Minisatellite instability and germline mutation.
Tandem-repeat DNA actively turns over in the genome by a variety of poorly understood dynamic mechanisms. Minisatellites, a class of tandem repeats, have been shown to cause disease by influencing gene expression, modifying coding sequences within genes or generating fragile sites. There has been recent rapid progress towards understanding molecular turnover processes at human minisatellites. Instability at GC-rich minisatellites appears to involve distinct mutation processes operating in somatic and germline cells. In the germline, complex conversion-like events occur, probably during meiosis. Repeat turnover appears to be controlled by intense recombinational activity in DNA flanking the repeat array, suggesting that minisatellites might evolve as by-products of localised meiotic recombination in the human genome. In contrast, AT-rich minisatellites appear to evolve by intra-allelic processes such as replication slippage. Curiously, minisatellites in other organisms appear to be more stable than their human counterparts, suggesting species-specific differences in turnover processes. Some yeast models display human-like minisatellite turnover processes at meiosis. However, all attempts to transfer human germline instability to transgenic mice have failed. Finally, tandem repeat instability in various species appears to be extremely sensitive to environmental agents such as radiation via a mechanism which remains enigmatic.


Calcium-prostaglandin interaction on the action of antidiuretic hormone in the dog.
The effect of interaction between calcium and prostaglandin (PG) on the action of antidiuretic hormone (ADH) was studied in the water-diuresing anesthetized dog. Maximal urinary osmolality after 100 mU or ADH was 331 +/- 24 in the normocalcemic state versus only 228 +/- 31 mosmol/kg (P less than 0.01) in dogs made acutely hypercalcemic when their serum Ca concentration was increased from 8.9 +/- 0.2 to 11.6 +/- 0.4 mg/100 ml (P less than 0.001). To define the role of PG in this effect, studies were performed in the presence of PG inhibition with indomethacin (10 mg/kg). The antidiuretic response to 100 mU of ADH was decreased by hypercalcemia, as maximal osmolality was 1,096 +/- 65 in the normocalcemic PG-inhibited dog but only 555 +/- 50 mosmol/kg in the acutely hypercalcemic PG-inhibited dog (P less than 0.001). Conversely, the effect of PG inhibition to enhance the hydroosmotic effect of ADH was also demonstrable in acutely hypercalcemic dogs, as maximal urinary osmolality following 100 mU of ADH was 257 +/- 9 before and 557 +/- 60 mosmol/kg after PG inhibition (P less than 0.001). These studies demonstrate, therefore, that the effect of acute hypercalcemia on the hydroosmotic response to vasopressin is not dependent on the synthesis of an endoperoxide metabolite. Likewise, hypercalcemia blunts but does not abolish the effect of PG inhibitors to potentiate the hydroosmotic effect of ADH.


Diagnosis and screening for cytomegalovirus infection in pregnant women in Cuba as prognostic markers of congenital infection in newborns: 2007-2008.
Human cytomegalovirus (HCMV) has established itself as the most significant cause of congenital infection in the developed world. The objective of this research was prenatal identification of pregnant women at risk for developing active infection due to HCMV as well as to diagnose congenitally infected newborns. A diagnostic algorithm based on specific immunoglobulin G (IgG), IgM, and, IgG avidity was used to screen serum from 1131 pregnant women enrolled prospectively from 3 municipalities from Havana City, Cuba during 2007-2008. Qualitative multiplex nested PCR and quantitative real time-based PCR testing for HCMV DNA were performed on urine and saliva specimens from women detected with active infection and from their newborns. Most women were seropositive to HCMV (92.7%), with 2.38% (27 women) having active infection. Primary infection was detected in 20 pregnant women (1.77%) while 7 patients (0.62%) had active nonprimary infection. HCMV DNA was detected in specimens from 9 of the 27 pregnant women by both PCR methods. HCMV congenital infection was diagnosed in 12 (1.06%) of the 26 live children born from 25 mothers with active infection, for a vertical transmission rate of 46.2%. Two fetal deaths were reported from 2 women with active infection; furthermore 2 newborns were symptomatic at birth and 2 showed sequelae during the follow-up done until 6 months age. Mothers with active infection during the pregnancy and with HCMV excretion had significant risks, RR = 1.16 and RR = 1.35, respectively, to have congenitally infected children.


Predictive Role of ERCC1 Expression in Head and Neck Squamous Cell Carcinoma Patients Treated with Surgery and Adjuvant Cisplatin-Based Chemoradiation.
ERCC1 (excision repair cross-complementation group 1) expression predicts survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation. In order to evaluate the predictive role in the adjuvant setting, we investigated ERCC1 expression in radically resected HNSCC patients who underwent surgery and cisplatin chemoradiation. ERCC1 expression levels were determined by immunohistochemistry in primary tumor tissues from 48 patients with stage III-IV cancers. The median follow-up was 38.5 months (range: 5-121). High ERCC1 expression was observed in 36 (75%) patients. Univariate analysis showed that patients with high levels of ERCC1 had significantly worse disease-free survival and overall survival (OS) than patients with low levels (HR = 7.15; 95% CI, 1.68-30.35; p = 0.008 and HR = 9.90; 95% CI, 1.33-73.96; p = 0.025, respectively). In the multivariate analysis, high ERCC1 expression (HR = 7.36; 95% CI, 1.72-31.4; p = 0.007) together with high-risk category (HR = 2.69; 95% CI, 1.01-7.18; p = 0.048) were the best predictors for relapse. High ERCC1 expression was the only unfavorable independent determinant for OS (HR = 9.53; 95% CI, 1.27-71.35; p = 0.028). This investigation suggests that ERCC1 expression might be useful to predict prognosis in radically resected HNSCC patients treated with surgery and chemoradiation.


Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells.
Umbilical cord matrix stem cells (UCMSCs) are able to differentiate into mesodermal and ectodermal lineages. The present study investigates the differentiation potential of human UCMSCs into hepatic lineage. We isolated human UCMSCs and characterized them in vitro by measuring their expansion potential, by assessing expression of mesenchymal stem cell (MSC) markers, and by evaluating their ability to differentiate into adipocytes and osteocytes. UCMSCs were thereafter subjected to a hepatogenic differentiation protocol. Expression of hepatic and MSC markers in differentiated cells was analyzed by reverse-transcription polymerase chain reaction, flow cytometry, and immunocytochemical assays and compared with undifferentiated UCMSCs and freshly isolated liver cells. UCMSCs were transplanted into livers of hepatectomized-SCID mice, and engraftment capacity was investigated by detection of human nucleus and mitochondria and human hepatic-specific proteins. In vitro expanded UCMSCs constitutively expressed markers of hepatic lineage, including albumin, alpha-fetoprotein, cytokeratin-19, connexin-32, and dipeptidyl peptidase IV. In vitro-differentiated UCMSCs exhibited hepatocyte-like morphology, up-regulated several hepatic markers, stored glycogen, produced urea, and exhibited an inducible CYP 3A4 activity. However, absence of some hepatic markers in differentiated UCMSCs, as HepPar1 or hepatocyte nuclear factor 4 (HNF-4), implied that their differentiation did not reach the level of mature hepatocytes. We also noticed that differentiated UCMSCs partially preserved MSC markers. Engraftment capacity of UCMSCs was observed, and expression of human albumin and alpha-fetoprotein was detected 2, 4, and 6 weeks after transplantation in mice livers, while cytokeratin 19 was completely down-regulated. We conclude that UCMSCs, with a newly demonstrated endodermic differentiation potential, might be an alternative source for liver-directed cell therapies.


Manipulation of Glucose and Hydroperoxide Metabolism to Improve Radiation Response.
Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review outlines the preclinical and clinical data for targeting glucose and hydroperoxide metabolism in cancer, with a focus on drug strategies that have the most available evidence. In particular, inhibition of glycolysis using 2-deoxyglucose, and inhibition of redox metabolism using the glutathione pathway inhibitor buthionine sulfoximine and the thioredoxin pathway inhibitor auranofin, have shown promise in preclinical studies to increase sensitivity to chemotherapy and radiation by increasing intracellular oxidative stress. Combined inhibition of glycolysis, glutathione, and thioredoxin pathways sensitizes highly glycolytic, radioresistant cancer models in vitro and in vivo. Although the preclinical data support this approach, clinical data are limited to exploratory trials using a single drug in combination with either chemotherapy or radiation. Open research questions include optimizing drug strategies for targeting glycolysis and redox metabolism, determining the appropriate timing for administering this therapy with concurrent chemotherapy and radiation, and identifying biomarkers to determine the cancers that would benefit most from this approach. Given the quality of preclinical evidence, dual targeting of glycolysis and redox metabolism in combination with chemotherapy and radiation should be further evaluated in clinical trials.


A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells.
Mitogen-activated protein kinase phosphatase (MKP)-1 is a dual-specificity phosphatase that negatively regulates the activity of mitogen-activated kinases and that is overexpressed in human tumors. Contemporary studies suggest that induction of MKP-1 during chemotherapy may limit the efficacy of clinically used antineoplastic agents. Thus, MKP-1 is a rational target to enhance anticancer drug activity, but suitable small-molecule inhibitors of MKP-1 are currently unavailable. Here, we have used a high-content, multiparameter fluorescence-based chemical complementation assay for MKP activity in intact mammalian cells to evaluate the cellular MKP-1 and MKP-3 inhibitory activities of four previously described, quinone-based, dual-specificity phosphatase inhibitors, that is, NSC 672121, NSC 95397, DA-3003-1 (NSC 663284), and JUN-1111. All compounds induced formation of reactive oxygen species in mammalian cells, but only one (NSC 95397) inhibited cellular MKP-1 and MKP-3 with an IC(50) of 13 mumol/L. Chemical induction of MKP-1 by dexamethasone protected cells from paclitaxel-induced apoptosis but had no effect on NSC 95397. NSC 95397 phenocopied the effects of MKP-1 small inhibitory RNA by reversing the cytoprotective effects of dexamethasone in paclitaxel-treated cells. Isobologram analysis revealed synergism between paclitaxel and NSC 95397 only in the presence of dexamethasone. The data show the power of a well-defined cellular assay for identifying cell-active inhibitors of MKPs and support the hypothesis that small-molecule inhibitors of MKP-1 may be useful as antineoplastic agents under conditions of high MKP-1 expression.


[Music-induced chills as a strong emotional experience].
While enjoying music and other works of art, people sometimes experience "chills," a strong emotional response characterized by a sensation of goose bumps or shivers. Such experiences differ from having goose bumps as a defense response or from shivering in reaction to cold temperatures. The current paper presents the phenomenon of music-induced chills and reviews the chill-related emotional response, autonomic nervous system activity, and brain activity. It also reviews the musico-acoustic features, listening contexts, and individual differences that cause chills. Based on the review, we propose a hypothetical model regarding the evocation of music-induced chills. Furthermore, we investigate the strong emotional response associated with chills by exploring the relationship between music-related chills and non-music-related chills, and discuss future research directions.


Preoperative radio-chemotherapy treatment in locally advanced rectal carcinoma. Results of 8-year follow-up.
Preoperative radio-chemotherapy (RCT) may play an important role in decreasing local recurrence and possibly improving survival for patients with advanced rectal carcinoma. Between 1995 and 1998 we treated 30 patients (pts) (median age 61.5 years) with advanced low rectal cancer. Radiotherapy was administered using a 10-MV linear accelerator delivering a total dose of 45 Gy to the pelvis over 5 weeks. 5-FU (500 mg/m2/d i.v.) was given concomitantly on days 1-3 and 29-31. Surgery was performed 2-4 weeks after RCT and included abdomino-perineal resection (APR) in 15 pts, anterior resection in 11 pts, transanal resection in 1 pt, and explorative laparotomy in 1 pt; 2 pts refused surgery. There were no serious toxicities associated with RCT. Mild to moderate transient radiation dermatitis was noted in 3 pts, and grade II diarrhea in 4 pts. Postoperative pathologic staging was as follows: no tumor found (CR): 4 pts, MAC B1 (T2N0M0): 5 pts, MAC B2 (T3N0M0): 17 pts, B3 (vaginal involvement): 1 pt, MAC C2 (T3N1M0): 2 pts, and MAC D: 1 pt. Necrosis and/or fibrosis was noted as a prominent histopathologic feature. Preoperative RCT in this series of 30 pts with advanced rectal cancer was well tolerated and associated with a high response rate (13% CR, 17% PR, 57% NC). 5-year overall survival was 70%, and 8-year survival was 58%.


Placental peptides metabolism and maternal factors as predictors of risk of gestational diabetes in pregnant women. A case-control study.
Gestational diabetes is a risk factor for perinatal complications; include shoulder dystocia, birth injuries such as bone fractures and nerve palsies. It is associated with later development of type 2 diabetes, the risk of macrosomia and other long-term health effects of infants born to diabetic mothers. The study assesses placental peptides and maternal factors as potential predictors of gestational diabetes among pregnant women. A total of 200 pregnant women were recruited for the study, 150 pregnant women without pre gestational diabetes including 50 women with low risk factors of diabetes as controls and 50 other pregnant women with pregestational diabetes as control. Fasting blood glucose and the lipid profile were determined by enzymatic methods using Envoy® 500 reagents (Vital Diagnostics, USA). Glycated haemoglobin was assessed using the Cation Exchange resin method. Leptin and the Human Placenta Lactogen were assayed using the Sandwich-ELISA technique. Beta chorionic gonadotrophin, insulin, progesterone and estradiol were determined using chemilumiscence imunoassay technique on MAGLUMI 600 analyzer. Anthropometry, including BMI and blood pressure were also measured. Fasting plasma glucose (FBG), insulin, insulin resistance, glycated haemoglobin and Human Placenta Lactogen(HPL)were significantly (p<0.0001) increased in the pregestational diabetic women whereas progesterone and estradiol were significantly decreased. In the second trimester however, there was no significant difference (p>0.05) in estradiol, insulin, insulin resistance and HPL between the pregnant women who developed gestational diabetes and those who did not. Leptin, progesterone and FBG were significantly increased in those who developed GDM. The risk of developing gestational diabetes increased with overweight (OR = 1.76, P = 0.370) and family history of diabetes (OR = 2.18, P = 0.282). Leptin, progesterone, estradiol estimated in this study were increased in the gestational diabetes mellitus women and fairly predicted gestational diabetes in the non-diabetics pregnant women. Obesity, aging and family history of diabetes were strongly predictive of gestational diabetes.


Hyperbaric oxygen therapy for lower-extremity soft-tissue sports injuries.
Lower-extremity injuries have become increasingly common as sports performance demands have risen. Hyperbaric oxygen therapy is one method used to return athletes to competition as quickly as possible, but it has received criticism and lacks support. This review examines the literature on hyperbaric oxygen therapy and soft-tissue sports injuries. In the various studies, the location of the injury seemed to influence the effectiveness of treatment. Injuries at areas of reduced perfusion such as muscle-tendon junctions and ligaments seemed to benefit more from hyperbaric oxygen treatment than injuries at the muscle belly. Differences in the magnitude of the injury and in the time between injury and treatment may also affect outcomes. The authors sought to explore these variables as they relate to soft-tissue sports injuries and to weigh the benefits of hyperbaric oxygen therapy against its potential risks and high cost. More randomized controlled clinical trials with larger sample sizes must be conducted before hyperbaric oxygen can be established as a safe adjunctive therapy for soft-tissue sports injuries.


Non-tuberculous mycobacterial infections-A neglected and emerging problem.
Non-tuberculous mycobacteria (NTM) are ubiquitous dwellers of environmental niches and are an established cause of natural and nosocomial infections. The incidence of NTM infections is rising owing to a growing population of immunocompromised and vulnerable individuals, complex medical and surgical procedures, as well as increased awareness and diagnostic capabilities. The prevalence of different NTM varies between continents, regions, and countries. The true global burden of pulmonary and extrapulmonary disease is unknown and estimates are subject to under and/or over-estimation. Diagnosis requires confirmation by isolation of NTM along with clinical and radiological criteria, which may be suboptimal at all levels. Susceptibility testing is complex and clinical breakpoints are not available for many of the drugs. Frequently, NTM infections are not considered until late in the course of disease. Improved and rapid detection of tuberculosis cases in high-burden countries has, however, also brought NTM infections into the limelight, and has identified a need for research efforts towards rapid diagnostic tests and the identification of biomarkers to monitor the treatment response in patients with NTM infections.


Retroviral-mediated expression of the P140A, but not P140A/G156A, mutant form of O6-methylguanine DNA methyltransferase protects hematopoietic cells against O6-benzylguanine sensitization to chloroethylnitrosourea treatment.
O(6)-Benzylguanine (6-BG) inactivates mammalian O(6)-methylguanine DNA methyltransferase (MGMT), an important DNA repair protein that protects cells against chloroethylnitrosourea (CENU) cytotoxicity. 6-BG is being tested as an approach to treat CENU-resistant tumors that overexpress endogenous MGMT. However, in addition to restoring CENU tumor cell sensitivity, 6-BG also increases the cytotoxic effects of CENUs on hematopoietic cells. Several 6-BG-resistant human MGMT mutants have been characterized in Escherichia coli and are predicted to protect mammalian cells against the combination of 6-BG and CENU treatment in vivo. Two mutants, P140A and P140A/G156A, demonstrated 20- and 1200-fold more resistance to 6-BG depletion of MGMT activity compared with wild-type MGMT (WTMGMT). Here, we analyzed retroviral vectors that express either WTMGMT, the P140A or P140A/G156A mutant forms of MGMT. Retroviral-infected L1210 hematopoietic cells demonstrated similar levels of RNA in all transduced clones. However, the amount of MGMT protein and DNA repair activity was reduced in clones expressing the P140A/G156A mutant compared with those expressing WTMGMT or P140A. Expression of P140A was associated with a 4- to 8-fold increase in resistance to 6-BG depletion of MGMT in transduced L1210 clones and a 1, 3-bis(2-chloroethyl)-1-nitrosourea IC(50) of 50 microM (compared with 27.5 microM for WTMGMT) in primary murine hematopoietic cells. These results demonstrate the utility of screening 6-BG-resistant MGMT proteins in hematopoietic cells and provide evidence that the P140A mutant form of MGMT generates 6-BG- and CENU-resistant hematopoietic cells. Retrovirus vectors expressing this mutant may be useful in future human gene therapy trials.


Analysis of 3 Different Operative Techniques for Extra-articular Fractures of the Phalanges and Metacarpals.
Background: Several techniques have been described for treating metacarpal and phalangeal fractures. We sought to compare the 3 techniques most frequently used for extra-articular metacarpal and phalangeal fractures: plate screw (PS), Kirschner wire (KW), and retrograde intramedullary screw (RIS) fixation. We aimed to determine whether using an RIS provides better clinical outcomes than using either a PS or a KW fixation. Methods: We conducted a retrospective review of patients who underwent surgical treatment of metacarpal and phalangeal fractures from January 2011 to December 2017 in our department. Only patients with an acutely displaced short oblique or transverse extra-articular metacarpal or phalangeal fracture were included. Patients were classified into 3 groups depending on the treatment they received: PS, KW, or RIS fixation. The duration of each procedure was recorded. Clinical assessments included measuring total active motion (TAM), grip strength, and an evaluation of plain radiographs through to ultimate healing. A Disabilities of the Arm, Shoulder and Hand (QuickDASH) score was collected on all patients. Data were analyzed by analysis of variance or Kruskal-Wallis rank test, as indicated. Results: A total of 253 fractures (202 metacarpal and 51 phalangeal) in 230 patients were included in analysis. In all, 135 fractures (53.3%) underwent PS fixation; 53 (20.9%), KW fixation; and 65 (25.6%), RIS fixation. In the KW fixation group, Bouquet pinning was performed for metacarpal fractures and cross pinning for phalangeal fractures. When more than 1 fracture coexisted in the same patient, they were considered separate instances. No differences among the 3 groups were observed when evaluating mean time to radiological union, grip strength, TAM, or QuickDASH score. Mean surgery time was significantly shorter with KW (20 minutes) and RIS (25 minutes), than with PS (32 minutes). Mean return to work or routine activities time was significantly less in the RIS (7.8 weeks) group than in the PS and KW groups (8.3 and 9.2 weeks, respectively). Conclusions: Surgical treatment is recommended in patients with unstable metacarpal and phalangeal fractures. The use of RIS was associated with shorter mean surgery duration and return to work times than PS and KW, respectively.


LINC00115 promotes gastric cancer partly by the miR-212-5p/ATPAF1 axis.
LncRNAs are known to be key regulators in the initiation and development of diverse cancers. Whether LINC00115 is involved in the regulation of gastric cancer (GC) progression remains unclear. Here, we aimed to show the function of LINC00115 in GC. RT-qPCR was used to measure gene expression in GC tissues and cells. Colony formation, EdU, TUNEL, and wound healing assays were used to analyze cellular processes in GC. The in vivo GC xenograft model was established. We observed that LINC00115 was highly expressed in GC. Functionally, silencing LINC00115 inhibited GC cell proliferation, and migration but facilitated GC apoptosis. Mechanistically, LINC00115 sponged miR-212-5p, while miR-212-5p targeted ATPAF1 in GC cells. Rescue assays showed ATPAF1 overexpression countervailed the inhibitory role of LINC00115 depletion in GC progression in vitro and in vivo. Overall, LINC00115 promoted GC progression by upregulating ATPAF1 via miR-212-5p.


Analysis 33 patients of non-DS-AMKL with or without acquired trisomy 21 from multiple centers and compared to 118 AML patients.
Acute megakaryoblastic leukemia (AMKL) without Down syndrome (non-DS-AMKL) usually a worse outcome than DS-AMKL. Acquired trisomy 21(+21) was one of the most common cytogenetic abnormalities in non-DS-AMKL. Knowledge of the difference in the clinical characteristics and prognosis between non-DS-AMKL with +21 and those without +21 is limited. Verify the clinical characteristics and prognosis of non-DS-AMKL with +21. We retrospectively analyzed 33 non-DS-AMKL pediatric patients and 118 other types of AML, along with their clinical manifestations, laboratory data, and treatment response. Compared with AMKL without +21, AMKL with +21 has a lower platelet count (44.04 ± 5.01G/L) at onset (P > 0.05). Differences in remission rates between AMKL and other types of AML were not significant. Acquired trisomy 8 in AMKL was negatively correlated with the long-term OS rate (P < 0.05), while +21 may not be an impact factor. Compared with the other types of AML, AMKL has a younger onset age (P < 0.05), with a mean of 22.27 months. Anemia, hemorrhage, lymph node enlargement, lower white blood cell, and complex karyotype were more common in AMKL (P < 0.05). AMKL has a longer time interval between onset to diagnosis (53.61 ± 71.15 days) (P < 0.05), and patients with a diagnosis delay ≥3 months always presented as thrombocytopenia or pancytopenia initially. Due to high heterogeneity, high misdiagnosis rate, and myelofibrosis, parts of AMKL may take a long time to be diagnosed, requiring repeated bone marrow punctures. Complex karyotype was common in AMKL. +21 may not be a promising indicator of a poor prognosis.


Mapping the substrate-binding subsite specificity of a Porphyromonas gingivalis Tpr peptidase.
Calcium-dependent peptidases of the calpain family are widespread in eukaryotes but uncommon in prokaryotes. A few bacterial calpain homologs have been discovered but none of them have been characterized in detail. Here we present an in-depth substrate specificity analysis of the bacterial calpain-like peptidase Tpr from Porphyromonas gingivalis. Using the positional scanning hybrid combinatorial substrate library method, we found that the specificity of Tpr peptidase differs substantially from the papain family of cysteine proteases, showing a strong preference for proline residues at positions P2 and P3. Such a degree of specificity indicates that this P. gingivalis cell-surface peptidase has a more sophisticated role than indiscriminate protein degradation to generate peptide nutrients, and may fulfil virulence-related functions such as immune evasion.


"We Used to Have Four Seasons, but Now There Is Only One": Perceptions Concerning the Changing Climate and Environment in a Diverse Sample of Israeli Older Persons.
Solastalgia is the pain caused by the loss of solace and isolation from one's environment. Solastalgia is contrasted with nostalgia, which is defined as melancholy characterized by homesickness or the distance from one's home. The present study examines the two concepts of solastalgia and nostalgia in the context of climate change among diverse populations of older Israelis. In total, 50 older persons from four different population groups (e.g., veteran Israeli Jews, Israeli Arabs, immigrants from the former Soviet Union, and Ethiopian immigrants) were interviewed. All interviews were transcribed and analyzed thematically. Members of all four groups expressed emotional distress and grief associated with the changing climate, increased environmental pollution, and the disappearance of nature. Perceptions around the undesirability of these changes were quite unanimous, thus leading us to conclude that the outcomes associated with solastalgia and nostalgia are quite similar despite different etiological explanations.


The F-actin bundler α-actinin Ain1 is tailored for ring assembly and constriction during cytokinesis in fission yeast.
The actomyosin contractile ring is a network of cross-linked actin filaments that facilitates cytokinesis in dividing cells. Contractile ring formation has been well characterized in Schizosaccharomyces pombe, in which the cross-linking protein α-actinin SpAin1 bundles the actin filament network. However, the specific biochemical properties of SpAin1 and whether they are tailored for cytokinesis are not known. Therefore we purified SpAin1 and quantified its ability to dynamically bind and bundle actin filaments in vitro using a combination of bulk sedimentation assays and direct visualization by two-color total internal reflection fluorescence microscopy. We found that, while SpAin1 bundles actin filaments of mixed polarity like other α-actinins, SpAin1 has lower bundling activity and is more dynamic than human α-actinin HsACTN4. To determine whether dynamic bundling is important for cytokinesis in fission yeast, we created the less dynamic bundling mutant SpAin1(R216E). We found that dynamic bundling is critical for cytokinesis, as cells expressing SpAin1(R216E) display disorganized ring material and delays in both ring formation and constriction. Furthermore, computer simulations of initial actin filament elongation and alignment revealed that an intermediate level of cross-linking best facilitates filament alignment. Together our results demonstrate that dynamic bundling by SpAin1 is important for proper contractile ring formation and constriction.


Natural Killer Cells - Their Role in Tumour Immunosurveillance.
An important component of the innate immune system, the natural killer cells that originate from the lymphoid cell lineage, hold tremendous potential as an effective therapeutic tool to combat a variety of cancers. Their vast capability to kill altered cells such as opsonized cells (antibody coated), tumour cells, genotoxically changed cells without affecting the healthy cells of the body, make them an effective therapeutic agent for various types of cancers. Besides, through interplay and molecular crosstalk via several cytokines, they also augment the adaptive immune response by, promoting the differentiation, activation and recruitment of component cells of the system. With the current advance knowledge of Natural Killer (NK) cells, their receptor-ligand interactions involved in functional regulation, various mechanistic approaches involving the role of cytokines led to desired modulation of NK cell activity in a tailor-made manner, for triggering clinically relevant responces. Several strategies have been adopted by researchers, to augment the efficacy of NK cells. Still many challenges exist for increasing the therapeutic relevance of these cells.


Urocortin Expression in Endometriosis: A Systematic Review.
Urocortin (UCN) is a neuropeptide that belongs to the corticotrophin-releasing hormone family and is expressed by eutopic and ectopic human endometria. The past years, this expression has been thoroughly investigated in the field of endometriosis. The objective of this systematic review is to accumulate current evidence related to the expression of UCN in tissue and blood samples of patients suffering from endometriosis. Literature search was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and primarily conducted using the Medline (1966-2018), Scopus (2004-2018), EMBASE (1947-2018) and Clinicaltrials.gov (2008- 2018) databases, along with the reference lists of electronically retrieved full-text papers. Overall, eight studies were retrieved. Current evidence suggests that the expression of UCN is increased in patients with ovarian endometriomas and that its levels may correlate with the severity of the disease. The diagnostic efficacy of UCN1 plasma levels was evaluated in three studies. Two of them suggested that the sensitivity and specificity of the method may reach, and even exceed, 80%. However, the wide variation in outcome reporting and outcome reporting measures in endometriosis among the included studies precludes meta-analysis of available data. Therefore, although UCN seems to be a promising biomarker for the identification and follow-up of patients that suffer from endometriosis, more studies are needed to reach firm conclusions with respect to its predictive accuracy.


Neural transplantation in Huntington's disease: the NEST-UK donor tissue microbiological screening program and review of the literature.
Neural transplantation of human fetal tissue for Huntington's disease (HD) is now entering the clinical arena. The safety of the procedure has now been demonstrated in a number of studies, although the efficacy of such an approach is still being investigated. Stringent but practicable screening of the donor tissue for potential pathogens is an essential prerequisite for successful implementation of any novel transplant program that uses human fetal tissue. In this article we summarize the UK-NEST protocol for the screening of human fetal tissue being grafted to patients with mild to moderate HD. We describe the results of microbiological screening of 87 potential tissue donors in a pilot study, and of the first four donor-recipient patients included in the UK-NEST series. The rationale for the adoption and interpretation of the various tests is described and our methodology is compared with those previously used by other centers. This article therefore presents a comprehensive, logical yet pragmatic screening program that could be employed in any clinical studies that use human fetal tissue for neurotransplantation.


Use of natural substances in the treatment of renal stones and other urinary disorders in the medieval Levant.
Urinary disorders were common in the ancient world, especially in the Mediterranean region. In semi-arid zones and countries with unreliable water sources, renal stones and other urinary problems occur with greater frequency. A lack of water and correspondingly high levels of calcium saturation are among the main reasons for the formation of calcium sediments in the urinary tract, and it is hardly surprising, therefore, that many generations of physicians and healers have been called upon to treat these disorders, or at least alleviate the pain associated with them. Down the ages, many natural substances have been used for this purpose. This article focuses on 62 plants, 9 animal-based remedies, 1 mineral preparation and 4 medicinal substances of different or uncertain origin, traced in a recent survey of relevant historical literature (both medical and non-medical). Many of these materials, used to treat urinary disorders in the Levant between the 8th and the 18th centuries, had already been in use since the classical period, and several are still used today in traditional medicine.


Urticaria is associated with birch-pollen sensitization.
Urticaria is a common condition, seldom of allergic origin. It is however not always possible to find the provoking allergen. The aim of the present study was to analyze if there was a relationship between urticaria and sensitization to common airborne allergens. A representative sample of 402 12 to 13-yr-old children answered a questionnaire on allergic diseases, 397 were interviewed by the study nurse and 371 underwent skin prick tests to cat, dog, horse, birch, timothy-grass, house dust mites and Cladosporium mould. Specific IgE-antibodies were analyzed to birch pollen and cat dander. Urticaria was more common in sensitized children, but the relationship between urticaria and sensitization was only statistically significant for birch pollen sensitization (OR 1.99, 95% CL 1.04-3.83), when tested in a multiple logistic regression model with the specified allergens as independent variables. A similar pattern was seen for birch-specific IgE-antibody levels, which was higher in children reporting urticaria than in those without. IgE-levels to cat dander did not show such a difference. Urticaria was statistically significantly associated with sensitization to birch-pollen, but not to other common inhalant allergens. We propose that intake of birch-pollen cross-reactive food-stuffs may be a neglected cause of urticaria and relapsing urticaria, in birch-pollen sensitized subjects.


Circulatory response of digital arteries associated with electrical stimulation of calf muscle in healthy subjects.
The purpose of this study was to investigate the effects of electrical stimulation (2,500-Hz sine wave modulated at 50 bursts per second) of the posterior calf musculature on the blood circulation of an unexercised part of the body, the ipsilateral digital arteries. Intensities of electrical stimulation sufficient to produce 15% and 30% of isometric maximum voluntary contraction (MVC) of the plantar flexor muscles were used. Twenty-four healthy subjects participated in this study and were assigned either to an Experimental Group receiving electrical stimulation (n = 13) or to a Control Group not receiving electrical stimulation (n = 11). Analysis of data revealed significant differences in finger blood flow when the calf musculature was stimulated electrically. We found significant differences in blood flow of the finger when torques produced by electrical stimulation of the calf musculature were raised to 15% and 30% of MVC. The results of the study indicate that blood flow in the ipsilateral finger decreases significantly when the posterior calf musculature is exercised artificially with electrical stimulation bursts.


Differentiation among populations with migration, mutation, and drift: implications for genetic inference.
Populations may become differentiated from one another as a result of genetic drift. The amounts and patterns of differentiation at neutral loci are determined by local population sizes, migration rates among populations, and mutation rates. We provide exact analytical expressions for the mean, variance, and covariance of a stochastic model for hierarchically structured populations subject to migration, mutation, and drift. In addition to the expected correlation in allele frequencies among populations in the same geographic region, we demonstrate that there is a substantial correlation in allele frequencies among regions at the top level of the hierarchy. We propose a hierarchical Bayesian model for inference of Wright's F-statistics in a two-level hierarchy in which we estimate the among-region correlation in allele frequencies by substituting replication across loci for replication across time. We illustrate the approach through an analysis of human microsatellite data, and we show that approaches ignoring the among-region correlation in allele frequencies underestimate the amount of genetic differentiation among major geographic population groups by approximately 30%. Finally, we discuss the implications of these results for the use and interpretation of F-statistics in evolutionary studies.


The Mycobacterial LexA/RecA-Independent DNA Damage Response Is Controlled by PafBC and the Pup-Proteasome System.
Mycobacteria exhibit two DNA damage response pathways: the LexA/RecA-dependent SOS response and a LexA/RecA-independent pathway. Using a combination of transcriptomics and genome-wide binding site analysis, we demonstrate that PafBC (proteasome accessory factor B and C), encoded in the Pup-proteasome system (PPS) gene locus, is the transcriptional regulator of the predominant LexA/RecA-independent pathway. Comparison of the resulting PafBC regulon with the DNA damage response of Mycobacterium smegmatis reveals that the majority of induced DNA repair genes are upregulated by PafBC. We further demonstrate that RecA, a member of the PafBC regulon and principal regulator of the SOS response, is degraded by the PPS when DNA damage stress has been overcome. Our results suggest a model for the regulation of the mycobacterial DNA damage response that employs the concerted action of PafBC as master transcriptional activator and the PPS for removal of DNA repair proteins to maintain a temporally controlled stress response.


Bacteriophage Therapy to Control Bovine Mastitis: A Review.
Bovine mastitis is a polymicrobial disease characterised by inflammation of the udders of dairy and beef cattle. The infection has huge implications to health and welfare of animals, impacting milk and beef production and costing up to EUR 32 billion annually to the dairy industry, globally. Bacterial communities associated with the disease include representative species from Staphylococcus, Streptococcus, Enterococcus, Actinomyces, Aerococcus, Escherichia, Klebsiella and Proteus. Conventional treatment relies on antibiotics, but antimicrobial resistance, declining antibiotic innovations and biofilm production negatively impact therapeutic efficacy. Bacteriophages (phages) are viruses which effectively target and lyse bacteria with extreme specificity and can be a valuable supplement or replacement to antibiotics for bovine mastitis. In this review, we provide an overview of the etiology of bovine mastitis, the advantages of phage therapy over chemical antibiotics for the strains and research work conducted in the area in various model systems to support phage deployment in the dairy industry. We emphasise work on phage isolation procedures from samples obtained from mastitic and non-mastitic sources, characterisation and efficacy testing of single and multiple phages as standalone treatments or adjuncts to probiotics in various in vitro, ex vivo and in vivo bovine mastitis infection models. Furthermore, we highlight the areas where improvements can be made with focus on phage cocktail optimisation, formulation, and genetic engineering to improve delivery, stability, efficacy, and safety in cattle. Phage therapy is becoming more attractive in clinical medicine and agriculture and thus, could mitigate the impending catastrophe of antimicrobial resistance in the dairy sector.


[Significance of biochemical tests in the diagnosis of chronic viral hepatitis C].
The purpose of the investigation was to study whether there was a correlation between the laboratory parameters and the pathomorphological pattern of a liver biopsy specimen in chronic viral hepatitis C. Analysis of the results of studies (general clinical blood analysis, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyltranspeptidase, serum immunoglobulins, and a study of liver biopsy specimens) led to the conclusion that there was a correlation between the level of the enzymes and the histological liver tissue sclerosis index. There was no correlation with the histological activity index. Based on the statistical analysis, the authors defined the threshold points for ALT (over 122 U/l, diagnostic efficiency 72%) and ACT (over 48 U/l, diagnostic efficiency 81%), indicating the stage of disease, which had a histological sclerosis index of more than 1.


Chalcogen and pnicogen bonds in complexes of neutral icosahedral and bicapped square-antiprismatic heteroboranes.
A systematic quantum mechanical study of σ-hole (chalcogen, pnicogen, and halogen) bonding in neutral experimentally known closo-heteroboranes is performed. Chalcogens and pnicogens are incorporated in the borane cage, whereas halogens are considered as exo-substituents of dicarbaboranes. The chalcogen and pnicogen atoms in the heteroborane cages have partial positive charge and thus more positive σ-holes. Consequently, these heteroboranes form very strong chalcogen and pnicogen bonds. Halogen atoms in dicarbaboranes also have a highly positive σ-hole, but only in the case of C-bonded halogen atoms. In such cases, the halogen bond of heteroboranes is also strong and comparable to halogen bonds in organic compounds with several electron-withdrawing groups being close to the halogen atom involved in the halogen bond.


Occurrence of Plesiomonas shigelloides--associated diarrhoea in Calabar, Nigeria.
The prevalence, clinical profiles and virulence factors of Plesiomonas shigelloides were determined in patients attending the University of Calabar Teaching Hospital, Microbiology Laboratory. P. shigelloides was isolated from 12 (1.4%) of 880 patients with diarrhoea and from none of the controls (P less than 0.05). Isolates were mostly from febrile children less than or equal to 10 years with most of the infections occurring during the rainy months. Although our findings suggest the significance of Plesiomonas in acute diarrhoea in this environment, our isolates did not seem to show any of the proxy indicators of virulence usually associated with other enteric pathogens.


MDcons: Intermolecular contact maps as a tool to analyze the interface of protein complexes from molecular dynamics trajectories.
Molecular Dynamics (MD) simulations of protein complexes suffer from the lack of specific tools in the analysis step. Analyses of MD trajectories of protein complexes indeed generally rely on classical measures, such as the RMSD, RMSF and gyration radius, conceived and developed for single macromolecules. As a matter of fact, instead, researchers engaged in simulating the dynamics of a protein complex are mainly interested in characterizing the conservation/variation of its biological interface. On these bases, herein we propose a novel approach to the analysis of MD trajectories or other conformational ensembles of protein complexes, MDcons, which uses the conservation of inter-residue contacts at the interface as a measure of the similarity between different snapshots. A "consensus contact map" is also provided, where the conservation of the different contacts is drawn in a grey scale. Finally, the interface area of the complex is monitored during the simulations. To show its utility, we used this novel approach to study two protein-protein complexes with interfaces of comparable size and both dominated by hydrophilic interactions, but having binding affinities at the extremes of the experimental range. MDcons is demonstrated to be extremely useful to analyse the MD trajectories of the investigated complexes, adding important insight into the dynamic behavior of their biological interface. MDcons specifically allows the user to highlight and characterize the dynamics of the interface in protein complexes and can thus be used as a complementary tool for the analysis of MD simulations of both experimental and predicted structures of protein complexes.


A neural-network architecture for syntax analysis.
Artificial neural networks (ANN's), due to their inherent parallelism, offer an attractive paradigm for implementation of symbol processing systems for applications in computer science and artificial intelligence. This paper explores systematic synthesis of modular neural-network architectures for syntax analysis using a prespecified grammar--a prototypical symbol processing task which finds applications in programming language interpretation, syntax analysis of symbolic expressions, and high-performance compilers. The proposed architecture is assembled from ANN components for lexical analysis, stack, parsing and parse tree construction. Each of these modules takes advantage of parallel content-based pattern matching using a neural associative memory. The proposed neural-network architecture for syntax analysis provides a relatively efficient and high performance alternative to current computer systems for applications that involve parsing of LR grammars which constitute a widely used subset of deterministic context-free grammars. Comparison of quantitatively estimated performance of such a system [implemented using current CMOS very large scale integration (VLSI) technology] with that of conventional computers demonstrates the benefits of massively parallel neural-network architectures for symbol processing applications.


The relationship between patient data and pooled clinical management decisions.
A strong relationship between patient data and preoperative clinical decisions could potentially be used to support clinical decisions in preoperative management. The aim of this exploratory study was to determine the relationship between key patient data and pooled clinical opinions on management. In a previous study, panels of anaesthetists compared the quality of computer-assisted patient health assessments with outpatient consultations and made decisions on the need for preoperative tests, no preoperative outpatient assessment, possible postoperative intensive care unit/high dependency unit requirements and aspiration prophylaxis. In the current study, the relationship between patient data and these decisions was examined using binomial logistic regression analysis. Backward stepwise regression was used to identify independent predictors of each decision (at P >0.15), which were then incorporated into a predictive model. The number of factors related to each decision varied: blood picture (four factors), biochemistry (six factors), coagulation studies (three factors), electrocardiography (eight factors), chest X-ray (seven factors), preoperative outpatient assessment (17 factors), intensive care unit requirement (eight factors) and aspiration prophylaxis (one factor). The factor types also varied, but included surgical complexity, age, gender, number of medications or comorbidities, body mass index, hypertension, central nervous system condition, heart disease, sleep apnoea, smoking, persistent pain and stroke. Models based on these relationships usually demonstrated good sensitivity and specificity, with receiver operating characteristics in the following areas under curve: blood picture (0.75), biochemistry (0.86), coagulation studies (0.71), electrocardiography (0.90), chest X-ray (0.85), outpatient assessment (0.85), postoperative intensive care unit requirement (0.88) and aspiration prophylaxis (0.85). These initial results suggest modelling of patient data may have utility supporting clinicians' preoperative decisions.


Heterotopic expression of class B floral homeotic genes supports a modified ABC model for tulip (Tulipa gesneriana).
In higher eudicotyledonous angiosperms the floral organs are typically arranged in four different whorls, containing sepals, petals, stamens and carpels. According to the ABC model, the identity of these organs is specified by floral homeotic genes of class A, A+B, B+C and C, respectively. In contrast to the sepal and petal whorls of eudicots, the perianths of many plants from the Liliaceae family have two outer whorls of almost identical petaloid organs, called tepals. To explain the Liliaceae flower morphology, van Tunen et al. (1993) proposed a modified ABC model, exemplified with tulip. According to this model, class B genes are not only expressed in whorls 2 and 3, but also in whorl 1. Thus the organs of both whorls 1 and 2 express class A plus class B genes and, therefore, get the same petaloid identity. To test this modified ABC model we have cloned and characterized putative class B genes from tulip. Two DEF- and one GLO-like gene were identified, named TGDEFA, TGDEFB and TGGLO. Northern hybridization analysis showed that all of these genes are expressed in whorls 1, 2 and 3 (outer and inner tepals and stamens), thus corroborating the modified ABC model. In addition, these experiments demonstrated that TGGLO is also weakly expressed in carpels, leaves, stems and bracts. Gel retardation assays revealed that TGGLO alone binds to DNA as a homodimer. In contrast, TGDEFA and TGDEFB cannot homodimerize, but make heterodimers with PI. Homodimerization of GLO-like protein has also been reported for lily, suggesting that this phenomenon is conserved within Liliaceae plants or even monocot species.


Beyond meatless, the health effects of vegan diets: findings from the Adventist cohorts.
Vegetarians, those who avoid meat, and vegans, additionally avoiding dairy and eggs, represent 5% and 2%, respectively, of the US population. The aim of this review is to assess the effects of vegetarian diets, particularly strict vegetarian diets (i.e., vegans) on health and disease outcomes. We summarized available evidence from three prospective cohorts of Adventists in North America: Adventist Mortality Study, Adventist Health Study, and Adventist Health Study-2. Non-vegetarian diets were compared to vegetarian dietary patterns (i.e., vegan and lacto-ovo-vegetarian) on selected health outcomes. Vegetarian diets confer protection against cardiovascular diseases, cardiometabolic risk factors, some cancers and total mortality. Compared to lacto-ovo-vegetarian diets, vegan diets seem to offer additional protection for obesity, hypertension, type-2 diabetes, and cardiovascular mortality. Males experience greater health benefits than females. Limited prospective data is available on vegetarian diets and body weight change. Large randomized intervention trials on the effects of vegetarian diet patterns on neurological and cognitive functions, obesity, diabetes, and other cardiovascular outcomes are warranted to make meaningful recommendations.


Antibodies to the enterobacterial common antigen: standardization of the passive hemagglutination test and levels in normal human sera.
The passive hemagglutination test for antibodies against the enterobacterial common antigen (ECA) of Kunin was standardized for diagnostic purposes. Human erythrocytes were coated with a soluble ECA+ preparation from Salmonella typhimurium or, as specificity controls, with a similar ECA- preparation from congenic ECA-negative bacteria with saline, and the hemagglutination assay was performed on microtiter plates. The specificity of the test was ascertained further by inhibition assays with purified ECA and with crude ECA+ and ECA- preparations. The reproducibility of the tests was 96.4%; on this basis, a fourfold or larger difference in titers was regarded as significant. The anti-ECA titers in 649 serum samples from healthy persons ranged from less than 4 to 8,192. The titers increased with age, so that th geometric mean titers were 57 at 1.5 years of age and 201 at 45 years of age. After this, the titers decreased again, to a low of 52 in persons more than 70 years old. Women had higher titers than men up to the age of 40 years.


International workshop on non-ionizing radiation protection in medicine.
An international workshop brought together a range of stakeholders to consider protection from non-ionizing radiation used in medicine, research and cosmetics. Presentations on specific topics were followed by a general discussion on possible improvements in protection. Participants considered that adherence to science-based, harmonized exposure guidelines to limit exposures for clinical staff and other workers was a key prerequisite to safety in all situations. In addition, to engender an awareness of the risks involved to both the patient as well as the operator, equipment should be operated only by suitably qualified persons who have received appropriate training in the safe use of that device. This training should be carried out under the auspices of an accredited safety provider, and preferably offer a recognized qualification. Specific advice included the necessity for correct eye protection with higher power optical radiation sources, and avoiding the use of ultrasound for all exposures without medical benefit. Finally, the possibility of a harmonized approach to safety for both non-ionizing and ionizing radiation was considered worthy of further discussion.


SLC13A3 variants cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation.
SLC13A3 encodes the plasma membrane Na+ /dicarboxylate cotransporter 3, which imports inside the cell 4 to 6 carbon dicarboxylates as well as N-acetylaspartate (NAA). SLC13A3 is mainly expressed in kidney, in astrocytes, and in the choroid plexus. We describe two unrelated patients presenting with acute, reversible (and recurrent in one) neurological deterioration during a febrile illness. Both patients exhibited a reversible leukoencephalopathy and a urinary excretion of α-ketoglutarate (αKG) that was markedly increased and persisted over time. In one patient, increased concentrations of cerebrospinal fluid NAA and dicarboxylates (including αKG) were observed. Extensive workup was unsuccessful, and a genetic cause was suspected. Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher. WES analysis revealed variants in SLC13A3. A homozygous missense mutation (p.Ala254Asp) was found in the first patient. The second patient was heterozygous for another missense mutation (p.Gly548Ser) and an intronic mutation affecting splicing as demonstrated by reverse transcriptase polymerase chain reaction performed in muscle tissue (c.1016 + 3A > G). Mutations and segregation were confirmed by Sanger sequencing. Functional studies performed on HEK293T cells transiently transfected with wild-type and mutant SLC13A3 indicated that the missense mutations caused a marked reduction in the capacity to transport αKG, succinate, and NAA. SLC13A3 deficiency causes acute and reversible leukoencephalopathy with marked accumulation of αKG. Urine organic acids (especially αKG and NAA) and SLC13A3 mutations should be screened in patients presenting with unexplained reversible leukoencephalopathy, for which SLC13A3 deficiency is a novel differential diagnosis. ANN NEUROL 2019;85:385-395.


Risk Factors of Coronary Artery Abnormality in Children With Kawasaki Disease: A Systematic Review and Meta-Analysis.
While coronary artery abnormality (CAA) has been established as the most serious complication of Kawasaki disease (KD), there have been no detailed systematic reviews of the risk factors associated with this condition. We searched six databases and performed a systematic review and meta-analysis. Study-specific odds ratios (ORs) for each factor were pooled using a random effects model. We identified four risk factors for CAA children with KD: gender (OR, 1.75; 95% confidence interval [CI], 1.59-1.92), intravenous immunoglobulin (IVIG) resistance (OR, 3.43; 95% CI, 2.07-5.67), IVIG treatment beyond 10 days of onset of symptoms (OR, 3.65; 95% CI, 2.23-5.97), and increased C-reactive protein levels (OR, 1.02; 95% CI, 1.01-1.02). More number of the five typical symptoms of KD was identified as a protective factor against CAA (OR, 0.47; 95% CI, 0.33-0.66). Pediatric patients with IVIG resistant were more likely to develop CAA within 1 month of the onset of KD than the general population, even in patients with other risk factors for CAA. Thus, there is a potential risk of CAA misdiagnosis if echocardiography is not carried out frequently. In summary, we report four risk factors for CAA and a protective factor against CAA in children with KD. We recommend that pediatricians consider these factors much more closely. With accurate prediction and early preventive treatment in high-risk patients, we can expect a reduction in CAA rates. Further research is now required to investigate the associations between CAA and other factors including the interval between KD onset and IVIG administration, platelet count, and the duration of fever. We also need to confirm whether the frequency of echocardiography within a month of KD onset should be increased in IVIG-resistant patients.


Intrahypothalamic clonidine infusion prevents NaCl-sensitive hypertension.
We have previously shown that dietary NaCl supplementation increases blood pressure and sympathetic nervous system activity in association with decreased norepinephrine release and increased alpha 2-adrenergic receptor number in the anterior hypothalamic area of salt-sensitive spontaneously hypertensive rats (SHR-S) but not in salt-resistant spontaneously hypertensive rats (SHR-R) or Wistar-Kyoto (WKY) rats. Further, acute microinjection of clonidine into the anterior hypothalamic area produced depressor responses that were augmented by high salt feeding in SHR-S but not in SHR-R or WKY rats. The current study tested the hypothesis that chronic infusion of clonidine into the anterior hypothalamic area prevents salt-sensitive hypertension in SHR-S. Beginning at age 7 weeks, immediately before initiation of 1% or 8% salt diets, clonidine (2 ng/min) or saline vehicle was infused into the anterior hypothalamic area or femoral vein of male SHR-S via osmotic minipump for 20 days. In SHR-S fed an 8% salt diet, chronic microinfusion of clonidine into the anterior hypothalamic area offset the hypertensive effect of the dietary salt supplementation and reduced the enhancing effects of dietary salt on left ventricular weight and plasma norepinephrine levels. In contrast, chronic microinfusion of clonidine into the anterior hypothalamic area did not significantly affect any of these measures in 1% salt-fed SHR-S. Intravenous infusion of clonidine at the rate used for the anterior hypothalamic area infusion did not alter any of these measures in 8% salt-fed SHR-S.(ABSTRACT TRUNCATED AT 250 WORDS)


Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes.
Unlike conventional major histocompatibility complex-restricted T cells, Valpha14-Jalpha18 NKT cell lineage precursors engage in cognate interactions with CD 1 d-expressing bone marrow-derived cells that are both necessary and sufficient for their thymic selection and differentiation, but the nature and sequence of these interactions remain partially understood. After positive selection mediated by CD1d-expressing cortical thymocytes, the mature NKT cell lineage undergoes a series of changes suggesting antigen priming by a professional antigen-presenting cell, including extensive cell division, acquisition of a memory phenotype, the ability to produce interleukin-4 and interferon-gamma, and the expression of a panoply of NK receptors. By using a combined transgenic and chimeric approach to restrict CD1d expression to cortical thymocytes and to prevent expression on other hematopoietic cell types such as dendritic cells, macrophages, or B cells, we found that, to a large extent, expansion and differentiation events could be imparted by a single-cognate interaction with CD1d-expressing cortical thymocytes. These surprising findings suggest that, unlike thymic epithelial cells, cortical thymocytes can provide unexpected, cell type-specific signals leading to lineage expansion and NKT cell differentiation.


Comparison of Macintosh, McCoy and C-MAC D-Blade video laryngoscope intubation by prehospital emergency health workers: a simulation study.
The aim of the this study is to evaluate the intubation success rates of emergency medical technicians using a Macintosh laryngoscope (ML), McCoy laryngoscope (MCL), and C MAC D-Blade (CMDB) video laryngoscope on manikin models with immobilized cervical spines. This randomized crossover study included 40 EMTs with at least 2 years' active service in ambulances. All participating technicians completed intubations in three scenarios-a normal airway model, a rigid cervical collar model, and a manual in-line cervical stabilization model-with three different laryngoscopes. The scenario and laryngoscope model were determined randomly. We recorded the scenario, laryngoscope method, intubation time in seconds, tooth pressure, and intubation on a previously prepared study form. We performed Friedman tests to determine whether there is a significant change in the intubation success rate, duration of tracheal intubation, tooth pressure, and visual analog scale scores due to violations of parametric test assumptions. We performed the Wilcoxon test to determine the significance of pairwise differences for multiple comparisons. An overall 5 % type I error level was used to infer statistical significance. We considered a p value of less than 0.05 statistically significant. The CMDB and MCL success rates were significantly higher than the ML rates in all scenario models (p < 0.05). The CMDB intubation duration was significantly shorter when compared with ML and MCL in all models. CMDB and MCL may provide an easier, faster intubation by prehospital emergency health care workers in patients with immobilized cervical spines.


Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity.
Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes' size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02-1.9; χ2 test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76-1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.


Clinical activity of mammalian target of rapamycin inhibitors in solid tumors.
The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is vital for cell metabolism, growth, and proliferation. mTOR is frequently upregulated in many tumor types and hence has become an important target in cancer treatment. Sirolimus and its derivatives (rapalogs) interact with the intracellular receptor FK506 binding protein 12 (FKBP12), forming a complex with high affinity for mTOR and thus disrupting its activity. Rapalogs are being evaluated extensively in cancer patients with different formulations and schedules. Significant clinical activity has led to their approval for the treatment of kidney cancer, mantle cell lymphoma, and subependymal giant cell astrocytoma; however, despite increasing knowledge about cancer cell biology, their activity in other malignancies is unclear. Further research is needed to identify optimal dosage, administration and targeted combination as well as the subset of patients likely to respond to mTOR/PI3K inhibition. This review focuses on a discussion of the pathway, its implications in cancer biology and results of clinical trials of rapalogs alone or in combination, organizing them by common malignancy type.


Sexual risk behaviour of men who have sex with men: emerging patterns and new challenges.
Antiretroviral treatment means that an increasing number of men who have sex with men (MSM) are living with HIV. The present review focuses on continuing transmission of HIV, risk factors for HIV infection in HIV-negative MSM, risk behaviour and risk reduction interventions among HIV-positive MSM, sexually transmitted infections, HIV and ageing and new and emerging populations of MSM communities. Transmission of HIV infection continues in populations of MSM; transmission may be particularly high from main partners. Serosorting offers limited protection against HIV infection for HIV-negative MSM; negotiated safety and strategic positioning may be partially protective. For HIV-positive men, serosorting is a strategy to prevent HIV transmission, but has contributed to high rates of new non-HIV sexually transmitted infections. Sexual networks are important to the understanding of emerging sexually transmitted infections; ageing brings a new dimension to research on HIV. Strategies other than exclusive condom use have emerged in communities of MSM to reduce the risk of HIV transmission, including serosorting and strategic positioning. 'Combination prevention' - using social structural, behavioural and biomedical approaches in tandem - could reduce the risk of HIV transmission, and may be particularly suited to HIV-positive MSM.


Progressive-overload whole-body vibration training as part of periodized, off-season strength training in trained women athletes.
The purpose was to examine the effects of progressive-overload, whole-body vibration (WBV) training on strength and power as part of a 15-week periodized, strength training (ST) program. Eighteen collegiate women athletes with ≥1 year of ST and no prior WBV training participated in the crossover design. Random assignment to 1 of the 2 groups followed pretests of seated medicine ball throw (SMBT), single-leg hop for distance (LSLH, RSLH), countermovement jump (CMJ), 3 repetition maximum (3RM) front squat (FS), pull-up (PU), and 3RM bench press (BP). Whole-body vibration was two 3-week phases of dynamic and static hold body weight exercises administered 2 d·wk in ST sessions throughout the 15-week off-season program. Total WBV exposure was 6 minutes broken into 30-second bouts with 60-second rest (1:2 work-to-relief ratio). Exercises, frequency, and amplitude progressed in intensity from the first 3-week WBV training to the second 3-week phase. Repeated-measures analysis of variances were used to analyze the SMBT, CMJ, LSLH, RSLH, FS, PU, and BP tests. Alpha level was p ≤ 0.05. Front squat, LSLH, and RSLH increased (p = 0.001) from pre- to posttest; FS increased from mid- to posttest. Pull-up increased (p = 0.008) from pre- to posttest. Seated medicine ball throw and BP showed a trend of increased performance from pre- to posttest (p = 0.11). Two 3-week phases of periodized, progressive-overload WBV + ST training elicited gains in strength and power during a 15-week off-season program. Greatest improvements in performance tests occurred in the initial WBV phase. Implementing WBV in conjunction with ST appears to be more effective in the early phases of training.


Impact of Cataract Surgery on Income in Rural Southern China: The SUCCESS Randomized Controlled Trial.
Visual impairment from cataracts is closely associated with low income, but trial evidence regarding the impact of surgery on income is lacking. We investigated whether cataract surgery could increase personal income. A 2-arm, parallel-group, open-label, randomized controlled trial (ClinicalTrials.gov, NCT03020056). Persons aged 50 years or older in rural Guangdong, China, with best-corrected visual acuity <6/19 in both eyes due to cataracts were randomly assigned (1:1) to receive surgery within 4 weeks (intervention group), or 1 year later (control group). All participants were interviewed at baseline and end-line regarding demographic characteristics, income, and quality of life. Among the 292 eligible persons (5.40%, mean age = 74.0 y, 61.0% women) randomly assigned to intervention (n = 146) or control (n = 146) groups, 12 participants (8.22%) in the intervention group and 1 (0.68%) in the control did not receive the allocated intervention. By study closeout, 18 participants (6.16%) were lost to follow-up. The mean 1-year income increase of the intervention group ($2469-$3588; change = $1119) was significantly larger than that of the controls ($2258-$2052; change = $-206), a between-group difference of $1325 (relative increase = 54.0%; 95% CI = $739 to $1911; P < 0.001). In multivariable modeling, intervention group membership was associated with greater income increase (β = 1143.2; 95% CI = 582.0 to 1704.3; P < 0.001). Greater improvement in best-corrected visual acuity was associated with income increase in univariable modeling (β = 1626.9; 95% CI = 1083.6 to 2170.1; P < 0.001). Cataract surgery substantially increases personal income in rural China, offering a strategy for poverty alleviation. The strong association between increased income and change in visual acuity enhances the biological plausibility of the result.


Clinical significance of p16INK4A and p14ARF promoter methylation in renal cell carcinoma: a meta-analysis.
The inactivation of p16INK4A and p14ARF via promoter methylation has been investigated in various cancers. However, the clinical effects of p16INK4A and p14ARF promoter methylation on renal cell carcinoma (RCC) remain to be clarified. The pooled data were calculated and summarized. Finally, an investigation of 14 eligible studies with 1231 RCC patients and 689 control patients was performed. Methylated p16INK4A and p14ARF were observed to be significantly higher in RCC than in control subjects without malignancies (OR = 2.77, P = 0.005; OR = 11.73, P < 0.001, respectively). Methylated p16INK4A was significantly associated with the risk of RCC in the tissue subgroup, but not in the serum and urine subgroups. Methylated p16INK4A was significantly associated with tumor size. We did not find that p16INK4A promoter methylation was associated with sex, tumor grade, lymph node status, and tumor histology. Methylated p14ARF was significantly correlated with sex and tumor histology. Three studies reported that p16INK4A methylation was not significantly correlated with the prognosis of RCC. The results suggested that p16INK4A and p14ARF promoter methylation may be correlated with the carcinogenesis of RCC, and that methylated p14ARF , especially, can be a major susceptibility gene. We also found the different clinicopathological significance of 16INK4A and p14ARF in RCC. Additional studies with sufficient data are essential to further evaluate the clinical features and prognostic effect of p16INK4A and p14ARF promoter methylation in RCC.


Spontaneous Cingulate High-Current Spikes Signal Normal and Pathological Pain States.
Prominent 7-12 Hz oscillations in frontal cortical networks in rats have been reported. However, the mechanism of generation and the physiological function of this brain rhythm have not yet been clarified. Multichannel extracellular field potentials of the ACC were recorded and analyzed using the current source density method in halothane-anesthetized rats. Spontaneous high-current spikes (HCSs) were localized in the deep part of layer II/III and upper part of layer V of the ACC. The frequency of HCSs in the ACC was 7-12 Hz, with an amplitude of 6.5 ± 0.76 mV/mm2 and duration of 55.24 ± 2.43 ms. The power density significantly decreased (84.56 ± 6.93%, p < 0.05, t test) after pinching the hindpaw and significantly increased (149.28 ± 15.96%) after treatment with morphine. The suppressive effect of pinching was reversed by naloxone (0.7 mg/kg, i.p.). HCSs coincided with initiation of the depolarization of cingulate neurons and remained in a depolarized upstate. The occurrence of cingulate HCSs was persistently preceded by a hyperpolarization phase and a burst of multiunit spike activity in the medial dorsal thalamic nucleus. Spontaneous field-potential oscillations changed from 10 Hz to a lower band (i.e., ∼7.5 Hz) when a central poststroke pain condition was induced. The central poststroke pain group had a higher average coherence coefficient compared with the control group. Our results indicate that spontaneous cingulate cortical HCSs could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms in physiological and pathological pain states.SIGNIFICANCE STATEMENT This study elucidated the mechanism of generation and physiological function of prominent 7-12 Hz frequency oscillations in frontal cortical networks in rats. Spontaneous cingulate cortical high-current spikes in anesthetized rats could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms. Suppression of the anterior cingulate cortex-filtered EEG during noxious stimulation may have resulted from the desynchronization of high-current spikes in the ACC. The enhancement of fast Fourier transform power after a systemic morphine injection suggested that the opioid system may play an important role in synchronizing cingulate cortical neuronal networks. Spontaneous cingulate high-current spikes may also play an important role in thalamocortical dysrhythmia in central poststroke pain.


Keloidal basal cell carcinoma: not a distinctive clinicopathological entity.
Keloidal basal cell carcinoma (BCC) has been reported as a rare but distinctive variant of BCC. To determine the frequency of keloidal collagen in BCC and to correlate it with clinical, histopathological and immunohistochemical features. Over 12 months, all cases of BCC with thick sclerotic collagen were collected and studied for clinical diagnosis, site, histopathological features and immunohistochemistry (collagen I, III, IV, laminine) in comparison with five keloids. Of 1011 BCCs seen, 18 showed thick sclerotic collagen. In two cases, these stained positive for collagen type IV or laminine, indicating basement membrane material. In 16 cases, sclerotic bundles stained positive for collagen type I but not for types III, IV, and laminine, as do keloids. The clinical diagnosis was BCC (13), squamous cell carcinoma (one) or keloid (one). Fourteen lesions came from the face, nine of them from the ear. Keloidal collagen was extensive in 10 lesions, including all from the ear. Histologically, tumours often had morphoeiform zones (14), necrosis en masse (eight) and ulceration (nine). Keloidal collagen in BCC is not as rare as reported and consists of type I collagen, the same as in keloids. It does not characterize a distinctive clinicopathological entity but is found in different histological types of BCC with varying clinical appearance. Keloidal collagen in BCC is associated with morphoeiform features, ulceration and necrosis. Interestingly, extensive keloidal collagen is more often seen in BCC on the ear, a site prone to develop keloids.


The impact of the host on fungal infections.
Outcomes of fungal infections in immunocompromised individuals depend on a complex interplay between host and pathogen factors, as well as treatment modalities. Problems occur when host responses to an infection are either too weak to effectively help eradicate the pathogen, or when they become too strong and are associated with host damage rather than protection. Immune reconstitution syndrome (IRS) can be generally defined as a restoration of host immunity in a previously immunosuppressed patient that becomes dysregulated and overly robust, resulting in host damage and sometimes death. IRS associated with opportunistic mycoses presents as new or worsening clinical symptoms or radiographic signs consistent with an inflammatory process that occur during receipt of an appropriate antifungal, and that cannot be explained by a newly acquired infection. Because there are currently no established tests or biomarkers for IRS, it can be difficult to distinguish from progression of the original infection, although culture and biomarkers for the fungal pathogen or infection are typically negative during diagnostic workup. IRS was originally characterized in human immunodeficiency virus-infected patients receiving antiretroviral therapy, but has subsequently been described in solid-organ transplant recipients, neutropenic patients, women in the postpartum period, and recipients of tumor necrosis factor-α inhibitor therapy. In each of these cases, recovery of the host's immunity during treatment of an initial infection results in a powerful proinflammatory environment that overshoots and leads to host damage. Optimal management of IRS has not been established at present, but often involves treatment with a corticosteroid or other anti-inflammatory compounds. This article uses a number of patient cases to explore the intricacies of diagnosing and managing a patient with IRS, as well as the other extreme, namely patients who are so immunocompromised without immune recovery that they essentially become breeding grounds for a wide range of opportunistic pathogens, often simultaneously.


Intrauterine infection and cord immunoglobulin M. I. Analysis of methods of assay and levels of immunoglobulin M in normal newborns.
An analysis of methods of assay and levels of immunoglobulin M in the cord serum of 100 normal newborn infants is reported. The geometric mean level of cord IgM was found to be 9.8 mg.%. The 95th percentile value was 19.6 mg.%. IgM levels on day one were not significantly different from cord levels, while by day five a significant increase had occurred (geometric mean 13.6 mg.%). IgA was present in only 3/100 cord sera (in levels above 6.0 mg.%). Any increment of day five IgM over cord levels greater than threefold is thought to be abnormal and this parameter will be further evaluated as an index of neonatal sepsis. Use of locally produced reagents in the IgM assay was found to be more accurate and inexpensive than the commercially available reagents.


Optically Forged Diffraction-Unlimited Ripples in Graphene.
In nanofabrication, just as in any other craft, the scale of spatial details is limited by the dimensions of the tool at hand. For example, the smallest details of direct laser writing with far-field light are set by the diffraction limit, which is approximately half of the used wavelength. In this work, we overcome this universal assertion by optically forging graphene ripples that show features with dimensions unlimited by diffraction. Thin sheet elasticity simulations suggest that the scaled-down ripples originate from the interplay between substrate adhesion, in-plane strain, and circular symmetry. The optical forging technique thus offers an accurate way to modify and shape 2D materials and facilitates the creation of controllable nanostructures for plasmonics, resonators, and nano-optics.


Immobilization of gold nanoparticles on cell culture surfaces for safe and enhanced gold nanoparticle-mediated laser transfection.
In comparison to standard transfection methods, gold nanoparticle-mediated laser transfection has proven to be a versatile alternative. This is based on its minor influence on cell viability and its high efficiency, especially for the delivery of small molecules like small interfering RNA. However, in order to transfer it to routine usage, a safety aspect is of major concern: The avoidance of nanoparticle uptake by the cells is desired. The immobilization of the gold nanoparticles on cell culture surfaces can address this issue. In this study, we achieved this by silanization of the appropriate surfaces and the binding of gold nanoparticles to them. Comparable perforation efficiencies to the previous approaches of gold nanoparticle-mediated laser transfection with free gold nanoparticles are demonstrated. The uptake of the immobilized particles by the cells is unlikely. Consequently, these investigations offer the possibility of bringing gold nanoparticle-mediated laser transfection closer to routine usage.


Identification of EpCAM as the gene for congenital tufting enteropathy.
Congenital tufting enteropathy (CTE) is a rare autosomal recessive diarrheal disorder presenting in the neonatal period. CTE is characterized by intestinal epithelial cell dysplasia leading to severe malabsorption and significant morbidity and mortality. The pathogenesis and genetics of this disorder are not well understood. The objective of this study was to identify the gene responsible for CTE. A family with 2 children affected with CTE was identified. The affected children are double second cousins providing significant statistical power for linkage. Using Affymetrix 50K single nucleotide polymorphism (SNP) chips, genotyping was performed on only 2 patients and 1 unaffected sibling. Direct DNA sequencing of candidate genes, reverse-transcription polymerase chain reaction, immunohistochemistry, and Western blotting were performed on specimens from patients and controls. SNP homozygosity mapping identified a unique 6.5-Mbp haplotype of homozygous SNPs on chromosome 2p21 where approximately 40 genes are located. Direct sequencing of genes in this region revealed homozygous G>A substitution at the donor splice site of exon 4 in epithelial cell adhesion molecule (EpCAM) of affected patients. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 in affected patients. Immunohistochemistry and Western blot of patient intestinal tissue revealed decreased expression of EpCAM. Direct sequencing of EpCAM from 2 additional unrelated patients revealed novel mutations in the gene. Mutations in the gene for EpCAM are responsible for CTE. This information will be used to gain further insight into the molecular mechanisms of this disease.


Vitamin D status and food security in North-East Asia.
The functions of vitamin D are pleiotropic affecting all body organs and systems in some way. Its adequacy depends principally on sunshine for UV light to stimulate its synthesis in skin and on foods which contain it, either animal-derived or obtained from fungi or mushrooms, with the UV-responsive substrates dehydrocholesterol for vitamin D-3 or ergosterol for vitamin D-2, respectively. Thus, vitamin D health is very environmentally dependent. With ecosytem degradation, whether by atmospheric pollution or food systems which do not derive UV irradiation, as with fish farming or mushroom processing, then this nutrient input into human biology may falter. Vitamin D deficiency is now common and widespread in North-East Asia as elsewhere. When discovered early in the 20th century it was linked to rickets in children and osteomalacia in adults and, for a generation or so, children were given fish, usually cod, liver oil to prevent bone disease. Now cod as a species and many edible fish are threatened. Over-exposure to sun-light increases the risk of skin cancer. We may tackle this problem by vitamin D supplementation with an alternative to fish liver. But the demographic pressures of population size and ageing (when the skin is less UV responsive) make the clinical and public health decisions and strategies demanding. Vitamin D health has become indicative of food security whose usual indicator is food diversity; such diversity may allow lesser concentrations to be more effective in organ and system function, but we have little evidence to support this at present.


[Chronic cholecystitis--some lithogenic aspects].
A total of 100 patients were examined: 35 patients with biliary dyskinesia, 44 patients with chronic acalculous cholecystitis, 21 patients with chronic calculous cholecystitis. The patients were evaluated clinically with investigation of motor-evacuation function of the gall-bladder, activity of inflammation in the gall-bladder, bile lithogenicity, morphofunctional characteristics of the stomach APUD-cells and degree of Helicobacter pylori contamination. Chronic calculous cholecystitis is characterized by clearcut symptoms, hypomotor dyskinesia, high cholesterol, signs of diffuse atrophic gastritis. Chronic acalculous cholecystitis with hypomotor dyskinesia was accompanied by mild intoxication, presence of C-reactive protein, high cholesterol, diffuse atrophic gastritis.


Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer: ITGB4 as prognostic marker.
Integrins control the cell attachment to the extracellular matrix and play an important role in mediating cell proliferation, migration and survival. A number of important cancer-associated integrin genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3' untranslated regions. We examined the effect of single-nucleotide polymorphisms (SNPs) in predicted miRNA target sites of six integrin genes (ITGA3, ITGA6, ITGAv, ITGB3, ITGB4 and ITGB5) on breast cancer (BC) risk and clinical outcome. Six SNPs were genotyped in 749 Swedish incident BC cases with detailed clinical data and up to 15 years of follow-up together with 1493 matched controls. We evaluated associations between genotypes and BC risk and clinical tumour characteristics. Survival probabilities were compared between different subgroups. As a novel finding, several SNPs seemed to associate with the hormone receptor status. The strongest association was observed between the A allele of the SNP rs743554 in the ITGB4 gene and oestrogen receptor-negative tumours [odds ratio 2.09, 95% confidence intervals (CIs) 1.19-3.67]. The same SNP was associated with survival. The A allele carriers had a worse survival compared with the wild-type genotype carriers (hazard ratio 2.11, 95% CIs 1.21-3.68). The poor survival was significantly associated with the aggressive tumour characteristics: high grade, lymph node metastasis and high stage. None of the SNPs was significantly associated with BC risk. As the ITGB4 SNP seems to influence tumour aggressiveness and survival, it may have prognostic value in the clinic.


Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies.
As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use.


Pierre Louis Moreau de Maupertuis (1698-1759).
Maupertuis was one of the most important scientists and original thinkers of the 18th century. He refuted the preformationist theories of the time, and from his study of the inheritance of genetic traits proposed various ideas which forecast the genetic theory of inheritance. He applied the concept of probability to genetic problems and introduced experimental breeding as a means of studying the inheritance of genetic traits in animals. However, he considered his greatest contribution to science to be the 'Principle of Least Action'. Yet paradoxically it was this, through the vitriolic attacks by Voltaire which it engendered, which resulted in his work being largely ignored until recent times.


The role of serum transferrin receptor in the diagnosis of iron deficiency.
Iron deficiency anemia (IDA) is often associated with inflammatory disorders. The most conventional parameters of iron metabolism are therefore affected, making the evaluation of iron status difficult. Serum transferrin receptor (sTfR) levels are raised in iron deficiency but are not influenced by inflammatory changes. The aim of this study was to investigate the role of sTfR in differentiating IDA with inflammatory features. A diagnostic study of sTfR measured by immunoassay was carried out in IDA and anemia of chronic disorders (ACD). The cut-off points of sTfR and the ratio of sTfR/serum ferritin, which were obtained after comparing IDA and ACD, were applied to a group of 64 patients with mixed iron patterns (MIX) (16 with ACD and 48 with IDA). The best cut-off point of sTfR between IDA and ACD was 4.7 mg/L. Applying this cut-off to the MIX group, an efficiency of 87% was obtained (sensitivity 92% and specificity 81%). This level of sTfR correctly classified 53 out of 64 cases of the MIX group (83%). Using the ratio of sTfRx 100/serum ferritin, the best cut-off point was 8 (efficiency 100%), which correctly classified 62 out of 64 cases of the MIX group (97%). This study demonstrates that sTfR in conjunction with other iron parameters is very useful in iron deficiency evaluation, especially in hospital practice. Iron treatment should be considered in patients with mixed patterns of iron status, in which the diagnosis of IDA versus ACD is difficult, when the levels of sTfR exceed the cut-off point.


A short-term incubation with high glucose impairs VASP phosphorylation at serine 239 in response to the nitric oxide/cGMP pathway in vascular smooth muscle cells: role of oxidative stress.
A reduction of the nitric oxide (NO) action in vascular smooth muscle cells (VSMC) could play a role in the vascular damage induced by the glycaemic excursions occurring in diabetic patients; in this study, we aimed to clarify whether a short-term incubation of cultured VSMC with high glucose reduces the NO ability to increase cGMP and the cGMP ability to phosphorylate VASP at Ser-239. We observed that a 180 min incubation of rat VSMC with 25 mmol/L glucose does not impair the NO-induced cGMP increase but reduces VASP phosphorylation in response to both NO and cGMP with a mechanism blunted by antioxidants. We further demonstrated that high glucose increases radical oxygen species (ROS) production and that this phenomenon is prevented by the PKC inhibitor chelerythrine and the NADPH oxidase inhibitor apocynin. The following sequence of events is supported by these results: (i) in VSMC high glucose activates PKC; (ii) PKC activates NADPH oxidase; (iii) NADPH oxidase induces oxidative stress; (iv) ROS impair the signalling of cGMP, which is involved in the antiatherogenic actions of NO. Thus, high glucose, via oxidative stress, can reduce the cardiovascular protection conferred by the NO/cGMP pathway via phosphorylation of the cytoskeleton protein VASP in VSMC.


Review Article: Autophagy Behavior in Endothelial Cell Regeneration.
Autophagy plays a crucial role in maintaining endothelial cell homeostasis through the turnover of intracellular components during stress conditions in a lysosomal-dependent manner. The regeneration strategy involves several aspects, including autophagy. Autophagy is a catabolic degenerative lysosomal-dependent degradation of intracellular components. Autophagy modifies cellular and subcellular endothelial cell functions, including mitochondria stress, lysosomal stress, and endoplasmic reticulum unfolded protein response. Activation of common signaling pathways of autophagy and regeneration and enhancement of intracellular endothelial cell metabolism serve as the bases for the induction of endothelial regeneration. Endothelial progenitor cells include induced pluripotent stem cells (iPSC), embryonic stem cells, and somatic cells, such as fibroblasts. Future strategies of endothelial cell regeneration involve the induction of autophagy to minimize the metabolic degeneration of the endothelial cells and optimize the regeneration outcomes.


Establishing a postgraduate course in endodontics.
A proposal was first made to the University of London in 1985 to establish an MSc degree in Endodontics. It was finally approved in 1988. The first course started in 1988, and is now offered by two schools of the University, the United Medical and Dental Schools of Guy's and St Thomas's Hospitals and the Institute of Dental Surgery. The course has three main components: a taught part, clinical practice and a research project. The taught part is a course common to both the schools, while clinical practice and the research are carried out at the students' respective schools.


Methodologies to assess brain drug delivery in lead optimization.
In the area of lead optimization for potential CNS-active drugs in medicinal chemistry, there is a great need for experimental methodologies that can generate data relevant to estimates of free (unbound) drug exposure within the CNS. The methods chosen have to be efficient and have to measure a pharmacologically relevant entity. The lack of methods for generating such data is probably linked with the lack of successful lead optimization strategies within CNS drug discovery. This article evaluates available methods for estimating drug delivery to the brain, and discusses the relevance of the methods from the perspective of CNS exposure to free drug. It is suggested that the extent of drug delivery is the most important investigative parameter, since permeability (rate of transfer) can vary within a relatively wide range and still allow effects within the CNS. Following this suggestion would shift the focus from the current way of thinking and could lead to the development of less lipophilic compounds than are currently being investigated. It is concluded that an extensive collection of quality data on brain drug delivery, transporter affinities and in vivo behavior is urgently required so as to be able to build relevant predictive in vitro and in silico models for the future. These models need to be much more focused on the asymmetry of active transport across the BBB than on permeability data.


Modifying the Catalytic Activity of Lipopeptide Assemblies with Nucleobases.
Biohybrid catalysts that operate in aqueous media are intriguing for systems chemistry. In this paper, we investigate whether control over the self-assembly of biohybrid catalysts can tune their properties. As a model, we use the catalytic activity of functional hybrid molecules consisting of a catalytic H-dPro-Pro-Glu tripeptide, derivatized with fatty acid and nucleobase moieties. This combination of simple biological components merged the catalytic properties of the peptide with the self-assembly of the lipid, and the structural ordering of the nucleobases. The biomolecule hybrids self-assemble in aqueous media into fibrillar assemblies and catalyze the reaction between butanal and nitrostyrene. The interactions between the nucleobases enhanced the order of the supramolecular structures and affected their catalytic activity and stereoselectivity. The results point to the significant control and ordering that nucleobases can provide in the self-assembly of biologically inspired supramolecular catalysts.