Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to Hydroxychloroquine.
We present a case of a syncopal episode resulting from significant QT interval prolongation in a patient on hydroxychloroquine for the treatment of systemic lupus erythematosus and end stage renal disease. The patient had been treated with hydroxychloroquine for two years prior to presentation. After thorough workup for secondary causes of QT interval prolongation hydroxychloroquine was discontinued and the patient's QT interval shortened. The patient was treated with mexiletine to prevent sudden ventricular arrhythmias, which was unique compared to other documented cases in which lidocaine was used. The patient was noted to have mild prolongation of the QT interval on electrocardiogram prior to initiation of hydroxychloroquine therapy which was exacerbated by its use and may have been caused due to toxicity from underlying renal failure.


[Daily medical device surveillance].
In France the manufacturer, the user of a medical device and all those informed of an event or a risk for an event caused by the device and resulting in death or the deterioration of the health status of a patient must declare the event without delay to the appropriate administrative authority. The witness of the event informs either the local correspondent for materiovigilance, when available, or the ministry directly. A major objective of the local correspondent is to act as a filter and to select among the declarations of events those to be transmitted without delay or quarterly to the ministry, and those to be registered only locally. Within 48 hours the ministry: a) returns an acknowledgement with instructions how to proceed with the involved device; b) communicates the declaration to the chairman of the ad hoc subcommission; c) informs the manufacturer of the device. The chairman decides on the degree severity (major event requiring an immediate investigation, event requiring an investigation, event to be entered in a follow-up programme). In the first two cases an investigation is undertaken by one or several members of the subcommission in co-operation with the manufacturer and the declarant of the event. Conservative measures can be undertaken to prevent the re-occurrence of an event either with the involved and/or with similar devices and to facilitate the investigation.


Kinetic analysis of arsenic-metalation of human metallothionein: significance of the two-domain structure.
Metallothionein (MT) is ubiquitous in Nature, underlying MT's importance in the cellular chemistry of metals. Mammalian MT consists of two metal-binding domains while microorganisms like cyanobacteria consist of a single metal-binding domain MT. The evolution of a two-domain protein has been speculated on for some time; however, no conclusive evidence explaining the evolutionary necessity of the two-domain structure has been reported. The results presented in this report provide the complete kinetic analysis and subsequent mechanism of the As(3+)-metalation of the two-domain beta alpha hMT and the isolated single domain fragments using time- and temperature-resolved electrospray ionization mass spectrometry. The mechanism for beta alpha hMT binding As(3+) is noncooperative and involves six sequential bimolecular reactions in which the alpha domain binds As(3+) first followed by the beta domain. At room temperature (295 K) and pH 3.5, the sequential individual rate constants, k(n) (n = 1-6) for the As(3+)-metalation of beta alpha hMT starting at k(1beta alpha) are 25, 24, 19, 14, 8.7, and 3.7 M(-1)s(-1). The six rate constants follow an almost linear trend directly dependent on the number of unoccupied sites for the incoming metal. Analysis of the temperature-dependent kinetic electrospray ionization mass spectra data allowed determination of the activation energy for the formation of As(1)-H(17)-beta alpha hMT (14 kJ mol(-1)) and As(2-6)-beta alpha hMT (22 kJ mol(-1)). On the basis of the increased rate of metalation for the two-domain protein when compared with the isolated single-domain, we propose that there is an evolutionary advantage for the two-domain MT structures in higher organism, which allows MT to bind metals faster and, therefore, be a more efficient metal scavenger.


Diabetes mellitus, smoking, and the risk for asymptomatic peripheral arterial disease: whom should we screen?
To describe coexisting medical conditions and lifestyle factors associated with asymptomatic peripheral arterial disease (PAD) in a population of white, African American, and Hispanic patients. White, African American, and Hispanic patients 50 years or older were recruited for this cross-sectional study from 4 primary care clinics in Houston, TX. Patients with an ankle-brachial index (ABI) < 0.9 and without leg symptoms typical of PAD were diagnosed with asymptomatic PAD. 403 patients were screened for PAD. Of these, 25 (6.2%) had asymptomatic PAD. Compared with patients without PAD, diabetes mellitus ([OR] 3.8; 95% CI 1.6, 9.0) and a history of smoking at least 1 pack of cigarettes per day ([OR] 2.5; 95% CI 1.1, 6.0) were significantly associated with asymptomatic PAD. An interaction effect existed between diabetes mellitus and smoking at least 1 pack of cigarettes per day. Diabetes mellitus combined with heavy smoking showed the highest predicted value positive (15%) and the highest specificity (92%). A lack of both demonstrated low rates for predicting asymptomatic PAD (predicted value positive, 1%). The ankle-brachial index could become routine screening among patients with diabetes mellitus and/or who smoke.


Older people's connectedness with people in the community in contemporary contexts: A concept analysis.
This study aimed to clarify the concept of older people's connectedness with people in the community within the literature. This study was based on Walker and Avant's concept analysis method. We used PubMed, MEDLINE, CINAHL, and Web of Science databases and included peer-reviewed articles that were published in English between January 2010 and April 2023. After assessing eligibility and applying exclusion criteria, 25 articles were analyzed. Attributes included sense of belonging to the community achieved through interactions and feeling of togetherness through interrelationships, which consequently led to the maintenance of healthy physical and mental states and independent living, the acquisition of the ability to overcome difficulties, and the creation of a sense of meaning in life through coexistence. We identified the concept of older people's connectedness with people in the community in a contemporary context. Connectedness is a useful concept to consider in nursing care because it seems to evolve into comprehensive health, including the physical and psychosocial health of older adults.


Esophageal cancer phospholipid characterization by 31P NMR.
Phospholipid extracts of surgical tissue specimens from 18 patients, consisting of normal esophagus, distal esophageal tumor and normal stomach, were analyzed using 31P NMR. The prominent phospholipids detected in these tissues included cardiolipin (CL), phosphatidylethanolamine plasmalogen, phosphatidylethanolamine (PE), phosphatidylserine (PS), sphingomyelin (SPH), phosphatidylinositol (PI), phosphatidylcholine plasmalogen and phosphatidylcholine (PC). Very small quantities of the phospholipids lysophosphatidylcholine, phosphatidic acid, phosphatidylglycerol, and an uncharacterized phospholipid at -0.13 delta also were detected in some of the 54 tissue specimens analyzed. The mean relative concentrations of these phospholipids, in mole percentages of total detected phosphorus, were determined from the acquired spectra and used to differentiate among the three tissue groups. The relative concentrations of the following phospholipids differed significantly (p < 0.001) among the respective tissue groups: normal esophagus vs esophageal tumor, PS, SPH, PI, PC; normal esophagus vs normal stomach, CL, PE, PS, SPH; esophageal tumor vs normal stomach, CL, PE. Membrane phospholipids implicated in modulating the growth and metastases of tumors of epithelial origin can be profiled to discriminate among normal esophagus, distal esophageal tumor and normal stomach using 31P NMR.


Open total talus dislocation: a case report.
Total talus dislocation is a rare injury and is commonly accompanied by associated fractures. Common worrisome sequelae are infection, avascular necrosis and post-traumatic arthritis. We report here on a patient who sustained an open total talus dislocation with an ipsilateral medial malleolus fracture. Following early debridement, reduction and a combination of internal and external fixations, early recovery was good with no evidence of avascular necrosis. Total talus dislocation, avascular necrosis, infection, outcome.


Shape Memory Hybrid Composites.
Smart structures can help to resolve many issues related to conventional materials that are being used in different industries. Shape memory alloys (SMAs) are smart materials with better actuation response, vibration damping characteristics, and large strain recovery, making them good candidates due to their high strength and corrosion resistance for various engineering applications. The performance of fiber-reinforced polymer (FRP) composite materials that are replacing many conventional materials due to their good strength, stiffness, and lightweight potential especially in fuel-consuming industries such as aerospace and automotive, can further be improved by impregnation with SMAs. This review discusses the SMA-reinforced FRP composites, leading to shape memory hybrid composite materials, the issues and limitations in composite manufacturing, and their uses in different research arenas including impact and damping applications, seismic protection applications, crack closure applications, shape morphing applications, and self-deployable structures.


PER3, a novel target of miR-103, plays a suppressive role in colorectal cancer in vitro.
Colorectal cancer has become the third most common cancer and leads to high mortality worldwide. Although colorectal cancer has been studied widely, the underlying molecular mechanism remains unclear. PER3 is related to tumor differentiation and the progression of colorectal cancer. High expression of miR-103 is associated with poor prognosis in patients with colorectal cancer. However, the relationship between miR-103 and PER3 in CRC cells remains unclear. In this study, we found that PER3 was downregulated in CRC tissues and CRC cell lines, whereas miR-103 was upregulated in CRC cell lines. We also found that PER3 promoted CRC cells apoptosis. These results indicate that PER3 plays a suppressive role in CRC cells. Moreover, we found that PER3 was targeted, at least partially, by miR-103. Taken together, we provide evidence to characterize the role of PER3 in CRC, which may be a new therapeutic target for CRC.


Safety and immunogenicity of Haemophilus influenzae type B vaccine given in combination with DTwP at 6, 10 and 14 weeks of age.
To assess the immunogenicity and reactogenicity of a tetanus conjugate Haemophilus influenzae type b vaccine (Act-Hib) when extemporaneously mixed and administered as a DTwP-Hib combination using an Indian DTwP vaccine (BE DTwP) in comparison with a licensed DTwP-Hib combination vaccine. 378 healthy infants were enrolled and randomly allocated to receive either three doses, at 6, 10 and 14 weeks of age, of Act-Hib in combination with BE DTwP (Group A, n = 160), TetrAct-Hib (Group B, n = 160), or BE DTwP and Act-Hib as separate injections (Group C, n = 58). Sera collected before the first dose and one month after the third dose were tested for antibodies to vaccine antigens. Safety was determined using parental diary cards. Anti-Hib antibody concentrations indicative of short-term protection (> 0.15 g/ml) were elicited in all but one subject in Group A (99.3%), and all subjects in Groups B and C. The concentration of 1 g/ml, considered to provide long-term protection, was achieved in 96.7%, 100% and 98.2% of the infants in Groups A, B and C, respectively. All children displayed satisfactory responses to the three DTwP component antigens, TetrAct-Hib eliciting higher titers against diphtheria and tetanus than BE DTwP. No vaccine-associated serious adverse events occurred. The BE DTwP vaccine was associated with more reports of fever than TetrAct-Hib, but most symptoms were regarded as mild and all resolved without sequelae. Combining Act-Hib and a local DTwP vaccine did not affect the anti-Hib response. In countries where DTwP vaccine available for use in the EPI program is manufactured by a local or other developing country manufacturer, mixing it with lyophilised Act-Hib is a reasonable option though the immunogenicity may have to be documented before routine use. However, use of TetrAct-Hib combination vaccine would be preferable in view of its lower reactogenicity and superior immunogenicity with respect to diphtheria and tetanus.


Spin-Enhanced O-H Cleavage in Electrochemical Water Oxidation.
Herein we report the vital role of spin polarization in proton-transfer-mediated water oxidation over a magnetized catalyst. During the electrochemical oxygen evolution reaction (OER) over ferrimagnetic Fe3 O4 , the external magnetic field induced a remarkable increase in the OER current, however, this increment achieved in weakly alkaline pH (pH 9) was almost 20 times that under strongly alkaline conditions (pH 14). The results of the surface modification experiment and H/D kinetic isotope effect investigation confirm that, at weakly alkaline pH, during the nucleophilic attack of FeIV =O by molecular water, the magnetized Fe3 O4 catalyst polarizes the spin states of the nucleophilic attacking intermediates. The spin-enhanced singlet O-H cleavage and triplet O-O bonding occur synergistically, which promotes the O2 generation more significantly than the strongly alkaline case involving only spin-enhanced O-O bonding.


Chronic inflammation promotes retinoblastoma protein hyperphosphorylation and E2F1 activation.
Chronic inflammation contributes to tumorigenesis. The retinoblastoma protein (pRb), in its hyperphosphorylated form, releases E2 promoter binding factor-1 (E2F1), which drives cell proliferation. Here, we show that pRb is hyperphosphorylated in both mouse and human colitis. In turn, pRb hyperphosphorylation is associated with release of E2F1 from pRb, resulting in the activation of E2F1 target molecules involved in proliferation and apoptosis. These observations provide insight into the in vivo mechanisms associated with chronic colon inflammation and increased colon cancer risk.


Dissection of the HLA-DR4 peptide repertoire in endocrine epithelial cells: strong influence of invariant chain and HLA-DM expression on the nature of ligands.
Class II MHC (MHC II) expression is restricted to professional APCs and thymic epithelium but it also occurs in the epithelial cells of autoimmune organs which are the unique targets of the CD4 autoreactive T cells in endocrine autoimmune diseases. This specificity is presumably conditioned by an epithelium-specific peptide repertoire associated to MHC II at the cell surface. MHC II expression and function is dependent on the action of two main chaperones, invariant chain (Ii) and DM, whose expression is coregulated with MHC II. However, there is limited information about the in vivo expression levels of these molecules and uncoordinated expression has been demonstrated in class II-positive epithelial cells that may influence the MHC-associated peptide repertoires and the outcome of the autoimmune response. We have examined the pool of peptides associated to DR4 molecules expressed by a neuroendocrine epithelial cell and the consequences of Ii and DM coexpression. The RINm5F rat insulinoma cell line was transfected with HLA-DRB1*0401, Ii, and DM molecules in four different combinations: RIN-DR4, -DR4Ii, -DR4DM, and -DR4IiDM. The analysis of the peptide repertoire and the identification of the DR4 naturally processed ligands in each transfected cell were achieved by mass spectrometry. The results demonstrate that 1) the expression of Ii and DM affected the DR4 peptide repertoires by producing important variations in their content and in the origin of peptides; 2) these restrictions affected the stability and sequence of the peptides of each repertoire; and 3) Ii and DM had both independent and coordinate effects on these repertoires.


The effects of hoarding disorder on families: an integrative review.
Compulsive hoarding affects approximately 2-5% of the adult population. Increasing recognition has led to its inclusion as a distinct condition in forthcoming revisions to the Diagnostic and Statistical Manual V. Hoarding behaviour can have a detrimental effect on the health and well-being of family members. A rigorous review of available evidence using a novel three-stage literature search was undertaken: (1) an extensive scoping review; (2) a traditional search of databases including Cumulative Index to Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System Online, and psycINFO using combinations of keywords; and (3) review of cited references and hand-searching of selected journals. Evidence was selected using predefined inclusion criteria. Papers included two surveys, one qualitative study and one case study. An integrative review methodology was used to synthesize the evidence presented. Analysis revealed three overriding themes: quality of life, shattered families and rallying around. These illuminated the experiences of family members. These papers revealed families under strain and often at breaking point but with the resolve to pull together if the right support is available. This review concludes that further research is needed to investigate the effects of hoarding on family members and how these may best be met.


[Review and reflection on study of four properties of traditional Chinese medicine].
To summarize the biological effects of four natures of traditional Chinese medicine (TCM) in the recent 40 years, including cold, hot, warm and cool, which have the effect on central nervous system, endocrine system on the activity of sympathetic nerves, basal metabolic rate, the function of organs and tissues and secretion of cytokine out of body. And to review the new concepts and new hypotheses in recent 10 years which proposed on the four natures of traditional Chinese medicine. Based on the above summary we pointed out that the previous studies on biological effects have shortage in the following aspects: The studies had little connection with the TCM theory; The research highly concentrated on the biological effects of the cold and heat natures of drug; There is almost no research on the biological effects of the neutral nature; The research on the biological effects of the natures of traditional Chinese medicine had no combination with effects of drugs. And pointed out that studies on four natures of traditional Chinese medicine will be a multi-level, multi-disciplinary, multi-factor, multi-targe research, connecting Chinese medicine theory. The research will be a combination of the macro research and the micro research, the qualitative research and the quantitative research and the experimental research and the clinical research.


Current trends in the development of molecularly imprinted polymers in CEC.
This review focused on the developments in the field of molecularly imprinted polymers (MIPs) for CEC since 2009. New preparation techniques of MIP-based CEC, such as, portable microchip with macroporous monolithic imprinted microchannel, and low cross-linking MIPs based on liquid crystalline monomers, were discussed. Using selected cases rather than a comprehensive review of the entire field, our goal is to highlight the studies of the interest with an emphasis on recent work, and offers suggestions for future development in the field of imprinted materials for CEC separation.


Knowledge of the General Community in Cordoba, Argentina, on Human Papilloma Virus Infection and its Prevention.
Most studies of human papilloma virus (HPV) are aimed at the natural history of the infection and its relation to cancer; however, there are few studies to assess knowledge of the general population. Our aim was analyze the degree of knowledge of Argentinians about HPV infection and its prevention. We conducted a voluntary, anonymous and non-binding survey with 27 multiple-choice items, in twelve private and public establishments, selected to include a broad population in terms of education, age and gender. The survey consisted of three sections: individual characteristics of the volunteer, HPV infection basic knowledge, its prevention and the virus relationship with other cancers. One thousand two hundred ninety seven volunteers aged 18 to 80 participated. The total number of correct answers was 45.1%. The correct answers for relationship HPV and cervical cancer was 62.1%. Almost 55% did not know about types of HPV that the vaccines for protection. Statistical analysis showed that women, single people, workers, the better educated, those who have had a STDs or HPV and receiving information through medical or educational establishments had greater knowledge of the topic. Only 0.2% of participants answered all questions correctly. Knowledge plays an important role in health care and the deficiency found in our population could influence the success of the measures taken in the fight against cervical cancer. In this regard, we believe it would be appropriate, not only to emphasize early diagnosis and vaccine implementation, but also incorporate new communication strategies, facilitating reception of accurate and precise information by all strata of society.


Reducing the heterogeneity in hepatocellular carcinoma. A cluster analysis based on clinical variables in patients treated at a quaternary care hospital.
Even though the term hepatocellular carcinoma designates the most common type of primary liver cancer, the disease has a high level of heterogeneity due to its etiology, geographic variation, behavior, and association with specific genetic alterations. The aim of the present study was to establish, through a cluster analysis, the clinical characteristics that enable homogeneous conglomerates to be defined. An exploratory cluster analysis was developed utilizing the K-means method for sub-classifying 119 cases of patients with hepatocellular carcinoma. Sixty-two of those patients met the inclusion criteria, as well as none of the exclusion criteria. For the cluster analysis, an n-dimensional space was defined, in which n was equal to the number of variables included in the study (n = 17). The spatial coordinates corresponded to any possible magnitude between the minimum and maximum values of the variables analyzed (age, sex, tumor volume, AFP, AST, DB, Alb, Na, INR, Cr, HBV, HCV, OH, NASH, cirrhosis, multiple tumors, and neotumor). Four patterns with homogeneous clinical characteristics were identified, in which age at presentation, history of hepatitis B virus infection, altered liver profile with cholestatic dominance, and low albumin levels were associated with an apparently worse outcome. How heterogeneity in hepatocellular carcinoma could be reduced was shown through utilizing an unsupervised learning method to define specific subgroups, in whom known pathophysiologic mechanisms could better explain tumor behavior and define the determining prognostic factors related to the subgroups.


Electrophysiological (EEG-SSEP) monitoring during middle cerebral aneurysm surgery.
SSEPs were monitored during 38 procedures for aneurysms of the middle cerebral artery. In 13 selected patients intraoperative barbiturate protection with sodium thiopental was performed during temporary M1 occlusion. Combined EEG monitoring, showing burst suppression typical pattern of electrical cortical activity, allows a minimal dosage (3-6.5 mg/kg) of thiopental to achieve brain protection. Any patient with TYPE I SSEP changes had a new postoperative neurological deficit. Five patients during temporary middle cerebral artery clipping showed TYPE II SSEP changes and only one, not achieving burst suppression EEG pattern, had transient postoperative neurological deficit. In two other patients, a progressive worsening of TYPE II SSEP was observed; this was due to excessive brain retraction without brain protection and had a prolonged postoperative neurological deficit. Four patients showed TYPE IV SSEP changes during temporary M1 occlusion, one of whom was a 52-year-old woman, who, in spite of brain protection with thiopental, had serious postoperative neurological sequelae. In this patient N20 amplitude and central conduction time did not have full recovery to the preocclusive values. This study suggests that combined electrophysiological monitoring may reduce complications due to excessive retraction of cerebral tissue, make temporary clipping safer and improve the results of middle cerebral artery aneurysm surgery.


Polyphenol Stability and Physical Characteristics of Sweetened Dried Cranberries.
There is little research on how product matrix and processing affect phenolic compounds in sweetened dried cranberries over time. The objective of this research was to assess polyphenol content and stability in sweetened dried cranberries between product matrix types. This research assessed five commercially available sweetened dried cranberry matrices: (1) sliced apple juice infused, (2) whole apple juice infused, (3) sliced sucrose infused, (4) whole sucrose infused, and (5) sliced soluble corn fiber, glycerin, sucrose, and sucralose infused (three replicates/treatment). Proanthocyanidins, anthocyanins (HPLC), total phenolic content (Folin-Ciocalteu), water activity, moisture content, color, and texture were evaluated over 12 months at 21 °C. Data were analyzed by ANOVA (p < 0.05). Results demonstrate that sweetened dried cranberry polyphenols are unstable regardless of product matrix. More research is needed to determine optimal processing parameters for sweetened dried cranberries to maintain polyphenol stability as healthier food options for consumers.


Versatile tabletop setup for picosecond time-resolved resonant soft-x-ray scattering and spectroscopy.
We present a laser-driven, bright, and broadband (50 to 1500 eV) soft-x-ray plasma source with <10 ps pulse duration. This source is employed in two complementary, laboratory-scale beamlines for time-resolved, magnetic resonant scattering and spectroscopy, as well as near-edge x-ray absorption fine-structure (NEXAFS) spectroscopy. In both beamlines, dedicated reflection zone plates (RZPs) are used as single optical elements to capture, disperse, and focus the soft x rays, reaching resolving powers up to E/ΔE > 1000, with hybrid RZPs at the NEXAFS beamline retaining a consistent E/ΔE > 500 throughout the full spectral range, allowing for time-efficient data acquisition. We demonstrate the versatility and performance of our setup by a selection of soft-x-ray spectroscopy and scattering experiments, which so far have not been possible on a laboratory scale. Excellent data quality, combined with experimental flexibility, renders our approach a true alternative to large-scale facilities, such as synchrotron-radiation sources and free-electron lasers.


Associations Between Interpersonal Violence, Psychological Distress, and Suicidal Ideation Among Formerly Incarcerated Men and Women.
Survivors of interpersonal violence are at increased risk of negative mental health outcomes; however, scant research has explored the relationship between violence exposure and mental health symptoms among formerly incarcerated individuals. This cross-sectional survey study investigates the demographic characteristics and mental health symptoms (i.e., psychological distress and suicidal ideation) associated with interpersonal violence exposure, including physical and sexual intimate partner violence, non-partner sexual violence, and sexual violence perpetrated by prison employees in a sample of formerly incarcerated men and women, with the aim that the findings both deepen the understanding of the effects of sexual violence exposure and help inform prison and jail policies. Surveys were administered to English-speaking adults ages 18 and older to recruit a sample of adults who were formerly incarcerated (N = 201). Questions on the survey included questions regarding demographic details, sexual violence exposure, mental health symptoms, and time incarcerated. Findings show that higher levels of sexual violence exposure were significantly associated with higher levels of psychological distress and reporting of suicidal ideation. Results also suggest that higher levels of income and education and younger age were significantly associated with sexual violence perpetrated by prison employees. In addition, most forms of interpersonal violence were independently associated with psychological distress and suicidal ideation in this population. The findings make recommendations for prison and jail policies to include targeted treatment for individuals with sexual victimization histories, to mitigate the risk of revictimization and appropriately treat adverse mental health outcomes from sexual victimization within and outside the confines of incarceration.


Interchangeable endotoxin-binding domains in proteins with opposite lipopolysaccharide-dependent activities.
Host defense against microorganisms involves proteins that bind specifically to bacterial endotoxins (LPS), causing different cellular effects. Although LPS-binding protein (LBP) can enhance LPS activities, while bactericidal/permeability-increasing protein (BPI) and Limulus anti-LPS factor (LALF) neutralize LPS, it has been proposed that their LPS-binding domains possess a similar structure. Here, we provide evidence that the LBP/LPS-binding domain is, as in the LALF structure, solvent exposed and therefore available for LPS binding. Our investigations into the activity of LPS-binding domains of different LPS-binding proteins, in the context of LBP, provide the first functional analysis of these domains in a whole protein. We constructed domain exchange hybrid proteins by substituting 12 amino acids of the LBP/LPS-binding domain with those of BPI and LALF and expressed them in Chinese hamster ovary cells. Although discrete point mutations within the LPS-binding domain of LBP disrupted its specific functions, the hybrid proteins were still able to bind LPS and, in addition, retained the wild-type LBP activity of enhancing LPS priming for FMLP-induced oxygen radical production by neutrophils and transferring LPS aggregates to CD14. Although BPI and LALF display opposite activities to LBP, and LALF does not share any sequence homology with LBP, our data provide strong evidence that LBP, BPI, and LALF possess a solvent-exposed, interchangeable LPS binding motif that is functionally independent of LPS transport or neutralization.


Rehabilitation of swallowing by exercise in tube-fed patients with pharyngeal dysphagia secondary to abnormal UES opening.
We evaluated the effect of a novel rehabilitative exercise on restoration of deglutition in a group of patients with deglutitive failure caused by abnormal upper esophageal sphincter (UES) opening manifested by postswallow residue and aspiration necessitating percutaneous tube feeding. We studied a total of 27 patients by videofluoroscopy and functional assessment of swallowing scores before and after 6 weeks of a head-raising exercise program. Seven of 27 patients, assigned randomly, participated in a sham exercise before entering the tested exercise program. Eleven of 27 were randomized to the real exercise program. Although there was no change in swallow function and biomechanics after the sham exercise, following 6 weeks of real exercise, all 11 patients exhibited a significant improvement in their UES opening, anterior laryngeal excursion (P < 0.01), as well as resolution of postdeglutitive aspiration and were able to resume oral feeding. Similar results were found when the 7 patients in the sham group were crossed over to the real exercise group. Comparison of before and after exercise values for anteroposterior UES opening (P < 0.01) and laryngeal anterior excursion (P < 0.05), as well as functional outcome assessment of swallowing (P < 0.05) in the entire group of 27 patients also showed significant improvement. Etiology and duration of dysphagia did not affect the outcome. The proposed suprahyoid muscle strengthening exercise program is effective in restoring oral feeding in some patients with deglutitive failure because of abnormal UES opening.


Fibroblast growth factor 2 (FGF2) is present in human spermatozoa and is related with sperm motility. The use of recombinant FGF2 to improve motile sperm recovery.
Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate several functions of somatic cells. In a previous work, we reported FGFR expression in human spermatozoa and their involvement in motility. This study aimed to evaluate the presence and localization of fibroblast growth factor 2 (FGF2) in human spermatozoa, to determine the relationship of FGF2 levels with conventional semen parameters and to assess the effect of recombinant FGF2 (rFGF2) on sperm recovery in a selection procedure. Western immunoblotting analysis using an antibody against FGF2 revealed an 18-kDa band in sperm protein extracts. The protein was immunolocalized in the sperm flagellum and acrosomal region, as well as in all germ cells. Sperm FGF2 levels, assessed by flow cytometry, showed a positive (p < 0.05) correlation with sperm concentration, motility, total sperm number and total motile cells per ejaculate. Moreover, samples with abnormal motility depicted diminished (p < 0.01) FGF2 levels compared to those with normal motility. Spermatozoa exposed to rFGF2 bound the protein, exhibited higher (p < 0.05) total and motile sperm recoveries, and increased (p < 0.01) kinematic parameters after the swim-up. Findings herein presented lead to consider sperm FGF2 level as a potential marker of sperm quality, and rFGF2 as a supplement for improving sperm recovery in selection techniques.


Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity.
Pocket proteins retinoblastoma (pRb), p107 and p130 are negative regulators of cellular proliferation and multifunctional proteins regulating development, differentiation and chromatin structure. The retinoblastoma protein is a potent tumor suppressor mutated in a wide range of human cancers, and oncogenic viruses often interfere with cell cycle regulation by inactivating pRb. The LxCxE and pRb AB groove short linear motifs (SLiMs) are key to many pocket protein mediated interactions including host and viral partners. A review of available experimental evidence reveals that several core residues composing each motif instance are determinants for binding. In the LxCxE motif, a fourth hydrophobic position that might allow variable spacing is required for binding. In both motifs, flanking regions including charged stretches and phosphorylation sites can fine-tune the binding affinity and specificity of pocket protein SLiM-mediated interactions. Flanking regions can modulate pocket protein binding specificity, or tune the high affinity interactions of viral proteins that hijack the pRb network. The location of SLiMs within intrinsically disordered regions allows faster evolutionary rates that enable viruses to acquire a functional variant of the core motif by convergent evolution, and subsequently test numerous combinations of flanking regions towards maximizing interaction specificity and affinity. This knowledge can guide future efforts directed at the design of peptide-based compounds that can target pocket proteins to regulate the G1/S cell cycle checkpoint or impair viral mediated pRb inactivation.


[Consensus on diagnosis and treatment of invasive fungal infection in patients with severe liver disease].
The prognosis of severe liver disease combined with invasive fungal infection (IFI) is poor, and the clinical manifestations are often atypical. Moreover, most of the antifungal drugs are metabolized in the liver, with severe toxicities and side effects, making clinical diagnosis and treatment difficult. The Professional Committee for Hepatology, the Chinese Research Hospital Association and the Hepatology Branch of China Medical Association organized relevant experts to formulate an expert consensus based on the characteristics of patients with severe liver disease combined with IFI, in order to provide reference for medical personnel in making decisions on the diagnosis and treatment.


Carcinoma ex pleomorphic adenoma: A diagnostic challenge on cytology.
Carcinoma ex pleomorphic adenoma (Ca ex PA) is a malignant neoplasm arising from primary or recurrent benign pleomorphic adenoma. It is rare with an annual incidence rate of 0.17 tumors per million. Histopathology remains the gold standard for the diagnosis of Ca ex PA, with only a handful of cases reported on cytology. In our case a 66-year-old male presented with the right parotid mass for 5 years rapidly increasing for the last 3 months. Fine needle aspiration cytology (FNAC) smears showed malignant tumor cells in clusters along with benign myoepithelial cells in chondromyxoid background. Histopathologically, highly pleomorphic malignant epithelial cells in sheets along with foci of comedonecrosis and areas corresponding to benign pleomorphic adenoma were observed on careful scrutiny. Immunohistochemistry revealed positivity for cytokeratin (CK 7) and gross cystic disease fluid protein 15 (GCDFP-15) while CK5/6 and high molecular weight CK (34 βE12) were negative in the malignant tumor cells. So, the final impression was Ca ex PA with salivary duct carcinoma as malignant component. We hereby report this case to highlight the significance of FNAC in the diagnosis of Ca ex PA which can be easily missed on cytopathology. However, it is important to corroborate the cytological findings with clinical suspicion of malignancy as well as radiology. Diagn. Cytopathol. 2017;45:651-654. © 2017 Wiley Periodicals, Inc.


[Biological age estimation based on the spectral analysis of the human brain bioelectric activity.]
For the first time, the research work offers a method of estimating human biological age based on the spectral analysis of the brain bioelectric activity. IDC decentralization index, which could consider summary degree of reduction of the background neurotrophic influences of the brain activating system on the peripheral tissues and organs, was developed. The close to linear dependence of the IDC index on the age of healthy people aged 10-90 as well as on the oncological patients' cancer G1-G4 cells differentiation was obtained. The cell disorders and mutations in relation with the age from 10 to 90 could be seen in growth of the IDC index from 100 to 900 units. The greater amount of the cell mutations in the oncological patients with the G1-G4 differentiation resulted in the IDC index growth up to the 3 000 units and more. All the obtained data allowed estimating the real biological age after a 10-minute registration of the human brain bioelectric activity. The accuracy increased with the averaging several surveys taken from one particular person. The technology will be highly efficient for scientific researches in the field of gerontology, monitoring of healthy people, revealing of risk groups, and for controlling of the cancer patients' medical treatment.


Serologic evidence of Toxoplasma gondii infection among cancer patients. A prospective study from Qassim region, Saudi Arabia.
To determine the frequency of antibody seropositivity of Toxoplasma gondii infection in a cancer patient population. We also explored on association of Toxoplasma gondii seropositivity with selected variables. Methods: This is a prospective cross-sectional study conducted at Prince Faisal bin Bandar cancer center, Qassim, Saudi Arabia, from November 2014 to March 2015. One hundred thirty seven patients were involved in the study. Demographic data was collected using structured questionnaire, and clinical information was retrieved from the patient's medical reports. Enzyme-linked immunosorbent assay technique was used for antibody assay. Results: The frequency of seropositivity for Toxoplasma gondii infection was 30.6%. The patient's age range from 1.5-84 years with a geometric mean of 42.7 years. The seropositivity was significantly higher (p<0.05) among the 40-80 years age group (71.4%) as compared to 0-39 years one (28.6%). Conclusion: The prevalence of Toxoplasma gondii increases with increasing age among cancer patients in this region of central Saudi Arabia. More research is advisable for better understanding of ageing in pathogenesis of toxoplasmosis among patients with malignancies.


E-Cadherin gene expression in oral cancer: Clinical and prospective data.
Low protein expression of E-cadherin in oral squamous cell carcinoma (OSCC) has been associated with clinical and histopathological traits such as metastases, recurrence, low survival and poor tumor differentiation, and it is considered a high-risk marker of malignancy. However, it is still unknown whether low expression of E-cadherin is also present at the mRNA level in OSCC cases. The aim of this study was to compare E-cadherin mRNA expression in OSCC patients and controls and to correlate the expression with clinical and prospective characteristics. Forty patients and 40 controls were enrolled. E-cadherin mRNA expression was evaluated by quantitative real-time polymerase chain reaction using TaqMan probes. E-cadherin mRNA expression was significantly decreased in OSCC patients compared to that of controls (p<0.001). Whereas no significant association between clinical parameters and E-cadherin expression levels was observed, we noted lower E-cadherin expression levels in patients with positive lymph node metastasis. E-cadherin mRNA expression was markedly diminished in OSCC, in agreement with previous results that examined E-cadherin expression at the protein level. E-cadherin is downregulated in the early clinical stages of OSCC, and its mRNA levels do not change significantly in the advanced stages, suggesting that there is limited usefulness of this parameter for predicting disease progression.


Synchronization law for a van der Pol array.
We explore the transition to in-phase synchronization in globally coupled oscillator arrays, and compare results for van der Pol arrays with Josephson junction arrays. Our approach yields in each case an analytically tractable iterative map; the resulting stability formulas are simple because the expansion procedure identifies natural parameter groups. A third example, an array of Duffing-van der Pol oscillators, is found to be of the same fundamental type as the van der Pol arrays, but the Josephson arrays are fundamentally different owing to the absence of self-resonant interactions.


[Usefulness of enhanced computed tomography in the diagnosis of pulmonary thromboembolism].
Pulmonary thromboembolism (PTE) was diagnosed in 22 patients at Saga Medical School between 1981 and 1994. Enhanced computed tomography (CT) was done in 8 patients, and filling defects in the central pulmonary artery were identified in 6. Parenchymal shadows (wedge shaped shadows, subpleural consolidation, or nodular shadow's) were noted in 5. When enhanced CT was done during acute severe respiratory failure in 3 patients, pulmonary artery filling defects were found in all. These findings suggest that enhanced CT is useful as a diagnostic tool for acute PTE with respiratory failure. Electron beam CT may be a sensitive and specific means of diagnosing PTE because it can be done quickly and without breath-holding. We conclude that enhanced CT should be used as the first diagnostic procedure in patients with severe respiratory failure who may have PTE.


A novel thermally stable heteropolysaccharide-based bioflocculant from hydrocarbonoclastic strain Kocuria rosea BU22S and its application in dye removal.
A new bioflocculant named pKr produced by hydrocarbonoclastic strain Kocuria rosea BU22S (KC152976) was investigated. Gas chromatography-flame ionization detector (GC-FID) analysis confirmed the high potential of the strain BU22S in the degradation of n-alkanes. Plackett-Burman experimental design and response surface methodology were carried out to optimize pKr production. Glucose, peptone and incubation time were found to be the most significant factors affecting bioflocculant production. Maximum pKr production was about 4.72 ± 0.02 g/L achieved with 15.61 g/L glucose, 6.45 g/L peptone and 3 days incubation time. Chemical analysis of pKr indicated that it contained 71.62% polysaccharides, 16.36% uronic acid and 2.83% proteins. Thin layer chromatography analysis showed that polysaccharides fraction consisted of galactose and xylose. Fourier transform infrared analysis revealed the presence of many functional groups, hydroxyl, carboxyl, methoxyl, acetyl and amide that likely contribute to flocculation. K. rosea pKr showed high flocculant potential using kaolin clay at different pH (2-11), temperature (0-100°C) and cation concentrations. The bioflocculant was particularly effective in flocculating soluble anionic dyes, Reactive Blue 4 and Acid Yellow, with a decolorization efficiency of 76.4% and 72.6%, respectively. The outstanding flocculating performances suggest that pKr could be useful for bioremediation applications.


Excretion of cephalothin and cefamandole by the normal pancreas and in acute pancreatitis in dogs.
Nine mongrel dogs were studied to evaluate the excretion of cefamandole (five dogs) and cephalothin (four dogs) in the pancreatic fluid. Each dog was studied before and after the induction of pancreatitis, with 2 weeks between studies. After intravenous administration of a 25-mg/kg dose of either cephalosporin, serum and pancreatic fluid concentrations were monitored for 6 h. Both cephalothin and cefamandole were excreted in bactericidal concentrations in the normal pancreas and in acute pancreatitis. Clearance of cefamandole (290 ml/min) and cephalothin (348 ml/min) were similar pre- and postinduction of pancreatitis. Serum albumin concentration was less during the post-pancreatitis phase compared with the prepancreatitis phase. Penetration of cephalothin was reduced in pancreatitis, whereas cefamandole penetration increased in pancreatitis.


Regional differences of expression of bone morphogenetic protein-2 and RANKL in the rat dental follicle.
Tooth eruption requires alveolar bone resorption and bone formation. The coronal half of the dental follicle probably mediates the bone resorption seen in the coronal region of the alveolar bony crypt, and the basal half of the follicle mediates bone growth in the basal region. We hypothesized that the expression of a gene for bone resorption--receptor activator of nuclear factor kappa B ligand (RANKL)--would be higher in the coronal than in the basal region of the follicle. Conversely, the level of expression of bone morphogenetic protein-2 (BMP-2), a gene for bone formation, would be higher in the basal region. Results obtained using laser-capture microdissection and real-time reverse transcription-polymerase chain reaction (RT-PCR) confirmed the hypothesis. Scanning electron micrographs of the bony crypt showed that the coronal area of the crypt was scalloped in appearance (bone resorption), whereas the basal area was trabecular (bone formation). Thus, the differences in bone activity at opposite poles of the crypt appear to be caused by differences in the regional expression of genes in the dental follicle and suggest a molecular mechanism whereby the dental follicle could regulate both the alveolar bone resorption and formation needed for eruption.


Psychiatry in primary care and training: a Singapore perspective.
Proactive steps have been taken by the public healthcare sector in Singapore to bring about awareness of mental health in terms of mental health promotion, early recognition and seeking help, with an increasing focus on making mental healthcare accessible and delivering it within the community setting where possible. Examples are the Mental Health General Practitioner Partnership Programme, National Mental Health Blueprint and Community Mental Health Masterplan. The current challenge is to train and involve more primary care doctors in the care of persons with mental health conditions. This paper describes the goals of psychiatric training in primary care and the avenues for training that are available to family medicine residents and family physicians.


Endovascular treatment of ACom intracranial aneurysms. Report on series of 280 patients.
The immediate and long-term outcomes, complications, recurrences and the need for retreatment were analyzed in a series of 280 consecutive patients with anterior communicating artery aneurysms treated with the endovascular technique. From October 1992 to October 2001 280 patients with 282 anterior communicating artery aneurysms were addressed to our center. For the analysis, the population was divided into two major groups: group 1, comprising 239 (85%) patients with ruptured aneurysms and group 2 comprising of 42 (15%) patients with unruptured aneurysms. In group 1, 185 (77.4%) patients had a good initial pre-treatment Hunt and Hess grade of I-III. Aneurysm size was divided into three categories according to the larger diameter: less than 4 mm, between 4 and 10 mm and larger than 10 mm. The sizes of aneurysms in groups 1 and 2 were identical but a less favorable neck to depth ratio of 0.5 was more frequent in group 2. Endovascular treatment was finally performed in 234 patients in group 1 and 34 patients in group 2. Complete obliteration was more frequently obtained in group 2 unlike a residual neck or opacification of the sac that were more frequently seen in group 1. No peri-treatment complications were recorded in group 2. In group 1 the peri-treatment mortality and overall peri-treatment morbidity were 5.1% and 8.1% respectively. Eight patients (3.4%) in group 1 presented early post treatment rebleeding with a mortality of 88%. The mean time to follow-up was 3.09 years. In group 1, 51 (21.7%) recurrences occurred of which 14 were minor and 37 major. In group 2, eight (23.5%) recurrences occurred, five minor and three major. Two patients (0.8%) presented late rebleeding in group 1. Twenty-seven second endovascular retreatments were performed, 24 (10.2%) in group 1 and three (8.8%) in group 2, seven third endovascular retreatments and two surgical clippings in group 1 only. There was no additional morbidity related to retreatments. Endovascular treatment is an effective method for the treatment of anterior communicating artery aneurysms allowing late rebleeding prevention. Peri-treatment rebleeding warrants caution in anticoagulation management. This is a single center experience and the follow-up period is limited. Patients should be followed-up in the long-term as recurrences may occur and warrant additional treatment.


Further studies on the attachment of bacteria to skin.
1. A proportion of the bacterial flora of the skin is present in the surrounding water film and can be removed by adequate rinsing. 2. The remainder of the flora is attached to the skin in such a manner that numbers can be reduced only 10-fold during spray-cooling or spin-chilling. 3. The reduction process was found to be independent of bacterial type or the extent of previous contamination. 4. The significance of the "water film flora" is discussed with respect to the attachment of bacteria and the cleaning of carcasses.


Catalytic Bismuth(V)-Mediated Oxidation of Hydrazones into Diazo Compounds.
A new bismuth(V) oxidative catalytic system has been developed and applied for the conversion of hydrazones into diazo compounds. With the use of low catalytic amounts of Ph3Bi and AcOH with NaBO3·H2O as a terminal oxidant, the in situ formation of Ph3Bi(OAc)2 is capable of oxidizing hydrazones in excellent yields. The reaction was applied for the synthesis of diazocarbonyls and 2,2,2-trifluoromethyl diazoalkanes in good to excellent yields.


An easy and efficient approach for testing identifiability.
The feasibility of uniquely estimating parameters of dynamical systems from observations is a widely discussed aspect of mathematical modelling. Several approaches have been published for analyzing this so-called identifiability of model parameters. However, they are typically computationally demanding, difficult to perform and/or not applicable in many application settings. Here, an approach is presented which enables quickly testing of parameter identifiability. Numerical optimization with a penalty in radial direction enforcing displacement of the parameters is used to check whether estimated parameters are unique, or whether the parameters can be altered without loss of agreement with the data indicating non-identifiability. This Identifiability-Test by Radial Penalization (ITRP) can be employed for every model where optimization-based parameter estimation like least-squares or maximum likelihood is feasible and is therefore applicable for all typical systems biology models. The approach is illustrated and tested using 11 ordinary differential equation (ODE) models. The presented approach can be implemented without great efforts in any modelling framework. It is available within the free Matlab-based modelling toolbox Data2Dynamics. Source code is available at https://github.com/Data2Dynamics. email@example.com. Supplementary data are available at Bioinformatics online.


Coarse-Graining ddCOSMO through an Interface between Tinker and the ddX Library.
The domain decomposition conductor-like screening model is an efficient way to compute the solvation energy of solutes within a polarizable continuum medium in a linear scaling computational time. Despite its efficiency, the application to very large systems is still challenging. A possibility to further accelerate the algorithm is resorting to coarse-graining strategies. In this paper we present a preliminary interface between the molecular dynamics package Tinker and the ddX library. The interface was used to test a united atom coarse-graining strategy that allowed us to push ddCOSMO to its limits by computing solvation energies on systems with up to 7 million atoms. We first present benchmarks to find an optimal discretization, and then, we discuss the performance and results obtained with fine- and coarse-grained solvation energy calculations.


Daytime Variation in Kidney Perfusion, Oxygenation, and Sodium Concentration Assessed by Multiparametric MRI in Healthy Volunteers.
MRI can provide information on kidney structure, perfusion, and oxygenation. Furthermore, it allows for the assessment of kidney sodium concentrations and handling, allowing multiparametric evaluation of kidney physiology. Multiparametric MRI is promising for establishing prognosis and monitoring treatment responses in kidney diseases, but its intraindividual variation during the day is unresolved. To investigate the variation in multiparametric MRI measurements from the morning to the evening. Prospective. Ten healthy volunteers, aged 29 ± 5 without history of kidney disease. 3 T/T1 mapping, blood-oxygen level dependent imaging, arterial spin labeling perfusion imaging, diffusion weighted imaging, and sodium imaging. A multiparametric MRI protocol, yielding T1, R2*, ADC, renal blood flow and renal sodium levels, was acquired in the morning, noon, and evening. The participants were fasting prior to the first examination. Urine biochemical analyses were performed to complement MRI data. The cortex and medulla were analyzed separately in a semi-automatic fashion, and gradients of total sodium concentration (TSC) and R2 * gradients were calculated from outer cortex to inner medulla. Analyses of variance and mixed-effects models to estimate differences from time of day. Coefficients of variation to assess variability within and between participants. A P-value <0.05 was considered statistically significant. The coefficients of variation varied from 5% to 18% for proton-based parametric sequences, while it was 38% for TSC over a day. Multiparametric MRI is stable over the day. The coefficients of variation over a day were lower for proton multiparametric MRI, but higher for sodium MRI. 2 TECHNICAL EFFICACY: Stage 2.


New Genotypes of Enterocytozoon bieneusi Isolated from Sika Deer and Red Deer in China.
To examine the occurrence and genotype distribution of Enterocytozoon bieneusi in cervids, 615 fecal samples were collected from red deer (Cervus elaphus) and sika deer (Cervus nippon) on 10 different farms in Henan and Jilin Province. Enterocytozoon bieneusi was identified and genotyped with a nested PCR analysis of the internal transcribed spacer (ITS) region of the rRNA genes, showing an average infection rate of 35.9% (221/615). In this study, 25 ITS genotypes were identified including seven known genotypes (BEB6, EbpC, EbpA, D, HLJDI, HLJD-IV, and COS-I) and 18 novel genotypes (designated JLD-I to JLD-XIV, HND-I to HND-IV). Among these, BEB6 (131/221, 59.3%) was the predominant genotype (P < 0.01), followed by HLJDI (18/221, 8.1%) and JLD-VIII (16/221, 7.2%). BEB6 has recently been detected in humans and nonhuman primates in China. The phylogenetic analysis showed that BEB6, HLJDI, HLJD-IV, COS-I, and 10 novel genotypes (JLD-VII to JLD-XIV, HND-III to HND-IV) clustered in group 2. Genotype D, EbpC, and EbpA, known to cause human microsporidiosis worldwide, clustered in group 1, the members of which have zoonotic potential, together with eight novel genotypes (JLD-I to JLD-VI, HND-I to HND-II). Therefore, deer may play a role in the transmission of E. bieneusi to humans.


Metastatic mixed acinar-endocrine carcinoma of the pancreas treated with a multidisciplinary approach: a case report.
Pancreatic neoplasms are usually characterized by ductal, acinar, or endocrine differentiation. Mixed exocrine and endocrine pancreatic tumours are extremely rare. Here, we report a case of pancreatic mixed acinar-endocrine carcinoma (MAEC) with multiple synchronous liver metastases that were treated with surgery and transcatheter arterial chemoembolization (TACE) that later recurred in the stomach. A 45-year-old female with severe anaemia was referred to our hospital. Computed tomography (CT) demonstrated a hypervascular tumour, 17 cm in diameter, that was in the tail of the pancreas. In addition, there were multiple hypervascular tumours in the liver. She underwent a distal pancreatectomy with splenectomy after the liver metastases were treated with TACE. Pathology confirmed that the pancreatic tumour was MAEC. After 4.5 years, a follow-up CT showed a hypervascular tumour at the upper part of the stomach. Gastric endoscopy showed a big tumefactive lesion with surface irregularities, gastric erosion, and multiple dilated vessels in the fornix and greater curvature of the stomach. She underwent a proximal gastrectomy and survived 7 years and 2 months after the start of the treatment. This is the first report of a metastatic stomach tumour from pancreatic MAEC, which was successfully treated with a multidisciplinary approach. Additionally, we review the literature and discuss the treatment of MAEC.


Chemical Probes to Control and Visualize Lipid Metabolism in the Brain.
Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological processes, including pain sensation, appetite, memory formation, stress, and anxiety. Unlike classical neurotransmitters, lipid messengers are produced on demand and degraded by metabolic enzymes to control their lifespan and signaling actions. Chemical biology approaches have become one of the main driving forces to study and unravel the physiological role of lipid messengers in the brain. Here, we review how the development and use of chemical probes has allowed one to study endocannabinoid signaling by (i) inhibiting the biosynthetic and metabolic enzymes; (ii) visualizing the activity of these enzymes; and (iii) controlling the release and transport of the endocannabinoids. Activity-based probes were instrumental to guide the discovery of highly selective and in vivo active inhibitors of the biosynthetic (DAGL, NAPE-PLD) and metabolic (MAGL, FAAH) enzymes of endocannabinoids. These inhibitors allowed one to study the role of these enzymes in animal models of disease. For instance, the DAGL-MAGL axis was shown to control neuroinflammation and the NAPE-PLD-FAAH axis to regulate emotional behavior. Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. These experimental drugs are now in clinical trials for multiple indications, including multiple sclerosis and post-traumatic stress disorders. Activity-based probes have also been used to visualize the activity of these lipid metabolizing enzymes with high spatial resolution in brain slices, thereby showing the cell type-specific activity of these lipid metabolizing enzymes. The transport, release, and uptake of signaling lipids themselves cannot, however, be captured by activity-based probes in a spatiotemporal controlled manner. Therefore, bio-orthogonal lipids equipped with photoreactive, photoswitchable groups or photocages have been developed. These chemical probes were employed to investigate the protein interaction partners of the endocannabinoids, such as putative membrane transporters, as well as to study the functional cellular responses within milliseconds upon irradiation. Finally, genetically encoded sensors have recently been developed to monitor the real-time release of endocannabinoids with high spatiotemporal resolution in cultured neurons, acute brain slices, and in vivo mouse models. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling.


[Does liraglutide have a place in psychiatry ?]
The relative risk of developing MetS is higher in patients with severe mental illness (SMI) than in the general population. Similarly, the risk of developing obesity or type 2 diabetes (T2DM) is also higher in patients with SMI. GLP-1 receptor agonists, such as liraglutide, have been shown to be effective in the treatment of T2DM and, more recently, in obesity or overweight associated with at least one metabolic disease. Their psychiatric adverse effect profiles seem to be reassuring, thus not represent a limitation for prescribing in psy chiatry. We aimed to explore the therapeutic usefulness of liraglutide in patients with psychiatric disorders associated with somatic comorbidities such as obesity, T2DM or MetS.


Simple compressive method for treatment of auricular haematoma using dental silicone material.
Most of the previous treatment methods for auricular haematoma are inconvenient for both patients and doctors because they are time-consuming and complex and must be performed under sterile conditions. The purpose of this study was to evaluate the effectiveness of a simple compressive method using a dental (silicone) impression material and comparing it with other methods for treatment of auricular haematomas. The authors aspirated a haematoma and then placed a mixed base and catalyst of silicone putty material on the anterior and posterior surfaces of the auricle in the shape of an inverted U for seven days. From the 24 cases managed with this method, 23 cases (95.8 per cent) were successfully healed. Eight patients were treated with a collodion-cotton wool cast and 16 of 19 patients were successfully treated with dental cotton-wool rolls. The average number of those visiting the hospital was 2.7 for the collodion-cotton wool cast, 6.9 for the dental cotton-wool roll, and 3.1 for dental silicone. The mean treatment durations were 8.1 days for the collodion-cotton wool cast, 13.8 days for the dental cotton-wool roll, and 8.6 days for dental silicone. The authors believe that this compressive method using dental silicone material is simple and appropriate for the treatment of auricular haematoma.


Saponins in Cancer Treatment: Current Progress and Future Prospects.
Saponins are steroidal or triterpenoid glycoside that is distinguished by the soap-forming nature. Different saponins have been characterized and purified and are gaining attention in cancer chemotherapy. Saponins possess high structural diversity, which is linked to the anticancer activities. Several studies have reported the role of saponins in cancer and the mechanism of actions, including cell-cycle arrest, antioxidant activity, cellular invasion inhibition, induction of apoptosis and autophagy. Despite the extensive research and significant anticancer effects of saponins, there are currently no known FDA-approved saponin-based anticancer drugs. This can be attributed to a number of limitations, including toxicities and drug-likeness properties. Recent studies have explored options such as combination therapy and drug delivery systems to ensure increased efficacy and decreased toxicity in saponin. This review discusses the current knowledge on different saponins, their anticancer activity and mechanisms of action, as well as promising research within the last two decades and recommendations for future studies.


The pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part IV: the 1984 coronary primary prevention trial ends it--almost.
As of the early 1980s, despite the wealth of evidence from experimental animal models, the extensive epidemiologic evidence, the powerful genetic evidence, and the strongly suggestive clinical intervention trial results, most clinicians still remained unpersuaded regarding the relevance of the lipid hypothesis. What was needed was a well-designed, large-scale, long-term, double-blind study demonstrating a statistically significant impact of treatment on coronary heart disease events. The National Institutes of Health (NIH) had laid the groundwork for such a study as early as 1970, but the study was not completed and the results published until 1984. This study, the Coronary Primary Prevention Trial, showed that treatment with a bile acid binding resin reduced major coronary events in hypercholesterolemic men by 19%, with a P value of 0.05. The NIH followed this up with a national Consensus Development Conference on Lowering Blood Cholesterol to Prevent Heart Disease. For the first time, the NIH now went on record advocating screening for hypercholesterolemia and urging aggressive treatment for those at high risk. The Institute initiated a national cooperative program to that end, the National Cholesterol Education Program. For the first time, preventing coronary heart disease became a national public health goal.


[ENTERAL NUTRITION IN PERU]
Drawbacks of Nutritional Support diffusion in Peru are presented within current Latin-American technological reality. That reality is compared to widespread use of antibiotic therapy versus a marked lack of use of Nutritional Support. Those factors are against immunity of seriously compromised patients as Enteral Nutrition has positive effects on a patient s immunity.Four patients treated with three kinds of enteral formulas during a prospective study serve as examples to show the suitable consequences of using Enteral Nutrition and why Nutritional Support should be legally enforced and regulated in Peru.


A modified three-term PRP conjugate gradient algorithm for optimization models.
The nonlinear conjugate gradient (CG) algorithm is a very effective method for optimization, especially for large-scale problems, because of its low memory requirement and simplicity. Zhang et al. (IMA J. Numer. Anal. 26:629-649, 2006) firstly propose a three-term CG algorithm based on the well known Polak-Ribière-Polyak (PRP) formula for unconstrained optimization, where their method has the sufficient descent property without any line search technique. They proved the global convergence of the Armijo line search but this fails for the Wolfe line search technique. Inspired by their method, we will make a further study and give a modified three-term PRP CG algorithm. The presented method possesses the following features: (1) The sufficient descent property also holds without any line search technique; (2) the trust region property of the search direction is automatically satisfied; (3) the steplengh is bounded from below; (4) the global convergence will be established under the Wolfe line search. Numerical results show that the new algorithm is more effective than that of the normal method.


Encephalopathy complicating Whipple's disease: failure to respond to antibiotics.
Progressive dementia, vertical ophthalmoplegia, and prominent hypothalamic dysfunction developed in one patient with documented intestinal Whipple's disease despite ongoing antibiotic therapy with intestinal remission. A clinical diagnosis of central nervous Whipple's disease was made on the basis of the patient's presentation. High-dose parenteral penicillin and chloramphenicol were administered for 4 1/2 weeks. There was no improvement in results of daily mental status examination or neuropsychologic testing. Deterioration was noted in the electroencephalographic findings after therapy. Vigorous antibiotic therapy with agents that cross the blood-brain barrier had no immediate beneficial effect. Irreversible neurologic damage or a slow, delayed response may account for this observation.


Universal modesty in signal-burying games.
Why would individuals hide positive information about themselves? Evolutionary game theorists have recently developed the signal-burying game as a simple model to shed light on this puzzle. They have shown that the game has an equilibrium where some agents are better off deliberately reducing the visibility of the signal by which they broadcast their positive traits. However, this equilibrium also features individuals who fully broadcast their positive traits. Here, we show that the signal-burying framework can also explain modesty norms that everyone adheres to: the game contains an equilibrium where all agents who send a signal voluntarily reduce its conspicuousness. Surprisingly, the stability of the two kinds of equilibria rely on very different principles. The equilibrium where some agents brag is stable because of costly signalling dynamics. By contrast, the universal modesty equilibrium exists because buried signals contain probabilistic information about a sender's type, and receivers make optimal use of this information. In the latter equilibrium, burying a signal can be understood as a handicap which makes the signal more honest, but honesty is not achieved through standard costly signalling dynamics.


Tuberculous meningitis in BCG vaccinated and unvaccinated children.
A modified clinical presentation of tuberculous meningitis (TBM) in children vaccinated with BCG has been described in the literature. However, most reports are old and not based on actual comparisons and tests of significance. Also, neuroimaging features were not compared. With large scale BCG coverage, it becomes pertinent to describe the "modified" presentation and identify any significant differences between vaccinated and unvaccinated children with TBM. A total of 150 consecutive hospitalised children (96 unvaccinated, 54 vaccinated) were enrolled. They all satisfied predefined criteria for diagnosis of TBM. Clinical and radiological features of children with/without a BCG scar were compared. Univariate analysis revealed that the vaccinated children with TBM had significantly lower rates of altered sensorium (68.5% v 85.4% unvaccinated; OR 2.2 (1.1 to 6.2); p = 0.019) and focal neurological deficits (20.3% v 39.5% unvaccinated; OR 2.6 (1.1 to 6.0); p = 0.016), and higher mean (SD) Glasgow Coma Scale score (10.2 (3.4) v 8.76 (2.7) unvaccinated; p = 0.010) and cerebrospinal fluid cell count (210.9 v 140.9 unvaccinated; p = 0.019). No significant radiological differences were seen. Short term outcome was significantly better in the vaccinated group with 70% of the total severe sequelae and 75% of the total deaths occurring in the unvaccinated group (p = 0.018). Children with TBM who have been vaccinated with BCG appear to maintain better mentation and have a superior outcome. This may in part be explained by the better immune response to infection, as reflected in the higher CSF cell counts in this group in the present study.


[Sjögren's syndrome].
The authors present an account on Sjögren's syndrome--clinical manifestations, diagnosis, pathogenetic aspects and treatment. The diagnosis was based on three findings: keratoconjunctivitis sicca, stomatodynia--xerostomia and other immunological, diseases. The authors used different immunological examinations, bioptic examination of the oral mucosa and parotid glands. As to gastroenterological examinations, the gastric secretion is examined according to Lambling's method, the gastroduodenum is subjected to radiographic examination, endoscopy is performed as well as a bioptic examination of the gastroduedenal mucosa.


Electrically tunable wetting defects characterized by a simple capillary force sensor.
We present a concept of a wetting defect of continuously variable strength based on electrowetting, along with a capillary force sensor adapted for the characterization of macroscopically heterogeneous surfaces. Patterned electrodes submerged under an insulating layer are used to generate potential wells for drops of electrically conductive liquids on the solid surface, with a well depth that scales with the diameter of the drop and square of the applied alternating (AC) voltage. We characterize the strength of the electrowetting trap and the hysteretic motion of the drop along the surface, using a simple force sensor based on optical imaging of a thin bendable capillary. A force resolution of approximately 0.1 μN is achieved.


Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA.
The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.


[Ogilvie syndrome in the elderly: retrospective study of 40 cases].
To assess, in a population of elderly patients, the circumstances clinical and progressive characteristics and form of management of an acute colonic pseudo-obstruction (ACPO). Retrospective study of the files of 40 patients aged 70 and more having presented an acute colonic pseudo-obstruction and hospitalised in the university hospital in Dijon from January 1995 to June 2000. The population was composed of 24 men (60%) and 16 women (40%) with a mean age of 80.8 years. The reasons for hospitalisation were varied: only 15 patients had been referred for an occlusive syndrome. 39 patients presented with abdominal distension, 30 suffered from abdominal pain. In this population, 17 patients exhibited reduced or clearly limited mobility, 20 patients had altered cognitive capacity with an MMS < 20. Thirty-eight patients suffered from a progressive heart disease and 8 patients presented with advanced dementia. The usual treatment of these patients to help the intestinal transit included diuretics in 25 cases and agents slowing the transit in 19 cases. Biologically speaking, hypokalaemia was observed in 21 cases and increased thyroid stimulating hormone (TSH) in 3 cases. An image was obtained of the abdomen without preparation in all patients: the mean caecum diameter was of 9.8 cm. A colon aspiration was performed in 20 patients and molecules to improve peristaltism were administered in 21 cases, with neostigmine prescribed for 9 patients. Surgery was required for 7 patients and 3 of them subsequently died. In terms of progression, 20 patients were cured after treatment, 13 relapsed and 7 patients worsened. Unfortunately, 10 patients died in our series. In our study, the clinical profiles of acute colonic pseudo-obstruction were similar to those described in the literature: they occurred in varying circumstances, in medical or surgical settings ina predominantly male population of elderly, heavily dependent,patients. Treatment of this affection is not clearly codified for fragile patients with multiple diseases and the mortality rate observed should stimulate further studies, notably on pharmacological level.


Fat mass and obesity-associated gene enhances oxidative stress and lipogenesis in nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, hyperlipidemia, and type 2 diabetes mellitus. Several studies have found that fat mass and the obesity-associated (FTO) gene is linked to obesity. The aim of this work is to investigate the expression and function of FTO in liver with lipid metabolism diseases. We investigated the basal FTO expression in an NAFLD rat model and compared it with control subjects. The function of FTO in lipid metabolism was further studied in L02 cells through overexpression experiments. A significant increase in FTO mRNA and protein levels was found in the NAFLD group. In addition, the FTO levels were positively associated with malondialdehyde and superoxide dismutase concentrations. FTO overexpression in L02 cells enhanced lipogenesis and oxidative stress. This study demonstrates that increased FTO levels in the liver are involved in oxidative stress and lipid deposition, which characterize NAFLD.


The metabolic syndrome and risk of myocardial infarction in familial hypertension (hypertension heredity in Malmö evaluation study).
The aim of this study was to examine whether three main definitions of the metabolic syndrome (MetS)--WHO, National Cholesterol Education Program--Adult Treatment Panel III and International Diabetes Federation--identify the same individuals and are able to predict incident myocardial infarction (MI) in families with essential hypertension. The tested definitions were prospectively related to data on MI in a cohort of approximately 1700 individuals with overt essential hypertension and their normotensive first-degree relatives. At baseline, 616 participants had MetS, yet only 209 of them (33.9%) were identified by all definitions, and compatibility rate for each pair of definitions was approximately 50%. During follow-up (Tmean approximately 6.6 years) 53 participants developed MI and they were generally older and more dysmetabolic than the rest of the cohort. There were also more men, smokers and diabetic individuals in this group. After adjustment for all conventional cardiovascular risk factors, including hypertension and diabetes, only the National Cholesterol Education Program definition could predict the increased risk of MI [odds ratio (OR) = 2.2, confidence interval (CI) = 1.2-4.0, P = 0.01]. Among individual MetS components, incident MI was independently associated with three of them: low high-density lipoprotein-cholesterol (OR = 2.03, CI = 1.09-3.78, P = 0.025) insulin resistance (OR = 2.02, CI = 1.08-3.78, P = 0.028) and increased albumin excretion rate (OR = 1.24, CI = 0.99-1.55, P = 0.060). The presence of MetS in hypertensive and genetically hypertension prone individuals may signal the increased risk of future MI. However, only the National Cholesterol Education Program criteria appear to have a sufficient predictive accuracy.


The relationship between discrimination and articulation training in children with misarticulations.
In the context of a training study, the functional relationship between discrimination and production was investigated. Four subjects were selected for study. For two subjects, Condition I consisted of production training followed by a discrimination probe and Condition II consisted of discrimination training followed by a production probe. For the other two subjects, the conditions were reversed. In production training, the subjects were trained to correctly articulate three consonant-vowel (CV) syllables in response to nonsense pictures. In discrimination training the subjects were trained to find nonsense pictures in response to three CV syllables. Probe measures were administered to determine if changes occurred in one modality after training the other modality. Results indicated that production training was effective in changing both articulation and discrimination; however, discrimination training was effective in changing only discrimination.


Abstract PS6-55: The prognostic utility of AR/ER ratio in young women with breast cancer.
World over, less than a quarter of breast cancer diagnoses are in premenopausal women. However, in India premenopausal women constitute half of all women with breast cancer in most hospital case series. Most of these women present at advanced stages with aggressive subtypes of disease and hence the high mortality.The role and utility of detecting androgen receptor (AR) expression in the different sub-types of breast cancer, especially the ones without hormone receptor expression is yet to be firmly established. Evidence from previous studies is suggestive of its beneficial role in hormone receptor positive (HR+) breast cancer. The biological function of AR on the mammary epithelium is determined by the Estrogen receptor (ER) context, in that, it is found to be anti-proliferative in ER positive tumors while it is thought to promote growth in the absence of ER activity. An interesting approach to representing this interplay is as a ratio between AR/ER expressions. As expected, the ratio has been shown to be positively correlated with better outcomes in hormone receptor cancers, mostly in postmenopausal women. The effect of a high ratio in ER negative tumors seems more complicated. In this study, we have evaluated the AR/ER ratio specifically in patients younger than 50 years in whom the estrogenic influence is dominant due to their premenopausal status. Tumor samples from patients 50 years or younger were chosen from a larger cohort of 275 patients with median follow up of 72 months. Expression of ER and AR proteins were detected by immunohistochemistry (IHC), and the transcript levels of ESR1 and AR were determined by quantitative PCR. Relative normalized units of their gene expression were used to calculate the AR/ER ratio. A cut-off at the 3rd quartile was used to divide tumors into categories of high and low ratios. Clinical characteristics were compared between the low and high ratio groups along with IHC subtype distribution (HR+, HER2+ and Triple negative (TNBC)). Kaplan Meier curves was used for survival analysis and Cox proportional hazard analysis model was used to calculate the hazard ratio (HR). The results were validated in METABRIC dataset. Eighty-eight (32%) patients were <50 years with a mean age of 43 years. AR/ER ratio ranged between 0.6 to 3.5 with a mean of 1.5. Sixty-six tumors were categorized as low and 22 were high based on the 3Q cut off (1.7). Clinical characters such as age, tumor size, grade, stage of disease was not different between the high and low ratio categories. Distribution of IHC subtypes among each group showed high ratio category had 64% TNBC tumors (p<0.0001). Tumors with high ratio had poor disease-free survival, (HR-2.6(95% CI-1-6.9) p-0.03). Trends in the METABRIC dataset was similar with 411(21%) patients <50 years. Ninety-seven patients with high ratio had significantly poor disease-free survival (HR-1.95 (95% CI-1.3-2.7) p-0.000). Interaction between AR and ER is known to influence the AR activity and our results reiterate prognostic ability of AR/ER ratio even in young patients of breast cancer. Our results suggest androgenic influences on clinical progression of breast cancer in this age group mediated through AR, has to be examined by its level in relation to the activity of ER, particularly in hormone receptor negative breast cancers. Even more importantly, examining these influences in the context of the menopausal status might help identify subgroups of patients most likely to benefit from interventions targeted at AR.


A case of excessive autophagocytosis with multiorgan involvement and low clinical penetrance.
An autopsy and microscopic analyses of a 74-year-old female with a clinical history of cardiac hypertrophy and hypertension disclosed a pronounced distension of lysosomal compartment with signs of excessive autophagocytosis, predominantly in cardiomyocytes, hepatocytes and smooth muscle cells of the small intestine. The histological storage pattern did not correspond to the usual changes seen in defined lysosomal storage disorders. The amount of age-related lipopigment was low in all tissues. Confocal microscopy of liver tissue samples documented a progressive loss of mitochondrial epitopes in the distended lysosomal compartment along the porto-central axis of hepatic lobules. The possibility to detect subunit c of mitochondrial ATP synthase (SCMAS) indicated extensive intra-lysosomal degradation of mitochondria, both in hepatocytes and smooth muscle cells. The SCMAS epitope can thus be considered a valuable immunohistochemical marker of autophagocytic mitochondrial degradation. The distended lysosomes also displayed tissue specific ubiquitination. Absence of immuno-detectable p62 protein excluded aggresome formation. An inherent dysfunction of the late endosomal/lysosomal LAMP2 protein (Danon disease), was excluded on the basis of LAMP2 gene sequence analysis and LAMP2 protein levels. Whether the observed process reflects a primary dysregulation of the constitution of the autophagosomal membrane or was induced by defects in other cellular components, remains unanswered. Whatever mechanism involved, the findings should be considered relevant in differential diagnostics, despite their low clinical penetrance, should be registered and thus rendered available for future definition.


A Morita-Baylis-Hillman based route to C-5a-chain-extended 4-epi-isofagomine type glycosidase inhibitors.
By Morita-Baylis-Hillman reaction of 2,3-O-isopropylidene-D-glyceraldehyde with α,β-unsaturated carbonyl as well as hetero analogous carbonyl compounds such as acrylonitrile, suitable precursors of isofagomine and of 4-epi-isofagomine are available. Elaboration of the structures by amine introduction, followed by intramolecular ring closure and subsequent hydroboration of the double bond provides 4-epi-isofagomine derivatives featuring chain extensions at C-5a which are determined by the structures of the carbonyl compounds employed. As an example, the synthesis of C-(5aR)- and C-(5aS)-5a-C-pentyl-4-epi-isofagomines, powerful inhibitors of β-galactosidases, is outlined. In line with reported data, the (C-5aR) epimer was found a highly potent experimental pharmacological chaperone for GM1-associated human lysosomal β-galactosidase mutant R201C.


Direct site-specific glycoform identification and quantitative comparison of glycoprotein therapeutics: imiglucerase and velaglucerase alfa.
Gaucher disease, the most common lysosomal metabolic disorder, can be treated with enzyme replacement therapy (ERT). Recombinant human glucocerebrosidase imiglucerase (Cerezyme(®)), produced in Chinese hamster ovary cells, has been used for ERT of Gaucher disease for 20 years. Another recombinant glucocerebrosidase velaglucerase alfa (VPRIV), expressed in a human fibroblast cell line, was approved by the US Food and Drug Administration in 2010. The amino acid sequence difference at residue 495 of these two products is well documented. The overall N-linked qualitative glycan composition of these two products has also been reported previously. Herein, employing our recently developed approach utilizing isobaric tandem mass tag (TMT) labeling and an LTQ Orbitrap XL electron transfer dissociation (ETD) hybrid mass spectrometer, the site-specific glycoforms of these products were identified with ETD and collision-induced dissociation (CID) spectra. The quantitative comparison of site-specific glycans was achieved utilizing higher-energy collisional dissociation (HCD) spectra with a NanoMate used as both a fraction collector and a sample introduction device. From the trypsin-digested mixture of these two products, over 90 glycopeptides were identified by accurate mass matching. In addition to those previously reported, additional glycopeptides were detected with moderate abundance. The relative amount of each glycoform at a specific glycosylation site was determined based on reporter signal intensities of the TMT labeling reagents. This is the first report of site-specific simultaneous qualitative and quantitative comparison of glycoforms for Cerezyme(®) and VPRIV. The results demonstrate that this method could be utilized for biosimilarity determination and counterfeit identification of glycoproteins.


Rod and cone input to horizontal cells in the rabbit retina.
In the rabbit retina, there are two types of horizontal cell (HC). The A-type HC is axonless and extensively coupled. The B-type HC is axon bearing; the somatic dendrites are radially symmetric and form a second coupled network, while the axon branches expansively to form a complex terminal structure. The B-type axon terminals (ATs) are independently coupled to form a third network in the outer plexiform layer. We have modified our dye-injection methods to obtain detailed fills of the three different horizontal cell networks for analysis via confocal microscopy. We have confirmed that A-type HCs and the somatic dendrites of B-type HCs receive input exclusively from cones, whereas the B-type ATs receive input only from rods. A single B-type AT may receive input from as many as 1,000 rods, but, surprisingly, our data reveal only one end terminal per rod spherule. The somatic dendrites of A- and B-type HCs form clusters at each cone pedicle coincident with GluR2/3 and GluR4 glutamate receptor subunits. The B-type ATs have GluR2/3- or GluR4-labeled glutamate receptors in two locations: small puncta on the end terminals within the rod spherule invagination and large clusters on the terminal stalks, approximately 1.5 microm from the rod synaptic ribbon. We conclude that AMPA receptors of the same or similar composition mediate photoreceptor input to all types of HCs.


Malignant fibrous histiocytoma of the spermatic cord. A case report.
A case of malignant fibrous histiocytoma of the spermatic cord treated by primary local excision, followed 5 days later by radical inguinal orchidectomy and hemi-scrotectomy is reported. At 30 months' follow-up the patient is free from local recurrence.


Towards a model of the organisation of planar polarity and pattern in the Drosophila abdomen.
The abdomen of adult Drosophila consists of a chain of alternating anterior (A) and posterior (P) compartments which are themselves subdivided into stripes of different types of cuticle. Most of the cuticle is decorated with hairs and bristles that point posteriorly, indicating the planar polarity of the cells. Here we research the link between pattern and polarity. Previously we showed that the pattern of the A compartment depends on the local concentration (the scalar) of a Hedgehog morphogen produced by cells in the P compartment. Here we present evidence that the P compartment is patterned by another morphogen, Wingless, which is induced by Hedgehog in A compartment cells and then spreads back into the P compartment. We also find that both Hedgehog and Wingless appear to specify pattern by activating the optomotor blind gene, which encodes a transcription factor. We re-examine our working model that planar polarity is determined by the cells reading the gradient in concentration (the vector) of a morphogen 'X' which is produced on receipt of Hedgehog. We present evidence that Hedgehog induces X production by driving optomotor blind expression. We tried but failed to identify X and present data that X is not likely to operate through the conventional Notch, Decapentaplegic, EGF or FGF transduction pathways, or to encode a Wnt. However, we argue that Wingless may act to enhance the production or organise the distribution of X. A simple model that accommodates our results is that X forms a monotonic gradient extending from the back of the A compartment to the front of the P compartment in the next segment, a unit constituting a parasegment.


Cross-validation of independent ultra-low-frequency magnetic recording systems for active fault studies.
When working with ultra-low-frequency (ULF) magnetic datasets, as with most geophysical time-series data, it is important to be able to distinguish between cultural signals, internal instrument noise, and natural external signals with their induced telluric fields. This distinction is commonly attempted using simultaneously recorded data from a spatially remote reference site. Here, instead, we compared data recorded by two systems with different instrumental characteristics at the same location over the same time period. We collocated two independent ULF magnetic systems, one from the QuakeFinder network and the other from the United States Geological Survey (USGS)-Stanford network, in order to cross-compare their data, characterize data reproducibility, and characterize signal origin. In addition, we used simultaneous measurements at a remote geomagnetic observatory to distinguish global atmospheric signals from local cultural signals. We demonstrated that the QuakeFinder and USGS-Stanford systems have excellent coherence, despite their different sensors and digitizers. Rare instances of isolated signals recorded by only one system or only one sensor indicate that caution is needed when attributing specific recorded signal features to specific origins.


Compensating for alcohol-induced impairment: alcohol expectancies and behavioral disinhibition.
Studies have shown that expectations of alcohol-induced impairment can produce adaptive responses to alcohol that serve to reduce the degree of behavioral impairment displayed. The present research examined how an expectancy-induced adaptive response could reduce the impairing effects of alcohol on response activation, while at the same time increase its impairing effect on response inhibition. Social drinkers (N = 48) practiced a stop-signal choice reaction time (RT) task that measured their speed of responding and their ability to inhibit responses to stop signals. Subjects then received 0.65 g/kg of alcohol, a placebo beverage, or no beverage. Prior to performing the task again, one-half of the sample was given information to expect that alcohol would slow (i.e., impair) their RT. The others received no expectancy treatment. Subjects led to expect slowed RT displayed faster RTs but fewer inhibitions under alcohol, compared with those who received no such expectancy The same pattern of results was observed under the placebo condition. In the "no beverage" condition, the expectancy treatment had no significant effect on subjects' RT or inhibitions. The findings demonstrate that an alcohol expectancy can reduce impairment of one aspect of performance under the drug while increasing its impairing effect on another. The study contributes to a growing body of research that highlights the importance of understanding interactions between the expected and pharmacological effects of alcohol.


Order of application determines the interaction between phorbol esters and GTP-gamma-S in dorsal raphe neurons: evidence that the effect of 5-HT is modified upstream of the G protein Ca channel interaction.
Phorbol esters activating protein kinase C (PKC) partially uncouple the inhibitory effect of serotonin (5-HT) from serotonergic neuron Ca2+ current. Presently the site of action of PKC is not known and may be the receptor, G protein, or ion channel. We recorded Ca2+ current from acutely isolated neurons with the use of the patch-clamp technique to study the site of action of PKC. Activation of the G protein with internal guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) occluded the response to 5-HT, but unexpectedly this effect was not reversed by the addition of the phorbol ester phorbol 12-myristate 13-acetate (PMA) despite the voltage-dependent reversal of the effect of GTP-gamma-S by long depolarizing steps to +80 mV. PMA was, however, able to partially reverse 5-HT-induced inhibition of Ca2+ current. The rate of reinhibition of the Ca2+ current (related to the concentration of activated G proteins) by GTP-gamma-S after the addition of PMA at -50 mV was identical to the rate when only GTP-gamma-S was present. By contrast, when cells were exposed first to PMA, and then GTP-gamma-S was perfused into the cell, GTP-gamma-S lost about half of its ability to activate the G protein. The rate of reinhibition of the Ca2+ current by internal GTP-gamma-S was also reduced in cells pretreated with PMA. The original result in which PMA did not reverse the action of GTP-gamma-S suggested that the channel was not the functional site of action of PMA, nor was the site on the G protein that binds to the channel, but it did not rule out the receptor. When the receptor was bypassed, after prior PKC activation, it was found that direct activation of the G protein by a nonhydrolyzable analogue of GTP was reduced; taken as a whole, this indicates that in dorsal raphe, and perhaps other neurons, the site of the critical phosphorylation may be on the G protein and possibly at the GTP binding site.