[Chemotherapy in cervical cancer. Assessment of 267 palliative treatments and current trends (author's transl)].
Over the last 10 years 267 treatments with cervical cancer have been treated with chemotherapy in 4 anticancer centers. The analysis of these results shows: 1) 9 per cent of the treatments were discontinued because of clinical and hematological intolerance reactions; these intolerance reactions were responsible for 1 per cent of the therapeutic deaths; 2) an effect on the functional symptoms in 52 per cent of the patients with multiple drug regimens; 3) an objective global response in 18 per cent of the patients treated with single drug therapy (3 regressions greater than 50% out of 6 cases treated with cis-platinum) and in 22 per cent of the patients treated with various associations. Comparison of these results to recent data in the literature confirms: 1) the hope of improving objective results by developing more rational protocols of association, since, for the moment more active drugs are not available; 2) a much more marked chemotherapeutic action on lesions which have not been previously irradiated (statistically significant differences in response). Chemoresistance in cervical cancers may not be as frequent or as insurmountable as generally believed. The role of chemotherapy may be visualized from: 1) the palliative point of view, for efficacy while reducing toxicity); 2) induction sequence in curative treatment programs for advanced local forms with unfavorable prognosis (logical and attractive orientation of therapeutic studies); 3) the point of view of adjuvant treatment which remains to be defined. Rigorous studies are required to assess whether chemotherapy can give eventual long term improvement in high risk cervical cancers.


Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43.
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.


Expression of cGMP-dependent protein kinase in Escherichia coli.
Cyclic GMP-dependent protein kinase (cGMP kinase) is involved in the relaxation of smooth muscle. The enzyme has been cloned and expressed in eukaryotic cell lines but so far not in prokaryotic cells. Three vectors were constructed for the expression of I alpha cGMP kinase in Escherichia coli. Transformation with the pET3a/cgk vector which uses the T7 RNA polymerase/promotor system resulted in efficient accumulation of cGMP kinase. Most of the protein was in an insoluble and catalytic inactive form. Various solubilization and refolding conditions did not yield an active enzyme. A small fraction of the cGMP kinase was present in the soluble cell extract. This fraction bound cGMP with high affinity but had no cGMP stimulated kinase activity. To prevent aggregation two additional vectors were constructed. (I) A bacterial leader sequence, which directs the export of proteins into the periplasmic space, was fused to the amino-terminus of the cGMP kinase. (II) A gram/gram+ shuttle vector for expression under the control of the tac promotor was used. Both constructs directed the synthesis of an insoluble and inactive cGMP kinase. These results suggest that large amounts of cGMP kinase can be expressed in E. coli, but mainly in an insoluble and inactive form. In contrast to eukaryotic cells, bacteria may lack systems for correct protein folding and/or posttranslational modification that are crucial for the productive folding and/or activation of cGMP kinase.


Subclass restriction of anti-SS-B (La) autoantibodies.
Antibodies to the SS-B (La) nuclear ribonucleoprotein particle are relatively specific for the diagnoses of Sjögren's syndrome or systemic lupus erythematosus. The formation of such autoantibodies is likely, then, to reflect the basic immunopathogenesis of these disorders. We have studied the isotype distribution of anti-SS-B antibodies as a clue to their immunoregulation. Using specific ELISA assays, we found that nearly all anti-SS-B antibodies in 39 patients were IgG, and, of these, only the IgG1 and, to a much lesser extent, IgG3 subclasses were represented. Both kappa and lambda light chain antibodies were found in most sera, and the overall kappa/lambda ratio approximated that of normal serum immunoglobulin. These results suggest that the formation of anti-SS-B antibodies is T-cell dependent and that the response is polyclonal in most patients.


Noncovalent π Interactions in Mutated Aquomet-Myoglobin Proteins: A QM/MM and Local Vibrational Mode Study.
Protein dynamics and function is strongly connected to the energy flow taking place. Myoglobin (Mb) and its mutations are ideal systems to study the process of vibrational energy transfer (VET) at the molecular level. Anti-Stokes ultraviolet resonance Raman studies using a tryptophan (Trp) probe, introduced at different Mb positions by amino acid replacement, have suggested that the amount of VET depends on the position of the Trp probe relative to the heme group. Inspired by this experimental work, we explored the strength of noncovalent π interactions, as well as covalent interactions for both the axial and distal ligands bound to iron in aquomet-Mb with the local vibrational mode analysis (LMA), originally developed by Konkoli and Cremer. Two sets of noncovalent interactions were investigated: (1) the interaction between the water ligand and Trp rings and (2) the interaction between the Trp and the porphyrin rings of the heme group. We assessed the strength of these noncovalent interactions via a special local mode force constant. Various Trp-modified water-bound ferric Mb proteins in the ground state were studied (6 in total) using gas-phase and QM/MM calculations followed by LMA. Our results disclose that VET is indeed dependent on the position of the Trp probe relative to the heme group but also on the tautomeric nature of distal histidine. They provide new guidelines on how to assess noncovalent π interactions in proteins utilizing LMA and how to use these data to explore VET, and more generally protein dynamics and function.


Major operative trauma increases peripheral amino acid release during the steady-state infusion of total parenteral nutrition in man.
The effect of major operative trauma on skeletal muscle metabolism was examined in nine patients receiving a constant infusion of calories (1460 kcal/m2/day) and protein (75 gm of amino acids/m2/day) for 5 days before and 4 days after an operation. Compared with the preoperative state, 72 hours after the operation there was a significant rise in arterial levels of glucagon, cortisol, norepinephrine, and inactive triiodothyronine and a drop in concentrations of insulin, active triiodothyronine, and amino acids. Forearm blood flow increased, as well as the efflux from forearm muscle of lactate, taurine, serine, glycine, valine, methionine, isoleucine, leucine, phenylalanine, lysine, arginine, and total amino acid nitrogen (440%). This loss of muscle protein after trauma is associated with increased muscle proteolysis, as measured by increased urinary 3-methylhistidine excretion (83%), and accounts for increased nitrogen loss (54%) from the body. Increased activity of the sympathetic nervous system is manifested by increased levels of epinephrine and norepinephrine, a relative lack of insulin, and increased levels of glucagon. This hormonal milieu plays an important role in the production of hypoaminoacidemia, increased efflux of amino acids and lactate from muscle, and negative nitrogen balance observed in these traumatized patients.


Growth inhibitory activity of Ankaferd hemostat on primary melanoma cells and cell lines.
Ankaferd hemostat is the first topical hemostatic agent about the red blood cell-fibrinogen relations tested in the clinical trials. Ankaferd hemostat consists of standardized plant extracts including Alpinia officinarum, Glycyrrhiza glabra, Thymus vulgaris, Urtica dioica, and Vitis vinifera. The aim of this study was to determine the effect of Ankaferd hemostat on viability of melanoma cell lines. Dissimilar melanoma cell lines and primary cells were used in this study. These cells were treated with different concentrations of Ankaferd hemostat to assess the impact of different dosages of the drug. All cells treated with different concentrations were incubated for different time intervals. After the data had been obtained, one-tailed T-test was used to determine whether the Ankaferd hemostat would have any significant inhibitory impact on cell growth. We demonstrated in this study that cells treated with Ankaferd hemostat showed a significant decrease in cell viability compared to control groups. The cells showed different resistances against Ankaferd hemostat which depended on the dosage applied and the time treated cells had been incubated. We also demonstrated an inverse relationship between the concentration of the drug and the incubation time on one hand and the viability of the cells on the other hand, that is, increasing the concentration of the drug and the incubation time had a negative impact on cell viability. The findings in our study contribute to our knowledge about the anticancer impact of Ankaferd hemostat on different melanoma cells.


Understanding factors influencing home delivery in the context of user-fee abolition in Northern Ghana: Evidence from 2014 DHS.
User-fee exemption for skilled delivery services has been implemented in Ghana since 2003 as a way to address financial barriers to access. However, many women still deliver at home. Based on data from the 2014 Ghana Demographic and Health Survey, we estimated the prevalence of home delivery and determined the factors contributing to homebirths among a total of 622 women in the Northern region in the context of the user-fee exemption policy in Ghana. Binary and multivariate logistic regression analyses were employed. Results suggest home delivery prevalence of 59% (365/622). Traditional birth attendants attended majority of home deliveries (93.4%). After adjusting for potential confounders, making less than four antenatal care visits (aOR = 2.42; CI = 1.91-6.45; p = 0.001), being a practitioner of traditional African religion (aOR = 16.40; CI = 3.10-25.40; p = 0.000), being a Muslim (aOR 2.10; CI = 1.46-5.30; p = 0.042), not having a health insurance (aOR = 1.85; CI = 1.773-4.72; p = 0.016), living in a male-headed household (aOR = 2.07; CI = 1.02-4.53; p < 0.01), and being unexposed to media (aOR = 3.10; CI = 1.12-5.38; p = 0.021) significantly predicted home delivery. Our results suggest that unless interventions are implemented to address other health system factors like insurance coverage, and socio-cultural and religious beliefs that hinder uptake of skilled care, the full benefits of user-fee exemption may not be realized in Ghana.


Jamming and pattern formation in models of segregation.
We investigate the Schelling model of social segregation, formulated as an intrinsically nonequilibrium system, in which the agents occupy districts (or patches) rather than sites on a grid. We show that this allows the equations governing the dynamical behavior of the model to be derived. Analysis of these equations reveals a jamming transition in the regime of low-vacancy density, and inclusion of a spatial dimension in the model leads to a pattern forming instability. Both of these phenomena exhibit unusual characteristics which may be studied through our approach.


Vaginal birth after one previous caesarean section in a tertiary institution in Nigeria.
Vaginal birth after one previous lower segment caesarean section represents one of the most significant and challenging issues in obstetric practice. A 5-year retrospective study was carried out at the University of Benin Teaching Hospital between January 1999 and December 2003, to determine the incidence, the maternal and fetal outcome following vaginal delivery after one previous caesarean section with a view to evaluating its safety and efficacy. There were 5234 deliveries, with 395 cases of one previous caesarean section, giving an incidence of 7.5%. The incidences of emergency caesarean section, elective caesarean section and spontaneous vaginal delivery following trial of vaginal delivery were 34.7%, 9.4% and 48.1%, respectively. During the study period there were 1317 cases of caesarean section, giving an incidence of 25.2% caesarean section rate. The incidence of one previous section among all caesarean section births was 30%. The major morbidity following vaginal delivery was uterine rupture with an incidence of 1.5% and hysterectomy of 0.8%. Three of the uterine ruptures occurred before admission because the patients laboured at home. One maternal death occurred as a result of uterine rupture and postpartum haemorrhage, giving a maternal mortality ratio of 19/100,000 and a case fatality rate of 0.3%. The corrected perinatal mortality rate was 15.2/1000, mainly from obstructed labour, abruptio placenta and fetal distress. Both maternal and fetal mortalities from vaginal birth after one previous section were significantly less than the respective overall maternal and fetal mortality from the institution. The 1-minute apgar score of babies delivered by elective section was significantly (P < 0.001) higher than the apgar score of babies delivered by emergency section and vaginally. There was only one patient with wound dehiscence at elective section without associated perinatal death. Vaginal delivery following caesarean section is relatively safe. However, women in developing countries will continue to require counselling to counter the myths of aversion to operative delivery even at the expense of losing their lives. Our hospitals should have adequate monitoring equipment for high-risk pregnancies so that patients and their babies can be assured of survival.


An Explainable and Personalized Cognitive Reasoning Model Based on Knowledge Graph: Toward Decision Making for General Practice.
General practice plays a prominent role in primary health care (PHC). However, evidence has shown that the quality of PHC is still unsatisfactory, and the accuracy of clinical diagnosis and treatment must be improved in China. Decision making tools based on artificial intelligence can help general practitioners diagnose diseases, but most existing research is not sufficiently scalable and explainable. An explainable and personalized cognitive reasoning model based on knowledge graph (CRKG) proposed in this paper can provide personalized diagnosis, perform decision making in general practice, and simulate the mode of thinking of human beings utilizing patients' electronic health records (EHRs) and knowledge graph. Taking abdominal diseases as the application point, an abdominal disease knowledge graph is first constructed in a semiautomated manner. Then, the CRKG designed referring to dual process theory in cognitive science involves the update strategy of global graph representations and reasoning on a personal cognitive graph by adopting the idea of graph neural networks and attention mechanisms. For the diagnosis of diseases in general practice, the CRKG outperforms all the baselines with a precision@1 of 0.7873, recall@10 of 0.9020 and hits@10 of 0.9340. Additionally, the visualization of the reasoning process for each visit of a patient based on the knowledge graph enhances clinicians' comprehension and contributes to explainability. This study is of great importance for the exploration and application of decision making based on EHRs and knowledge graph.


A Secure and Smart Home Automation System with Speech Recognition and Power Measurement Capabilities.
The advancement in the internet of things (IoT) technologies has made it possible to control and monitor electronic devices at home with just the touch of a button. This has made people lead much more comfortable lifestyles. Elderly people and those with disabilities have especially benefited from voice-assisted home automation systems that allow them to control their devices with simple voice commands. However, the widespread use of cloud-based services in these systems, such as those offered by Google and Amazon, has made them vulnerable to cyber-attacks. To ensure the proper functioning of these systems, a stable internet connection and a secure environment free from cyber-attacks are required. However, the quality of the internet is often low in developing countries, which makes it difficult to access the services these systems offer. Additionally, the lack of localization in voice assistants prevents people from using voice-assisted home automation systems in these countries. To address these challenges, this research proposes an offline home automation system. Since the internet and cloud services are not required for an offline system, it can perform its essential functions, while ensuring protection against cyber-attacks and can provide quick responses. It offers additional features, such as power usage tracking and the optimization of linked devices.


RAPID AND REPEATED INVASIONS OF FRESH WATER BY THE COPEPOD EURYTEMORA AFFINIS.
Invasions of fresh water by marine organisms have been of great interest to evolutionary biologists and paleontologists because they typically constitute major evolutionary transitions. Recent (< 200 years) invasions of fresh water by brackish or marine species offer an opportunity to understand mechanisms underlying these events, but pathways of invasion from salt water have not been confirmed using genetic data. This study employed mitochondrial DNA sequences (652 base pairs from the cytochrome oxidase I (COI) gene) to reconstruct the geographic and evolutionary history of freshwater invasion by the common estuarine and saltmarsh crustacean Eurytemora affinis (Copepoda; Poppe 1880). Phylogenetic analysis of populations from North America, Europe, and Asia revealed at least eight independent invasions of fresh water from genetically distinct lineages. At least five of these freshwater invasions most likely arose independently in different river drainages, recently from saltwater sources within each river drainage. An analysis of molecular variance (AMOVA) was performed at three geographic scales (among continents, among drainages, and within drainages) to assess the hierarchical distribution of genetic variance. Results indicated that 52% of the genetic variance was explained by differences among drainages, 43% by differences among continents, but only 5% by differences within drainages, thus supporting geographic patterns of invasions inferred from the phylogeny. Physiological experiments were performed to determine whether adults and larvae from saltwater populations could tolerate freshwater conditions. Transfer to zero salinity resulted in high mortalities, but with some survival to the second generation in one population. This study provides genetic evidence and physiological support for rapid transitions from a saline life history into fresh water, with repeated invasions on a global scale.


The effects of heatwaves on hospital admissions in the Edirne province of Turkey: A cohort study.
Studies show that heat waves (HWs) are among the most important atmospheric phenomena that negatively affect human health. This study aims to determine the effects of HWs on hospital admissions (HA) in the Edirne province of Turkey. Polyclinic admission and atmospheric data, including daily maximum temperatures, were used. HW is defined as temperature at the % 90 threshold of daily maximum temperatures that persists for at least 3 consecutive days or more. With this definition, a 6-day HW was detected, and a lag of 3 days was added to this HW. Logarithmic Z test was used for the analysis. As a result of the study, The Risk Ratio (RR) showing the relationship between 9-day HW and HAs was calculated as 1.19 (95% confident interval [CI]: 1.17-1.21, P < .05), and it was determined that there were 2557 extra HAs in total. When HAs were analyzed according to sex, it was observed that female admissions were higher than male admissions. To analyze admissions by age, the data were divided into 3 groups: children (<15 years), adult (15-64 years), and elderly (≥65 years). As a result of the analysis, the highest increase was observed in patients < 15 years of age, and the RR was 1.33 (95% CI: 1.24-1.42 P < .05). When the patient density in polyclinics was analyzed, the Cardiology polyclinic had the highest number of patient admissions with an RR, 1.36 (95% CI: 1.30-1.43 P < .05). The results of this study will guide measures to be taken against HWs.


Higher order language competence and adolescent mental health.
Clinic and community-based epidemiological studies have shown an association between child psychopathology and language impairment. The demands on language for social and academic adjustment shift dramatically during adolescence and the ability to understand the nonliteral meaning in language represented by higher order language becomes essential. : This article reports on the association between difficulties in higher order language skills, reading, cognition, and social-emotional adjustment in adolescents. : 144 clinic-referred and 186 comparison youth aged 12-18 years were administered a battery of standardized tests of intelligence, working memory, structural and higher order language, and reading achievement. Parent ratings on the Child Behavior Checklist were used as a measure of severity of social-emotional problems. : Clinic-referred youth scored significantly lower than comparison youth on measures of structural and higher order language, working memory, and reading. Of the clinic-referred youth, 45% had some type of higher order language impairment, whereas this was the case for 15% of youth in the comparison group. Lower levels of nonverbal ability and working memory as well as lower level of mothers' education were associated with greater risk of having higher order language impairment. : Findings have implications for practitioners' seeking to understand and treat adolescents since therapeutic techniques rely on skills where higher order language is at play including the ability to discuss opinions flexibly and to weigh interpretations. Therapists must be aware that there are areas that have potential for miscommunication with some adolescents and where inaccurate inferences may be made about their behavior. Furthermore, educators must consider resources for youth who may increasingly struggle in high school because of such difficulties.


Medical Modeling for Precision Ulna Reconstruction Using a Microvascular Fibula Free Flap.
Despite the growing use of medical modeling in other surgical specialties, its utilization in extremity reconstruction has remained limited. We present the application of medical modeling for ulna reconstruction using a microvascular fibula free flap. Following a motor vehicle accident, the patient suffered segmental loss of the right radius and ulna with concomitant forearm soft tissue and muscle loss. Using medical modeling, imaging from the unaffected contralateral forearm and lower extremity was used to plan a reconstruction that restored the anatomic length and orientation of the ulna. Accurate ulna length was recreated from the contralateral ulna, which served as a template. Cutting guides for the osteotomies on both the fibula and ulna maximized surface contact at the native ulna and fibula junction to aid in osseous healing of the fibula flap, stabilized the fibula orientation on the ulna, and allowed for lag screw placement for additional fixation.


Structural modifications of interleukin-2 at positions 47 and 65.
Interleukin-2 (IL-2) is a cytokine essential for the growth and proliferation of T-cells. The purpose of this research was to study the effects of altering the "kink" caused by Pro in an alpha-helix of the protein. The Pro-47 residue was chosen because it was originally, but mistakenly, traced to the kink of an alpha-helix [1]. Pro-65 is now recognized to be situated in the middle of helix B [2]. To study the significance of this Pro for the bioactivity and overall conformation of IL-2 it was mutated to Gly and Ala. We successfully obtained 17 different mutants at position 47 and two mutants at position 65. Certain amino acid substitutions representing different categories of amino acids, namely, acidic, neutral and helix stabilizing, were chosen for more thorough investigation. The results showed that Asn-47 and Asp-47 decreased the bioactivity of these mutants by 50- and 700-fold respectively, while the Kd to its high affinity receptors was increased 180- and 90-fold respectively, compared to IL-2. The intermediate binding affinity of Asn-47 and Asp-47 was decreased 8- and 37-fold, respectively. On the other hand, Gly-47, Gly-65 and Ala-65 showed less dramatic decreases in bioactivity and high affinity binding. The intermediate binding affinity of these mutants decreased from 5- to 3-fold and low affinity binding decreased approximately 4-fold suggesting some structural and conformational changes. From these observations, we conclude that Asn-47 or Asp-47 disrupt the hydrophobic packing of the core and thus changed the overall conformation of the protein, thereby giving rise to partial agonists. Although Pro-65 lies within the helix, it may be near the surface of the protein but may not be the actual binding site and thus any conservative mutation can be better tolerated.


Contrasting roles for axonal degeneration in an autoimmune versus viral model of multiple sclerosis: When can axonal injury be beneficial?
Although demyelination is a cardinal feature in multiple sclerosis, axonal injury also occurs. We tested whether a delay in axonal degeneration could affect the disease severity in two models for multiple sclerosis: experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus (TMEV) infection. We compared wild-type C57BL/6 (B6) mice with C57BL/Wld(s) (Wld) mice, which carry a mutation that delays axonal degeneration. In EAE, both mouse strains were sensitized with myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide and showed a similar disease onset, MOG-specific lymphoproliferative responses, and inflammation during the acute stage of EAE. However, during the chronic stage, B6 mice continued to show paralysis with a greater extent of axonal damage, demyelination, and MOG-specific lymphoproliferative responses compared with Wld mice, which showed complete recovery. In TMEV infection, only Wld mice were paralyzed and had increased inflammation, virus antigen-positive cells, and TMEV-specific lymphoproliferative responses versus infected B6 mice. Because TMEV can use axons to disseminate in the brain, axonal degeneration in B6 mice might be a beneficial mechanism that limits the virus spread, whereas slow axonal degeneration in Wld mice could favor virus spread. Therefore, axonal degeneration plays contrasting roles (beneficial versus detrimental) depending on the initiator driving the disease.


[Human Primordial Germ Cell Specification--Breakthrough In Culture and Hopes for Therapeutic Utilization].
Germ cells are the precursors to the gametes that carry genetic and epigenetic information between human generations and generate a new individual. Because germ cells are specified early during embryogenesis, at the time of embryo implantation, they are inaccessible for research. Our understanding of their biology has therefore developed slowly since their identification over one hundred years ago. As a result of research into the properties of human and mouse embryonic stem cells and primordial germ cells, scientists have now succeeded in efficiently generating human primordial germ cells in culture by embryonic stem cell and induced pluripotent stem cell culture. In this review we will discuss the state of our knowledge of human primordial germ cells and how research into the pluripotent properties of human and mouse embryonic germ cells has led to this breakthrough. In addition we will discuss the possible utilization of a cell culture system of human primordial germ cells for research into and treatment of germ cell related abnormalities.


Low-temperature growth of uniform ZnO particles with controllable ellipsoidal morphologies and characteristic luminescence patterns.
Uniform ellipsoidal ZnO particles have been synthesized in an aqueous solution in the presence of triethonalamine (TEA) mediated by sonication at the temperature below 80 degrees C. Scanning electron microscopy observations reveal that the ellipsoidal particles are highly uniform with a hexagonal cross-section. The morphologies of the ZnO particles can be systematically controlled from elongated rugby ball-like ellipsoidal to half-ellipsoidal by increasing the TEA concentration. Spatial resolved cathodoluminescence measurements at room temperature show that the ellipsoidal ZnO particles are intrinsically encoded with barcode-like ultraviolet luminescence patterns, which are of either a wide stripe or a narrow stripe perpendicular to the length at the core of the particles depending on the growth temperature. Moreover, the luminescence spectra of the ellipsoidal particles can be tuned by heat treatments at elevated temperatures, while maintaining the luminescence patterns. We believe that the well-defined uniform ellipsoidal ZnO particles embedded with unique luminescence characteristics hold great potential for use in bioengineering and photonics, such as biological labeling and optical probes.


B cell responses to paramyosin. Isotypic analysis and epitope mapping of filarial paramyosin in patients with onchocerciasis.
To examine the fine specificity of the human immune response to filarial paramyosin, the antigenicity of an expressed rcDNA (2.55 kb) of Dirofilaria immitis paramyosin was detailed by ELISA. Using sera from patients infected with Onchocerca volvulus, we analyzed both the entire paramyosin molecule and six subcloned fragments for their IgG, IgG subclasses, and IgE responses. Patients from both Guatemala (64% positive) and Ghana (100% positive) reacted to paramyosin with specific IgG levels above normal controls. Although there was no anti-paramyosin subclass restriction common to all patients, the IgG3 response in the Ghananians was significantly greater than that of Guatemalans (p less than 0.001). IgE anti-paramyosin responses showed positive correlations with IgG2 (p less than 0.001), IgG4 (p less than 0.002), and IgG1 (p less than 0.04) responses. Epitope mapping using the IgG response to the six subclones demonstrated preferential recognition of the amino terminal end of the molecule (nucleotides 1 to 360). IgG2 reactivity was clearly localized to the most amino-terminal 120 amino acids, and the IgG4 antibodies recognized amino acids immediately adjacent to this fragment. These studies examining the fine specificity of anti-filarial immune reactions should provide a method for understanding how parasites either evade or induce host immune responses.


Airway reconstruction in children.
Airway anomalies are infrequent but potentially life threatening in children. A program to care for these difficult children was set up at our institution, and this paper summarizes our experience. A total of 34 children were enrolled in the program over a period of three years. These children were evaluated as per the standard protocols. Treatment was individualized. Of these 34 children, 28 had their airways restored and are doing well. Four children continue to remain on tracheostomy and two will require long term tracheostomy. There were two deaths. All children are under surveillance as there is a risk of recurrence. Airway anomalies are complex problems with significant morbidity and mortality. Current therapeutic modalities allow for good results. Most children were successfully decannulated and did well.


Multi-step microfluidic polymerization reactions conducted in droplets: the internal trigger approach.
We report the application of the "internal trigger" approach to multistep microfluidic polymerization reactions conducted in droplets, namely, polyaddition and polycondensation. We hypothesized and experimentally established that heat generated in an exothermic free radical polymerization of an acrylate monomer (Reaction 1) triggers the polycondensation of the urethane oligomer (Reaction 2). Completion of two microfluidic polymerization reactions led to the continuous synthesis of polymer particles with an interpenetrating polymer network (IPN) structure. Use of this microfluidic synthesis allowed us (i) to conduct efficient screening of the compositions of the monomer mixtures; (ii) to achieve control of the stoichiometric ratios of reactants in Reaction 2 by varying the flow rates of liquids; (iii) to reach control over the morphology of the resulting particles; and (iv) to produce polymer particles with a narrow size distribution and a predetermined size.


An evaluation and comparison of myeloperoxidase enzymatic activity during initial orthodontic alignment: an in vivo study.
Tooth movement during orthodontic treatment is possible because of mechanical force-induced inflammation and remodelling in the periodontal ligament. Variation in the inflammatory response might be anticipated with initial aligning archwires of different composition. Myloperoxidase (MPO) is an enzyme found in neutrophil granules that represents an important marker of inflammation. The aim of this study was to measure MPO enzyme activity during initial alignment with orthodontic arch wires of different alloy types. MPO activity was determined in gingival crevicular fluid (GCF) from a sample of 60 patients divided into three groups during initial orthodontic alignment with three types of arch wire (0.016-inch superelastic (SE) NiTi; 0.016-inch heat-activated (HANT) NiTi and 0.00175-inch multistranded stainless steel). MPO activity was measured at baseline, 2 hours, 7 and 14 days after appliance activation. MPO activity was significantly increased in GCF at 2 hours (P < 0.01), 7 and 14 days in all groups compared to baseline. Enzymatic activity was highest in the SE NiTi group followed by HANT and multistranded stainless steel groups but with no significant difference between SE NiTi and HANT groups. SE and HANT NiTi arch wires produce an increased inflammatory response based upon MPO activity during initial levelling and alignment compared to multistranded stainless steel.


Intraerythrocytic inclusions associated with iridoviral infection in a fer de lance (Bothrops moojeni) snake.
Intraerythrocytic inclusions associated with infection by an iridovirus were observed in a fer de lance (Bothrops moojeni) snake that was being evaluated for the presence of renal carcinoma. The erythrocytes contained two types of inclusions, one viral and one crystalline, usually concomitantly. The snake was markedly anemic and exhibited a marked regenerative response. Ultrastructural analysis identified the virus to be an iridovirus consistent with snake erythrocyte virus and the crystalline structures to be of a different nature than hemoglobin.


Protective effect of diallyl disulfide on cyclophosphamide-induced testicular toxicity in rats.
This study investigated the protective effects of diallyl disulfide (DADS) against cyclophosphamide (CP)-induced testicular toxicity in male rats. DADS was gavaged to rats once daily for 3 days at 100 mg/kg/day. One hour after the final DADS treatment, the rats were given a single intraperitoneal dose of 150 mg/kg CP. All rats were killed and necropsied on day 56 after CP treatment. Parameters of testicular toxicity included reproductive organ weight, testicular sperm head count, epididymal sperm motility and morphology, epididymal index, and histopathologic examinations. The CP treatment caused a decrease in body weight, testicular sperm head count, epididymal sperm motility, and epididymal index. The histopathological examination revealed various morphological alterations, characterized by degeneration of spermatogonia/spermatocytes, vacuolization, and decreased number of spermatids/spermatocytes in the testis, and cell debris and mild oligospermia in the ductus epididymis. In contrast, DADS pretreatment effectively attenuated the testicular toxicity caused by CP, including decreased sperm head count, epididymal sperm motility, and epididymal index and increased histopathological alterations in the testis and epididymis. These results indicate that DADS attenuates testicular toxicity induced by CP in rats.


Reproduction and embryonic diapause in a marsupial: insights from captive female Honey possums, Tarsipes rostratus (Tarsipedidae).
The reproductive physiology of the polyoestrous Honey possum (Tarsipes rostratus) is virtually unknown except that it shares with the kangaroos and wallabies the phenomenon of embryonic diapause. Its tiny size necessitates an alternate approach to study their reproductive cycle. We have accordingly utilised faecal steroid analysis. Baseline faecal cortisol levels in the Honey possum, at 4.1+/-0.3 mug g-1, are approximately 100-fold those of other mammals and are associated with adrenal glands that, on a mass-specific basis, are almost 10 times larger than the adrenals of other mammalian, including marsupial, species. Histological examination of the adrenal glands revealed no abnormalities, however, but their hypertrophy and the peaks recorded in faecal levels following disturbance suggest that the Honey possum is vulnerable to chronic stressors in the captive situation. Mean faecal progestagens (124.4+/-107.3 ng g-1) and oestradiol-17beta (4.1+/-1.1 ng g-1) in 4 non-pregnant females maintained long term were not different from those of 5 pregnant females (101.4+/-61.0 ng g-1 and 4.3+/-1.5 ng g-1, respectively) and, on analysis, revealed a cyclicity of 24+/-1.2 days. We would predict from this evidence that the gestation period, in the absence of lactation, is approximately 23 days. Four of the pregnant females, monitored from July to November under conditions of 10:14 L:D photoperiod, showed a fall in levels of progestagens from 175.9+/-10.8 ng g-1 in July and August to 30.9+/-9.4 ng g-1 in October, while mean faecal levels of oestradiol-17beta increased from 3.8+/-0.4 ng g-1 in July to 5.7+/-0.3 ng g-1 in October. September and October are months of peak reproductive activity in the wild and we suggest that these hormonal modulations may represent an entrained reproductive rhythm. Blastocysts appear to develop at varying rates, both within the one uterus, and between the two uteri of a single female. In addition, the time taken to reach the blastocyst stage may be longer than in any other marsupial studied to date. An association of the age of the pouch young with the stage reached by the developing blastocyst does not support the conclusion that blastocysts, once formed, grow slowly during lactation or diapause. Contrary to previous reports, we have documented what appears to be a lactational inhibition on blastocysts in diapause and have estimated the length of the 'delayed' reproductive cycle in two females as less than 2 weeks. Reactivation of blastocysts in Tarsipes has been shown to be stimulated by shortening day lengths after the summer solstice, a response similar to the annual breeding period of macropodid marsupials. Results from studying Honey possums in captive conditions suggest that the control of diapause in Tarsipes appears to be three-fold; lactational, photoperiodic and an entrained rhythm.


[Current concepts of the role of the thymol test in the laboratory diagnosis of viral hepatitis A].
Current notions on the role of the thymol test (TT) in the diagnosis of viral hepatitis A are discussed. Changes in TT results over the course of the disease are presented, starting from the incubation period up to the second-third week; these values are compared to those of hepatitis A specific markers. The earliest TT shifts in hepatitis A are detectable already 15-18 days before the first clinical manifestations, when this parameter surpasses the upper threshold of the range of normal values. The incubation period TT values are 6.9-8.4 U S-H, those during the 3 weeks of the acute period are 9.1-9.7 U S-H. This test earlier reacts to liver inflammation than alanine aminotransferase (a hepatic enzyme) measurement, which fact recommends TT for active early detection of hepatitis A patients in epidemic foci in collective bodies. One more TT advantage over the detection of hepatitis A specific markers in epidemic foci is that it permits the diagnosis of hepatitis whatever its etiology.


Antiapoptotic protein partners fortilin and MCL1 independently protect cells from 5-fluorouracil-induced cytotoxicity.
Fortilin, a potent 172-amino acid antiapoptotic polypeptide (Li, F., Zhang, D., and Fujise, K. (2001) J. Biol. Chem. 276, 47542-47549), binds MCL1, a protein of the antiapoptotic Bcl-2 family. The fortilin-MCL1 interaction stabilizes and increases the half-life of fortilin but not necessarily of MCL1 (Zhang, D., Li, F., Weidner, D., Mnjoyan, Z. H., and Fujise, K. (2002) J. Biol. Chem. 277, 37430-37438). It is not known to what extent each protein depends on the other for its apoptotic activity. Here, we present evidence that fortilin and MCL1 are capable of functioning as antiapoptotic proteins independently of each other. Using a robust small interfering RNA (siRNA)-mediated gene silencing system developed in our laboratory, we analyzed the cytoprotective effects of fortilin and MCL1 together and apart in U2OS cell lines exposed to 5-fluorouracil (5-FU) in both monoclonal and polyclonal cell populations. When MCL1 was silenced by MCL1-targeted siRNA, fortilin was still able to protect cells from 5-FU-induced cytotoxicity in a dose-dependent manner. Conversely, when fortilin was silenced by fortilin-targeted siRNA, MCL1 was also able to protect cells from 5-FU-induced cytotoxicity in a dose-dependent manner. Together, these data clearly suggest that fortilin and MCL1 can exert their cytoprotective activities independently of each other. The silencing of fortilin and MCL1 did not qualitatively change the subcellular localization of MCL1 and fortilin, respectively. The biological significance of fortilin-MCL1 interaction may be that it increases cellular resistance to apoptosis by allowing MCL1, an independently antiapoptotic protein, to stabilize another independently antiapoptotic protein, fortilin.


Evolution of initiation rites during the Austronesian dispersal.
As adaptive systems, kinship and its accompanying rules have co-evolved with elements of complex societies, including wealth inheritance, subsistence, and power relations. Here we consider an aspect of kinship evolution in the Austronesian dispersal that began from about 5500 BP in Taiwan, reaching Melanesia about 3200 BP, and dispersing into Micronesia by 1500 BP. Previous, foundational work has used phylogenetic comparative methods and ethnolinguistic information to infer matrilocal residence in proto-Austronesian societies. Here we apply Bayesian phylogenetic analyses to a data set on Austronesian societies that combines existing data on marital residence systems with a new set of ethnographic data, introduced here, on initiation rites. Transition likelihoods between cultural-trait combinations were modeled on an ensemble of 1000 possible Austronesian language trees, using Reversible Jump Markov Chain Monte Carlo (RJ-MCMC) simulations. Compared against a baseline phylogenetic model of independent evolution, a phylogenetic model of correlated evolution between female and male initiation rites is substantially more likely (log Bayes factor: 17.9). This indicates, over the generations of Austronesian dispersal, initiation rites were culturally stable when both female and male rites were in the same state (both present or both absent), yet relatively unstable for female-only rites. The results indicate correlated phylogeographic evolution of cultural initiation rites in the prehistoric dispersal of Austronesian societies across the Pacific. Once acquired, male initiation rites were more resilient than female-only rites among Austronesian societies.


[Multifocal glioma. Apropos of 10 cases].
The authors report 10 cases of multifocal glioma of the brain. There are distinguished in multicentric tumors, when lesions develop independently in the space and time and multiples tumors when they are in connection by spreading process. They analyzed the factors that could permit to distinguish these gliomas. Multicentric tumors are histologically of low grade with gradual evolution, and from different histological nature and topography. In other hand, multiple gliomas are from malignant histology and develop simultaneously. The CT scan and biopsy in stereotaxic condition could permit to recognize these two parts which the prognosis is different.


A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels.
The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited to the comparisons among known binding sites, and do not consider several additional important 3D patterns such as allosteric sites or other conserved motifs. In the present work, we introduce Geomfinder2.0, which is a new and improved version of our previously described algorithm for the deep exploration and discovery of similar and druggable 3D patterns. As compared with the original version, substantial improvements that have been incorporated to our software allow: (i) to compare quaternary structures, (ii) to deal with a list of pairs of structures, (iii) to know how druggable is the zone where similar 3D patterns are detected and (iv) to significantly reduce the execution time. Thus, the new algorithm achieves up to 353x speedup as compared to the previous sequential version, allowing the exploration of a significant number of quaternary structures in a reasonable time. In order to illustrate the potential of the updated Geomfinder version, we show a case of use in which similar 3D patterns were detected in the cardiac ions channels NaV1.5 and TASK-1. These channels are quite different in terms of structure, sequence and function and both have been regarded as important targets for drugs aimed at treating atrial fibrillation. Finally, we describe the in vitro effects of tafluprost (a drug currently used to treat glaucoma, which was identified as a novel putative ligand of NaV1.5 and TASK-1) upon both ion channels' activity and discuss its possible repositioning as a novel antiarrhythmic drug.


Relationships between hydrogen bonds and halogen bonds in biological systems.
The recent recognition that halogen bonding (XB) plays important roles in the recognition and assembly of biological molecules has led to new approaches in medicinal chemistry and biomolecular engineering. When designing XBs into strategies for rational drug design or into a biomolecule to affect its structure and function, we must consider the relationship between this interaction and the more ubiquitous hydrogen bond (HB). In this review, we explore these relationships by asking whether and how XBs can replace, compete against or behave independently of HBs in various biological systems. The complex relationships between the two interactions inform us of the challenges we face in fully utilizing XBs to control the affinity and recognition of inhibitors against their therapeutic targets, and to control the structure and function of proteins, nucleic acids and other biomolecular scaffolds.


On defining the rules for interactions between the T cell receptor and its ligand: a critical role for a specific amino acid residue of the T cell receptor beta chain.
The specificity of T cell-mediated immune responses is primarily determined by the interaction between the T cell receptor (TCR) and the antigenic peptide presented by the major histocompatibility complex (MHC) molecules. To refine our understanding of interactions between the TCR and the antigenic peptide of vesicular stomatitis virus (VSV) presented by the class I MHC molecule H-2Kb, we constructed a TCR alpha chain transgenic mouse in a TCR alpha-deficient background to define specific structural features in the TCR beta chain that are important for the recognition of the VSV/H-2Kb complex. We found that for a given peptide, a peptide-specific, highly conserved amino acid could always be identified at position 98 of the complementarity-determining region 3 (CDR3) loop of TCR beta chains. Further, we demonstrated that substitutions at position 6, but not position 1, of the VSV peptide induced compensatory changes in the TCR in both the amino acid residue at position 98 and the length of the CDR3beta loop. We conclude that the amino acid residue at position 98 of the CDR3beta loop is a key residue that plays a critical role in determining the specificity of TCR-VSV/H-2Kb interactions and that a specific length of the CDR3beta loop is required to facilitate such interactions. Further, these findings suggest that the alpha and beta chains of TCRs interact with amino acid residue(s) toward the N and C termini of the VSV peptide, respectively, providing functional evidence for the orientation of a TCR with its peptide/MHC ligand as observed in the crystal structures of TCR/peptide/MHC complexes.


Hepatic adenosine in rats fed ethanol: effect of acute hyperoxia or hypoxia.
The level of adenosine was measured in monthly biopsied livers from rats fed ethanol and a high fat/low protein diet in order to test a hypothesis that hepatic adenosine is increased due to enhanced breakdown of adenine nucleotides in which ATP and total adenylate pool were decreased by chronic ethanol feeding. The ethanol-fed rats showed a significantly higher average level of adenosine compared to the pair-fed controls. When investigated monthly, however, adenosine in ethanol-fed rats increased only after the decrease in ATP had stabilized and AMP remained unchanged, indicating that these changes were not temporarily related. The average percentage of change in adenosine after acute hyperoxia or hypoxia were variable both in ethanol-fed and pair-fed rats. There was a tendency for a positive correlation between the percentage of change of adenosine and AMP after hyperoxia regardless of ethanol feeding. A negative correlation between the percentage of change of adenosine and energy charge, and a positive correlation between the percentage of change of adenosine and AMP were seen after hypoxia regardless of ethanol feeding. Adenosine levels changed rapidly in response to changes in systemic of pO2 in both the ethanol-fed and control rats, indicating that the liver maintained its normal response to the changes in energy state. The results indicate that chronic ethanol feeding does increase the level of adenosine in the liver and that this level remains responsive to acute changes in pO2.(ABSTRACT TRUNCATED AT 250 WORDS)


Acute bilateral basal ganglia lesions in patients with diabetic uremia: an FDG-PET study.
Head CT and MRI show characteristic changes in the syndrome of acute bilateral basal ganglia lesions in patients with diabetic uremia. However, they do not provide further insight into the underlying pathophysiology. To further clarify the biologic mechanism of the syndrome, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) was used in 2 patients. PET studies were performed in 2 diabetic uremic patients with acute movement disorders. The cerebral glucose metabolic rates in these 2 patients were compared with 11 normal age-matched controls. The images were further analyzed with statistical parametric mapping to identify regions of significant metabolic abnormality. The cases showed markedly reduced glucose metabolism in the bilateral basal ganglia, especially in the bilateral putamens, where the glucose uptake was nearly absent. FDG-PET correlates better with the clinical conditions and provides more pathophysiological information than head CT or MRI scans in bilateral basal ganglia lesions in patients with diabetic uremia. We propose that acute exacerbation of a long-term glucose utilization failure in the basal ganglia cells produced these lesions.


Ethnic identity and the daily psychological well-being of adolescents from Mexican and Chinese backgrounds.
Protective effects of ethnic identity on daily psychological well-being were examined in a sample of 415 ninth graders from Mexican and Chinese backgrounds. Utilizing daily diary assessments and multilevel modeling, adolescents with a greater regard for their ethnic group exhibited greater levels of daily happiness and less daily anxiety averaged over the 2-week study period. Ethnic regard moderated the daily association between normative stressful demands and happiness, and between stressful demands and happiness experienced 1 day after stressors occurred. Moderating effects were significant even after controlling for self-esteem. Although no buffering effects of ethnic centrality were found, the results point to the positive influence of ethnic regard in the daily lives of adolescents from ethnic minority backgrounds.


Neutrophil expansion defines an immunoinhibitory peripheral and intratumoral inflammatory milieu in resected non-small cell lung cancer: a descriptive analysis of a prospectively immunoprofiled cohort.
The biological underpinnings of the prognostic and predictive significance of a relative neutrophilia in patients with non-small lung cancer (NSCLC) are undefined. We sought to comprehensively examine the relationships between circulating and intratumoral neutrophil populations and features of the immune contexture in patients undergoing NSCLC resection. Preoperative soluble cytokine and angiogenic factors; tumor multiplex immunofluorescence; RNA, whole exome, and T-cell receptor sequencing; and flow cytometry were analyzed for relationships with populations of circulating (from complete blood counts) and intratumoral neutrophils (transcriptional signatures) in a prospectively enrolled resected NSCLC cohort (n=66). In a historical cohort (n=1524), preoperative circulating neutrophil and lymphocyte counts were analyzed for associations with overall survival (OS). Circulating neutrophil populations were positively correlated with increased tumor burden, and surgical tumor resection was followed by a subsequent reduction in peripheral neutrophil counts. Expansion of the circulating neutrophil compartment was associated with increased levels of pro-granulopoietic (IL-1β, IL-17A, TNFα, IL-6) and TH2-associated (IL-5, IL-13) cytokines. Tumors with high intratumoral neutrophil burden were marked by a blunted T-cell response characterized by reduced expression of cytotoxic T-cell genes (CD8A, CD8B, GZMA, GZMB), decreased CD3+CD8+ cell infiltration, and diminished expression of IFNγ-related genes. The associations between increased intratumoral neutrophil burden and reduced CD3+CD8+ infiltration persisted after adjustment for tumor size, histology, mutational burden, and PD-L1 expression. In 1524 patients, elevated preoperative circulating neutrophil count was independently associated with worse OS (main effect HR 1.82, 95% CI 1.24 to 2.68, p=0.002). Our findings demonstrate that neutrophil expansion reflects protumorigenic and immunosuppressive processes that manifest as worse OS in patients undergoing NSCLC resection. These results justify further investigation of therapeutic strategies targeting neutrophil-associated immune evasion.


The promoter of miR-663 is hypermethylated in Chinese pediatric acute myeloid leukemia (AML).
There is growing evidence supporting a role for microRNAs (miRNA) as targets in aberrant mechanisms of DNA hypermethylation. Epigenetic silencing of tumor suppressor miRNAs, including miR-663, which has recently been reported to be inactivated by hypermethylation in several cancers, may play important roles in pediatric acute myeloid leukemia (AML). However, expression of miR-663 and its promoter methylation remain status unclear in childhood leukemia. Promoter methylation status of miR-663 was investigated by methylation specific PCR (MSP) and bisulfate genomic sequencing (BGS). Transcriptional expression of miR-663 was evaluated by semi-quantitative and real-time PCR, and the relationship between expression of miR-663 and promoter methylation was confirmed using 5-aza-2'-deoxycytidine (5-Aza) demethylation reagent. MiR-663 was aberrantly methylated in 45.5% (5/11) leukemia cell lines; BGS showed that the promoter was significantly methylated in three AML cell lines; methylation of miR-663 was significantly higher in Chinese pediatric AML patients [41.4% (29/70)] compared to normal bone marrow (NBM) control samples [10.0% (3/30)]. These results were confirmed by both BGS and 5-Aza demethylation analysis. In addition, miR-663 transcript expression was significantly lower in AML patients, both with and without miR-663 methylation, compared to controls; however, there were no significant differences in clinical features or French-American-British (FAB) classification between patients with and without miR-663 methylation. Expression of miR-663 was significantly lower in pediatric AML cells compared to NBM controls; furthermore, a high frequency of miR-663 promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Inactivation of miR-663 by promoter hypermethylation could be affected by 5-Aza demethylation. These findings suggest that hypermethylation of the miR-663 promoter may be an early event in the development of pediatric AML.


Laparoscopic and percutaneous ablative techniques in the treatment of renal cell carcinoma.
Widespread use of computed tomography, ultrasound, and magnetic resonance imaging has led to an increase in detection of relatively small renal masses, and approaches to managing them have evolved in the last two decades. Indications for nephron-sparing surgery have expanded, and minimally invasive procedures, which can confer advantages over open surgery, are now available. Ablative techniques offer a combination of nephron-sparing and minimally invasive approaches. Ablative techniques include cryoablation, radiofrequency ablation (RFA), and high-intensity focused ultrasound (HIFU). Cryoablation and RFA have been relatively safe. HIFU has been associated with serious side effects in animal models, and is not yet acceptable for use in humans. Ablative techniques require long-term studies to confirm lasting efficacy. The best modality for tumor targeting, monitoring of therapy, and follow-up is still under investigation. Debate exists regarding the best method for ensuring adequate intraoperative tumor cryoablation. For minimally invasive ablative measures to gain a place as nephron-sparing approaches, they should show both equivalent efficacy and reduced morbidity relative to those of open partial nephrectomy. These techniques should currently be reserved for selected patients and should be compared to the evolving modality of laparoscopic partial nephrectomy.


[Treatment by drawing lots in a therapeutic trial with a balance distribution of prognostic factors: the minimization method].
In a controlled clinical trial, a more powerful design can be obtained by balancing the treatment groups for the main prognostic factors rather than ignoring these factors in the randomization. The method of random permuted blocks within strata becomes inadequate as the number of prognostic factors increases. Another method known as minimization is described, which balances the marginal distribution of prognostic factors; it was proposed by Taves, and generalized by Pocock and Simon. It avoids the problems arising from an imbalance in a major prognostic factor.


An intraluminal transducer/telemetry system for oviductal motility studies.
A method for measurement of changes in lumen diameter of the oviduct has been developed. Miniature intraluminal "doughnut-shaped" transducers, 1.0-1.2 mm in diameter, constructed from conductive silicone rubber are implanted in the rabbit isthmus and respond to localized changes--increases or decreases--in lumen diameter. Multiple transducer implants in the same tube permit rate as well as direction of contractions to be determined. A custom-designed, micropower dual-channel telemetry system was fabricated to record motility from unrestrained animals. Typical data collected using this system to determine the effects of induced ovulation on instantaneous changes in lumen diameter are presented.


Quadruplet Heterotopic Pregnancy Following In Vitro Fertilization and Embryo Transfer with Laparotomic Removal of Ruptured Twin Tubal Ectopic Pregnancy: A Case Report.
Heterotopic pregnancy (HP) is a rare occurrence in natural pregnancies. However, it can be a life-threatening condition and should be taken into account in all assisted reproductive treatments. Diagnosis and treatment of ectopic pregnancy are challenging issues in patients with HP. Here, we report a rare case of quadruplet HP following an in vitro fertilization-embryo transfer with a viable twin intrauterine pregnancy and ruptured live twin left tubal ectopic pregnancy. A 35-year-old woman (gravida 5, para 1, ectopic pregnancies 2, and abortion 1) was presented to the Emergency Department of Arash Women's Hospital (Tehran, Iran) in March 2021 with abdominal pain. The patient was at six weeks and five days of pregnancy following in vitro fertilization-embryo transfer. Transvaginal sonography (TVS) revealed a live twin intrauterine pregnancy with a ruptured live twin left tubal ectopic pregnancy. The latter was removed via laparotomy to preserve the intrauterine pregnancy. The patient subsequently delivered a female infant at 38 weeks of pregnancy.


Subclinical Systolic and Diastolic Dysfunction Is Evident in Youth With Elevated Blood Pressure.
Hypertension is associated with cardiovascular events in adults. Subclinical changes to left ventricular strain and diastolic function have been found before development of decreased left ventricular ejection fraction and cardiovascular events. Our objective was to study effects of blood pressure (BP) on ventricular function in youth across the BP spectrum. Vital signs and labs were obtained in 346 participants aged 11 to 19 years who had BP categorized as low-risk (N=144; systolic BP <75th percentile), mid-risk (N=83; systolic BP ≥80th and <90th percentile), and high-risk (N=119; systolic BP ≥90th percentile). Echocardiography was performed to assess left ventricular strain and diastolic function. Differences between groups were analyzed by ANOVA. General linear models were constructed to determine independent predictors of systolic and diastolic function. Mid-risk and high-risk participants had greater adiposity and more adverse metabolic labs (lower HDL [high-density lipoprotein], higher glucose, and higher insulin) than the low-risk group. Mid-risk and high-risk participants had significantly lower left ventricular ejection fraction and peak global longitudinal strain than the low-risk group (both P≤0.05). The E/e' ratio was higher in the high-risk group versus the low-risk and mid-risk groups, and the e'/a' ratio was lower in the high-risk versus the low-risk group (both P≤0.05). BP and adiposity were statistically significant determinants of left ventricular systolic and diastolic function. Subclinical changes in left ventricular systolic and diastolic function can be detected even at BP levels below the hypertensive range as currently defined.


Rehabilitation of patients with spondyloarthritis: a narrative review.
Nonpharmacological interventions are one of the mainstreams of treatment for patients with spondyloarthritis (SpA). They include education, measures regarding joint protection, posture and rest, therapeutic exercise, physical therapy modalities, orthoses, and acupuncture. A key component in the rehabilitation of patients with SpA entities is therapeutic exercise, which can be performed as land-based or water-based. Positive effects of the exercises are manifested in reducing pain, maintaining mobility, improving posture, increasing aerobic capacity and improving quality of life. The best effects can be obtained when exercise is performed under the supervision of a physiotherapist at a health institution. The majority of studies on therapeutic exercise in SpA are related to ankylosing spondylitis (AS), while there is a paucity of studies devoted to other conditions. Although progress has been made in the quantity and quality of research on this topic, there are still issues regarding the quality of studies and considerable variability among them, which makes it difficult to compare different methods and harmonize and develop rehabilitation protocols according to evidence-based medicine.


Involvement of insulin-like growth factor-binding protein-related protein 1 in decidualization of human endometrial stromal cells.
Uterine decidualization is crucial for successful implantation and the establishment of pregnancy. In the present study, the expression of insulin-like growth factor-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) in the human uterus and endometrial stromal cells (ESCs) and its physiological significance in decidualization were examined. IGFBP-rP1 protein was localized in the glandular epithelium and stromal cells, and blood vessels in the endometrium. Cultured stromal cells expressed IGFBP-rP1 and secreted it into the medium. IGFBP-rP1 was localized mostly in the cytoplasm near the nucleus. Knocking down the endogenous IGFBP-rP1 expression in stromal cells, by a small interfering (si)RNA, diminished the expression of prolactin and IGFBP-1 which serve as decidual markers. These results suggest that IGFBP-rP1 may play a role in decidualization of ESCs.


The Perceived Credibility of Complementary and Alternative Medicine: A Survey of Undergraduate and Graduate Students.
The popularity of complementary and alternative medicine (CAM) appears to be increasing, especially among college students. We surveyed 146 undergraduate and graduate students with the CAM Health Belief Questionnaire and obtained credibility and frequency ratings for a select group of CAM therapies: yoga, meditation, massage, chiropractic medicine, biofeedback, hypnosis, acupuncture, spirituality/religion, therapeutic touch, the use of herbs/vitamins, and aromatherapy/essential oils. Graduate students held more favorable views about integrating CAM into conventional medical practice. Female students reported using a wider variety of therapies than male students. Spirituality/religion and herbs/vitamins were the most popular CAM approaches. Students rated yoga, meditation, and massage as being highly credible practices. They rated hypnosis and therapeutic touch low in credibility. We discuss hypnosis as an example of a therapy that suffers from poor public perception despite having a relatively strong evidentiary base.


Evaluation of the Effect of Meatal Stenosis on the Urinary Tract by using Ultrasonography.
Circumcision is one of the oldest surgical procedures that originated for religious purposes. Circumcision in infancy is a common procedure in our country and secondary meatal stenosis due to circumcision is a common complication. The aim of our study is to determine the effect of meatal stenosis on the lower and upperurinary tract of circumcised boys by using ultrasonography. In this cross-sectional study, we enrolled 87 circumcised boys between 4 to 8 years old with severe meatal stenosis. Clinical findings of our subjects were gathered by a checklist that included: thin stream of urine, upward urine stream deviation, infrequent voiding, urinary tract infections, voiding dysfunction, and urge incontinency. In lab data analysis, complete blood cell count (CBC), urine analysis, urine culture, blood urea nitrogen (BUN), and plasma creatinine level were evaluated. Ultrasonography detected hydronephrosis, hydroureter, bladder wall thickening in a full and empty bladder, bladder volume, and residual urine volume. Narrowing of urine stream is commonly seen (about 54%) among patients with severe meatal stenosis, and similarly in sonographic evaluations the most common symptoms among patients was thickening of the bladder wall that increased in an empty and a full bladder (about 82%). The author of this study recommends performing long-term follow up after circumcision and ultrasonographyto detect meatal stenosis before permanent renal damage occurs.


Payment Reform Meets Pharmacy Practice and Education Transformation.
The pharmacy profession has for the greater part of four decades been associated with dispensing activities and product reimbursement. This has hindered the ability of pharmacists to evolve their roles in their respective sites of care. Payment reform efforts that create an outcomes marketplace offer an opportunity for professional transformation.


Social cognition psychometric evaluation (SCOPE) in people with early psychosis: A preliminary study.
Social cognition is an important outcome in schizophrenia research. Unfortunately, there has been a lack of consensus regarding which measures of social cognition best capture this domain of functioning. The Social Cognition Psychometric Evaluation (SCOPE) study was developed to address the need for a battery of measures that have sound psychometric properties and can be implemented in clinical trials for individuals with chronic schizophrenia. The current study expands upon the SCOPE study by examining the psychometric properties of the eight candidate measures administered to individuals early in the course of psychosis. Thirty-eight stable outpatients with first episode psychosis and thirty-nine healthy controls completed the battery at baseline and one-month follow-up assessments. The SCOPE battery was evaluated on a collection of psychometric properties, including: (1) Reliability - including test-retest and internal consistency, (2) Between group differences, (3) Utility as a repeated measure, (4) Relationship to social and occupational functioning, (5) Incremental validity - variance in functioning beyond neurocognition, and (6) Feasibility - including practicality of administration and tolerability. Social cognition accounted for substantially more variance in functional outcome than neurocognition. Only one measure, the Hinting task, displayed adequate psychometric properties to be recommended for use in clinical research with first episode psychosis. The remaining candidate measures would require modifications before implementation or cannot be recommended for use in clinical research with first episode psychosis.


Resolution of a large left ventricular thrombus with anticoagulation alone.
Dilated cardiomyopathy and the resultant left ventricular dysfunction are risk factors for thrombus formation in the heart, reflecting the intimate relationship between structure and function in this vital organ. Once formed, depending on size, location, and mobility, left ventricular thrombi have the tendency to embolize, sometimes with dire consequences. Proper management of these thrombi is still controversial. We present a case of an unusual large thrombus, which resolved with anticoagulation therapy alone, giving hope that more invasive intervention can safely be circumvented.


Alterations in lymphokine secretion during leukemogenesis.
The production of interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 3 (IL-3) and granulocyte/macrophage colony stimulating factor (G/M-CSF) by preleukemic and leukemic spleen cells from Balb/c mice infected with Moloney leukemia virus (MoLV) was examined. During the development of the leukemia, the secretion of IL-1 and IL-2 significantly decreased, while the secretion of IL-3 and G/M CSF was not affected and was even enhanced. In addition, a 10 fold increase in the number of colony forming units in cultures (CFU-C) was found in the leukemic spleen indicating a shift in hematopoiesis from the bone marrow (BM) to the spleen. The low levels of IL-2 found in the conditioned medium of Concanavalin A (Con A) activated leukemic spleen cells could not result from active consumption of IL-2 by the cells, pointing to a genuine defect in IL-2 production. This failure of IL-2 secretion could be partially overcome by the addition of phorbol 12 beta-myristate 13 alpha-acetate (PMA) to the cells but not by the addition of IL-1. The defect in IL-2 production and the enhancement in IL-3 and G/M-CSF production may be of significance in the progression of preleukemic cells to autonomous malignant cells.


Stability of colistin methanesulfonate in pharmaceutical products and solutions for administration to patients.
Colistin methanesulfonate (CMS) has the potential to hydrolyze in aqueous solution to liberate colistin, its microbiologically active and more toxic parent compound. While conversion of CMS to colistin in vivo is important for bactericidal activity, liberation of colistin during storage and/or use of pharmaceutical formulations may potentiate the toxicity of CMS. To date, there has been no information available regarding the stability of CMS in pharmaceutical preparations. Two commercial CMS formulations were investigated for stability with respect to colistin content, which was measured by a specific high-performance liquid chromatography method. Coly-Mycin M Parenteral (colistimethate lyophilized powder) was stable (<0.1% of CMS present as colistin) for at least 20 weeks at 4 degrees C and 25 degrees C at 60% relative humidity. When Coly-Mycin M was reconstituted with 2 ml of water to a CMS concentration of 200 mg/ml for injection, Coly-Mycin M was stable (<0.1% colistin formed) for at least 7 days at both 4 degrees C and 25 degrees C. When further diluted to 4 mg/ml in a glucose (5%) or saline (0.9%) infusion solution as directed, CMS hydrolyzed faster at 25 degrees C (<4% colistin formed after 48 h) than at 4 degrees C (0.3% colistin formed). The second formulation, CMS Solution for Inhalation (77.5 mg/ml), was stable at 4 degrees C and 25 degrees C for at least 12 months, as determined based on colistin content (<0.1%). This study demonstrated the concentration- and temperature-dependent hydrolysis of CMS. The information provided by this study has important implications for the formulation and clinical use of CMS products.


Effects of major histocompatibility genes and antigen delivery on induction of protective mucosal immunity to E. acervulina following immunization with a recombinant merozoite antigen.
Intramuscular immunization with the recombinant p250 surface antigen of Eimeria acervulina merozoite (rEAMZp250) or oral inoculation with live recombinant Escherichia coli expressing the rEAMZp250 protein resulted in antigen-specific T-cell and humoral responses and conferred a significant reduction in mucosal parasitism compared to immunization with the negative control antigen preparation. Among the major histocompatibility complex (MHC) (B)-congenic chickens receiving intramuscular immunization, strain .6-2 (B2-B2) showed significant (P less than 0.05) protection to live E. acervulina challenge compared to the other strains examined. In contrast, strains .C-12(B12B12) and .P-13 (B13B13) showed significant protection among the groups given live recombinant E. coli. In general, strains showing enhanced T-cell responses to the rEAMZp250 protein were better protected compared to those showing minimal or no T-cell responses. Thus the results suggest that the B haplotypes of the host and the mode of antigen presentation influence the outcome of protection following an immunization of chickens with recombinant coccidial antigen.


Longitudinal monitoring of Listeria monocytogenes and Listeria phages in seafood processing environments in Thailand.
Listeria monocytogenes is a foodborne pathogen commonly found in environments of seafood processing, thus presenting a challenge for eradication from seafood processing facilities. Monitoring the prevalence and subtype diversity of L. monocytogenes together with phages that are specific to Listeria spp. ("Listeria phages") will provide knowledge on the bacteria-phage ecology in food processing plants. In this work, a total of 595 samples were collected from raw material, finished seafood products and environmental samples from different sites of a seafood processing plant during 17 sampling visits in 1.5 years of study. L. monocytogenes and Listeria spp. (non-monocytogenes) were found in 22 (3.7%) and 43 (7.2%) samples, respectively, whereas 29 Listeria phages were isolated from 9 (1.5%) phage-positive samples. DNA fingerprint analysis of L. monocytogenes isolates revealed 11 Random Amplified Polymorphic DNA (RAPD) profiles, with two subtypes were frequently observed over time. Our data reveal a presence of Listeria phages within the same seafood processing environments where a diverse set of L. monocytogenes subtypes was also found. Although serotype 4b was observed at lower frequency, data indicate that isolates from this seafood processing plant belonged to both epidemiologically important serotypes 1/2a and 4b, which may suggest a potential public health risk. Phages (all showed a unique genome size of 65 ± 2 kb) were classified into 9 host range groups, representing both broad- and narrow-host range. While most L. monocytogenes isolates from this facility were susceptible to phages, five isolates showed resistance to 12-20 phages. Variations in phage host range among Listeria phages isolated from food processing plant may affect a presence of a diverse set of L. monocytogenes isolates derived from the same processing environment in Thailand.


Nondecomposable idiom understanding in children: recursive theory of mind and working memory.
Which skills are required to start understanding ambiguous, unfamiliar nondecomposable idioms in context? In this study, we examined the contributions of both second-order false-belief understanding and working memory to the understanding of unfamiliar nondecomposable idioms in children aged 6, 7 and 8 years old. We assumed that, in order to process these idioms, children would have to be able to (a) take a double perspective (Perner & Wimmer, 1985), (b) maintain both literal and figurative meanings as being different from the expression itself, and (c) take the context into account. Six-, 7- and 8-year-old children performed three, second-order false-belief tasks and three working-memory tasks, and listened to 15 nondecomposable idioms inserted into a context, before performing a multiple-choice task. Results indicated that nondecomposable idiom understanding was explained by theory-of-mind skills.


Podiatry services for patients with arthritis: an unmet need.
Foot problems are extremely common in patients with rheumatoid arthritis (RA). There is ample evidence that foot pain, either alone or as a comorbidity, contributes significantly to disability. Despite the high prevalence of foot disease in RA, this problem is often trivialised or underappreciated. The inequity in foot health provision for patients with rheumatic disorders in New Zealand has recently been highlighted. Expertise in dealing with foot problems is often limited among healthcare professionals, and it has been argued that better integration of podiatric services into rheumatology services would be beneficial. The aim of this paper is to highlight the major issues related to foot care for patients with arthritis and provide key recommendations that should implemented to improve access to podiatric services in New Zealand.


[Health and growth: a brief review of the literature].
Improving health around the world is an important social objective, which provides direct payoffs in terms of longer and better lives. There is also a large consensus that improving health can have equally large indirect payoffs through accelerating economic development. The role that health conditions play in affecting growth is mainly analyzed via two channels: the direct labour productivity effect and the indirect incentive effect. The labour productivity hypothesis asserts that individuals who are healthier have higher returns to labour input. This is well tested in the empirical literature with mixed conclusions. The incentive effect is borne of the theoretical literature, and individuals who are healthier and have a greater life expectancy will have the incentive to invest in education as the time horizon over which returns can be earned is extended. Education is the driver of economic growth, and thus health plays an indirect role. Other minor channels have developed in the literature through which health affect economic development. However, although cross-country empirical works show a strong correlation between measures of health (for example, life expectancy) and economic growth, a causal effect of health and disease on economic development has not been established in the literature. A recent study challenges the view that different health conditions explain cross-country income differences. This study suggests that an improvement in mortality rate due to more effective public health measures and the introduction of new chemicals and drugs starting in the 1940s determines an increase in the population size which in turn reduces income per capita and economic growth.


In vitro tools for photobiological testing: molecular responses to simulated solar UV of keratinocytes growing as monolayers or as part of reconstructed skin.
Epidermal keratinocytes are critical targets for UV-induced genotoxicity as their transformation by sunlight overexposure can lead to skin cancer such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Therefore, assessment of photoprotection should involve early markers associated with DNA photodamage. Here, the same normal human keratinocytes either in monoculture (KC) or in full thickness reconstructed skin (RS) were compared with respect to their response to simulated solar UV (SSUV) exposure. Irradiation conditions (spectral power distribution and doses) were designed to mimic environmental zenithal UV from sunlight. At doses where survival was higher than 80%, comet assay showed more single strand breaks (SSB) and cyclobutane pyrimidine dimers (CPD) in keratinocytes in RS than in KC one hour post-exposure. The transcription factor p53 was activated in both models. While in KC p53 accumulation displayed a linear dose-dependency up to 24 h post-exposure, in RS it followed a bell-shaped profile and reverted to its basal rate. QRT-PCR demonstrated that among genes controlled by p53, P21 and MDM2 were clearly induced by SSUV in KC, whereas GADD45 expression was strongly and almost exclusively up-regulated in RS. Nrf2-dependent antioxidant genes (Ferritin light chain, NQO1) were only induced in RS, yet at low doses for NQO1. In vitro models such as KC or RS allowing the development of quantitative methodologies should be used as surrogates for in vivo tests assessing photogenotoxicity.


[Palmoplantar epidermal atrophy with hypokeratosis, dys- and hypotrichosis, hypodontia, enamel and dentin hypoplasia, isolated cleft palate with cleft uvula, strabismus cryptorchism and other anomalies--an undescribed ecto-mesodermal dysplasia?].
A 15-year-old boy had suffered burning of both palms and all fingers during his 2nd year of life. Epitheliazation of the lesions did not occur. In his 6th year, erythema, desquamation and erosion-like alterations appeared spontaneously on the soles of both feet and on the plantar sides of the toes. These alterations were similar to those on the hands. Histologically the lesion on the right sole was covered with a very thin horny layer and thin epidermis. The cells of the epidermis had clear cytoplasm and probably derived from the ductal epithelium of the sweat glands. Under the atrophic epidermis, granulation tissue consisting of lymphocytes, plasma cells, histiocytes, and a few polynuclear cells and eosinophils was seen. The following symptoms were still present in the boy: dys- and hypotrichosis, oligodontia, enamel and dentin hypoplasia, cleft palate and uvula, concomitants strabismus (left eye), and cryptorchidism. Transplantation of the patient's skin from the right thigh to the lesion on the right sole was tried. The authors postulate a previously unreported form of ecto-mesodermal dysplasia in this case.


Local ordering in liquids: solvent effects on the hyperfine couplings of the cyclohexadienyl radical.
Ordering of solvent molecules in the vicinity of a dipolar free radical affects its hyperfine coupling constants (hfcs). Specifically, it is demonstrated how the variation of the experimental methylene proton and muon hfcs of the muoniated cyclohexadienyl radical in several solvents and solvent mixtures of varying polarity can be accounted for by a dipole-dipole reaction field model that is based on the model of Reddoch and Konishi (J. Chem. Phys. 1979, 70, 2121) which was developed to explain the solvent dependence of the 14N hfc in the di-tert-butyl-nitroxide radical. Ab initio calculations were carried out with the cyclohexadienyl radical in an electric field to model the electric field arising from the electric dipole moments of the surrounding solvent molecules. An extension of the model that includes the dipole-quadrupole interaction can account for the larger hfc in benzene compared with that in octadecane, and it is predicted that the hfc will be proportional to the concentration of quadrupole moments to the 4/3 power. The influence of hydrogen bonding between the radicals' pi electrons and the OH groups of the solvent on the hfcs is also discussed. Comparison with gas-phase data permits a separation of vibrational effects and reveals that approximately 28% of the temperature dependence in water is due to increasing solvent disorder.


COMPARISONS OF THE CLINICAL FEATURES AND OUTCOMES OF CHILDREN PRESENTING WITH INFLUENZA-LIKE ILLNESSES, INCLUDING A (H1N1) PDM09 AND SEASONAL INFLUENZA, IN A UNIVERSITY HOSPITAL, THAILAND.
In Thailand, during the A(H1N1)pdm2009 pandemic, 82% of fatal cases did not received the specific treatment within 48 hours of the onset of symptoms. Specific diagnostic tests, especially RT-PCR, were not available throughout the country. To assist early clinical diagnosis and treatment, this study compared the clinical features and treatment outcomes of children presenting with influenza-like illness (ILIs). These included confirmed cases of A(H1N1)pdm2009, as well as seasonal influenza and cases for which no cause could be specified. The medical records of patients aged less than 15 years with ILIs, who had RT-PCR performed for influenza virus between May 2009 and December 2011 at Srinagarind Hospital, were reviewed. Clinical features, chest radiographs and treatment outcomes were compared between those positive for A(H1N1)pdm2009, and those with seasonal influenza and/or the unspecified causes group. In 179 complete medical records, 27.4% were positive for A(H1N1)pdm2009, 13.4% for seasonal influenza and the cause of illness in the remainder was unspecified. Both A(H1N1)pdm2009 and seasonal influenza viruses infected older children more than did the unspecified group (group median ages 96,48 and 24 months, respectively). Sore throat, headache and myalgia were significantly more frequent in the A(H1N1)pdm2009 group than in the other two groups (p < 0.001). Half of all children had pneumonia but there were no significant differences among groups. There was no mortality in this study. In conclusion, sore throat, headache and myalgia were the significant clinical features suggestive of A(H1N1)pdm2009 infection in children and might be helpful indicators prompting early administration of specific treatments in the settings where definitive laboratory tests are not available.


Optical-ellipsometric study of the nematic-to-smectic transition in 8CB films adsorbed on silicon.
The nematic-to-smectic-A (NA) transition in 8CB (4-octyl-4'-cyanobiphenyl) is especially interesting because experimentally, it has been observed to be second order, but theoretically, it has been predicted that it must have a latent heat. The effect on the NA transition due to confinement in an adsorbed film has hitherto not been investigated. Previous study of adsorbed 8CB films on silicon for coverages less than 100 nm showed the existence of a broad coexistence region, identified by the formation of thick and thin islands on the surface that extends between the bulk NA and the isotropic-to-nematic transition temperatures. In this paper, optical and ellipsometric measurements of 8CB films as a function of temperature are used to identify the location of the NA transition in the film in relation to the coexistence region. The NA transition temperature in the film is found to occur at 32.2+/-0.4 degrees C independent of film thickness for films between 62 to 270 nm thick, based on the decrease in the film anisotropy. This decrease in the anisotropy is found to be surprisingly abrupt. For thicknesses below 62 nm, the NA transition line is joined to the thin-thick coexistence region found previously.


Night blindness and conjunctival xerosis caused by vitamin A deficiency in patients with cystic fibrosis.
Forty three patients with cystic fibrosis, aged 8-44 years (median 16 years), were examined for evidence of vitamin A deficiency. Eight patients had abnormal dark adaptation tests and three had conjunctival xerosis. Serum vitamin A and retinol binding protein concentrations were significantly lower in the affected patients who were also more likely to have abnormal liver function tests. Five patients were treated with 100,000-200,000 IU water miscible vitamin A orally and their daily vitamin supplements were increased to maintain normal concentrations. In four patients dark adaptation tests were repeated. Three were normal, but one patient required three further doses of water miscible vitamin A and a daily supplement of 12,000 IU vitamin A before her dark adaptation threshold returned to normal. Adolescents with cystic fibrosis are liable to develop night blindness and conjunctival xerosis, particularly if they have liver disease or fail to take daily vitamin supplements.


The End-to-Side Anastomosis: A Comparative Analysis of Arterial Models in the Rat.
The end-to-side anastomosis is 1 of the most common anastomosis configurations used in cerebrovascular surgery. Although several living practice models have been proposed for this technique, few involve purely arterial vessels. The purpose of the present study was to compare 2 arterial models using common carotid arteries (CCAs) and common iliac arteries (CIAs) in rats. The CIAs and CCAs were exposed in 10 anesthetized rats, and their lengths and diameters were measured. Also, the mobilization extent of each vessel along its contralateral counterpart was measured after each artery had been transected at its proximal exposure point. We also studied the technical advantages and disadvantages of each model for practicing end-to-side anastomosis. The average diameters of the CCA and CIA were 1.1 and 1.3 mm, respectively. The average extent of mobilization along the contralateral vessel was 13.9 mm and 10.3 mm for CCA and CIA, respectively. The CCA model had the advantages of greater arterial redundancy (allowing completion of both suture lines extraluminally) and a minimal risk of venous injury. The main disadvantage of the CCA model was the risk of cerebral ischemia. The CIA model was not limited by the ischemic time and provided the technical challenge of microsurgical dissection of the common iliac vein from the CIA, although it had limited CIA redundancy. Both CCA and CIA models could be efficiently used for practicing the end-to-side anastomosis technique. Each model provides the trainee with a specific set of advantages and disadvantages that could help with the optimal selection of the practice model according to trainee's skill level.


Nesfatin-1 inhibits voltage gated K+ channels in pancreatic beta cells.
The anorexigenic neuropeptide NEFA/nucleobindin 2 (NUCB2)/nesfatin-1-containing neurons are distributed in the brain regions involved in feeding regulation. In spite of the growing knowledge of its physiological functions through extensive studies, its molecular mechanism of reaction, including its receptor, remains unknown. NUCB2/nesfatin-1 is also involved in various peripheral regulations, including glucose homeostasis. In pancreatic beta-cells, NUCB2/nesfatin-1 is reported to enhance glucose-stimulated insulin secretion (GSIS) but its exact mechanism remains unknown. To clarify this mechanism, we measured the effect of nesfatin-1 on the electrical activity of pancreatic beta-cells. Using mouse primary beta cells, we measured changes in the ATP-sensitive K+ (KATP) channel current, the voltage-gated K+ (Kv) channel current, and insulin secretion upon application of nesfatin-1. Nesfatin-1 inhibited the Kv channel, but KATP channel activity was unaffected. Nesfatin-1 enhanced insulin secretion to a same level as Kv channel blocker tetraethylammonium (TEA). The effect was not further enhanced when nesfatin-1 and TEA were applied simultaneously. The inhibition binding assay with [125I]nesfatin-1 in Kv2.1 channels, major contributor of Kv current in beta cell, expressing HEK239 cells indicated the binding of nesfatin-1 on Kv2.1 channel. Because Kv channel inhibition enhances insulin secretion under high glucose conditions, our present data suggest a possible mechanism of nesfatin-1 on enhancing GSIS through regulation of ion channels rather than its unidentified receptor.


Modeling L2,3-Edge X-ray Absorption Spectroscopy with Real-Time Exact Two-Component Relativistic Time-Dependent Density Functional Theory.
X-ray absorption spectroscopy is a powerful technique to probe local electronic and nuclear structure. There has been extensive theoretical work modeling K-edge spectra from first principles. However, modeling L-edge spectra directly with density functional theory poses a unique challenge requiring further study. Spin-orbit coupling must be included in the model, and a noncollinear density functional theory is required. Using the real-time exact two-component method, we are able to variationally include one-electron spin-orbit coupling terms when calculating the absorption spectrum. The abilities of different basis sets and density functionals to model spectra for both closed- and open-shell systems are investigated using SiCl4 and three transition metal complexes, TiCl4, CrO2Cl2, and [FeCl6]3-. Although we are working in the real-time framework, individual molecular orbital transitions can still be recovered by projecting the density onto the ground state molecular orbital space and separating contributions to the time evolving dipole moment.


The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH.
Clathrin-mediated endocytosis requires cargo-specific adaptor proteins that recognize specific receptors and recruit them into coated pits. ARH [also called low-density lipoprotein receptor (LDLR) adaptor protein] serves as an adaptor for LDLR endocytosis in liver. However, ARH is dispensable for LDL uptake by some other cell types. Here, we show that the adaptor Dab2 plays a major role in LDLR internalization in HeLa cells and fibroblasts. Dab2 mediates internalization of LDLRs but not transferrin receptors independently of ARH and the classic clathrin adaptor AP-2. If Dab2 is absent, ARH can mediate LDLR endocytosis, but its action requires AP-2. Furthermore, the rate of LDLR endocytosis is decreased when Dab2 is absent and Dab2, but not ARH, catalyzes the efficient clustering of LDLR into coated pits. Dab2 activity requires its binding to clathrin, LDLR and phospholipids. Dab2 is also involved in moving LDLRs off filopodia. We suggest that Dab2 is a cargo-specific endocytic adaptor protein, stably associating with phospholipids and clathrin to sort LDLR to nascent-coated pits, whereas ARH might accelerate later steps in LDLR endocytosis in cooperation with AP-2.


Clonal relationships of memory B cell subsets in autoimmune mice.
Immunological memory protects our body from re-infection and it is composed of a cellular and a humoral arm. The B-cell branch with its memory B cells (MBCs), plasma cells and antibodies, formed either in a germinal centre (GC) -dependent or -independent manner, ensure that we can rapidly mount a recall immune response. Previous work in immunised wildtype (WT) mice have identified several subsets of MBCs whereas less is known under autoimmune conditions. Here, we have investigated the heterogeneity of the MBC compartment in autoimmune mouse models and examined the clonal relationships between MBC subsets and GC B cells in one of the models. We demonstrate the presence of at least four different MBC subsets based on their differential expression pattern of CD73, CD80 and PD-L2 in surrogate light chain-deficient (SLC-/-), MRL+/+ and MRLlpr/lpr mice, where most of the MBCs express IgM. Likewise, four MBC subsets could be identified in WT immunised mice. In SLC-/- mice, high-throughput sequencing of Ig heavy chains demonstrates that the two CD73-positive subsets are generally more mutated. Lineage tree analyses on expanded clones show overlaps between all MBC subsets and GC B cells primarily in the IgM sequences. Moreover, each of the three IgM MBC subsets could be found both as ancestor and progeny to GC B cells. This was also observed in the IgG sequences except for the CD73-negative subset. Thus, our findings demonstrate that several MBC subsets are present in autoimmune and WT mice. In SLC-/- mice, these MBC subsets are clonally related to each other and to GC B cells. Our results also indicate that different MBC subsets can seed the GC reaction.