Keratocystic odontogenic tumour: systematic review.
The aim of this review is to evaluate the principal clinical and conventional radiographic features of non-syndromic keratocystic odontogenic tumour (KCOT) by systematic review (SR), and to compare the frequencies between four global groups. The databases searched were the PubMed interface of Medline and LILACS. Only those reports of KCOTs that occurred in a series of consecutive cases, in the reporting authors' caseload, were considered. 51 reports, of 49 series of cases, were included in the SR. 11 SR-included series were in languages other than English. KCOTs affected males more frequently and were three times more prevalent in the mandible. Although the mean age at first presentation was 37 years, the largest proportion of cases first presented in the third decade. The main symptom was swelling. Over a third were found incidentally. Nearly two-thirds displayed buccolingual expansion. Over a quarter of cases recurred. Only a quarter of all SR-included reported series of cases included details of at least one radiological feature. The East Asian global group presented significantly as well-defined, even corticated, multilocular radiolucencies with buccolingual expansion. The KCOTs affecting the Western global group significantly displayed an association with unerupted teeth. Long-term follow-up of large series that would have revealed detailed radiographic description and long-term outcomes of non-syndromic KCOT was lacking.


Local injection of BDNF producing mesenchymal stem cells increases neuronal survival and synaptic stability following ventral root avulsion.
The present study proposed to graft mesenchymal stem cells (MSCs), which continuously produce BDNF, into the spinal cord ventral horn, after ventral root avulsion. Neurotrophin expression was naturally achieved by culturing MSCs in an undifferentiated state for at least 10 weeks. Lewis rats were subjected to unilateral avulsion of lumbar ventral roots, receiving 3 x 10(5) cells injected through the lateral funiculus. Two weeks after surgery, the animals were sacrificed and neuronal survival, astroglial reaction and synaptic inputs within the motor nucleus analyzed. The results indicated that the MSCs treatment significantly rescued avulsed motoneurons. Such neuronal survival was related to in vivo mRNA up regulation as well as expression of BDNF and GDNF. Such increase was correlated to the preservation of synaptophysin- positive nerve terminals. Thus it was proposed that when maintained undifferentiated for a period of 10 weeks, MSCs may be used as a continuous source of BDNF, positively influencing neuronal survival and synaptic plasticity.


Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access.
The aim of the study was to determine which, and to what extent, haemodynamic parameters contribute to the remodelling of the venous limb of the Brescia-Cimino haemodialysis access. The dimensions of the radial artery and the venous limb of the haemodialysis access were measured by an echo-tracking technique. In six ESRD patients undergoing primary arteriovenous fistula (AVF) formation, vessel diameter, wall thickness, blood pressure and blood flow were measured after the operation, and at 1 and 3 months follow-up. The contralateral forearm vessels in their native position served as baseline values for comparison. The diameter of the proximal antecubital vein progressively increased over the study period without reaching significant differences (4430, 5041 and 6620 microm at weeks 1, 4 and 12 respectively), whereas the intima-media thickness remained unchanged. The venous dilatation was associated with a reduction of the mean shear stress that culminated after the operation and progressively returned to normal venous values at 3 months (24.5 vs 10.4 dyne/cm(2), P<0.043). Thus the venous limb of the AVF undergoes eccentric hypertrophy as demonstrated by the increase in wall cross-sectional area (4.42 vs 6.32 mm(2) at week 1 vs week 12, P<0.028). At the time of the operation, the blood pressure in the AVF was 151+/-14/92.4+/-11 mmHg vs 49+/-19/24.5+/-6 mmHg (means+/-SEM) for the radial artery and the venous limb of the vascular access, respectively. One year after the operation the blood pressure in the venous limb had not changed: 42+/-14/25.3+/-7 mmHg (means+/-SEM). Under these conditions, the systolo-diastolic diameter changes observed in the radial artery and the antecubital vein were within a similar range at all time points: 56+/-17 vs 90+/-26 microm (means+/-SEM) at week 12. The increased circumferential stress resulting from the flow-mediated dilatation rather than the elevation of blood pressure appears to represent the main contributing factor to the eccentric hypertrophy of the venous limb of Brescia-Cimino haemodialysis access.


Female sex hormone and nephropathy in Cohen diabetic rat (genetically selected sucrose-fed).
In the Cohen diabetic rat (genetically-selected sucrose-fed) ovariectomy resulted in a significantly decreased incidence of nephropathy, while estradiol treatment to the ovariectomized animal increased the rate of nephropathy to the levels occurring in the uncastrated untreated diabetic female. In the male diabetic animal orchidectomy caused a slight decrease in the rate of nephropathy whereas estradiol treatment to the orchidectomized animal resulted in a slight increase in the rate. No difference was found between the ovariectomized and the uncastrated diabetic female as to the spontaneous blood glucose, plasma insulin, serum cholesterol or TG levels, but a significant difference was found in their plasma estradiol levels.


Future nanomedicine for the diagnosis and treatment of osteoarthritis.
Current treatments for osteoarthritis (OA) are largely palliative until the joints become totally dysfunctional and prosthetic replacement becomes necessary. Effective methods are needed for diagnosing OA and monitoring its progression during its early stages, when the effects of therapeutic drugs or biological agents are most likely to be effective. Theranostic nanosomes and nanoparticles have the potential to noninvasively detect, track and treat the early stages of OA. As articular cartilage does not regenerate once it is degraded, cell-based treatments aided by superparamagnetic iron oxide nanoparticle tracking are attractive future treatment modalities for the later stages of OA progression, when significant cartilage replacement is needed. This article will describe the current and future translational approaches for the detection and noninvasive treatment of degenerative OA.


Targeted Gene Therapy of Cancer: Second Amendment toward Holistic Therapy.
It seems solid tumors are developing smart organs with specialized cells creating specified bio-territory, the so called "tumor microenvironment (TME)", in which there is reciprocal crosstalk among cancer cells, immune system cells and stromal cells. TME as an intricate milieu also consists of cancer stem cells (CSCs) that can resist against chemotherapies. In solid tumors, metabolism and vascularization appears to be aberrant and tumor interstitial fluid (TIF) functions as physiologic barrier. Thus, chemotherapy, immunotherapy and gene therapy often fail to provide cogent clinical outcomes. It looms that it is the time to accept the fact that initiation of cancer could be generation of another form of life that involves a cluster of thousands of genes, while we have failed to observe all aspects of it. Hence, the current treatment modalities need to be re-visited to cover all key aspects of disease using combination therapy based on the condition of patients. Perhaps personalized cluster of genes need to be simultaneously targeted.


Tendency to catastrophize somatic sensations: pain catastrophizing and anxiety sensitivity in predicting headache.
General catastrophic thinking styles about uncomfortable bodily sensations may predispose the development of common health pathologies, such as persistent headache. The purpose of this research was to explore the relationships between the Pain Catastrophizing (PC) Scale and Anxiety Sensitivity (AS) Index, which measure tendencies to catastrophize pain- and anxiety-related somatic sensations, respectively. A non-clinical sample completed the PC Scale, AS Index, and health outcome questionnaires regarding headache (n = 1018). Results revealed that: (i) AS and PC are empirically separate constructs; (ii) the overlap between PC and AS lies within the domain of fearing physical catastrophe; (iii) AS independently predicts weekly headache, headache pain intensity, and the number of a wide range of physical symptoms associated with headache; and (iv) PC independently predicts the presence of weekly headache. Limitations and implications of this research, as well as recommendations for future research directions are discussed.


Changing Epidemiology of Varicella Outbreaks in the United States During the Varicella Vaccination Program, 1995-2019.
We describe the changing epidemiology of varicella outbreaks informed by past and current active and passive surveillance in the United States by reviewing data published during 1995-2015 and analyzing new data from 2016 to 2019. Varicella outbreaks were defined as ≥5 varicella cases within 1 setting and ≥1 incubation period. During the 1-dose varicella vaccination program (1995‒2006), the number of varicella outbreaks declined by 80% (2003-2006 vs 1995-1998) in 1 active surveillance area where vaccination coverage reached 90.5% in 2006. During the 2-dose program, in 7 states with consistent reporting to the Centers for Disease Control and Prevention, the number of outbreaks declined by 82% (2016-2019 vs 2005-2006). Over the entire program (1995-2019), outbreak size and duration declined from a median of 15 cases/outbreak and 45 days duration to 7 cases and 30 days duration. The proportion of outbreaks with <10 cases increased from 28% to 73%. During 2016‒2019, most (79%) outbreak cases occurred among unvaccinated or partially vaccinated persons eligible for second-dose vaccination, highlighting the potential for further varicella control.


Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3.
Smad3 is phosphorylated by ERK MAP kinase upon EGF treatment. We have mapped the ERK phosphorylation sites to Ser 207, Ser 203, and Thr 178 in Smad3. We show that, upon EGF treatment, Smad3 is rapidly phosphorylated in these sites, peaking at approximately 15-30 min and that MEK1 inhibitors PD98059 and U0216 inhibit Smad3 phosphorylation induced by EGF. Ser 207 is the best ERK site in Smad3. Its phosphorylation shows the highest EGF induction in Smad3. It is also a very sensitive site to EGF treatment, significantly responding to low concentrations of EGF. These three sites are also phosphorylated by recombinant ERK2 in vitro. We have compared the kinetic parameters of Smad3 with those of ELK1 and MBP for ERK2. We further show that mutation of the ERK phosphorylation sites increases the ability of Smad3 to stimulate a Smad target gene, suggesting that ERK phosphorylation inhibits Smad3 activity.


The tibial eminence fracture in skeletally immature patients.
Although tibial eminence fractures are uncommon, their importance cannot be overemphasized in skeletally immature patients because of the fracture's close proximity to both the tibial physis as well as the attachment between the tibial eminence and the anterior cruciate ligament, the latter being a key component in maintaining knee stability. This review focuses on recent trends in treatment concepts and devices. Recent literature on this topic addresses the existence of a variety of treatment modalities, but the majority of these articles analyzed a limited number of cases and insisted on the merits of their own methods. Nevertheless, some consensus has been reached regarding treatment direction and how much laxity should be considered acceptable. Although the review failed to reveal a gold standard modality in treating tibial eminence fractures, most studies agreed on several issues. Displaced intra-articular fractures should be fixed operatively.


New Food Frequency Questionnaire to Estimate Vitamin K Intake in a Mediterranean Population.
Vitamin K is a multifunctional micronutrient essential for human health, and deficiency has been linked to multiple pathological conditions. In this study, we aimed to develop and validate a new food frequency questionnaire (FFQ) to estimate total vitamin K intake, over the course of a 30-day interval, in a Portuguese, Mediterranean-based, population. We conducted a prospective study in a non-random sample of 38 healthy adult volunteers. The FFQ was designed based on a validated Portuguese FFQ used in nationally representative studies and on literature reviews, to include foods containing ≥5 μg of vitamin K/100 g and foods with a lower vitamin K content, yet commonly included in a Mediterranean diet. Vitamin K intake was estimated from 24 h recalls and six days of food records. The final FFQ included 54 food items which, according to regression analyses, explains 90% of vitamin K intake. Mean differences in vitamin K intake based on food records (80 ± 47.7 μg/day) and on FFQ (96.5 ± 64.3 μg/day) were statistically non-significant. Further, we found a strong correlation between both methods (r = 0.7; p = 0.003). Our results suggest that our new FFQ is a valid instrument to assess the last 30 days of vitamin K intake in the Portuguese Mediterranean population.


[Cranial arteritis - An Overview].
Cranial arteritis is one of the most important emergency situations in ophthalmology. Recommendations of the literature how to diagnose and how to treat the disease are described. The basic diagnostic steps such as the "Five Criteria Classification" together with certain exceptions of the classification criteria and the recognition of different facets of the varying clinical picture are emphasised. Special arteritic appearances of the facial artery, the occipital artery and the vertebral artery should be noted and identified. It is pointed out that an arteritis without headache is of great clinical importance, known as occult arteritis, because of the lack of classical symptoms, often leading to a wrong diagnosis. Anterior ischaemic optic neuropathy (AION) is the most frequent cause of blindness. Differential diagnosis between non-arteritic and arteritic AION is emphasised. The different arguments concerning the performance of unilateral or bilateral arterial resection ("biopsy") and the findings of colour duplex ultrasonography in comparison to the histological results are discussed. It is also pointed out that some new diagnostic procedures such as the MRI examination with gadolinium and the PET-Scan examination may be helpful in supporting the diagnosis. Cranial arteritis is more often diagnosed in recent years. The diagnosis should be made in cooperation by the ophthalmologist and internists and neurologists. Blindness caused by cranial arteritis is preventable in the majority of patients if diagnosed early and treated properly. For decades of clinical experience it has been well established that early diagnosis and systemic treatment with high doses of systemic corticosteroids are essential in preventing blindness in one or both eyes.


Schizophrenia sex offenders: a clinical and epidemiological comparison study.
While the incidence of criminal offense in individuals with schizophrenia does not necessarily differ from that of the normal population, in contrast, the rate of sexual crimes among individuals with schizophrenia is relatively low. Due to low numbers, description of sexual criminal behavior among schizophrenia patients remains relatively unexplored. In order to investigate clinical, socio-demographic and sexual factors associated with deviant sexual behavior in schizophrenia sex offenders we retrospectively compared a large subgroup of schizophrenia sex offenders with a group of schizophrenia patients incarcerated for other criminal behaviors and a group of sex offenders without schizophrenia. Results indicated significant differences distinguishing schizophrenia sex offenders from schizophrenia non-sex offenders, the former of whom were more likely to be married, employed, non-heterosexual (homosexual and bisexual orientations) and demonstrated less hospitalization, antisocial personality, substance abuse, negative symptoms and overall illness severity. Individuals with schizophrenia had a tendency towards female victims compared to non-schizophrenia sex offenders whose victims tended to be male. Study observations indicate important differences between the 3 subgroups suggesting that the schizophrenia sex offender subpopulation may be a unique subgroup of comorbid conditions.


Maturation of peptide-positive synaptic arbors in the medicinal leech requires rhythmic target activity.
The formation and refinement of synaptic connections are dependent on the activity that emerges from nascent synaptic connections. Such activity has the effect of regulating the production and release of specific neurotransmitters. To determine the role of activity in regulating the production of peptide-positive synapses, we used antibodies against Phe-Met-Arg-Phe-NH₂ and acetylated α-tubulin as well as intracellular injections of Neurobiotin to examine varicosities belonging to heart excitor (HE) neurons on the heart tubes of medicinal leeches, Hirudo spp. We found that the production of peptide-positive varicosities increased considerably during the last week of embryogenesis, which coincided with the emergence of rhythmic activity of the heart tube. When we compromised central input to HE neurons with bicuculline or by surgical ablation of the central pattern generator during early embryogenesis, we found that activity in the heart tubes and its rhythmicity were greatly diminished. Furthermore, the activity of HE neurons had also lost its rhythmicity and appeared tonic, and production of peptide-positive varicosities was substantially reduced as well. Partial surgical ablations that preserved rhythmic activity in the heart tube while disrupting heart tube innervation by some HE neurons still resulted in peptide-positive varicosity production. Taken together, our results suggest that postsynaptic rhythmic activity of the heart tube is necessary and sufficient for the development and maturation of peptide-positive synapses.


Two regions of mature periplasmic maltose-binding protein of Escherichia coli involved in secretion.
Six mutations in malE, the structural gene for the periplasmic maltose-binding protein (MBP) from Escherichia coli, prevent growth on maltose as a carbon source, as well as release of the mutant proteins by the cold osmotic-shock procedure. These mutations correspond to insertion of an oligonucleotide linker, concomitant with a deletion. One of the mutations (malE127) affects the N-terminal extension (the signal peptide), whereas the five others lie within the mature protein. As expected, the export of protein MalE127 is blocked at an early stage. This protein is neither processed to maturity nor sensitive to proteinase K in spheroplasts. In contrast, in the five other mutants, the signal peptide is cleaved and the protein is accessible to proteinase K added to spheroplasts. This indicates that the five mutant proteins are, at least in part, exported through the inner membrane. We propose that the corresponding mutations define two regions of the mature protein (between residues 18 and 42 and between residues 280 and 306), which are important for release of the protein from the inner membrane into the periplasm. We discuss the results in terms of possible conformational changes at this late step of export to the periplasm.


Identification, cloning, and purification of protein antigens of Treponema pallidum.
Difficulties in culturing the bacterium Treponema pallidum have greatly hindered syphilis research. In recent years, several laboratories have begun applying recombinant DNA technology to the study of this organism. Recent work is summarized concerning the expression of T. pallidum DNA in Escherichia coli. A number of E. coli clones expressing treponemal protein antigens have been identified. In one instance, a recombinant protein was purified to homogeneity and shown to be identical to a highly immunogenic, native T. pallidum membrane protein of molecular weight 39,000, which was designated the basic membrane protein (BMP) of this organism. In addition, recent experiments are described that were designed to identify cell-surface proteins that would serve as the primary focus of our cloning efforts. Results obtained with use of several different approaches strongly suggest that the outer membrane of T. pallidum is an antigenically inert structure largely devoid of protein. However, a class of low-molecular-weight protein antigens have been identified that are actively secreted into the extracellular medium. Attempts currently are being made to clone these secreted proteins and investigate their roles in the pathogenesis and immunobiology of syphilis.


Sox9 Determines Translational Capacity During Early Chondrogenic Differentiation of ATDC5 Cells by Regulating Expression of Ribosome Biogenesis Factors and Ribosomal Proteins.
In addition to the well-known cartilage extracellular matrix-related expression of Sox9, we demonstrated that chondrogenic differentiation of progenitor cells is driven by a sharply defined bi-phasic expression of Sox9: an immediate early and a late (extracellular matrix associated) phase expression. In this study, we aimed to determine what biological processes are driven by Sox9 during this early phase of chondrogenic differentiation. Sox9 expression in ATDC5 cells was knocked down by siRNA transfection at the day before chondrogenic differentiation or at day 6 of differentiation. Samples were harvested at 2 h and 7 days of differentiation. The transcriptomes (RNA-seq approach) and proteomes (Label-free proteomics approach) were compared using pathway and network analyses. Total protein translational capacity was evaluated with the SuNSET assay, active ribosomes were evaluated with polysome profiling, and ribosome modus was evaluated with bicistronic reporter assays. Early Sox9 knockdown severely inhibited chondrogenic differentiation weeks later. Sox9 expression during the immediate early phase of ATDC5 chondrogenic differentiation regulated the expression of ribosome biogenesis factors and ribosomal protein subunits. This was accompanied by decreased translational capacity following Sox9 knockdown, and this correlated to lower amounts of active mono- and polysomes. Moreover, cap- versus IRES-mediated translation was altered by Sox9 knockdown. Sox9 overexpression was able to induce reciprocal effects to the Sox9 knockdown. Here, we identified an essential new function for Sox9 during early chondrogenic differentiation. A role for Sox9 in regulation of ribosome amount, activity, and/or composition may be crucial in preparation for the demanding proliferative phase and subsequent cartilage extracellular matrix production of chondroprogenitors in the growth plate in vivo.


Maintenance of CCL5 mRNA stores by post-effector and memory CD8 T cells is dependent on transcription and is coupled to increased mRNA stability.
Immunological memory is associated with the display of improved effector functions by cells of the adaptive immune system. The storage of untranslated mRNA coding for the CCL5 chemokine by CD8 memory cells is a new process supporting the immediate display of an effector function. Here, we show that, after induction during the primary response, high CCL5 mRNA levels are specifically preserved in CD8 T cells. We have investigated the mechanisms involved in the long-term maintenance of CCL5 mRNA levels by memory CD8 T cells. We demonstrate that the CCL5 mRNA half-life is increased in memory CD8 T cells and that these cells constitutively transcribe ccl5 gene. By inhibiting ccl5 transcription using IL-4, we demonstrate the essential role of transcription in the maintenance of CCL5 mRNA stores. Finally, we show that these stores are spontaneously reconstituted when the inhibitory signal is removed, indicating that the transcription of ccl5 is a default feature of memory CD8 T cells imprinted in their genetic program.


Expression of NALPs in adipose and the fibrotic progression of non-alcoholic fatty liver disease in obese subjects.
Visceral obesity is often accompanied by non-alcoholic fatty liver disease (NAFLD). Activation of NACHT, LRR and PYD domains-containing proteins (NALPs) may contribute to the release of pro-inflammatory cytokines by adipose and the obesity-associated progression of NAFLD to non-alcoholic steatohepatitis (NASH). We analyzed visceral adipose expression of various NALPs and its downstream effectors caspase-1, ASC (Apoptosis-associated speck-like protein containing a CARD), IL-18 (Interleukin-18) and IL-1β (Interleukin- 1Beta) in obese subjects (BMI ≥ 35) with biopsy proven NAFLD. In adipose samples collected from NASH and pericellular fibrosis patients cohorts, expression levels of NALPs and IL-1β were lower than that in non-NASH patients. In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated. The expression levels of all NALPs were significantly co-correlated. Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis. Our observations point at a possible shift in inflammation and fibrotic response from adipose tissue to liver and a possible negative feedback regulation of tissue inflammation that may instigate NAFLD severity.


Identification of specific language impairment in bilingual children: I. Assessment in English.
This study was designed to derive cut scores for English testing for use in identifying specific language impairment (SLI) in bilingual children who were learning English as a second language. In a 1-gate design, 167 children received comprehensive language assessments in English and Spanish during their first-grade year. The reference standard was identification by a team of expert bilingual speech-language pathologists. Receiver operating curve (ROC) analyses were used to identify the optimal prediction model for SLI. The original, English EpiSLI criteria (Tomblin, Records, & Zhang, 1996) yielded a sensitivity of .95 and a specificity of .45 (LR+ = 1.73, LR- = 0.11, and AUC = .79) for our bilinguals. Revised cutoff scores yielded a sensitivity of .86 and a specificity of .68 (LR+ = 2.67, LR- = 0.21, and AUC = .77). An optimal prediction model yielded a sensitivity of .81 and a specificity of .81 (LR+ = 4.37, LR- = 0.23 and AUC = .85). The results of English testing could be used to make a reasonably accurate diagnostic decision for bilingual children who had attended public school for at least 1 year and were using English at least 30% of the time.


Exploring a blue-light-sensing transcription factor to double the peak productivity of oil in Nannochloropsis oceanica.
Oleaginous microalgae can produce triacylglycerol (TAG) under stress, yet the underlying mechanism remains largely unknown. Here, we show that, in Nannochloropsis oceanica, a bZIP-family regulator NobZIP77 represses the transcription of a type-2 diacylgycerol acyltransferase encoding gene NoDGAT2B under nitrogen-repletion (N+), while nitrogen-depletion (N-) relieves such inhibition and activates NoDGAT2B expression and synthesis of TAG preferably from C16:1. Intriguingly, NobZIP77 is a sensor of blue light (BL), which reduces binding of NobZIP77 to the NoDGAT2B-promoter, unleashes NoDGAT2B and elevates TAG under N-. Under N+ and white light, NobZIP77 knockout fully preserves cell growth rate and nearly triples TAG productivity. Moreover, exposing the NobZIP77-knockout line to BL under N- can double the peak productivity of TAG. These results underscore the potential of coupling light quality to oil synthesis in feedstock or bioprocess development.


Interactions between gastric and enteric infections: clues to the pathogenesis of inflammatory bowel disease?
Whereas the worldwide incidence of Crohn's disease (CD) continues to rise, Maori and Pacific Islanders living in New Zealand remain largely unaffected. The reason for this is currently unknown but may be linked to emerging evidence suggesting a role for Campylobacter spp in the aetiology of CD. Rates of campylobacteriosis are notably lower among Maori and Pacific Islanders and while this may reflect poorer access to primary care and diagnostic services, resulting in lower rates of notified disease, we consider it may also reflect a level of protective immunity in Maori and Pacific Islanders as a result of chronic infection from an early age with the closely related gastric pathogen Helicobacter pylori. Understanding the interactions between these antigenically-related bacteria may provide us with clues that ultimately help unravel the complex aetiology of CD.


Bakuchiol modulates acetylcholine synthesis and alleviates Aβ proteotoxicity.
The transmission of acetylcholine (ACh) is critically important for memory, learning, and behaviour. The most promising approaches for the treatment of cholinergic dysfunction involve the enhancement of ACh via nootropic phytomolecules. In the same line, the present study identifies the active molecule Bakuchiol derived from Psoralea corylifolia. Bakuchiol demonstrated significant elevation of ACh transmission, reduction of reactive oxygen species (ROS) levels, and extension of lifespan. Further investigation indicated that modulation of mRNA expression of genes encoding choline transporter, choline acetyltransferase, and acetylcholine transporter as possible effectors of amassed neural transmission. Moreover, Bakuchiol showed efficacy in reducing amyloid β and lipid levels, possibly through the upregulation of heat shock transcription factor 1 (hsf-1) and autophagy (lgg-1) genes. Overall, our findings establish the efficacy of Bakuchiol in modulating cholinergic dysfunction.


Intratubular germ cell neoplasia of the testis: identification by placental alkaline phosphatase immunostaining and argyrophilic nucleolar organizer region quantification.
We assessed the value of placental alkaline phosphatase (PLAP) immunostaining and argyrophilic nucleolar organizer region (AgNOR) quantification as techniques for the identification of intratubular germ cell neoplasia (ITGCN), and compared them with hematoxylin-eosin and periodic acid-Schiff staining. We examined 46 malignant testicular germ cell tumors for the presence of ITGCN; 43 had sufficient tubules available for assessment. We also examined 16 cryptorchid testes, 16 testicular biopsies from 10 subfertile men, and 12 normal adult intrascrotal testes. In tubules adjacent to invasive tumors, hematoxylin-eosin staining identified 30 cases (70%) of ITGCN, while PLAP and AgNOR staining identified 36 cases (84%). All the seminomas (18) and 22 of 28 nonseminomatous germ cell tumors were PLAP-positive and had high AgNOR counts. Intratubular germ cell neoplasia was not identified in the other groups examined; germ cells in these groups were PLAP-negative and had low AgNOR counts. Cells of ITGCN showed cytoplasmic block positivity with periodic acid-Schiff staining but this was not a consistent finding. We conclude that ITGCN is present adjacent to most invasive germ cell tumors, and is reliably identified by hematoxylin-eosin staining when fully developed. Periodic acid-Schiff staining was not helpful as normal spermatogonia were also positive. Staining with PLAP and AgNOR were useful diagnostic adjuncts, but results with PLAP were easier to interpret.


[Multixenobiotic defense mechanism (MDMX) in bivalves].
Multixenobiotic defence mechanism (MXDM) consists in a cellular system that functions as membrane extrusion pumps effluxing organic compounds out of the cells. In bivalves, it represents a primordial protection against toxic effects of organic xenobiotics in preventing their cellular accumulation. It has raised attention during the last decade for its potential to be used as a biomarker of pollution. This article reviews the fundamental knowledge on the MXDM system in bivalves and the methods proposed to assess its activity. Finally, it reviews the major results of laboratory and field studies that enabled to hypothesise that MXDM could be used as a biomarker of environmental stress rather than of pollutant exposure.


Positive regulatory role of c-Src-mediated TRIM25 tyrosine phosphorylation on RIG-I ubiquitination and RIG-I-mediated antiviral signaling pathway.
Retinoic acid-inducible gene I (RIG-I) detects viral RNAs and induces antiviral responses. During viral RNA recognition by RIG-I, tripartite motif protein 25 (TRIM25) plays a critical regulatory role by inducing K63-linked RIG-I polyubiquitination. Previous proteomics analysis revealed several phosphorylation sites on TRIM25, including tyrosine 278 (Y278), yet the roles of these modifications remain elusive. Here, we demonstrated that TRIM25 interacted with c-Src and underwent tyrosine phosphorylation by c-Src kinase upon viral infection and the phosphorylation is required for the complete activation of RIG-I signaling. Analysis using a c-Src inhibitor and TRIM25 mutant, in which tyrosine 278 is substituted by phenylalanine (Y278F), suggested that the phosphorylation positively regulates K63-linked polyubiquitination of RIG-I and subsequent antiviral signaling. The TRIM25 Y278F mutant displayed decreased E3-ubiquitin ligase activity in vitro, suggesting that this phosphorylation event affects the E3-ligase activity of TRIM25. Thus, we provide a molecular mechanism of c-Src-mediated positive regulation of RIG-I signaling.


Effectiveness and satisfaction with zolmitriptan 5 mg nasal spray for treatment of migraine in real-life practice: results of a postmarketing surveillance study.
Addressing the needs of migraineurs by actively seeking patient feedback on disease-related disability and treatment satisfaction may lead to improved management and treatment outcomes. Patient feedback can be collected in postmarketing surveillance (PMS) studies. The objective of this PMS study was to evaluate the efficacy and tolerability of zolmitriptan 5 mg nasal spray in the acute treatment of migraine attacks. Patients received zolmitriptan 5 mg nasal spray to treat migraine attacks of any severity and were followed up after a maximum of 4 months. Patients evaluated the efficacy and tolerability of zolmitriptan nasal spray, and were asked whether they wished to continue using zolmitriptan nasal spray and their preference compared with previous treatments. Physicians also assessed the efficacy and tolerability of zolmitriptan nasal spray. A total of 1838 patients (84.8% females) participated in the study. Within 30 minutes of administration of zolmitriptan nasal spray, 85.0% of patients reported improvements in headache pain, with 25.1% reporting an improvement within 10 minutes. At 1 hour post-dose, 57.9% of patients were pain free and 61.7% were able to resume usual daily activities. Most patients (72.9%) rated zolmitriptan nasal spray as 'better' than previous therapy. The majority (88.8%) expressed a wish to continue using zolmitriptan nasal spray. Physicians evaluated the efficacy of zolmitriptan nasal spray as 'excellent' or 'good' in 89.4% of patients. Tolerability was evaluated as 'excellent' or 'good' in 91.6% of patients. Zolmitriptan 5 mg nasal spray provides favourable efficacy and tolerability in the acute treatment of migraine attacks. Most patients assessed zolmitriptan nasal spray as 'better' than previous treatment, with nearly all wishing to continue using it.


Labour management: an appraisal of the role of false labour and latent phase on the delivery mode.
Achieving normal vaginal delivery requires an orderly transition from early labour to an established active labour. We analysed retrospectively the outcome of labour and the delivery mode based on the diagnosis of labour from the first examination of 3,130 parturients. A total of 1,847 (59.1%) delivered mothers had the first vaginal examination performed by the senior house officer (SHO). The majority (74.4%) of the mothers presented in established labour (cervical dilatation > or =4 cm), 25.6% in early labour, while 11.3% in latent phase. Patients who presented in established labour had a statistically significant higher spontaneous vertex delivery (SVD) rate (Pearson chi2 = 29.74, p = 0.000). A total of 62 parturients (17.5%) who presented in the latent phase and 204 (29.1%) in early labour had an unfavourable delivery mode; 46 had a caesarean section. There was a significant correlation between delivery mode and prolonged latent phase (Pearson correlation coefficient R = -0.066, p = 0.000). Linear regression analysis showed that the total number of VEs was the most significant predictor of the delivery mode of SVD (Regression beta-coefficient = 0.278, t = 10.37, p = 0.000). Early admissions in labour and a prolonged (abnormal) latent phase are significant predictors of difficult mode of delivery (poor labour outcome). We suggest that the first vaginal examination should be undertaken by the most experienced medical personal present at admission.


Gas6 Prevents Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells via Production of PGE2, PGD2 and Their Receptors.
The epithelial-mesenchymal transition (EMT) is important in organ fibrosis. We hypothesized that growth arrest-specific protein 6 (Gas6) and its underlying mechanisms play roles in the prevention of EMT in alveolar epithelial cells (ECs). In this study, to determine whether Gas6 prevents TGF-β1-induced EMT in LA-4 and primary alveolar type II ECs, real-time PCR and immunoblotting in cell lysates and ELISA in culture supernatants were performed. Migration and invasion assays were performed using Transwell chambers. Pretreatment of ECs with Gas6 inhibited TGF-β1-induced EMT based on cell morphology, changes in EMT marker expression, and induction of EMT-activating transcription factors. Gas6 enhanced the levels of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) and PGD2 as well as of their receptors. COX-2 inhibitors and antagonists of PGE2 and PGD2 receptors reversed the inhibition of TGF-β1-induced EMT, migration, and invasion by Gas6. Moreover, knockdown of Axl or Mer reversed the enhancement of PGE2 and PGD2 and suppression of EMT, migration and invasion by Gas6. Our data suggest Gas6-Axl or -Mer signalling events may reprogram ECs to resist EMT via the production of PGE2, PGD2, and their receptors.


COVID-19-Fear Affects Current Safety Behavior Mediated by Neuroticism-Results of a Large Cross-Sectional Study in Germany.
Objectives: Although many research studies concerning changes in personality and behavior in time of COVID-19 pandemic emerged, important questions still have not been answered. This study with a large sample aimed to give insights into the impact of personality on pandemic fear and behavior by investigating the Big Five traits, COVID-19-fear, and associated behavioral changes in a large German-speaking sample. Methods: About 14,048 healthy respondents (65.5% female, 34.2% male, and 0.32% other gender/gender queer; range = 18-85 years, median age 35-44 years) participated in the survey during the COVID-19 pandemic. Two scales, "adherent" safety behavior (ASB, α = 0.857) and "dysfunctional" safety behavior (DSB, α = 0.876), three items each, measured pandemic-associated behavior. The Big Five Inventory-10 (BFI-10) tested personality traits. Results: While ASB correlated negatively with extraversion (rho = -0.053, ≤ 0.001), the other four traits were positively associated, with the highest association for neuroticism (rho = 0.116, ≤ 0.001), whereas neuroticism showed a positive correlation (rho = 0.142, ≤ 0.001) with DSB, extraversion (rho = -0.042, ≤ 0.001), agreeableness (rho = -0.028, ≤ 0.001), and conscientiousness (rho = -0.025, ≤ 0.001) correlated negatively with it. Regression analyses showed a small extent of the effect of personality traits. Moreover, neuroticism mediated the association between COVID-19-fear and DSB (positive-directed). Conclusions: Even though our results on correlations between personality, pandemic fear, and related behavior are in line with the existing literature studies, the analyses clearly show that the impact of personality traits, including neuroticism, on pandemic behavior is very small. Rather, pandemic fear has a much larger influence on the safety behavior mediated through neuroticism. Further studies should bear in mind that personality traits can not only have influencing effects but also mediating effects.


The role of calpains in ventilator-induced diaphragm atrophy.
Controlled mechanical ventilation (CMV) is associated with diaphragm dysfunction. Dysfunction results from muscle atrophy and injury of diaphragm muscle fibers. Enhanced proteolysis and reduced protein synthesis play an important role in the development of atrophy. The current study is to evaluate the effects of the calpains inhibitor calpeptin on the development of diaphragm atrophy and activation of key enzymes of the ubiquitin-proteasome pathway in rats under CMV. Three groups of rats were studied: control animals (CON, n = 8), rats subjected to 24 h of MV (CMV, n = 8), and rats subjected to 24 h of MV after administration of the calpain inhibitor calpeptin (CMVC, n = 8). The diaphragm was analyzed for calpain activity, myosin heavy chain (MHC) content, and cross-sectional area (CSA) of diaphragmatic muscle fibers as a marker for muscle atrophy. In addition, key enzymes of the ubiquitin-proteasome pathway (MAFbx and MuRF1) were also studied. CMV resulted in loss of both MHCfast and MHCslow. Furthermore, the CSA of diaphragmatic muscle fibers was significantly decreased after 24 h of CMV. However, calpain inhibitor calpeptin prevented loss of MHC and CSA after CMV. In addition, calpeptin prevented the increase in protein expression of calpain1 and calpain2 and reduced calpain activity as indicated by reduced generation of the calpain cleavage product αII-spectrin in the diaphragm. CMV-induced upregulation of both MAFbx and MuRF1 protein levels was attenuated by treatment with calpeptin. The calpain inhibitor calpeptin prevents MV-induced muscle atrophy. In addition, calpeptin attenuated the expression of key proteolytic enzymes known to be involved in ventilator-induced diaphragm atrophy, including MAFbx and MuRF1.


Immunotherapy-on-Chip Against an Experimental Sepsis Model.
Lipopolysaccharide (LPS) is commonly used in murine sepsis models, which are largely associated with immunosuppression and collapse of the immune system. After adapting the LPS treatment to the needs of locally bred BALB/c mice, the present study explored the protective role of Micrococcus luteus peptidoglycan (PG)-pre-activated vaccine-on-chip technology in endotoxemia. The established protocol consisted of five daily intraperitoneal injections of 0.2 μg/g LPS, allowing longer survival, necessary for a therapeutic treatment application. A novel immunotherapy technology, the so-called vaccine-on-chip, consists of a 3-dimensional laser micro-textured silicon (Si) scaffold loaded with macrophages and activated in vitro with 1 μg/ml PG, which has been previously shown to exert a mild immunostimulatory activity upon subcutaneous implantation. The LPS treatment significantly decreased CD4 + and CD8 + cells, while increasing CD11b + , Gr1 + , CD25 + , Foxp3 + , and class II + cells. These results were accompanied by increased arginase-1 activity in spleen cell lysates and C-reactive protein (CRP), procalcitonin (PCT), IL-6, TNF-a, IL-10, and IL-18 in the serum, while acquiring severe sepsis phenotype as defined by the murine sepsis scoring. The in vivo application of PG pre-activated implant significantly increased the percentage of CD4 + and CD8 + cells, while decreasing the percentage of Gr1 + , CD25 + , CD11b + , Foxp3 + cells, and arginase-1 activity in the spleen of LPS-treated animals, as well as all serum markers tested, allowing survival and rescuing the severity of sepsis phenotype. In conclusion, these results reveal a novel immunotherapy technology based on PG pre-activated micro-texture Si scaffolds in LPS endotoxemia, supporting thus its potential use in the treatment of septic patients.


Single-nucleotide substitution T to A in the polypyrimidine stretch at the splice acceptor site of intron 9 causes exon 10 skipping in the ACAT1 gene.
β-ketothiolase (T2, gene symbol ACAT1) deficiency is an autosomal recessive disorder, affecting isoleucine and ketone body metabolism. We encountered a patient (GK03) with T2 deficiency whose T2 mRNA level was <10% of the control, but in whom a previous routine cDNA analysis had failed to find any mutations. Genomic PCR-direct sequencing showed homozygosity for c.941-9T>A in the polypyrimidine stretch at the splice acceptor site of intron 9 of ACAT1. Initially, we regarded this variant as not being disease-causing by a method of predicting the effect of splicing using in silico tools. However, based on other findings of exon 10 splicing, we eventually hypothesized that this mutation causes exon 10 skipping. cDNA analysis was performed using GK03's fibroblasts treated with/without cycloheximide (CHX), since exon 10 skipping caused a frameshift and nonsense-mediated mRNA decay (NMD). Minigene splicing experiment was done to confirm aberrant splicing. cDNA analysis using fibroblasts cultured with cycloheximide indeed showed the occurrence of exon 10 skipping. A minigene splicing experiment clearly showed that the c.941-9T>A mutant resulted in transcripts with exon 10 skipping. There are few reports describing that single-nucleotide substitutions in polypyrimidine stretches of splice acceptor sites cause aberrant splicing. We showed that c.941-9T>A induces aberrant splicing in the ACAT1 gene. Our ability to predict the effects of mutations on splicing using in silico tools is still limited. cDNA analysis and minigene splicing experiments remain useful alternatives to reveal splice defects.


Nucleophilic addition reaction in coordinated non-linear pseudohalides: experimental charge density analysis in trans-bis(cyanamidonitrato-N:O)bis-(imidazole-N(3))copper(II) complex.
The experimental crystal charge density of the complex [Cu(iz)(2)(can)(2)] (I) (where iz = imidazole, can = cyanamidonitrate anion), [Cu(C(3)H(4)N(2))(2)(CN(3)O(2))(2)], crystallizing in centrosymmetric space group P2(1)/c, has been determined at 120.0 (2) K, using Hansen and Coppens' aspherical atom multipole model. The central Cu atom is pseudo-octahedrally coordinated by four N atoms in an equatorial plane [two from iz molecules, 1.9660 (4) A, two from can anions, 2.0273 (5) A] and by two O atoms (from two adjacent molecules) in axial positions [2.5566 (5) A]. The d-orbital population analysis shows that the oxidation state for the copper is +2 with the d(9) configuration and that there is a hole in the d(x(2) - y(2)) orbital, located in the plane of the four nitrogen-ligating atoms. Electron lone pairs of these four N atoms are pointing into these regions of depleted electron density. In accordance with the medium-length Cu-O axial bonds, the d(z(2)) orbital is almost fully occupied [1.79 (3) electrons]. The non-bonding d(xy) orbital is fully occupied [2.05 (3) electrons]. Analysis of the atomic charges does indicate a deficit of +0.35 (4) e(-) on the nitrile carbon, which provides evidence of beta-carbon activation for a possible nucleophilic addition reaction. This reaction has been indirectly confirmed experimentally.


Characteristics of medical schools related to the choice of family medicine as a specialty.
Previous research has identified five characteristics of medical schools that are related to the choice of family medicine as a specialty: (1) the amount of time devoted to required training in family medicine, (2) the timing of the required family medicine training, (3) the type of ownership of the school (public or private), (4) the geographic location of the school, and (5) the administrative structure of family medicine within the school. These five characteristics of U.S. medical schools during the mid-1980s, together with the school tuition levels, were examined with both univariate and multivariate analysis to observe their relationships to the percentage of U.S. medical graduates entering family medicine between July 1986 and December 1987. With univariate analysis, each characteristic was significantly related to the percentage of graduates entering family medicine. Using multivariate analysis, only the number of weeks required and the type of ownership of the school were significantly related to the percentage of graduates entering family medicine, with the higher percentages related to greater numbers of required weeks of family medicine training and to public ownership of the school.


Characteristics of colored passive layers on titanium: morphology, optical properties, and corrosion resistance.
Electrochemically formed colored passive layers on titanium and their optical, surface morphology, and corrosion properties are presented and discussed. With the application of progressively higher AC voltages (VAC) during preparation of these passive layers, they are found to become more protective of the underlying metal, as determined from corrosion resistance measurements employing electrochemical polarization curve and inductively coupled plasma mass spectrometry experiments. The passive layers on titanium were found to be uniform in their surface morphology with no apparent cracks or pits. Surface morphology, and its relation to optical properties, was also investigated using visible light microscopy, profilometry, and near-infrared ultraviolet visible reflectance spectroscopy measurements. A correlation between the light reflected from the entire sample surface and the coloration of surface grains was also observed through these measurements. The reflectance spectra showed a red-shift of wavelength maxima (λmax) values as AC voltages and, therefore, thicknesses were increased. Overall, these passive layers are protective of an already remarkable metal, and with greater knowledge of the properties of colored protective layers, their potential may be employed in a wide range of applications.


Correlation of penicillin Binding protein 2a detection with oxacillin resistance in Staphylococcus aureus and discovery of a novel penicillin binding protein 2a mutation.
We compared a rapid slide latex agglutination test (LAT; Oxoid, Basingstoke, United Kingdom) that detects penicillin binding protein 2a (PBP2a) with MicroScan conventional panels (Dade Behring, West Sacramento, CA) for detection of oxacillin resistance in Staphylococcus aureus. The PBP2a LAT demonstrated 99% agreement with MicroScan oxacillin MIC results for 388 isolates of S. aureus. All 249 oxacillin-resistant isolates gave strong positive reactions in the LAT (100% sensitivity). Three of the 139 oxacillin-susceptible isolates were also strongly positive and one was weakly positive in the LAT (97.1% specificity). The three oxacillin-susceptible isolates with strongly positive reactions were further characterized. The mecA gene was detected in all three by PCR; one isolate was determined to be resistant to oxacillin by reference broth microdilution testing (MIC, 8 microg/ml), one isolate was inducibly resistant to oxacillin (MIC of 16 microg/ml after overnight induction), and one isolate remained susceptible regardless of the method used for testing. Sequence analysis of a 2.1-kb gene fragment of the mecA gene from the susceptible isolate revealed a one-base substitution at nucleotide position 1449 which results in a Met-to-Ile change for amino acid residue 483. This amino acid substitution has not been previously reported and may be associated with a change in the function of PBP2a resulting in oxacillin susceptibility. An additional 487 isolates were tested in parallel with the both the LAT and MicroScan panels using criteria in which only strong (3 to 4+) or repeatedly weak (1 to 2+) LAT reactions were considered positive, and the results showed 99.4% agreement. The PBP2a LAT provided rapid and reliable detection of oxacillin resistance and proved a useful adjunct to the phenotypic method. Both methods provided reliable detection of oxacillin-resistant S. aureus and facilitated the discovery of a novel, functionally impaired form of PBP2a.


Pretreatment inflammatory markers predicting treatment outcomes in colorectal cancer.
We aimed to review whether pretreatment inflammatory markers reflect the short- and long-term outcomes of patients with colon cancer, rectal cancer, colon and rectal cancers, and metastatic colorectal cancer (CRC). We found that pretreatment complete blood count and blood chemistry tests reflect short-term and long-term oncological outcomes in patients with CRC. Specifically, in patients with colon cancer, hypoalbuminemia was associated with worse postoperative morbidity, mortality, and inferior survival. In patients with rectal cancer, elevated neutrophil-lymphocyte ratio (NLR) and thrombocytosis were associated with postoperative complications, poor overall survival (OS), and disease-free survival (DFS). A high C-reactive protein/albumin ratio (CAR) was associated with poor OS and DFS. In patients with metastatic CRC, increased NLR and platelet-lymphocyte ratio (PLR) were associated with poor OS, DFS, and progression-free survival (PFS). In addition, high CAR and a low albumin/globulin ratio on blood chemistry tests were associated with poor OS and PFS. Although universal cut-off values were not available, various types of pretreatment laboratory markers could be utilized as adjuncts to predict prognosis in patients with CRC.


Autoimmune pancreatitis diagnosed on the basis of immunohistology alone. A case report.
The differential diagnosis between autoimmune pancreatitis and pancreatic cancer is sometimes difficult, especially for those patients in whom laboratory and radiological criteria are lacking. A 72-year-old woman was found to have a tumor in the head of the pancreas. Laboratory data showed no abnormal values, including gammaglobulins or autoantibodies. Endoscopic retrograde cholangiopancreatography showed extrinsic stenosis of the main pancreatic and lower common bile ducts. Computed tomography showed a lesion in the head of the pancreas. With a tentative diagnosis of head of the pancreas cancer, the patient underwent pancreaticoduodenectomy. Macroscopically, a tumor 2 cm in diameter not having clear margins was evident in the head of the pancreas. Histological examination showed the infiltration of lymphocytes, plasma cells, and eosinophils with lymphoid follicles around the main pancreatic duct. Immunohistological examination demonstrated that the main pancreatic duct was surrounded by abundant IgG4-positive plasma cells. The patient was diagnosed as having autoimmune pancreatitis on the basis of the immunohistological findings alone, without any well-defined criteria such as high serum level of IgG4 and presence of autoantibodies before or after surgery.


Accuracy of clinical diagnosis of influenza in outpatient children.
In a prospective study, children < or =13 years of age with respiratory infections were examined. At each visit, a nasal swab specimen was obtained for the detection of influenza, and the physician recorded his or her opinion on whether the child had influenza. Among 2288 infections, the overall sensitivity of the clinical diagnosis of influenza was 38% and the positive predictive value was 32%.


Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine.
We report 2 patients with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency whose urine was devoid of, or contained only trace, 3-methylcrotonylglycine, the pathognomonic marker for this disorder. The first patient, a girl with trisomy 21, was detected through newborn screening with an elevated 5 carbon hydroxycarnitine species level, and the second patient came to clinical attention at the age of 5 months because of failure to thrive and developmental delay. Investigation of urinary organic acids revealed an elevated 3-hydroxyisovaleric acid level but no demonstrable 3-methylcrotonylglycine in both patients. Enzyme studies in cultured fibroblasts confirmed isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency with residual activities of 5% to 7% and 12% of the median control value, respectively. Incorporation of 14C-isovaleric acid into intact fibroblasts was essentially normal, showing that the overall pathway was at least partially functional and potentially explaining the absence of 3-methylcrotonylglycine in urine. Mutation analysis of the MCCA and MCCB genes revealed that both patients were compound heterozygous for a missense mutation, MCCB-c.1015G-->A (p.V339M), and a second mutation that leads to undetectable MCCB messenger (poly A+) RNA. Absent or trace 3-methylcrotonylglycine levels in urine raises the potential for misdiagnosis in the clinical biochemical genetics laboratory based solely on urine organic acid analysis using combined gas chromatography-mass spectrometry.


[The role of scintigraphy with the use of 99mTc-HYNIC-TOC in the diagnosis of medullary thyroid carcinoma].
Recently a new somatostatin analogue labelled with (99m)Tc ((99m)Tc-HYNIC-TOC) has been synthetized. Aim of this study was to evaluate the utility of (99m)Tc-HYNIC-TOC in the radionuclide imaging in patients with medullary thyroid carcinoma (MTC). 30 patients with MTC aged 22-83 years in different stages of the disease were investigated. In 6 patients (group 1) scintigraphy was performed before surgery directly after diagnosis of MTC. Four patients (group 2) were qualified to the study in the phase of remission after surgical treatment that had been confirmed by low concentrations of calcitonin. Twenty patients (group 3) were investigated due to stagnation or recurrence confirmed by persistent hypercalcitoninemia. The scintigraphy using (99m)Tc-HYNIC-TOC (Tektrotyd, POLATOM) was performed 2 and 4 hours post injection of 20 mCi (740 MBq) of the tracer. Other imaging techniques were also employed and analysed in individual cases (US, CT, (99m)Tc(V)-DMSA, (131)I-MIBG, (99m)Tc-MDP, (111)In-octreotide and FDG-PET). Images obtained 2 and 4 hours p.i. were similar. In group 1, uptake of the tracer was found in the primary tumour of MTC in all patients. In group 2, a false positive result was found in 1 of 6 patients. In the remaining 5 of 6 cases no pathological foci were visualised. In group 3, uptake in the thyroid bed was found in 3 of 20 cases and in the lymph nodes in 14 of 20 patients. In 3 of 20 cases uptake in the bone metastases was found. Globally, sensitivity of the scintigraphy using (99m)Tc-HYNIC-TOC was 86.4%, specificity - 75.0%, and accuracy - 84.6%. The scintigraphy using (99m)Tc-HYNIC-TOC showed high utility in the diagnosis of MTC. Confirmation of the presence of somatostatin receptors with this method may be used for treatment planning: surgery or radionuclide therapy.


Experience of 100 surgical cases of encapsulating peritoneal sclerosis: investigation of recurrent cases after surgery.
Since 1993, we have performed enterolysis for encapsulating peritoneal sclerosis (EPS) in 86 patients. Five patients died after surgery, but the remaining 81 patients achieved symptomatic improvement. However, some of the surviving patients developed symptoms of intestinal obstruction after several months, and EPS recurrence remains our greatest challenge. In the present study, we identified factors related to recurrence by clinically comparing 47 recurrent and nonrecurrent patients that we were able to follow for more than 2 years after surgery. In the 47 patients we followed, 11 (23.4%) experienced recurrence, and 10 of those patients underwent a second surgery. Four patients needed a third surgery. The mean time to recurrence was 15.2 months, and all patients with recurrence, except one, experienced their recurrence within 20 months. We observed no differences between the recurrent and nonrecurrent patients in follow-up period, age, history of peritoneal dialysis, use or nonuse of steroids after surgery, thickness of the submesothelial compact zone, or inflammatory cell infiltration. However, the number of microvessels was significantly higher in the recurrent patients. Our surgical experience with EPS shows recurrence in approximately 23% of patients. The results of the present study suggest that peritoneal microvascular hyperplasia is a factor involved in recurrence, and that patients with recurrence may have an irreversible pathologic condition and may experience repeated recurrences.


Hyperthermic survival of Chinese hamster ovary cells as a function of cellular population density at the time of plating.
The survival of synchronous G1 or asynchronous Chinese hamster ovary cells in vitro to heat treatment may depend on the cellular population density at the time of heating and/or as the cells are cultured after heating. The addition of lethally irradiated feeder cells may increase survival at 10(-3) by as much as 10- to 100-fold for a variety of conditions when cells are heated either in suspension culture or as monolayers with or without trypsinization. The protective effect associated with feeder cells appears to be associated with close cell-to-cell proximity. However, when cells are heated without trypsinization about 24 hr or later after plating, when adaptation to monolayer has occurred, the protective effect is reduced; i.e., addition of feeder cells enhances survival much less, for example, about 2- to 3-fold at 10(-2)-10(-3) survival. Also, the survival of a cell to heat is independent of whether the neighboring cell in a microcolony is destined to live or die. Finally, if protective effects associated with cell density do occur and are not controlled, serious artifacts can result as the interaction of heat and radiation is studied; for example, survival curves can be moved upward, and thus changed in shape as the number of cells plated is increased with an increase in the hyperthermic treatment or radiation dose following hyperthermia. Therefore, to understand mechanisms and to obtain information relevant to populations of cells in close proximity, such as those in vivo, these cellular population density effects should be considered and understood.


Efficient Fine Tuning for Fashion Object Detection.
Pre-trained models have achieved success in object detection. However, challenges remain due to dataset noise and lack of domain-specific data, resulting in weaker zero-shot capabilities in specialized fields such as fashion imaging. We addressed this by constructing a novel clothing object detection benchmark, Garment40K, which includes more than 140,000 human images with bounding boxes and over 40,000 clothing images. Each clothing item within this dataset is accompanied by its corresponding category and textual description. The dataset covers 2 major categories, pants and tops, which are further divided into 15 fine-grained subclasses, providing a rich and high-quality clothing resource. Leveraging this dataset, we propose an efficient fine-tuning method based on the Grounding DINO framework to tackle the issue of missed and false detections of clothing targets. This method incorporates additional similarity loss constraints and adapter modules, leading to a significantly enhanced model named Improved Grounding DINO. By fine-tuning only a small number of additional adapter module parameters, we considerably reduced computational costs while achieving performance comparable to full parameter fine tuning. This allows our model to be conveniently deployed on a variety of low-cost visual sensors. Our Improved Grounding DINO demonstrates considerable performance improvements in computer vision applications in the clothing domain.


Lessons premier hospitals learned about implementing electronic health records.
Implementing health information technology (IT) is a major strategic objective for providers. To pinpoint considerations that tie to success, the Premier health care alliance surveyed hospitals to develop an electronic health record best-practices library. Compiled from diverse health care organizations, the library outlines considerations to support "meaningful use" in the areas of computerized physician order entry, medication management, clinical documentation, reporting of measures, privacy, information exchange, management of populations' health, and personal health records. Best practices also uncovered strategies for securing executive leadership, culture change, communication, and support for clinicians. This paper summarizes lessons from the library, providing recommendations to speed up health IT implementation.


Lack of data on depression-like states and antidepressant pharmacotherapy in patients with epilepsy: randomised controlled trials are badly needed.
The prevalence of depression in patients with epilepsy (PWE) is high. To elucidate the nature of depression in PWE, a comparison was made between PWE and patients with idiopathic depression (PWID), applying 3 test batteries: Beck Depression Inventory II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D) and Buss-Perry Aggression Questionnaire (BAQ). The former 2 rating scales were developed to measure depressive symptoms, while the latter was designed to detect anger and aggressive states. As a result, the group of patients with PWE showed significantly higher BAQ scores in comparison to those with PWID. Further, the BAQ and BDI scores were closely related within a group of PWE, while BAQ and BDI scores were not correlated with each other within a group of PWID. With regard to pharmaceutical therapy, the safety of antidepressants, especially SSRIs, is well established. However, there has been only one randomized controlled trial (RCT) thus far, which failed to show a significant difference in efficacy between placebo and various antidepressants. In contrast, there are two RCTs regarding the efficacy of LTG. The clinical profile of the depressiolytic effects of LTG in PWE may be different from that of antidepressants in patients with idiopathic depression, in that BAQ is more sensitive measure than BDI or CES-D. It is now widely recognized that the failure to treat depression in PWE can result in serious consequences. However, even a fundamental question, such as whether antidepressants are as effective in this population as in PWID, remains to be answered.


The Consumption of Synbiotic Bread Containing Lactobacillus sporogenes and Inulin Affects Nitric Oxide and Malondialdehyde in Patients with Type 2 Diabetes Mellitus: Randomized, Double-Blind, Placebo-Controlled Trial.
To our knowledge, no reports are available indicating the effects of synbiotic bread consumption on nitric oxide (NO), biomarkers of oxidative stress, and liver enzymes among patients with type 2 diabetes mellitus (T2DM). This study was performed to determine the effects of the daily consumption of synbiotic bread on NO, biomarkers of oxidative stress, and liver enzymes in patients with T2DM. This randomized, double-blind, placebo-controlled trial was performed among 81 patients with diabetes, aged 35-70 years old. After a 2-week run-in period, patients were randomly divided into 3 groups: group A (n = 27) received synbiotic bread containing viable and the heat-resistant probiotic Lactobacillus sporogenes (1 × 108 CFU) and 0.07 g inulin per 1 g, group B (n = 27) received probiotic bread containing Lactobacillus sporogenes (1 × 108 CFU), and group C (n = 27) received control bread for 8 weeks. Patients were asked to consume the synbiotic, probiotic, or control breads 3 times a day in 40 g packages for a total of 120 g/day. Fasting blood samples were taken at baseline and after an 8-week intervention for quantificationof related markers. After 8 weeks, the consumption of synbiotic bread compared to the probiotic and control breads resulted in a significant rise in plasma NO (40.6 ± 34.4 vs 18.5 ± 36.2 and -0.8 ± 24.5 µmol/L, respectively, p < 0.001) and a significant reduction in malondialdehyde (MDA) levels (-0.7 ± 0.7 vs 0.6 ± 1.7 and 0.5 ± 1.5 µmol/L, respectively, p = 0.001). We did not find any significant effect of the synbiotic bread consumption on plasma total antioxidant capacity (TAC), plasma glutathione (GSH), catalase, serum liver enzymes, calcium, iron, magnesium levels, and blood pressure compared to the probiotic and control breads. In conclusion, consumption of the synbiotic bread for 8 weeks among patients with T2DM had beneficial effects on plasma NO and MDA levels; however, it did not affect plasma TAC, GSH, catalase levels, serum liver enzymes, calcium, iron, magnesium levels, and blood pressure.


Chronic morphine treatment impaired hippocampal long-term potentiation and spatial memory via accumulation of extracellular adenosine acting on adenosine A1 receptors.
Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20-100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-alpha/beta activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.


Prediction of survival benefit when deciding between chemotherapy and best supportive therapy in elderly patients with advanced gastric cancer: A retrospective cohort study.
It remains unclear whether elderly patients (EPs) with advanced gastric cancer (AGC) benefit from chemotherapy. The aim of the present study was to examine the prognostic factors for EPs with AGC in order to generate a prognosis-predicting scoring system. This single-center retrospective study examined consecutive patients with AGC between April 2012 and July 2017. Risk factors for survival in EPs aged ≥75 years were identified using a Cox proportional hazards model, and a prognostic scoring system was generated and retrospectively evaluated to determine its usefulness for predicting patient prognosis. A total of 61 patients were enrolled as EPs (mean age, 81 years) and compared with 80 non-EPs (mean age, 66 years). The median survival time (MST) was significantly longer for non-EPs compared with that for EPs (3.8 vs. 10.1 months, respectively; P=0.0447). Among the EPs, 29 (48%) received chemotherapy and 32 received best supportive care (BSC). A total of 68 non-EPs (85%) received chemotherapy and 12 non-EPs received BSC. Among EPs with AGC, age-adjusted multivariate analysis revealed that performance status (PS), neutrophil/lymphocyte ratio (NLR)<4, intestinal-type histology and chemotherapy were significant prognostic factors. To predict EPs too frail for chemotherapy prior to treatment, one point was assigned for a PS of 1, diffuse-type histology and NLR≥4, whereas 2 points were assigned for PS≥2, and the point totals for each patient were calculated. A cut-off point of 2 had the best P-value by the log-rank test and was used to divide the patients into low-risk (LoR: Score 0-1) and high-risk (HiR: Score 2-4) groups. The MST of the LoR and HiR groups was 23.6 and 3.6 months, respectively (P<0.001). As regards treatment strategies and risk groups, the LoR chemotherapy group had the best prognosis (P=0.0010), and LoR EPs who were administered chemotherapy had a longer MST (30.3 months) compared with EPs who received BSC (8.7 months). In conclusion, scoring systems using PS, histology and NLR may be useful when considering chemotherapy in EPs with AGC.


Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection.
In establishing a respiratory infection, vaccinia virus (VACV) initially replicates in airway epithelial cells before spreading to secondary sites of infection, mainly the draining lymph nodes, spleen, gastrointestinal tract, and reproductive organs. We recently reported that interferon gamma (IFN-γ) produced by CD8 T cells ultimately controls this disseminated infection, but the relative contribution of IFN-γ early in infection is unknown. Investigating the role of innate immune cells, we found that the frequency of natural killer (NK) cells in the lung increased dramatically between days 1 and 4 postinfection with VACV. Lung NK cells displayed an activated cell surface phenotype and were the primary source of IFN-γ prior to the arrival of CD8 T cells. In the presence of an intact CD8 T cell compartment, depletion of NK cells resulted in increased lung viral load at the time of peak disease severity but had no effect on eventual viral clearance, disease symptoms, or survival. In sharp contrast, RAG(-/-) mice devoid of T cells failed to control VACV and succumbed to infection despite a marked increase in NK cells in the lung. Supporting an innate immune role for NK cell-derived IFN-γ, we found that NK cell-depleted or IFN-γ-depleted RAG(-/-) mice displayed increased lung VACV titers and dissemination to ovaries and a significantly shorter mean time to death compared to untreated NK cell-competent RAG(-/-) controls. Together, these findings demonstrate a role for IFN-γ in aspects of both the innate and adaptive immune response to VACV and highlight the importance of NK cells in T cell-independent control of VACV in the respiratory tract. Herein, we provide the first systematic evaluation of natural killer (NK) cell function in the lung after infection with vaccinia virus, a member of the Poxviridae family. The respiratory tract is an important mucosal site for entry of many human pathogens, including poxviruses, but precisely how our immune system defends the lung against these invaders remains unclear. Natural killer cells are a type of cytotoxic lymphocyte and part of our innate immune system. In recent years, NK cells have received increasing levels of attention following the discovery that different tissues contain specific subsets of NK cells with distinctive phenotypes and function. They are abundant in the lung, but their role in defense against respiratory viruses is poorly understood. What this study demonstrates is that NK cells are recruited, activated, and contribute to protection of the lung during a severe respiratory infection with vaccinia virus.


Gunshot injuries seen at Johannesburg Hospital during 1982.
Gunshot injuries seen at Johannesburg Hospital during 1982 are reviewed. The incidence of these injuries has been increasing over the last few years, and they now cause a significant problem in terms of workload and number of beds occupied. The use of a rifle or handgun is becoming more common, not only for suicidal purposes but also as a weapon of assault.


Induced antibodies to von Willebrand factor.
Plasma from 15 patients with haemophilia A and 4 patients with von Willebrand's disease (VWD) has been investigated for the presence of antibodies to von Willebrand factor (VWF) using ELISA and immunoblotting systems. All plasma samples were also analyzed for anticoagulant activity against factor VIII coagulant activity (FVIII:C) and ristocetin co-factor activity of VWF (RCof). The patients were on regular prophylaxis or treated 'on demand' with different commercial FVIII-VWF complex concentrates. Neutralizing activity against FVIII:C was only found in haemophiliacs (in 3 out of 15), whereas anti-RC of was only found in VWD patients (in 2 out of 4). In ELISA, antibodies to VWF were detected in 3 of the VWD patients. However, using the immunoblotting system, antibodies to the multimeric structure of VWF were found not only in VWD patients (in 3 out of 4); remarkably 9 out of 15 haemophiliacs also reacted with VWF, including some that did not show FVIII:C inhibitors. The pattern of VWF multimers obtained with the antibodies showed differences among the patients. These findings are discussed together with the mechanisms by which such antibodies could have developed in haemophilia A patients who are not deficient in this particular protein (VWF).


The Effectiveness of Internet- and Field-Based Methods to Recruit Young Adults Who Use Prescription Opioids Nonmedically.
Nonmedical prescription opioid (NMPO) use is a problem among young adults, yet young NMPO users are a diverse population that has been challenging to engage in overdose prevention and harm reduction programs. This study compared the effectiveness and characteristics of persons recruited through two different sampling strategies to inform research and intervention efforts with young adult NMPO users. We analyzed data from the Rhode Island Young Adult Prescription Drug Study (RAPiDS), which enrolled persons aged 18 to 29 who reported past 30-day NMPO use. We compared the characteristics of two samples recruited simultaneously between February 2015 and February 2016. One sample was recruited using field-based strategies (e.g., respondent-driven sampling, transit ads), and a second from internet sources (e.g., online classifieds). Among 198 eligible participants, the median age was 25 (IQR: 22, 27), 130 (65.7%) were male, 123 (63.1%) were white, and 150 (78.1%) resided in urban areas. A total of 79 (39.9%) were recruited using field-based strategies and 119 (60.1%) were recruited from internet sources. Internet-recruited persons were younger (median = 24 [IQR: 21, 27] vs. 26 [IQR: 23, 28] years) and more likely to reside in rural areas (16.2% vs. 5.3%), although this finding was marginally significant. Field-recruited participants were more likely to have been homeless (36.7% vs. 17.7%), have been incarcerated (39.7% vs. 21.8%), and engage in daily NMPO use (34.6% vs. 14.5%). Multipronged outreach methods are needed to engage the full spectrum of young adult NMPO users in prevention and harm reduction efforts.


Rhinitis medicamentosa.
Rhinitis medicamentosa, the syndrome of rebound nasal congestion secondary to prolonged topical intranasal use of vasoconstrictors, is reviewed. In this condition, the nasal airway is very obstructed; atrophic rhinitis is the most serious complication. Management consists of withdrawing the offending nasal spray and alleviating the nasal obstruction by means of any of several treatment modalities.


Reactivity to tyrosinase: expression in cancer (melanoma) and autoimmunity (vitiligo).
Anti-tyrosinase antibodies are found in the sera of patients with diffuse vitiligo, metastatic melanoma and in sera of patients with melanoma and hypopigmentation (MAH). The autoantigen is tyrosinase itself, the enzyme that participates in pigment (melanin) formation by both melanocytes and melanoma cells. The production of autoantibodies in both diseases is associated with the development of white patches on the patients' skin. The presence of these autoantibodies in patients with melanoma may suggest a better prognosis. Cross-antigenicity between melanoma cells and normal melanocytes is most probably the key mechanism leading to the appearance of MAH. Anti-tyrosinase antibodies are absorbed by melanocytes and by melanoma cells in all the 3 situations (melanoma, vitiligo, MAH). However, since the production of antibodies in vitiligo exceeds that in melanoma or MAH, the antibodies are detected in significantly higher levels only in vitiligo. It is suggested here that anti-tyrosinase antibodies may be responsible, or at least participate in destruction of normal melanocytes during the immune response to melanoma antigens. This mechanism may be responsible for the phenomenon of MAH in patients with melanoma, and for the formation of the autoimmune vitiligo. Anti-tyrosinase antibodies may serve for two clinical applications. One is a marker for monitoring and follow up of patients with melanoma treated by immune therapy. The second is active (or passive) immunotherapy. We have recently shown that C57BL/6J mice immunized with tyrosinase generated a high titer of antityrosinase antibodies, and following the inoculation of melanoma cells developed lower number of lung metastases, compared to the unvaccinated control group.


A natural heme-signature variant of CYP267A1 from Sorangium cellulosum So ce56 executes diverse ω-hydroxylation.
A novel naturally occurring heme-signature variant of CYP267A1 from myxobacterium Sorangium cellulosum So ce56 and its mutant L366F, the actual mimic of the 'conserved' heme-signature of cytochromes P450, were heterologously expressed in Escherichia coli in a soluble form and purified. The UV-visible characteristics of both variants were highly similar. Although leucine replaced the phenylalanine in the heme-signature domain of CYP267A1, EPR measurements of the ligand-free wild-type CYP267A1 and the mutant L366F showed low-spin rhombic species suggesting a conserved heme environment of the P450s. The need of primary redox partners for the orphan P450 was sustained by the bovine redox system and a class-I electron transfer path was provided during fatty acid hydroxylation. CYP267A1 showed higher activity and produced more diverse ω-hydroxylated products compared with L366F. In both enzymes the regioselectivity of the fatty acid hydroxylation shifted towards the inner carbon atoms of the fatty acid chains with increasing carbon chain lengths. Our docking results in a homology model of the protein showed that longer fatty acids need to be folded to fit into the binding pocket. In the mutant L366F, the ω-1 and ω-2 positions which exhibit the largest electron density of the highest occupied molecular orbital are preferred. It is speculated that the leucine heme-signature variant of P450 might have evolved under selective evolutionary pressure, which confers an increased advantage to generate a broader spectrum of related alcohols and carboxylic acids required for the bacterial homeostasis or metabolism in a particular ecological niche.


Maternal ancestry and hematological cancer risk: case-control study in an Argentinean population.
Aim: We investigated the role of maternal ancestry in neoplastic hematological malignancies (HMs) risk in a population from Central Argentina. Materials & methods: We analyzed 125 cases with HMs and 310 controls from a public hospital, and a set of 202 colorectal, breast, lung, and hematologic cancer patients from a private hospital. Results: A decreased risk for HMs was associated with the Native American haplogroup B2 (odds ratio = 0.49; 95% CI: 0.25-0.92; p = 0.02). The sub-Saharan African parahaplogroup L was associated with higher susceptibility for disease (odds ratio = 3.10; 95% CI: 1.04-9.31; p = 0.043). Although the mean ancestral proportions in the total studied population was as published (61.7% Native American, 34.6% European and 3.7% African), an unequal distribution was observed between hospitals. Conclusion: We confirmed the tri-hybrid nature of the Argentinean population, with proportions varying within the country. Our finding supports the notion that associated haplogroup is population and cancer specific.


Using record linkage to investigate perinatal factors and neonatal thyroid-stimulating hormone.
Studies examining the relationship between maternal and infant thyroid parameters have shown conflicting results. Record linkage provides an opportunity to examine the association between maternal and infant thyroid-stimulating hormone (TSH) levels. Our aim was to demonstrate the feasibility of record linkage of newborn screening (NBS), laboratory and birth databases for research by investigating the association between maternal and newborn TSH levels. The records of 2802 women with first trimester serum TSH concentrations were linked with population-based birth data and NBS data containing infant TSH levels. Association between moderately high neonatal TSH levels (>5 mIU/L) and maternal and infant characteristics was evaluated. The correlation and association between maternal and infant TSH levels were assessed using Pearson's correlation coefficient and multivariable linear regression, respectively. Of maternal and birth records, 99.3% linked with an NBS record. Mother's country of birth, gestational age (>41 weeks) and lower birthweight were associated with neonatal TSH levels >5 mIU/L. Neonatal and maternal first trimester TSH levels were not correlated, although statistically significant (r = 0.05, P = 0.008). The association between neonatal TSH and maternal TSH, after adjusting for maternal age, gestational age and age at NBS testing, was also small (b = 0.039, P = 0.009). Record linkage is a feasible and cost-efficient way to investigate the association between maternal factors and neonatal hormone levels. First trimester maternal thyroid levels are not correlated with neonatal TSH levels. This method of outcome assessment can be used for future research examining long-term outcomes for infants with different NBS results.


The pyrethroids permethrin and cyhalothrin are potent inhibitors of the mitochondrial complex I.
The synthetic pyrethroid derivatives permethrin and cyhalothrin are widely used insecticides that are considered to be relatively nontoxic to higher animals. However, a variety of toxic effects on mammals have been reported. We investigated the effect of these drugs on energy coupling by mitochondria and on the activity of the individual respiratory complexes. Using isolated rat liver mitochondria, a concentration-dependent inhibition of glutamate and succinate sustained state 3 respiration was found for both compounds in the micromolar range. The effect of pyrethroids on the activities of the complexes I to V were assessed individually in submitochondrial particles (complex I) and in freeze-thawed mitochondria (complexes II-V). Complex I (EC 22.214.171.124) was found to be the most sensitive link within the electron transport chain. Half-maximal inhibition was observed at 0.73 microM permethrin and 0.57 microM cyhalothrin, respectively, and exhibited sigmoidal inhibition kinetics. Complexes II, III, IV and V (EC 188.8.131.52, 184.108.40.206, 220.127.116.11, 188.8.131.52) were not significantly inhibited by up to 50 microM of these drugs. Thus, our results reveal a model of action of synthetic pyrethroid insecticides not previously reported.


Anti-Inflammatory and Antinociceptive Effects of Boesenbergia rotunda Polyphenol Extract in Diabetic Peripheral Neuropathic Rats.
Diabetic peripheral neuropathy (DPN) is still one of the most prevailing complication of diabetes and it affects a huge diabetic population. Boesenbergia rotunda is a ginger species that has both culinary and medicinal applications. Recent studies have revealed that B. rotunda has potential applications in diabetes, pain and inflammatory related disorders. As such this study investigated the potential of B. rotunda extract (EBR) in attenuating DPN in rats. DPN was induced in male Sprague Dawley rats using a combination of 30% fructose solution and streptozotocin (40 mg/kg). Afterwards diabetic rats were treated with EBR (100 and 400 mg/kg) for 5 weeks. DPN was assessed using thermal hyperalgesia, cold and mechanical allodynia and rotarod test, while nociceptive responses were assessed by formalin and acetic acid test. In addition, serum proinflammatory cytokine levels were determined using ELISA kits. EBR displayed hypoglycemic effect by significantly reducing the blood glucose concentration of treated diabetic rats, while simultaneously alleviating the reduced body weight. Furthermore, EBR markedly alleviated thermal hyperalgesia, cold and mechanical allodynic responses as well as ameliorated motor coordination in the treated diabetic rats. In addition, EBR significantly reduced nociceptive responses in the formalin and acetic acid test, as well as decreased serum levels of proinflammatory cytokines (TNF-α and IL-1β). The results suggested that EBR exerted anti-inflammatory and anti-nociceptive effects, thus alleviating diabetic painful neuropathy.


Capmatinib Could Alter NSCLC Treatment Landscape.
Capmatinib may be effective in patients with advanced non-small cell lung cancer who have MET exon 14 skipping mutations. In the phase II GEOMETRY mono-1 trial, the drug elicited high overall response rates and relatively durable responses in newly diagnosed and previously treated patients, including those with brain metastases.


The glucocorticoid receptor: molecular mechanism and new therapeutic opportunities.
Synthetic glucocorticoids are among the most effective anti-inflammatory drugs available. The activity of this drug class is mediated by the glucocorticoid receptor, a nuclear steroid receptor whose endogenous ligand is the adrenal hormone cortisol. Chronic glucocorticoid treatment is accompanied by serious side-effects, reflecting the symptoms of cortisol excess seen in Cushing's syndrome patients. During the past 50 years advances to this drug class have been limited largely to reducing systemic exposure through inhaled delivery and increasing glucocorticoid receptor selectivity. However, a safer oral drug for the treatment of conditions such as rheumatoid arthritis, inflammatory bowel disease, and transplant rejection, still represents a major unmet medical need. Over the past 20 years, mechanisms of glucocorticoid receptor action have been elucidated. Before the gene was even cloned, the glucocorticoid receptor was known to be a ligand-induced DNA binding protein. Identification of hormone response elements in the promoters of metabolic target genes in the liver provided a model for its broad activities. It was since revealed that much of its anti-inflammatory activity is not DNA-dependent after all, but instead is the result of a complex set of protein-protein interactions which lead to transcriptional inhibition of pro-inflammatory targets. Thus, a glucocorticoid receptor ligand that dissociates the DNA binding and protein interaction mediated activities is expected to show improved safety. This review will focus on the scientific advances, which impact the development of this hypothesis and will present a survey of current preclinical drug candidates employing this strategy.


Prognostic value of clinical variables in invasive cervical cancer.
To test the hypothesis that clinical variables, such as patients' symptoms, symptom severity, and co-morbidity, affect the survival rate of patients with invasive cervical cancer. From the medical records of 251 cases of invasive cervical cancer treated at Yale-New Haven Hospital between 1984 and 1988, information was extracted for patients' demographic characteristics, symptoms, symptom severity, comorbidity, physical findings, laboratory data, treatment, and subsequent course. Three-year survival data were available for 250 (99%) of the 251 cases. For a composite clinical predictive system based on symptom status and co-morbidity, the 3-year survival rates were as follows: 85% (64 of 75) for the patients who were asymptomatic without co-morbidity; 63% (58 of 92) for the group that was either symptomatic or co-morbid, but not both; and 40% (33 of 83) for symptomatic patients with co-morbidity or patients with systemic, metastatic, or severe symptoms (P < .0001, chi 2 for linear trend). When entered into a Cox proportional hazards model along with other variables that might affect prognosis, including International Federation of Gynecology and Obstetrics stage, the composite symptom-co-morbidity stage remained statistically significant. Our findings demonstrate the importance of clinical variables, such as symptoms and co-morbidity, in estimating prognosis in cervical cancer, even after stage and other factors are controlled. Unless the clinical variables are suitably analyzed, prognostic estimates based on morphology alone will be imprecise and therapeutic evaluations may be misleading.


[Studies on the mycotic and bacterial risk of contamination and the use of nipagin in the artificial insemination of cryosperm].
Primary bacterial and mycological contamination was studied in random human ejaculates. After various phases of cryopreservation secondary microbiological contamination was investigated. Furthermore, semen samples of several donors were inoculated with suspension of different concentrations of yeasts and with the test bacteria Escherichia coli K12 and Staphylococcus aureus SG 511. Microbiological results were then compared before an after cryopreservation. The cryopreserving process was carried out with and without antibiotics to test the antibacterial effectiveness of antibiotics under these conditions. Moreover, we investigated the usability of a chemical preservative (Nipagin) at cryopreservation. The following results were obtained: 9.8 per cent of samples showed primary mycological contamination (1.9 per cent with Candida albicans). Cryopreservation reduced the concentration of fungi by more than 90 per cent on average. The bacteriological investigations have shown, that with one exception the semen was without pathogenetic bacteria. This situation was altered scarcely during the cryopreserving process (also by use of cryoprotective medium without antibiotics). Out of 25 ejaculates 11 had primary non-pathogenetic bacteria. Test bacteria inoculated into semen were not influenced by the addition of antibiotics to the cryoprotective medium (CPM). Nipagin prevented respectively reduced a bacterial or a mycological contamination of the CPM during a storage of 14 days dependent of nipagin concentration but reduced the motility of human spermatozoa after cryopreservation. The results suggest the conclusion to prefer a portionate storage without nipagin at a temperature of nearly + 1 degree C, thereby the microbiological contamination may be neglected.


Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines.
The Pictet-Spengler reaction (PSR) involves the condensation and ring closure between a β-arylethylamine and a carbonyl compound. The combination of dopamine and ketones in a PSR leads to the formation of 1,1'-disubstituted tetrahydroisoquinolines (THIQs), structures that are challenging to synthesize and yet are present in a number of bioactive natural products and synthetic pharmaceuticals. Here we have discovered that norcoclaurine synthase from Thalictrum flavum (TfNCS) can catalyse the PSR between dopamine and unactivated ketones, thus facilitating the facile biocatalytic generation of 1,1'-disubstituted THIQs. Variants of TfNCS showing improved conversions have been identified and used to synthesize novel chiral 1,1'-disubstituted and spiro-THIQs. Enzyme catalysed PSRs with unactivated ketones are unprecedented, and, furthermore, there are no equivalent stereoselective chemical methods for these transformations. This discovery advances the utility of enzymes for the generation of diverse THIQs in vitro and in vivo.


Talking with Patients about Surgical Trainees.
AbstractTraining of resident physicians is essential for the care of future patients. While surgical trainee involvement is necessary, its disclosure to patients can often be omitted or underplayed by surgeons. The informed consent process and the underlying ethical principles make evident that patients should be informed of trainee involvement. In this review we explore the importance of disclosure, current themes in practice, and the optimal discussion for which we should strive.


Alloimmune-induced intragraft lymphoid neogenesis promotes B-cell tolerance breakdown that accelerates chronic rejection.
Antibody-mediated rejection (AMR) has emerged as a leading cause of allograft loss in solid organ transplantation. A better understanding of AMR immunopathology is a prerequisite to improve its management. The prevalent dogma considers that AMR is the consequence of a thymo-dependent B-cell response against donor-specific polymorphic antigens (mainly mismatched human leukocyte antigen molecules).Nevertheless, antibodies directed against nonpolymorphic antigens expressed by the graft are also generated during chronic rejection and can contribute to allograft destruction. This implies that a breakdown of self-tolerance occurs during chronic rejection. Accumulating evidence suggests that this event occurs inside the ectopic 'tertiary' lymphoid tissue that develops within rejected allografts.Thus, AMR should be viewed as a complex interplay between allo- and autoimmune humoral responses. The interplay between allo- and autoimmune humoral responses in chronic rejection highlights several unmet medical issues like better diagnosis tools are needed to screen recipients for nonhuman leukocyte antigen alloantibodies and autoantibodies, therapeutic strategies shall aim at blocking the response against alloantigens but also the breakdown of self-tolerance that occurs within tertiary lymphoid tissue.