Mass spectrometry to complement standardization of house dust mite and other complex allergenic extracts.
In the United States, the Center for Biologics Evaluation and Research of the US Food and Drug Administration regulates biologics used for diagnosis and treatment of allergic diseases. The Code of Federal Regulations 21CFR680.3(e) states that when measured, the potency of an allergenic extract is assessed according to its allergenic activity. As of 2016, 19 allergenic extracts are standardized for potency in the United States. While these standardized extracts constitute a minority of those available, they treat the most prevalent allergies (e.g. grass and ragweed pollens, dust mites, and cat) and those that induce life-threatening anaphylaxis (e.g. Hymenoptera venom). Standardization for potency enhances safety and efficacy of immunotherapy by minimizing the risks of variations in allergen dosing when switching from one lot of manufactured extract to another, and by providing an objective measure of stability of each lot of allergenic extract over time. Allergenic extracts that have multiple immunodominant allergenic proteins are standardized with little or no information about compositional differences among extracts. Here, we propose application of mass spectrometry towards measurement of compositional differences among extracts that may affect the efficacy and safety of allergen immunotherapy. In addition, we discuss of house dust mite allergen extracts as a prototypical complex extract that may be standardized by mass spectrometry.


Advances in antidepressants for treating post-stroke depression.
Post-stroke depression (PSD) is a common and serious complication after stroke, occurring in nearly one third of stroke survivors, and affecting mortality rate, functional outcome, rehabilitation results and quality of life. However, in the common clinical practice only a minority of patients are properly treated. A relatively small number of scientific reports are available on clinical usefulness and safety of antidepressants (ADs) in PSD. Areas covered: This report provides an updated review about pharmacological state of art of PSD, including efficacy and safety of different drugs and their role on prevention, treatment and functional outcome. Expert opinion: Even if currently an antidepressant treatment can improve depressive symptoms, neither the optimal drug nor the optimal lengths of treatment, have been identified. Serotonergic drugs are preferable because of their better safety profile, but in the recent years there has been an important debate on possible association between selective serotonin reuptake inhibitor use and increased mortality. Another issue is the potential role of ADs for improving functional recovery. Newer ADs have interesting properties, in particular vortioxetine, due to its properties of enhancing cognitive functions, but further research is needed to clarify its/their role in treatment of PSD.


Malignant lymphomas of follicular center cell origin in man. I. Immunologic studies.
Lymphomas with histologic features indicating a follicular center cell (FCC) origin were analyzed from 26 patients of a group of 45 consecutive non-Hodgkin's lymphoma patinets whose tumors were studied for B- and T-cell characteristics. They were compared with benign, reactive lymphoid tissue from 14 patients. Cell suspensions from biopsy material, blood, or bone marrow were examined for surface Ig and for rosette formation with sheep erythrocytes (E rosettes). Of the 26 patients with FCC lymphomas, 22 had 40% or more Ig-bearing cells; all patients with FCC lymphoma tissues had 25% or less E rosette-forming cells. Cells from most FCC lymphomas of the cleaved type had surfac IgM; those from several FCC lymphomas had both IgM and IgD. Cells from lymphomas of noncleaved cell type had surface IgG or IgA. Light-chain analysis showed that cells from FCC lymphomas bore a predominant light-chain type, which indicated their monoclonal nature. Neoplastic cells from several FCC lymphomas synthesized the surface Ig which they bore. Reactive tissues usually contained fewer Ig-bearing and more E rosette-forming cells than FCC lymphomas; the Ig-bearing cells, with one exception, had a polyclonal distribution. Correlation of histologic and immunologic observations indicates that most lymphomas identified as FCC in origin by light micorscopic criteria mark as B cells with the use of immunologic techniques and that FCC lymphomas are the most common type of non-Hodgkin's lymphoma.


Total Abdominal Wall Transplantation: An Anatomical Study and Classification System.
Candidates for multivisceral transplantation present with complex defects often beyond traditional reconstructive options. In this study, the authors describe a dissection technique for a total abdominal wall vascularized composite flap. In addition, the authors suggest a classification system for complex abdominal wall defects. Forty fresh, cadaveric hemiabdomens were dissected, with care taken to preserve the iliofemoral, deep circumflex iliac, superficial circumflex iliac, deep inferior epigastric, and superficial inferior epigastric arteries and corresponding veins. Perfusion patterns of the flaps were then studied using computed tomographic angiography. The deep circumflex iliac, superficial circumflex iliac, deep inferior epigastric, and superficial inferior epigastric arteries were identified along a 5-cm cuff of the iliofemoral artery centered on the inguinal ligament. Perfusion with an intact deep circumflex iliac artery yielded improvement in lateral perfusion based on computed tomographic angiography. The authors propose an algorithm for abdominal wall reconstruction based on defect size and abdominal wall perfusion, and their technique for harvesting a total vascularized composite abdominal wall flap for allotransplantation. Total abdominal wall transplantation should be considered in the subset of patients already receiving visceral organ transplants who also have concomitant abdominal wall defects.


Establishment of a secondary screening assay for P/Q-type calcium channel blockers.
Development of calcium channel blockers is attractive, but has in the past been hampered by lack of high throughput electrophysiological technology. This limitation has been overcome by the implementation of automated patch clamp systems that allow identification of state-dependent compounds, which preferentially target pathologically overactive channels. We recently presented a fluorescence-based high-throughput screen for P/Q-type calcium channels followed by automated electrophysiology. Here, we provide a detailed description of the development of the secondary screen, and show the full analysis of the inactivation kinetics of the recombinant P/Q channel that served as a basis for the automated patch clamp protocol. Increasing the length of pre-depolarization shifted the inactivation to more hyperpolarized potentials. No steady-state inactivation was reached up to pre-depolarization durations of 3 min, while stability of the recordings progressively declined. As a compromise, a 3s pre-depolarization protocol was proposed for functional screening. In order to validate the electrophysiological screening, we compared kinetics and pharmacology of recombinant P/Q-type channels between automated and manual patch clamp measurements. Channel activation was similar under both conditions. By contrast, inactivation occurred at more hyperpolarized potentials in the automated system. Therefore, P/Q-type calcium channel inactivation is sensitive to the applied technological platform and needs to be adjusted when performing automated patch clamp recordings. Our results indicate that a thorough analysis of the inactivation kinetics is mandatory, when establishing an electrophysiological screening protocol for calcium channel blockers. As some data obtained by automated recordings may not be identical to manual patch clamp analysis, we recommend a proper initial validation of the screening assay and--if necessary--a posthoc adjustment of automated patch clamp values. The protocol presented here supports hit-to-lead and lead optimization efforts during the development of novel P/Q-type calcium channel blockers, and may be valuable for the generation of assays in other ion channel programs.


[Localization of in vivo administered peroxidase in the cells of Ehrlich carcinoma].
Distribution of peroxidase was studied in structures and soluble fractions of cytoplasma and nuclei of washed cells of Erhlich carcinoma, obtained from mice, previously administered intraperitoneally with the enzyme. Peroxidase was shown to penetrate in all the cell fractions studied; the most specific activity of the extraneous enzyme was observed in mitochondria.


Resilience of family caregivers of children and adolescents in treatment of neoplasms and associated factors.
analyze the level of resilience of family caregivers of children and adolescents hospitalized for cancer treatment and associated factors. cross-sectional study, carried out in 2018, with 62 family caregivers in a university hospital in the state of Rio Grande do Sul, Brazil. The instruments CDRisc-10-Br, SRQ20, PSS-14 and WHOQOL-Bref were used to measure resilience, minor psychological disorders, stress, and quality of life, respectively. Inferential statistics were used. female caregivers, married, with one child and who practice some predominated religion. They were classified as having a moderate level of resilience (48.4%); with suspicion for minor psychological disorders (45%) and high level of stress (41%). In terms of quality of life, they were satisfied in the Physical, Psychological and Social Relations domains; and dissatisfied in the Environment domain. there were direct weak to moderate correlations between the level of resilience and quality of life and inversely with stress and minor psychological disorders.


Advanced nitrogen removal from municipal wastewater treatment plant secondary effluent using a deep bed denitrification filter.
With the improvement of wastewater discharge standards, wastewater treatment plants (WWTPs) are continually undergoing technological improvements to meet the evolving standards. In this study, a quartz sand deep bed denitrification filter (DBDF) was used to purify WWTP secondary effluent, utilizing high nitrate nitrogen concentrations and a low C/N ratio. Results show that more than 90% of nitrate nitrogen (NO3-N) and 75% of chemical oxygen demand (COD) could be removed by the 20th day of filtration. When the filter layer depth was set to 1,600 mm and the additional carbon source CH3OH was maintained at 30 mg L-1 COD (20 mg L-1 methanol), the total nitrogen (TN) and COD concentrations of DBDF effluent were stabilized below 5 and 30 mg L-1, respectively. Analysis of fluorescence revealed that DBDF had a stronger effect on the removal of dissolved organic matter (DOM), especially of aromatic protein-like substances. High throughput sequencing and qPCR results indicate a distinctly stratified microbial distribution for the main functional species in DBDF, with quartz sand providing a good environment for microbes. The phyla Proteobacteria, Bacteroidetes, and Chloroflexi were found to be the dominant species in DBDF.


[Physiological role of vegetable oils during penicillin biosynthesis].
Addition of liquid vegetable oils to nutrient media decreased the intensity of penicillin biosynthesis. The unfavourable effect of the oils was more pronounced at the beginning of the process while they were not completely utilized. Sunflower oil is a readily assimilated source of carbon. The rate of its consumption is higher than that of whale oil or lactose. Like the majority of readily oxidized sources of carbon, sunflower oil must be a repressor of beta-galactosidase and the enzymes of penicillin biosynthesis.


Binocular Combination of Projected Images.
Two color-separation positive transparencies of a scene, one projected with "red" light and the other with tungsten lamp light, were superimposed on a screen. The light was polarized so that an observer wearing an appropriate viewer could either see both images in each eye or the "red" image in one eye and the "white" image in the other. These two situations gave different results, not the same results, as some previous investigators have claimed. Land's major results cannot be "obtained stereoscopically." We conclude that the process by which color is formed could possibly be a process of the retina or the lateral geniculate body, and does not necessarily have to be a process of the cerebral cortex as implied by the binocular experiments which purported to give the fuller gamut of color.


Determinants of MTT reduction in rat hepatocytes.
The determinants of reduction of the dye MTT (3-[4,5dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) in rat hepatocytes have been investigated. NADH, NADPH, and succinate were substrates for MTT reduction in rat liver homogenate, activity being greatest with NADH and least with succinate. Similar results were obtained with submitochondrial particles isolated from rat liver. NAD(P)Hdependent reduction of MTT was also detected in rat liver microsomes and cytosol. Rotenone, at a concentration that inhibited NAD(P)H-dependent MTT reduction in submitochondrial particles, did not inhibit MTT reduction in rat hepatocytes. Malonate, at a concentration that inhibited succinate-dependent MTT reduction in liver homogenate, did not inhibit MTT reduction in rat hepatocytes. Incubation of rat hepatocytes with ethanol or lactate (increase NADH levels), dicoumarol (inhibitor of DT-diaphorase), aminopyrine or hexobarbitone (substrates for the NADPH-requiring cytochrome P450-dependent microsomal monooxygenase) led to significant increases in the level of cellular MTT reduction. From these data, it is concluded that extramitochondrial NAD(P)H is the principal reductant for MTT reduction in rat hepatocytes, with mitochondrial dehydrogenase activity being only a minor contributor. It is also possible that cellular generation of superoxide (as might be expected on redox cycling of endogenous quinones following inhibition of DT diaphorase by dicoumarol) may be another source of MTT reduction. Caution should be exercised in ascribing an alteration in the level of cellular MTT reduction to a change in mitochondrial performance in the absence of corroborating evidence.


Cardio-metabolic disease risk factors among South Asian labour migrants to the Middle East: a scoping review and policy analysis.
This paper aims to explore the burgeoning burden of cardiovascular and metabolic disease (CMD) risk factors among South Asian labor migrants to the Middle East. We conducted a qualitative synthesis of literature using PubMed/Medline and grey literature searches, supplemented by a policy review of policies from the South Asian countries. We found a high burden of cardio-metabolic risk factors among the migrants as well as among the populations in the home and the host countries. For example, two studies reported the prevalence of diabetes mellitus (DM) ranging between 9 and 17% among South Asian migrants. Overweight and obesity were highly prevalent amongst South Asian male migrants; prevalence ranged from 30 to 66% (overweight) and 17-80% (obesity) respectively. The home country population had a significant CMD risk factor burden. Nearly 14 to 40% have three or more risk factors: such as hypertension (17 to 37%), diabetes (3 to 7%), overweight (18 to 41%), and obesity (2 to 15%). The host country also exhibited similar burden of risk factors: hypertension (13 to 38%), diabetes (8 to 17%), overweight (33 to 77%) and obesity (35 to 41%). Only Nepal, Bangladesh and Sri Lanka have some provisions related to screening of CMDs before labor migration. Further, analysis of policy papers showed that none of the reviewed documents had requirements for screening of any specific CMDs, but chronic diseases were used generically, failing to specify specific screening target. Given the high burden of risk factors, migrants' health should become an urgent priority. The lack of specific focus on screening during different stages of labor migration should receive attention. The International Labour Organization and the International Office for Migration, through their country coordination teams should engage local stakeholders to create policies and plans to address this concern. Similarly, there is a need for the host country to become an equal partner in these efforts, as migrant's better cardiometabolic health is in the benefit of both host and home countries.


Hypoplastic left heart syndrome: a review.
Hypoplastic left heart syndrome (HLHS) is an etiologically multifactorial congenital heart disease affecting one in 5,000 newborns. Thirty years ago there were no treatment options for this pathology and the natural course of the disease led to death, usually within the first weeks of life. Recently surgical palliative techniques have been developed allowing for a five-year survival in more than half the cases. We reviewed literature available on HLHS, specifically its anatomy, embryology and pathophysiology, and treatment. The Pubmed and ClinicalKey databases were searched using the key words hypoplastic left heart syndrome, foetal aortic valvuloplasty, foetal septoplasty, Norwood procedure, bidirectional Glenn procedure, Fontan procedure, hybrid procedure. The relevant literature was reviewed and included in the article. We reported a case from Children's Clinical University Hospital, Riga, to illustrate treatment tactics in Latvia. There are three possible directions for therapy in newborns with HLHS: orthotopic heart transplantation, staged surgical palliation and palliative non-surgical treatment or comfort care. Another treatment mode - foetal therapy - has arisen. Staged palliation and full Fontan circulation is a temporary solution, however, the only means for survival until heart transplantation. Fifty to 70% of patients who have gone through all three stages of palliation live to the age of five years. The superior mode of treatment is not yet clear and the management must be based on each individual case, the experience of each clinic, as well as the financial aspects and will of the patient's parents.


Mineralogical controls on aluminum and magnesium in uranium mill tailings: Key Lake, Saskatchewan, Canada.
The mineralogy and evolution of Al and Mg in U mill tailings are poorly understood. Elemental analyses (ICP-MS) of both solid and aqueous phases show that precipitation of large masses of secondary Al and Mg mineral phases occurs throughout the raffinate neutralization process (pH 1-11) at the Key Lake U mill, Saskatchewan, Canada. Data from a suite of analytical methods (ICP-MS, EMPA, laboratory- and synchrotron-based XRD, ATR-IR, Raman, TEM, EDX, ED) and equilibrium thermodynamic modeling showed that nanoparticle-sized, spongy, porous, Mg-Al hydrotalcite is the dominant mineralogical control on Al and Mg in the neutralized raffinate (pH ≥ 6.7). The presence of this secondary Mg-Al hydrotalcite in mineral samples of both fresh and 15-year-old tailings indicates that the Mg-Al hydrotalcite is geochemically stable, even after >16 years in the oxic tailings body. Data shows an association between the Mg-Al hydrotalcite and both As and Ni and point to this Mg-Al hydrotalcite exerting a mineralogical control on the solubility of these contaminants.


[Do temporomandibular disorders really exist?].
Temporomandibular Disorders (TMD) is a collective term embracing a number of clinical problems that involve the muscles of mastication, the temporomandibular joint (TMJ) and associated structures or both. This group of disorders has been identified as the chief cause of pain, which is not of dental origin, in the orofacial area, and is defined as a subgroup in the category of musculoskeletal disorders. These disorders impair the quality of life of those suffering from them due to the extent of the pain and the chronic nature of its symptoms. It is known that chronic pain causes the development of psychological disturbances (anxiety, depression, etc.). The most common symptoms of TMD are the pain that usually appears as the result of mandibular activity (speaking or chewing), and is usually located in the masticulatory muscles, in the preauricular area and the temporomandibular joint (TMJ). Additional common symptoms are: a. restriction in jaw movement; b. asymmetry in jaw movement; c. noises from the joint. Patients suffering from TMD are likely to exhibit additional symptoms: hypertrophy of the muscles of mastication (an adaptive and asymptomatic phenomenon), abnormal occlusar erosion due to nighttime or daytime bruxism, or teeth grinding. Most functional temporomandibular disorders have similar signs and symptoms. As a result, diagnosis of the various disorders presents a serious problem. Functional temporomandibular disorders are often accompanied by mental symptoms such as depression, anxiety and/or somatization on various levels. One of today's accepted methods of classification also refers to the mental aspect and thus enables, for the first time, a suitable scientific comparison of the epidemiological, diagnostic and treatment data in the various studies. This method, initiated by Dworkin and LeResche (1992) is known as Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The purpose of this method is to classify every subgroup of TMD according to agreed upon, clear and measurable diagnostic criteria, both from the physical (AXIS I) and the mental (AXIS II) aspect. The method includes a scale which grades the extent of severity, damage and limitations caused by the illness, in a manner which now can make scientific comparisons between the various studies and between the population of patients and the general population. Temporomandibular disorders are very common and affect between 30%-50% of the population, and appear to be more prevalent among women than among men. Studies conducted on youth revealed significant relationships between oral parafunctions (especially chewing gum and "jaw playing"), and functional temporomandibular disorders. The significance of this finding is in the need to warn young people of the possible risks of engaging in intensive oral practices. The high prevalence of signs and symptoms among the Israeli population obligates us, in our opinion, to change the physical examination for identification of these disorders, to a routine procedure in all dental clinics in Israel.


Empathic Accuracy in Clinical Populations.
Empathy, broadly defined as the ability to understand the other and to share others' emotions, motivates prosocial behavior and underlies successful interpersonal relations. Dysfunctions in this ability may cause fundamental difficulties in social communication. Empathy has been measured in various ways, from self-report questionnaires to laboratory objective performance tests. Empathic accuracy (EA), i.e., the ability to accurately empathize, is measured using more complex and ecological paradigms, such as asking participants to infer filmed interactions, or having people narrate personal emotional stories then assessing the correspondence between the perceiver and the target of empathy as the criteria for empathic ability. This measure is particularly useful in the study of clinical populations, where deconstructing the multifaceted concept of empathy may contribute to a more complete understanding of specific clinical profiles. This paper presents a scoping review of the literature on EA in clinical populations, and on EA and clinical traits and states in nonclinical or high-risk populations. Following an exhaustive literature search, 34 studies were found eligible to be included in this review. The largest category was studies focused on EA in people with schizophrenia (31%; 11 papers), followed by studies focused on EA in autism spectrum disorders (ASD) and autistic traits in a nonclinical population (22%; 8 papers). Studies were also found on EA and depression tendencies, psychopathy, social anxiety, behavior disorders, and personality disorders, and a few other clinical conditions. The included studies varied on research aims, designs, sample sizes, and male:female ratios. The overall synthesized results suggest that EA is reduced in schizophrenia and ASD. In other clinical populations, the number of studies was very limited. We urge researchers to further examine EA in these less-studied populations. The review reveals a general underrepresentation of female participants in studies on EA in clinical populations. We suggest that future research address understudied clinical populations, such as those diagnosed with psychopathy. Subject, target, and situational variables should also be considered, with special attention to gender differences (and similarities), the association between EA abilities and adaptive functioning, and the study of individuals with clinical conditions as targets, not just observers, in EA tasks.


Diagnosis and management of atypical Mycobacterium spp. infections in established laboratory zebrafish (Brachydanio rerio) facilities.
Two established zebrafish colonies experienced increased mortality and decreased reproductive performance. Initial examination of several fish from one facility revealed hyperemic gills, petechia around the opercula, abdominal distention, and emaciation. Affected fish had congested liver with inflammation and multifocal hepatic necrosis. Large numbers of acid-fast-positive, rod-shaped bacteria were evident in multiple tissues and the blood. Mycobacterium fortuitum was subsequently isolated from several fish. Zebrafish from the second facility had skin erosions and ulceration along the flank just caudal to the pectoral fins. Large numbers of acid-fast-positive, rod-shaped bacteria were observed within the necrotic centers of well-demarcated, multifocal granulomas in gonads, liver, and peritoneum from affected fish. Mycobacterium abscessus and M. chelonae were isolated and identified biochemically. Definitive diagnosis in these outbreaks was obtained by culture on selective media. Because Mycobacterium spp. grow extremely slowly and positive confirmation may require 45 to 60 days, Mycobacterium species-specific polymerase chain reaction analysis was used to provide a rapid screening assay for Mycobacterium spp. as well as for verification of culture results. To our knowledge, this is the first documentation of mycobacterial infection in laboratory-maintained zebrafish and provides guidelines for diagnosis, management, and prevention of atypical mycobacteriosis in laboratory zebrafish colonies.


Influence of deposition parameters on laser-damage threshold of silica-tantala AR coatings.
A series of 4-layer silica-tantala antireflection coatings was deposited under 18 different combinations of substrate temperature (175, 250, and 325 degrees C), oxygen pressure (0.5,1.0, and 2.0 x 10(-4) Torr), and rate of deposition (1.5 and 5 A/sec). Measurements of laser-damage threshold for 1064-nm, 1-nsec pulses, average absorption, net stress, and reflectivity were then made on these coatings. Coatings deposited at the lowest temperature had the highest damage thresholds. Damage thresholds were found not to be directly related to average absorption or net stress. Coatings deposited on fused silica substrates which had been polished by a bowl-feed process had generally higher damage thresholds than coatings deposited on conventionally polished fused silica or on BK-7 glass polished by either conventional or bowl-feed processes. Baking coatings in air for 4 h at 400 degrees C generally reduced average absorption and net stress, changed the net stress from compression to tension and, in some cases, increased the damage threshold.


An IKBKE variant conferring functional cGAS/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis.
The mechanisms underlying susceptibility to recurrent herpes simplex virus type 2 (HSV-2) meningitis remain incompletely understood. In a patient experiencing multiple episodes of HSV-2 meningitis, we identified a monoallelic variant in the IKBKE gene, which encodes the IKKε kinase involved in induction of antiviral IFN genes. Patient cells displayed impaired induction of IFN-β1 (IFNB1) expression upon infection with HSV-2 or stimulation with double-stranded DNA (dsDNA) and failed to induce phosphorylation of STING, an activation marker of the DNA-sensing cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway. The patient allele encoded a truncated IKKε protein with loss of kinase activity and also capable of exerting dominant-negative activity. In stem cell-derived microglia, HSV-2-induced expression of IFNB1 was dependent on cGAS, TANK binding kinase 1 (TBK1), and IKBKE, but not TLR3, and supernatants from HSV-2-treated microglia exerted IKBKE-dependent type I IFN-mediated antiviral activity upon neurons. Reintroducing wild-type IKBKE into patient cells rescued IFNB1 induction following treatment with HSV-2 or dsDNA and restored antiviral activity. Collectively, we identify IKKε to be important for protection against HSV-2 meningitis and suggest a nonredundant role for the cGAS/STING pathway in human antiviral immunity.


Immunohistochemical and neurochemical studies on nigral and striatal functions in the circling (ci) rat, a genetic animal model with spontaneous rotational behavior.
Asymmetrical spontaneous turning behavior or circling phenomena are often related to components of the dopaminergic system, particularly to an imbalance of nigrostriatal function. When a rotational preference is observed, it is typically in a direction away from the brain hemisphere with higher striatal dopaminergic transmission. We have recently described a rat mutant (ci) with spontaneous circling behavior and other signs of functional brain asymmetry. Neurochemical determinations showed that mutants of both genders have significantly lower concentrations of dopamine and dopamine metabolites in the striatum ipsilateral to the preferred direction of rotation. In the present study, we used immunohistochemical, neurochemical, and autoradiographic techniques to characterize the dopaminergic abnormalities of the ci rat mutant in more detail. Age-matched non-affected controls of the same strain were used for comparison. Immunohistochemical labeling of dopaminergic neurons and fibers in substantia nigra pars compacta, ventral tegmental area, and striatum did not indicate any significant neurodegeneration or asymmetry that could explain the lateralization in dopamine levels in striatum of ci rats. Neurochemical determinations substantiated that ci rats of both genders have a significant imbalance in striatal dopamine metabolism, but a similar significant lateralization was also seen in non-affected female controls. Comparison of dopamine, serotonin, noradrenaline and several monoamine metabolite levels in substantia nigra, striatum, nucleus accumbens and frontal cortex of ci rats and controls did not disclose any marked difference between affected and non-affected animals which was consistently found in both genders. Quantitative autoradiographic determination of binding densities of dopamine transporter and D1 and D2 receptors in several parts of the striatum and substantia nigra indicated that ci rats have a significantly higher binding density of dopamine transporter and receptors than controls. Taken together, ci mutant rats of both genders exhibit an asymmetry in striatal dopamine and metabolite levels and an enhanced dopamine transporter and receptor binding, but the link of these differences in dopaminergic parameters with the rotational behavior of the animals is not clear yet. The lack of any significant dopaminergic cell loss in the substantia nigra and the locomotor hyperactivity observed in the mutants clearly suggest that the ci rat is not suited as a model of Parkinsonism but rather constitutes a model of a hyperkinetic motor syndrome.


Antibody binding of deletion mutants of Asp f 2, the major Aspergillus fumigatus allergen.
Asp f 2, a 268 amino acid major allergen from Aspergillus fumigatus (Af) demonstrated nine linear IgE binding regions. It is not known whether any of these linear epitopes are also conformatory epitopes. Hence, we constructed deletion mutants of Asp f 2 devoid of one or more epitopes, and the IgE binding of these proteins with sera from patients with ABPA was compared with the full-length Asp f 2 expressed in E. coli and Pichia. The Pichia expressed protein reacted weakly with IgE, but strongly with IgG of ABPA sera compared to E. coli expressed Asp f 2. Weak IgE binding only was seen when the C-terminal or N-terminal was deleted, while depletion of both ends negated all reactivity. The monoclonal antibody IL-B8 and IgE and IgG of ABPA sera bound significantly to the Asp f 2 E-4 fragment indicating that the major B-cell epitope is located at the N-terminal end of Asp f 2.


Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion.
Signal transducer and activator of transcription 3 (Stat3) is an oncogenic transcriptional factor that plays a critical role in carcinogenesis and cancer progression and is a potential therapeutic target. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified previously as a novel inhibitor of survivin that selectively kills prostate cancer cells over "normal" prostate epithelial cells. DU145, C4-2B, and LNCaP cells were treated with sanguinarine. The phosphorylation status of Stat3 and related proteins were measured with Western blots. Activation of transcription by Stat3 was measured with luciferase reporter assay. The effect of sanguinarine on anchorage-independent growth was examined with soft agar assay, and on cell migration and invasion of DU145 cells were measured with scratch assay and invasion assay, respectively. In this study, we identified sanguinarine as a potent inhibitor of Stat3 activation which was able to suppress prostate cancer growth, migration, and invasion. Sanguinarine inhibits constitutive as well as IL6-induced phosphorylation of Stat3 at both Tyr705 and Ser727 in prostate cancer cells. The inhibition of Stat3 phosphorylation by sanguinarine correlates with reduction of Janus-activated Kinase 2 (Jak2) and Src phosphorylation. Sanguinarine downregulates the expression of Stat3-mediated genes such as c-myc and survivin and inhibits the Stat3 responsive element luciferase reporter activity. Sanguinarine inhibits the anchorage-independent growth of DU145 and LN-S17 cells expressing constitutively activated Stat3. Migration and invasion abilities of DU145 cells were also inhibited by sanguinarine in a manner similar to the dominant negative form of Stat3. These data demonstrate that sanguinarine is a potent Stat3 inhibitor and it could be developed as a therapeutic agent for prostate cancer with constitutive activation of Stat3.


Evidence for a plasma membrane mating receptor in the myxomycete Didymium iridis.
Haploid isolates Panamanian 2-7A8 and Honduran 1-2A1 of the heterothallic myxomycete Didymium iridis were investigated in order to determine whether membrane mating factors or receptors were present and necessary in order that cell fusion could occur and zygote formation take place. Haploid and diploid controls grown on half strength cornmeal media, and experimental crosses grown on the same media plus concanavalin A, were analysed by quantitative cytophotometry employing the Feulgen nuclear reaction. Nuclear DNA analysis demonstrated that Con A treated cells when crossed did not produce zygotes or plasmodia, while those left untreated did so almost all of the time. On rare occasion plasmodia did develop in treated cultures (1.8% or two out of 110). These plasmodia demonstrated low viability and upon analysis were shown to be haploid. It was concluded that they had developed by apogamy, and therefore did not require plasma membrane bound mating receptors, cell fusion, or zygote formation.


Bioactivities and Mechanisms of Action of Diphyllin and Its Derivatives: A Comprehensive Systematic Review.
Natural products are treasure houses for modern drug discovery. Diphyllin is a natural arylnaphthalene lignan lactone isolated from the leaf of Astilboides tabularis. Studies have found that it possesses plenty of bioactivity characteristics. In this paper, we reviewed the structure, bioactivity, and mechanism of action of diphyllin and its derivatives. The references were obtained from PubMed, Web of Science, and Science Direct databases up to August 2023. Papers without a bio-evaluation were excluded. Diphyllin and its derivatives have demonstrated V-ATPase inhibition, anti-tumor, anti-virus, anti-biofilm, anti-inflammatory, and anti-oxidant activities. The most studied activities of diphyllin and its derivatives are V-ATPase inhibition, anti-tumor activities, and anti-virus activities. Furthermore, V-ATPase inhibition activity is the mechanism of many bioactivities, including anti-tumor, anti-virus, and anti-inflammatory activities. We also found that the galactosylated modification of diphyllin is a common phenomenon in plants, and therefore, galactosylated modification is applied by researchers in the laboratory to obtain more excellent diphyllin derivatives. This review will provide useful information for the development of diphyllin-based anti-tumor and anti-virus compounds.


Painful vaso-occlusive crisis as a prodromal phase of acute chest syndrome. Is only one chest X-ray enough? A case report.
The predominant pathophysiological feature of homozygous sickle cell anemia (SCA) is the vaso-occlusion. Vaso-occlusion can be associated with painful crises, which are the primary reason for those patients to seek medical care. Vaso-occlusion is responsible for the acute chest syndrome (ACS) with large morbidity and mortality or more rarely (and especially in adults) for priapism and acute neurological events (strokes). A 10-year-old boy with homozygous SCA was admitted to the Pediatric Emergencies with painful vaso-occlusive crisis and fever. Initially he had normal chest X-ray but, after 24-hour-hospitalization, he developed ACS with new chest X-ray findings. He was treated with broad spectrum antibiotics, blood transfusions and bronchodilators and after a six-day treatment, he was significantly improved. The patient was discharged 13 days later with no other therapy at home. The possibility of ACS development should be still considered, even when a known patient with SCA presents a painful vaso-occlusive crisis with an initial normal chest X-ray. Therefore, repeated clinical examination is required and possible changes in the clinical status could indicate the necessity of a new radiographic examination. In this way, early ACS could be recognized and the catastrophic consequences due to this syndrome could be avoided.


[The value basis of future medicine].
The aim of this article is to propose a way of structuring the values that should constitute the basis of future medical practice, starting with the values that are common in contemporary medical practice. First, medicine must acknowledge that human worth is inviolable. This leads to activities aimed at strengthening autonomy as well as protecting the weak and vulnerable aspects of human life. Second, medicine must be based on sound professional practice. Medical knowledge should be developed by scientific means, but not only by biomedical methods. The fundamentally stochastic nature of medicine must be acknowledged. The third set of values relates to equity in the access to medical care. Services for the weakest among us should have high priority. Finally, medical practice has to be predictable and transparent.


Preliminary description of a late Middle Pleistocene mammalian fauna prior to the extinction of Gigantopithecus blacki from the Yixiantian Cave, Guangxi ZAR, South China.
In recent years, nearly 20 cave sites with rich assemblages of mammalian fossils have been found and excavated in the Chongzuo area, Guangxi Zhuang Autonomous Region, China. Their ages are distributed throughout the entire Pleistocene Epoch. These discoveries have greatly facilitated our understanding of the evolution of the Stegodon-Ailuropoda fauna and the environmental context of human evolution in southern China. Here, we present a preliminary report on a diverse late Middle Pleistocene mammalian fauna from the Yixiantian Cave in southern China, which is a typical representative of the Stegodon-Ailuropoda fauna (sensu lato). The fossil mammals are represented by isolated dental remains only. In 2010 and 2011, two seasons of systematic excavations at the Yixiantian Cave yielded a total of 4,958 identifiable mammalian teeth. They were identified as belonging to 37 species and 6 orders of mammals. In addition, the tooth type of all the teeth representing each species was also determined where possible. A single fragmentary molar was identified as belonging to Gigantopithecus blacki, indicating that its population had declined sharply at this time and was on the brink of extinction. Description of the Yixiantian fauna will not only help better characterize the composition of the Stegodon-Ailuropoda fauna during the late Middle Pleistocene, but also clarify our understanding of the paleoenvironmental context at a time just prior to the extinction of G. blacki.


Scar contracture prevention with local steroid injections in transoral videolaryngoscopic surgery.
The aim of this study was to evaluate the efficacy and safety of local steroid injections to prevent scar contracture after transoral videolaryngoscopic surgery (TOVS) in hypopharyngeal cancer patients. Patients were enrolled in this study if they had received a local steroid injection during TOVS and had attended an outpatient clinic after at least three months. All patients were being treated for hypopharyngeal cancer and received a single session of triamcinolone acetonide, injected using a 21-gage needle. Retrospective chart reviews were performed, and the degree of scar contracture, pharyngeal stenosis, vocal fold movements, and adverse events were evaluated. Scar contracture was assessed using a scoring system, which compared the endoscopic findings of treatment and matched pair control groups. A total of 20 patients received local steroid injections during TOVS and were enrolled in the treatment. Scar contracture was seen in 14 patients (70%); however, the degree of scar contracture was significantly decreased when compared to control cases. Vocal fold immobility was observed in five patients, but no pharyngeal stenosis was noted. Adverse effects, such as postoperative laryngeal chondritis or cervical spondylitis, were seen in three patients who had previously been treated with resection to the muscularis propria or definitive irradiation. Local steroid injection during TOVS significantly reduced the degree of postoperative scar contracture. However, caution should be used when treating with local steroid injection during TOVS, as this may complicate wound healing in patients who have already received treatment.


[Partial laryngectomies with difficult presentations. Apropos of the surgical treatment of laryngeal epithelial tumors].
Difficult indications for certain partial laryngectomies are presented. Anatomically, the difficulties stem from the thyroid cartilage and paraglottic space in which invasion (difficult to determine), is contradictory for partial surgery. The principal objective is the cure of the laryngeal cancer all in maintaining laryngeal function. The surgeon must conserve a "minimal arytenoid unit" (the whole formed by the pharyngo-epiglottic fold, the ary-epiglottic fold, the arytenoid and the corresponding cord). Other difficulties not carcinologic are found: physical conditions, social and professional situation, and preexisting local problems (associated laryngocele or previous vocal palsy). Finally, carcinologic difficulties can be seen: the situation of the tumor, the rapidity of its evolution, anatomopathological types, presence of nodes and metastasis and previous physio and chemotherapy.


Analysis of flexural mode focusing by a semianalytical finite element method.
Focusing is one of the most promising techniques for the detection of small defects in pipe works, in which guided waves including longitudinal and flexural modes are tuned so that ultrasonic energy can be focused at a target point in a pipe, and analysis of reflected waves gives information on defects such as location and size. In this paper, the focusing technique is discussed by way of a simulation of guided wave propagation in pipe by a semianalytical finite element method (SAFE). Experiments and SAFE calculations were compared for waveforms transmitted by a single transducer and received at different circumferential positions initially, and then the focusing phenomena were experimentally observed using focusing parameters obtained by calculations. Calculation and visualization were conducted to clarify focusing phenomena in pipe in investigating the potential of the focusing technique. These results show that the time-reversal idea helps in understanding focusing and that resolution of focusing is strongly affected by incident waveforms as well as the number of channels available in an experiment.


Broadband two-dimensional electronic spectroscopy in an actively phase stabilized pump-probe configuration.
We introduce a novel configuration for two-dimensional electronic spectroscopy (2DES) that combines the partially collinear pump-probe geometry with active phase locking. We demonstrate the method on a solution sample of CdSe/ZnS nanocrystals by employing two non-collinear optical parametric amplifiers as the pump and probe sources. The two collinear pump pulse replicas are created using a Mach-Zehnder interferometer phase stabilized by active feedback electronics. Taking the advantage of separated paths of the two pump pulses in the interferometer, we improve the signal-to-noise ratio with double modulation of the individual pump beams. In addition, a quartz wedge pair manipulates the phase difference between the two pump pulses, enabling the recovery of the rephasing and non-rephasing signals. Our setup integrates many advantages of available 2DES techniques with robust phase stabilization, ultrafast time resolution, two-color operation, long delay scan, individual polarization manipulation and the ease of implementation.


Identification of collagen-binding proteins in Lactobacillus spp. with surface-enhanced laser desorption/ionization-time of flight ProteinChip technology.
Biosurfactants produced by Lactobacillus fermentum RC-14, L. rhamnosus GR-1 and 36, and L. casei Shirota were found to contain proteins that bind to both collagen types III and VI, as determined by surface-enhanced laser desorption/ionization (SELDI)-time of flight mass spectrometry. Both collagen types III and VI immobilized on SELDI preactivated ProteinChip arrays detected several different sizes (2 to 48 kDa) of collagen-binding proteins. Overall, the RC-14-produced biosurfactant contained the greatest number of collagen-binding proteins (RC-14 > GR-1 > 36 > Shirota), including the mature form of a previously cloned 29-kDa collagen-binding protein (referred to in its mature 26-kDa form). Although biosurfactants isolated from L. casei Shirota and L. rhamnosus 36 and GR-1 also contain several collagen-binding proteins, they do not contain the 26-kDa collagen-binding protein. Together, these results demonstrate the utility of the SELDI system as a means of rapidly characterizing clinically important but complex biosurfactant solutions.


Statistical process control for cancelled operations at the paediatric surgery department of a university hospital.
Being a cause of delayed patient management and underutilization of resources, cancelled operations are considered a low quality service. Moreover, anticipation of surgery is stressful for both patients and families, particularly if the patient is a child; additional anxiety posed by last-minute cancellation is, therefore, of primary concern. The present study was done to estimate the rate and explore the determinant causes of cancellation of planned operations on the day of surgery at the paediatric surgery department of a university hospital in Alexandria. A cross sectional study was performed, interviewing some paediatric surgeons and anaesthesiologists practising at the hospital to collect in depth information about causes of cancelled operations, in addition to revising daily operation sheets for 181 operations to calculate cancellation rate and causes of cancelled operations. To Study patterns of variation in cancellation rate, a control chart (p-chart) was drawn. The overall cancellation rate was almost 25%. Analysis of the control chart showed an average cancellation rate of 25%, upper control limit of 74% and a Lower control limit of zero. Of the cancelled operations, 64.4% were of avoidable causes. Pareto chart showed that not being fit for anaesthesia either for electrolyte disturbances, low haemoglobin level or fever was the commonest reason for cancellation of operation, followed by patient having chest infection and patient or doctors not showing on the day of operation (those formed more than 85% of causes). Implementation of outpatient preoperative assessment and preparation for surgery, in addition to the improvement of communication between patient, doctors and nurses are highly recommended.


Partnering for change: an innovative school-based occupational therapy service delivery model for children with developmental coordination disorder.
Developmental coordination disorder (DCD) is a common, chronic health condition that is poorly recognized and understood in school settings. Without appropriate support, children with DCD are at increased risk of depression, decreased fitness, and obesity. Evidence shows that occupational therapy intervention needs to shift from remediation of impairment to chronic disease management. This paper describes Partnering for Change (P4C), an innovative, empirically derived school health service delivery model for children with DCD. The model emphasizes the partnership of the occupational therapist with educators and parents to change the life and daily environment of a child. The P4C partnership focuses on capacity building through collaboration and coaching in context. The model uses a tiered approach which includes whole class instruction, dynamic performance analysis, and monitoring response to intervention. P4C is a model that responds to the needs of this population, addresses issues identified in research, and provides a continuum of services designed to build capacity.


Induction of hepatic differentiation in embryonic stem cells by co-culture with embryonic cardiac mesoderm.
Modifications in vitro have been used to direct embryonic stem (ES) cells toward endodermal phenotypes including hepatocytes; however, developmental correlates and evidence of biologic activity is lacking, and critical cell-cell interactions have not been investigated. In this study, we hypothesized that cardiac mesoderm (CM) signals ES cells in co-culture to undergo differentiation toward early hepatocyte lineage as determined by morphology and induction of genes essential for endodermal competence and hepatocyte development. Green fluorescent protein ES derived from A129 mice were cultured with or without embryonic chick cardiac mesoderm. Cultures from day 1, 2, and 4 were analyzed for colony formation and ES morphology and 10(6) ES-derived cells were isolated for mRNA analysis. ES in co-culture with CM displayed colony formation, polymorphic appearance, and definitive interface with CM. In addition, ES + CM co-culture activated crucial transcription factors (sox 17alpha, HNF3beta, and GATA 4) required for hepatocyte development by day 1. mRNA for albumin and especially a-fetoprotein were also increased by culture days 2 and 4. ES cells co-cultured with CM display morphology and gene expression pattern required for hepatocyte differentiation and appear to recapitulate the molecular events of hepatogenesis.


Cervical perimedullary arteriovenous shunts: a study of 22 consecutive cases with a focus on angioarchitecture and surgical approaches.
Reports of cervical perimedullary arteriovenous shunt (PMAVS) are limited, and treatment strategies have not been established. To describe angioarchitecture and optimal treatment strategies for cervical PMAVS. We treated 22 patients with cervical PMAVS between 2000 and 2012 (8 women and 14 men; age, 9-80 years). According to the classification, our patients included type IVa (4 patients), type IVb (16 patients), and type IVc (2 patients). Seventeen patients presented with subarachnoid hemorrhage. A total of 41 shunting points were localized in 22 patients, of which 34 points were located ventral or ventrolateral to the spinal cord. The anterior spinal artery (ASA) contributed to the shunts in 16 patients. Aneurysm formation was identified in 8 patients. Endovascular treatment was attempted in 3 patients, resulting in complete obliteration in 1 patient (type IVc). Overall, 21 patients underwent open surgery. An anterior approach with corpectomy was elected for 2 patients; the other 19 patients underwent the posterior approaches using indocyanine green videoangiography, intraoperative angiography, endoscopy (8 patients), and neuromonitoring. Twenty patients were rated as having a good recovery at 6 months after surgery. No recurrence was observed in any patients during the follow-up (mean, 59.7 months). Shunting points of the cervical PMAVS were predominantly located ventral or ventrolateral to the spinal cord and were often fed by the ASA. Even for ventral lesions, posterior exposure assisted with neuromonitoring and endoscopy, and intraoperative angiography provided a view sufficient to understand the relationships between the shunts and the ASA and contributed to good surgical outcomes.


Serological diagnosis of hydatid disease by enzyme linked immunosorbent assay (ELISA) using partially purified hydatid cyst fluid antigens.
Experimentally, two hydatid cyst fluid (HCF) antigens (antigens 4 and 5) were found to be the most immunogenic antigens in HCF. The two antigens were precipitated together from HCF. This was done by adding 2M phosphotungstic acid and 2M magnesium chloride solutions to clarified HCF while continuously stirring the mixture. The precipitate formed was suspended in physiological saline (P.S.). This antigens' solution was used to coat microtitre plates for indirect ELISA. Indirect ELISA was performed on 180 randomly selected bovine sera. The sensitivity of the test was found to be 98% while the specificity was 70%. The predictive value was 89%. Although the specificity of the test was relatively low, the test using these partially purified antigens was found to be useful because of its high sensitivity.


Efficacy and Safety of Biologic Agents in Chronic Urticaria, Asthma and Atopic Dermatitis - A Real-life Experience.
Several biologic agents have been approved for the treatment of asthma, chronic urticaria and atopic dermatitis. These therapeutic agents are especially useful for patients with severe or refractory symptoms. We present the real-life experience of four of the commonly used biologic agents in the United Arab Emirates. In this retrospective observational study, we reviewed the demographic, clinical, laboratory and treatment parameters for all patients treated with biologic agents. 270 patients received biologics at our centre between May 2015 and December 2019 with a median age of 36.5 years. Omalizumab was the most prescribed agent (n=183, 67.8%) followed by dupilumab (n=54, 20%), benralizumab (n=22, 8.1%) and mepolizumab (n=11, 4.1%). Urticaria was the commonest treatment indication (n=148, 55%) followed by asthma (n=105, 39%) and atopic dermatitis (n=13, 5%). All chronic urticaria patients were treated with omalizumab and showed improvement in the mean urticaria control test score from 6.7±4.47 to 12.02±4.17, with a p-value of 0.001. Dupilumab was found to be the most commonly prescribed drug for asthma (37%), followed by omalizumab (32%), benralizumab (21%) and mepolizumab (10%). The mean Asthma control test score for all asthmatics combined increased from 17.06 ± 5.4 to 19.44 ± 5.6, with p-value 0.0012 with treatment; FeNO reduced from 60.02 ± 45.74 to 29.11 ± 27.92, with p-value 0.001 and mean FEV1 improved from 2.38L ± 0.8 to 2.67L ± 0.78, with p-value 0.045. Only 4 patients in the entire cohort reported adverse events. Our study demonstrated that biological agents are a safe and effective treatment for atopic asthma, chronic urticaria and atopic dermatitis.


Tobacco exposure as a major modifier of oncologic outcomes in human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma.
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients. We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002-2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p < 0.05). Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p = 0.002, p = 0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ > 30 PY patients didn't differ significantly from HPV- patients (p = 0.72, p = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively. Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.


[Impairment of lipid metabolism in the liver and its correction after exposure to ethanol and antitubercular agents].
Impairments in the lipid spectrum of rat liver tissue, developed as a result of long-term simultaneous effect of ethanol and antituberculosis drugs isoniazid ann rifampycin, were effectively corrected by means of phospholipid preparations as well as by legalone (sylimarine). Pyridoxine, tocopherol and ATP did not normalize the lipid metabolism under these conditions.


MicroRNAs, the DNA damage response and cancer.
Many carcinogenic agents such as ultra-violet light from the sun and various natural and man-made chemicals act by damaging the DNA. To deal with these potentially detrimental effects of DNA damage, cells induce a complex DNA damage response (DDR) that includes DNA repair, cell cycle checkpoints, damage tolerance systems and apoptosis. This DDR is a potent barrier against carcinogenesis and defects within this response are observed in many, if not all, human tumors. DDR defects fuel the evolution of precancerous cells to malignant tumors, but can also induce sensitivity to DNA damaging agents in cancer cells, which can be therapeutically exploited by the use of DNA damaging treatment modalities. Regulation of and coordination between sub-pathways within the DDR is important for maintaining genome stability. Although regulation of the DDR has been extensively studied at the transcriptional and post-translational level, less is known about post-transcriptional gene regulation by microRNAs, the topic of this review. More specifically, we highlight current knowledge about DNA damage responsive microRNAs and microRNAs that regulate DNA damage response genes. We end by discussing the role of DNA damage response microRNAs in cancer etiology and sensitivity to ionizing radiation and other DNA damaging therapeutic agents.


Active versus passive listening to auditory streaming stimuli: a near-infrared spectroscopy study.
We use near-infrared spectroscopy (NIRS) to assess listeners' cortical responses to a 10-s series of pure tones separated in frequency. Listeners are instructed to either judge the rhythm of these "streaming" stimuli (active-response listening) or to listen to the stimuli passively. Experiment 1 shows that active-response listening causes increases in oxygenated hemoglobin (oxy-Hb) in response to all stimuli, generally over the (pre)motor cortices. The oxy-Hb increases are significantly larger over the right hemisphere than over the left for the final 5 s of the stimulus. Hemodynamic levels do not vary with changes in the frequency separation between the tones and corresponding changes in perceived rhythm ("gallop," "streaming," or "ambiguous"). Experiment 2 shows that hemodynamic levels are strongly influenced by listening mode. For the majority of time windows, active-response listening causes significantly larger oxy-Hb increases than passive listening, significantly over the left hemisphere during the stimulus and over both hemispheres after the stimulus. This difference cannot be attributed to physical motor activity and preparation related to button pressing after stimulus end, because this is required in both listening modes.


Ontario accelerator dose intercomparison study.
An ionometric dose intercomparison has been carried out on eight accelertors, with maximum photon energies from 6 to 32 meV, at five radiotherapy centres in Ontario. The ratio of the dose based on the clinically-employed rad/monitor unit to the dose measured by the committee representative had a mean value of 0.994, with a range of 7.3% and a coefficient of variation of 2.5%. The ratio of the dose measured by the institution's physicist to the dose measured by the committee representative had a mean value of 1.000 with a range of 6.9% and a coefficient of variation of 2.3%. Eight recommendations regarding dose calibration procedures are presented.


Metacognitive Skills Training and Computerized Cognitive Remediation among Individuals with First-Episode Psychosis: Influence on Social Cognition.
Metacognitive skills training (MST) is often integrated into cognitive remediation programs for psychosis. Social cognition - the mental processes underlying social perception and behavior - is robustly related to outcomes in psychosis and is increasingly addressed with targeted treatments. Though metacognition and social cognition are related constructs, little is known about how MST may influence social cognition among individuals with psychosis participating in broad-based, non-social cognitive remediation. Individuals with first-episode psychosis who completed six months of metacognitive remediation (MCR; n=12) were compared to a historical control group who received six months of computerized cognition remediation (CCR; n=10) alone (ClinicalTrials.gov Identifier NCT01570972). Though individuals receiving MCR experienced gains in emotion processing and theory of mind, these changes were not significantly different when compared to individuals receiving CCR. MST did not contribute to social cognitive change in the context of CCR. Though MST may be relevant to facilitating social cognitive gains within broader cognitive remediation programs for first-episode psychosis, these benefits are limited and may not exceed those conferred by standard cognitive remediation. Opportunities for investigation of other potential mechanisms of social cognitive response to interventions remain.


A case of generalized lichen nitidus successfully treated with narrow-band ultraviolet B treatment.
Lichen nitidus (LN) is a rare skin disorder presenting with multiple, small and bright papules located on the chest, abdomen, penis glans and upper extremities. It usually presents with limited involvement; however, it can present as generalized involvement. There is no consensus on treatment. Corticosteroid, astemizole, phototherapy has been used; however, the results are controversial. A 15-year-old male with clinical and histopathological diagnosis of LN was treated with narrow-band ultraviolet B (NB-UVB). The lesions completely regressed with post-inflammatory hypopigmentation on the second month of the therapy (25 sessions). We believe that NB-UVB is an effective treatment on generalized LN.


[Asthma--a condition of our time, a condition in change?].
This article reviews causative factors for asthma and allergy during childhood and describes current trends in prevalence and hospitalisation for childhood asthma. A review of the prevalence of childhood asthma in Norway over the last 50 years together with recent trends in hospitalisation for childhood asthma, is given. Possible causative factors for childhood asthma are reviewed, and recent theories for the current increase in prevalence are discussed. During the last 50 years, a steady increase in the prevalence of childhood asthma has been documented through published studies from 1948 and onwards. From 1980 and until 1990, an increase in hospital admissions due to acute asthma was observed; later, admissions have leveled off, particularly as regards readmissions. Smoking during pregnancy and childhood decreases lung function. Allergic sensitisation is related to asthma development and may occur already during pregnancy. Increased allergic sensitisation may occur due to reduced load of infections. However, respiratory virus infections, and especially RS virus and rhinovirus infections, are closely related to asthma development and symptoms during childhood. A reduction in readmissions for asthma may be related to increased use of antiinflammatory therapy for asthma.


Internet gambling and risk-taking among students: An exploratory study.
Internet gambling is undergoing a massive worldwide expansion. The relationship between the convenience, anonymity, and the 24-hour availability of Internet gambling and problem gambling in young people presents a serious concern. This study explored general gambling behavior, including Internet gambling (with and without money), problem gambling, and risk-approach motivation in a sample of university students aged 18 to 20 years. University undergraduates (N = 465) in two urban universities completed in-class paper-and-pencil questionnaires concerning Internet gambling, risk taking, and a checklist of the DSM-IV criteria for problem gambling. Overall, 8.0% of participants reported past-year gambling for money on the Internet, with significantly higher rates among males (11.8%) than females (0.6%). Based on DSM-IV criteria, 3.7% of respondents were classified as problem gamblers (i.e., endorsed 3 or more items). There were higher rates of problem gambling among those who had gambled on the Internet, and students who had gambled on the Internet had higher risk-approach scores. The results of this study suggest that students who have gambled on the Internet have greater risk-taking motivation than students who have not gambled online, and those classified as problem gamblers have greater risk-taking motivation than non-gamblers. Results also suggest both higher risk taking scores and classification as a high risk-taker predict online gambling. Gambling on the Internet may be harmful for some individuals; young males, those with high risk-approach motivation, and, most certainly, those already exhibiting problem gambling behaviors.


Can antihypertensive medication interfere with the vicious cycle between hypertension and vascular calcification?
Vascular calcification is a phenomenon of disturbed calcium deposition, as part of the calcium that is supposed to be deposited to our bones, is lodged to our vessels. There are two forms of vascular calcification, each with a distinct anatomical distribution and clinical relevance, namely the intimal and medial calcification. Studies have demonstrated that hypertension may cause vascular calcification but also that both types of calcification, especially medial, promote arterial rigidity and hence hypertension. Implications of this two-way road are largely unknown as there is no consensus yet on their exact clinical value. However, several antihypertensive medications seem to be able to interfere with the cycle of high blood pressure and vascular calcium deposits. The present review summarizes the up-to-date data regarding the effect of antihypertensive medication on vascular calcification.


Autonomic restoration of electrical conductivity.
Self-healing of an electrical circuit is demonstrated with nearly full recovery of conductance less than one millisecond after damage. Crack damage breaks a conductive pathway in a multilayer device, interrupting electron transport and simultaneously rupturing adjacent microcapsules containing gallium-indium liquid metal (top). The released liquid metal flows to the area of damage, restoring the conductive pathway (bottom).


Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: clinicopathological correlations.
To better characterize the heavy proteinuria occasionally described in cholesterol atheroembolic renal disease (CAE), we reviewed the clinical features and histological findings of 24 patients found at renal biopsy to have CAE. Twelve (50%) had a typical clinical presentation soon after an invasive vascular procedure. Eight (33%) underwent biopsies to evaluate proteinuria and four (17%) with insidiously developing renal failure to exclude rapidly progressive glomerulonephritis. All had usual and similar risk factors for CAE; 71% were male, 96% had peripheral vascular disease, 79% had recently undergone an invasive vascular procedure, 74% were hypercholesterolemic, and all were hypertensive. Proteinuria was higher and serum creatinine lower in the proteinuria group. In the nine (38%) nephrotic patients, serum creatinine measurements were lower (2.7 +/- 1.2 v 5.6 +/- 2.4 mg/dL), duration of renal disease to biopsy longer, and time from biopsy to dialysis greater (23.5 +/- 14.8 v 0.03 +/- 0.098 mo, P < 0.05 for all). Focal segmental glomerulosclerosis (FSGS) was observed in 15 (63%) of the biopsy specimens. Although FSGS itself did not occur more commonly in nephrotic patients, these patients did have a higher fraction of segmentally sclerosed glomeruli (0.158 +/- 0.097 v 0.026 +/- 0.050, P < 0.01). A variant of FSGS, the cellular lesion with epithelial cell prominence and capillary loop collapse, was observed in 7 of 9 (78%) patients with nephrotic-range proteinuria, but in only 3 of 12 (25%) patients with lesser degrees of protein excretion (P < 0.05). The cellular lesion was accompanied by higher mean proteinuria, 7.6 +/- 4.3 versus 2.1 +/- 2.4 g/24 hr (P < 0.01). In a larger group of patients with a similar age range as the CAE group who were identified by search of a computerized biopsy database, membranous nephropathy was the only other form of idiopathic glomerulonephritis that occurred with CAE. One of 82 (1.2%) patients with membranous nephropathy also had CAE, compared with 20 of 102 (19.6%) with FSGS (P < 0.0002, chi2). Thus, the finding of FSGS with CAE was not coincidence. Mean follow-up was 20 +/- 26 months (range, 0 to 103 months). Six patients (25%) were followed-up at least 3 years after renal biopsy. These findings indicate that extended survival in CAE is not rare and that heavy proteinuria occurs as part of a chronic disorder with distinctive histological features. Cholesterol atheroembolism with FSGS should be considered in the differential diagnosis of nephrotic syndrome in elderly patients with advanced atherosclerosis.


[Atraumatic Restorative Treatment (ART). A special tissue preservative and patient-friendly approach].
The number of studies investigating aspects of the ART-approach has increased in recent years. This tissue preservative treatment concept appears to be less painful and is, therefore, more patient-friendly than conventional treatments. The investigations so far have shown that the ART-approach is indicated for treating single-surface cavities in both primary and permanent dentitions. There appears to be no difference in survival results between single-surface ART restorations and comparable amalgam restorations in the permanent dentition after 3 years. ART sealants using high-viscosity glass-ionomers seem to be retained longer than ART sealants using low-viscosity glass-ionomers after 3 years. The surface wear of ART restorations using high-viscosity glass-ionomers after two years is low. It can be concluded that the ART approach is beneficial in improving the oral health of many people, not only in developing but also in more advanced countries. The full benefit of the ART-approach is not yet known.


Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies.
Ultrasound can be used to noninvasively produce different bioeffects via viscous heating, acoustic cavitation, or their combination, and these effects can be exploited to develop a wide range of therapies for cancer and other disorders. In order to accurately localize and control these different effects, imaging methods are desired that can map both temperature changes and cavitation activity. To address these needs, the authors integrated an ultrasound imaging array into an MRI-guided focused ultrasound (MRgFUS) system to simultaneously visualize thermal and mechanical effects via passive acoustic mapping (PAM) and MR temperature imaging (MRTI), respectively. The system was tested with an MRgFUS system developed for transcranial sonication for brain tumor ablation in experiments with a tissue mimicking phantom and a phantom-filled ex vivo macaque skull. In experiments on cavitation-enhanced heating, 10 s continuous wave sonications were applied at increasing power levels (30-110 W) until broadband acoustic emissions (a signature for inertial cavitation) were evident. The presence or lack of signal in the PAM, as well as its magnitude and location, were compared to the focal heating in the MRTI. Additional experiments compared PAM with standard B-mode ultrasound imaging and tested the feasibility of the system to map cavitation activity produced during low-power (5 W) burst sonications in a channel filled with a microbubble ultrasound contrast agent. When inertial cavitation was evident, localized activity was present in PAM and a marked increase in heating was observed in MRTI. The location of the cavitation activity and heating agreed on average after registration of the two imaging modalities; the distance between the maximum cavitation activity and focal heating was -3.4 ± 2.1 mm and -0.1 ± 3.3 mm in the axial and transverse ultrasound array directions, respectively. Distortions and other MRI issues introduced small uncertainties in the PAM∕MRTI registration. Although there was substantial variation, a nonlinear relationship between the average intensity of the cavitation maps, which was relatively constant during sonication, and the peak temperature rise was evident. A fit to the data to an exponential had a correlation coefficient (R(2)) of 0.62. The system was also found to be capable of visualizing cavitation activity with B-mode imaging and of passively mapping cavitation activity transcranially during cavitation-enhanced heating and during low-power sonication with an ultrasound contrast agent. The authors have demonstrated the feasibility of integrating an ultrasound imaging array into an MRgFUS system to simultaneously map localized cavitation activity and temperature. The authors anticipate that this integrated approach can be utilized to develop controllers for cavitation-enhanced ablation and facilitate the optimization and development of this and other ultrasound therapies. The integrated system may also provide a useful tool to study the bioeffects of acoustic cavitation.


Monitoring and evaluation of the immune status of female Kunming mice maintained in different biosafety level laboratories.
High-level biosafety laboratories (BSL), such as BSL-3 and BSL-4, which deal with high infectivity and virulence pathogens, have become indispensable. Mice are frequently used in animal BSL (ABSL) to establish animal models for infection and to evaluate in vivo immune responses. A project of monitoring and evaluation on the physiology and immune status of mice housed in different ABSL labs was performed in the ABSL-2/3/4 labs of Kunming National High-level Biosafety Research Center, China. Female Kunming mice were housed in the ABSL-2/3/4 labs for 1 month, and mouse behavior, body physiology/immune status, pulmonary immune status and respiratory bacteria composition were evaluated and compared among mice from the different labs. Mice settled in their new housing environment of the different labs after transfer and gained weight steadily. Blood hematology testing, serum cytokine/chemokine profiles and blood/spleen lymphocyte constitutions were comparable between the ABSL-2/3/4 labs. The numbers of different pulmonary leukocytes in the bronchoalveolar lavage fluid were at baseline levels in mice from the ABSL-2/3/4 labs. Diversity and dominance of mice respiratory bacteria were semblable among the ABSL-2/3/4 labs. Our results confirm the stability of physiology and immune status of Kunming mice maintained in different ABSL-2/3/4 labs for at least 1 month.


Oligonucleotide aptamers for pathogen detection and infectious disease control.
During an epidemic or pandemic, the primary task is to rapidly develop precise diagnostic approaches and effective therapeutics. Oligonucleotide aptamer-based pathogen detection assays and control therapeutics are promising, as aptamers that specifically recognize and block pathogens can be quickly developed and produced through simple chemical synthesis. This work reviews common aptamer-based diagnostic techniques for communicable diseases and summarizes currently available aptamers that target various pathogens, including the SARS-CoV-2 virus. Moreover, this review discusses how oligonucleotide aptamers might be leveraged to control pathogen propagation and improve host immune system responses. This review offers a comprehensive data source to the further develop aptamer-based diagnostics and therapeutics specific for infectious diseases.


A kit formulation for the preparation of 188Re-lipiodol: preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma.
A lyophilized kit formulation for the efficient labelling of lipiodol with generator-produced rhenium-188 is described. The preliminary preparation of the lipophilic complex bis-(diethyldithiocarbamato)nitrido rhenium-188 (188ReN-DEDC) was carried out using a two-vial kit containing S-methyl-N-methyl-dithiocarbazate, SnCl2 and sodium oxalate in the first vial, and diethyldithiocarbamate and a carbonate buffer in the second vial. After mixing of the reaction solution with lipiodol, the complex 188ReN-DEDC was quantitatively extracted and retained by this hydrophobic substance, thus allowing the stable incorporation of the beta-emitting radionuclide. The radiochemical purity of the complex 188ReN-DEDC was 97+/-2%. The activity extracted into the lipiodol phase was 96+/-3% of the initial activity, indicating that the complex 188ReN-DEDC was almost quantitatively removed from the aqueous reaction solution. In vitro stability studies in human plasma, at 37 degrees C, demonstrated the release of less than 15% of the activity within three half-lives. The biodistribution of Re-lipiodol in non-tumour-bearing Wistar rats at 6, 24, 48 and 72 h after intraportal venous injection showed one-third of total activity in the liver at 6 h, declining to 2% retention at 72 h. Bowel uptake at 6 and 24 h declined to low levels at 48 and 72 h. Renal activity peaked at 1.7%, diminishing to 0.6% over 48 h. Rat whole body gamma imaging showed gut activity in addition to hepatic uptake at 6 and 24 h, but only liver was evident from 48 to 72 h. Kidneys were not demonstrable at any imaging time point. In nine patients, activity was localized in the tumours immediately following intrahepatic arterial injection. Computed tomography/single-photon emission computed tomography (CT/SPECT) imaging at 1 and 24 h confirmed the retention of 188Re-lipiodol in the hepatoma, with minimal gut uptake and no lung activity over 24 h. These patients were subsequently treated with activities of 2.5-5 GBq of 188Re-lipiodol fractions without adverse effects. Six patients followed for up to 2 years in the pilot study achieved stable disease and there was objective partial response in one patient. Repeated treatments were performed on two to three occasions in three patients without evident toxicity. An additional patient given 6 GBq of 188Re-lipiodol demonstrated myelosuppression, which recovered with granulocyte colony-stimulating factor (GCSF) and platelet support. It is concluded that 188Re-lipiodol, prepared using our novel kit formulation, is stable in vivo and provides safe and effective therapy of unresectable hepatocellular carcinoma when given via the hepatic artery, either alone or in combination with transarterial chemoembolization.


Effects of low molecular weight heparin in the treatment of venous thromboembolism in patients with gastrointestinal cancer.
This study aimed to observe the safety and effectiveness of different dosing regimens of low molecular weight heparin in the prevention of venous thromboembolism (VTE) and to provide a guideline for the treatment of individualized VTE prophylaxisin patients with postoperative gastrointestinal tumors. Forty patients with high risk for VTE after surgery for gastrointestinal tumors treated in Hongqi Hospital of Mudanjiang Medical University in the period October 2016 to May 2017 were included in the study. The patients were randomly divided into two groups, group A that included 24 patients treated with low molecular weight heparin (LMWH) 5000 IU every 12 hours, and group B comprised of 16 patients treated with LMWH 5000IU every 24 hours. On the seventh day post-surgery anti-Xa activity values reached effective anticoagulation (>0.5 IU/mL) in both groups. In group A, there was one case of anti-Xa activity exceeding 1.0 IU/mL, but no bleeding complications occurred. Using LMWH 5000 IU subcutaneous injection every 12 hours could also prevent postoperative VTE of gastrointestinal tumor, but the risk of bleeding complications is higher compared with 24-hour administration. Monitoring of plasma D-dimer within 7 days after gastrointestinal surgery did not show a great value for VTE monitoring. This study demonstrated that subcutaneous injection of LMWH can prevent VTE after gastrointestinal tumor surgery and provide a new alternative for VTE prevention.


Large Cell Neuroendocrine Carcinoma of the Head and Neck: A Clinicopathologic Series of 10 Cases With an Emphasis on HPV Status.
Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine neoplasm first described in the lung and subsequently well documented in many other anatomic sites. It has only recently been recognized that LCNEC can also occasionally arise in the head and neck. The role of human papillomavirus (HPV), which is associated with some small cell carcinomas of the head and neck, has not been investigated for LCNEC. We sought to further characterize the histologic, immunophenotypic, and clinical features of LCNEC and also investigate the role of HPV in this newly described group of tumors. The surgical pathology archives of 2 large academic institutions were searched for cases of LCNEC arising in the head and neck. p16 immunohistochemistry and HPV in situ hybridization were performed, and clinical information was obtained from electronic medical records. Ten cases of head and neck LCNEC were identified. The tumors arose in 6 men and 4 women ranging in age from 14 to 70 years (median, 63.5 y). The primary tumor sites were the oropharynx (n=4), the sinonasal tract (n=3), and the larynx (n=3). The LCNECs consisted of nests and trabeculae of medium-large cells with abundant cytoplasm, coarse chromatin, and prominent nucleoli with very high mitotic rates. The tumor nests were often associated with necrosis, peripheral palisading, and rosette formations. The LCNECs were positive for pan-cytokeratin and at least 1 neuroendocrine marker (most often synaptophysin) and were largely negative for p63 (focal staining in 2/10) and CK5/6 (staining in 1/10). The LCNECs demonstrated aggressive clinical behavior: 8 of 10 presented with advanced disease, 5 of 10 died, with 4 more living but with persistent tumor. Three of 10 LCNECs were HPV-related (HPV-LCNEC); they arose in the oropharynx (n=2) and sinonasal tract (n=1). The HPV-LCNECs did not differ from the HPV-negative tumors in histologic appearance or behavior: 2 patients with HPV-LCNEC have died because of their disease and 1 remains alive but with widespread metastases. LCNEC is a rare but distinct form of head and neck carcinoma that exhibits aggressive clinical behavior. A subset of oropharyngeal and sinonasal LCNEC is HPV related, but the presence of HPV may not impart a more favorable prognosis. Because of its aggressive behavior, LCNEC should be distinguished from moderately differentiated neuroendocrine carcinoma and squamous cell carcinoma. The morphology of LCNEC overlaps considerably with the nonkeratinizing appearance of HPV-related squamous cell carcinoma, and as a result a high index of suspicion is needed to identify LCNEC. Immunohistochemical studies for synaptophysin and p63 are helpful tools for making this distinction.


p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2.
The INK4a/ARF locus encodes two distinct tumor suppressors, p16INK4a and p14ARF. Although the contribution of p16INK4a to human tumorigenesis through point mutation, deletion, and hypermethylation has been widely documented, little is known about specific p14ARF lesions and their consequences. Recent data indicate that p14ARF suffers inactivation by promoter hypermethylation in colorectal cancer cells. Because it is known that p14ARF prevents MDM2 nucleocytoplasmic shuttling and thus stabilizes p53 by attenuating MDM2-mediated degradation, we studied the relationship of p14ARF epigenetic silencing to the expression and localization of MDM2 and p53. Cancer cell lines with an unmethylated p14ARF promoter showed strong nuclear expression of MDM2, whereas in a colorectal cell line with p14ARF hypermethylation-associated inactivation, MDM2 protein was also seen in the cytosol. Treatment with the demethylating agent 5-aza-2'-deoxycytidine was able to reinternalize MDM2 to the nucleus, and p53 expression was restored. No apparent changes in retinoblastoma localization were observed. We also studied the profile of p14ARF promoter hypermethylation in an extensive collection of 559 human primary tumors of different cell types, observing that in colorectal, gastric, renal, esophageal, and endometrial neoplasms and gliomas, aberrant methylation of p14ARF was a relatively common epigenetic event. MDM2 expression patterns revealed that lack of p14ARF promoter hypermethylation was associated with tumors showing exclusive nuclear MDM2 staining, whereas MDM2 cytosolic staining was frequently observed in neoplasms with aberrant p14ARF methylation. Taken together, these data support that epigenetic silencing of p14ARF by promoter hypermethylation is a key mechanism in the disturbance of the MDM2 nuclear localization in human cancer.


Optimization of a suite of flathead catfish (Pylodictis olivaris) microsatellite markers for understanding the population genetics of introduced populations in the northeast United States.
Flathead catfish are rapidly expanding into nonnative waterways throughout the United States. Once established, flathead catfish may cause disruptions to the local ecosystem through consumption and competition with native fishes, including species of conservation concern. Flathead catfish often become a popular sport fish in their introduced range, and so management strategies must frequently balance the need to protect native and naturalized fauna while meeting the desire to maintain or enhance fisheries. However, there are currently few tools available to inform management of invasive flathead catfish (Pylodictis olivaris). We describe a suite of microsatellite loci that can be used to characterize population structure, predict invasion history, and assess potential mitigation strategies for flathead catfish. Our panel of 13 microsatellite loci were polymorphic and appear to be informative for population genetic studies of flathead catfish. We found moderate levels of diversity in four nonnative collections of flathead catfish in the Pennsylvania and Maryland sections of the Susquehanna River and the Schuylkill River, Pennsylvania. Analyses suggested patterns of genetic differentiation within- and among-rivers, highlighting the utility of this marker panel for understanding the structure and assessing the degree of connectivity among flathead catfish populations.


Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy.
By triggering immunogenic cell death, some anticancer compounds, including anthracyclines and oxaliplatin, elicit tumor-specific, interferon-γ-producing CD8(+) αβ T lymphocytes (Tc1 CTLs) that are pivotal for an optimal therapeutic outcome. Here, we demonstrate that chemotherapy induces a rapid and prominent invasion of interleukin (IL)-17-producing γδ (Vγ4(+) and Vγ6(+)) T lymphocytes (γδ T17 cells) that precedes the accumulation of Tc1 CTLs within the tumor bed. In T cell receptor δ(-/-) or Vγ4/6(-/-) mice, the therapeutic efficacy of chemotherapy was compromised, no IL-17 was produced by tumor-infiltrating T cells, and Tc1 CTLs failed to invade the tumor after treatment. Although γδ T17 cells could produce both IL-17A and IL-22, the absence of a functional IL-17A-IL-17R pathway significantly reduced tumor-specific T cell responses elicited by tumor cell death, and the efficacy of chemotherapy in four independent transplantable tumor models. Adoptive transfer of γδ T cells restored the efficacy of chemotherapy in IL-17A(-/-) hosts. The anticancer effect of infused γδ T cells was lost when they lacked either IL-1R1 or IL-17A. Conventional helper CD4(+) αβ T cells failed to produce IL-17 after chemotherapy. We conclude that γδ T17 cells play a decisive role in chemotherapy-induced anticancer immune responses.


Response to rapamycin analogs but not PD-1 inhibitors in PTEN-mutated metastatic non-small-cell lung cancer with high tumor mutational burden.
In non-small-cell lung cancer (NSCLC) refractory to standard therapy and which lacks well-known oncogenic drivers, genomic profiling can still identify genomic alterations that may suggest potential sensitivity to targeted therapy. PTEN mutation in NSCLC may be sensitizing to analogs of rapamycin such as everolimus or temsirolimus, but more investigation is needed. We report the case of a patient with metastatic NSCLC harboring a PTEN mutation as well as high tumor mutational burden and PD-L1 positivity with a durable response to temsirolimus, but refractory to a checkpoint inhibitor. Even in the event of failure of treatment with checkpoint inhibitors in the background of a case with a higher tumor mutational burden and PD-L1 positivity, targeting specific genomic alterations may still result in patient benefit.


Expression of the lactose transposon Tn951 in Escherichia coli, Proteus and Pseudomonas.
The control of beta-galactosidase specified by the lactose transposon Tn951 (inserted into RP1 to give pGC9114) has been studied in Escherichia coli K12, Proteus mirabilis, Pseudomonas aeruginosa and Pseudomonas putida; in the first two species comparison could be made with Flac. In E. coli K12, the Tn951 and chromosomally encoded enzymes showed marked qualitative differences in regulatio, the former giving a substantially lower maximum induced level and induction ratio. Several parameters were slightly affected by strain background. In P. mirabilis, beta-galactosidase control determined by both Flac (in accord with earlier work) and pGC9114 was markedly different from E. coli in that maximal induced levels were about an order of magnitude lower and the induction ratio was reduced to 3 to 5. In Ps. aeruginosa and Ps. putida, Tn951-specified lac expression was qualitatively similar to that in P. mirabilis. Possible reasons for anomalous expression in Proteus and Pseudomonas are discussed.


Pathogenesis of oral FIV infection.
Feline immunodeficiency virus (FIV) is the feline analogue of human immunodeficiency virus (HIV) and features many hallmarks of HIV infection and pathogenesis, including the development of concurrent oral lesions. While HIV is typically transmitted via parenteral transmucosal contact, recent studies prove that oral transmission can occur, and that saliva from infected individuals contains significant amounts of HIV RNA and DNA. While it is accepted that FIV is primarily transmitted by biting, few studies have evaluated FIV oral infection kinetics and transmission mechanisms over the last 20 years. Modern quantitative analyses applied to natural FIV oral infection could significantly further our understanding of lentiviral oral disease and transmission. We therefore characterized FIV salivary viral kinetics and antibody secretions to more fully document oral viral pathogenesis. Our results demonstrate that: (i) saliva of FIV-infected cats contains infectious virus particles, FIV viral RNA at levels equivalent to circulation, and lower but significant amounts of FIV proviral DNA; (ii) the ratio of FIV RNA to DNA is significantly higher in saliva than in circulation; (iii) FIV viral load in oral lymphoid tissues (tonsil, lymph nodes) is significantly higher than mucosal tissues (buccal mucosa, salivary gland, tongue); (iv) salivary IgG antibodies increase significantly over time in FIV-infected cats, while salivary IgA levels remain static; and, (v) saliva from naïve Specific Pathogen Free cats inhibits FIV growth in vitro. Collectively, these results suggest that oral lymphoid tissues serve as a site for enhanced FIV replication, resulting in accumulation of FIV particles and FIV-infected cells in saliva. Failure to induce a virus-specific oral mucosal antibody response, and/or viral capability to overcome inhibitory components in saliva may perpetuate chronic oral cavity infection. Based upon these findings, we propose a model of oral FIV pathogenesis and suggest alternative diagnostic modalities and translational approaches to study oral HIV infection.


Pubertal development at age 14 is associated with male adolescents' combustible cigarette smoking and dual use, but not with e-cigarette use - Findings from the UK Millennium Cohort Study.
Adolescent nicotine exposure via electronic cigarettes (e-cigarettes) is a global health concern. Pubertal development earlier than peers increases the risk of tobacco smoking compared to peers experiencing on-time or late maturation, yet relationships of pubertal timing with e-cigarettes are unknown. We examine whether early pubertal timing is associated with risk for e-cigarette use, tobacco cigarettes, or both by age 14. The Millennium Cohort Study follows a representative cohort of 18,552 9-month-old children born 2000-2002 in the United Kingdom. Our sample includes 11,445 adolescents (5697 boys, 5748 girls) classified at age 14 as early, on-time, or late in pubertal development timing (PDT) relative to same-age, same-sex peers using the Pubertal Development Scale. Outcomes were use of e-cigarettes, tobacco cigarettes, or both by age 14. We included childhood liability confounders and demographics measured from age 7-11. For girls, no PDT differences in age 14 e-cigarette or tobacco cigarette use were observed. All relative to on-time PDT boys, early maturing boys' odds of tobacco cigarette use were 59% higher (OR=1.59, 95% confidence interval (CI)=1.08,2.35), and odds of dual-use were 49% higher (OR=1.49, CI=1.11,1.99), both compared to odds of never use. Among late PDT boys, dual-use odds were lower than never use by 35% (OR=0.65, CI=0.47,0.91) and lower than e-cigarette use only by 36% (OR=0.64, CI=0.42,0.97). At age 14, PDT was not associated with e-cigarette use for either sex, yet it was linked with tobacco use and dual use among boys.


Rabbit liver glycogen synthase kinases. Characterization of a protein kinase (PC0.7) able to phosphorylate glycogen synthase and phosvitin.
A rabbit liver protein kinase (PC0.7), able to phosphorylate glycogen synthase and phosvitin, has been extensively purified. The enzyme had apparent Mr = 170,000-190,000 as judged by gel filtration and was associated with two major polypeptide species, alpha (Mr = 43,000) and beta (Mr = 25,000). Two other polypeptides, Mr = 38,000 and Mr = 35,000, were also detected. Treatment with trypsin led to an enzyme composed only of polypeptides of Mr = 35,000 and Mr = 25,000. The beta-polypeptide underwent autophosphorylation when incubated with Mg2+ and ATP or GTP. The protein kinase was effective in utilizing both ATP and GTP as the phosphoryl donor (apparent Km values 5-11 microM and 9-19 microM, respectively). The enzyme phosphorylated phosvitin, casein, and glycogen synthase but not histone or phosphorylase and was inhibited by heparin. Phosphorylation of glycogen synthase proceeded to approximately 0.5 phosphate/subunit with little inactivation of the glycogen synthase. The phosphorylation occurred predominantly in a 21,000-dalton CNBr fragment of glycogen synthase that had been previously shown to reside toward the COOH terminus of the molecule. The liver PC0.7 appeared very similar to an analogous enzyme isolated from rabbit muscle (DePaoli-Roach, A. A., Ahmad, Z., and Roach, P. J. (1981) J. Biol. Chem. 256, 8955-8962). The present work, therefore, provides a point of contact between the Ca2+ and cyclic nucleotide-independent glycogen synthase kinases of rabbit liver and muscle.