beta2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart.
Recent studies of beta-adrenergic receptor (beta-AR) subtype signaling in in vitro preparations have raised doubts as to whether the cAMP/protein kinase A (PKA) signaling is activated in the same manner in response to beta2-AR versus beta1-AR stimulation. The present study compared, in the intact dog, the magnitude and characteristics of chronotropic, inotropic, and lusitropic effects of cAMP accumulation, PKA activation, and PKA-dependent phosphorylation of key effector proteins in response to beta-AR subtype stimulation. In addition, many of these parameters and L-type Ca2+ current (ICa) were also measured in single canine ventricular myocytes. The results indicate that although the cAMP/PKA-dependent phosphorylation cascade activated by beta1-AR stimulation could explain the resultant modulation of cardiac function, substantial beta2-AR-mediated chronotropic, inotropic, and lusitropic responses occurred in the absence of PKA activation and phosphorylation of nonsarcolemmal proteins, including phospholamban, troponin I, C protein, and glycogen phosphorylase kinase. However, in single canine myocytes, we found that beta2-AR-stimulated increases in both ICa and contraction were abolished by PKA inhibition. Thus, the beta2-AR-directed cAMP/PKA signaling modulates sarcolemmal L-type Ca2+ channels but does not regulate PKA-dependent phosphorylation of cytoplasmic proteins. These results indicate that the dissociation of beta2-AR signaling from cAMP regulatory systems is only apparent and that beta2-AR-stimulated cAMP/PKA signaling is uncoupled from phosphorylation of nonsarcolemmal regulatory proteins involved in excitation-contraction coupling.


A cohort study of breast cancer risk in breast reduction patients.
Surgical reduction of the female breast (reduction mammaplasty) is very common in plastic surgery. The purpose of this study was to determine whether women who have undergone breast reduction surgery are at the same, greater, or lesser risk of developing breast cancer than women who have not undergone breast reduction surgery. This study incorporates a population-based, non-concurrent cohort linkage methodology. The Canadian Institute for Health Information hospital records were used to identify all Ontario women who had undergone breast reduction surgery in Ontario between 1979 and 1992. Three computerized probabilistic record linkages were performed. The first linkage was between a file of the 28,042 Ontario women who had undergone bilateral breast reduction surgery between April 1, 1979, and December 31, 1992, and a file of incident cancer cases among Ontario women for the calendar period 1979 to 1993. Follow-up of the cohort was undertaken starting from the date of breast reduction surgery, and vital status was ascertained as of December 31, 1993, by record linkage with the Ontario Mortality Database maintained at the Ontario Cancer Registry. The incidence of cancer in the Ontario breast reduction cohort was compared with the cancer incidence of the general Ontario population after appropriate adjustments for age and calendar time period. The expected number of cancers was calculated using the "PERSON YEARS" computer program. Within the cohort, followed for an average of 6.5 years after bilateral breast reduction surgery, 101 breast cancers were observed and 165.8 were expected, for a standardized incidence ratio of 0.61 (0.50 to 0.74, 95 percent confidence interval). This effect was independent of patient age at breast reduction. This study demonstrates that there is no increased risk of breast cancer after bilateral breast reduction surgery and, in fact, a significant decreased risk existed in women followed for an average of 6.5 years.


Psychometric properties of goal-attainment scaling in the assessment of mann's time-limited psychotherapy.
This study tested the reliability and validity of Goal-Attainment Scaling (GAS) in assessing outcome in Mann's Time-Limited Psychotherapy (TLP). Judges constructed GAS scales for 33 patients on five dimensions: severity of symptoms, self-esteem, same-sex friendships, romantic relationships, and work performance. Patients in the treatment group received 12 sessions of TLP, whereas controls were in a waiting list for the same period of time (12 weeks) before starting time-limited psychotherapy. Judges rated all patients on GAS before beginning therapy, at termination, and follow-up. Mean interrater reliability of scores between pairs of judges was r = .88. Convergent validity of the GAS was confirmed by moderate to high correlations with the Health-Sickness Rating Scale (r = .70, p < .001), the Target Complaints Scale (r = .50, p <.01), and the Brief Symptom Inventory (r = .38, p < .05). The findings are discussed and recommendations are made for the reliable and valid use of the GAS in psychotherapy outcome research.


Analysis of materials for splinting of the thermally injured patient.
Good results have been achieved in the treatment of patients with burns with new splinting materials and proper splinting techniques. This article focuses on the thermoplastic splinting materials Clinic and Spectrum (Northcoast Medical Inc., San Jose, Calif.) and the comparable thermoplastic products Polyform (Smith & Nephew Rolyan, Inc., Menomonee Falls, Wis.) and Orthoplast (Johnson & Johnson Orthopedics, New Brunswick, N.J.). Qualities such as self-bonding, recyclability, and rigidity were tested for these materials. Splint rigidity was measured by a calibrated hook scale and determined by the force per pound needed to bend the material 20 degrees. Spectrum and Clinic products were judged more economical and, we contend, they are therefore better choices for splinting the thermally injured patient.


[Jakairá project: the adolescent parents as authors and actors of their own future].
The purpose of the following paper is to present a project developed within the framework of collaboration between two foundations, Fundación Kaleidos (Argentina) and Children Action (Switzerland). The aim of this project is to developed diverse programs to support and empower adolescent mothers and fathers as well as their children. Adolescents whose rights are very often not respected and who find themselves alone having to confront the negative prejudices of the adults around them regarding the parenthood, which they now face. The objectives of the programs are as follows: the promotion of the well-being of the adolescents and the development of a personal project around education or work, the promotion of early child development of their infants, to address the problems around gender inequality and the promotion of an intersectional network between distinct sectors of society (public, private and NGO). By means of an integral program, we aim to tackle the diverse aspects of the lives of the adolescents in question and their children. Their rights and their environment are key to developing the maximum potential of each individual and their families.


Metal-Free Intermolecular Coupling of Arenes with Secondary Amides: Chemoselective Synthesis of Aromatic Ketimines and Ketones, and N-Deacylation of Secondary Amides.
The direct transformation of common secondary amides into aromatic ketimines and aromatic ketones with C-C bond formation is described. The reaction can also be used for N-deacylation of secondary amides to release amines. This method consists of in situ amide activation with triflic anhydride and intermolecular capture of the resulting highly electrophilic nitrilium intermediate with an arene. The reaction is applicable to various kinds of secondary amides (electrophiles), but only electron-rich and moderately electron-rich arenes can be used as nucleophiles. Thanks to the use of bench stable arenes instead of reactive and basic organometallics as nucleophiles, the reaction proceeded with high chemoselectivity at the secondary amido group in the presence of a series of sensitive functional groups such as aldehyde, ketone, ester, cyano, nitro, and tertiary amido groups. The reaction can be viewed as a Friedel-Crafts-type reaction using secondary amides as acylating agents or as an intermolecular version of the Bischler-Napieralski reaction.


Value of genetic and epigenetic testing as biomarkers of response to antidepressant treatment.
Major depressive disorder (MDD) is one of the most prevalent and disabling psychiatric disorders worldwide and therefore an important public health priority. The selection process of antidepressant treatment is primarily guided by trial and error, and the outcomes with current antidepressant strategies are disappointing. The biological background of the disease is heterogeneous with presumably multiple biological systems involved. With the aim to individualize antidepressant treatment, multiple candidate gene and a few genome-wide association studies have been performed, but so far with very limited success. To address the dynamic changes of depressive symptoms and their response to treatment, recent studies focus on epigenetic mechanisms, as these are modulated by environmental stimuli and adaptive to different stages of the disorder. In the present paper, after a brief summary of the most important results from pharmacogenetic studies in MDD, we comment on the current and potential future value of genetic testing as a biomarker of response to antidepressant treatment. The new and exciting field of epigenetic mechanisms in antidepressant drug treatment will be presented in the second part of this review.


Urea recycling in muskrats (Ondatra zibethicus): a potential nitrogen-conserving tactic?
The rate of 14C-urea hydrolysis was determined in 32 field-acclimatized muskrats maintained on natural diets during spring, summer, fall, and winter. We hypothesized that urea recycling occurs in muskrats during all seasons and that the conservation of tissue nitrogen via this mechanism is most prevalent in fall and winter, when forage protein levels are lowest. Muskrats exhibited higher rates of urea hydrolysis and a lower serum urea nitrogen-to-creatinine ratio in fall and winter than in spring and summer. Even after correcting for seasonal differences in blood urea pool size, the adjusted rate of urea hydrolysis was 67% higher in fall and winter than in spring and summer. There was no evidence that the maintenance nitrogen requirements of muskrats fed natural vegetation were affected by seasonal changes in the amino acid composition of the diet. We suggest that increased levels of urea recycling, coupled with adaptive mechanisms for reducing nitrogen excretion and possibly conserving carbon skeletons of essential amino acids, may allow muskrats to reduce their nitrogen requirements on fall and winter diets. Our finding that 14C-urea hydrolysis occurred during all four sampling periods suggests that nitrogen derived from this source may also be critical to supporting large hindgut microbe populations that enable this rodent to exploit the appreciable fiber content of its aquatic plant diet throughout the year.


[Thalidomide inhibits the angiogenic activity of culture supernatants of multiple myeloma cell line].
To investigate the pro-angiogenic effects of several multiple myeloma (MM) cell line culture supernatants on human bone marrow endothelial cell (HBMEC) proliferation, migration, and capillary formation, and the anti-angiogenic effects of thalidomide. HBMEC was cultured in the presence of MM cell lines (IM9, XG1, U266 and MOLP-5) supernatants. Proliferation and migration of HBMEC were determined, capillary-like tubule formation of HBMEC was examined in fibrin and Matrigel. The inhibiting effect of thalidomide was investigated by adding it into myeloma cell line culture supernatants. Vascular endothelial growth factor (VEGF) was measured by ELISA. (1) MM cell lines culture supernatants promoted HBMEC proliferation and migration. (2) In fibrin and Matrigel, capillary-like tubule network formation promoted by the supernatants. (3) All of these effects could be inhibited by thalidomide. (4) This effect was not related to VEGF in the supernatants. MM cell line promote proliferation, migration and tubule formation by secreting VEGF or other several cytokines. Thalidomide can inhibit these effects.


Epidemics due to imported syphilis in Finland.
Russia and other states of the former Soviet Union experienced a huge increase in syphilis beginning in the early 1990s. At first these epidemics were not well known in neighboring countries such as Finland. In 1995 the incidence of syphilis in Finland doubled to 3.3/100,000 and a local cluster of 18 cases was detected in the city of Tampere. The reasons for this epidemic were analyzed and the occurrence of syphilis was carefully monitored up to 2001. The main reason for the increased incidence in Finland was the import of syphilis from Russia; only a few cases were acquired from Estonia or elsewhere. The source partners of Finnish men who contracted syphilis abroad were mostly sex workers or other casual partners. Mobile prostitution to Finland was not involved in the transmission. Most syphilis cases were found sporadically in southern Finland, in areas where foreign travel is frequent. Secondary transmission in Finland was usually limited to one or two partners. The only isolated cluster was further away and developed due to unawareness of the risk of syphilis by the cases and local healthcare providers. From 1995 onward, syphilis was carefully monitored by national reporting and a special sexually transmitted disease (STD) surveillance network, and the incidence remained at a constant level even though travel to and from Russia more than tripled. Nationwide serologic surveillance in STD and maternity clinics and among blood donors showed no major changes in the prevalence of syphilis. An epidemic of syphilis imported mainly by heterosexual men from Russia caused one sporadic cluster in Finland in 1995. Thereafter, general awareness by the public and healthcare providers about the risks of contracting syphilis from abroad, in addition to effective use of national surveillance and notification systems, was needed to protect the country from further spread of syphilis to an endemic infection.


Evaluation of neglected idiopathic ctev managed by ligamentotaxis using jess: a long-term followup.
Background. This study was conducted with the aim of evaluating the role of Ligamentotaxis in the management of neglected clubfeet managed by ligamentotaxis using Joshi's External Stabilisation System (JESS). Method & Material. Total 20 subjects (28 feet) were studied, which were corrected by differential ligamentotaxis using JESS. All were evaluated clinically, radiologically, podogrammically, and by Catterall Pirani Scoring System, both before and after the correction. Results. Severity of the deformities and clinical correction was assessed by Pirani score. All patients achieved good clinical results as per Pirani score, which was statistically significant. Radiological evaluation showed that all subjects achieved the normal range of values. The pre- and postcorrection difference in FBA was statistically significant. Conclusion. Differential distraction by fixator for the correction of neglected idiopathic CTEV is an effective and patient-friendly method of management.


Misalignment of global COVID-19 breastfeeding and newborn care guidelines with World Health Organization recommendations.
Recommendations for the clinical management of new mothers with suspected or confirmed COVID-19 and their infants are required. Guidance must weigh the risk posed by transmission of SARS-CoV-2 against the protection that maternal proximity and breastfeeding provide infants. Our aim was to review international COVID-19 guidance for maternal and newborn care, assessing alignment with WHO recommendations and the extent to which policy supported or undermined breastfeeding. Guidance documents from 33 countries on the care of infants whose mothers were suspected or confirmed as having COVID-19 were assessed for alignment with WHO recommendations regarding: (1) skin-to-skin contact; (2) early initiation of breastfeeding; (3); rooming-in; (4) direct breastfeeding; (5) provision of expressed breastmilk; (6) provision of donor human milk; (7) wet nursing; (8) provision of breastmilk substitutes; (9) psychological support for separated mothers; and (10) psychological support for separated infants. Considerable inconsistency in recommendations were found. Recommendations against practices supportive of breastfeeding were common, even in countries with high infant mortality rates. None of the guidance documents reviewed recommended all aspects of WHO guidance. The presence of influential guidance conflicting with WHO recommendations and an undervaluing of the importance of maternal proximity and breastfeeding to infant health appeared to contribute to this poor alignment. Those developing guidance in the COVID-19 pandemic and other infectious disease outbreaks need to appropriately consider the importance of skin-to-skin contact, early initiation of breastfeeding, rooming-in and breastfeeding to maternal and infant physical and psychological health. In weighing the value of recommendations of others in future guidance development, countries should consider past reliability and value placed on breastfeeding. Recommendations against maternal proximity and breastfeeding should not be made without compelling evidence that they are necessary, and less harmful than maintaining dyad integrity.


Suppressor lymphocytes during open heart surgery.
Open heart surgery is associated with a moderate to severe postoperative of cell-mediated immunity. To characterize this defect, T-suppressor lymphocytes were studied in nine patients undergoing elective aortic/mitral valve replacement surgery. A decrease of the number of T-suppressor lymphocytes was observed after the operation. At the same time the activity of concanavalin A (Con A)- and phytohaemagglutinin (PHA)-induced suppressor cells decrease. Thus the decrease of cell-mediated immunity after open heart surgery seems not to be due to activation of suppressor lymphocytes.


Toward a more complete understanding of reactions to hooking up among college women.
Hooking up, a relatively common behavior among young adults, refers to a casual sexual encounter, ranging from kissing to sexual intercourse, without an expectation of ongoing physical encounters or relational commitment. Reactions to hooking up have examined psychosocial outcomes as a proxy for specific reactions. The present study examined the reactions of 190 college women, with a specific focus on the effect of hooking up on their social/peer network, their sexual/romantic sense of self, and their academic performance. Results demonstrated large positive effects for sexual/romantic reactions and social/academic engagement reactions in comparison with negative personal reactions. In addition, higher ratings of anxious attachment, loneliness, and relational/intimacy sex motives were related to less positive reactions, highlighting the importance of attachment and motivations behind hookup experiences. Implications for educational practice and future research are offered.


The picture of health: examining school-based health environments through photographs.
Health-promoting schools (HPS) is an effective approach to enhance the health and well-being of children and youth, but its measurement remains a challenge considering contextual differences across school environments. The purpose of this study was to qualitatively explore the physical features of the school environment through photographs of schools that had implemented an HPS approach compared with schools that had not. This study used a descriptive approach, wherein physical features of the school environment were distilled through visual images and qualitatively analyzed. School environment data were collected from 18 elementary schools (10 HPS, 8 comparison schools) from a school board in rural Nova Scotia (Canada). Evaluation assistants captured photographs of the physical school environment as part of a broader environment audit. Overarching themes included the promotion, access and availability of opportunities for healthy eating and physical activity, healthy school climate and safety and accessibility of the school. The photographs characterized diverse aspects of the school environment and revealed differences between schools that had implemented an HPS approach compared with schools that had not. There were increased visual cues to support healthy eating, physical activity and mental well-being, and indications of a holistic approach to health among schools that implemented an HPS approach. This research adds to understanding the environmental elements of HPS. The use of photographic data to understand school environments provided an innovative method to explore the physical features of schools that had implemented an HPS approach.


Regional population projections: a multiple base-point approach.
Some alternative population projections are presented for Poland's major regions, based on a series of selected base years from 1977 to 1985. The author "interprets the corresponding observed demographic patterns as alternative model patterns on which consecutive projection runs are based." The projections, which are extended to 2050, exclude estimates for international migration.


Mucosal vaccination against tuberculosis using Ag85A-loaded immunostimulating complexes.
Tuberculosis (TB) is one of the major devastating diseases in the world, mainly caused by Mycobacterium tuberculosis. Furthermore, multi-drug resistant TB and extremely drug resistant TB are becoming big problems globally. Bacillus Calmette-Guerin (BCG) is the only available vaccine which provides protection against TB. The BCG vaccine is effective in children but not recommended in adults and elderly patients due to an associated low risk of infection with Mycobacterium tuberculosis and variable effectiveness of the vaccine. The main aim of this research study is to develop such a vaccine which will provide a better and safer profile in children and adults, as well as in elderly patients. In this present study, we prepared pulmonary tubercular vaccine by using an Antigen 85 complex (Ag85)-loaded nanocarrier such as the immunostimulating complex (ISCOM). Immunological outcomes clearly indicated significant improvement in humoral as well as cellular immune responses after pulmonary immunization with ISCOMs containing Quil A in mice.


Developmental pharmacokinetics.
The advances in developmental pharmacokinetics during the past decade reside with an enhanced understanding of the influence of growth and development on drug absorption, distribution, metabolism, and excretion (ADME). However, significant information gaps remain with respect to our ability to characterize the impact of ontogeny on the activity of important drug metabolizing enzymes, transporters, and other targets. The ultimate goal of rational drug therapy in neonates, infants, children, and adolescents resides with the ability to individualize it based on known developmental differences in drug disposition and action. The clinical challenge in achieving this is accounting for the variability in all of the contravening factors that influence pharmacokinetics and pharmacodynamics (e.g., genetic variants of ADME genes, different disease phenotypes, disease progression, and concomitant treatment). Application of novel technologies in the fields of pharmacometrics (e.g., in silico simulation of exposure-response relationships; disease progression modeling), pharmacogenomics and biomarker development (e.g., creation of pharmacodynamic surrogate endpoints suitable for pediatric use) are increasingly making integrated approaches for developmentally appropriate dose regimen selection possible.


Restoration of spermatogenesis by hormone treatment after cytotoxic therapy.
Cytotoxic therapy is effective in treating various cancers, but many of the agents used can cause sterility in men, regardless of the age at which they were treated. Originally, it was thought that infertility in individuals who had undergone cytotoxic therapy resulted from the destruction of stem spermatogonia. However, studies using rats suggest that some stem spermatogonia can survive cytotoxic therapy and that infertility is caused by the inability of these spermatogonia to differentiate. The author believes that the failure of these cells to differentiate may be related to the high levels of intratesticular testosterone encountered in these situations. In rats that have previously received cytotoxic therapy, the administration of a gonadotrophin-releasing hormone (GnRH) agonist restores the ability of spermatogonia to differentiate, and as a result normal spermatogenesis returns. This finding suggests that GnRH agonists show promise as a treatment for male sterility induced by cytotoxic therapy, although further studies are required.


Bioactive daphnane diterpenes from Wikstroemia chuii with their potential anti-inflammatory effects and anti-HIV activities.
A phytochemical investigation on the stems and leaves of Wikstroemia chuii resulted in the isolation of three new daphnane diterpenes, wikstroechuins A-C (1-3), together with eight known analogues (4-11). The structures of new daphnane diterpenes (1-3) were determined on the basis of extensive spectroscopic methods and the known daphnane diterpenes (4-11) were identified by comparing their observable spectroscopic data with those reported spectral data in the literature. The anti-inflammatory effects as well as anti-HIV activities in vitro of all isolated daphnane diterpenes 1-11 were assessed. As a consequence, daphnane diterpenes 1-11 displayed remarkable inhibitory activities on NO (nitric oxide) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells showing IC50 values in the range of 0.12 ± 0.03 to 10.58 ± 0.16 µM. Meanwhile, daphnane diterpenes 1-11 displayed significant anti-HIV-1 reverse transcriptase (RT) effects showing EC50 values ranging from 0.09509 to 8.62356 µM. These research results indicated that the discovery of these new daphnane diterpenes with remarkable anti-inflammatory and anti-HIV activities from W. chuii, especially these new ones, could be extremely meaningful to the discovery of new anti-inflammatory agents and anti-HIV drugs as well as their potential practical values in the health and pharmaceutical products.


P-glycoprotein substrate binding domains are located at the transmembrane domain/transmembrane domain interfaces: a combined photoaffinity labeling-protein homology modeling approach.
P-glycoprotein (P-gp) is an energy-dependent multidrug efflux pump conferring resistance to cancer chemotherapy. Characterization of the mechanism of drug transport at a molecular level represents an important prerequisite for the design of pump inhibitors, which resensitize cancer cells to standard chemotherapy. In addition, P-glycoprotein plays an important role for early absorption, distribution, metabolism, excretion, and toxicity profiling in drug development. A set of propafenonetype substrate photoaffinity ligands has been used in this study in conjunction with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to define the substrate binding domain(s) of P-gp in more detail. The highest labeling was observed in transmembrane segments 3, 5, 8, and 11. A homology model for P-gp was generated on the basis of the dimeric crystal structure of Vibrio cholerae MsbA, an essential lipid transporter. Thereafter, the labeling pattern was projected onto the 3D atomic-detail model of P-gp to allow a visualization of the binding domain(s). Labeling is predicted by the model to occur at the two transmembrane domain/transmembrane domain interfaces formed between the amino- and carboxyl-terminal half of P-gp. These interfaces are formed by transmembrane (TM) segments 3 and 11 on one hand and TM segments 5 and 8 on the other hand. Available data on LmrA and AcrB, two bacterial multidrug efflux pumps, suggest that binding at domain interfaces may be a general feature of polyspecific drug efflux pumps.


Impact of BMI, Physical Activity, and Sitting Time Levels on Health-Related Outcomes in a Group of Overweight and Obese Adults with and without Type 2 Diabetes.
Physical activity level and sedentary behaviors affect health status in people with obesity and type 2 diabetes (DM2); their assessment is mandatory to properly prescribe exercise programs. From January 2011 to February 2014, 293 overweight/obese adults (165 women and 128 men, mean age of 51.9 ± 9.5 years and 54.6 ± 8.3 years, respectively), with and without DM2, participated in a three-month intensive exercise program. Before starting, participants were allocated into three subgroups (overweight, body mass index or BMI = 25-29.9; class 1 of obesity, BMI = 30-34.4; or class 2 (or superior) of obesity, BMI > 35). The international physical activity questionnaire (IPAQ-it) was used to evaluate participants' baseline sitting time (SIT) and physical activity level (PAL). Stratified multiple analyses were performed using four subgroups of SIT level according to Ekelund et al., 2016 (low, 8 h/day of SIT) and three subgroups for PAL (high, moderate, and low). Health-related measures such as anthropometric variables, body composition, hematic parameters, blood pressure values, and functional capacities were studied at the beginning and at the end of the training period. An overall improvement of PAL was observed in the entire sample following the three-month intensive exercise program together with a general improvement in several health-related measures. The BMI group factor influenced the VO2 max variations, leg press values, triglycerides, and anthropometric variables, while the SIT group factor impacted the sitting time, VO2 max, glycemic profile, and fat mass. In this study, baseline PAL and SIT did not seem to influence the effects of an exercise intervention. The characteristics of our educational program, which also included a physical exercise protocol, allowed us to obtain positive results.


Discernment Counseling for "Mixed-Agenda" Couples.
This article describes discernment counseling, an approach to working with couples where one partner is leaning toward divorce and the other wants to preserve the relationship and work on it in couples therapy. These "mixed-agenda" couples are common in clinical practice but have been neglected in the literature. The goal of discernment counseling is clarity and confidence regarding the next steps for the relationship, based on a deeper understanding of each partner's contributions. Sessions emphasize individual conversations with each partner. An analysis of 100 consecutive cases found that about half of the couples chose to start couples therapy in order to reconcile, with most of the rest choosing the divorce path. Longer term follow-up information is also presented.


Low peripheral lymphocyte count before focal radiotherapy plus concomitant temozolomide predicts severe lymphopenia during malignant glioma treatment.
Malignant glioma patients treated with the golden standard therapy, focal radiotherapy plus concomitant daily temozolomide (radiotherapy/TMZ), often suffer severe lymphopenia. The frequency of severe lymphopenia and its predictors were analyzed by assessing adverse effects including decrease in white blood cell counts, lymphocyte counts, and neutrocyte counts according to the Common Toxicity Criteria version 3.0 (CTC) in 28 consecutive patients with pathologically verified malignant gliomas treated with radiotherapy/TMZ. Eighty-two percent of the patients suffered one or more adverse effects; lymphopenia (68%) was the most frequent adverse effect, with 32% of patients suffering CTC grade 4 lymphopenia. CTC grade 4 lymphopenia was associated with the incidence of other CTC grade 3 or 4 adverse effects and discontinuance of TMZ. Minimal lymphocyte counts during radiotherapy/TMZ and lymphocyte counts before radiotherapy/TMZ showed close linear correlation by linear regression analysis (p < 0.0001, R(2) = 0.569), and the most important predictor for CTC grade 4 lymphopenia was lymphocyte count before radiotherapy/TMZ less than 1200/microl by multivariate analysis (p < 0.0321, Exp = 13.2). Lymphocyte counts before radiotherapy/TMZ of less than 1200/microl predict severe lymphopenia during radiotherapy/TMZ.


[Lateralized distribution of motor areas involved in voluntary movement].
To investigate the brain functional laterality in motor areas during motor execution systematically. Functional magnetic resonance imaging (fMRI) was employed combined with right hand sequential finger movement task to investigate brain activation pattern and laterality in 8 right-handed subjects. 3dDeconvolve program of AFNI was used to estimate the hemodynamic response function and to generate activation maps. Then the laterality index (LI) was calculated and tested statistically. All motor areas including the areas which were previously considered to be engage in movement preparation only were activated in movement execution. In the activation map, it appeared left lateralization in cerebra and right lateralization in cerebella. After further statistical test, it was found that in primary motor area (M1), supplementary motor area (SMA) and posterior parietal cortex (PPC), there were left lateralization. While in premotor cortex (PMC), cingulate gyrus and basal ganglia (BG), the lateralization tendency was not obvious. The activation in cerebella is characterized with right lateralization. Though there are tiny differences among subjects, most of the motor areas appear lateralized activation. Past studies only observed laterality in several motor areas. It may be due to the difficulty of the task or the experimental design.


Cardiac intracrine renin angiotensin system. Part of genetic reprogramming?
The hypothesis that intracrine renin-angiotensin system activated during heart failure is part of the tendency of the heart to return to embryological conditions when organogenesis is possible is presented and discussed. The hypothesis proposes that the change in genetic makeup, which is known to occur during heart failure, includes a drastic change of intercellular chemical and electrical communication such as second messengers and other signal molecules which are involved in cell proliferation and growth. The role of angiotensin II, which is a growth factor, reduces cell coupling in the failing heart through the activation of AT1 receptors and intracellular pathways, such as PKC, MAPK family and increment of intracellular calcium, might play a key role in the genetic reprogramming of the failing heart.


Antibacterial and osteoinductive properties of demineralized bone matrix treated with silver.
The problems incurred by storage of demineralized bone allograft material and its potential use in contaminated operative sites make an antibacterial property desirable. Silver was considered for this role because of its wide spectrum of antibacterial susceptibility, low incidence of resistance, and its ability to persistently inhibit bacteria after binding to collagen matrices. Demineralized bone matrix prepared from rat diaphyseal bone segments was treated by exposure fo AgCl, AgNO3 and NaNO3 solutions prior to lyophilization. The resulting material was tested for bacterial inhibition after incubation in saline solutions for various times and showed inhibition persisting for at least four weeks (Ag-treated material only). Silver treating the matrix was found to partially inhibit the osteoinductive capacity at 10(-3) and 10(-2) M but not at 10(-5) M as measured by intramuscular implantation in the rat for six weeks. Control and NaNo3-treated specimens showed normal bone growth as measured by ashing and by 99mTc binding, and confirmed by radiologic densities. Histologic sections showed dense microdeposits on dense material predominately near the decalcified bone surfaces, but also within the matrix. The results suggest that pretreatment with silver at concentrations in the 10(-4) range would render the implant material antibacterial, protect its sterility, and leave the osteoinductive capacity intact.


Advances in Indocyanine Green-Based Codelivery Nanoplatforms for Combinatorial Therapy.
Indocyanine green (ICG), a near-infrared (NIR) agent with an excellent imaging performance, has captivated enormous interest from researchers owing to its excellent therapeutic and imaging abilities. Although various nanoplatforms-based drug delivery systems (DDS) with the ability to overcome the clinical limitations of ICG has been reported, ICG-medicated conventional cancer diagnosis and photorelated therapies still lack in exhibiting the therapeutic efficacy, resulting in incomplete or partly tumor elimination. In the view of addressing these concerns, various DDSs have been engineered for the efficient codelivery of combined therapeutic agents with ICG, aiming to achieve promising therapeutic results due to multifunctional imaging-guided synergistic antitumor effects. In this article, we will systematically review currently available nanoplatforms based on polymers, inorganic, proteins, and metal-organic frameworks (MOFs), among others, for codelivery of ICG along with other therapeutic agents, providing a foundation for future clinical development of ICG. In addition, codelivery systems for ICG and different mechanism-based therapeutic agents will be illustrated. In summary, we conclude the review with the challenges and perspectives of ICG-based versatile nanoplatforms in detail.


Formation, architecture and polarity of female germline cyst in Xenopus.
Little is known about the formation of germline cyst and the differentiation of oocyte within the cyst in vertebrates. In the majority of invertebrates in the initial stages of gametogenesis, male and female germ cells develop in full synchrony as a syncytia of interconnected cells called germline cysts (clusters, nests). Using electron microscopy, immunostaining and three-dimensional reconstruction, we were able to elucidate the process of cyst formation in the developing ovary of the vertebrate Xenopus laevis. We found that the germline cyst in Xenopus contains 16 cells that are similar in general architecture and molecular composition to the cyst in Drosophila. Nest cells are connected by cytoplasmic bridges that contain ring canal-like structures. The nest cells contain a structure similar to the Drosophila fusome that that is probably involved in anchoring of the centrioles and organization of the primary mitochondrial cloud (PMC) around the centriole. We also find that in contrast to other organisms, in Xenopus, apoptosis is a rare event within the developing ovary. Our studies indicate that the processes responsible for the formation of female germline cysts and the establishment of germ cell polarity are highly conserved between invertebrates and vertebrates. The dissimilarities between Drosophila and Xenopus and the uniqueness of each system probably evolved through modifications of the same fundamental design of the germline cyst.


Humic-acid-driven escape from eye parasites revealed by RNA-seq and target-specific metabarcoding.
Next generation sequencing (NGS) technologies are extensively used to dissect the molecular mechanisms of host-parasite interactions in human pathogens. However, ecological studies have yet to fully exploit the power of NGS as a rich source for formulating and testing new hypotheses. We studied Eurasian perch (Perca fluviatilis) and its eye parasite (Trematoda, Diplostomidae) communities in 14 lakes that differed in humic content in order to explore host-parasite-environment interactions. We hypothesised that high humic content along with low pH would decrease the abundance of the intermediate hosts (gastropods), thus limiting the occurrence of diplostomid parasites in humic lakes. This hypothesis was initially invoked by whole eye RNA-seq data analysis and subsequently tested using PCR-based detection and a novel targeted metabarcoding approach. Whole eye transcriptome results revealed overexpression of immune-related genes and the presence of eye parasite sequences in RNA-seq data obtained from perch living in clear-water lakes. Both PCR-based and targeted-metabarcoding approach showed that perch from humic lakes were completely free from diplostomid parasites, while the prevalence of eye flukes in clear-water lakes that contain low amounts of humic substances was close to 100%, with the majority of NGS reads assigned to Tylodelphys clavata. High intraspecific diversity of T. clavata indicates that massively parallel sequencing of naturally pooled samples represents an efficient and powerful strategy for shedding light on cryptic diversity of eye parasites. Our results demonstrate that perch populations in clear-water lakes experience contrasting eye parasite pressure compared to those from humic lakes, which is reflected by prevalent differences in the expression of immune-related genes in the eye. This study highlights the utility of NGS to discover novel host-parasite-environment interactions and provide unprecedented power to characterize the molecular diversity of cryptic parasites.


Membrane ATPase from the aceticlastic methanogen Methanothrix thermophila.
A new isolate of the aceticlastic methanogen Methanothrix thermophila utilizes only acetate as the sole carbon and energy source for methanogenesis (Y. Kamagata and E. Mikami, Int. J. Syst. Bacteriol. 41:191-196, 1991). ATPase activity in its membrane was found, and ATP hydrolysis activity in the pH range of 5.5 to 8.0 in the presence of Mg2+ was observed. It had maximum activity at around 70 degrees C and was specifically stimulated up to sixfold by 50 mM NaHSO3. The proton ATPase inhibitor N,N'-dicyclohexylcarbodiimide inhibited the membrane ATPase activity, but azide, a potent inhibitor of F0F1 ATPase (H(+)-translocating ATPase of oxidative phosphorylation), did not. Since the enzyme was tightly bound to the membranes and could not be solubilized with dilute buffer containing EDTA, the nonionic detergent nonanoyl-N-methylglucamide (0.5%) was used to solubilize it from the membranes. The purified ATPase complex in the presence of the detergent was also sensitive to N,N'-dicyclohexylcarbodiimide, and other properties were almost the same as those in the membrane-associated form. The purified enzyme revealed at least five kinds of subunits on a sodium dodecyl sulfate-polyacrylamide gel, and their molecular masses were estimated to be 67, 52, 37, 28, and 22 kDa, respectively. The N-terminal amino acid sequences of the 67- and 52-kDa subunits had much higher similarity with those of the 64 (alpha)- and 50 (beta)-kDa subunits of the Methanosarcina barkeri ATPase and were also similar to those of the corresponding subunits of other archaeal ATPases. The alpha beta complex of the M. barkeri ATPase has ATP-hydrolyzing activity, suggesting that a catalytic part of the Methanothrix ATPase contains at least the 67- and 52-kDa subunits.


Benzopyran derivative CDRI-85/287 induces G2-M arrest in estrogen receptor-positive breast cancer cells via modulation of estrogen receptors α- and β-mediated signaling, in parallel to EGFR signaling and suppresses the growth of tumor xenograft.
In an endeavor to develop novel and improved selective estrogen receptor modulators as anti-breast cancer agents, the benzopyran compounds have been synthesized and identified which act as potent anti-estrogen at uterine level. The present study evaluates the anti-tumor activity of 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) and explores the mechanism of action with a view to describe its potential to inhibit proliferation in ER-positive breast cancer cells MCF-7 and T47D. The compound decreased the expression of ERα while increased the expression of ERβ thereby altering ERα/ERβ ratio in both cell lines. Although the compound showed low binding affinity to ERs, it acted as ERα antagonist and ERβ agonist in decreasing ERE- or AP-1-mediated transcriptional activation in these cells. Transactivation studies in ERα/β-transfected MDA-MB231 cells suggested that at cyclin D1 promoter, compound antagonized the action of ERα-mediated E2 response while acted as estrogen agonist via ERβ. Further, the compound led to decreased expression of ERα-dependent proliferation markers and ERβ-dependent cell cycle progression markers. The expression of cell cycle inhibitory protein p21 was increased leading to G2/M phase arrest. In parallel, compound also interfered with EGFR activation, caused inhibition of PI-3-K/Akt pathway and subsequent induction of apoptosis via intrinsic pathway. A significant reduction in tumor mass and volume was observed in 85/287-treated mice bearing MCF-7 xenograft. We conclude that compound 85/287 exhibits significant anti-tumor activity via modulation of genomic as well as non-genomic mechanisms involved in cellular growth and arrested the cells in G2 phase in both MCF-7 and T47D breast cancer cells. Study suggests that CDRI-85/287 may have therapeutic potential in ER-positive breast cancer.


Impact of Different Layer Housing Systems on Eggshell Cuticle Quality and Salmonella Adherence in Table Eggs.
The bacterial load on the eggshell surface is a key factor in predicting the bacterial penetration and contamination of the egg interior. The eggshell cuticle is the first line of defense against vertical penetration by microbial food-borne pathogens such as Salmonella Enteritidis. Egg producers are increasingly introducing alternative caging systems into their production chain as animal welfare concerns become of greater relevance to today's consumer. Stress that is introduced by hen aggression and modified nesting behavior in furnished cages can alter the physiology of egg formation and affect the cuticle deposition/quality. The goal of this study was to determine the impact of caging systems (conventional, enriched, free-run, and free-range), on eggshell cuticle parameters and the eggshell bacterial load. The cuticle plug thickness and pore length were higher in the free-range eggs as compared to conventional eggs. The eggshells from alternative caging (enriched and free-range) had a higher total cuticle as compared to conventional cages. A reduction in bacterial cell counts was observed on eggshells that were obtained from free-range eggs as compared to the enriched systems. An inverse correlation between the contact angle and Salmonella adherence was observed. These results indicate that the housing systems of layer hens can modify the cuticle quality and thereby impact bacterial adherence and food safety.


Probiotics: from functional foods to pharmaceutical products.
The concept of probiotics now has been around for more than a century, with its consumption increasing exponentially; owing to exciting scientific and clinical findings, limiting side effects of existing pharmaceutical agents and increased consumer demand for natural products. But, the evidence for their safety and efficacy has largely been anecdotal, lacking an integrated scientific basis. Clinical studies conducted with probiotics were of inadequate design and resulted in unreliable data. That is the reason why despite having innumerable potential therapeutic uses probiotics are not being universally accepted. The purpose of present article is to amalgamate various branches of research which would help in development of "better", "commercial" and "pharmaceutical" probiotic products with defined strength, mechanism of action and indication. Probiotics have been classified into oral and vaginal in accordance to their route of administration, describing the health benefits. The article summarizes the research on significance of strain selection, interactions with co-administered agents and appropriate clinical studies uncovering the safety issues. There is a special emphasis on pharmaceutical issues including probiotic delivery systems, technological challenges during formulation, regulatory concerns, quality control and market potential. Developments in the techniques for in vitro evaluation have also been discussed.


Femtosecond applications for anterior segment surgery.
To review the currently available femtosecond lasers that are used for anterior segment surgery and to compare those lasers with mechanical microkeratomes. The author reviewed the literature and websites of the manufacturers of femtosecond lasers to compare the hardware and software features of each system. A further review of the mechanical microkeratome literature and how these instruments compare with femtosecond lasers was performed. The known and published outcomes and risks of using a mechanical microkeratome are compared in tabular format with femtosecond lasers. The many applications of femtosecond laser technology for anterior segment surgery are summarized. New risks and complications associated with femtosecond lasers not found with mechanical microkeratomes are discussed. Femtosecond laser technology has greatly improved on the ability to perform numerous anterior segment procedures that cannot be performed with mechanical microkeratomes. The increased predictability and safety of femtosecond laser in situ keratomileusis flap creation over mechanical microkeratomes are now well accepted.


Clinical pharmacodynamics and pharmacokinetics of antimanic and mood-stabilizing medications.
A number of medications are now available or are in development as antimanic and/or mood-stabilizing agents. We reviewed the clinical pharmacodynamics and pharmacokinetics of these agents to provide a summary of these properties relevant to clinical practice. We conducted a MEDLINE search augmented by a manual search of bibliographies and a review of textbooks to identify articles regarding the clinical pharmacology of lithium, valproate, carbamazepine, oxcarbazepine, olanzapine, clozapine, risperidone, ziprasidone, quetiapine, lamotrigine, and topiramate. Not surprisingly, there are a number of clinically relevant pharmacodynamic and pharmacokinetic differences among these medications, and these differences are discussed. Knowledge of the clinical pharmacology of established and putative antimanic and mood-stabilizing medications is important in administering these agents safely and effectively.


Prediction and prevention of contrast nephropathy.
Over the last 10 years, the main advances in RCN have come in our ability to predict outcomes for an individual patient. Treatment trials have been almost all uniformly disappointing. Recent positive trials with acetylcysteine and PGE1 will require confirmation in larger trials that are adequately powered for meaningful end points in the PCI population. In the meantime, adequate prehydration and maintenance of post-PCI urine flow rates of > 150 mL/min remain the most prudent measures. As the population ages, breakthroughs with respect to new contrast agents or effective prevention measures will be needed to offer PCI to the spectrum of patients at risk for renal injury.


Perception of Implants among Breast Reconstruction Patients in Montreal.
In light of the recent surge of media coverage and social media influence regarding breast implants, it is essential to understand patients' concerns and misconceptions so that we can better serve them. The authors designed a survey study for assessing the awareness and perception of patients toward breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and breast implant illness (BII). In total, 130 patients presenting to the senior author's breast reconstruction clinic completed the survey. The survey assessed patients' knowledge on and their perception of BIA-ALCL and BII. "News article" and "Television" were most often selected as sources of information for BIA-ALCL (21% and 20%, respectively) and BII (20% and 25%, respectively). A total of 100 patients (77%) had previous knowledge of BIA-ALCL. Forty-seven percent (n = 47/100) responded that they were unsure of the fate of a person diagnosed with BIA-ALCL, and 25% (n = 25/100) were unaware of the association between BIA-ALCL and specific implant type. Patients who were unaware of BIA-ALCL prognosis reported being less likely to receive breast implants in the future (P = 0.012, χ2 = 19.48). Eighty-nine patients (68%) had previous knowledge of BII. A total of 60 symptoms were mentioned by patients, with "Fatigue" (12%, n = 26) being cited the most often. The present survey highlights the importance for plastic surgeons to frequently discuss these entities with their patients. This should be done despite the obscurity of BII, in an effort to offer the best available evidence to our patients.


Australian Halobacteria and their retinal-protein ion pumps.
Halophiles collected in Western Australia have been found to be examples of extremely halophilic rod-shaped archaebacteria, members of the genus Halobacterium. Most of them contain retinal proteins, and these proteins differ from one another and also from both bacteriorhodopsin (bR) and halorhodopsin [and sensory rhodopsins (sR)] isolated from Halobacterium salinarium (halobium), as revealed by their peptide maps and amino acid sequences. However, these retinal proteins still have the ability to pump protons or chloride ions in the light. These new ion pumps, designated archaerhodopsins (aR) [Mukohata et al. (1988) Biochem. Biophys. Res. Commun. 151, 1339-1345], are almost identical in terms of their molecular sizes and transient photochemical properties to the ion pumps identified previously. Differences are found in the: (1) apparent extinction coefficient of dark/light-adapted aR-2; (2) titration profiles at acidic pH of the absorption spectra of all aRs; and (3) circular dichroism spectra, which are influenced by the coexistent isoprenoid bacterioruberin. The amino acid sequences of two proton pumps from the Australian halobacteria, namely aR and aR-2, are approximately 90% homologous and both sequences are about 60% homologous with that of bR. Hydropathy plots suggest that these pumps also have a seven-helical structure similar to that of bR. The amino acid residues are highly conserved in the helical regions, in particular in the case of helices C and G (91 and 84%, respectively), among the three proton pumps.


Role of PNPLA3 in the Assessment and Monitoring of Hepatic Steatosis and Fibrosis in Patients with Chronic Hepatitis C Infection Who Achieved a Sustained Virologic Response.
Background and Objectives: Hepatic diseases are an important public health problem. All patients with chronic hepatitis C virus (HCV) infection receive treatment, regardless of hepatic fibrosis severity. However, evaluation of hepatic fibrosis and steatosis is still useful in assessing evolution, prognosis and monitoring of hepatic disease, especially after treatment with direct-acting antivirals (DAAs). The aim of this study was to assess the link between patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism and the degree of hepatic steatosis and fibrosis in patients with chronic HCV infection, as well as changes in steatosis and fibrosis three monthsafter obtaining a sustained viral response (SVR). Materials and Methods:Ourstudy included 100 patients with chronic hepatitis C (CHC) infection and compensated cirrhosis who received DAA treatment and who were evaluated using Fibromax prior to and 3 months after SVR. The influence of PNPLA3 (CC, CG, GG) genotype among these patients on the degree of post-treatment regression of steatosis and fibrosis was assessed. Results: Regression was noticed in the degree of both hepatic steatosis and hepatic fibrosis post-DAA treatment (three months after SVR). Analysis of the correlation between PNPLA3 genotype and fibrosis indicated that the average level of fibrosis (F) before DAA treatment was higher in patients with the GG genotype than in patients with the CC or CG genotype. Three months after SVR, the average level of fibrosis decreased; however, it remained significantly increased in GG subjects compared to that in CC or CG patients. The degree of hepatic steatosis before treatment was not significantly different among patients with different PNPLA3 genotypes, and no significant correlations were observed three months after SVR. Conclusions: The genetic variants of PNPLA3 influence the evolution of hepatic fibrosis. The GG subtype plays an important role in the degree of hepatic fibrosis both before and after treatment (three months after SVR)and could be a prognostic marker for assessment of post-SVR evolution.


Phenotypic variability among first-degree relatives with carnitine palmitoyltransferase II deficiency.
Carnitine palmitoyltransferase (CPT) II deficiency disorders are clinically very variable. To examine the cause(s) of variable symptoms in first-degree relatives with CPT II deficiency, four sisters with various combinations of mutations and polymorphisms in the CPT2 gene were studied, together with 20 sedentary and 24 trained healthy female subjects. One sister, whose symptoms began at age 7 years, was more severely affected than her older sister, whose symptoms began at age 16 years; both were compound heterozygotes for the common S113L mutation and Q413fs, and for the common CPT2 polymorphisms, V3681 and M647V. A third sister became hypoglycemic with fasting, was heterozygous for the S113L mutation, and homozygous for the polymorphism variants. The fourth sister was asymptomatic, heterozygous for the Q413fs mutation, and homozygous for the normal polymorphisms. Residual CPT II activity in skeletal muscle and cultured skin fibroblasts from the two myopathic sisters, and palmitate oxidation in fibrobasts, were abnormally low; cellular and total body fat oxidation were also diminished. Muscle function and fat oxidation were nomal at rest, but a switch to carbohydrate utilization occurred at lower exercise intensities than in sedentary and trained individuals, respectively. Reliance on carbohydrates during stress and hormonal alterations may explain, in part, the variance in ages of onset and serverity of symptoms in myopathic patients.


Phase II study of uracil-tegafur in patients with metastatic pancreatic cancer.
Uracil-tegafur (UFT) has been reported to have a broad anti-tumor activity in a variety of malignancies including colorectal cancer and breast cancer. However, its activity in pancreatic cancer has not been fully evaluated. The aim of the present study was to evaluate the anti-tumor activity and toxicity of UFT in patients with metastatic pancreatic cancer. All patients were required to have a pathologic diagnosis of pancreatic adenocarcinoma with measurable metastatic lesions, and no prior chemotherapy. A dose of 360 mg/m2/day of UFT was administered orally until the appearance of disease progression or unacceptable toxicity. Twenty-two patients were entered into this study. Of 21 patients evaluable for response, no patient achieved an objective tumor response; one showed no change, and the remaining 20 showed progressive disease. The median survival time for all patients was 4.2 (range: 0.9-9.0) months. The most common toxicities were nausea/vomiting and anorexia. Five patients (23%) had to discontinue UFT treatment because of gastrointestinal toxicity. This schedule of UFT did not demonstrate a significant anti-tumor activity against metastatic pancreatic cancer.


Efficacy and Cardiovascular Safety of Thiazolidinediones.
Type 2 diabetes mellitus (T2DM) is characterized by a progressive beta cell dysfunction in the setting of peripheral insulin resistance. Insulin resistance in subjects with type 2 diabetes and metabolic syndrome is primarily caused by an ectopic fat accumulation in the liver and skeletal muscle. Insulin sensitizers are particularly important in the management of T2DM. Though thiazolidinediones (TZDs) are principally insulin sensitizers, they possess an ability to preserve pancreatic β-cell function and thereby exhibit durable glycemic control. Cardiovascular outcome trials (CVOTs) have shown that Glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose transporter-2 inhibitors (SGLT2i) have proven cardiovascular safety. In this era of CVOTs, drugs with proven cardiovascular (CV) safety are often preferred in patients with preexisting cardiovascular disease or at risk of cardiovascular disease. In this review, we will describe the three available drugs belonging to the TZD family, with special emphasis on their efficacy and CV safety.


Diagnosis and management of ejaculatory duct obstruction.
Ejaculatory duct obstruction is a rare but important cause of male infertility. The differential diagnosis, evaluation and treatment of patients with suspected ejaculatory duct obstruction is described herein. New minimally invasive techniques that can be utilized in both the diagnosis and treatment of ejaculatory duct obstruction are described.


Growth potential of peripheral ossifying fibroma.
The peripheral ossifying fibroma (POF), a benign gingival overgrowth, occurs mainly in the anterior portion of the maxilla in young adults. The size of the lesion is usually less than 1.5 cm. A unique case of POF in the posterior mandible of a 70-year-old female is presented. The lesion was 6 cm in the largest diameter. It is apparent that POF can become a sizeable tumor unless it is surgically excised in an early stage.


Site-specific analysis of changes in the glycosylation of proteins in liver cirrhosis using data-independent workflow with soft fragmentation.
Cirrhosis of the liver is associated with increased fucosylation of proteins in the plasma. We describe a data-independent (DIA) strategy for comparative analysis of the site-specific glycoforms of plasma glycoproteins. A library of 161 glycoforms of 25 N-glycopeptides was established by data-dependent LC-MS/MS analysis of a tryptic digest of 14 human protein groups retained on a multiple affinity removal column. The collision-induced dissociation conditions were adjusted to maximize the yield of selective Y-ions which were quantified by a data-independent mass spectrometry workflow using a 10-Da acquisition window. Using this workflow, we quantified 125 glycoforms of 25 glycopeptides, covering 10 of the 14 proteins, without any further glycopeptide enrichment. Comparison of the proteins in the plasma of healthy controls and cirrhotic patients shows an average 1.5-fold increase in the fucosylation of bi-antennary glycoforms and 3-fold increase in the fucosylation of tri- and tetra- antennary glycoforms. These results show that the adjusted glycopeptide DIA workflow using soft collision-induced fragmentation of glycopeptides is suitable for site-specific analysis of protein glycosylation in complex mixtures of analytes without glycopeptide enrichment.


Two-site Kondo effect in atomic chains.
Linear CoCu(n)Co clusters on Cu(111) fabricated by atomic manipulation represent a two-site Kondo system with tunable interaction. Scanning tunneling spectroscopy reveals oscillations of the Kondo temperature T(K) with the number n of Cu atoms for n≥3. Density functional calculations show that the Ruderman-Kittel-Kasuya-Yosida interaction mediated by the Cu chains causes the oscillations. Calculations find ferromagnetic and antiferromagnetic interaction for n=1 and 2, respectively. Both interactions lead to a decrease of T(K) as experimentally observed.


[Immunology of liver diseases].
Acute hepatitis A is diagnosed by IgM-anti-HAV antibodies. Cytotoxic immune reactions seem to play a key role in the pathogenesis of hepatitis A, which is an acute self-limited disease. - Acute hepatitis B is diagnosed by IgM-anti-HBc antibodies and can thus be differentiated from other HBV-associated liver diseases. The detection of HBV-DNA in serum serves to differentiate between HBsAg/anti-HBe positive patients, with active viral replication and progressive chronic liver disease, and HBV-DNA negative asymptomatic HBsAg-carriers usually with normal liver histology. In the pathogenesis of HBV-associated liver diseases cytotoxic immune reactions against virus-infected hepatocytes are thought to mediate liver cell destruction. Membrane expressed virus as well as host antigens are candidate target antigens for these immune reactions. Hepatitis delta is always associated with acute and chronic HBV infection. Acute hepatitis delta is diagnosed by delta-RNA in serum and later by antibodies against the delta virus. Little is known about the pathogenesis of delta virus infection. Autoimmune type chronic active hepatitis (CAH) is classified into classical autoimmune type "lupoid CAH" with antinuclear antibodies and liver membrane antibodies as markers, liver-kidney-microsomal (LKM) antibody positive CAH, CAH associated with autoantibodies against a soluble liver antigen (SLA), and CAH associated with high titers of anti-smooth muscle antibodies (SMA). In the pathogenesis of autoimmune type CAH an antibody-mediated cellular cytotoxicity (ADCC) may play a significant role. Primary biliary cirrhosis is to be differentiated as a clinical syndrome associated with cholestasis and anti-mitochondrial antibodies (AMA). By immunoblotting and radioimmunoassay at least two PBC-specific subtypes of AMA can be defined. Immune reactions against self-antigens are thought to be involved in the pathogenesis of PBC, although the precise reactions are unknown.


From pathways to targets: understanding the mechanisms behind polyglutamine disease.
The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington's disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment.


[The HIV-epidemic in North-East Tanzania].
A series of seven population-based HIV-screening surveys were conducted in Arusha region between November 1991 and April 1994. Communities included three wards within Arusha town, two townships along major highways in Arusha region, and two rural villages. A total of 3,440 people completed an interview to assess AIDS-related knowledge, attitudes and practices, and of these, 1,932 consented to be tested for HIV (56.2%). Across communities, 7.4% of the participating women and 1.9% of the men tested HIV-positive. For both sexes the HIV-prevalence was significantly higher in urban than in rural areas. As many as 12.5% among young women from Arusha town were HIV-positive. HIV-prevalence was higher among participants from urban areas characterized by lower socio-economic status than among participants living in areas of higher socio-economic status. These surveys tend to confirm that women and poor people are the most vulnerable to HIV-infection. The local HIV-epidemic seems to spread from urban to rural areas along major highways.


Type II diabetes in mild cognitive impairment and Alzheimer's disease: results from a prospective population-based study in Germany.
Diabetes mellitus type 2 (T2DM) is considered to be an important risk factor for mild cognitive impairment (MCI) and subsequent Alzheimer's disease (AD). The majority of studies relating T2DM to MCI and AD were performed in North America. We investigated the potential impact of T2DM on the development of MCI and AD in the Interdisciplinary Longitudinal Study on Adult Development and Aging which involves a representative birth cohort of subjects born between 1930 and 1932 in Germany. Subjects received a thorough psycho-geriatric examination and neuropsychological testing; particular care was taken to exclude subjects with severe medical or neurological conditions sufficient to explain the cognitive deficits, or other major psychiatric disorders. When compared to healthy subjects (n=159), patients with MCI (n=108) or AD (n=26) showed a tendency towards increased prevalence rates for T2DM (17% vs. 23%; chi2=1.7, p=0.18). In both patients with MCI and controls, T2DM was associated with psychomotor slowing but not deficits in other cognitive domains typically involved in MCI. Our findings indicate that T2DM is involved in MCI and may aggravate the clinical picture as a concomitant factor.


Differentiation of the genus Listeria from other gram-positive species based on low molecular weight (LMW) RNA profiles.
Low molecular weight RNA (LMW RNA; 5S rRNA and tRNAs) profiles of several Gram-positive species were generated on 9% denaturing polyacrylamide gels. The profiles of five Listeria spp. (L. innocua, L. ivanovii, L. monocytogenes, L. seeligeri and L. welshimeri) were identical when cultured in three different media (APT, BHI and TSBYE), either shaken or statically, both at 30 and 37 degrees C. Twenty-six strains from 15 other species representing seven different genera were also compared. Each species exhibited a characteristic profile. Strain variants of the same species gave identical profiles. The technique represents a simple, reproducible approach to the identification of species and possibly of relationships between species. The taxonomic and phylogenetic implications, particularly with respect to Listeria spp., Brochothrix thermosphacta and the lactic acid bacteria, are considered.


Joint proprioception before and after total knee arthroplasty.
To investigate the effects of total knee arthroplasty on joint proprioception, the absolute angular error of the knee in 38 consecutive patients before and after total knee arthroplasty for osteoarthritis and in 23 age-matched control subjects were examined. Varus and valgus laxity of the knee and muscle strengths of the thigh were measured using appropriate instruments. There were no significant differences in absolute angular error before and after total knee arthroplasty, independent of retaining or substituting the posterior cruciate ligament. The absolute angular error of the knee with a normal appearing anterior cruciate ligament was larger than that with a missing anterior cruciate ligament before total knee arthroplasty and decreased significantly after surgery. The absolute angular error correlated with the varus and valgus laxity of the knee, but did not correlate with the strength of thigh muscles after total knee arthroplasty. These results suggest that deficiency of the anterior cruciate ligament may not adversely affect proprioception in severe knee osteoarthritis. In addition, proper ligament balance may partly contribute to better proprioception after total knee arthroplasty.


[Influence of different processes on bactericidal and tumoricidal effects of gamboges].
The different processes for preparing gamboge could influence its bactericidal activity and cytotoxicity. The gamboge processed with high pressure steam has been proved the most powerful in killing Staphylococcus aureus and tumor cells. The most suitable condition for processing gamboge is to steam it at 126 degrees C for 30 minutes.


Milton controller introduced.
Hamworthy Heating has recently introduced the Milton boiler sequence controller, a microprocessor based control system designed for use with Hamworthy Sherborne modulating boilers and the newly launched Wessex 220M Series of fully modulating boilers.


Importance of Deubiquitination in Macrophage-Mediated Viral Response and Inflammation.
Ubiquitination and deubiquitination play a fundamental role in the signaling pathways associated with innate and adaptive immune responses. Macrophages are key sentinels for the host defense, triggering antiviral and inflammatory responses against various invading pathogens. Macrophages recognize the genetic material of these pathogens as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through the activation of its pattern recognition receptors (PRRs), initiating the cascade of immune signaling, which leads to the production of pro- and anti-inflammatory cytokines that initiates the appropriate immune response. Macrophage-mediated immune response is highly regulated and tightly controlled by the ubiquitin system since its abnormal activation or dysregulation may result in the severe pathogenesis of numerous inflammatory and autoimmune diseases. Deubiquitinating enzymes (DUBs) play a crucial role in reversing the ubiquitination and controlling the magnitude of the immune response. During infection, pathogens manipulate the host defense system by regulating DUBs to obtain nutrients and increase proliferation. Indeed, the regulation of DUBs by small molecule inhibitors has been proposed as an excellent way to control aberrant activation of immune signaling molecules. This review is focused on the complex role of DUBs in macrophage-mediated immune response, exploring the potential use of DUBs as therapeutic targets in autoimmune and inflammatory diseases by virtue of small molecule DUB inhibitors.


Gold nanoparticle-sensitized quartz crystal microbalance sensor for rapid and highly selective determination of Cu(II) ions.
A novel quartz crystal microbalance (QCM) sensor for rapid, highly selective and sensitive detection of copper ions was developed. As a signal amplifier, gold nanoparticles (Au NPs) were self-assembled onto the surface of the sensor. A simple dip-and-dry method enabled the whole detection procedure to be accomplished within 20 min. High selectivity of the sensor towards copper ions is demonstrated by both individual and coexisting assays with interference ions. This gold nanoparticle mediated amplification allowed a detection limit down to 3.1 μM. Together with good repeatability and regeneration, the QCM sensor was also applied to the analysis of copper contamination in drinking water. This work provides a flexible method for fabricating QCM sensors for the analysis of important small molecules in environmental and biological samples.


Erotomania in relation to childbirth.
A case of erotomania in relation to childbirth is reported. There was a good response to treatment and no evidence of relapse at 18-month follow-up.


Cardiovascular effects of dipeptidyl peptidase-4 inhibitor in diabetic patients with and without established cardiovascular disease: a meta-analysis and systematic review.
We aim to conduct a meta-analysis, by stratifying diabetic patients with or without clinical cardiovascular diseases (CVD), to explore whether there are different cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP-4is) on these two different classes of diabetic patients. We searchedMedline,Embase, theCochrane Libraryand ClinicalTrials.gov for relevant randomized controlled trials (RCTs). The included trials are divided into CVD (+) trials (subjects with established CVD), and CVD (-) trials (subjects with no CVD). We use all-cause mortality and cardiovascular outcomes as primary endpoints. (1) Three CVD (+) trials were included and 36,895 subjects were enrolled with a mean follow-up duration of 127.1 weeks. The pooled results showed that DPP-4is treatment, compared with the placebo, did not significantly affect all-cause mortality (RR, 1.03; 95% CI, 0.95 to 1.11), cardiovascular death (1.01, 0.91 to 1.12), myocardial infarction (0.98, 0.88 to 1.08) or stroke (1.02, 0.88 to 1.18) in diabetic patients with coexisting CVD history; however, it significantly increased the risk of heart failure (1.14, 1.01 to 1.27) in this population. 2) Thirty-five CVD (-) trials were included, and 29,600 patients were enrolled with a mean follow-up duration of 77.8 weeks. The analysis comparing DPP-4is with the placebo control showed that DPP-4is treatment did not significantly affect the risk of all-cause mortality or cardiovascular outcomes in diabetic patients free of CVD history. However, when compared with the active control, the pooling data showed that DPP-4is had a significant reduction on the risk of stroke (0.58, 0.34 to 0.99) but did not significantly affect the risk of all-cause mortality and other cardiovascular outcomes. DPP-4is may have no cardiovascular protective effects in diabetic patients with coexisting CVD, while there is a lack of definitive evidence supporting the cardiovascular benefits of DPP-4is treatment among diabetic patients free of CVD history.


Coexistence of Malaria and Thalassemia in Malaria Endemic Areas of Thailand.
Hemoglobinopathy and malaria are commonly found worldwide particularly in malaria endemic areas. Thalassemia, the alteration of globin chain synthesis, has been reported to confer resistance against malaria. The prevalence of thalassemia was investigated in 101 malaria patients with Plasmodium falciparum and Plasmodium vivax along the Thai-Myanmar border to examine protective effect of thalassemia against severe malaria. Hemoglobin typing was performed using low pressure liquid chromatography (LPLC) and α-thalassemia was confirmed by multiplex PCR. Five types of thalassemia were observed in malaria patients. The 2 major types of thalassemia were Hb E (18.8%) and α-thalassemia-2 (11.9%). There was no association between thalassemia hemoglobinopathy and malaria parasitemia, an indicator of malaria disease severity. Thalassemia had no significant association with P. vivax infection, but the parasitemia in patients with coexistence of P. vivax and thalassemia was about 2-3 times lower than those with coexistence of P. falciparum and thalassemia and malaria without thalassemia. Furthermore, the parasitemia of P. vivax in patients with coexistence of Hb E showed lower value than coexistence with other types of thalassemia and malaria without coexistence. Parasitemia, hemoglobin, and hematocrit values in patients with coexistence of thalassemia other than Hb E were significantly lower than those without coexistence of thalassemia. Furthermore, parasitemia with coexistence of Hb E were 2 times lower than those with coexistence of thalassemia other than Hb E. In conclusion, the results may, at least in part, support the protective effect of thalassemia on the development of hyperparasitemia and severe anemia in malaria patients.


Frequency of haemoglobinopathies at premarital health screening in Dohuk, Iraq: implications for a regional prevention programme.
beta-thalassaemia major and sickle-cell disease are important health problems in Iraq. To provide information for a prevention programme, the frequency of haemoglobin disorders was mapped in Dohuk governorate. A total of 591 couples (1182 individuals) attending health centres for premarital health screening were tested; 44 (3.7%) were found to be carriers of ,-thalassaemia, 14 (1.2%) of the sickle-cell gene and 1 (0.1%) of deltabeta3-thalassaemia. A total of 3 couples (i.e. 5/1000) were at risk of having a child with beta-thalassaemia major, and the estimated number of affected children with a major haemoglobinopathy was 39 per year. The findings stress the importance of a regional prevention programme for haemoglobinopathies based on premarital screening, counselling and prenatal diagnosis.


Towards MRI-Based Autonomous Robotic US Acquisitions: A First Feasibility Study.
Robotic ultrasound has the potential to assist and guide physicians during interventions. In this work, we present a set of methods and a workflow to enable autonomous MRI-guided ultrasound acquisitions. Our approach uses a structured-light 3D scanner for patient-to-robot and image-to-patient calibration, which in turn is used to plan 3D ultrasound trajectories. These MRI-based trajectories are followed autonomously by the robot and are further refined online using automatic MRI/US registration. Despite the low spatial resolution of structured light scanners, the initial planned acquisition path can be followed with an accuracy of 2.46 ± 0.96 mm. This leads to a good initialization of the MRI/US registration: the 3D-scan-based alignment for planning and acquisition shows an accuracy (distance between planned ultrasound and MRI) of 4.47 mm, and 0.97 mm after an online-update of the calibration based on a closed loop registration.


[GIN's activity in the past five years].
This letter summarises the main activities of the journal during the last five years. The quality of the journal has been improved and it is now included in the Library of Medicine in Bethesda. Moreover, the journal is listed in the Index Medicus and its articles appear in Medline. I believe that the new Editor-in-chief, Francesca Mallamaci, with her enthusiasm will continue to improve the journal.


Evaluating the persistence and stability of a DNA-barcoded microbial system in a mock home environment.
Recent advancements in engineered microbial systems capable of deployment in complex environments have enabled the creation of unique signatures for environmental forensics operations. These microbial systems must be robust, able to thrive in specific environments of interest and contain molecular signatures, enabling the detection of the community across conditions. Furthermore, these systems must balance biocontainment concerns with the stability and persistence required for environmental forensics. Here we evaluate the stability and persistence of a recently described microbial system composed of germination-deficient Bacillus subtilis and Saccharomyces cerevisiae spores containing nonredundant DNA barcodes in a controlled simulated home environment. These spore-based microbial communities were found to be persistent in the simulated environment across 30-day periods and across multiple surface types. To improve the repeatability and reproducibility in detecting the DNA barcodes, we evaluated several spore lysis and sampling processes paired with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) -CRISPR-associated proteins (Cas) detection (Sherlock). Finally, having optimized the detectability of the spores, we demonstrate that we can detect the spores transferring across multiple material types. Together, we further demonstrate the utility of a recently described microbial forensics system and highlight the importance of independent validation and verification of synthetic biology tools and applications. Graphical Abstract.


A novel screening method for transition metal-based anticancer compounds using zebrafish embryo-larval assay and inductively coupled plasma-mass spectrometry analysis.
As novel metallodrugs continue to emerge, they are evaluated using models, including zebrafish, that offer unique sublethal endpoints. Testing metal-based anticancer compounds with high-throughput zebrafish toxicological assays requires analytical methods with the sensitivity to detect these sublethal tissue doses in very small sample masses (e.g., egg mass 100 μg). A robust bioanalytical model, zebrafish embryos coupled with inductively coupled plasma-mass spectrometry (ICPMS) for measurement of delivered dose, creates a very effective means for screening metal-based chemotherapeutic agents. In this study, we used ICPMS quantitation with the zebrafish embryo assays to detect metal equivalents at multiple response endpoints for two compounds, the chemotherapeutic agent cisplatin and ruthenium (Ru)-based prospective metallodrug, PMC79. We hypothesized that cisplatin and PMC79 have different mechanisms for inducing apoptosis and result in similar lesions but different potencies following water-borne exposure. An ICPMS method was developed to detect the metal in waterborne solution and tissue (detection limit: 5 parts per trillion for Ru or platinum [Pt]). The Ru-based compound was more potent (LC50 : 7.8 μm) than cisplatin (LC50 : 158 μm) and induced disparate lesions. Lethality from cisplatin exposure exhibited a threshold (values >15 mg/L) while no threshold was observed for delayed hatching (lowest observed adverse effect level 3.75 mg/L cisplatin; 8.7 Pt (ng)/organism). The Ru organometallic did not have a threshold for lethality. Cisplatin-induced delayed hatching was investigated further by larval-Pt distribution and preferentially distributed to the chorion. We propose that zebrafish embryo-larval assays coupled with ICPMS serve as a powerful platform to evaluate relative potency and toxic effects of metallodrug candidates.


Corrector combination therapies for F508del-CFTR.
These are exciting times in the development of therapeutics for cystic fibrosis (CF). New correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) are being developed in academic laboratories and pharmaceutical companies, and the field is just beginning to understand their mechanisms of action. Studies of CFTR modulators are also yielding insight into the general principles and strategies that can be used when developing pharmacological chaperones, a new class of drugs. Combining two or even three correctors with a potentiator is an especially promising approach which should lead to further improvements in efficacy and clinical benefit for patients.


Sphingosine-1-Phosphate Signaling in Endothelial Disorders.
Numerous preclinical studies indicate that sustained endothelial activation significantly contributes to tissue edema, perpetuates the inflammatory response, and exacerbates tissue injury ultimately resulting in organ failure. However, no specific therapies aimed at restoring endothelial function are available as yet. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of endothelial function and endothelial responses to injury. Recent studies indicate that S1PR are attractive targets to treat not only disorders of the arterial endothelium but also microvascular dysfunction caused by ischemic or inflammatory injury. In this article, we will review the current knowledge of the role of S1P and its receptors in endothelial function in health and disease, and we will discuss the therapeutic potential of targeting S1PR not only for disorders of the arterial endothelium but also the microvasculature. The therapeutic targeting of S1PR in the endothelium could help to bridge the gap between biomedical research in vascular biology and clinical practice.


Human epidermal growth factor receptor-1 expression renders Chinese hamster ovary cells sensitive to alternative aldosterone signaling.
The epidermal growth factor (EGF) regulates cell proliferation, differentiation, and ion transport using ERK1/2 as a downstream effector. Furthermore, the EGF receptor (EGFR) is involved in signaling by G-protein-coupled receptors, growth hormone, and cytokines via transactivation. It has been suggested that steroids interact with peptide hormones. Previously, we have shown that aldosterone modulates EGF responses in Madin-Darby canine kidney cells (Gekle, M., Freudinger, R., Mildenberger, S., and Silbernagl, S. (2002) Am. J. Physiol. 282, F669-F679). Here, we tested the hypothesis that human EGFR-1 can confer alternative aldosterone responsiveness with respect to ERK1/2 phosphorylation to Chinese hamster ovary cells, which do not express EGFR. Wild-type Chinese hamster ovary cells did not respond to EGF or aldosterone. After transfection of human EGFR-1, the cells responded to EGF, but not to aldosterone. However, when submaximal concentrations of EGF were used, nanomolar concentrations of aldosterone potentiated the action of EGF within minutes, resulting in a leftward shift of the EGF dose-response curve. This was not the case in mock-transfected cells. The EGFR kinase inhibitor tyrphostin AG1478 or the MEK1/2 inhibitor U0126 completely prevented the effect. Furthermore, aldosterone enhanced Tyr phosphorylation of c-Src and EGFR, and an inhibitor of cytosolic tyrosine kinases (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyriociaine) prevented the action of aldosterone. Our data show that aldosterone uses the EGF-EGFR-MEK1/2-ERK1/2 signaling cascade to elicit its alternative effects. In the presence of EGF, aldosterone leads to EGFR transactivation via cytosolic tyrosine kinases of the Src family.


Highly Green Emissive Nitrogen-Doped Carbon Dots with Excellent Thermal Stability for Bioimaging and Solid-State LED.
In this study, nitrogen-doped green emissive carbon dots (N-doped CDs) are synthesized via a convenient one-step solid state reaction method. The N-doped CDs show excitation-dependent fluorescence behavior with a maximum emission of 540 nm. Upon the optimum excitation at 400 nm, the quantum yield (QY) of the green emissive CDs is determined to be 13.4% and 50.3% in deionized water and ethanol, respectively. The higher quantum yield of N-doped CDs in ethanol could be caused by a strong hydrogen-bonding. In addition, the obtained N-doped CDs demonstrate excellent thermal stability, which is supported by the fact that the emission intensity nearly has no change after keeping the sample at 90 °C for 120 min. Moreover, the N-doped CDs exhibit green emission after entering into the HeLa cell membrane, indicating their potential to be used as bioimaging agent. Furthermore, the N-doped CDs are dispersed in PVA matrix for solid state film, where the solid-state quenching is effectively avoided. A green LED is fabricated by packing the CDs-PVA composite on the top of a 395 nm n-UV-Chip, which provides a potentially healthy green light.


Frequency and Association Of GSTM1 and GSTT1 Gene Polymorphisms with Survival in Breast Cancer Patients.
Glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) are the key detoxification enzymes of xenobiotics, including chemotherapeutic drugs. The deletion polymorphisms of GSTM1 and GSTT1 genes are associated with reduced enzyme activity that influenced clinical outcomes of chemotherapeutic agents in breast cancer. However, there is limited information among Thai patients. This research aims to explore the frequency and role of GSTM1 and GSTT1 polymorphisms on survival among Thai patients with breast cancer. The retrospective cohort study was performed. Demographic data and clinicopathology characteristics were collected from hospital base registry data and medical records. A multiplex qualitative real-time PCR method was used to detect the presence or absence of the GSTM1 and GSTT1 gene in the genomic DNA samples of the participants. The frequencies of the GSTM1 and GSTT1 null genotypes in 198 breast cancer patients were 65.70% and 33.30%, respectively. The overall survival at 1, 3 and 5 years were 95.00%, 83.00%, 71.00% respectively. The log rank test and Cox proportional hazards revealed a significant different in the 5-years overall survival according to lymph node metastasis and tumor stage (P = 0.014 and P < 0.001). No associations between overall survival and GSTM1 or GSTT1 genotype were found in single or combined genotypes analyses (P = 0.76 and P= 0.15). The results of our study provided the epidemiological information for prognostic of survival in breast cancer patients treated with chemotherapy.<br />.


Curative-Intent Surgery for Stage IV Advanced Gastric Cancer: Who Can Undergo Surgery and What Are the Prognostic Factors for Long-Term Survival?
A retrospective study was performed to evaluate the predictive factors for performing curative-intent surgery and prognostic factors for long-term survival of patients undergoing surgery for stage IV gastric cancer. Between 2001 and 2017, 271 patients with stage IV gastric cancer with distant metastasis who underwent systemic chemotherapy were enrolled. Logistic regression analysis was performed to evaluate predictive factors for curative-intent surgery. Cox proportional hazards regression model was applied for patients who were subsequently treated with curative-intent surgery to identify prognostic factors for long-term survival. Curative-intent surgery was performed in 48 patients (17.7%). Median survival time was significantly longer in the surgery group than in the nonsurgery group (53 vs. 11 months, p < 0.0001). R0 resection was performed in 35 patients (72.9%). The three-year overall survival (OS) rates of the R0, R1, and R2 surgery groups were 75.4%, 33.3%, and 25.0%, respectively (p = 0.0002). Logistic regression analysis revealed that lymphogenous distant metastasis alone (odds ratio = 3.276, p = 0.004), positive lavage cytology alone (6.394, 0.014), doublet or triplet chemotherapy (4.064, 0.034), and high Glasgow prognostic score (0.276, 0.001) were independent predictive factors for performing curative-intent surgery. Among patients undergoing surgery, the Cox proportional hazards regression model for OS showed that R0 surgery was an independent prognostic factor for favorable OS (hazard ratio 0.188, p = 0.022). Patients with lymphogenous distant metastasis alone, P0CY1 alone, good immunonutritional status, and doublet/triplet chemotherapy are candidates for performing effective curative-intent surgery. R0 surgery is crucial for improving long-term survival after surgery.


Post-translational processing of human procorticotrophin-releasing factor in transfected mouse neuroblastoma and Chinese hamster ovary cell lines.
The mouse neuroblastoma cell line (Neuro 2 A) has been shown to contain the mRNA of a prohormone converting enzyme, PC2. The Chinese hamster ovary cell line (CHO) does not express PC2 mRNA, but is thought to contain the ubiquitous protease, furin. The enzyme(s) responsible for releasing corticotrophin-releasing hormone (CRH) from its precursor (proCRH) have not been identified, therefore to investigate the possible function(s) of PC2 or furin in the processing of proCRH, stable Neuro 2 A and CHO cell lines that express the 21 kDa human (h)proCRH were established. A specific two-site IRMA for CRH demonstrated that the hpreproCRH-expressing Neuro 2 A cell line cleaved the CRH precursor to the CRH peptide, and was able to release the mature peptide into cell medium at levels that were 4-fold higher than produced by the hproCRH-expressing CHO cells. RIA showed that the CHO cells secreted levels of CRH-containing peptides that were 10-fold higher than produced by the Neuro 2 A cells. Medium from the transfected CHO and Neuro 2 A cells was analysed by HPLC; this showed that CHO cells released a single protein corresponding to the unprocessed CRH precursor, whereas Neuro 2 A cells secreted two peptides, which could be identified as the 5 kDa CRH(1-41) and residual 16 kDa CRH peptides. These results suggest that Neuro 2 A cells, which contain PC2, can process proCRH to the mature peptide.


Probiotics in primary prevention of allergic disease--follow-up at 8-9 years of age.
Long-term effects of probiotics in primary prevention of allergic disease need further evaluation. We previously reported a reduced cumulative incidence of infant eczema by feeding Lactobacillus paracasei ssp paracasei F19 (LF19) during weaning. Therefore, we assessed effects of LF19 on the prevalence of allergic disease at school age. In a double-blind placebo-controlled trial infants were randomized to daily intake of cereals with (n = 89) or without LF19 10(8) CFU (n = 90) from 4-13 months of age. At age 8-9, we evaluated the prevalence of allergic disease (eczema, allergic rhinitis, asthma, and food allergy) by clinical examination and validated questionnaires. IgE sensitization was assessed by skin prick test (inhalant allergens) and specific IgE levels (food allergens). Lung function was evaluated by a spirometry reversibility test. Fractional exhaled nitric oxide (FENO ) was measured. Of 171 children that completed the intervention, 121 were assessed at age 8-9. In the probiotic group, 15/59 (25%) were diagnosed with any allergic disease vs 22/62 (35%) in the placebo group [OR (95% CI) 0.62 (0.28-1.36)]. Corresponding numbers for IgE-associated allergic disease were 9/53 (17%) vs 12/59 (20%) [0.80 (0.31-2.09)]. Median (25th-75th percentile) FENO was 9 (8-12) in the probiotic vs 8 (7-12) ppb in the placebo group (P > 0.05). There was no effect of LF19 on lung function measures (P > 0.05). There was no long-term effect of LF19 on any diagnosed allergic disease, airway inflammation or IgE sensitization. This suggests delayed eczema onset but to fully examine long-term benefits a larger study population had been needed.


Massive Coronary Air Embolism Treated Successfully by Simple Aspiration by Guiding Catheter.
Coronary air embolism remains a recognized complication of coronary catheterization despite a strong emphasis on prevention. It is almost always iatrogenic. It occurs mostly when catheters used for vascular procedures have not been adequately aspirated and flushed. Current treatment consists of supportive measures with 100% oxygen and analgesia and use of aspiration catheter. Here we report a case of massive coronary air embolism of left anterior descending artery and left circumflex artery because of loose Y-adapter connection during percutaneous coronary intervention. Patient suddenly developed hypotension, chest pain, ST elevation and finally asystole. Simple vigorous aspiration was done through guiding catheter restoring the flow and finally successful intervention. Thus simple aspiration can also do the wonder as bail-out measures in the standard treatment of air embolism.


Metathesis catalysts in confining reaction fields--confinement effects vs. surface effects.
It has been recognized previously that inside nanosized cavities like in mesoporous materials a small ensemble situation can be realized. The limited number of reactants per confinement leads to unusual chemical behaviour whenever inter- vs. intramolecular pathways compete against each other. Therefore, the metathesis reaction might represent a chemical process for which the product distribution is influenced by a confining reaction field. In the current paper we report about the unusual reactivity of the Grubbs generation I catalyst inside mesoporous silica materials. It has been observed that due to a combination of confinement and surface effects the Grubbs catalyst is not stable inside small pores. It quickly rearranges to a variety of unexpected products. However, the undesired deactivation of the catalyst can be prohibited by surface modification of the silica surfaces.