Comparison of accuracy cone-beam computed tomography and digital bitewing radiography for detection of recurrent caries under various restorative materials: in vitro study.
The aim of this study was to compare and evaluate diagnostic accuracy of two different CBCT scan modes and digital bitewing radiography for detection of recurrent caries under five different restorative materials, and determine the relationship between the types of restorative materials. In this in vitro study, 200 caries-free upper and lower premolars and molars were selected. A standard deep Class II cavities was created in the middle of the mesial surface of all teeth. In 100 teeth of the experimental and control groups, secondary caries was artificially demineralized. All teeth were filled with five types of restorative material including two types of conventional composite resins, flow composite resin, glass ionomer and amalgam. The teeth were imaged with high resolution (HIRes) and standard CBCT scan modes and digital bitewing. The AUC, sensitivity, specificity and areas under the ROC curve were calculated and verified through SPSS. CBCT technique was the best option in diagnosing recurrent caries. The diagnostic accuracy and specificity of HIRes CBCT scan mode was significantly higher than standard mode (P = 0.031) and bitewing (P = 0.029) for detection of recurrent caries, especially under composite group. There were no significant differences in accuracy value of bitewing and standard CBCT scan mode. CBCT showed higher accuracy and specificity on the detection of recurrent caries which was more accurate than bitewing radiography. The HIRes CBCT scan mode achieved the highest accuracy and performed the best in recurrent caries detection.


A comparison of the insulin-sensitive transport of chromium in healthy and model diabetic rats.
In response to insulin, chromium(III) is moved from the blood to the tissues where it is ultimately lost in the urine, apparently as the oligopeptide chromodulin; this transfer of chromium is mediated by the protein transferrin. To examine the effects of type 1 and type 2 diabetes on the transport of chromium, the fate of chromium from intravenously introduced (51)Cr(2)-labelled transferrin was monitored after 2 h in healthy and diabetic model rats; the effects of insulin on the transport of chromium in these groups were also examined. Diabetic rats had greater urinary chromium loss, greater movement of chromium from the blood to the tissues, most notably to the skeletal muscle, and an alteration of the distribution of chromium in the blood plasma.


Celebrate Birth: Experiencing Profound Joy on the Other Side of Fear: My Unexpected Journey Through Pregnancy and Childbirth.
The author shares her story of moving beyond fear of childbirth, preparing for the birth of her baby, and the profound experience of giving birth. She shares the details of her preparation and education from childbirth classes, and the support she received from her nurse (her angel) and her husband (her steadfast star). It is a story of overcoming fear, working intensely during labor, leaning on a chosen support team and savoring the joy of finally giving birth to her son.


Selective enhancement of shock avoidance responding elicited by GABA blockade in the posterior hypothalamus of rats.
Recent studies have shown that blockade of gamma-aminobutyric acid (GABA) in the posterior hypothalamus in anesthetized rats elicits cardio-respiratory stimulation similar to that seen in emotional defense reactions and, in conscious rats, locomotor arousal suggesting a flight response. The present study was conducted in order to test the hypothesis that the behavioral effects elicited by GABA blockade in the posterior hypothalamus were the results of disinhibiting a mechanism whose activation selectively enhances reactivity to aversive stimuli. Male rats were trained on a Sidman shock avoidance schedule (RS20:SS10) as well as a food-reinforced approach schedule (VI 1). Under anesthesia, guide cannulae were stereotaxically implanted bilaterally in the posterior hypothalamus at sites where microinjection of the GABA antagonist, bicuculline methiodide (BMI) 25 ng, increased heart rate. After recovery, rats were tested in both the avoidance and VI 1 schedules after hypothalamic microinjection of saline, BMI 25 ng, and the GABA agonist, muscimol 25 ng. Microinjection of BMI significantly increased the avoidance responses but had no effect on the approach responses. Muscimol decreased both the avoidance and approach responses. When microinjected into the lateral hypothalamic area, BMI had no effect on the response rates in either schedule while muscimol decreased the approach responding only. Therefore, GABA blockade at the discrete area of the posterior hypothalamic nucleus appears to elicit a selective enhancement of avoidance responses. These results suggest that an endogenous GABAergic system in the posterior hypothalamus may tonically inhibit a constellation of autonomic, locomotor and motivational responses that are necessary for some types of defense reaction.


The kindlin 3 pleckstrin homology domain has an essential role in lymphocyte function-associated antigen 1 (LFA-1) integrin-mediated B cell adhesion and migration.
The protein kindlin 3 is mutated in the leukocyte adhesion deficiency III (LAD-III) disorder, leading to widespread infection due to the failure of leukocytes to migrate into infected tissue sites. To gain understanding of how kindlin 3 controls leukocyte function, we have focused on its pleckstrin homology (PH) domain and find that deletion of this domain eliminates the ability of kindlin 3 to participate in adhesion and migration of B cells mediated by the leukocyte integrin lymphocyte function-associated antigen 1 (LFA-1). PH domains are often involved in membrane localization of proteins through binding to phosphoinositides. We show that the kindlin 3 PH domain has binding affinity for phosphoinositide PI(3,4,5)P3 over PI(4,5)P2. It has a major role in membrane association of kindlin 3 that is enhanced by the binding of LFA-1 to intercellular adhesion molecule 1 (ICAM-1). A splice variant, kindlin 3-IPRR, has a four-residue insert in the PH domain at a critical site that influences phosphoinositide binding by enhancing binding to PI(4,5)P2 as well as by binding to PI(3,4,5)P3. However kindlin 3-IPRR is unable to restore the ability of LAD-III B cells to adhere to and migrate on LFA-1 ligand ICAM-1, potentially by altering the dynamics or PI specificity of binding to the membrane. Thus, the correct functioning of the kindlin 3 PH domain is central to the role that kindlin 3 performs in guiding lymphocyte adhesion and motility behavior, which in turn is required for a successful immune response.


Connector design effects on the in vitro fracture resistance of 3-unit monolithic prostheses produced from 4 CAD-CAM materials.
Studies that compared the fracture strength of monolithic lithium disilicate and 5-mol% yttria partially stabilized zirconia multiunit fixed dental prostheses are sparse. As the connector is the weakest part of a fixed dental prosthesis, the purpose of this in vitro study was to investigate the effect of connector designs and material on the fracture strength of 3-unit monolithic fixed dental prostheses. Resin-ceramic canine and premolar teeth (N=144) were prepared for fixed dental prosthesis abutments. Prostheses with 3 connector designs (width=height, width<height, and width>height) were made from 2 types of lithium disilicate (IPS e.max CAD and Amber Mill) and 5-mol% yttria partially stabilized zirconia (3M Lava Esthetic and Katana Zirconia UTML). Fracture strengths were measured after 200 000 cycles of dynamic loading of 50 N and thermocycling at 5 °C and 55 °C, and the fracture patterns were analyzed. Two-way analysis of variance and the Fisher exact test were used for statistical analysis (α=.05). The material and connector design affected the fracture strength of fixed dental prostheses (P<.05), and a significant interaction was found between the material and connector design (P<.05). The IPS e.max CAD material had significantly lower fracture strength than Amber Mill, 3M Lava Esthetic, or Katana Zirconia UTML (P<.05). Connector designs with a greater width versus height showed significantly lower fracture strengths than other designs (P<.05). The connector design of 3-unit fixed dental prostheses, particularly the connector height, may affect fracture strength depending on the prosthesis material.


[Validation of the Geriatric Check in a cohort of hospitalized neurological patients].
The Geriatrie-Check was developed as a screening tool for the identification of older patients with geriatric treatment requirements in hospitals. It was recommended by the Baden-Wuerttemberg Hospitals Association for routine use in hospitals in 2014 although no published validation studies are available. The test takes 3-5 min. Validation of the Geriatrie-Check in a prospective cohort of hospitalized neurological patients with and without geriatric characteristics. In this prospective cross-sectional observational study at the University Hospital Tübingen, Germany the Geriatrie-Check was compared with a comprehensive geriatric assessment in 107 neurological inpatients aged 70 years and older (41% women, mean age 76.7 years). The Geriatrie-Check classified 61 patients (57%) as geriatric patients. These patients with a positive result in the Geriatrie-Check had a higher percentage of frailty (according to Fried et al.), higher values in the Gérontopôle frailty screening tool, higher values in the geriatric screening according to Lachs et el., slower gait speed, lower grip force, needed longer for the timed up-and-go test, had a greater fear of falling in the Falls Efficacy Scale - International, lower scores in the Mini Mental State Examination, needed more time to perform the Trail Making Test A and B, had higher values in the Beck's Depressions Inventar II and lower values in the visual analogue scale of the EQ-5D. A higher percentage of patients took more than five different drugs. The Geriatrie-Check has been shown to be a useful and valid tool for the identification of geriatric inpatients in neurological wards due to the good agreement with the results of the geriatric assessment.


Gender Differences in Pre- and Postoperative Health-Related Quality of Life Measures in Patients Who Have Had Decompression Surgery for Lumbar Spinal Stenosis.
Retrospective chart audit. This study aimed to investigate the gender difference in pre- and postoperative health-related quality of life (HRQOL) in patients who have had decompression surgery for lumbar spinal stenosis (LSS). Gender differences may contribute to variations in disease presentations and health outcomes. The influence of gender on pre- and postoperative HRQOL in spinal disorders remains unclear. We reviewed 125 patients (79 men and 46 women) who had lumbar spinous process splitting laminectomy (LSPSL) for LSS. We assessed the following clinical information: Japanese Orthopedic Association (JOA) score; numerical rating scale (NRS) for low back pain (LBP), leg pain, and leg numbness; Zurich Claudication Questionnaire; JOA Back Pain Evaluation Questionnaire; Roland- Morris Disability Questionnaire (RMDQ); and Short Form 8 (SF-8) as HRQOL. We compared the HRQOLs of men and women pre- and postoperatively. Although the preoperative NRS results for LBP were significantly higher in women (p <0.05), there were no significant differences in clinical outcomes between men and women postoperatively. For HRQOL, the RMDQ scores were significantly worse in women preoperatively (p <0.05), but no significant differences were found postoperatively between men and women. Similarly, the SF-8 mental health score was also significantly lower in women preoperatively (p <0.05), but no significant differences were noted between the two groups postoperatively. LSPSL greatly reduced LBP, leg pain, and leg numbness in both genders. There were limited differences in pain and several HRQOL questionnaire responses between men and women after surgery. We found that women had greater sensitivity to and/or lower tolerance for pain than men, which led to lower HRQOL mental health scores preoperatively.


A prospective study of household smoking bans and subsequent cessation related behaviour: the role of stage of change.
To assess the degree to which smokers living with a full household ban on smoking change their cessation related behaviour. Prospective cohort study; follow up of a population based cohort of 1133 smokers, identified from a 1997 telephone survey of adult Oregonians. After a median of 21 months, 565 were located and reinterviewed. Quit attempts, time until relapse, and smoking cessation, defined as seven day and 90 day sustained abstinence at follow up. A full ban at baseline was associated with a doubling of the odds of a subsequent quit attempt (odds ratio (OR) = 2.0, 95% confidence interval (CI), 1.0 to 3.9). Among respondents in the preparation stage at baseline (intention to quit in the next month with a quit attempt in the previous year), a full ban was associated with a lower relapse rate (hazard ratio = 0.5 (95% CI, 0.2 to 0.9)), while for those in precontemplation/contemplation (no intention to quit or intention to quit within the next six months, respectively), there was no significant association between full ban and relapse rate. For respondents in preparation, those with a full ban had over four times the odds of being in cessation for seven or more days before the follow up call (OR = 4.4 (1.1 to 18.7)), but for those in precontemplation/contemplation, full bans were unrelated to cessation. Full household bans may facilitate cessation among smokers who are preparing to quit by increasing quit attempts. They may also prolong time to relapse among those smokers.


Meningitis.
Meningitis is defined as inflammation of the meninges, in almost all cases identified by an abnormal number of white blood cells in the cerebrospinal fluid and specific clinical signs/symptoms. Onset may be acute or chronic, and clinical symptoms of acute disease develop over hours to days. This article reviews the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of acute meningitis, and provides a list of key points for primary care practitioners. Aseptic and bacterial meningitis vary significantly and are discussed separately.


Conservation and Management of Salmon in the Age of Genomics.
Salmon were among the first nonmodel species for which systematic population genetic studies of natural populations were conducted, often to support management and conservation. The genomics revolution has improved our understanding of the evolutionary ecology of salmon in two major ways: (a) Large increases in the numbers of genetic markers (from dozens to 104-106) provide greater power for traditional analyses, such as the delineation of population structure, hybridization, and population assignment, and (b) qualitatively new insights that were not possible with traditional genetic methods can be achieved by leveraging detailed information about the structure and function of the genome. Studies of the first type have been more common to date, largely because it has taken time for the necessary tools to be developed to fully understand the complex salmon genome. We expect that the next decade will witness many new studies that take full advantage of salmonid genomic resources.


Synthesis of constrained alpha-amino acid derivatives via ring-closing olefin metathesis.
Five and seven membered constrained alpha-amino acid derivatives were synthesized using ring-closing metathesis reaction as a key step.


An Algorithm for the Factorization of Split Quaternion Polynomials.
We present an algorithm to compute all factorizations into linear factors of univariate polynomials over the split quaternions, provided such a factorization exists. Failure of the algorithm is equivalent to non-factorizability for which we present also geometric interpretations in terms of rulings on the quadric of non-invertible split quaternions. However, suitable real polynomial multiples of split quaternion polynomials can still be factorized and we describe how to find these real polynomials. Split quaternion polynomials describe rational motions in the hyperbolic plane. Factorization with linear factors corresponds to the decomposition of the rational motion into hyperbolic rotations. Since multiplication with a real polynomial does not change the motion, this decomposition is always possible. Some of our ideas can be transferred to the factorization theory of motion polynomials. These are polynomials over the dual quaternions with real norm polynomial and they describe rational motions in Euclidean kinematics. We transfer techniques developed for split quaternions to compute new factorizations of certain dual quaternion polynomials.


Rapid detection of 17β-estradiol based on shaddock peel derived fluorescent aptasensor for forensic examination.
17β-estradiol (E2) detection technique had been shown to a potent method for identification of female blood in forensic practice since it was abundant in the healthy female body. Herein, we developed a fluorescent aptasensor based on carbon quatum dots (CQDs) derived from shaddock peel green synthesis for rapid detection of E2 as a useful auxiliary tool of forensic examination. The CQDs conjugated to the aptamer achieved fluorometric detection of E2 in blood and the blood of healthy female from 12 to 60 years old could be sensitive detected with the limit of detection of 0.025 ng/ml, and the analytical process could be completed within 10 min. The aptasensor was also used to assay E2 in forensic samples including blood and blood stain. In all instances, the results were positive when mixed samples involving female sample. This fluorescent aptasensor was proved to be a green, rapid and sensitive detection method of E2, and it exhibited great potential in discrimination of female samples in forensic practice.


Sensory enhancing insoles improve athletic performance during a hexagonal agility task.
Athletes incorporate afferent signals from the mechanoreceptors of their plantar feet to provide information about posture, stability, and joint position. Sub-threshold stochastic resonance (SR) sensory enhancing insoles have been shown to improve balance and proprioception in young and elderly participant populations. Balance and proprioception are correlated with improved athletic performance, such as agility. Agility is defined as the ability to quickly change direction. An athlete's agility is commonly evaluated during athletic performance testing to assess their ability to participate in a competitive sporting event. Therefore, the purpose of this study was to examine the effects of SR insoles during a hexagonal agility task routinely used by coaches and sports scientists. Twenty recreational athletes were recruited to participate in this study. Each athlete was asked to perform a set of hexagonal agility trials while SR stimulation was either on or off. Vicon motion capture was used to measure feet position during six successful trials for each stimulation condition. Stimulation condition was randomized in a pairwise fashion. The study outcome measures were the task completion time and the positional accuracy of footfalls. Pairwise comparisons revealed a 0.12s decrease in task completion time (p=0.02) with no change in hopping accuracy (p=0.99) when SR stimulation was on. This is the first study to show athletic performance benefits while wearing proprioception and balance improving equipment on healthy participants. With further development, a self-contained sensory enhancing insole device could be used by recreational and professional athletes to improve movements that require rapid changes in direction.


Contaminant back-diffusion from layered aquitards subjected to barrier-controlled source zones.
Low-permeability aquitards may serve as secondary sources of slow-releasing contaminants into the adjacent aquifer system, creating considerable obstacles to groundwater cleanup. Accurately capturing the exchange of contaminant mass between aquitards and aquifers can facilitate site management and remediation. Previous simulation studies were mainly limited to one-dimensional (1D) back diffusion from aquitards during the remediation of the source zone. In this study, a novel two-dimensional (2D) back-diffusion model is developed to investigate the storage and release of contaminants in aquitards after source isolation. This model coupled the dynamical decay of isolated sources and the diffusion-sorption process of contaminants in the layered aquitards. Exact analytical solutions for the present 2D multilayer model were derived using the finite cosine transform, Duhamel Theorem, separation of variables, and transfer matrix method. Results indicated that the previous 1D model would overestimate the contaminant concentration in the aquitard and the back-diffusion risk when the source zone was isolated. The proposed 2D back-diffusion model enables quantitative prediction of how source zone width, source concentration, and aquitard heterogeneity impact plume trailing time, thus aiding in understanding the mechanisms of aquifer contamination beyond barrier-controlled source zones.


Lipids in regulating oligodendrocyte structure and function.
Oligodendrocytes enwrap central nervous system axons with myelin, a lipid enriched highly organized multi-layer membrane structure that allows for fast long-distance saltatory conduction of neuronal impulses. Myelin has an extremely high lipid content (∼80 % of its dry weight) and a peculiar lipid composition, with a 2:2:1 cholesterol:phospholipid:glycolipid ratio. Inherited neurodegenerative diseases of the lipids (caused by mutations in lipogenic enzymes) often present oligodendrocyte and/or myelin defects which contribute to the overall disease pathophysiology. These phenomena triggered an increasing number of studies over the functions lipid exert to shape and maintain myelin, and brought to the finding that lipids are more than only structural building blocks. They act as signaling molecules to drive proliferation and differentiation of oligodendrocyte progenitor cells, as well as proliferation of premyelinating oligodendrocytes, and their maturation into myelinating ones. Here, we summarize key findings in these areas, while presenting the main related human diseases. Despite many advances in the field, various questions remain open which we briefly discuss. This article is part of a special issue entitled "Role of Lipids in CNS Cell Physiology and Pathology".


Clinical and immunologic progression in HIV-infected US women before and after the introduction of highly active antiretroviral therapy.
To examine factors associated with clinical and immunologic HIV disease progression in a cohort of US women. Analysis of data from a prospective, longitudinal, case-control study of HIV-infected women followed every 6 months for 7 years. Four urban clinical centers in the United States. 648 HIV-infected women who did not have AIDS at time of entry into the study. Structured clinical and behavioral interviews; protocol-directed physical examinations; CD4 lymphocyte counts; plasma HIV RNA; infectious pathogen serologies. RESULTS With 2304 women-years of follow-up, 46.1% of the women developed AIDS; however, 93.3% of the diagnoses were based on CD4 counts dropping to <200 cells/mm(3). Only 10.6% of the women with CD4 counts <200 cells/mm(3) developed an opportunistic infection. Baseline CD4 count was the strongest predictor of subsequent clinical progression. Illicit substance use, multiple pregnancies, demographic variables, and other infections were not associated with progression. Among women with CD4 counts >500 cells/mm(3) at baseline, those who were anemic or had hepatitis C were more likely to progress to AIDS. By the end of the study, only 52% of the participants were on highly active antiretroviral therapy (HAART). Despite underutilization of HAART in this multicenter cohort of urban women, opportunistic infections were uncommon, despite CD4 declines.


A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and oxaliplatin in patients with advanced solid tumors.
To evaluate the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of the combination of pegylated liposomal doxorubicin (PEG-LD), paclitaxel and oxaliplatin (L-OHP) administered every 2 weeks in patients with advanced solid tumors. Thirty-nine pretreated patients with advanced solid tumors received escalated doses of PEG-LD (10-16 mg/m(2)), paclitaxel (100-120 mg/m(2)) and L-OHP (50-70 mg/m(2)) every 2 weeks. As one cycle of treatment was considered the administration of both drugs on days 1 and 15 of a 4-week cycle. The MTDs were PEG-LD 14 mg/m(2), paclitaxel 120 mg/m(2) and L-OHP 70 mg/m(2). Neutropenia was the DLT in all but one case with only one episode of febrile neutropenia and no toxic deaths. Four (4%) and 13 (12%) cycles were complicated by grades 4 and 3 neutropenia, respectively. Grades 2-3 fatigue and neurotoxicity occurred in 13 and 12% of cycles, respectively. Responses were observed in patients with breast, endometrial and ovarian carcinomas. This is a quite well-tolerated regimen which merits further evaluation in phase II studies.


[A nasal congenital malformation not published in the literature: About 5 cases].
Five cases of the same congenital malformation of the nose, affecting the nasal dorsum and the supra-tip, were supported in our university plastic surgery center. This malformation has not been described in the literature known to the authors. The aim of this study is to analyze this nasal deformity. Five children presented this congenital deformity between 1994 and 2014. The patients were examined and the malformation precisely described. Genetic and histological examinations were carried on. The diagnosis and treatment of this pathology were discussed. This malformation associated 4 anomalies: hypertrophy of soft tissue of the dorsum located in the middle third of the nasal bridge, deformed alar cartilages turned back downward and outside, advanced support default and median skin brand similar to a scar. These patients showed no other abnormalities of the midline or respiratory disorders. No genetic disorder was found for these five patients, and no histological arguments were found. Three patients were operated, one until adulthood with a satisfying cosmetic result. Bibliographic research has not allowed us to make an accurate diagnosis of this malformation that appears to be non-syndromic and to have a genetic origin. Our therapeutic approach became more clear and it now seems legitimate to propose early excision of fat mass to prevent alar deformations, associated with a cortico-cancellous graft, which in our experience grows with age, to support the tip.


gamma delta+ T cells are increased in patients with Parkinson's disease.
The etiology of Parkinson's disease is mainly unknown. Immune abnormalities have been reported, including the occurrence of autoantibodies against neuronal structures and abnormal T cell functions. gamma delta+ T cells represent a recently recognized T cell subpopulation which is considered to play a role in immune responses in infections and autoimmunity. We examined by three-colour flow cytometry the proportions of gamma delta+ T cells in blood and cerebrospinal fluid (CSF) from patients with Parkinson's disease. Increased proportions of gamma delta+ T cells were found in CSF in Parkinson's disease compared to other neurological diseases (OND) and tension headache. In peripheral blood, patients with Parkinson's disease had higher numbers of gamma delta+ T cells compared to OND patients. No differences between gamma delta+ T cells in CSF compared to blood were demonstrable in the individual patient groups. CD25 was not expressed on gamma delta+ T cells in blood of the majority of cases, but 50% of patients with Parkinson's disease and 30% with OND and tension headache had CD25+ gamma delta+ T cells in CSF arguing for a preferential activation of gamma delta+ T cells in the CSF compartment. Whether the elevated gamma delta+ T cell population in Parkinson's disease reflects previously unrecognized inflammation or may occur also in non-inflammatory disorders remains to be elucidated.


Effect of BCG vaccine on tuberculin skin tests in 1-6-year-old children.
Bacillus Calmette Guerin (BCG) vaccination used in the prevention of tuberculosis may cause problems in interpreting the tuberculin skin test (TST), which is commonly used in the diagnosis of infection. A limited number of studies have been undertaken to investigate how length of time after BCG vaccination affects TST results. TST induration values of unvaccinated children were compared with those of children vaccinated once in order to determine the changes in TST responses after BCG vaccination. Mantoux TSTs were administered to 1145 children aged 1-6 y and induration was measured at 72 h. BCG scar status and average TST induration diameters were identified for each age group. Average TST induration in vaccinated children is significantly higher than that in unvaccinated children, and in the vaccinated group there is no statistically significant difference between induration values in the different age groups. BCG vaccination at the age of 0-2 mo affects TST for a long period and this condition does not change until 6 y of age.


Chemistry of the "molecular trap" of protease-catalyzed splicing reaction of complementary segments of alpha-subunit of hemoglobin A.
The complementary fragments of human Hb alpha, alpha1-30, and alpha31-141 are spliced together by V8 protease in the presence of 30% n-propanol to generate the full-length molecule (Hb alpha-semisynthetic reaction). Unlike the other protease-catalyzed protein/peptide splicing reactions of fragment complementing systems, the enzymic condensation of nonassociating segments of Hb alpha is facilitated by the organic cosolvent induced alpha-helical conformation of product acting as the "molecular trap" of the splicing reaction. The segments alpha24-30 and alpha31-40 are the shortest complementary segments that can be spliced by V8 protease. In the present study, the chemistry of the contiguous segment (product) alpha24-40 has been manipulated by engineering the amino acid replacements to the positions alpha27 and alpha31 to delineate the structural basis of the molecular trap. The location of Glu27 and Arg31 residues in the contiguous segment alpha24-40 (as well as in other larger segments) is ideal to generate (i, i + 4) side-chain carboxylate-guanidino interaction in its alpha-helical conformation. The amino acid residue replacement studies have confirmed that the side chains at alpha27 and alpha31 facilitate the semisynthetic reaction. The relative influence of the substitute at these sites on the splicing reaction depends on the chemical nature of the side chain and the location. The gamma-carboxylate guanidino side-chain interaction appears to contribute up to a maximum of 85% of the thermodynamic stability of the molecular trap. The studies also demonstrate that the thermodynamic stability of the molecular trap is determined by two interdependent conformational aspects of the peptide. One is an amino acid-sequence-specific event that facilitates the induction of an alpha-helical conformation to the contiguous segment in the presence of organic cosolvent that imparts some amount of protease resistance to Glu30-Arg31 peptide bond. The second structural aspect is a site-specific event, an i, i + 4 side-chain interaction in the alpha-helical conformation of the peptide which imparts an additional thermodynamic stability to the molecular trap. The results suggest that conformationally driven "molecular traps" of protease-mediated ligation reactions of peptides could be designed into products to facilitate the modular assembly of peptides/proteins.


Consequences of a single Ir-gene defect for the pathogenesis of lymphocytic choriomeningitis.
The H-2Ld allele has been identified by others as the sole Ir gene in the H-2d haplotype for the cytotoxic T lymphocyte (CTL) response to mouse lymphocytic choriomeningitis virus (LCMV). The BALB/c-H-2dm2 (C-H-2dm2) mutant lacks H-2Ld, and thus should be ideal for assessing the contribution of virus-immune CTL to LCM immunopathology. Comparison of the C-H-2dm2 mice with congenic BALB/c mice revealed that there is a delay of about 24 h in the onset of severe inflammatory process and symptoms in the mutant strain, but the absence of H-2Ld did not prevent the later development of fatal disease in mice injected intracerebrally (i.c.) with neurotropic LCMV. This could indicate that virus-immune CTL are not the major mediators of clinical LCM. Spleen cells from LCMV-primed BALB/c mice did not show CTL activity for LCMV-infected C3H.OH, C-H-2dm2, or (CBA X C-H-2dm2)F1 target cells. However, immune lymphocytes from both the mutant and the F1 strains lyse virus-infected BALB/c cells. Furthermore, B10.HTG and, in some experiments, B10.A(5R) mice generated CTL lytic for LCMV-infected BALB/c, C-H-2dm2, and (CBA X C-H-2dm2)F1 macrophages. Apparently H-2Ld is immunodominant in the H-2d-restricted response to LCMV. However, in the absence of H-2Ld, it seems that H-2Kd and, to a lesser extent, H-2Dd also serve as Ir genes for the CTL response in this infection. Even so, the absence of the H-2Ld-restricting element results in a disease process which is either delayed in onset or less severe.


New perspectives on effector mechanisms in uveitis.
Experimental autoimmune uveitis (EAU) in its several variants represents human autoimmune uveitis and has been instrumental in obtaining insights into the basic mechanisms of disease. Studies have uncovered that in addition to CD4+ Th1 cells, uveitis can be induced also by CD8+ T cells. Antibodies may have a secondary role after the blood-retinal barrier has been broken. The role in uveitis of a recently discovered IL-17-producing effector T cell type, Th17, is being intensively studied. Th17 cells elicit EAU, can be found in uveitic eyes along with Th1 cells, and are dominant in some types of EAU. In other types of EAU, Th1 cells have a dominant role. The dominant effector type is at least in part determined by conditions under which initial exposure to self-antigen occurs. These findings shed light on the heterogeneity of human disease and may ultimately help to develop better and more rational treatment strategies for human uveitis.


Internet and smartphone application usage in eating disorders: A descriptive study in Singapore.
Eating disorders are associated with significant morbidity and mortality. The Internet is a popular medium for individuals with eating disorders to discuss and reinforce their affliction. However, the available literature on Internet usage and eating disorders is scarce, especially in the area of social media and smartphone application ("app") usage. This study looked at the Internet and smartphone app usage patterns of participants who presented with an eating disorder in Singapore, and whether it corresponded to severity of illness. Individuals who presented to the Eating Disorders clinic at the Singapore General Hospital completed a self-reported questionnaire on Internet and app usage. They also completed the EDE-Q, EAT-26 and CIA 3.0. 55 participants completed the study. 41.8% had anorexia nervosa, 34.5% had bulimia nervosa, and 9.1% were ED-NOS. 41.8% felt that apps helped to perpetuate their illness while 32.7% felt that the apps were helpful for recovery. Overall, any smartphone application usage was associated with younger age and greater eating disorder psychopathology and psychosocial impairment. While 30.9% had encountered eating disorder-related content on Facebook, only 12.7% visited Facebook groups related to eating disorders. For YouTube, "Cooking and Food" and "Beauty and Fashion" videos were among the top 3 types of videos that participants watched. In conclusion, Internet and smartphone app usage is significant, and they are associated with greater severity of illness. It is necessary to include interventions in this aspect as part of treatment of eating disorders.


Selected isotope ratio measurements of light metallic elements (Li, Mg, Ca, and Cu) by multiple collector ICP-MS.
The unique capabilities of multiple collector inductively coupled mass spectrometry (MC-ICP-MS) for high precision isotope ratio measurements in light elements as Li, Mg, Ca, and Cu are reviewed in this paper. These elements have been intensively studied at the Geological Survey of Israel (GSI) and other laboratories over the past few years, and the methods used to obtain high precision isotope analyses are discussed in detail. The scientific study of isotopic fractionation of these elements is significant for achieving a better understanding of geochemical and biochemical processes in nature and the environment.


Conversion of recent-onset atrial fibrillation or flutter with amiodarone after ibutilide has failed: a rapid, efficient, and safe algorithm.
Ibutilide and amiodarone are used for the pharmacological conversion of atrial fibrillation (AF) or flutter (AFl), but their efficacy is rather moderate. To test whether the use of ibutilide as a first-choice drug and of amiodarone as a second-line treatment provides a rapid, effective, and safe algorithm for conversion of recent-onset AF or AFl to sinus rhythm (SR), 85 consecutively recruited patients (59 women; mean age 69.7+/-0.9 years) with AF or AFl of recent onset received 1 or 2 mg of ibutilide infusion. In the case of ibutilide failure, amiodarone was given (6 mg/kg IV infusion over 60 minutes followed by 1200 mg IV infusion over 24 hours) 4 hours later. Ten patients with AF or AFl of recent onset were used as controls. The maximum rate-corrected QT interval was calculated in all patients and controls before the start of the study (baseline electrocardiogram (ECG)), 30 minutes later (30-min ECG), and 4 hours later (4-h ECG). Fifty-eight (68%) patients reversed to SR within the first 4 hours after the end of ibutilide infusion. In those 27 patients in whom ibutilide failed, amiodarone was given. Twenty-four of them (28%) were converted to SR during amiodarone infusion. Therefore, in total, 82 (96%) patients with recent-onset AF or AFl were converted to SR. The 10 controls were monitored for the same time period as the study patients and 5 (50%) out of them were spontaneously converted to SR (P<0.0001). No pro-arrhythmia or any other side effects were noticed in the study patients or in the controls. QTc was moderately decreased before the start of amiodarone infusion in patients group, while it did not differ among the three ECGs in controls. The combination of ibutilide as a first-choice drug and of amiodarone infusion in the case of ibutilide failure provides an effective, rapid, and safe algorithm for restoration of SR in patients with AF or AFl of recent onset.


Just the Facts: Ovarian torsion in the emergency department setting.
A 23-year-old female presents with right lower quadrant pain that has been intermittent for the past several days. The pain suddenly worsened 1 hour ago. She denies vaginal bleeding or discharge, dysuria, fever, and back pain, but she has had several episodes of nausea with nonbloody, nonbilious vomiting. On examination, she is tender in the right lower quadrant, but her abdomen is not rigid.


Focused ultrasound (HIFU) induces localized enhancement of reporter gene expression in rabbit carotid artery.
The development of accurate, safe, and efficient gene delivery remains a major challenge towards the realization of gene therapeutic prevention and treatment of cardiovascular diseases. In this study, we investigated the ability of high-intensity focused ultrasound (HIFU), a form of mechanical wave transmission, to act as a noninvasive tool for the enhancement of in vivo gene transfer into rabbit carotid arteries. Segments of the common carotid arteries of New Zealand white rabbits were isolated and infused with plasmid DNA encoding the reporter beta-galactosidase either with or without the addition of ultrasound contrast agent consisting of small (approximately 2-5 microm) gas-filled human albumin microspheres to augment cavitation. Infused arteries were exposed to pulsed ultrasound for 1 min (frequency 0.85 MHz, burst length 50 ms, repetition frequency 1 Hz, duration 60 s, peak pressure amplitude of 15 MPa). At 6.3 MPa, HIFU enhanced gene expression eight-fold, and 17.5-fold in the presence of contrast. We found increasing amounts of beta-galactosidase expression in the carotid vessel with increasing pressure amplitude. This dose-response relation was present with and without contrast. Without contrast, no vessel damage was detected up to 15 MPa, while the addition of contrast induced side effects above a threshold of 6.3 MPa peak pressure. The entire procedure was feasible and safe for the animals, and the results suggest that HIFU has the potential to assist in the noninvasive spatial regulation of gene transfer into the vascular system.


[Tolerance of the association sucralfate / Cu-Zn salts in radiation dermatitis].
The aim of this study was to evaluate the tolerance of topical application of the combination sucralfate / copper zinc salts in radiation dermatitis in women suffering from breast cancer and treated by radiotherapy. 47 patients (average age : 57,5 years) that have to be treated by radiation therapy on non lesional areas, were included into this open multicentric study. They had to apply Cicalfate cream twice a day, from the fi rst radiation therapy session and during 10 weeks. Patients were treated by photon- or electrontherapy (72 % et 28 %, respectively; cumulated total dose : 58,6Gy). Tolerance was considered to be excellent. The radiation dermatitis (score NCIC > or = 2) was noted at the 3rd week of radiotherapy only in 5 % of the subjects and in 53 % of the subjects, the last week of treatment. Pruritus was significantly increased at D21. Pain and discomfort were increased at D28, but remained low intensity. The soothing effect of the combination of sucralfate/ copper zinc salts were considered satisfying or very satisfying by investigators and patients during the study, varying from 94 to 100 % of satisfaction. The impact of radiation therapy on the patients'quality of life, assessed by DLQI, evaluated at the end of the study was not statistically different from the score calculated at D7 (DLQI=0,8 et D7 versus DLQI=1 at D70). Thus, topical application of the combination sucralfate / copper zinc salts can be used in the indication radiation dermatitis.


Dictyostelium MEGAPs: F-BAR domain proteins that regulate motility and membrane tubulation in contractile vacuoles.
PCH family proteins are fundamentally important proteins, linking membrane curvature events with cytoskeletal reorganisation. One group, the MEGAPs (also called srGAPs and WRPs) contain RhoGAP domains in addition to the F-BAR domain. We disrupted MEGAP1 and MEGAP2 in Dictyostelium both singly and in combination. We found a strong cytoskeletal phenotype in MEGAP1(-) cells and a subtle phototaxis defect in MEGAP2(-) slugs. MEGAP1(-)/2(-) cells have an overabundance of filopodia and slug motility and function are affected. The most dramatic changes, however, are on contractile vacuoles. MEGAP1(-)/2(-) cells empty their contractile vacuoles less efficiently than normal and consequently have three times the usual number. GFP-tagged MEGAP1 localises to tubules of the contractile vacuole network and when vacuoles start to empty they recruit cytosolic GFP-MEGAP1. Mutants in the Saccharomyces homologues RGD1 and RGD2 also show abnormal vacuoles, implying that this role is conserved. Thus, MEGAP is an important regulator of the contractile vacuole network, and we propose that tubulation of the contractile vacuole by MEGAP1 represents a novel mechanism for driving vacuole emptying.


Muslim Spirituality, Religious Coping, and Reactions to Terrorism Among Pakistani University Students.
Pakistani Muslim university students (N = 207) displayed Personal Distress, Public Distress, and Personal Defeat Reactions to Terrorism. All three reactions predicted poorer mental health with Personal Defeat being especially disturbed in its adjustment implications. In line with the assumptions of coping theory, scores on the Negative Religious Coping Scale correlated positively with Personal Distress and with Personal Defeat. However, Positive Religious Coping, the spirituality of Muslim Experiential Religiousness, and the Intrinsic and Extrinsic Personal Religious Orientations exhibited positive rather than the expected negative linkages with Personal Distress and Public Distress. Muslim Experiential Religiousness moderated associations of Positive and Negative Religious Coping with Public Distress. When spirituality was high, these relationships were negative. When spirituality was low, they became positive. These data documented the negative impacts that terrorism can have on Pakistanis and suggested that Muslim religious commitments may have an important role to play in resisting those influences.


Cell-autonomous and -nonautonomous contributions of STAT1 in murine models of tumorigenesis.
In this issue of Cancer Cell, Kovacic and colleagues have reexamined the role of STAT1 in murine models of leukemogenesis. Their studies shed new light on the complex interplay between cell-autonomous contributions and host responsiveness to cancer and elucidate a previously unknown role of STAT1 in tumor progression.


Fluorescence detection of intracellular pH changes in the mitochondria-associated process of mitophagy using a hemicyanine-based fluorescent probe.
Intracellular pH behaves as a vital parameter in the physiological and pathological processes. Novel small molecule probes for precise and dynamic monitoring of pH fluctuations in cellular physiological processes are still highly required. Herein, we present a hemicyanine-based probe (HcPH) detection of the pH changes during the intracellular process of mitochondria-associated autophagy. HcP-H exhibits highly reversible and ratiometric fluorescence detection of pH variation due to the deprotonation/protonation process, showing orange fluorescence (λem = 557 nm) in basic media (pH 8.0) and green fluorescence (λem = 530 nm) in acidic media (pH 6.2), respectively. Organelle localization experiment in HeLa cells demonstrates that this probe could selectively accumulate in mitochondria, showing almost overlap with that of Mito-Tracker Green FM. More importantly, Fluorescence imaging of HcP-H in HeLa cells subjected to the nutrient deprivation has demonstrated that this probe could monitor the intracellular pH changes in the mitochondria-associated process of mitophagy. It is clearly confirmed that HcP-H would serve as a promising fluorescent probe for tracing mitophagy in living cells.


Comparison of different theoretical models estimating peak power output and maximal oxygen uptake in trained and elite triathletes and endurance cyclists in the velodrome.
The aim of this study was to assess which of the equations that estimate peak power output and maximal oxygen uptake (VO2max) in the velodrome adapt best to the measurements made by reference systems. Thirty-four endurance cyclists and triathletes performed one incremental test in the laboratory and two tests in the velodrome. Maximal oxygen uptake and peak power output were measured with an indirect calorimetry system in the laboratory and with the SRM training system in the velodrome. The peak power output and VO2max of the field test were estimated by means of different equations. The agreement between the estimated and the reference values was assessed with the Bland-Altman method. The equation of Olds et al. (1995) showed the best agreement with respect to the peak power output reference values, and that of McCole et al. (1990) was the only equation to show good agreement with respect to the VO2max reference values. The VO2max values showed a higher coefficient of determination with respect to maximal aerobic speed when they were expressed in relative terms. In conclusion, the equations of Olds et al. (1995) and McCole et al. (1990) were best at estimating peak power output and VO2max in the velodrome, respectively.


Enhancement of performance by methyl beta-carboline-3-carboxylate, in learning and memory tasks.
Benzodiazepines are known to induce a profound anterograde amnesia in man. In this report, it is shown that methyl beta-carboline-3-carboxylate (beta-CCM), an inverse agonist of the benzodiazepine receptor, has the opposite effect; it enhances performance in learning and memory tasks. Three different learning models were used: habituation to a new environment and passive avoidance in mice and imprinting in chicks. The opposite effects of both beta-CCM and the benzodiazepine diazepam were blocked by administration of the benzodiazepine receptor antagonist Ro 15-1788, providing evidence that the benzodiazepine receptor is involved in these effects.


In vivo modulation of ventral tegmental area dopamine and glutamate efflux by local GABA(B) receptors is altered after repeated amphetamine treatment.
The activity of dopamine neurons in the ventral tegmental area is modulated by excitatory (glutamatergic) and inhibitory (GABAergic) afferents. GABA, released by intrinsic neurons and by projection neurons originating in the nucleus accumbens and other regions, inhibits dopamine neurons via activation of GABA(A) and GABA(B) receptor subtypes. Using in vivo microdialysis in freely moving rats, we investigated the role of ventral tegmental area GABA(B) receptors in modulating levels of dopamine and glutamate within the ventral tegmental area, both in naive rats and in rats treated repeatedly with saline or amphetamine (5 mg/kg i.p., for 5 days). In naive rats, administration of a potent and selective GABA(B) receptor antagonist (CGP 55845A) into the ventral tegmental area elicited a concentration-dependent increase in dopamine levels, but did not alter glutamate levels. In rats tested 3 days after discontinuing repeated amphetamine administration, 50 microM CGP 55845A increased dopamine levels to a greater extent than in saline controls. This difference was no longer present in rats tested 10-14 days after discontinuing repeated amphetamine injections. CGP 55845A (50 microM) had no effect on glutamate levels in the ventral tegmental area of saline-treated rats. However, it produced a robust increase in glutamate levels in rats tested 3 days, but not 10-14 days, after discontinuing repeated amphetamine injections. These results suggest that somatodendritic dopamine release is normally under strong tonic inhibitory control by GABA(B) receptors. Repeated amphetamine administration enhances GABA(B) receptor transmission in the ventral tegmental area during the early withdrawal period, increasing inhibitory tone on both dopamine and glutamate levels. This is the first demonstration, in an intact animal, that drugs of abuse alter GABA(B) receptor transmission in the ventral tegmental area.


3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: biochemical studies and family investigation of four generations.
3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) lyase activity was determined by the recently described spectrophotometric method of Wanders et al. (1988a) in polymorphonuclear leukocytes and lymphocytes obtained from 33 members of a highly consanguineous Arab-Bedouin family belonging to four generations. Seven subjects were obligatory heterozygotes (parents and grandparents of three propositi); in seven additional subjects enzyme activity in both cell types was in the heterozygote range. No asymptomatic homozygotes were found. The results support the proposed autosomal recessive mode of inheritance of this disorder.


Determination of the geographical origin of maize (Zea mays L.) using mineral element fingerprints.
Maize (Zea mays L.) is a staple cereal crop and feed crop throughout the world. In this article, a mineral element fingerprinting technique was applied to single out suitable element indicators to determine the geographical origin of maize. A total of 90 fresh maize samples were collected in 2107 from Jilin, Gansu, and Shandong provinces in China. The contents of 25 mineral elements in all maize samples were measured by inductively coupled plasma mass spectrometry (ICP-MS). The composition of mineral elements was analyzed by multivariate statistical analysis, including one-way analysis of variance (one-way ANOVA), principal component analysis (PCA), k-nearest neighbor (KNN) analysis, and stepwise linear discriminant analysis (SLDA). As compared by one-way ANOVA, the contents of 19 mineral elements in maize samples were significantly different among three provinces. Principal component analysis based on these 19 elements could obtain preliminary visual classification groups of maize samples. K-nearest neighbor analysis produced a total correct classification rate of 83.9% on the training set, and 82.2% on the prediction set. The SLDA model, based on eight indicative elements (Na, Cr, Rb, Sr, Mo, Cs, Ba, and Pb) obtained a total correct classification rate of 92.2% with cross-validation. The mineral element fingerprinting technique combined with multivariate statistical analysis could be a helpful method to identify the geographical origin of maize. © 2019 Society of Chemical Industry.


Prophylactic pacemaker implantation in familial amyloid polyneuropathy.
Familial amyloid polyneuropathy (FAP) is an autosomic dominant disease with a high rate of conduction disorders and increased risk of sudden death. Prophylactic cardiac pacing may be considered in asymptomatic patients with FAP. However, the potential benefits are unknown. To document conduction disorders in a large series of FAP and the incidence of high-degree atrioventricular (AV) block in patients with prophylactic pacemaker (PM). From January 1999 to January 2010, 262 patients with FAP were retrospectively evaluated. Prophylactic PM was implanted in patients with His-ventricular interval ≥ 70 ms, His-ventricular interval >55 ms associated with a fascicular block, a first-degree AV block, or a Wenckebach anterograde point ≤ 100 beats/min. The spontaneous AV conduction was then analyzed by temporarily inhibiting the PM. As compared with patients with prophylactic PM (n = 100) and patients implanted given a class I/IIa indication (n = 18), the patients who did not require PM (n = 144) were younger and displayed less severe cardiac involvement. Follow-up after prophylactic PM implantation was analyzed in 95 of the 100 patients over 45 ± 35 months, and a high-degree AV block was documented in 24 of the 95 patients (25%). The risk of high-degree AV block was higher in patients with first-degree AV block or Wenckebach anterograde point ≤ 100 beats/min (hazard ratio 3.5; 95% confidence interval 1.2-10) while microvoltage on surface electrocardiogram reduced the risk (hazard ratio 0.2; 95% confidence interval 0.1-0.7). In FAP with conduction disorders, prophylactic PM implantation prevented major cardiac events in 25% of the patients over a 45-month mean follow-up. It is suggested that prophylactic PM implantation prevented symptomatic bradycardia in these patients.


Relationship of protamine dosing with postoperative complications of carotid endarterectomy.
Protamine sulfate (PS) neutralization of heparin (HEP) given during carotid endarterectomy (CEA) has been previously associated with an increased postoperative stroke rate. Dosing regimens of PS have varied in previous studies. The accuracy of PS dosing and its effect on postoperative complications was analyzed. The medical records of all patients undergoing elective CEAs from January 1993 to June 1996 in our institution were reviewed. A hematoma was defined as either an event requiring return to the operating room or when repeatedly identified in the medical record. The accuracy of dosing PS was determined utilizing a formula calculating the logarithmic exponential decay of HEP, which determined the residual HEP at the time of PS dosing. An ideal PS dose was then calculated and compared to the dose given. Statistical analyses was performed using a Fisher's exact test as well as the Student's t-test. Four hundred-seven CEAs were performed in 365 patients. There were 10/407 (2.5%) postoperative strokes (STROKE) and 11/407 (2.7%) hematomas, 3 of which required reoperation. Results indicate that (1) the administration of PS significantly reduced the incidence of postoperative hematoma; (2) there appears to be an association between the administration of PS and STROKE; (3) the inaccuracy in dosing PS appears to be based on a decision to dose PS to the total HEP given rather than the residual HEP on board at the time of neutralization. The effect of PS overdosing is unclear, but it may play a role in STROKE.


Isolation and identification of epithelial-like cells in culture by a collagenase-separation technique.
An operational criterion for the identification and isolation of epithelial-like (E) cells, based on their ability to cover and protect a collagen gel from the action of collagenase, has been developed. The E cells isolated by this collagenase-separation technique (CST) exhibited the ultrastructural features, including desmosomes and abundant tonofilaments, that are considered characteristic of this cell type. Unlike confluent cultures of fibroblast-like (F) cells, E cells were not found to have large external transformation-sensitive (LETS) protein on their surface membranes. The CST provides a nondestructive and efficient means of identifying and isolating E cells from mixed populations.


Applicability of Kübler-Ross's stages of dying to the suicidal individual: a review of the literature.
Evidence from the literature is presented that suicidal people may experience the emotions described by Kübler-Ross in her description of the dying process.


Intentional chloroquine overdosage.
Twenty-six episodes of intentional chloroquine overdosage are documented. The over-all mortality rate of 19%, and 50% incidence of cardiac arrest for ingestion of 2.25 g or more of chloroquine base indicate the risk of overdosage. Life-threatening cardiac arrhythmias may be the first sign of overdosage. However, gastrointestinal and neurological symptoms generally precede this sign. Early recognition and attempts to decrease drug uptake are important as current therapy after absorption of the drug is inadequate.


Acinar-endocrine cell tumor of the pancreas. Report of a pancreatic tumor containing both zymogen and neuroendocrine granules.
A case of pancreatic tumor with features of both an acinar cell and an endocrine cell tumor is presented. The histologic appearance of the tumor by light microscopy was consistent with the appearance of either an islet cell tumor or an acinar cell tumor. Electron microscopy revealed two distinct populations of membrane bound granules within the same tumor cells; namely, a small granule measuring 100-200 nanometers in diameter with a narrow halo separating it from the granule membrane, and a large granule measuring 400-500 nanometers in diameter and having a closely applied membrane. The smaller granules have the characteristic appearance of gastroenteropancreatic (GEP) endocrine-cell granules. The large granules are greater in size than neuroendocrine granules, their morphologic structure is most consistent with that of zymogen granules, and a positive lipase stain supported the presence of zymogen granules within the tumor. The occurrence of both neuroendocrine and zymogen granules within the same cell has been previously described in the "intermediate cell" of the pancreas, but not to our knowledge in a tumor of the pancreas. The finding of both endocrine and exocrine granules within a single cell indicates a histogenetic relationship between the pancreatic endocrine and exocrine cells, and may represent the first reported case of a neoplastic proliferation of intermediate cells.


[Hepatitis B in children in 4 university centers in The Netherlands].
To evaluate the prevalence and the natural course of hepatitis B infection in children. Retrospective longitudinal. Four university pediatric centres. To explore the possibility of starting a trial with interferon alpha, data of viral and biochemical tests and biopsies of children younger than 16 years were studied. In a period of 10 years (1980-1990) 145 patients, of whom 74% were not of original Dutch descent, were found positive for HBsAg. The data of 142 patients could be analysed. Seroconversion was seen in 27 patients and 42 were already anti-HBe positive at the time of presentation. Chronic hepatitis, representing the category which could benefit from interferon alpha treatment, was found in 24 patients. Severe complications of the hepatitis were found in 4% of the children, including hepatocellular carcinoma and cirrhosis. Follow-up was insufficient so the seroconversion rate could only be estimated at 12% for the first year following the diagnosis. As a result of this study the authors present a proposal for a therapeutic trial with interferon alpha. This is a national protocol under the auspices of the section for pediatric gastroenterology of the Nederlandse Vereniging voor Kindergeneeskunde (Netherlands Pediatric Association).


A cross-linked polymeric micellar delivery system for cisplatin(IV) complex.
A polymeric cisplatin(IV) prodrug in the form of cross-linked micelles (M(Pt(IV)) was prepared by first constructing MPEG-b-PCL-b-PLL micelles and then attaching a cisplatin(IV) complex with two axial succinic moieties to the lysine residues of the carrier polymer in aqueous medium. The micelles obtained were characterized by TEM, DLS, and zeta potential measurement. Their in vitro release experiments were carried out at pH 7.4 and 5.0 or in the presence of 5mM sodium ascorbate (NaAsc). Results showed that the micelles were sensitive to both acidic hydrolysis and mild reducing agents; in the presence of 5mM NaAsc, cisplatin(II) was directly released and the released cisplatin(II) could chelate with nucleobases; the micelles displayed comparable cytotoxicities to cisplatin; and the micelles were much more efficiently internalized by the cells than cisplatin(II) and cisplatin(IV) counterparts. Moreover, in vivo study showed accumulation of more Pt species in the tumor site and lower systematic toxicity compared to free cisplatin(II) and cisplatin(IV). This polymeric prodrug of cisplatin is expected to be used more for future study and applications.


Application of linear solvation energy relationships to a custom-made polyaniline solid-phase microextraction fiber and three commercial fibers.
The term linear solvation energy relationships, LSERs, is considered to be a specific subset of a larger group of thermodynamic relationships called linear free energy relationships. Overall, the LSERs model represents a three-step thermodynamic process. The most recently accepted notation for the LSER equation, proposed by Abraham is given as follows: SP= c+eE+sS+aA+bB+vV where SP is any free energy related property of a solute, such as log K, and each term in the equation represents a specific type of chemical interaction. In this work, LSERs were applied to a custom-made polyaniline (PANI) solid-phase microextraction fiber and three commercial fibers immersed in water in order to aid in the assessment of a diverse series of solutes' partitioning behavior. By experimentally determining the log K for a series of solutes with known solute descriptors (E, S, A, B, and V) and performing multi-linear regression, the unknown system coefficients (e, s, a, b, and v) were obtained. The sign and magnitude of the system coefficients reflect the relative strengths of chemical interactions that affect partitioning between the two phases (fiber and water). The LSER study showed that the system properties having the greatest influence on log K were ease of cavity formation and hydrogen bond donating ability. The differences in dipolarity/polarizability as well as in hydrogen bond accepting ability further showed that all four fibers offer a unique environment for solute partitioning. The PANI fiber may offer greater flexibility in the choice of fibers to use for solid-phase microextraction.


Interleukin-6 producing pheochromocytoma presenting with acute inflammatory syndrome.
Pheochromocytomas are tumors able to produce catecholamines and a variety of biologically active neuropeptides. We report the case of a 36-yr-old female patient with pheochromocytoma exhibiting headache, intermittent fever, thrombocytosis, and marked inflammatory signs. Nonsteroidal anti-inflammatory drugs were ineffective in lowering the body temperature, while a corticosteroid agent obtained excellent results. IL-6 was found elevated (20 pg/ml); it fell to 4.5 pg/ml 3 weeks after the adrenalectomy, in parallel to normalization of other laboratory data. The interleukin-6 (IL-6) over-production can either be ascribed directly to the tumor (as confirmed by immunohistochemistry) or indirectly accounted for by tumoral production, as a consequence of the high levels of circulating norepinephrine. To our knowledge, our paper represents the 6th case report of IL-6 secreting pheochromocytoma associated with clinical markers of inflammatory response.


Cooperation, optimal density and low density thresholds: yet another modification of the logistic model.
A modification of the logistic model is proposed which incorporates the principles of optimal density and cooperation. Three components have been added defining effectivity, "saturation" and exponentiality of cooperation. By adequate choice of constants a wide array of population characteristics may be represented including threshholds of growth. The main application of the model concerns, low density problems such as colonization and extinction.


Neurocysticercosis.
Neurocysticercosis is a leading cause of seizures and epilepsy in the developing world and is an increasingly important health issue in the United States. Recent results from the Cysticercosis Working Group in Peru provide new evidence supporting the use of antiparasitic agents in highly selected patients with active cysts and seizures.


Computational study on constant and sinusoidal heating of skin tissue using radial basis functions.
This paper concerns the study of heat distribution in skin tissue with constant and sinusoidal heat flux at the skin surface. Three types of heat transfer models, i.e., Pennes bioheat model, single-phase lag model, and dual-phase lag model based on Fourier and non-Fourier heat conduction, are taken into consideration. Also, Fourier, as well as non-Fourier boundary conditions, are considered at both the end of skin tissue for the single and dual-phase lag model of heat conduction. The resulting models are solved using finite difference and radial basis function (RBF) approximations for the temporal and spatial variables, respectively. The effects of these three models and other parameters involved in models on heat transfer in skin tissue are studied. The effects of Fourier and non-Fourier boundary conditions on heat transfer for single and dual-phase lag models are also studied.


Acetaminophen metabolism in subjects fed charcoal-broiled beef.
The effects of consumption of charcoal-broiled beef on the metabolism of acetaminophen by conjugation were determined in nine normal subjects. We had reported that beef prepared in this manner accelerates the oxidative metabolism of drugs, including the oxidation of phenacetin to N-acetyl-p-aminophenol (acetaminophen). In nine normal subjects, a control diet was followed by a charcoal-broiled beef diet, which was followed by the control diet. The charcoal-broiled beef had little or no effect on the plasma-level profile of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate, or on the urinary excretion of acetaminophen, acetaminophen glucuronide, acetaminophen sulfate, 3-methoxy-acetaminophen, or the cysteine and mercapturic acid conjugates of acetaminophen. Results indicate that the enzyme systems that conjugate acetaminophen in man are subject to little or no influence by charcoal-broiled beef. Therefore dietary factors that increase drug oxidations cannot be assumed to have a similar effect on drug conjugation.


High-affinity binding of [3H]muscimol to subcellular particles of a neurone-enriched culture of embryonic rat brain.
High-affinity, Na+-independent binding of [3H]muscimol (KB approximately equal to 1.6 x 10(-8) M; Bmax approximately equal to 0.14 nmol/g pellet) occurred to a frozen-thawed particulate fraction of 74-h-old neurone-enriched cultures prepared from the cerebra of 12-13-day-old rat embryos. This finding provides evidence that GABA-receptors exist on cultured neurones which contain only a few synaptic connections.


Chemistry and weak antimicrobial activities of phomopsins produced by mangrove endophytic fungus Phomopsis sp. ZSU-H76.
Three metabolites named phomopsin A (1), B (2) and C (3), together with two known compounds cytosporone B (4) and C (5), were isolated from the mangrove endophytic fungus, Phomopsis sp. ZSU-H76 obtained from the South China Sea. Their structures were elucidated by spectroscopic methods, mainly by 1D and 2D NMR spectroscopic techniques. The medium-sized cyclic phenol ether based on 1 or 2 is rare in natural products. In bioassays, compounds 1, 2, and 3 had no significant antibiotic activities, but compounds 4 and 5 inhibited two fungi Candida albicans and Fusarium oxysporum with an MIC ranging from 32 to 64 microg/ml.


Effect of sodium chloride on gene expression of Streptococcus mutans and zeta potential of demineralized dentin.
In this work, the effects of sodium chloride (NaCl) on gene expression of planktonic Streptococcus mutans cells are investigated. Also assessed are the effects of NaCl on zeta potential of sound and demineralized dentin. The relative level of glucosyltransferase B (gtfB), gtfC and gtfD transcription of S. mutans in the presence of NaCl was evaluated by quantitative polymerase chain reaction (qPCR). The osmolality of varying salt (NaCl) concentrations and their influence on the zeta potential of sound and demineralized dentin was investigated as well. NaCl significantly reduced the expression of gtfB and C genes in planktonic S. mutans; whereas, gtf D gene expression significantly increased in the presence of NaCl (P < 0.05). NaCl at concentrations of 37.5 mg/ml reduced zeta potential of demineralized dentin, while no significant decrease of zeta potential was found when sound dentin was exposed to this concentration. NaCl reduces the expression of some gtfs in S. mutans and increases negative potential charge of demineralized dentin.


Capacitance measurements at the calyx of Held in the medial nucleus of the trapezoid body.
We have recently applied Lindau-Neher's capacitance measurement technique to study vesicle trafficking at the calyx-type synapse in the rat medial nucleus of the trapezoid body (MNTB) in slice conditions. This application made the MNTB synapse an excellent model for the study of exocytosis and endocytosis at conventional active zones. However, the application was only made at calyces that are presumably equivalent to a single-compartment circuit because their passive current transients decayed mono-exponentially. Here, we determined whether the application could be extended to majority of calyces whose passive current transients decayed bi-exponentially. By comparison of calyces with mono- or bi-exponential decay in their passive current transients, we found similar properties in respect to: (1) the capacitance jump induced by trains of action-potential equivalent stimuli, which reflects exocytosis; (2) the size of a releasable vesicle pool; (3) the time course of the decay after the capacitance jump, which reflects endocytosis; and (4) the transient capacitance artifact observed in the presence of Cd(2+) that blocks exocytosis. These similar properties were also obtained from modeling calyces as a single- or two-compartment circuit. Thus, capacitance measurements may be extended to the majority of calyces, which may facilitate the study of rapid vesicle trafficking at conventional active zones.


Attraction to mammals of male mosquitoes with special reference to Aedes diantaeus in Sweden.
During investigations in central Sweden on the ecology of mosquito vectors of Ockelbo disease, large numbers of Aedes diantaeus males and lesser numbers of Ae. communis, Ae. excrucians and Ae. intrudens males were captured in animal-baited (rabbit, guinea pig, hen, dove, unbaited control) suction- and net-traps. In the five suction-traps, 57% of the diantaeus captured (N = 1,896) were males. Although the guinea pig-baited suction-trap captured the highest mean number of diantaeus males, data showed that these males, like the females, were mainly attracted to the largest mammal, i.e., the rabbit. These males assembled in the vicinity of the rabbit presumably to intercept females coming to feed. The net-trap data showed that orientation by the males to the rabbit presumably involved olfactory cues emanating from the mammal.


Pneumoendoscopic single port approach to breast cancer. How we do it?
Endoscopic procedures have not become the gold standard in breast surgery. In order to improve today's outcomes we have developed a pilot study in the Breast Pathology Unit of Hospital Germans Trias i Pujol. A surgical procedure was performed creating a pneumoendoscopic cavity by using a Single Incision Laparoscopic Surgery (Single port) approach with a follow up of four years. Four patients underwent pneumoendoscopic single-port breast surgery receiving skin-sparing quadrantectomy and axillary surgery requiring lymphadenectomy in all of them. All patients had immediate reconstruction with a Latisimus Dorsi flap. No perioperative complications appeared. Mean operative time was 290 min (range 240-315 min) and mean hospital stay was 3,2 days. Surgical margins of all cases were pathologically negative and all patients were disease free after four years of monitoring. All patients were satisfied with the cosmetic outcome in the immediate postoperative and during the follow up. Although all innovative techniques generate hesitation on their beginnings and are liable to improve, we believe that pneumoendoscopic single-port breast surgery can be suitable for breast cancer, offering better cosmetic outcomes with oncological safety.


Original dataset used in the article "Does Pokémon Go lead to a more physically active life style?"
The data presented in this article are related to the research article entitled "Does Pokémon Go lead to a more physically active life style?" (Gabbiadini et al., in press) [1]. In the study, 981 individuals completed a web survey, in which frequency of Pokémon Go usage, overall physically active behavior, and amount of Pokémon Go related physical activity were measured. Regression analyses revealed that Pokémon Go related physical activity significantly reversed the positive effects of the app on participants' overall physically active behavior, suggesting that the mere adoption of the app does not reliably change people׳s behavior in general. The increase in physical activity levels is rather explained by the exercise required by the game. The data set is made publicly available to enable critical or extended analyzes.


Measuring pressure under burns pressure garments using the Oxford Pressure Monitor.
Pressure garments are used extensively in the treatment of hypertrophic scarring following burn injuries. The Oxford Pressure Monitor was used to measure garment-scar interface pressure (mmHg) using a number of fabric types over various body parts. The results indicate a wide range of pressure values between different garments and body parts with the greatest pressures found over the dorsum of hands and feet. The problems of achieving 'optimal pressure' over hypertrophic scarring are discussed with emphasis on the need for more accurate measuring equipment.


Effect of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on bacteriuria and urinary tract infection in subjects with type 2 diabetes enrolled in a 12-week, phase 2 study.
To examine the effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor that lowers blood glucose by increasing urinary glucose excretion (UGE), on asymptomatic bacteriuria and urinary tract infections (UTIs). In a randomized, double-blind, placebo-controlled, multicenter, dose-ranging phase 2 study, subjects with type 2 diabetes with inadequate glycemic control while receiving metformin were enrolled and randomized to one of seven arms - placebo; canagliflozin doses 50 mg, 100 mg, 200 mg, 300 mg daily, or 300 mg twice daily; and sitagliptin 100 mg daily - for 12 weeks. This study is registered under Clinicaltrials.gov identification number NCT00642278. Canagliflozin increased renal glucose excretion by 35.4-61.6 mg/mg creatinine in the five dose groups. In the placebo group renal glucose excretion was increased by 1.9 mg/mg creatinine, and in the sitagliptin group it decreased by 1.9 mg/mg creatinine. Asymptomatic bacteriuria (ASB) were present in 6.4% of canagliflozin and 6.5% of placebo/sitagliptin (control) subjects at randomization and, at 12 weeks, in 7.7% and 6.3% of subjects, respectively (odds ratio [OR] 1.23; 95% confidence interval [CI], 0.45-3.89). For subjects with initially negative urine cultures at baseline, 3 out of 82 (3.7%) who received controls and 10 out of 207 (4.8%) who received canagliflozin developed bacteriuria (p = 0.76) at week 12. There were 21 adverse event (AE) reports of UTI; 16 (5.0%) in canagliflozin subjects and 5 (3.8%) in control subjects (OR 1.31; 95% CI, 0.45-4.68). In this trial, when compared with control subjects, canagliflozin increased UGE but was not associated with increased bacteriuria or AE reports of UTI. However, further studies enrolling larger numbers of subjects with longer term exposure to canagliflozin will be necessary to more fully understand the impact of this agent on the risk of developing UTI.


A survey of drug-target interaction and affinity prediction methods via graph neural networks.
The tasks of drug-target interaction (DTI) and drug-target affinity (DTA) prediction play important roles in the field of drug discovery. However, biological experiment-based methods are time-consuming and expensive. Recently, computational-based approaches have accelerated the process of drug-target relationship prediction. Drug and target features are represented in structure-based, sequence-based, and graph-based ways. Although some achievements have been made regarding structure-based representations and sequence-based representations, the acquired feature information is not sufficiently rich. Molecular graph-based representations are some of the more popular approaches, and they have also generated a great deal of interest. In this article, we provide an overview of the DTI prediction and DTA prediction tasks based on graph neural networks (GNNs). We briefly discuss the molecular graphs of drugs, the primary sequences of target proteins, and the graph reSLBpresentations of target proteins. Meanwhile, we conducted experiments on various fundamental datasets to substantiate the plausibility of DTI and DTA utilizing graph neural networks.


Nuclear translocation of the cardiac L-type calcium channel C-terminus is regulated by sex and 17β-estradiol.
The cardiac voltage gated l-type Ca(2+) channel (Cav1.2) constitutes the main entrance gate for Ca(2+) that triggers cardiac contraction. Several studies showed that the distal C-terminus fragment of Cav1.2 α1C subunit (α1C-dCT) is proteolytically cleaved and shuttles between the plasma membrane and the nucleus, which is regulated both developmentally and by Ca(2+). However, the effects of sex and sex hormone 17β-estradiol (E2, estrogen) on α1C-dCT nuclear translocation are still unexplored. To investigate the sexual disparity in the α1C-dCT nuclear translocation, we first generated an antibody directed against a synthetic peptide (GRRASFHLE) located in α1C-dCT, and used it to probe ventricular myocytes from adult female and male mice. Immunocytochemistry of isolated mouse primary adult ventricular myocytes revealed both nuclear staining and cytosolic punctuate staining around the T-tubules. The ratio of nuclear to cytosolic intensity (Inuc/Icyt) was significantly higher in isolated female cardiomyocytes (1.42±0.05) compared to male cardiomyocytes (1.05±0.02). Western blot analysis of nuclear fraction confirmed these data. Furthermore, we found a significant decrease in nuclear staining intensity of α1C-dCT in both female and male cardiomyocytes upon serum withdrawal for 18h (Inuc/Icyt 1.05±0.02 and 0.89±0.02, respectively). Interestingly, subsequent E2 treatment (10(-8)M) for 8h normalized the intracellular distribution of α1C-dCT in male cardiomyocytes (Inuc/Icyt 1.04±0.02), but not in female cardiomyocytes. Acute treatment of male cardiomyocytes with E2 for 45min revealed a similar effect. This effect of E2 was revised by ICI indicating the involvement of ER in this signaling pathway. Taken together, our results showed that the shuttling of α1C-CT in cardiomyocytes is regulated in a sex-dependent manner, and E2-activated ER may play a role in the nuclear shuttling of α1C-dCT in male cardiomyocytes. This may explain, at least partly, the observed sex differences in the regulation of cardiac Cav1.2 channel activity.


Early-onset group B streptococcal disease in a risk factor-based prevention setting: A 15-year population-based study.
Intrapartum chemoprophylaxis reduces early-onset group B streptococcal disease (EOGBSD) in newborns. Some guidelines advise that intrapartum antibiotics should be offered following universal antenatal screening for GBS carriage and others recommend intrapartum antibiotics based on clinical risk factors alone. Since 1999, Queensland guidelines have recommended a risk factor-based approach. We examined trends in EOGBSD rates over time in Queensland in the setting of these guidelines and whether management of cases reflected the recommendations. A state-wide retrospective search of pathology databases, allowing near-complete, population-based case identification, was conducted to detect live-born infants from January 2000 to December 2014 with GBS cultured from blood or cerebrospinal fluid within seven days of age. A nested audit of EOGBSD cases comparing two epochs, 2000-2010 and 2011-2014, was performed to determine patient characteristics and guideline adherence for each case. Mean incidence of EOGBSD in Queensland from 2000 to 2014 was 0.33 per 1000 live births (SD± 0.08) with no changing trend over time. The case-mortality rate in the 2011-2014 epoch was 1.2% compared to 11.9% in 2000-2004 (odds ratio (OR) 0.09, 95% confidence interval (CI) 0.002-0.67). The proportion of EOGBSD cases who were preterm infants decreased from 29.8% to 13.3% (OR 0.36, 95% CI 0.14-0.84). Of cases with risk factors in the 2011-2014 epoch, 46% received intrapartum antibiotics compared to 25% in 2000-2004 (OR 2.49, 95% CI 0.86-7.58, P = 0.09). EOGBSD incidence rate in Queensland remained low during 2000-2014. However, both the 2011-2014 case-mortality rate and the proportion of preterm cases significantly decreased. Missed opportunities for intrapartum chemoprophylaxis remain.


A feasibility study of immediate versus deferred antiretroviral therapy in children with HIV infection.
To evaluate the feasibility of a large immediate versus deferred antiretroviral therapy (ART) study in children. We conducted an open-label pilot randomized clinical trial study in 43 Thai children with CD4 15 to 24% of starting generic AZT/3TC/NVP immediately (Arm 1) or deferring until CD4 < 15% or CDC C (Arm 2). Primary endpoints were recruitment rate, adherence to randomized treatment and retention in trial. Secondary endpoints were % with CDC C or CD4 < 15%. Children were in the trial until the last child reached 108 weeks. Intention to treat and on treatment analyses were performed. Recruitment took 15 months. Twenty-six of 69 (37.7%) were not eligible due mainly to low CD4%. Twenty four and 19 were randomized to arms 1 and 2 respectively. All accepted the randomized arm; however, 3 in arm 1 stopped ART and 1 in arm 2 refused to start ART. Ten/19 (53%) in arm 2 started ART. At baseline, median age was 4.8 yrs, CDC A:B were 36:7, median CD4 was 19% and viral load was 4.8 log. All in arm 1 and 17/19 in arm 2 completed the study (median of 134 weeks). No one had AIDS or death. Four in immediate arm had tuberculosis. Once started on ART, deferred arm children achieved similar CD4 and viral load response as the immediate arm. Adverse events were similar between arms. The deferred arm had a 26% ART saving. Almost 40% of children were not eligible due mainly to low CD4% but adherence to randomized treatment and retention in trial were excellent. A larger study to evaluate when to start ART is feasible.


Hemostatic properties of the SV-40 transfected human microvascular endothelial cell line (HMEC-1). A representative in vitro model for microvascular endothelium.
HMEC-1 is a SV-40T transfected human microvascular endothelial cell line that constitutively expresses RNA transcripts for plasminogen activator inhibitor 1 (PAI-1), tissue-type plasminogen activator (t-PA), protein S (PS), von Willebrand factor (vWF), and thrombomodulin. Tissue factor (TF) can be induced in response to stimulation with tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1alpha) and phorbol 12-myristate 13-acetate (PMA). Proteins corresponding to PAI-1, t-PA, protein S and vWF genes were constitutively released in the culture supernatant. This cell line is a model that will be useful to investigate coagulation/fibrinolytic properties of microvascular endothelium.


Purification and characterization of GP-55, a protein associated with actin-based cytoplasmic gels derived from brain tissue.
Incubation of rat brain cytoplasmic extracts results in the formation of three-dimensional gels that can be collapsed by low-speed centrifugation. Electrophoresis in polyacrylamide gels indicate that these cytoplasmic gels are composed of actin and several associated proteins. Among the latter we have identified a component with an apparent molecular mass of 55,000 daltons. The results of two-dimensional electrophoresis, peptide mapping, and in vivo labeling experiments with [35S]methionine, indicate that the 55-kDa protein is composed of two different gene products we have named alpha and beta; a third polypeptide, named beta', probably derives from the beta polypeptide as a result of some posttranslational modification(s). These three polypeptides, which have the same molecular weight but different isoelectric points, are present in a rather pure preparation of the 55-kDa protein, obtained from cytoplasmic gels by ion-exchange chromatography. In vitro, purified 55-kDa protein interacts in a specific manner with F-actin, as shown by viscosimetry and electron microscopy, leading to the formation of a complex network of cross-linked microfilament bundles. The results of immunofluorescence experiments indicate that the 55-kDa protein is located intracellularly in structures belonging to the Golgi apparatus, and that it is not only present in every type of rat cell tested but also in primary cultures of chick embryo neurons. Based on its intracellular location, we have named the 55-kDa protein as Golgi Protein-55 (GP-55).


Polymeric biomaterial-inspired cell surface modulation for the development of novel anticancer therapeutics.
Immune cell-based therapies are a rapidly emerging class of new medicines that directly treat and prevent targeted cancer. However multiple biological barriers impede the activity of live immune cells, and therefore necessitate the use of surface-modified immune cells for cancer prevention. Synthetic and/or natural biomaterials represent the leading approach for immune cell surface modulation. Different types of biomaterials can be applied to cell surface membranes through hydrophobic insertion, layer-by-layer attachment, and covalent conjugations to acquire surface modification in mammalian cells. These biomaterials generate reciprocity to enable cell-cell interactions. In this review, we highlight the different biomaterials (lipidic and polymeric)-based advanced applications for cell-surface modulation, a few cell recognition moieties, and how their interplay in cell-cell interaction. We discuss the cancer-killing efficacy of NK cells, followed by their surface engineering for cancer treatment. Ultimately, this review connects biomaterials and biologically active NK cells that play key roles in cancer immunotherapy applications.


Physiological responses to changes in relative humidity under thermally neutral, warm and hot conditions.
Four hypothetical thermophysiological responses to changes in relative humidity (Rh) under thermally neutral, warm, and hot conditions were proposed for a person at rest. Under thermally neutral and warm conditions, the first hypothetical response to an increase in Rh was a decrease in mean skin temperature (T¯sk) due to increase in mean evaporation rate (E¯sk), and the second hypothetical response to a decrease in Rh was a decrease, an increase, or no change in T¯sk, depending on changes in the E¯sk. Under hot conditions, the third hypothetical response to an increase in the Rh was an increase in T¯sk or decrease in T¯sk upon decrease in the Rh due to changes in E¯sk, and the forth hypothetical response to an increase in Rh was an increase in T¯sk due to increase in the peripheral blood flow rate (SkBF). To test these hypotheses, the T¯sk and E¯sk of four young male volunteers were measured at 28°C, 30°C, or 32°C while the Rh was maintained at 40% or 80% Rh for 60min after 20min exposure at 60% Rh (control condition). In a second experiment, the T¯sk, E¯sk, and SkBF of five young male volunteers were measured at 34°C-40% Rh or 36°C-40% Rh, or 34°C-70% Rh or 36°C-70% Rh for 60min after 20min exposure at 28°C-60% Rh (control condition). The first hypothesis was partly supported by the findings that the T¯sk was lower than the control values at 28°C-80% Rh and the E¯sk was higher than the control values at 80% Rh at any tested temperature. The second hypothesis was partly supported by the findings that the T¯sk was lower than the control values at 28°C-40% Rh, and there were small changes in both T¯sk and E¯sk at 30°C-40% Rh. The third and fourth hypotheses were supported by the findings that the T¯sk at 36°C-70% Rh was significantly higher (p<0.01) than at 36°C-40% Rh, the E¯sk was significantly higher (p<0.01) at 70% Rh than at 40% Rh, and SkBF was positively correlated with T¯sk.


Unbound free fatty acids from preterm infants treated with intralipid decouples unbound from total bilirubin potentially making phototherapy ineffective.
Extremely low birth weight (ELBW; <1,000 g) infants have poor outcomes, often compromised by bilirubin neurotoxicity. We measured unbound bilirubin (Bf) and unbound free fatty acid (FFAu) levels in 5 ELBW infants in a trial examining the effects of pharmacologic ductal closure on infants treated with Intralipid infusion (3 g/kg/day). The levels for all infants (mean ± SD) were: total serum bilirubin (TSB) 4.6 ± 1.7 mg/dl, FFAu 376 ± 496 nM, and Bf 42 ± 30 nM. Of the 3 infants who died, 2 had TSB <5.9 mg/dl but FFAu >580 nM and Bf >75 nM. Multiple regression revealed a major effect on Bf levels due to FFAu, indicating that Intralipid elevated levels of FFAu and Bf. Indomethacin or ibuprofen reduced Bf levels, most likely by reducing FFAu levels through lipase inhibition. Because displacement of Bf by FFAu decouples Bf from TSB, phototherapy may not reduce the risk of bilirubin or FFAu toxicity in Intralipid-treated ELBW infants.


Measuring the relationships between various urban green spaces and local climate zones.
Urban green spaces (UGS) improve living conditions in cities by mitigating the Urban Heat Island effect. While the cooling effect of UGS seems unequivocal, the relationship between the types of UGS and types of residential areas has not yet been well explored. In this study, we systematically analysed the cooling effect of 71 UGS in Prague, a central European city, on residential areas within 400 m of the UGS. The UGS are classified according to their spatial characteristics (size, shape, and tree density), and the residential areas according to three Local Climate Zones (LCZ 2, 5, 6) typical for European cities. The cooling effect is evaluated using a regression model of the Land Surface Temperature (LST) in residential zones according to the LCZ type and distance from the various UGS. The results show that compact UGS of 10-25 ha with dense trees have the most pronounced cooling effect. This type of UGS was associated with a mean decrease in LST within 400 m of 2.3 °C compared to the least effective UGS type (long with sparse trees) across LCZs. The results of the presented study can be applied in urban planning and urban design to improve microclimates in cities.


Determination of backbone nitrogen-nitrogen J correlations in proteins.
Recently, a quantitative J correlation technique has been presented which makes use of homonuclear Hartmann-Hahn cross-polarization (TOCSY) to measure (3)J(C)'(C)' in proteins isotopically enriched with (13)C [Grzesiek, S. and Bax, A. (1997) J. Biomol. NMR, 9, 207-211]. Since homonuclear Hartmann-Hahn is twice as fast as conventional COSY transfer, this method is much less sensitive to transverse relaxation, which is the principal limiting factor in achieving long-range J-coupling correlations in macromolecules. Here we describe a similar experiment which is used to measure(3) J(NN) coupling constants between sequential amide(15) N nuclei in the backbone of ubiquitin. As expected from the low magnetic moment of (15)N, the (3)J(NN) coupling constants are exceedingly small, with values between 0.14 and 0.36 Hz for residues in β-conformations and values below 0.15 Hz for residues in α-conformations. In contrast to what is expected from a Karplus-type dependence on the backbone angle ψ, large differences in the values of(3) J(NN) are observed for a number of residues with very similar backbone ψ angles. A quantitative description of statistical and systematic errors, in particular of relaxation effects during the TOCSY transfer, shows that these differences are highly significant.


Discover immunotherapy biomarkers from single-cell cytometry data.
Currently, identifying novel biomarkers remains a crucial need for cancer immunotherapy. By leveraging single-cell cytometry data, Greene et al. developed an interpretable machine learning method, FAUST, to discover cell populations associated with clinical outcomes.


Expanding character sampling for the molecular phylogeny of euplotid ciliates (Protozoa, Ciliophora) using three markers, with a focus on the family Uronychiidae.
Although euplotida ciliates are widely used as model organisms in multiple fields of biology, details of their phylogenetic relationships remain unresolved despite a rich history of investigation with small subunit (SSU) rDNA sequences and other characters. Here, six genera in Diophrys-like complex and three other euplotid genera are sampled for SSU-rDNA, ITS1-5.8S-ITS2 and LSU-rDNA, and their phylogenies were inferred with unconstrained and constrained analyses. In general, the concatenated analyses infer more reliable, less ambiguous phylogenies with higher node support values. The following conclusions can be made: (1) four well-supported clades are consistently detected in the family Uronychiidae, forming into two subgroups, which challenge the traditional arrangement based on morphological similarities; (2) the subfamily Diophryinae is paraphyletic; (3) the monophyly of Paradiophrys and the establishment of Apodiophrys and Diophryopsis is fully supported by concatenated data; (4) Apodiophrys and Paradiophrys form independent lineages, at the subfamily level, from other Diophrys-like genera; and (5) the highly specialized Pseudodiophrys nests within Diophrys.


Regulation of calcitonin gene-related peptide and TRPV1 in a rat model of osteoarthritis.
Pain in osteoarthritis (OA) remains an intractable problem in a majority of patients, with many of the commonly prescribed analgesics providing insufficient relief and considerable side effects. However, the structural or mechanistic cause of OA pain is still unknown. Animal models to address this issue have only recently been established, with much of the research to date focused on tissue pathology rather than pain. We have previously compared the surgically induced partial medial meniscectomy and chemically induced intra-articular iodoacetate injection rat models of OA in the rat, with reference to pain behaviour. This demonstrated relevant tissue pathology in both models, but greater evidence of pain related behaviour in the iodoacetate induced model. Here we further investigate the iodoacetate model using Fast Blue backlabelling from the articular joint space to identify the cell bodies of primary sensory afferents from the knee at the L4 dorsal root ganglion. Expression of calcitonin gene-related peptide (CGRP) and the vanilloid receptor TRPV1 was quantified in these backlabelled cells and was enriched in the knee afferents in all animals studied, compared to the expression in neurons across the whole dorsal root ganglia (DRG). Analysis of the backlabelled population in the osteoarthritis model and controls showed an increase in both CGRP and TRPV1 expression in the iodoacetate model compared with control animals. Therefore, there is a potential role for CGRP and TRPV1 in the manifestation of pain behaviour accompanied by OA changes in the knee in the iodoacetate induced model.


The dilemma of Crohn's disease: ileosigmoidal fistula complicating Crohn's disease.
Between 1965 and 1975, 27 patients underwent surgical treatment for ileosigmoidal fistulas complicating Crohn's disease at the Cleveland Clinic. There was no death and no anastomotic leak. The preferred procedure is resection of the ileocecal area involved by Crohn's disease with ileocolic anastomosis and a separate segmental resection of the sigmoid colon with colocolic anastomosis. A covering temporary loop ileostomy is used when there is associated pelvic sepsis or small-bowel obstruction.