APOE modulates the correlation between triglycerides, cholesterol, and CHD through pleiotropy, and gene-by-gene interactions.
Relationship loci (rQTL) exist when the correlation between multiple traits varies by genotype. rQTL often occur due to gene-by-gene (G × G) or gene-by-environmental interactions, making them a powerful tool for detecting G × G. Here we present an empirical analysis of apolipoprotein E (APOE) with respect to lipid traits and incident CHD leading to the discovery of loci that interact with APOE to affect these traits. We found that the relationship between total cholesterol (TC) and triglycerides (ln TG) varies by APOE isoform genotype in African-American (AA) and European-American (EA) populations. The e2 allele is associated with strong correlation between ln TG and TC while the e4 allele leads to little or no correlation. This led to a priori hypotheses that APOE genotypes affect the relationship of TC and/or ln TG with incident CHD. We found that APOE*TC was significant (P = 0.016) for AA but not EA while APOE*ln TG was significant for EA (P = 0.027) but not AA. In both cases, e2e2 and e2e3 had strong relationships between TC and ln TG with CHD while e2e4 and e4e4 results in little or no relationship between TC and ln TG with CHD. Using ARIC GWAS data, scans for loci that significantly interact with APOE produced four loci for African Americans (one CHD, one TC, and two HDL). These interactions contribute to the rQTL pattern. rQTL are a powerful tool to identify loci that modify the relationship between risk factors and disease and substantially increase statistical power for detecting G × G.


High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN): an interventional study.
Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA. Postprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number. We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.


Toll-like receptor agonists are potent inhibitors of human immunodeficiency virus-type 1 replication in peripheral blood mononuclear cells.
Innate immune responses to microbial pathogens are initiated following the binding of ligand to specific pattern recognition receptors. Each pattern recognition receptor, which includes members of the Toll-like receptor (TLR) family, is specific for a particular type of pathogen associated molecular pattern ensuring that the organism can respond rapidly to a wide range of pathogens including bacteria, viruses, and fungi. We studied the extent to which agonists to endosomal TLR could induce anti-HIV-1 activity in peripheral blood mononuclear cells (PBMCs). When agonists to TLR3, TLR7, TLR8 and TLR9 were added prior to infection with HIV-1, they significantly reduced infection of peripheral blood mononuclear cells. Interestingly, agonists to TLR8 and TLR9 were highly effective at blocking HIV replication even when added as late as 48 h or 72 h, respectively, after HIV-1 infection, indicating that the anti-viral effect was durable and long lasting. Analysis of the induction of anti-viral genes after agonist activation of TLR indicated that all of the agonists induced expression of the type I interferons and interferon stimulated genes, although to variable levels that depended on the agonist used. Interestingly, only the agonist to TLR9, ODN2395 DNA, induced expression of type II interferon and the anti-HIV proteins Apobec3G and SAMHD1. By blocking TLR activity using an inhibitor to the MyD88 adaptor protein, we demonstrated that, at least for TLR8 and TLR9, the anti-HIV activity was not entirely mediated by TLR activation, but likely by the activation of additional anti-viral sensors in HIV target cells. These findings suggest that agonists to the endosomal TLR function to induce expression of anti-HIV molecules by both TLR-mediated and non-TLR-mediated mechanisms. Moreover, the non-TLR-mediated mechanisms induced by these agonists could potentially be exploited to block HIV-1 replication in recently HIV-exposed individuals.


Concomitant radiosurgical and targeted oncological treatment improves the outcome of patients with brain metastases from gastrointestinal cancer.
So far, only limited studies exist that evaluate patients with brain metastases (BM) from GI cancer and associated primary cancers who were treated by Gamma Knife Radiosurgery (GKRS) and concomitant immunotherapy (IT) or targeted therapy (TT). Survival after GKRS was compared to the general and specific Graded Prognostic Assessment (GPA) and Score Index for Radiosurgery (SIR). Further, the influence of age, sex, Karnofsky Performance Status Scale (KPS), extracranial metastases (ECM) status at BM diagnosis, number of BM, the Recursive Partitioning Analysis (RPA) classes, GKRS1 treatment mode and concomitant treatment with IT or TT on the survival after GKRS was analyzed. Moreover, complication rates after concomitant GKRS and mainly TT treatment are reported. Multivariate Cox regression analysis revealed IT or TT at or after the first Gamma Knife Radiosurgery (GKRS1) treatment as the only significant predictor for overall survival after GKRS1, even after adjusting for sex, KPS group, age group, number of BM at GKRS1, RPA class, ECM status at BM diagnosis and GKRS treatment mode. Concomitant treatment with IT or TT did not increase the rate of adverse radiation effects. There was no significant difference in local BM progression after GKRS between patients who received IT or TT and patients without IT or TT. Good local tumor control rates and low rates of side effects demonstrate the safety and efficacy of GKRS in patients with BM from GI cancers. The concomitant radiosurgical and targeted oncological treatment significantly improves the survival after GKRS without increasing the rate of adverse radiation effects. To provide local tumor control, radiosurgery remains of utmost importance in modern GI BM management.


Rumen-protected methionine supplementation during the peripartal period alters the expression of galectin genes associated with inflammation in peripheral neutrophils and secretion in plasma of Holstein cows.
The work described in this research communication aimed to investigate whether rumen-protected methionine (Met) supplementation during the periparturient period would affect the expression of galectins in blood-derived neutrophils, and secretion of galectins, IL (interleukin)-1β, IL-6, myeloperoxidase (MPO), and glucose in plasma. Because supplementation of rumen-protected Met would alleviate inflammation and oxidative stress during the peripartal period, we hypothesized that enhancing Met supply would benefit the innate immune response at least in part by altering the expression of galectin genes associated with neutrophil activity and inflammation. Galectins (Gal) have an immuno-modulating effect acting like cell-surface receptors whose activation often results in signaling cascades stimulating cells such as neutrophils. This study revealed an association between Met supplementation and galectin expression and secretion. This implies that galectin expression and secretion can be modulated by Met supplementation. Further studies are needed to evaluate the regulation of galectin gene expression for therapeutic and dietary intervention in the peripartal cow.


Repeated Mild Closed Head Injuries Induce Long-Term White Matter Pathology and Neuronal Loss That Are Correlated With Behavioral Deficits.
An estimated 5.3 million Americans are living with a disability from a traumatic brain injury (TBI). There is emerging evidence of the detrimental effects from repeated mild TBIs (rmTBIs). rmTBI manifests its own unique set of behavioral and neuropathological changes. A subset of individuals exposed to rmTBI develop permanent behavioral and pathological consequences, defined postmortem as chronic traumatic encephalopathy. We have combined components of two classic rodent models of TBI, the controlled cortical impact model and the weight drop model, to develop a repeated mild closed head injury (rmCHI) that produces long-term deficits in several behaviors that correlate with neuropathological changes. Mice receiving rmCHI performed differently from 1-hit or sham controls on the elevated plus maze; these deficits persist up to 6 months postinjury (MPI). rmCHI mice performed worse than 1-hit and control sham mice at 2 MPI and 6 MPI on the Morris water maze. Mice receiving rmCHI exhibited significant atrophy of the corpus callosum at both 2 MPI and 6 MPI, as assessed by stereological volume analysis. Stereological analysis also revealed significant loss of cortical neurons in comparison with 1-hit and controls. Moreover, both of these pathological changes correlated with behavioral impairments. In human tau transgenic mice, rmCHI induced increases in hyperphosphorylated paired helical filament 1 tau in the hippocampus. This suggests that strategies to restore myelination or reduce neuronal loss may ameliorate the behavioral deficits observed following rmCHI and that rmCHI may model chronic traumatic encephalopathy in human tau mice.


Choroidal amelanotic tumours: clinical differentiation of benign from malignant lesions in 5586 cases.
To investigate demographics and clinical features of patients with amelanotic choroidal tumours. Retrospective analysis. Comparison of demographic and clinical features of various amelanotic choroidal tumours based on stratification by patient age, sex and tumour diameter. Included were all patients with amelanotic choroidal tumours evaluated on the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania, USA, over a 45-year time period. A total of 5586 amelanotic choroidal tumours in 4638 eyes of 4441 patients were included with a mean age at presentation of 58 years (median 60, range 0.1-100 years). Most patients were white (95%), female (56%) and with unilateral lesion (96%). By comparison, amelanotic melanoma presented at a younger mean age (57 years) compared with metastasis (60 years, p<0.001), nevus (61 years, p<0.001), lymphoma (65 years, p<0.001), sclerochoroidal calcification (70 years, p<0.001) and peripheral exudative haemorrhagic chorioretinopathy (80 years, p<0.001). Melanoma presented at an older mean age compared with osteoma (30 years, p<0.001), granuloma (42 years, p<0.001), haemangioma (49 years, p<0.001) and inflammatory choroidal lesions (49 years, p<0.001). Differences in race and sex were also seen between the various amelanotic choroidal lesions. With few exceptions, amelanotic melanoma had significantly larger basal diameter, greater thickness, more frequent association with subretinal fluid and more often ultrasonographically hollow, compared with other amelanotic choroidal lesions. Understanding the demographic and clinical features of amelanotic choroidal melanoma and other amelanotic lesions could lead to an earlier and more accurate diagnosis.


Assessing regional public health preparedness: a new tool for considering cross-border issues.
To provide regional, state, and local public health officials a conceptual framework and checklist for assessing regional public health emergency preparedness, specifically in regard to cross-border public health preparedness needs. The project had four phases that are as follows: defining the scope, conducting a literature review, soliciting expert opinion, and creating the assessment framework and checklist. A conceptual framework was developed to define the scope of the project on the basis of the kinds of resources likely to be shared across borders in a public health response (eg, data, supplies, staff), in support of the public health functions likely to be important in a health emergency (eg, epidemiology, laboratory). A literature review was then conducted to identify key articles and tools addressing regional preparedness. Key informant interviews (n = 23) were conducted with public health and emergency management professionals in the Pacific Northwest to identify a set of systems, agreements, and protocols that should be systematically considered in assessing regional public health preparedness. Using the literature review and themes from interviews, a checklist was developed. A checklist was developed for use by public health leaders, which recommends 24 specific agreements, protocols, systems, and management structures that should be considered to foster cross-border public health preparedness. Regional public health preparedness represents not only the sum of state-level preparedness of the states in a region but also the capacity of those states to collaborate across state and international borders during a public health emergency. This checklist provides a tool to systematically consider cross-border preparedness issues.


Sparse approximation through boosting for learning large scale kernel machines.
Recently, sparse approximation has become a preferred method for learning large scale kernel machines. This technique attempts to represent the solution with only a subset of original data points also known as basis vectors, which are usually chosen one by one with a forward selection procedure based on some selection criteria. The computational complexity of several resultant algorithms scales as O(NM(2)) in time and O(NM) in memory, where N is the number of training points and M is the number of basis vectors as well as the steps of forward selection. For some large scale data sets, to obtain a better solution, we are sometimes required to include more basis vectors, which means that M is not trivial in this situation. However, the limited computational resource (e.g., memory) prevents us from including too many vectors. To handle this dilemma, we propose to add an ensemble of basis vectors instead of only one at each forward step. The proposed method, closely related to gradient boosting, could decrease the required number M of forward steps significantly and thus a large fraction of computational cost is saved. Numerical experiments on three large scale regression tasks and a classification problem demonstrate the effectiveness of the proposed approach.


Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors.
Investigative interest in atypical nevi and familial melanoma has contributed to the identification of several candidate melanoma loci within the human genome. Molecular defects in both tumor suppressor genes and oncogenes have been pathogenically linked to melanoma in recent studies. Of the loci currently characterized, the major gene resides on chromosome 9p and encodes a tumor suppressor designated p16. This gene, which is also known as CDKN2A, is either mutated or deleted in a large majority of melanoma cell lines, as well as in many uncultured melanoma cells and in the germline of melanoma kindreds. A novel aspect of the p16 locus is that it encodes not just one but two separate gene products that are transcribed in alternative reading frames. Both products function as negative regulators of cell cycle progression. The p16 protein itself executes its effects by competitively inhibiting cyclin-dependent kinase 4, which is a factor necessary for cellular progression through a major regulatory transition of the cell division cycle. Inherited and acquired deletions or point mutations in the p16 gene increase the likelihood that potentially mutagenic DNA damage will escape repair before cell division. Notably, the second product of the locus, ARF (for alternative reading frame), regulates cell growth through independent effects on the p53 pathway. Although there is little evidence that ARF by itself is involved in the pathogenesis of melanoma, deletions at the p16 locus disable two separate pathways that control cell growth. These recent advances open up the possibility of genetic testing for melanoma susceptibility in the setting of familial melanoma and suggest novel therapeutic strategies for melanoma based on gene therapy or small molecule mimicry targeted to the correction of defects in the p16 regulatory pathway. (J Am Acad Dermatol 2000;42:705-22.) At the conclusion of this learning activity, participants should be familiar with the historical aspects of melanoma genetics and should have a greater understanding of the CDKN2A(p16)/ARF tumor suppressor genes.


A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis.
Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population. We noted single-nucleotide polymorphisms (SNPs) in the apoptotic cell-engulfment genes ELMO1, DOCK2, and RAC1 linked to rheumatoid arthritis. As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis. Surprisingly, Elmo1-deficient mice showed reduced joint inflammation in acute and chronic arthritis models. Genetic and cell-biology studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses. Further, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to chemokines linked to arthritis. These data identify 'noncanonical' roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis.


Sclerosing carcinoma of the right hepatic duct at the porta hepatis: anicteric presentation of early hilar cholangiocarcinoma.
Asymptomatic presentation of hilar cholangiocarcinoma is exceptional. We report an asymptomatic patient presenting with an abnormal alkaline phosphatase who proved to have a unilateral hilar cholangiocarcinoma obstructing the right heptic duct at the porta hepatis. Hyperbilirubinemia was absent. Subsequent to partial tumor resection and palliative decompression with right intrahepatic cholangiojejunostomy, the patient developed cholangitis with abscess formation. The efficacy of biopsy, tumor resection, and surgical decompression in hilar cholangiocarcinoma is discussed. Postmortem histology revealed biliary cirrhosis and acute cholangitis in the obstructed right liver lobe and minimal portal fibrosis in the unobstructed left liver lobe. The absence of bile stasis suggests compensatory bile excretion mechanism in the unobstructed left lobe. We believe the clinical and pathological findings in the patient to be part of the early natural history of hilar cholangiocarcinoma. Complete workup of asymptomatic alkaline phosphatase elevations in patients without previous history of hepatobiliary disease may prove fruitful in revealing incipient localized, unilateral bifurcation tumors.


Metabolomics study reveals increased deoxycholic acid contributes to deoxynivalenol-mediated intestinal barrier injury.
Deoxynivalenol (DON), namely vomitoxin, is one of the most prevalent fungal toxins in cereal crops worldwide. However, the underlying toxic mechanisms of DON remain largely unknown. DON exposure-caused changes in the murine plasma metabolome and gut microbiome were investigated by an LC-MS/MS-based nontargeted metabolomics approach and sequencing of 16S rRNA in fecal samples, respectively. Cellular models were then used to validate the findings from the metabolomics study. DON exposure increased intestinal barrier permeability evidenced by its-mediated decrease in colonic Claudin 5 and E-cadherin, as well as increases in colonic Ifn-γ, Cxcl9, Cxcl10, and Cxcr3. Furthermore, DON exposure resulted in a significant increase in murine plasma levels of deoxycholic acid (DCA). Also, DON exposure led to gut microbiota dysbiosis, which was associated with DON exposure-caused increase in plasma DCA. In addition, we found not only DON but also DCA dose-dependently caused a significant increase in the levels of IFN-γ, CXCL9, CXCL10, and/or CXCR3, as well as a significant decrease in the expression levels of Claudin 5 and/or E-cadherin in the human colonic epithelial cells (NCM460). DON-mediated increase in DCA contributes to DON-caused intestinal injury. DCA may be a potential therapeutic target for DON enterotoxicity.


Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium.
Mitochondria participate in various metabolic pathways, and their dysregulation results in multiple disorders, including aging-related diseases. However, the metabolic changes and mechanisms of mitochondrial disorders are not fully understood. Here, we found that induced pluripotent stem cells (iPSCs) from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) showed attenuated proliferation and survival when glycolysis was inhibited. These deficits were rescued by taurine administration. Metabolomic analyses showed that the ratio of the reduced (GSH) to oxidized glutathione (GSSG) was decreased; whereas the levels of cysteine, a substrate of GSH, and oxidative stress markers were upregulated in MELAS iPSCs. Taurine normalized these changes, suggesting that MELAS iPSCs were affected by the oxidative stress and taurine reduced its influence. We also analyzed the retinal pigment epithelium (RPE) differentiated from MELAS iPSCs by using a three-dimensional culture system and found that it showed epithelial mesenchymal transition (EMT), which was suppressed by taurine. Therefore, mitochondrial dysfunction caused metabolic changes, accumulation of oxidative stress that depleted GSH, and EMT in the RPE that could be involved in retinal pathogenesis. Because all these phenomena were sensitive to taurine treatment, we conclude that administration of taurine may be a potential new therapeutic approach for mitochondria-related retinal diseases.


Serum vitamin B6 in schizophrenic and schizoaffective patients with and without tardive dyskinesia.
There are several reports regarding the efficacy of vitamin B6 in the treatment of tardive dyskinesia (TD). Vitamin B6 plays a key role in the synthesis of several neurotransmitters, including serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid, all of which have been proposed to be involved in the development of TD. The purpose of this study was to examine whether there are special markers to distinguish long-term neuroleptic exposure patients who have TD from those patients who do not develop this side effect. In view of the pivotal role of vitamin B6 in the synthesis of all neurotransmitters believed to take part in the pathogenesis of TD, we decided to examine whether basal levels of vitamin B6 might explain the difference between these two groups. Such a finding could provide a predictive marker for vulnerable patients. The active metabolite of vitamin B6 is pyridoxal phosphate (PP). Pyridoxal phosphate blood levels were measured in 15 schizophrenic and schizoaffective patients with TD and compared with 15 patients without evidence of TD (matched by sex, age, smoking, and diagnosis). We found that, although patients in the TD group were exposed to neuroleptic drugs for significantly longer periods of time, there were no differences in serum PP levels between the groups. The reports of the effectiveness of vitamin B6 supplementation in the treatment of TD could therefore be explained by the assumption that central nervous system or intracellular vitamin B6 levels, which are involved in the pathogenesis of TD, are not the same as vitamin B6 peripheral serum levels. There is need for further studies, which will clarify the relationship between vitamin B6 and TD.


Challenges of the Health System in Preventing Non-Communicable Diseases; Systematized Review.
The basis of prevention of non-communicable diseases is the identification of primary risk factors and the prevention and control of these factors. The purpose is to prevent the spread of the disease and to control it as much as possible. If population growth continues at this rate, by 2030, 52 million people will die from these diseases each year. The aim of this study was to evaluate the challenges of preventing non-communicable diseases. The present study was a systematic review that conducted in July 2020 and the articles related to prevention of non-communicable diseases on databases of web of science, PubMed, Scopus, science direct, Ovid, Pro Quest and Google Scholar. Strategy for searching and selecting the articles was PRISMA Guidelines. Challenges of non-communicable disease prevention, in 4 main codes, including infrastructure, economic, demographic and management and 12 sub-codes that include, lack of preventive infrastructure, restrictions on access to medicine, restrictions on primary health care, restrictions on access to Technology, disease-oriented disease, unsustainable financial resources, failure to implement poverty reduction projects, increase in aging population, migration, rapid and unplanned urban planning, hasty planning and lack of internal and external coordination were classified. To reduce non-communicable diseases, strengthen global capacities, reduce risk factors for NCDs and place social determinants by creating health-promoting environments, strengthen health systems to implement prevention and control of NCDs, and place determinants Social can play an effective role through people-centered primary health care.


Photo-Fenton degradation of ethyl xanthate catalyzed by bentonite-supported Fe(II)/phosphotungstic acid under visible light irradiation.
In this study, using bentonite-supported Fe(II)/phosphotungstic acid composite (HPW-Fe-Organicbent) prepared by mechanochemical synthesis as heterogeneous catalyst, the photo-Fenton degradation of ethyl xanthate under visible light irradiation was studied in detail. The results showed that the degradation of ethyl xanthate was mainly impacted by H2O2 dosage, catalyst dosage and reaction time. HPW-Fe-Organicbent catalyst had a wide applicable range of pH and kept a high catalytic activity even at high pH in the photo-Fenton degradation of ethyl xanthate. It was found that the degradation of ethyl xanthate in the photo-Fenton process catalyzed by HPW-Fe-Organicbent mainly resulted from the hydroxyl radicals. HPW-Fe-Organicbent had an excellent stability in use, and retained almost all of its catalytic activity for four recycling times. Moreover, the kinetics study showed the degradation of ethyl xanthate, with the initial concentration below 50 mg/L, was well fitted by the pseudo-first-order rate model.


A rapid and sensitive, multiplex, whole mount RNA fluorescence in situ hybridization and immunohistochemistry protocol.
In the past few years, there has been an explosion in single-cell transcriptomics datasets, yet in vivo confirmation of these datasets is hampered in plants due to lack of robust validation methods. Likewise, modeling of plant development is hampered by paucity of spatial gene expression data. RNA fluorescence in situ hybridization (FISH) enables investigation of gene expression in the context of tissue type. Despite development of FISH methods for plants, easy and reliable whole mount FISH protocols have not yet been reported. We adapt a 3-day whole mount RNA-FISH method for plant species based on a combination of prior protocols that employs hybridization chain reaction (HCR), which amplifies the probe signal in an antibody-free manner. Our whole mount HCR RNA-FISH method shows expected spatial signals with low background for gene transcripts with known spatial expression patterns in Arabidopsis inflorescences and monocot roots. It allows simultaneous detection of three transcripts in 3D. We also show that HCR RNA-FISH can be combined with endogenous fluorescent protein detection and with our improved immunohistochemistry (IHC) protocol. The whole mount HCR RNA-FISH and IHC methods allow easy investigation of 3D spatial gene expression patterns in entire plant tissues.


NMR investigation of the interaction between the neuronal protein tau and the microtubules.
Whereas the interaction between Tau and the microtubules has been studied in great detail both by macroscopic techniques (cosedimentation, cryo-electron microscopy, and fluorescence spectroscopy) using the full-length protein or by peptide mapping assays, no detailed view at the level of individual amino acids has been presented when using the full-length protein. Here, we present a nuclear magnetic resonance (NMR) study of the interaction between the full-length neuronal protein Tau and paclitaxel-stabilized microtubules (MTs). As signal disappearance in the heteronuclear 1H-15N correlation spectra of isotope-labeled Tau in complex with MTs is due to direct association of the corresponding residue with the solid-like MT wall, we can map directly the fragment in interaction with the MT surface, and obtain a molecular picture of the precise interaction zones. The N-terminal region projects from the microtubule surface, and the lack of chemical shift variations when compared with free Tau proves that this region can regulate microtubular separation without adopting a stable conformation. Amino acids in the four microtubule binding repeats (MTBRs) lose all of their intensity, underscoring their immobilization upon binding to the MTs. The same loss of NMR intensity was observed for the proline-rich region starting at Ser214, underscoring its importance in the Tau:MT interaction. Fluorescence resonance energy transfer (FRET) experiments were used to obtain thermodynamic binding parameters, and led to the conclusion that the NMR defined fragment indeed is the major player in the interaction. When the same Ser214 is phosphorylated by the PKA kinase, the Tau:MT interaction strength decreases by 2 orders of magnitude, but the proline-rich region including the phospho-Ser214 does not gain sufficient mobility in the complex to make it observable by NMR spectroscopy. The presence of an intramolecular disulfide bridge, on the contrary, does lead to a partial detachment of the C-terminus of Tau, and decreases significantly the overloading of Tau on the MT surface.


Eosinophilic fasciitis induced by fire ant bites.
To describe a case of eosinophilic fasciitis likely related to proximate fire ant bites and review the literature to summarize the etiology and clinical, laboratory, histopathological, and therapeutic aspects of eosinophilic fasciitis. Report of a case of eosinophilic fasciitis and review of the English language literature using a Medline search from 1950 to January 2007. We describe the case of a New Orleans woman who developed eosinophilic fasciitis after fire ant bites post-Hurricane Katrina. A careful literature review confirms an association of eosinophilic fasciitis with unaccustomed vigorous exercise, arthropod bites, and borreliosis, among other etiologic agents. Eosinophilic fasciitis, a rare disorder with unclear pathogenic mechanisms, has been associated with arthropod bites and borreliosis. Fire ant bites should be added to the list of etiologic agents for this disorder.


[Juvenile xanthogranuloma: a form of histiocytosis with an excellent prognosis].
In three patients, a girl aged six weeks and two boys aged eight and three months, juvenile xanthogranuloma was diagnosed. This is a rare cutaneous disorder that predominantly occurs during infancy and early childhood. It is one of the non-malignant, non-Langerhans cell histiocytoses (class II histiocytoses). It is characterized by a circumscript, firm, yellow-brown and sometimes pink-red nodule or papule located mainly on the face or scalp. Diagnosis can be made on the clinical appearance. However, this may need to be confirmed by a histopathological investigation, which includes immunohistochemical stains. In contrast to generalized histiocytoses, the prognosis of juvenile xanthogranuloma is excellent: the cutaneous tumour disappears spontaneously in one to six years. However, extracutaneous involvement, which is most frequently located in the eye, can occur. Moreover, juvenile xanthogranuloma is associated with neurofibromatosis type I and juvenile chronic myeloid leukaemia. This rare but possibly life-threatening systemic involvement justifies meticulous follow-up.


Ultrasound in acute internal medicine; time to set a European standard.
Nowadays point-of-care ultrasound (POCUS) is considered indispensable for critical care and emergency physicians. POCUS is a noninvasive tool, can be done at the bedside, leads to instant diagnostic information and is safe in terms of radiation. POCUS could also be very suitable for internists in the field of acute internal medicine. There are differences between European internists in the use of POCUS from no use at all to more outlined educational programs. In literature there are examples of comprehensive POCUS guidelines which could serve as an example for the European Federation of Internal Medicine (EFIM). In this review some aspects of POCUS are highlighted and the authors encourage EFIM to set European standards for this important development.


Regulated membrane protein entry into flagella is facilitated by cytoplasmic microtubules and does not require IFT.
The membrane protein composition of the primary cilium, a key sensory organelle, is dynamically regulated during cilium-generated signaling [1, 2]. During ciliogenesis, ciliary membrane proteins, along with structural and signaling proteins, are carried through the multicomponent, intensely studied ciliary diffusion barrier at the base of the organelle [3-8] by intraflagellar transport (IFT) [9-18]. A favored model is that signaling-triggered accumulation of previously excluded membrane proteins in fully formed cilia [19-21] also requires IFT, but direct evidence is lacking. Here, in studies of regulated entry of a membrane protein into the flagellum of Chlamydomonas, we show that cells use an IFT-independent mechanism to breach the diffusion barrier at the flagellar base. In resting cells, a flagellar signaling component [22], the integral membrane polypeptide SAG1-C65, is uniformly distributed over the plasma membrane and excluded from the flagellar membrane. Flagellar adhesion-induced signaling triggers rapid, striking redistribution of the protein to the apical ends of the cells concomitantly with entry into the flagella. Protein polarization and flagellar enrichment are facilitated by cytoplasmic microtubules. Using a conditional anterograde IFT mutant, we demonstrate that the IFT machinery is not required for regulated SAG1-C65 entry into flagella. Thus, integral membrane proteins can negotiate passage through the ciliary diffusion barrier without the need for a motor.


Mental disorders and the incidence of migraine headaches in a community sample: results from the Baltimore Epidemiologic Catchment area follow-up study.
The cross-sectional relation between migraine headaches and affective disorders has been demonstrated in studies of clinical and community populations. Few studies have investigated the prospective relation between psychiatric disorders and migraine headaches. A prospective follow-up of the Baltimore, Md, cohort of the Epidemiologic Catchment Area Study assessed psychopathologic features in 1981 and again between 1993 and 1996. Interviews included a history of headaches at baseline and self-reported assessment of migraine headaches at follow-up. Risk estimates for incident migraine headaches by 1981 demographic variables and psychopathologic features were calculated. The cross-sectional association between prevalent migraine and lifetime psychiatric diagnoses was estimated. In the at-risk population of 1343, there were 118 incident cases of migraine headaches. The age- and sex-specific incident rates of migraine headaches followed the expected patterns, with younger age and female sex identified as risk factors. In cross-sectional analyses, major depression (odds ratio, 3.14; 95% confidence interval, 2.03-4. 84) and panic disorder (odds ratio, 5.09; 95% confidence interval, 2. 65-9.79) had the strongest associations, and alcohol and other substance abuse were not associated. In logistic regression models including age, sex, and psychiatric illness in 1981, only phobia was predictive of incident migraines (odds ratio, 1.70; 95% confidence interval, 1.11-2.58). Affective disorders were not predictive of incident migraine headaches. Including a history of tricyclic antidepressant use did not change the results. There is a strong cross-sectional relation between affective disorders and migraine headaches in this cohort. However, there is no association between antecedent affective disorders and incident migraine headaches in this population-based prospective study.


Linear growth and neurodevelopmental outcome of children with congenital hypothyroidism detected by neonatal screening: A controlled study.
Different growth and neuro-developmental outcomes have been associated with different doses of thyroxine given to infants with congenital hypothyroidism (CH). We studied the longitudinal growth pattern and assessed the neurodevelopment of 45 children with CH(25 girls, 20 boys) diagnosed through the national screening program in Qatar, for 6 years or more to examine the effects of initial T4 dosage (50 μg/day) with adjustment of T4 dose to maintain serum free T4 concentrations within the upper quartile of normal range and thyroid stimulating hormone < 4 mIU/mLThe birth size of newborns with CH diagnosed through the screening program before January 2003, was recorded and their growth in weight and stature was monitored every 3 months for at least 6 years of life. The IQ of children was assessed between 3 and 6 years of age using The Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Birth weight, length, and head circumference of patients (3.21 ± 0.43 kg, 50.5 ± 3.21 cm and 34.1 ± 1.5 cm, respectively) did not differ than those for 10,560 normal newborns with normal thyroid function (3.19 ± 0.59 kg, 50.5 ± 2.2 cm and 34.2 ± 1.7 cm). During the first year CH children growth (25.8 ± 2.8 cm/year) was similar to those for normal infants (25.5 ± 0.75 cm/year). During the first 6 years, stature growth was normal in all children with CH versus Center for disease control and prevention (CDC) data. The mean height standard deviation score (HtSDS) of children with CH showed adjustment (± 0.5 SD) toward their mid-parental height SDS (MPHtSDS) only during the second year of life. The children's mean HtSDS was higher by an average of 0.4 SD between the 2(nd) and 7(th) year of life. These data proved that effective screening and treatment completely assures normal neurodevelopment and linear growth in patients with CH. The data showed that their HtSDS slightly exceeds their MPHtSDS during childhood.


Fabrication and Characterization of Lignin/Dendrimer Electrospun Blended Fiber Mats.
Blending lignin as the second most abundant polymer in Nature with nanostructured compounds such as dendritic polymers can not only add value to lignin, but also increase its application in various fields. In this study, softwood Kraft lignin/polyamidoamine dendritic polymer (PAMAM) blends were fabricated by the solution electrospinning to produce bead-free nanofiber mats for the first time. The mats were characterized through scanning electron microscopy, Fourier transform infrared (FTIR) spectroscopy, zeta potential, and thermogravimetry analyses. The chemical intermolecular interactions between the lignin functional groups and abundant amino groups in the PAMAM were verified by FTIR and viscosity measurements. These interactions proved to enhance the mechanical and thermal characteristics of the lignin/PAMAM mats, suggesting their potential applications e.g. in membranes, filtration, controlled release drug delivery, among others.


Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway.
The role of receptors for endogenous metabolic danger signals-associated molecular patterns has been characterized recently as bridging innate immune sensory systems for danger signals-associated molecular patterns to initiation of inflammation in bone marrow-derived cells, such as macrophages. However, it remains unknown whether endothelial cells (ECs), the cell type with the largest numbers and the first vessel cell type exposed to circulating danger signals-associated molecular patterns in the blood, can sense hyperlipidemia. This report determined whether caspase-1 plays a role in ECs in sensing hyperlipidemia and promoting EC activation. Using biochemical, immunologic, pathological, and bone marrow transplantation methods together with the generation of new apoplipoprotein E (ApoE)(-/-)/caspase-1(-/-) double knockout mice, we made the following observations: (1) early hyperlipidemia induced caspase-1 activation in ApoE(-/-) mouse aorta; (2) caspase-1(-/-)/ApoE(-/-) mice attenuated early atherosclerosis; (3) caspase-1(-/-)/ApoE(-/-) mice had decreased aortic expression of proinflammatory cytokines and attenuated aortic monocyte recruitment; and (4) caspase-1(-/-)/ApoE(-/-) mice had decreased EC activation, including reduced adhesion molecule expression and cytokine secretion. Mechanistically, oxidized lipids activated caspase-1 and promoted pyroptosis in ECs by a reactive oxygen species mechanism. Caspase-1 inhibition resulted in accumulation of sirtuin 1 in the ApoE(-/-) aorta, and sirtuin 1 inhibited caspase-1 upregulated genes via activator protein-1 pathway. Our results demonstrate for the first time that early hyperlipidemia promotes EC activation before monocyte recruitment via a caspase-1-sirtuin 1-activator protein-1 pathway, which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations.


Synchronization of parallel intense electron beam accelerators based on single trigger generator.
In this study, the authors provide results of the precisely synchronized triggering of an intense electron beam accelerator (IEBA). The trigger generator was composed of a fractional-turn ratio saturable-pulse transformer and a compact six-stage Marx generator. The main switch of the IEBA was a corona-stabilized triggered switch (CSTS) based on the stabilized corona mechanism. The output voltage of a single IEBA exceeded 500 kV with less than 4 ns of jitter on a 50 Ω dummy load. We also conducted an experiment on the synchronous triggering of two IEBAs by using two independent trigger generators. The synchronization-related jitter was 6.1 ns, while the average time difference was 1.3 ns. We used this to attempt to trigger two parallel IEBAs by using a single trigger generator. The results showed a reduction in the synchronization-related jitter of 31% to 4.2 ns. The designs of the CSTS and the trigger generator guaranteed a precisely synchronous trigger by using a single trigger generator. Thus, the proposed method appears to be promising for accurately and synchronously triggering multiple IEBAs by using a single trigger generator. This provides an effective method to generate pulses with high power.


New soluble angiopoietin analog of Hepta-ANG1 prevents pathological vascular leakage.
Vascular leak is a key driver of organ injury in diseases, and strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the angiopoietin-1 (ANG1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANG1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo. Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANG1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein α. We refer to this new fusion protein biologic as Hepta-ANG1, which forms a stable heptamer and induces Tie2 phosphorylation in cultured cells, and in the lung following intravenous injection of mice. Injection of Hepta-ANG1 ameliorates vascular endothelial growth factor- and lipopolysaccharide-induced vascular leakage, in keeping with the known functions of Angpt1-Tie2 in maintaining quiescent vascular stability. The new Hepta-ANG1 fusion is easy to produce and displays remarkable stability with high multimericity that can potently activate Tie2. It could be a new candidate ANG1 mimetic therapy for treatments of inflammatory vascular leak, such as acute respiratory distress syndrome and sepsis.


Close is not enough: SNARE-dependent membrane fusion requires an active mechanism that transduces force to membrane anchors.
Is membrane fusion an essentially passive or an active process? It could be that fusion proteins simply need to pin two bilayers together long enough, and the bilayers could do the rest spontaneously. Or, it could be that the fusion proteins play an active role after pinning two bilayers, exerting force in the bilayer in one or another way to direct the fusion process. To distinguish these alternatives, we replaced one or both of the peptidic membrane anchors of exocytic vesicle (v)- and target membrane (t)-SNAREs (soluble N-ethylmaleimide-sensitive fusion protein [NSF] attachment protein [SNAP] receptor) with covalently attached lipids. Replacing either anchor with a phospholipid prevented fusion of liposomes by the isolated SNAREs, but still allowed assembly of trans-SNARE complexes docking vesicles. This result implies an active mechanism; if fusion occurred passively, simply holding the bilayers together long enough would have been sufficient. Studies using polyisoprenoid anchors ranging from 15-55 carbons and multiple phospholipid-containing anchors reveal distinct requirements for anchors of v- and t-SNAREs to function: v-SNAREs require anchors capable of spanning both leaflets, whereas t-SNAREs do not, so long as the anchor is sufficiently hydrophobic. These data, together with previous results showing fusion is inhibited as the length of the linker connecting the helical bundle-containing rod of the SNARE complex to the anchors is increased (McNew, J.A., T. Weber, D.M. Engelman, T.H. Sollner, and J.E. Rothman, 1999. Mol. Cell. 4:415-421), suggests a model in which one activity of the SNARE complex promoting fusion is to exert force on the anchors by pulling on the linkers. This motion would lead to the simultaneous inward movement of lipids from both bilayers, and in the case of the v-SNARE, from both leaflets.


Self-enhancement and the life script in future thinking across the lifespan.
Studies comparing memory and future event simulation find that future events are more positive, and more often depend on life script events (e.g., culturally normative landmark events) than past events. Previous research does not address the link between this positivity bias and the life stage of college-age participants or their reliance on these scripted events. To examine this positivity bias, narratives of past and anticipated future events were elicited from participants aged 18-74 years, and were examined for reliance on the life script and valence ratings. Results showed that, across age groups, future events were rated as more positive than past events, and that life script events were common in the distant future. Notably, whereas younger adult age groups wrote primarily about their own life script events, older participants more commonly wrote about attending the life script events of significant others, such as children and grandchildren. These findings suggest that simulated future events play a valuable role in self-enhancement across the lifespan. Furthermore, the life script can be viewed as a useful search mechanism when one is missing the episodic details that are more available in memories; however, it is not the source of positivity bias for future events.


Frequency of movement disorders in an Ethiopian university practice.
There is little information on the frequency of movement disorders seen by physicians in the continent of Africa. We performed a medical record review of all patients seen in a university-based neurology clinic in Addis Ababa, Ethiopia, over 1 year to determine the frequency of movement disorders seen, disease characteristics, diagnostic evaluations, and treatment. A total of 15.1% of the neurological patients were seen for movement disorders. Of these, most were for parkinsonism (47.7%), followed by ataxia (16.5%), dystonia (8.3%), essential tremor (8.3%), chorea (7.3%), and miscellaneous (11.9%). Diagnostic evaluations were limited, but treatment was available, although expensive. In spite of the limitations, patients with movement disorders require and seek care in Ethiopia in proportions comparable to developed nations. This finding underlines the need for adequate training in movement disorders for physicians and neurologists in Africa.


GIT proteins, A novel family of phosphatidylinositol 3,4, 5-trisphosphate-stimulated GTPase-activating proteins for ARF6.
ADP-ribosylation factor (ARF) proteins are key players in numerous vesicular trafficking events ranging from the formation and fusion of vesicles in the Golgi apparatus to exocytosis and endocytosis. To complete their GTPase cycle, ARFs require a guanine nucleotide-exchange protein to catalyze replacement of GDP by GTP and a GTPase-activating protein (GAP) to accelerate hydrolysis of bound GTP. Recently numerous guanine nucleotide-exchange proteins and GAP proteins have been identified and partially characterized. Every ARF GAP protein identified to date contains a characteristic zinc finger motif. GIT1 and GIT2, two members of a new family of G protein-coupled receptor kinase-interacting proteins, also contain a putative zinc finger motif and display ARF GAP activity. Truncation of the amino-terminal region containing the zinc finger motif prevented GAP activity of GIT1. One zinc molecule was found associated per molecule of purified recombinant ARF-GAP1, GIT1, and GIT2 proteins, suggesting the zinc finger motifs of ARF GAPs are functional and should play an important role in their GAP activity. Unlike ARF-GAP1, GIT1 and GIT2 stimulate hydrolysis of GTP bound to ARF6. Accordingly we found that the phospholipid dependence of the GAP activity of ARF-GAP1 and GIT proteins was quite different, as the GIT proteins are stimulated by phosphatidylinositol 3,4, 5-trisphosphate whereas ARF-GAP1 is stimulated by phosphatidylinositol 4,5-bisphosphate and diacylglycerol. These results suggest that although the mechanism of GTP hydrolysis is probably very similar in these two families of ARF GAPs, GIT proteins might specifically regulate the activity of ARF6 in cells in coordination with phosphatidylinositol 3-kinase signaling pathways.


Curcumin and its promise as an anticancer drug: An analysis of its anticancer and antifungal effects in cancer and associated complications from invasive fungal infections.
Invasive fungal infections (IFI) are important complications of cancer, and they have become a major cause of morbidity and mortality in cancer patients. Effective anti-infection therapy is necessary to inhibit significant deterioration from these infections. However, they are difficult to treat, and increasing antifungal drug resistance often leads to a relapse. Curcumin, a natural component that is isolated from the rhizome of Curcuma longa plants, has attracted great interest among many scientists studying solid cancers over the last half century. Interestingly, curcumin provides an ideal alternative to current therapies because of its relatively safe profile, even at high doses. To date, curcumin's potent antifungal activity against different strains of Candida, Cryptococcus, Aspergillus, Trichosporon and Paracoccidioides have been reported, indicating that curcumin anticancer drugs may also possess an antifungal role, helping cancer patients to resist IFI complications. The aim of this review is to discuss curcumin's dual pharmacological activities regarding its applications as a natural anticancer and antifungal agent. These dual pharmacological activities are expected to lead to clinical trials and to improve infection survival among cancer patients.


Dr(a) (Cromer-related blood group antigen)-incompatible renal transplantation.
Cromer system antigens, a series of blood group antigens of very high frequency, are not considered to be clinically significant in transfusion. In renal transplantation only the ABO blood group antigens are considered essential. The Drori blood group antigen is present in serum and has been found to reside on the renal tubular basement membrane and Bowman's capsule. The effect of anti-Dra on the renal parenchyma has not been evaluated. A unique case of renal transplantation of an incompatible Dr(a+) kidney to a Dr(a-) patient with anti-Dra in her serum is presented. Graft function was immediately good. The titer of anti-Dra remained unchanged following transplantation. The successful outcome of a case of a Drori (Dra)-incompatible kidney transplantation confirmed the lack of clinical significance of the anti-Dra relating to transplantation.


[Problems of bacterial infections of the sinuses (author's transl)].
Mechanisms of bacterial infections as well as problems of antibiotic therapy are discussed with particular reference to the human sinuses. Infectious diseases lost their importance as a result of modern chemotherapy. Wrong handling or misunderstanding of antibiotic agents, however, may give rise to new important problems in antibiotic therapy as a result of increasing resistance.


Development and Validation of the Metacognitions about Sex Scale: Exploring its Role as a Mediator between Negative Affect, Emotion Dysregulation Strategies, and Compulsive Sexual Behavior Disorder.
Metacognitions about sex are theorized to shape cognitive appraisal, coping mechanisms, and regulation or dysregulation before, during, and/or after exposure to sexual stimuli. In our study, we examined the construct structure and validity of the Metacognitions about Sex Scale (MSS) among a sample of adolescents. We estimated the convergent validity of the MSS by factors: negative affect, dysregulated thoughts, and impulsivity, and compulsive sexual behavior (CSB). We also ran a structural equation model in which we examined the possibility that metacognitions about sex would mediate the association between negative affect, dysregulated thoughts, and impulsivity on the one hand, and CSB on the other. The study population included 662 adolescents (252 boys and 410 girls, M = 16.70, SD = 1.32) between 13-18 years of age. The analyses indicated that the factorial structure of the MSS comprised the two expected factors. We also found that positive and negative metacognitions about sex significantly mediated the effect of negative affect, dysregulated thoughts, and impulsivity on CSB. The findings provide evidence that MSS among Israeli adolescents are psychometrically appropriate for use by researchers and practitioners in the prevention and treatment of CSB.


Functional differences of a Kv2.1 channel and a Kv2.1/Kv1.2S4-chimera are confined to a concerted voltage shift of various gating parameters.
When expressed in Xenopus oocytes, the voltage-dependent K+ channels Kv1.2 and Kv2.1 have similar steady state parameters of activation but the kinetics of activation is significantly faster in the Kv1.2 channels. Activation results from intramolecular arrangements which start with the movement of the voltage sensor and end with the opening of the pore. The S4-segment and the H5-loop comprise at least part of the respective involved structural elements. The molecular mechanism of coupling between sensing of voltage and opening of the pore is less well understood. We have measured whole cell and single channel ionic currents in the rapidly activating Kv1.2 channel of the rat, the slowly activating Kv2.1 channel of the human, and in an S4-chimera Kv2.1/Kv1.2S4. With respect to the Kv2.1 channel, steady state activation and steady state C-type inactivation of the chimeric channel are shifted by more than 50 mV in the depolarizing direction. The property of rapid activation in Kv1.2 channels was not transferred to the Kv2.1 channels with the transplanted S4-region. Instead, the kinetics of activation, deactivation, and recovery from C-type inactivation as well as the voltage sensitivity of the 4-aminopyridine block are similar to the corresponding processes in Kv2.1 channels if they are related to the steady state activation and inactivation, respectively. The unitary current and the mean open time of single channel openings of the S4-chimeric channels resemble the respective values of Kv2.1 channels. It is concluded that the insertion of the S4-segment of Kv1.2 channels into Kv2.1 channels modifies the gating at the early steps of activation leaving all properties associated with the open state(s) of the Kv2.1 channels unaffected.


An algorithm recommendation for the pharmacological management of allergic rhinitis in the UK: a consensus statement from an expert panel.
Allergic rhinitis is a frequent presenting problem in primary care in the UK, and has increased in prevalence over the last 30 years. When symptomatic, patients report significant reduction in their quality of life and impairment in school and work performance. Achieving adequate symptom control is pivotal to successful allergic rhinitis management, and relies mostly on pharmacotherapy. While it is recognised that most mild-moderate allergic rhinitis symptoms can be managed successfully in primary care, important gaps in general practitioner training in relation to allergic rhinitis have been identified. With the availability of new effective combination therapies, such as the novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in a single device (Dymista®; Meda), the majority of allergic rhinitis symptoms can be treated in the primary care setting. The primary objective of this consensus statement is to improve diagnosis and treatment of allergic rhinitis in primary care, and offer guidance on appropriate referral of difficult-to-treat patients into secondary care. The guidance provided herein outlines a sequential treatment pathway for allergic rhinitis in primary care that incorporates a considered approach to improve the management of allergic rhinitis symptoms and improve compliance and patient satisfaction with therapy. Adherence with this care pathway has the potential to limit the cost of providing effective allergic rhinitis management in the UK by avoiding unnecessary treatments and investigations, and avoiding the need for costly referrals to secondary care in the majority of allergic rhinitis cases. The fundamentals presented in this consensus article should apply in most health-care settings.


Modular model for Mercury's magnetospheric magnetic field confined within the average observed magnetopause.
Accurate knowledge of Mercury's magnetospheric magnetic field is required to understand the sources of the planet's internal field. We present the first model of Mercury's magnetospheric magnetic field confined within a magnetopause shape derived from Magnetometer observations by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging spacecraft. The field of internal origin is approximated by a dipole of magnitude 190 nT RM3, where RM is Mercury's radius, offset northward by 479 km along the spin axis. External field sources include currents flowing on the magnetopause boundary and in the cross-tail current sheet. The cross-tail current is described by a disk-shaped current near the planet and a sheet current at larger (≳ 5 RM ) antisunward distances. The tail currents are constrained by minimizing the root-mean-square (RMS) residual between the model and the magnetic field observed within the magnetosphere. The magnetopause current contributions are derived by shielding the field of each module external to the magnetopause by minimizing the RMS normal component of the magnetic field at the magnetopause. The new model yields improvements over the previously developed paraboloid model in regions that are close to the magnetopause and the nightside magnetic equatorial plane. Magnetic field residuals remain that are distributed systematically over large areas and vary monotonically with magnetic activity. Further advances in empirical descriptions of Mercury's magnetospheric external field will need to account for the dependence of the tail and magnetopause currents on magnetic activity and additional sources within the magnetosphere associated with Birkeland currents and plasma distributions near the dayside magnetopause.


Day/night differences in the stimulation of adenylate cyclase activity by calcium/calmodulin in chick pineal cell cultures: evidence for circadian regulation of cyclic AMP.
In chick pineal cell culture, stimulation of adenylate cyclase with the diterpene forskolin was greater during the subjective night than during the subjective day. This rhythm of cyclic AMP (cAMP) stimulation mimicked the rhythm of unstimulated cAMP measured previously during LD cycles from flow-through culture. Direct measurement of adenylate cyclase activity in permeabilized cells revealed an adenylate cyclase activity activated by Ca2+/calmodulin during the night but not during the day. However, this difference in adenylate cyclase activity at two times of the circadian cycle is apparent only when permeabilized cells were prewashed with buffer containing GTE When cAMP was measured from flow-through cultures maintained in continuous darkness to determine whether a circadian clock may regulate cAMP, a low-amplitude rhythm was measured. The circadian rhythm of cAMP was similar to the cAMP rhythm previously measured on LD cycles except that the rhythm in darkness had a lower amplitude. Similar to the suppression of melatonin, cAMP was suppressed by light presented during the middle of the night. LD differences in nocturnal cAMP levels were abolished with dipyridamole, an inhibitor of cyclic GMP (cGMP) phosphodiesterase. These results suggest that the rhythm of cAMP in chick pineal cells involves the stimulation of adenylate cyclase by Ca2+/calmodulin during the night and a GTP-dependent suppression of adenylate cyclase activity during the day. The photic suppression of cAMP at night involves the activation of a dipyridamole-sensitive, cGMP phosphodiesterase.


VEGF receptor-1 modulates amyloid β 1-42 oligomer-induced senescence in brain endothelial cells.
Aggregated amyloid β (Aβ) peptides in the Alzheimer's disease (AD) brain are hypothesized to trigger several downstream pathologies, including cerebrovascular dysfunction. Previous studies have shown that Aβ peptides can have antiangiogenic properties, which may contribute to vascular dysfunction in the early stages of the disease process. We have generated data showing that brain endothelial cells (ECs) exposed to toxic Aβ1-42 oligomers can readily enter a senescence phenotype. To determine the effect of Aβ oligomers on brain ECs, we treated early passaged human brain microvascular ECs and HUVECs with high MW Aβ1-42 oligomers (5 µM, for 72 h). For controls, we used no peptide treatment, 5 µM Aβ1-42 monomers, and 5 µM Aβ1-42 fibrils, respectively. Brain ECs treated with Aβ1-42 oligomers showed increased senescence-associated β-galactosidase staining and increased senescence-associated p21/p53 expression. Treatment with either Aβ1-42 monomer or Aβ1-42 fibrils did not induce senescence in this assay. We then measured vascular endothelial growth factor receptor (VEGFR) expression in the Aβ1-42 oligomer-treated ECs, and these cells showed significantly increased VEGFR-1 expression and decreased VEGFR-2 levels. Overexpression of VEGFR-1 in brain ECs readily induced senescence, suggesting a direct role of VEGFR-1 signaling events in this paradigm. More importantly, small interfering RNA-mediated knockdown of VEGFR-1 expression in brain ECs was able to prevent up-regulation of p21 protein expression and significantly reduced induction of senescence following Aβ1-42 oligomer treatment. Our studies show that exposure to Aβ1-42 oligomers may impair vascular functions by altering VEGFR-1 expression and causing ECs to enter a senescent phenotype. Altered VEGFR expression has been documented in brains of AD patients and suggests that this pathway may play a role in AD disease pathogenesis. These studies suggest that modulating VEGFR-1 expression and signaling events could potentially prevent senescence and rejuvenate EC functions, and provides us with a novel target to pursue for prevention and treatment of cerebrovascular dysfunction in AD.-Angom, R. S., Wang, Y., Wang, E., Pal, K., Bhattacharya, S., Watzlawik, J. O., Rosenberry, T. L., Das, P., Mukhopadhyay, D. VEGF receptor-1 modulates amyloid β 1-42 oligomer-induced senescence in brain endothelial cells.


Different peptic ulcer bleeding risk in chronic kidney disease and end-stage renal disease patients receiving different dialysis.
End stage renal disease (ESRD) patients receiving hemodialysis (HD) have a higher risk of peptic ulcer bleeding (PUB). Whether ESRD patients receiving peritoneal dialysis (PD) also carries a higher risk of PUB has not been studied. This was a cohort study using Taiwan's National Health Insurance research database, whereby 11,408 patients, including 2,239 PD, 2,328 HD, 2,267 chronic kidney disease (CKD) and 4,574 controls with age-sex matching were recruited. The log-rank test was used to analyze differences in accumulated PUB-free survival rates between groups. Cox proportional hazard regression was performed to evaluate independent risk factors for PUB in all the enrollees. During the 7-year follow-up, PD and CKD patients had a significantly higher rate of PUB than matched controls. The risk of PUB between PD and CKD was not significantly different. Moreover, patients receiving HD carried a higher risk of PUB than those receiving PD, with CKD and controls (p all <0.05, by log-rank test). Cox proportional hazard regression analysis showed that CKD (HR 3.99, 95 % CI 2.24-7.13), PD (HR 3.71, 95 % CI 2.00-6.87) and HD (HR 11.96, 95 % CI 7.04-20.31) were independently associated with an increased risk of PUB. Being elderly, male, having hypertension, diabetes, cirrhosis, and nonsteroidal anti-inflammatory drugs and steroid use were other independent risk factors of PUB in all enrollees. Patients with CKD and ESRD receiving PD or HD carried a higher risk for PUB. They should be screened for risk factors for PUB and receive some protective measures to prevent PUB.


Posterior fossa decompression and duraplasty with and without tonsillar resection for the treatment of adult Chiari malformation type I and syringomyelia.
The current surgical management of adult Chiari malformation type I (CM-I) with associated syringomyelia remains controversial. The objective of this study was to explore posterior fossa decompression and duraplasty (PFDD) with and without tonsillar resection in adult patients with CM-I and syringomyelia. A total of 116 adult patients suffering from both CM-I and syringomyelia who were scheduled to undergo surgical decompression at our institution between 2012 and 2020 were randomly divided into 2 groups: the PFDD group (n = 64) underwent PFDD without tonsillar resection, while the PFDD-T group (n = 52) underwent PFDD with tonsillar resection. The primary outcome was improvement or resolution of the syrinx. The secondary outcome was an improvement in clinical outcome based on Chicago Chiari Outcome Scale (CCOS) scores. All participants were followed-up to 1-year postoperatively. The proportions of patients who had >20% improvement in syrinx size were 60.9% and 78.8% in the PFDD and PFDD-T groups, respectively (P = .038). The improvement in clinical outcome based on CCOS scores was significantly different in the 2 groups (P = .004). The functionality sub-score was significantly different between the 2 groups (P = .027), but there were no significant differences in the pain symptoms, non-pain symptoms, and complications sub-scores. The total CCOS scores were higher in the PFDD-T group than in the PFDD group (P = .037). This study determined the role of tonsillar resection in achieving obvious syrinx improvement following PFDD-T. PFDD with tonsillar resection seems to be a safe and effective surgical option to treat adult CM-I patients with syringomyelia.


Dynamic examination of the lumbar spine by using vertical, open magnetic resonance imaging.
The aim of this study was to determine the relationship of different structures of the lower lumbar spine during interventional movement examination. Clinically healthy volunteers and patients suffering from degenerative disorders of the lumbar spine underwent vertical, open magnetic resonance (MR) imaging (0.5 tesla). Three functional patterns of lumbar spine motion were identified in 50 healthy volunteers (average age 25 years). The authors identified characteristic angles of the facet joints, as measured in the frontal plane. In 50 patients with degenerative disorders of the lumbar spine (41 with disc herniation, five with osteogenic spinal stenosis, and four with degenerative spondylolisthesis) the range of rotation was increased in the relevant spinal segments. Signs of neural compression were increased under motion. Dynamic examination in which vertical, open MR imaging is used demonstrated that the extent of neural compression as well as the increasing range of rotation are important signs of segmental instability.


Management of adult Jehovah's Witness patients with acute bleeding.
Because of the firm refusal of transfusion of blood and blood components by Jehovah's Witnesses, the management of Jehovah's Witness patients with severe bleeding is often complicated by medical, ethical, and legal concerns. Because of a rapidly growing and worldwide membership, physicians working in hospitals should be prepared to manage these patients. Appropriate management of a Jehovah's Witness patient with severe bleeding entails understanding of the legal and ethical issues involved, and meticulous medical management, including treatment of hypovolemic shock, local hemostatic interventions, and administration of prohemostatic agents, when appropriate. In addition, high-dose recombinant erythropoietin in combination with supplemental iron may enhance the speed of hemoglobin synthesis.


Campylobacter enteritis: a large outbreak traced to commercial raw milk.
From April 24 to May 11, 1981, an outbreak of approximately 200 cases of Campylobacter jejuni enteritis occurred in Arizona in persons who drank one brand of unpasteurized milk. Two cohort studies showed that households with members who drank raw milk reported diarrheal illness significantly more frequently than those in which no one drank raw milk (P=.003 and P=.001; relative risk 4.70 and 3.85, respectively). Of 19 serotyped C jejuni organisms isolated from persons who drank raw milk from the implicated dairy, 18 were of a single serotype.C jejuni was not detected in the milk or the milk filters cultured a week after the outbreak, but fecal excretion of Campylobacter of multiple serotypes was higher in the dairy herd that produced the implicated raw milk (48 percent) than in control herds (16 percent).


[Changes in the functional characteristics of the compound eye of the honeybee after mutations interfering with the metabolism of tryptophan].
The compound eye of worker honeybees with a genetic interruption of the ommochrome synthesis from tryptophan (mutations snow an laranja) showed a sharp increase in light sensitivity, more than 100-fold in snow and more than 10-fold in laranja with respect to the wild bee eye. Peaks of the spectral sensitivity curves recorded using ERG were shifted to 530 nm in snow and 550 nm in laranja while in the wild type it was at 545 nm. An unusual shape of the ERG in the both mutants was shown to result from an additional component of the receptor potential, the spike, which has been never observed in the normal bee eye. Since the pigment granules of ommatidium in both snow and laranja were strongly defective or immature due to blocking a normal process of ommochrome formation, It is suggested that the ommochrome granules, apart of their light protective functions, can be involved in biochemical process underlying the electrical passivity of the photoreceptor membrane.


International normalized ratio in anticoagulant therapy: understanding the issues.
Recently, a change in anticoagulation therapy occurred that is still partially ignored by the healthcare community. Understanding the controversy over the use of the internal normalized ratio in monitoring patients receiving warfarin therapy is important for nurses who provide care to these patients. Five questions related to current monitoring of patients treated with anticoagulants are addressed. Nurses must recognize the importance to their practice of changes in laboratory methods and move toward using the most useful measures available to influence patients' outcomes. The international normalized ratio is the most appropriate way to evaluate the effects of warfarin therapy. All healthcare providers should use this ratio as the standard in evaluating the effects of anticoagulation therapy.


Management of metabolic syndrome and associated cardiovascular risk factors.
Patients with metabolic syndrome have a 1.5- to 3-fold increase in the risk of coronary heart disease and stroke. The association between metabolic syndrome and cardiovascular diseases raises important questions about the underlying pathological processes, especially for designing targeted therapeutic interventions. Cardiovascular risk reduction in individuals with metabolic syndrome should include at least three levels of interventions: 1) control of obesity, unhealthy diet and lack of physical activity; 2) control of the individual components of metabolic syndrome, especially atherogenic dyslipidaemia, hypertension, dysglycaemia and prothrombotic state; and 3) control of insulin resistance, a defect closely linked to metabolic syndrome. Metabolic syndrome generally precedes and is often associated with type 2 diabetes. Because of this intimate relationship, appropriate management of metabolic syndrome should be able to prevent the progression from impaired glucose tolerance to frank diabetes and thus to prevent type 2 diabetes, another important cardiovascular risk factor. The importance of prevention of diabetes in high-risk individuals (such as people with metabolic syndrome are) is highlighted by the substantial and worldwide increase in the prevalence of type 2 diabetes in recent years. Owing to the complex pathophysiology and phenotypic expression of metabolic syndrome, lifestyle changes are crucial as they are able to positively and simultaneously influence almost all components of the syndrome. If such measures are not sufficient or not adequately followed, a pharmacological intervention may be considered. However, no official guidelines are available yet concerning the pharmacological management of individuals with metabolic syndrome.


Outcomes in multifocal neuroblastoma as part of the neurocristopathy syndrome.
The neurocristopathy syndrome occurs because of a germline mutation of the paired-like homeobox 2b (PHOX2B) gene at 4p12, a neurogenesis regulator gene. The result is abnormal neural crest cell development resulting in congenital central hypoventilation syndrome, Hirschsprung disease, and neuroblastoma (NB), which is often multifocal and disseminated in its presentation. Previously, such widespread disease was regarded as highly aggressive and treated either with palliative intent or, conversely, with very intense, high-dose chemotherapy. We now present a patient who had neurocristopathy syndrome who had multifocal NB associated with an underlying germline PHOX2B mutation. He was treated conservatively with surgery and low-dose chemotherapy. After treatment he had extensive residual disease that has continued to mature despite no further treatment. A literature review identified 26 similar patients presenting with multifocal NB as part of the neurocristopathy syndrome. In all cases the NB behaved in an indolent manner with no deaths from tumor reported when patients received appropriate treatment. These provocative findings suggest for the first time that children who have neurocristopathy-associated NB should be treated conservatively, despite the aggressive appearance of their disease.


Note: Making tens of centimeter long uniform microfluidic channels using commercial glass pipette.
Producing microchannels with diameters between 10 and 20 μm and with lengths in the tens of centimeters is reported. The method can be modified to obtain diameters as narrow as 350 nm. Length-to-diameter aspect ratios that surpass 104 can be produced for a fraction of current production costs. The controllable channel is produced by applying a flame to the narrow end of a commercial pipette that is made from a soda-lime silicate. In combination with a pulling mechanism, applying heat to the composite material lengthens the pipette in a highly uniform way. Given that the materials and methods in this research are cost-effective when compared to femtosecond laser micromachining on 2D silicon-based surfaces, further research into producing microchannels from soda-lime silicates may revolutionize access to 3D controllable microchannels.


Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birthweight infants.
To compare the efficacy of hydrocortisone with dopamine for the treatment of hypotensive, very low birthweight (VLBW) infants. Forty infants were randomly allocated to receive either hydrocortisone (n = 21) or dopamine (n = 19). All 19 infants randomised to dopamine responded; 17 of 21 (81%) did so in the hydrocortisone group. Three of the four non-responders in the hydrocortisone group had clinically significant left to right ductal shunting. The incidence of bronchopulmonary dysplasia, retinopathy of prematurity, intraventricular haemorrhage, necrotising enterocolitis, symptomatic patent ductus arteriosus, hyperglycaemia, sepsis (bacterial or fungal) or survival did not differ between groups. The adrenocorticotrophic hormone (ACTH) stimulated plasma cortisol activity, either before or after treatment, did not differ between the two groups of infants. Although a significant difference in efficacy between dopamine and hydrocortisone was not noted (P = 0.108), there were four treatment failures in the hydrocortisone group, compared with none in the dopamine group. Both hydrocortisone and dopamine are effective treatments for hypotension in very low birthweight infants.


PRMT3 is a distinct member of the protein arginine N-methyltransferase family. Conferral of substrate specificity by a zinc-finger domain.
S-Adenosyl-l-methionine-dependent protein arginine N-methyltransferases (PRMTs) catalyze the methylation of arginine residues within a variety of proteins. At least four distinct mammalian family members have now been described, including PRMT1, PRMT3, CARM1/PRMT4, and JBP1/PRMT5. To more fully define the physiological role of PRMT3, we characterized its unique putative zinc-finger domain and how it can affect its enzymatic activity. Here we show that PRMT3 does contain a single zinc-finger domain in its amino terminus. Although the zinc-liganded form of this domain is not required for methylation of an artificial substrate such as the glutathione S-transferase-fibrillarin amino-terminal fusion protein (GST-GAR), it is required for the enzyme to recognize RNA-associated substrates in RAT1 cell extracts. The recombinant form of PRMT3 is inhibited by high concentrations of ZnCl(2) as well as N-ethylmaleimide, reagents that can modify cysteine sulfhydryl groups. We found that we could distinguish PRMT family members by their sensitivity to these reagents; JBP1/PRMT5 and Hsl7 methyltransferases were inhibited in a similar manner as PRMT3, whereas Rmt1, PRMT1, and CARM1/PRMT4 were not affected. We were also able to define differences in these enzymes by their sensitivity to inhibition by Tris and free arginine. Finally, we found that the treatment of RAT1 cell extracts with N-ethylmaleimide leads to a loss of the major PRMT1-associated activity that was immune to inhibition under the same conditions as a GST fusion protein. These results suggest that native forms of PRMTs can have different properties than their GST-catalytic chain fusion protein counterparts, which may lack associated noncatalytic subunits.


Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study.
Evaluate efficacy and safety of the histamine-H1 antagonist doxepin at doses of 1 mg, 3 mg, and 6 mg in elderly adults with primary insomnia. A randomized, double-blind, placebo-controlled, crossover design was used in this population of elderly adults with primary insomnia (DSM-IV). Each treatment period consisted of 2 polysomnographic (PSG) assessment nights with a 5- or 12-day drug-free interval between periods. The study was conducted from September 2004 to January 2005. Sleep laboratories in 11 sleep centers in the United States. Elderly adults with primary insomnia. Doxepin 1 mg, 3 mg, and 6 mg. Efficacy was assessed using PSG and patient-reported measures. Seventy-six patients were randomly assigned. All 3 doxepin doses produced dose-related significant improvements in PSG-determined wake time during sleep (p < .0001), wake time after sleep onset (p < .0001), total sleep time (p < .0001), and overall sleep efficiency (p < .0001) versus placebo. At the 3-mg and 6-mg doses, sleep efficiency was significantly improved during all thirds of the night (p < .05). There was a dose-related decrease in patient-reported sleep latency, with the 6-mg dose achieving statistical significance in latency to sleep onset (p = .0181). The pattern of the remaining subjective efficacy results was consistent with PSG. All 3 doxepin doses had side effect profiles comparable to placebo, with no spontaneously reported anticholinergic effects, no memory impairment, and no significant next-day residual effects. In this 2-night study of elderly adults with primary insomnia, doxepin doses of 1 mg, 3 mg, and 6 mg were well tolerated and produced significant improvement in objective and subjective sleep maintenance and duration endpoints that persisted into the final hour of the night. Positive effects on patient-reported sleep onset were observed at the highest dose. All 3 doxepin doses had a safety profile comparable to placebo. These data demonstrate that doxepin was efficacious in improving sleep in elderly adults.


Effect of Lidocaine on Olfactory Perception in Humans.
The effect of local anesthesia to the nasal mucosa on olfactory acuity is the subject of some debate. This study was aimed to investigate the effect of local anesthesia on olfactory perception. Six healthy participants, five males and one female, were chosen from the academic population of Cardiff University. Olfactory perception was monitored at intervals following administration of 4% lidocaine to the nasal mucosa in the volunteers. Lidocaine was administered using a nasal spray as used in routine otolaryngological investigations. The olfactory stimulus (amyl acetate) was delivered directly to the nostril using an olfactometer. Olfactory perception was determined by the use of a 13 trial, forced choice scoring task. Lidocaine caused a small, transient reduction in olfactory perception. The maximum reduction in olfactory perception (35%) was achieved by 60 mg lidocaine 15 min following administration, but perception could be increased to almost normal levels by increasing the odor stimulus dose. Detection of the lowest stimulus strength returned to normal levels after 30 min. Intranasal application of lidocaine, caused a reduction in olfactory perception, however, did not abolish the olfactory function 15 min following administration. Physiological/psychometric olfactory testing would not be precluded under these circumstances, and the effects of anesthesia could be overcome by increasing the stimulus strength.


The deleterious role of the prostaglandin E2 EP3 receptor in angiotensin II hypertension.
Angiotensin II (ANG II) plays a key role in regulating blood pressure and inflammation. Prostaglandin E2 (PGE2) signals through four different G protein-coupled receptors, eliciting a variety of effects. We reported that activation of the EP3 receptor reduces cardiac contractility. More recently, we have shown that overexpression of the EP4 receptor is protective in a mouse myocardial infarction model. We hypothesize in this study that the relative abundance of EP3 and EP4 receptors is a major determinant of end-organ damage in the diseased heart. Thus EP3 is detrimental to cardiac function and promotes inflammation, whereas antagonism of the EP3 receptor is protective in an ANG II hypertension (HTN) model. To test our hypothesis, male 10- to 12-wk-old C57BL/6 mice were anesthetized with isoflurane and osmotic minipumps containing ANG II were implanted subcutaneously for 2 wk. We found that antagonism of the EP3 receptor using L798,106 significantly attenuated the increase in blood pressure with ANG II infusion. Moreover, antagonism of the EP3 receptor prevented a decline in cardiac function after ANG II treatment. We also found that 10- to 12-wk-old EP3-transgenic mice, which overexpress EP3 in the cardiomyocytes, have worsened cardiac function. In conclusion, activation or overexpression of EP3 exacerbates end-organ damage in ANG II HTN. In contrast, antagonism of the EP3 receptor is beneficial and reduces cardiac dysfunction, inflammation, and HTN.NEW & NOTEWORTHY This study is the first to show that systemic treatment with an EP3 receptor antagonist (L798,106) attenuates the angiotensin II-induced increase in blood pressure in mice. The results from this project could complement existing hypertension therapies by combining blockade of the EP3 receptor with antihypertensive drugs.


Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?
The increasing knowledge of the genomic landscape of hepatocellular carcinoma (HCC) and the development of molecular targeted therapies are a promising background for increasing the number of effective drugs for HCC patients. In recent years, many new drugs have been tested as an alternative to sorafenib or after sorafenib failure. In this review, our aim is to describe the randomized trials recently conducted in HCC patients, in order to understand the main reasons potentially related to the failures of many drugs. In addition, we briefly describe the main ongoing trials, that could potentially change the scenario of HCC treatment in the next years. Expert commentary: Heterogeneity of study populations, lack of understanding of critical drivers of tumor progression, risk of liver toxicity associated with experimental agents, flaws in trial design and marginal antitumoral potency can be considered the main reasons for failure of phase III clinical trials in HCC. Most ongoing trials are conducted without any molecular selection criteria, although many drugs could be probably better tested in a molecularly selected population. The knowledge of potential predictive factors for drug efficacy in patients with advanced HCC could improve the chance of obtaining positive results in clinical trials.


[Cushing syndrome and pregnancy].
Pregnancies in cases of Cushing syndrome are rare. When conception occurs the complication rate is high especially from hypertension and superimposed toxemia. Abortions, premature deliveries, and stillbirth occur more often. In the case described an adenoma of the adrenal gland was diagnosed early in pregnancy. Frequent prenatal care and treatment of the hypertension resulted in a pregnancy of 34 weeks gestation. At this time low HPL and estriol values and variable decelerations forced a Cesarean section. The premature infant was discharged in good condition after several weeks of cortico-steroid substitution. In the mother a well defined adrenal cortical tumour at right was found post-partum. The operative specimen showed an adenomatous nodular adrenal cortical hyperplasia. The described case shows that frequent prenatal care and early hospitalization permit an expectant treatment of pregnancy in cases of Cushing-Syndrome.


[Phototherapy in full-term neonates].
In view of the indistinctiveness of the use of phototherapy in jaundiced term newborn infants a study is reported. The study is a longitudinal one (1966-1984). The number of infants is given in the time period before the use of phototherapy, during phototherapy as well as during the period of less frequent use of phototherapy. It appears that the use of phototherapy did not influence the number of exchanged infants. It is concluded that in the term newborn infants phototherapy is frequently used unnecessary.


In vitro molecular genetics as a tool for determining the differential cleavage specificities of the poliovirus 3C proteinase.
We describe a completely in vitro system for generating defined poliovirus proteinase mutations and subsequently assaying the phenotypic expression of such mutations. A complete cDNA copy of the entire poliovirus genome has been inserted into a bacteriophage T7 transcription vector. We have introduced proteinase and/or cleavage site mutations into this cDNA. Mutant RNA is transcribed from the altered cDNA template and is subsequently translated in vitro. Employing such a system, we provide direct evidence for the bimolecular cleavage events carried out by the 3C proteinase. We show that specific genetically-altered precursor polypeptides containing authentic Q-G cleavage sites will not act as substrates for 3C either in cis or in trans. We also provide evidence that almost the entire P3 region is required to generate 3C proteinase activity capable of cleaving the P1 precursor to capsid proteins. However, only the 3C portion of P3 is required to generate 3C proteinase activity capable of cleaving P2 and its processing products.


Characterization of the expression pattern of p63 alpha and delta Np63 alpha in benign and malignant oral epithelial lesions.
The p53 homologue p63 is essential for ectodermal differentiation, such that p63-/- mice lack all squamous epithelia and teeth. The p63 gene expresses at least 6 different transcripts, but information regarding the expression, regulation and function of the different isoforms has remained sparse, due to the lack of adequate reagents directed specifically against the individual proteins. Here we characterize the expression of p63 alpha/delta Np63 alpha in benign and malignant lesions of the oral epithelium, using a specific antibody raised against a peptide derived from the C-terminus of p63 alpha, which does not cross-react with p53 or the other p53 homologue, p73. By immunohistochemical analysis, we show that these p63 isoforms are expressed in the nucleus of many cells. In normal and benign lesions, p63 alpha/delta Np63 alpha-expressing cells are mainly found suprabasally, whereas p53-expressing cells are restricted to the basal-cell layer. By RT-PCR, we show that delta Np63 alpha is the predominant isoform in cell lines from squamous-cell carcinomas of the head and neck, confirming our immunochemical observations. Our data are consistent with studies suggesting a role for p63 in the transit-amplifying population of epidermal cells. Over-expression of p63 alpha, and in particular the delta N form, was frequently seen in carcinomas. Taken together with previous analyses of p63 expression, our data suggest distinct roles for different p63 isoforms in the regulation of growth and/or differentiation of epithelial cells. Moreover, our data are compatible with the notion that p63 can act to promote neoplastic growth in the oral epithelium.


Eumycetoma caused by Cladophialophora bantiana in the United States.
A female presented in the sixth decade of life with a history of undifferentiated small cell carcinoma of the right breast in clinical remission, status-post chemotherapy and resection 6 years previously, presented with a chronic anterior knee skin nodule that grew in size over the prior 5-6 weeks. She had no history of opportunistic infections or recent immunosuppression. As it grew, the nodule became tender to touch. Examination revealed a 4-6 mm superficial purple-red nodule. Also, a similar lesion was present on the dorsum of her left foot for the past year, which also recently grew and became tender. The patient did report frequently kneeling on soil when gardening in Florida. She reported no other symptoms. Due to a concern for cutaneous metastasis of the patient's previously diagnosed small cell carcinoma of the breast, the anterior knee lesion was biopsied. Histology revealed histocyte-rich inflammation with foci of acute inflammation as well as pigmented fungal forms. Subsequent fungal culture of excised tissue grew Cladophialophora bantiana, identified by ribosomal gene DNA sequencing.


Kinetically forbidden transformations of water molecular assemblies in hydrophobic micropores.
Water adsorption hysteresis is one of the most important phenomena observed during the interaction of water with hydrophobic surfaces. Adsorption hysteresis in micropores has strong relevance to the structure of adsorbed water. We used three typical models (cluster, monolayer, and uniform distribution structure models) to determine the structure of the water molecules adsorbed in hydrophobic slit-shaped carbon micropores. In each model, stabilization energy profiles were calculated for various fractional fillings by using the interaction potential theory. Simultaneously, molecular dynamics (MD) simulations of water adsorbed in the micropore of 1.1 nm pore width, which shows significant adsorption hysteresis, were performed to determine the kinetics of the observed structural transformations. The transformations between monolayer and cluster were slow, that is, kinetically forbidden at the fractional filling of 0.2 and 0.6, whereas the cluster-uniform distribution structure and uniform distribution structure-monolayer transformations were kinetically allowed. The kinetically forbidden transformation resulted in the occurrence of metastable structure of adsorbed water and was responsible for the observed adsorption hysteresis.


Verbal suppression and strategy use: a role for the right lateral prefrontal cortex?
Verbal initiation, suppression and strategy generation/use are cognitive processes widely held to be supported by the frontal cortex. The Hayling Test was designed to tap these cognitive processes within the same sentence completion task. There are few studies specifically investigating the neural correlates of the Hayling Test but it has been primarily used to detect frontal lobe damage. This study investigates the components of the Hayling Test in a large sample of patients with unselected focal frontal (n = 60) and posterior (n = 30) lesions. Patients and controls (n = 40) matched for education, age and sex were administered the Hayling Test as well as background cognitive tests. The standard Hayling Test clinical measures (initiation response time, suppression response time, suppression errors and overall score), composite errors scores and strategy-based responses were calculated. Lesions were analysed by classical frontal/posterior subdivisions as well as a finer-grained frontal localization method and a specific contrast method that is somewhat analogous to voxel-based lesion mapping methods. Thus, patients with right lateral, left lateral and superior medial lesions were compared to controls and patients with right lateral lesions were compared to all other patients. The results show that all four standard Hayling Test clinical measures are sensitive to frontal lobe damage although only the suppression error and overall scores were specific to the frontal region. Although all frontal patients produced blatant suppression errors, a specific right lateral frontal effect was revealed for producing errors that were subtly wrong. In addition, frontal patients overall produced fewer correct responses indicative of developing an appropriate strategy but only the right lateral group showed a significant deficit. This problem in strategy attainment and implementation could explain, at least in part, the suppression error impairment. Contrary to previous studies there was no specific frontal effect for verbal initiation. Overall, our results support a role for the right lateral frontal region in verbal suppression and, for the first time, in strategy generation/use.