (HD; 30/60 mg/kg). Following 3 months of treatment, half of the rats in each group were euthanized, and the remaining rats received only water throughout a 1-month-long abstinence phase. In vitro autoradiography using [3H] PK 11195 was performed to measure microglial activation. HD MP rats showed increased [3H] PK 11195 binding compared to control rats in several cerebral cortical areas: primary somatosensory cortex including jaw (68.6%), upper lip (80.1%), barrel field (88.9%), and trunk (78%) regions, forelimb sensorimotor area (87.3%), secondary somatosensory cortex (72.5%), motor cortices 1 (73.2%) and 2 (69.3%), insular cortex (59.9%); as well as subcortical regions including the thalamus (62.9%), globus pallidus (79.4%) and substantia nigra (22.7%). Additionally, HD MP rats showed greater binding compared to LD MP rats in the hippocampus (60.6%), thalamus (59.6%), substantia nigra (38.5%), and motor 2 cortex (55.3%). Following abstinence, HD MP rats showed no significant differences compared to water controls; however, LD MP rats showed increased binding in pre-limbic cortex (78.1%) and ventromedial caudate putamen (113.8%). These findings indicate that chronic MP results in widespread microglial activation immediately after treatment and following the cessation of treatment in some brain regions.


[Expression and Clinical Significance of Helper T Cells 9 and Its Sytokines Interleukin 9 in Chronic Lymphocytic Leukemia].
To investigate the expression and clinical significance of T helper cell 9 (Th9) and its cytokine interleukin 9(IL-9) in peripheral blood of patients with chronic lymphocytic leukemia(CLL). A total of 43 newly diagnosed patients with chronic lymphocytic leukemia in the First Affiliated Hospital of Xinjiang Medical University from June 2021 to June 2022 were selected as the case group. The patients were divided into Binet A group (13 cases), Binet B group (20 cases) and Binet C group (10 cases) by Binet staging system, and 20 healthy volunteers who underwent physical examinationin in our hospital in the same period served as control group. The proportion of Th9 cells in peripheral blood was detected by flow cytometry, the expression level of Th9 specific transcription factors PU.1 and IRF4 was detected by Western blot, and the expression level of serum cytokine IL-9 was detected by ELISA. The proportion of Th9, the expression of PU.1, IRF4 and IL-9 in each group were compared, and the correlation between the proportion of Th9, IL-9 and clinicopathological indexes of CLL patients was analyzed. The proportion of Th9, the expression of PU.1, IRF4 and IL-9 in CLL group were significantly higher than those in control group (P<0.05), the proportion of Th9 and the expression of IL-9 in Binet B and C group were higher than those in Binet A group (P<0.05), but there was no significant difference in the proportion of Th9 cells between Binet B group and C group (P>0.05). The expression of IL-9 in Binet C group was significantly higher than that in Binet B group (P<0.05) . The proportion of Th9 cells and IL-9 were highly expression in patients with β2 microglobulin abnormality, IGHV unmutation, P53 abnormality and hepatosplenic lymph node enlargement(P<0.05), but not related to age and sex (P>0.05). The results of Spearman correlation analysis showed that the proportion of Th9 in patients with CLL was negatively correlated with the lymphocytic account and lymphocyte proportion(rs=-0.32,rs=-0.34). The proportion of Th9 and IL-9 were positively correlated with Binet stage, Rai stage and CLL-IPI Scoring (rs=0.79,rs=0.54,rs=0.58; rs=0.72,rs=0.63,rs=0.45), but not with WBC, CD4+ T cells and CD8+T cells (P>0.05). The proportion of Th9 was positively correlated with IL-9 (rs=0.53). Th9 cells and IL-9 are abnormally highly expressed in CLL, which is related to the poor prognosis of CLL.


The role of the temporoparietal junction (TPJ) in action observation: Agent detection rather than visuospatial transformation.
Recognizing and understanding the actions of others is usually coupled with perceiving someone else's body movements from a third person perspective (3pp) whereas we perceive our own actions from a first person perspective (1pp). From a neural viewpoint, a recent finding is that perceiving actions from a 3pp as compared to a 1pp activates the temporoparietal junction, a brain region associated with visuospatial transformation and perspective taking but also with mental state inference and Theory of Mind (ToM). The present fMRI study characterizes the response profile of TPJ to elucidate its role in action observation. Participants observed naturalistic and pixelized object-directed actions from a 3pp and 1pp. Critically, in the pixelized condition the action goal could only be inferred from the movement kinematics. Both left and right TPJ revealed an interaction: Neural activity in TPJ was enhanced for 3pp vs. 1pp actions in the naturalistic but not pixelized condition. This finding contradicts theories proposing that TPJ is generally involved in transforming the action into the observer's perspective to match perceived body movements with visuomotor representations in the observer's motor system, which would be particularly required when actions can only be inferred from movement kinematics. Instead, our results support the theory that perceptual 3pp-selective cues trigger ToM-related processes such as detection of other agents and reasoning about an action's underlying mental states.


Bioreactor concepts for cell culture-based viral vaccine production.
Vaccine manufacturing processes are designed to meet present and upcoming challenges associated with a growing vaccine market and to include multi-use facilities offering a broad portfolio and faster reaction times in case of pandemics and emerging diseases. The final products, from whole viruses to recombinant viral proteins, are very diverse, making standard process strategies hardly universally applicable. Numerous factors such as cell substrate, virus strain or expression system, medium, cultivation system, cultivation method, and scale need consideration. Reviewing options for efficient and economical production of human vaccines, this paper discusses basic factors relevant for viral antigen production in mammalian cells, avian cells and insect cells. In addition, bioreactor concepts, including static systems, single-use systems, stirred tanks and packed-beds are addressed. On this basis, methods towards process intensification, in particular operational strategies, the use of perfusion systems for high product yields, and steps to establish continuous processes are introduced.


Cigarette smoke increases BLT2 receptor functions in bronchial epithelial cells: in vitro and ex vivo evidence.
Leukotriene B(4) (LTB(4)) is a neutrophil chemotactic molecule with important involvement in the inflammatory responses of chronic obstructive pulmonary disease (COPD). Airway epithelium is emerging as a regulator of innate immune responses to a variety of insults including cigarette smoke, the major risk factor for COPD. In this study we have explored whether cigarette smoke extracts (CSE) or soluble mediators present in distal lung fluid samples (mini-bronchoalveolar lavages) from smokers alter the expression of the LTB(4) receptor 2 (BLT2) and peroxisome proliferator-activated receptor-α (PPAR-α) in bronchial epithelial cells. We also evaluated the effects of CSE on the expression of intercellular adhesion molecule 1 (ICAM-1) and on the binding of signal transducer and activator of transcription 1 (STAT-1) to ICAM-1 promoter as well as the adhesiveness of neutrophils to bronchial epithelial cells. CSE and mini-bronchoalveolar lavages from smokers increased BLT2 and ICAM-1 expression as well as the adhesiveness of neutrophils to bronchial epithelial cells and decreased PPAR-α expression. CSE induced the activation of STAT-1 and its binding to ICAM-1 promoter. These findings suggest that, in bronchial epithelial cells, CSE promote a prevalent induction of pro-inflammatory BLT2 receptors and activate mechanisms leading to increased neutrophil adhesion, a mechanism that contributes to airway neutrophilia and to tissue damage.


Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales.
The spread of metallo-β-lactamase (MBL)-producing Enterobacterales worldwide without the simultaneous increase in active antibiotics makes these organisms an urgent public health threat. This review summarizes recent advancements in diagnostic and treatment strategies for infections caused by MBL-producing Enterobacterales. Adequate treatment of patients infected with MBL-producing Enterobacterales relies on detection of the β-lactamase in the clinic. There are several molecular platforms that are currently available to identify clinically relevant MBLs as well as other important serine-β-lactamases. Once detected, there are several antibiotics that have historically been used for the treatment of MBL-producing Enterobacterales. Antimicrobials such as aminoglycosides, tetracyclines, fosfomycin, and polymyxins often show promising in vitro activity though clinical data are currently lacking to support their widespread use. Ceftazidime-avibactam combined with aztreonam is promising for treatment of infections caused by MBL-producing Enterobacterales and currently has the most clinical data of any available antibiotic to support its use. While cefiderocol has displayed promising activity against MBL-producing Enterobacterales in vitro and in preliminary clinical studies, further clinical studies will better shed light on its place in treatment. Lastly, there are several promising MBL inhibitors in the pipeline, which may further improve the treatment of MBL-producing Enterobacterales.


[Endotoxin aggression as a universal factor of pathogenesis of hemostatic disorders in children with urological pathology].
The role of the kidneys in development of endotoxin aggression and participation of the latter in impaired regulation of hemostasis was demonstrated basing on examination of 30 children with congenital urological pathology. In progressive decline of accumulative-excretory function of the kidneys, compensated chronic endotoxin aggression in children with urological diseases transforms into a subcompensated or uncompensated one with definite clinical manifestation: fever, aggravation of chronic pyelonephritis, marked DIC syndrome, macrohematuria.


Comparison of the adaptive implementation and evaluation of the Meeting Centers Support Program for people with dementia and their family carers in Europe; study protocol of the MEETINGDEM project.
The MEETINGDEM study aims to implement and evaluate an innovative, inclusive, approach to supporting community dwelling people with mild to moderate dementia and their family carers, called the Meeting Centers Support Program (MCSP), in three countries in the European Union (EU): Italy, Poland and United Kingdom. Demonstrated benefits of this person-centered approach, developed in The Netherlands, include high user satisfaction, reduced behavioral and mood problems, delayed admission to residential care, lower levels of caregiving-related stress, higher carer competence, and improved collaboration between care and welfare organizations. The project will be carried out over a 36 month period. Project partners in the three countries will utilize, and adapt, strategies and tools developed in the Netherlands. In Phase One (month 1-18) activities will focus on establishing an initiative group of relevant organizations and user representatives in each country, exploring pathways to care and potential facilitators and barriers to implementing the program, and developing country specific implementation plans and materials. In Phase Two (month 19‑36) training will be provided to organizations and staff, after which the meeting centers will be established and evaluated for impact on behavior, mood and quality of life of people with dementia and carers, cost-effectiveness, changes in service use, user satisfaction and implementation process. An overall evaluation will draw together findings from the three countries to develop recommendations for successful implementation of MCSP across the EU. If the Meeting Centers approach can be widely implemented, this could lead to major improvements in dementia care across Europe and beyond. The trial was retrospectively registered in May 2016: trial number: NTR5936 .


Induction of cellular genes is mediated by the Bel1 transactivator in foamy virus-infected human cells.
To gain insight into human foamy virus (HFV; also called spumaretrovirus)-induced alterations of cellular genes, the expression profiles of defined genes in HFV-infected primary human cells were analyzed by cDNA array assays. Several distinct cellular genes activated by HFV infection were identified; the identities of the cellular genes were confirmed by RNA blot analyses. Compared with mock-infected controls, the concentrations of cellular Kip2, Egr-1, COUP-TF1, insulin-like growth factor II (IGF-II), and EphB3 mRNAs were significantly increased in HFV-infected cells and showed a gene-specific and time-dependent induction. Immunoblot analyses with antibodies against some of the cellular gene products revealed increased levels of the corresponding proteins. To investigate mechanisms of HFV-induced alterations in cellular gene expression, the capacity of known HFV genes to increase expression of defined cellular genes was analyzed by transient expression experiments. Plasmids that encode the HFV Bel1 transcriptional transactivator were necessary and sufficient to strongly increase expression of p57Kip2, IGF-II, and EphB3 genes in 293T cells. Potential mechanisms and consequences of activation of cellular genes during HFV infection and Bel1 transactivation of the Kip2 gene are discussed.


Entering an Era of Protein Structuromics.
Sequence determines the structure, and the structure in turn determines the function, are the fundamental principles of protein chemistry. In the genomics era, the paradigm of mining protein functionality and evolutionary insights through sequence analysis has led to remarkable achievements. However, protein sequences often mutate faster than their structural counterparts during evolution. For protein sets characterized by highly divergent sequences, sequence-based analysis is often inadequate, whereas direct extraction of implicit information from the structures appears to be a more effective strategy.


Development of the Patient Activation Measure (PAM): conceptualizing and measuring activation in patients and consumers.
Controlling costs and achieving health care quality improvements require the participation of activated and informed consumers and patients. We describe a process for conceptualizing and operationalizing what it means to be "activated" and delineate the process we used to develop a measure for assessing "activation," and the psychometric properties of that measure. We used the convergence of the findings from a national expert consensus panel and patient focus groups to define the concept and identify the domains of activation. These domains were operationalized by constructing a large item pool. Items were pilot-tested and initial psychometric analysis performed using Rasch methodology. The third stage refined and extended the measure. The fourth stage used a national probability sample to assess the measure's psychometric performance overall and within different subpopulations. Convenience samples of patients with and without chronic illness, and a national probability sample (N=1,515) are included at different stages in the research. The Patient Activation Measure is a valid, highly reliable, unidimensional, probabilistic Guttman-like scale that reflects a developmental model of activation. Activation appears to involve four stages: (1) believing the patient role is important, (2) having the confidence and knowledge necessary to take action, (3) actually taking action to maintain and improve one's health, and (4) staying the course even under stress. The measure has good psychometric properties indicating that it can be used at the individual patient level to tailor intervention and assess changes.


Correlated defect nanoregions in a metal-organic framework.
Throughout much of condensed matter science, correlated disorder is a key to material function. While structural and compositional defects are known to exist within a variety of metal-organic frameworks (MOFs), the prevailing understanding is that these defects are only ever included in a random manner. Here we show--using a combination of diffuse scattering, electron microscopy, anomalous X-ray scattering and pair distribution function measurements--that correlations between defects can in fact be introduced and controlled within a hafnium terephthalate MOF. The nanoscale defect structures that emerge are an analogue of correlated Schottky vacancies in rocksalt-structured transition metal monoxides and have implications for storage, transport, optical and mechanical responses. Our results suggest how the diffraction behaviour of some MOFs might be reinterpreted, and establish a strategy of exploiting correlated nanoscale disorder as a targetable and desirable motif in MOF design.


High-risk human papillomavirus types in cytologically normal cervical scrapes from Kenya.
Seventy-seven women with normal cervical cytology on routine visit to a family planning clinic in Nairobi, Kenya, were analysed for genital human papillomavirus (HPV) types by polymerase chain reaction (PCR). We applied a general primer pair (GP60/GP124) recognising sequences conserved among HPV types 6, 11, 16, 18, 31 and 33. Of the 77 specimens tested 15 (19.5%) proved to be positive for genital HPV. Amplification products were examined for the presence of high-risk HPV types by Slot-blot hybridization. Out of the 15 PCR-positive samples, 4 were positive for HPV 16.3 for HPV 18, while 1 contained both HPV 16 and 33. HPV DNA prevalence in this group of women from a "high-risk" area is similar to that in "low-risk" Swedish women but much lower than in cervical cancer samples from the same region.


On the use of ultrasonic waves as a communications medium in biosensor networks.
In this paper, the problem of wireless communications in human tissue is addressed for biosensor network applications. Today's offered solutions involve the usage of RF communication systems, which have shown to provide adequate performance to ensure proper network functionality. Yet they do not ensure that human tissue is not harmfully affected. In order to overcome this issue, we propose the use of ultrasonic waves for wireless communications in biosensor networks, motivated by the fact that, in contrast to electromagnetic waves, ultrasound has been used for almost a century now for medical purposes without any reported side effects. A simple propagation model is used to evaluate ultrasonic waves as a communication medium, study the feasibility of our proposal, the effective bit rates that may be achieved, the power efficiency of the scheme, as well as other system issues.


The structure of a high-Mr subunit of durum-wheat (Triticum durum) gluten.
A high-Mr subunit was prepared from durum wheat (Triticum durum). Viscometric analysis showed that the molecule is rod-shaped, with molecular dimensions of about 50 nm x 1.75 nm (500 A x 17.5 A) in 0.05 M-acetic acid/0.01 M-glycine and 49 nm x 1.79 nm (490 A x 17.9 A) in aq. 50% (v/v) propan-1-ol (+/- 0.01 M-glycine) at 30 degrees C. C.d. spectroscopy in the same solvents indicated the presence of beta-turns, but little alpha-helix [7% in 50% (v/v) propan-1-ol] and no beta-sheet. However, when dissolved in trifluoroethanol the protein contains about 30% alpha-helix, and viscometric analysis gives dimensions of about 62 nm x 1.53 nm (620 A x 15.3 A). It is proposed, on the basis of these studies and previously published structural prediction, that the repetitive central domain of the high-Mr subunit forms a loose spiral based on repetitive beta-turns, whereas the shorter non-repetitive N- and C-terminal domains are alpha-helical in trifluoroethanol, but random coil in other solvents. The Mr of the high-Mr subunit determined from the intrinsic viscosity in 6.0 M-guanidinium chloride was 65,000, compared with 84,000 determined in 5.0 M-guanidinium thiocyanate. The latter value is consistent with the Mr values for related proteins whose complete amino acid sequences are known, and it was concluded that the protein is incompletely denatured in the former solvent. This was confirmed by c.d. spectroscopy in increasing concentrations (1-6 M) of guanidinium chloride.


Mortality and type of cigarette smoked.
Twenty-five years ago, cigarette smokers in the United Kingdom smoked plain cigarettes with an average tar yield of probably about 35 mg. Now smokers predominantly smoke filter cigarettes and average tar yields have been reduced by half. Epidemiological evidence comparing mortality in smokers of differing types of cigarettes is reviewed. Compared with smokers of higher tar plain cigarettes, smokers of lower tar filters cigarettes have a reduced mortality for lung cancer, for cancer of the buccal cavity, pharynx, larynx, oesophagus, and bladder, for chronic bronchitis and emphysema, and for cirrhosis of the liver. They also have a slightly significant. Problems of interpretation and limitations of the available evidence are discussed. No worthwhile evidence is yet available on smokers of "low tar' (0-10 mg) cigarettes and data are sparse on lifetime smokers of filter cigarettes. Continuing research is important to understand the situation fully, but the trends of lower mortality to be associated with lower tar and nicotine levels are promising.


An innovative synthetic support for immunocytochemical assessment of cytologically indeterminate (Bethesda III) thyroid nodules.
Fine needle aspiration (FNA) is the procedure of choice in the evaluation of thyroid nodules. Nodules with indeterminate cytological categories, Bethesda III and IV, pose challenges in clinical practice and are frequently submitted to diagnostic surgery. CytoFoam Core (CFCS) uses an absorbent foam device inserted into the needle hub to collect the cytological sample aspirated during FNA. Specimen is formalin-fixed and paraffin-embedded. Assessing diagnostic efficacy of CFCS, compared to traditional cytology, in re-evaluating thyroid nodules classified as Bethesda III, using post-surgical histology as reference standard. Retrospective study on 89 patients with a first indeterminate cytological report who were referred to the Department of Endocrinology of Regina Apostolorum Hospital (Albano L. Rome, Italy) for a second FNA. FNA was performed after at least one month under ultrasound guidance with a 23G needle according to the established procedure. During the second procedure, both traditional cytological (TC) smears and a single-pass CFCS specimen were obtained for each patient. On CFCS samples immunocytochemical staining for Galectin-3, HBME-1, and CK-19 was also performed. 51 patients eventually underwent surgery, and their histological diagnoses were compared to the TC and CFCS reports. Four parameters were evaluated: inadequacy rate, rate of persistent indeterminate (Bethesda III and IV) reports, rate of malignancy in persistently indeterminate nodules, and rate of cancer in lesions cytologically classified as malignant. Non-diagnostic samples were 6 (11.8%) in TC vs 3 (5.9%) in CFCS (p=0.4). Persistent indeterminate samples were 31 (60.8%) in TC vs 19 (37.2%) in CFCS (p=0.01). Rate of malignancy in persistently indeterminate nodules was 8/19 (42.1%) in CFCS vs 9/31 (29%) in TC group (p=0.3). Nine/51 (17.6%) samples were classified as benign by TC vs 21/51 (41.2%) samples by CFCS (p<0.01). All nodules resulted benign at post-surgical evaluation. Five/51 (9.8%) samples were classified as suspicious for malignancy/malignant in TC group against 8/51 (15.7%) samples in CFCS (p=0.5). Post-surgical evaluation confirmed malignancy in all these cases. CFCS demonstrated greater diagnostic accuracy than TC in repeat FNA assessment of cytologically indeterminate nodules. CFCS increased the conclusive diagnosis rate and decreased the number of cytologically indeterminate cases.


Intracoronary near-infrared spectroscopy: an overview of the technology, histologic validation, and clinical applications.
Intracoronary near-infrared spectroscopy (NIRS) imaging, which is now clinically available in a combined NIRS and intravascular ultrasound catheter, is a novel catheter-based imaging modality capable of identifying lipid core plaque within the coronary arteries of living patients. The present manuscript provides an overview of intracoronary NIRS imaging with a focus on several concepts essential to individuals seeking to better understand this novel imaging modality. One of the major assets of NIRS is that it has been rigorously validated against the gold standard of histopathology and has been shown to accurately identify histologically-proven fibroatheroma. Clinical studies of NIRS have demonstrated its ability to accurately identify large lipid core plaques at culprit lesions across the spectrum of acute coronary syndromes. NIRS has also been shown to detect lesions at increased risk of causing peri-procedural myocardial infarction during PCI. With regards to predicting future risk, NIRS is seemingly capable of identifying vulnerable patients at increased risk of experiencing subsequent patient-level cardiovascular events. In addition to these clinical applications of NIRS, there are several large prospective observational studies underway to determine if NIRS imaging will be able to identify vulnerable plaques at increased risk of triggering site-specific future coronary events. These studies, once completed, are anticipated to provide valuable data regarding the ability of NIRS imaging to identify plaque vulnerability.


Research Priorities in Critical Care Cardiology: JACC Expert Panel.
Over the last several decades, the cardiac intensive care unit (CICU) has seen a substantial evolution in the patient population, comorbidities, and diagnoses. However, the generation of high-quality evidence to manage these complex and critically ill patients has been slow. Given the scarcity of clinical trials focused on critical care cardiology (CCC), CICU clinicians are often left to extrapolate from studies that either exclude or poorly represent the patient population admitted to CICUs. The lack of high-quality evidence and limited guidance from society guidelines has led to significant variation in practice patterns for many of the most common CICU diagnoses. Several barriers, both common to critical care research and unique to CCC, have impeded progress. In this multinational perspective, we describe key areas of priority for CCC research, current challenges for investigation in the CICU, and essential elements of a path forward for the field.


Genetic interactions of ribosome maturation factors Yvh1 and Mrt4 influence mRNA decay, glycogen accumulation, and the expression of early meiotic genes in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae Yvh1, a dual-specificity protein phosphatase involved in glycogen accumulation and sporulation, is required for normal vegetative growth. To further elucidate the role of Yvh1, we generated dominant mutants suppressing the slow growth caused by YVH1 disruption. One of the mutant alleles, designated as SVH1-1 (suppressor of Δyvh1 deletion), was identical to MRT4 (mRNA turnover) that contained a single-base substitution causing an amino acid change from Gly(68) to Asp. Mrt4(G68D) restored the deficiencies in growth and rRNA biogenesis that occurs in absence of Yvh1. Here, we report that the interaction between Mrt4 and Yvh1 is also essential for normal glycogen accumulation and mRNA decay as well as the induction of sporulation genes IME2, SPO13 and HOP1. The Mrt4(G68D) could restore the plethora of phenotypes we observed in absence of Yvh1. We found that Yvh1 is not essential for wild-type induction of the transcriptional regulator of these genes, IME1, suggesting that either translation or post-translational modification to activate Ime1 has been compromised. Since a defect in ribosome biogenesis in general can be related to other various defects, the ribosome biogenesis defect caused by absence of Yvh1 might be an indirect cause of observed phenotypes.


Psychiatric-mental health nurses and the sex trafficking pandemic.
Nurses are in a unique position to treat survivors of human trafficking and are most likely to encounter patients who have been involved in the sex trade. In particular, psychiatric-mental health nurses can be effective because they are educated to think of clients holistically and can provide both short-term medical intervention and long-term psychotherapy. Additionally, they can recognize and refer these individuals for medical treatment. The purpose of this article is to present an overview of sex trafficking and what psychiatric-mental health nurses can do to treat survivors.


Production of ochratoxins A and B on country cured ham.
Two strains of Aspergillus ochraceus and six of Penicillium viridicatum isolated from country cured hams were screened for production of ochratoxins A and B. None of the isolated P. viridicatum strains yielded detectable amounts of ochratoxin A or B, whereas both strains of A. ochraceus produced ochratoxins A and B on rice, defatted peanut meal, and country cured ham. After 21 days of incubation on ham, one-third of the toxin was found in the mycelial mat on the ham surface, whereas two-thirds had penetrated into the meat to a distance of 0.5 cm.


Dominance of Cry1F resistance in Spodoptera frugiperda (Lepidoptera: Noctuidae) on TC1507 Bt maize in Brazil.
Dominance of resistance has been one of the major parameters affecting the rate of evolution of resistance to Bt crops. High dose is the capacity of Bt crops to kill heterozygous insects and has been an essential component of the most successful strategy to manage resistance to these crops. Experiments were conducted to evaluate directly and indirectly whether the TC1507 event is high dose to Spodoptera frugiperda (JE Smith). About 8% of heterozygote neonate larvae were able to survive, complete larval development and emerge as normal adults on TC1507 leaves, while susceptible larvae could not survive for 5 days. The estimated dominance of resistance was 0.15 ± 0.09 and significantly higher than zero; therefore, the resistance to Cry1F expressed in TC1507 was not completely recessive. A 25-fold dilution of TC1507 maize leaf tissue in an artificial diet was able to cause a maximum mortality of only 37%, with growth inhibition of 82% at 7 days after larval infestation. Resistance to Cry1F in TC1507 maize is incompletely recessive in S. frugiperda. TC1507 maize is not high dose for S. frugiperda. Additional or alternative resistance management strategies, such as the replacement of single-trait Bt maize with pyramided Bt maize, which produces multiple proteins targeting the same insect pests, should be implemented wherever this technology is in use and S. frugiperda is the major pest.


Pharmacology and biochemistry of dopamine receptors in the central nervous system and peripheral tissue.
A body of experimental and clinical data was generated over the last decade and now constitutes the basis for a new level of categorization of central dopamine (DA) receptors. Pharmacological and biochemical criteria were used in particular in our laboratories to separate those DA receptors which are linked in a stimulatory way to the enzyme adenylate cyclase and those which are not. We have indeed defined D1 and D2 receptors those DA receptors associated or unassociated to the generation of cyclic AMP, respectively. It should be stressed that the studies on DA receptors in the central nervous system and peripheral tissue were greatly facilitated following the discovery of specific agonist and antagonist drugs for the different DA receptors. As originally proposed by our group, DAergic ergot derivatives and substituted benzamides are now generally accepted as classes of drugs, endowed with agonist and antagonist properties, respectively, on DA D2 receptors. Taking into account the intracellular modifications following the interaction between DA and its own recognition sites, it can be suggested that in cerebral and peripheral tissue the recognition sites for DA are coupled to various of amplifier systems with different molecular mechanisms. According to the data presented and discussed in the text, DA D1 recognition sites appear to be linked to adenylate cyclase through a G/F protein (Ns unit) in a stimulatory way whereas DA D2 recognition sites are associated with adenylate cyclase through a G/F protein (Ns unit) in an inhibitory way or, at least in pituitary, are functionally coupled with inhibition of calcium entry into the cells.


Vascular changes in rhegmatogenous retinal detachment.
The author studied by fluorescein angiography the vascular conditions in 50 cases of rhegmatogenous detachment. Capillary dilatation and hyperpermeability were observed on the detached retina and can be considered as an autoregulation phenomenon secondary to tissular hypoxia. Diffuse peripheral vascular occlusions were a typical finding in detachments with peripheral holes. In these cases a preexisting retinal perfusion defect was probably exaggerated by the increased resistances secondary to the detachment.


The co-occurrence of PTSD and dissociation: differentiating severe PTSD from dissociative-PTSD.
A dissociative-posttraumatic stress disorder (PTSD) subtype has been included in the DSM-5. However, it is not yet clear whether certain socio-demographic characteristics or psychological/clinical constructs such as comorbid psychopathology differentiate between severe PTSD and dissociative-PTSD. The current study investigated the existence of a dissociative-PTSD subtype and explored whether a number of trauma and clinical covariates could differentiate between severe PTSD alone and dissociative-PTSD. The current study utilized a sample of 432 treatment seeking Canadian military veterans. Participants were assessed with the Clinician Administered PTSD Scale (CAPS) and self-report measures of traumatic life events, depression, and anxiety. CAPS severity scores were created reflecting the sum of the frequency and intensity items from each of the 17 PTSD and 3 dissociation items. The CAPS severity scores were used as indicators in a latent profile analysis (LPA) to investigate the existence of a dissociative-PTSD subtype. Subsequently, several covariates were added to the model to explore differences between severe PTSD alone and dissociative-PTSD. The LPA identified five classes: one of which constituted a severe PTSD group (30.5 %), and one of which constituted a dissociative-PTSD group (13.7 %). None of the included, demographic, trauma, or clinical covariates were significantly predictive of membership in the dissociative-PTSD group compared to the severe PTSD group. In conclusion, a significant proportion of individuals report high levels of dissociation alongside their PTSD, which constitutes a dissociative-PTSD subtype. Further investigation is needed to identify which factors may increase or decrease the likelihood of membership in a dissociative-PTSD subtype group compared to a severe PTSD only group.


The role of polymerase chain reaction in early diagnosis of human immunodeficiency virus infection in infants.
The prevalence of human immunodeficiency virus (HIV) infection is rising in Sub- Saharan Africa. The various indirect tests readily available have not been helpful in neonatal and early infant diagnosis of the disease. Polymerase chain reaction (PCR) is a direct test that can be used in these groups of children. Early infant diagnosis is important in achieving good outcome in the management of HIV infection. The aim of this article was to examine the role of PCR in the evaluation HIV-infected infants, with a view to achieve early diagnosis, early treatment, and good outcome. This was a prospective review of 174 infants delivered by HIV-infected mothers in a rural hospital from January 2007 to September 2008. The blood samples of the patients were collected and subjected to PCR analysis for detection of viral antigen. Two samples were collected, the first at 6 weeks and the second 6 weeks after that. The results were recorded, collated, and analyzed using SPSS version 17. There were 174 infants, 100 boys, and 74 girls. The age range was 6-8 weeks (median 6 weeks). PCR was positive for both the samples in 12 (6.9%) infants. PCR was negative in both samples in 162 (93.1%) infants. All infants who were negative in the first sampling were found to be negative in the second sampling as well. None of the infant was positive for only one sample. Analysis of 12 positive infants revealed that 5 (2.9%) infants were placed on anti-retroviral drugs, 3 (1.7%) infants were not placed on anti-retroviral drugs because of low CD+ count, and 1 (1.0%) infant was lost to follow-up, while 3 (1.7%) infants died from sepsis. PCR has a role as a direct test in early diagnosis of HIV infection in infancy, particularly where the other direct test are not readily available.


[Cycloferon and management of herpes virus infection].
The treatment of patients with various forms of herpes requires a complex approach with using chemo- and immunotropic drugs. The use of Cycloferon, an interferon inductor (12.5% injection solution, 150 mg tablets or 5% liniment) was shown efficient. It had antiviral and immunotropic action in the mono- and combination therapy of herpes simplex of the skin and mucosa, genital herpes, ophthalmoherpes, herpes zoster, infectious mononucleosis. Cycloferon lowered the level and period of the disease clinical signs, prolonged the remission, corrected the immunity shifts, prevented the complications. The results of the study presented a conclusive proof for recommending such a use of Cycloferon in wide medical practice.


What kind of patients and physicians value direct-to-consumer advertising of prescription drugs.
Direct-to-consumer (DTC) advertising of prescription drugs can enhance the physician-patient relationship, as well as benefiting its sponsor. However, overall benefits can only occur if the patients value the information enough to discuss it with their physicians and the physicians are not predisposed against the DTC information. We investigate the impact of demographics and exposure to marketing on consumers' and physicians' receptiveness to DTC advertising of prescription drugs, using data from two nationwide surveys. We find that consumers who have an ongoing need for health care, that is, those with children or with a chronic condition requiring medication, value prescription drug advertising more highly, while older consumers, consumers who have been sick recently, or more educated consumers are more likely to trust their physicians instead. We find that more experienced physicians, physicians who see more patients, or those who have more exposure to pharmaceutical advertisements are more accepting of DTC advertising of prescription drugs.