COVID-19 and Pediatric Asthma: Clinical and Management Challenges.
Asthma is the most frequent chronic condition in childhood and a current concern exists about asthma in the pediatric population and its risk for severe SARS-CoV-2 infection. Although all ages can be affected, SARS-CoV-2 infection has lower clinical impact on children and adolescents than on adults. Fever, cough and shortness of breath are the most common symptoms and signs in children; wheezing has not been frequently reported. Published studies suggest that children with asthma do not appear to be disproportionately more affected by COVID-19. This hypothesis raises two issues: is asthma (and/or atopy) an independent protective factor for COVID-19? If yes, why? Explanations for this could include the lower IFN-α production, protective role of eosinophils in the airway, and antiviral and immunomodulatory proprieties of inhaled steroids. Additionally, recent evidence supports that allergic sensitization is inversely related to ACE2 expression. Obesity is a known risk factor for COVID-19 in adults. However, in the childhood asthma-obesity phenotype, the classic atopic Th2 pattern seems to predominate, which could hypothetically be a protective factor for severe SARS-CoV-2 infection in children with both conditions. Finally, the return to school activities raises concerns, as asymptomatic children could act as vectors for the spread of the disease. Although this is still a controversial topic, the identification and management of asymptomatic children is an important approach during the SARS-CoV-2 epidemic. Focus on asthma control, risk stratification, and medication adherence will be essential to allow children with asthma to return safely to school.


Pink Cricket Balls May Be Visually Challenging at Sunset.
Cricket is one of the world's most popular sports, followed by hundreds of millions of people. It can be dangerous, played with a hard ball flying at great velocities, and accidents have occasionally been fatal. Traditionally, cricket has been played during the day, using a dark red ball. Since the late 1970s, a shorter form of one-day cricket has been played both during the day and at night under floodlights. To overcome visibility issues, one-day cricket uses a white ball, and players wear coloured clothing. There is now a desire to play a traditional form of cricket during the day and at night, using a 'pink' ball while players wear white clothing. Concerns regarding visibility, and player and umpire safety, have been raised in this context. Here, we report that these concerns have a sound basis.


Multifocal VZV vasculopathy with temporal artery infection mimics giant cell arteritis.
To address the incidence of varicella-zoster virus (VZV) infection in patients with biopsy-negative giant cell arteritis (GCA), we examined archived biopsy-negative temporal arteries from subjects with clinically suspected GCA for the presence of VZV antigen. Formalin-fixed, paraffin-embedded temporal arteries that were pathologically negative for GCA and normal temporal arteries were analyzed immunohistochemically for VZV and herpes simplex virus-1 (HSV-1) antigen. Five (21%) of 24 temporal arteries from patients who were clinically suspect but biopsy negative for GCA revealed VZV but not HSV-1 by immunohistochemical analysis. Thirteen normal temporal arteries did not contain VZV or HSV-1 antigen. All 5 subjects whose temporal arteries contained VZV antigen presented with clinical and laboratory features of GCA and early visual disturbances. Multifocal VZV vasculopathy can present with the full spectrum of clinical features and laboratory abnormalities characteristically seen in GCA.


Physicochemical properties and pharmacodynamics of desflurane.
Desflurane is a new volatile, inhaled anaesthetic that differs significantly from presently available inhaled agents in being halogenated solely with fluorine. This fluorination produces a lower solubility and increased resistance to biodegradation. The lower solubility provides a more precise control over, and a more rapid awakening from, anaesthesia. The resistance to biodegradation suggests that toxicity from desflurane may be minimal or non-existent. Limitations include a lesser potency and greater pungency at concentrations exceeding 1 minimum alveolar concentration (MAC). Other pharmacological properties are similar to those of isoflurane.


[Blood flow in the inferior vena cava measured by a Doppler ultrasound flowmeter in chronic experiments on cats].
Supercound Doppler's transducers indwelled in the cat v. cava posterior revealed that the higher blood flow values in chronic experiments as compared to acute ones were due to the effect of the chest suction action on the blood flow. The phasic changes of the venous blood flow occurring at resting and under various effects were related to respiration and heart activity, the respiratory component being more obvious than the cardiac one. A significant correlation existed between the mean value of the blood flow in the v. cava posterior and the respiratory changes of the blood flow amplitude.


[Recent advances in the roles of dendritic cells on contact dermatitis].
Dendritic cells are one of antigen presenting cells and are thought to play an important role in the establishment of immune responses. However, recent advances in immunology have revealed that there exist several dendritic cell subsets in the skin. In addition, a certain dendritic cell subset is able to regulate cutaneous immune responses. We used contact hypersensitivity as a cutaneous immune response model and review the recent advances in the roles of dendritic cells in contact hypersensitivity.


CPSP/HSE Postgraduate Overseas Rotational Programme: Residents' Perspective.
To get direct upward feedback from the residents of first batch of CPSP/HSE Postgraduate Scholarship Programme. Mixed methods qualitative research study. CPSP, Regional Office, Lahore, in June 2015. It is a mixed-method study that was conducted in June, 2015. Data was collected through an email survey with 33 medical residents doing their rotation in Ireland; and focus group discussions were carried out with 8 residents, who had successfully completed their rotation. Data were collected through pre-designed questionnaires comprising of open- and close-ended questions. The data were entered into SPSS version 21 and analyzed. The mean age of residents was 29.9 ±1.1 years, 7 (21.2%) were females and 24 (72.7%) respondents were males. Residents agreed that HSE programme has improved their evidence-based decision making (mean score of 3.3 ±1.2) and enhanced professionalism (mean score of 3.6 ±1.1). They disagreed that training has polished their procedural skills (mean score 2.4 ±1.2). The identified strengths of the programme are: adopting a systematic approach towards patients, evidence-based decision making, better exposure and opportunities, financial stability and development of communication skills. The weaknesses are: less exposure to procedural skills, difficulty in synopsis and dissertation writing and difficulty in adjustment with rotational schedules. Residents of CPSP/HSE Programme believed that CPSP/HSE has improved their professionalism, communication skills and increased their future opportunities for career growth. Better communication between CPSP focal person and residents will help sort out many minor but important issues.


Infrahyoid myocutaneous flap in head and neck reconstruction.
Infrahyoid myocutaneous flap is one of the alternatives to be considered for the reconstruction of moderate defects following resection of the oral cavity, oropharynx, or hypopharynx cancers. The flap is based on the uni- or bilateral superior thyroid pedicle; its major limitations are due to small flap volume and arc of rotation. The authors reviewed a series of 15 consecutive patients with carcinomas of the oral cavity or pharynx who underwent radical surgical resections followed by immediate reconstruction using an infrahyoid myocutaneous flap. Four of five cases with prior irradiation presented complications. The incidence of flap necrosis in this series (47%) was higher than that reported by others (10%). We consider the presence of massive neck metastasis and prior irradiation contraindications to the use of this flap.


Topological classifications of quadratic bosonic excitations in closed and open systems with examples.
The topological classifications of quadratic bosonic systems according to the symmetries of the dynamic matrices from the equations of motion of closed systems and the effective Hamiltonians from the Lindblad equations of open systems are analyzed. While the non-Hermitian dynamic matrix and effective Hamiltonian both lead to a ten-fold way table, the system-reservoir coupling may cause a system with or without coupling to a reservoir to fall into different classes. A 2D Chern insulator is shown to be insensitive to the different classifications. In contrast, we present a 1D bosonic Su-Schrieffer-Heeger model with chiral symmetry and a 2D bosonic topological insulator with time-reversal symmetry to show the corresponding open systems may fall into different classes if the Lindblad operators break the symmetry.


Neglected listeria infection in pregnancy in China: 93 cases.
Listeriosis is a foodborne disease that occurs in immunocompromised patients. Pregnant women are a high-risk group for the disease. Listeria infection during pregnancy is uncommon in China because of dietary habits, with little clinician attention and minimal therapeutic options due to its population-specific nature.This article studies the clinical characteristics of Listeria infection in pregnant women and the improvement of treatment methods. This study collected clinical data from 16 cases of pregnant patients with laboratory-confirmed Listeria monocytogenes infections at the Women and Children's Hospital of Jiaxing University. These data were combined with 77 cases that were reported in the literature for a total of 93 cases of Listeria monocytogenes infection in pregnancy that occurred in China over a 15-year interval. We collected the clinical data of 16 pregnant patients with listeriosis diagnosed in the laboratory of the Women and Children's Hospital of Jiaxing University from May 2013 to December 2020, and combined it with 77 cases of Listeria monocytogenes during pregnancy in China obtained from a literature search. We summarized the clinical features of listeriosis in pregnancy infection and investigated its treatment methods and prevention. Ninety-three cases of Listeria monocytogenes infection in pregnancy occurred in early, middle and late pregnancy in 31, 27, and 35 patients, respectively. The initial clinical presentation was fever in 90 patients, intermittent lower abdominal pain in 50 patients, and abnormal fetal movement and/or abnormal fetal heartbeat in 27 cases. Specimens with a positive bacterial culture included the following: 6 amniotic fluid cultures, 35 blood cultures, 37 maternal placenta and uterine secretion cultures, and 15 neonatal blood cultures. Fifty-seven cases of placental pathology, all showing of neutrophil infiltration, were 100% consistent with acute chorioamnionitis. Fifty-eight patients were initially treated with cephalosporin antibiotics, and only 24 cases were initially treated with broad-spectrum penicillins to cover the pathogenic bacteria. Drug sensitivity tests revealed resistant strains, 15 penicillin G-resistant, 14 oxacillin-resistant, and 13 ampicillin-resistant strains. After penicillin failure, vancomycin or meropenem was given. Maternal outcomes included the following: 20 cases of sepsis, 3 cases of pneumonia, 6 cases of acute pyelonephritis, 28 cases of intrauterine infection, 2 cases of multiple organ dysfunction syndromes, and 1 case of septic shock. The fetal and neonatal outcomes were as follows: 16 cases of abortion, 16 cases of intrauterine fetal death, 22 cases of death after birth, and 39 cases of cure. In our study and reported cases, Listeria monocytogenes in pregnancy is associated with fever as the primary manifestation, a high incidence of adverse pregnancy outcomes, and a significant increase in fetal and neonatal mortality. The low coverage of practical use of antimicrobial drugs and the emergence of drug-resistant strains in recent years have increased the difficulty of treatment, suggesting the need for clinicians to raise awareness of the disease and strengthen healthy diet promotion for women in pregnancy.


Long-Lasting Verbatim Memory for the Words of Books After a Single Reading Without Any Learning Intention.
The present study reveals an intriguing ability of our human memory: when reading a book once without any intention of learning, we store long-lasting verbatim memories of the words written in the book without being aware of it. Participants read a book chapter consisting of 32 pages (3,772 words) once without knowing that their memory would be tested later. In memory tests immediately after reading and 1 week after reading, they were asked to remember exactly which word was written at a specific position in the book chapter. Only memory for words was tested that were theme-unrelated and non-central. To measure memory, a two-alternative forced choice recognition test was used where a page was shown either as read before or with the replacement of one single word by a synonym. For each response, participants indicated whether the response was based on phenomenal memory experience (recollection or familiarity) or guessing. In the immediate test, participants claimed to have phenomenal memory experience for about a quarter of the tested positions, truly remembering the word in about half of cases. In the 1-week-delayed test, phenomenal memory experience was nearly entirely absent and completely uninformative. When claiming to have no phenomenal memory experience, participants still truly remembered the word for about 10% of the tested positions in both the immediate test and the 1-week-delayed test, without any forgetting. These findings demonstrate that we store more from read texts in memory than commonly believed.


Origins of DNA replication.
In all kingdoms of life, DNA is used to encode hereditary information. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter cell receives the full complement of chromosomes. DNA synthesis of daughter strands starts at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Here, we discuss commonalities and differences in replication origin organization and recognition in the three domains of life.


Reliability of angiography in the evaluation of renal adenocarcinoma.
The accuracy of angiography in TNM classification and its significance in the assessment of prognosis was evaluated in a series of 178 consecutive renal angiograms performed on patients with renal adenocarcinoma. The overall accuracy in the T category was 74.2%. Angiography was reliable in the assessment of the renal vein but not reliable in nodal involvement. Radiographic signs associated with an unfavorable prognosis were an additional vascular supply from sources other than the lumbar artery, nonvisualization of the renal vein and a poorly defined tumor margin.


Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22.
The class II cytokine receptor family includes the receptors for IFN-alphabeta, IFN-gamma, IL-10, and IL-10-related T cell-derived inducible factor/IL-22. By screening genomic DNA databases, we identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the IL-22 receptor and of the IL-20R/cytokine receptor family 2-8, respectively, but lacking the transmembrane and cytoplasmic domains. A lower but significant sequence identity was found with other members of this family such as the IL-10R (29%), cytokine receptor family 2-4/IL-10Rbeta (30%), tissue factor (26%), and the four IFN receptor chains (23-25%). This gene is located on chromosome 6q24, at 35 kb from the IFNGR1 gene, and is expressed in various tissues with maximal expression in breast, lungs, and colon. The recombinant protein was found to bind IL-10-related T cell-derived inducible factor/IL-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist IL-22BP for IL-22 binding protein.


Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix.
Antagonists of luteinizing hormone-releasing hormone (LH-RH), unlike the LH-RH agonists, suppress gonadotropins and sex steroid secretion immediately after administration, without initial stimulatory effects. [Ac-D-Nal(2)1,D-Ph(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-R H (SB-75; Cetrorelix) is a modern, potent antagonistic analog of LH-RH. In this study, the binding characteristics of receptors for LH-RH in membrane fractions from rat anterior pituitaries were investigated after a single injection of Cetrorelix at a dose of 100 microg per rat. To determine whether the treatment with Cetrorelix can affect the concentration of measurable LH-RH binding sites, we applied an in vitro method to desaturate LH-RH receptors by chaotropic agents such as manganous chloride (MnCl2) and ammonium thiocyanate (NH4SCN). Our results show that the percentages of occupied LH-RH receptors at 1, 3, and 6 h after administration of Cetrorelix were approximately 28%, 14%, and 10%, respectively, of total receptors. At later time intervals, we could not detect occupied LH-RH binding sites. Ligand competition assays, following in vitro desaturation, demonstrated that rat pituitary LH-RH receptors were significantly (P < 0.01) down-regulated for at least 72 h after administration of Cetrorelix. The lowest receptor concentration was found 3-6 h after Cetrorelix treatment and a recovery in receptor number began within approximately 24 h. The down-regulation of LH-RH binding sites induced by Cetrorelix was accompanied by serum LH and testosterone suppression. Higher LH-RH receptor concentrations coincided with elevated serum hormone levels at later time intervals. Our results indicate that administration of LH-RH antagonist Cetrorelix produces a marked down-regulation of pituitary receptors for LH-RH and not merely an occupancy of binding sites.


[Cutis marmorata telangiectatica congenita--case report].
Cutis marmorata telangiectatica congenita is a rare, usually congenital, localized or generalized cutaneous vascular abnormality characterized by a persistent cutis marmorata pattern, spider naevus-like telangiectasia and ulceration or atrophy of the involved skin, which frequently improves with age. Approximately 300 cases have been reported worldwide. The authors present a case of cutis marmorata telangiectatica congenita with typical clinical findings: phlebectasia of the scalp with ulceration, almost generalized persistent cutis marmorata, telangiectasia. No associated anomalies were detected. The relevant literature is also reviewed.


Endurance training decreases the non-linearity in the oxygen uptake-power output relationship in humans.
In this study, we hypothesized that 5 weeks of cycling endurance training can decrease the magnitude of the non-proportional increase in oxygen uptake (V(O(2))) to power output relationship (V(O(2)) 'excess') at exercise intensities exceeding the lactate threshold (LT). Ten untrained, physically active men performed a bout of incremental cycling exercise until exhaustion before and after training. The mitochondrial DNA copy number, myosin heavy chain composition and content of uncoupling protein 3 and sarcoplasmic reticulum Ca(2+)-ATPases (SERCAs) were analysed in muscle biopsies taken from vastus lateralis before and after training. The training resulted in an enhancement of the power-generating capabilities at maximal oxygen uptake (V(O(2)max)) by ∼7% (P = 0.002) despite there being no changes in V(O(2)max) (P = 0.49). This effect was due to a considerable reduction in the magnitude of the V(O(2)) 'excess' (P < 0.05) above the LT. A decrease in plasma ammonia concentration was found during exercise after training (P < 0.05). A downregulation of SERCA2 in vastus lateralis (P = 0.006) was observed after training. No changes in myosin heavy chain composition, selected electron transport chain proteins, uncoupling protein 3 or the mitochondrial DNA copy number (P > 0.05) were found after training. We conclude that the training-induced increase in power-generating capabilities at V(O(2)max) was due to attenuation of the V(O(2)) 'excess' above the LT. This adaptive response seems to be related to the improvement of muscle metabolic stability, as judged by a lowering of plasma ammonia concentration. The enhancement of muscle metabolic stability after training could be caused by a decrease in ATP usage at a given power output owing to downregulation of SERCA2 pumps.


CHOP is a multifunctional transcription factor in the ER stress response.
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) induces ER stress. To restore ER homeostasis, cells possess a highly specific ER quality-control system called the unfold protein response (UPR). In the case of prolonged ER stress or UPR malfunction, apoptosis signalling is activated. This ER stress-induced apoptosis has been implicated in the pathogenesis of several conformational diseases. CCAAT-enhancer-binding protein homologous protein (CHOP) is induced by ER stress and mediates apoptosis. Recent studies by the Gotoh group have shown that the CHOP pathway is also involved in ER stress-induced cytokine production in macrophages. The multifunctional roles of CHOP in the ER stress response are discussed below.


[Non-compliance with having a colonoscopy as a follow up to a positive result in colorectal cancer screening: a qualitative study].
This qualitative study examines the motivations of people who had a positive result as part of the colorectal cancer screening programme, and who did not follow-up with further recommended tests; whereas good medical practice requires the a colonoscopy subsequent to a positive Hemoccult test. Twelve semi-directed interviews were conducted. The quality of the doctor - patient relationship strongly influences the acceptance of having a colonoscopy. This data highlights the necessary capacity of the doctor to convey a rational message while also taking into account the emotional turmoil provoked by the uncertainty and worry linked to receiving a first positive result in a cancer screening test. Working with the medical profession to advocate for a systematic colonoscopy as an essential follow-up to a positive Hemoccult test is critical. For many of these doctors, doing the Hemoccult test is regarded as the screening standard, but in their view a subsequent colonoscopy is not currently a part of this norm. Recommendations are proposed, aiming to improve the acceptance of the organized screening by the population.


Media multitasking, depression, and anxiety of college students: Serial mediating effects of attention control and negative information attentional bias.
The COVID-19 epidemic provides an environment for frequent media multitasking, which might associate with an increase in depression and anxiety. Since many studies have found that media multitasking negatively affects cognitive capacity, we propose a cognitive perspective to explore how media multitasking may associate with mental health. This study examined the potential mediating role of attention control and negative information attentional bias in the relationship between media multitasking and anxiety and depression. Participants (n = 567) were recruited from college students in China. They completed an online survey that included the Media Multitasking Inventory (MMI), Attention Control Scale (ACS), Attention to Positive and Negative Information Scale (APNI), Generalized Anxiety Disorder Scale (GAD-7), and Patient Health Questionnaire (PHQ-9). After exploring the correlations between the measures, serial mediation models were examined. The results indicated significant positive correlations between media multitasking and anxiety and depression. Media multitasking, anxiety, and depression were negatively correlated with attention focusing, while positively correlated with negative information attention bias. Media multitasking did not correlate with attention shifting. Mediation modeling demonstrated that attention focusing and negative information attention bias played a serial mediating role in the relationship between media multitasking and anxiety and depression. However, the results did not support the serial mediation model through attention shifting and negative information attention bias. Media multitasking does not directly influence anxiety and depression, while attention focusing and negative information attention bias play serial mediating roles in their relationship. This study highlights the potential cognitive mechanisms between media multitasking and anxiety and depression, providing theoretical support for interventions in individual mental health during the epidemic.


Development of Lorentz force-type self-bearing motor for an alternative axial flow blood pump design.
A Lorentz force-type self-bearing motor was developed to provide delivery of both motoring torque and levitation force for an alternative axial flow blood pump design with an enclosed impeller. The axial flow pumps currently available introduce electromagnetic coupling from the motor's stator to the impeller by means of permanent magnets (PMs) embedded in the tips of the pump's blades. This design has distinct disadvantages, for example, pumping efficiency and electromagnetic coupling transmission are compromised by the constrained or poor geometry of the blades and limited pole width of the PMs, respectively. In this research, a Lorentz force-type self-bearing motor was developed. It is composed of (i) an eight-pole PM hollow-cylindrical rotor assembly supposedly to house and enclose the impeller of an axial flow blood pump, and (ii) a six-pole stator with two sets of copper wire and different winding configurations to provide the motoring torque and levitating force for the rotor assembly. MATLAB's xPC Target interface hardware was used as the rapid prototyping tool for the development of the controller for the self-bearing motor. Experimental results on a free/simply supported rotor assembly validated the design feasibility and control algorithm effectiveness in providing both the motoring torque and levitation force for the rotor. When levitated, a maximum orbital displacement of 0.3 mm corresponding to 1050 rpm of the rotor was measured by two eddy current probes placed in the orthogonal direction. This design has the advantage of eliminating the trade-off between motoring torques, levitating force, and pumping efficiency of previous studies. It also indicated the benefits of enclosed-impeller design as having good dynamic response, linearity, and better reliability. The nonmechanical contact feature between rotating and stationary parts will further reduce hemolysis and thromboembolitic tendencies in a typical blood pump application.


Comparing Somatostatin Analogs in the Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors.
The 2 approved somatostatin analogs (SSAs) in the first-line treatment of advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are octreotide long-acting release (Sandostatin LAR) and somatuline depot (Lanreotide). The study's objective was to compare progression-free survival (PFS) and overall survival (OS) of patients (pts) with GEP-NETs treated with somatuline or octreotide LAR. Pts and Methods: Pts with advanced well-differentiated GEP-NET who received either SSA at Emory University between 1995 and 2019 were included after institutional review board approval. The primary end point was PFS, defined as time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.1, or clinical progression) or death. The secondary end point was OS. Kaplan-Meier curves were generated, and log-rank tests were conducted to compare the survival outcomes. A total of 105 pts were identified. The mean age was 62.1 years (SD ± 11.8). The male-to-female ratio was 51:54. The majority (N = 69, 65.7%) were white. Most pts had grade 2 (G2) disease (N = 44, 41.9%). Primary location was small bowel in 58 (55.2%), pancreas in 27 (25.7%), and other in 20 (19.0%). Functional tumors were defined in 32 pts distributed equally between the 2 groups. Distribution of treatment was similar in the 2 groups, with 54 receiving octreotide LAR and 51 receiving somatuline depot. The median PFS for the octreotide LAR and somatuline depot groups was 12 months (95% CI, 6-18 months) and 10.8 months (95% CI, 6-15.6 months), respectively, and the difference was not statistically significant (p = 0.2665). For pts with G1 disease, the median PFS for the octreotide LAR and somatuline depot was 8.4 versus 32.4 months, respectively, and the difference was not statistically significant (p = 0.159). For G2 disease, the difference in median PFS between octreotide LAR and somutaline depot groups was statistically significant (12 vs. 7.2 months, respectively; p = 0.0372). The mean follow-up time for octreotide LAR was 21.6 months versus 11.3 months for somatuline depot. Overall, there was no difference in PFS between octreotide LAR and somatuline depot for pts with well-differentiated, metastatic GEP-NETs. A prospective study is worth designing selecting for G.


Oral health and personnel needs in the Pacific.
A regional review of oral health in the Pacific showed the major problems to be dental caries, periodontal diseases, poor dental health service management and lack of appropriate dental personnel. A strategy for training appropriate dentists to manage oral health services in the Pacific was suggested. Such a strategy must include training of ancillary and auxiliary dental health workers guided by dentists with clinical and managerial competencies. The training programme for dentists must be career-ladder, problem-based, and community-oriented with competency-based learning of a spiral of tasks with increasing sophistication. The curriculum content must contain about 50 percent on public health and clinical aspects, respectively.


Cloning of a cDNA encoding a 190-kDa insulin receptor substrate-1-like protein of simian COS cells.
Major insulin signals such as stimulation of glucose uptake and DNA synthesis and modification of hexose metabolism are mediated by the tyrosine-phosphorylated insulin receptor substrate-1 (IRS-1; pp180) in many species of cells. We cloned cDNA encoding a 190-kDa IRS-1-like protein (pp190) in simian COS cells and which is slightly larger than IRS-1 (pp180) of human, rat, and mouse cells. The deduced amino acid sequence of COS pp190 consisted of 1251 amino acids and was 96.4%, 87.9% and 88.7% identical to human, mouse and rat IRS-1. The COS pp190 bound to SH2 (src-homology 2) domains of p85, Grb2/Ash, and SH-PTP2, as did IRS-1. In IRS-1-knockout mice, insulin signals are thought to be mediated by IRS-2 (pp190), which is an alternative signaling molecule and is slightly larger than IRS-1. However, the COS pp190 may be a simian homologue of IRS-1, but not of IRS-2. The results of Southern blotting suggested the possibility that Chinese hamster ovary (CHO) cells have not only the IRS-1 gene but also a gene related to the COS pp190.


Relationship of symptoms with sleep-stage abnormalities in obstructive sleep apnea-hypopnea syndrome.
Patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) present with a variety of sleep-related symptoms. In polysomnography, sleep architecture is almost always abnormal, but it is not known which of the sleep-stage abnormalities are related to symptoms. Finding key sleep-stage abnormality that cause symptoms may be of therapeutic importance to alleviate symptoms. So far the mainstay of treatment is continuous positive airway pressure (CPAP)/bi-level positive airway pressure (BIPAP) therapy, but many patients are non-compliant to it. Correcting the sleep-stage abnormality that cause symptoms by pharmacotherapy may become an important adjunct to CPAP/BIPAP therapy. A cross-sectional study. Adult subjects who attended a sleep laboratory for diagnostic polysomnography for a period of 1 month were recruited consecutively. OSAHS was diagnosed using American Academy of Sleep Medicine criteria. Subjects filled a questionnaire for symptoms prior to polysomnography. Thirty subjects, of whom 83.3% were obese, met diagnostic criteria, with males constituting 46.7% and females constituting 53%. Mean age was 53.40±11.60 years. Sleep architecture comprised N1 19.50±19.00%, N2 53.93±13.39%, N3 3.90±19.50%, and rapid eye movement 8.92±6.21%. Excessive fatigue or sleepiness, waking up tired, falling asleep during the day, trouble paying attention, snoring and insomnia were significantly related to decreased N3 sleep. Most of the symptoms in OSAHS in adults are related to decreased stage N3 sleep. If confirmed by larger controlled studies, correcting N3 sleep deficiency by pharmacotherapy may become an important adjunct to CPAP/BIPAP therapy to alleviate symptoms.


A plea for a more physiological ICSI.
Intracytoplasmic sperm injection (ICSI) can be considered the most 'revolutionary' in vitro insemination technique because it has efficiently allowed the treatment of male factor infertility. Although ICSI has been successfully and safely applied worldwide for almost 20 years, currently, we have no real knowledge regarding the hypothetical long-term side effects on ICSI adults, given the increased likelihood of spermatozoa with defective nuclear content fertilising the oocytes. The aim of this review article is to investigate the most recent advances of performing ICSI in the safest possible manner, thus, minimising the theoretical hazards of this procedure. To allow for substantiated recommendation which male gametes to choose for physiological ICSI an updated search was performed in Medline and Embase, from 1996 to June 2011. Recent technical advances allow operators to more or less simulate physiological conditions in the laboratory, reducing potential damage to the gametes. It seems possible to prevent fertilisation by DNA-damaged and chromosomal-unbalanced spermatozoa by selecting ICSI sperm by motility and/or maturation markers such as hyaluronic acid or other zona pellucida receptors. Furthermore, novel non-invasive imaging techniques can be valid tools for helping in the morphological selection of ICSI spermatozoa.


Elevated inflammatory cytokine levels in bone marrow graft rejection.
Graft rejection and graft failure represent major obstacles in allogeneic bone marrow transplantation (BMT). Cytokines possibly play a central role in the inflammatory and allospecific components of allograft rejection. Therefore, we evaluated inflammatory cytokine levels following BMT in 12 consecutive patients with graft rejection (GR). Seven of the patients underwent BMT from siblings (6 matched and 1 mismatched), 4 patients received bone marrow from other family members (3 mismatched and 1 matched), and 1 patient underwent HLA-matched unrelated BMT. Nine of 12 had a sex-mismatched BMT and 5/12 had an ABO-mismatched BMT. Nine of 12 underwent T cell-depleted (Campath anti-CDw52 moAb) BMT. Rejection was defined as marrow hypoplasia with a peripheral white blood cell count < 0.5 x 10(9)/L 21 days after BMT, in conjunction with the absence of donor cells by polymerase chain reaction analysis using a sex-mismatched probe and/or a tumor-specific probe (BCR/ABL). Twenty-five patients who underwent uneventful BMT with no GR served as controls. The levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-1 (IL-1) were evaluated by a high sensitive RIA or an enzyme immunoassay. The levels of TNF and IL-6 were found to be higher in 10/12 and 7/7 evaluated GR patients, respectively, as compared with controls (P < 0.05). The level of IL-1 was high only in 2/12 patients. TNF elevation occurred in all patients immediately after GR. TNF and IL-6 levels were significantly higher for patients with early rejection (< 35 days after BMT) as compared with patients with late rejection (> 35 days after BMT) (P < 0.049 and P < 0.006, respectively). Eight patients engrafted after the second transplant (2 only transient). All 6 patients with stable engraftment are alive (4 with basic disease), while the 4 patients who did not engraft and the 2 patients with only transient engraftment died. In the 6 patients with no engraftment or only transient engraftment, the elevated TNF levels remained high; in the 6 patients who had stable engraftment after retransplant, TNF levels, but not IL-6 levels, decreased. In conclusion, a majority of the patients with GR displayed high levels of inflammatory cytokines (TNF and IL-6). Dysregulation of inflammatory cytokines may be involved in the pathogenesis of GR.


Oxygen uptake and H2O2 production by fermentative Mycoplasma spp.
Oxygen uptake and H2O2 accumulation during the metabolism of glucose and glycerol by whole cells, and of L-alpha-glycerophosphate (GP) and NADH by cells lysed with Triton, was determined for the type strains of six fermentative Mycoplasma species. Oxidation of glucose and of NADH by M. mycoides, M. pneumoniae and M. putrefaciens was accompanied by the accumulation of relatively small quantities of H2O2 (less than 0.05 mol/mol O2), though larger quantities (0.17-0.24 mol/mol O2) were produced by M. dispar. M. fermentans and M. canis were distinguished from the other strains used in that O2 uptake in the presence of glucose could not be demonstrated. However, metabolism of glucose was indicated by a reduction in the pH of the suspending medium and lysed cells oxidised NADH with the production of approximately 1.0 mol H2O2/mol O2 taken up. Glycerol was oxidised by all the strains studied except M. fermentans, and large quantities of H2O2 (0.48-1.07 mol/mol O2) accumulated. Cells of the glycerol-oxidising strains, lysed with Triton, oxidised GP with the production of approximately 1.0 mol H2O2/mol O2 utilised, which indicated the presence of a GP oxidase. The importance of H2O2 production as a factor in the pathogenicity of some mycoplasmas might depend upon the availability of glycerol in vivo.


Effects of silodosin and tamsulosin on the urethra and cardiovascular system in young and old dogs with benign prostatic hyperplasia.
We examined whether the effects (efficacy on the urethra and hypotension) of silodosin (alpha(1A)-adrenoceptor antagonist) and tamsulosin (alpha(1A+1D)-adrenoceptor antagonist) in dogs with benign prostatic hyperplasia altered with age. We used young and old dogs, diagnosed as having benign prostatic hyperplasia by veterinarian's palpation. Under anesthesia, the increase in intraurethral pressure evoked by hypogastric nerve stimulation was measured, together with the level of systemic mean blood pressure. Each drug was administered intravenously in progressively increasing doses. At the end of the experiment, the prostate was isolated from each dog, then weighed and investigated pathologically to confirm benign prostatic hyperplasia. The wet weight of the prostate was greater in old dogs with benign prostatic hyperplasia than in young dogs with benign prostatic hyperplasia. By light microscopy, hyperplasia in the prostatic epithelium was confirmed in both groups. Silodosin (0.3-300 microg/kg) dose-dependently inhibited the hypogastric nerve stimulation-induced increase in intraurethral pressure (without significant hypotensive effects) in both young and old dogs with benign prostatic hyperplasia. Tamsulosin (0.3-300 microg/kg) also dose-dependently inhibited the intraurethral pressure increase in both groups, but it had a hypotensive effect that was significantly greater in old than in young dogs with benign prostatic hyperplasia. In conclusion, as regards the effect of silodosin on intraurethral pressure, potency was similar between young and old dogs with benign prostatic hyperplasia, and it was without significant hypotensive effects. We therefore suggest that silodosin might be a good medication for lower urinary tract symptoms in patients with benign prostatic hyperplasia in all age groups.


Hypertrophic osteopathy associated with pulmonary adenosquamous carcinoma in a dog.
A six-year-old intact female Maltese dog weighing 3.8 kg presented with a history of mild lameness and swelling on both forelimbs. Radiographic and computed tomographic views revealed an extensive periosteal reaction in all four limbs and a large round mass on the right middle lung lobe. A total lobectomy was performed and pulmonary adenosquamous carcinoma was histologically confirmed. A diagnosis of hypertrophic osteopathy (HO) secondary to a lung tumor was made. Periosteal proliferation decreased significantly after surgery; however, there was evidence of dyspnea, mass recurrence, and periosteal reaction three months post-operatively. This is the first case report of pulmonary adenosquamous carcinoma with HO in a dog in which we describe clinical, imaging, surgical, and histological findings.


Challenges and solutions of extracting value-added ingredients from fruit and vegetable by-products: a review.
Every year, huge amounts of fruit and vegetable by-products in the food processing factories are produced. These by-products have great potential to be used for different targets especially the extraction of value-added ingredients. The target of this study is to review the challenges of extraction of value-added ingredients from fruit and vegetable by-products on the industrial scale and to describe current trends in solving these problems. In addition, some strategies such as multi-component extraction as well as application of fermentation before or after the extraction process, and production of biofuel, organic fertilizers, animal feeds, etc. on final residues after extraction of value-added ingredients are discussed in this review paper. In fact, simultaneous extraction of different value-added ingredients from fruit and vegetable by-products can increase the extraction efficiency and reduce the cost of value-added ingredients as well as the final volume of these by-products. After extraction of value-added ingredients, the residues can be used to produce biofuels, or they can be used to produce organic fertilizers, animal feeds, etc. Therefore, the application of several appropriate strategies to treat the fruit and vegetable by-products can increase their application, protect the environment, and improve the food economy.


Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts.
Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF) and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard) per os, on a daily basis for a period of 25 weeks. In vitro force measurements, biochemical and histochemical assays were employed to assess cardiomyocyte function and signaling. Vardenafil treatment increased cyclic guanosine monophosphate (cGMP) levels and decreased 3-nitrotyrosine (3-NT) levels in the left and right ventricles of ZDF animals, but not in Lean animals. Cardiomyocyte passive tension (Fpassive) was higher in LV and RV cardiomyocytes of ZDF rats than in those receiving preventive vardenafil treatment. Levels of overall titin phosphorylation did not differ in the four experimental groups. Maximal Ca2+-activated force (Fmax) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca2+-sensitivity of isometric force production (pCa50) was significantly higher in LV (but not in RV) cardiomyocytes of ZDF rats than in their counterparts in the Lean or Lean + Vard groups. In accordance, the phosphorylation levels of cardiac troponin I (cTnI) and myosin binding protein-C (cMyBP-C) were lower in LV (but not in RV) cardiomyocytes of ZDF animals than in their counterparts of the Lean or Lean + Vard groups. Vardenafil treatment normalized pCa50 values in LV cardiomyocytes, and it decreased pCa50 below control levels in RV cardiomyocytes in the ZDF + Vard group. Our data illustrate partially overlapping myofilament protein alterations for LV and RV cardiomyocytes in diabetic rat hearts upon long-term PDE-5A inhibition. While uniform patterns in cGMP, 3-NT and Fpassive levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa50 values implicate different responses for the systolic function.


[Urotensin II--new peptide which regulates function of cardiovascular system].
Human urotensin II is one of the new peptide which regulates function of cardiovascular system. It stimulates cardiomyocytes and vascular smooth muscle hypertrophy and also shows inotropic properties. Urotensin II has the potential pathophysiological role in cardiovascular, lung and kidney diseases. The vascular function of this peptide in humans, however, has yet to be determined. Human urotensin II is an endocrine hormone with range vasoactive properties dependent on the anatomic site and the species. Preliminary results showed strong expression of urotensin II in the cardiomyocytes, and to a lesser extent in the vascular smooth muscle cells, endothelial cells, and inflammatory cells of patients with end-stage chronic heart failure. The development of selective human urotensin II antagonists may be of utility in the management of cardiovascular disorders.


[Clinicopathological analysis of primary intestinal non-Hodgkin's lymphoma: a report of 32 cases].
To investigate the clinical and pathological features and prognostic factors of primary intestinal non-Hodgkin's lymphoma (NHL). Thirty-Two cases of intestinal NHL were studied clinically and pathologically. All cases were reclassified according to the WHO classification of lymphoma in 2001. Twenty-one cases (65.6%) were diagnosed as B-cell lymphomas, including 15 cases of diffuse large B-cell lymphoma, 2 cases of mantle cell lymphoma, 1 case of follicular lymphoma, 2 cases of MALT lymphoma and 1 case of Burkitt's lymphoma. Ten cases (31.2%) were diagnosed as T cell lymphomas, including 2 enteropathy-associated T cell lymphomas (EATCL) and 8 cases non-EATCL. One case (3.1%) was diagnosed as histiocytic lymphoma. Nine cases were at stage I-II and 23 cases were at stage III-IV. Follow-up information was available in all cases ranging from 4 to 168 months (mean 25.6 months). Fifteen cases died of the disease. The mortality rates were 33% for B cell lymphoma and 80% for T cell neoplasms. Based on Cox multivariate analysis, the clinical stage and histological types of the disease were important prognostic factors (P < 0.05). T cell lymphoma had a relatively poor prognosis. Diffuse large B cell lymphoma is the most common subtype of primary intestinal lymphomas. Colon is the most common site involved, followed by the small intestine. Early stage of the disease and low-grade lymphoma appear to have a better prognosis. T cell lymphoma has a very poor prognosis.


Use of actigraphy for monitoring sleep and activity levels in patients with fibromyalgia and depression.
The hallmark symptom of fibromyalgia (FM) is widespread chronic pain, but most patients are also impaired due to fatigue and sleep disturbance, and there is a strong association with depression. We compared levels of activity and sleep patterns in FM patients, with and without comorbid depression, to those of normal healthy controls and depressed patients. Actigraphy was carried out on 16 patients with uncomplicated FM, 6 FM patients with comorbid depression, 9 patients with recurrent major depression, and 28 healthy controls over a period of 5-7 days. The means of daytime activity levels, nighttime activity levels, and percentage time spent asleep during the daytime and nighttime were calculated and compared. Controls showed high levels of activity during the day and uninterrupted periods of sleep at night. Patients with FM alone showed similar levels of daytime activity, but disturbed sleep with significantly increased levels of activity at night compared to normal controls. Patients with depression alone also showed disturbed sleep compared to normal controls. However, patients with FM and comorbid depression showed the most impairment, with significantly reduced daytime activity and significantly increased daytime sleeping compared to controls, as well as more sleep interruption and movement during the night. Actigraphy is a useful means of studying activity levels and sleep patterns and demonstrated significant differences between FM patients with and without comorbid depression.


Oral bioavailability studies of niosomal formulations of Cyclosporine A in albino rabbits.
Cyclosporine A (CsA) is an immunosuppressant agent. Two niosomal formulations of CsA, FTS and FSB were formulated. Both formulations were studied in terms of size, polydispersity index (PDI), morphology and entrapment efficacy etc. Niosomal formulations FTS and FSB and plain aqueous dispersion were given to three assemblies of Albino rabbits (n=8 per group). CsA levels in plasma were determined at appropriate time intervals and pharmacokinetic parameters were evaluated. The percentage entrapment efficiencies of FTS and FSB were found to be 77.29 and 89.31% for respectively. Transmission electron microscopy results indicated spherical nature of niosomes. In vivo studies demonstrated that the value of Cmax for the FSB formulation was 1968.419 ng/ml and it was 1498.951 ng/ml and 1073.87 ng/ml for FTS and aqueous dispersion of CsA (control) respectively. It was found that both niosomal formulation FTS & FSB presented significantly high (p<0.05) Cmax, AUC0-t, MRT 0-inf and half-life (t1/2) as associated to plain drug dispersion. However niosomal formulation FSB exhibited better in-vivo performance as compared to FTS. It was established that CsA can be successfully entrapped in niosomes. So niosomes are promising vehicle for CsA oral delivery.


Structural insights into the assembly and activation of IL-1β with its receptors.
Interleukin 1β (IL-1β) is a key orchestrator of inflammation and host defense that exerts its effects through IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP). How IL-1RAcP is recruited by IL-1β-IL-1RI to form the signaling-competent complex remains elusive. Here we present the crystal structure of IL-1β bound to IL-1 receptor type II (IL-1RII) and IL-1RAcP. IL-1β-IL-1RII generated a composite binding surface to recruit IL-1RAcP. Biochemical analysis demonstrated that IL-1β-IL-1RI and IL-1β-IL-1RII interacted similarly with IL-1RAcP. It also showed the importance of two loops of IL-1 receptor antagonist (IL-1Ra) in determining its antagonism. Our results provide a structural basis for assembly and activation of the IL-1 receptor and offer a general cytokine-receptor architecture that governs the IL-1 family of cytokines.


Differential regulation of p21 by p53 and Rb in cellular response to oxidative stress.
Oxidative stress to mammalian cells causes cellular damage and triggers inducible cellular responses leading to cell death by apoptosis. In this paper, we report that p53 was required for programmed cell death induced by oxidative stress in both mouse and human cells and that p53 transactivation was involved in induction of oxidative cell death. Furthermore, we show that p21 was highly responsive to oxidative stress in a p53-dependent manner and that ectopic expression of p21 could increase cellular susceptibility to oxidative stress in the absence of p53. However, p21 was not required for p53-directed oxidative cell death because mouse embryo fibroblasts MEFs lacking p21(p21-/- MEFs) were still susceptible to oxidative cell death. Interestingly, bax, a cell-death mediator regulated by p53, was overexpressed in p21-/- MEFs that underwent cell death by oxidative stress, suggesting a compensation for loss of p21 that may be responsible for the existence of cell-death responses in p21-knockout mouse fibroblasts. Finally, we provide evidence that the retinoblastoma gene product (Rb) is a negative regulator of p21 and a repressor of the cellular apoptotic process. Because p21 is regulated by p53 positively and by Rb negatively, p21 may be a link between p53 and Rb in determining cell fate after oxidative damage.


Reflection-type hologram for atoms.
A cold metastable neon atomic beam was manipulated with a reflective amplitude hologram that was encoded on a silicon surface. A black-and-white pattern of atoms was reconstructed on a microchannel plate detector. The hologram used the enhanced quantum reflection developed by authors and was made of a two-dimensional array of rectangular low and high reflective cells. The surface of the high reflective cell was composed of regularly spaced roof-shaped ridges, while the low reflective cell was simply a flat surface. The hologram was the first demonstration of reflective atom-optical elements that used universal interaction between a neutral atom and solid surface.


Magnetic-Field-Dependent Equilibration of Fractional Quantum Hall Edge Modes.
Fractional conductance is measured by partitioning a ν=1 edge state using gate-tunable fractional quantum Hall (FQH) liquids of filling 1/3 or 2/3 for current injection and detection. We observe two sets of FQH plateaus 1/9, 2/9, 4/9 and 1/6, 1/3, 2/3 at low and high magnetic field ends of the ν=1 plateau, respectively. The findings are explained by magnetic field dependent equilibration of three FQH edge modes with conductance e^{2}/3h arising from edge reconstruction. The results reveal a remarkable enhancement of the equilibration lengths of the FQH edge modes with increasing magnetic field.


Variants in the dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidylate synthase genes predict early toxicity of 5-fluorouracil in colorectal cancer patients.
Adverse drug reactions to 5-fluorouracil (5-FU)-based chemotherapy have been reported to be due, in part, to genetic variants of the genes for the drug-related enzymes thymidylate synthase (TS; TYMS gene), methylenetetrahydrofolate reductase (MTHFR gene) and dihydropyrimidine dehydrogenase (DPD; DPYD gene). This study investigated whether selected genetic variants of the TYMS, MTHFR and DPYD genes predict 5-FU-related early toxicity. The prevalence of the genetic variants was determined in 122 colorectal cancer patients and in a reference population of 320 blood donors. Subgroup analysis of 68 of the colorectal cancer patients was carried out to determine the relationship between selected gene variants detected in peripheral mono nuclear cells and tolerability during the first or second cycle of 5-FU based treatment. Toxicity was linked to the TYMS 2R/2R variant (relative risk [RR] 1.66; sensitivity 0.37; specificity 0.77) and to the MTHFR c1298 C/C genetic variant (RR 1.77; sensitivity 0.17; specificity 0.91). Patients with the genetic variant IVS14+1 G/A or c1896 C/T in the DPYD gene had a statistically significant increased risk of experiencing toxicity (RR 2 and 6, respectively), both having a high specificity (0.97 and 0.98, respectively) and low sensitivity (0.04 and 0.13, respectively). It is concluded that pre-treatment detection of genetic variants can help to predict early toxicity experienced by patients receiving 5-FU-based chemotherapy.


Two outward K+ currents in bovine pigmented ciliary epithelial cells: IK(Ca) and IK(V).
Pigmented ciliary epithelial cells were studied using the whole cell voltage-clamp technique. Depolarizing steps from a holding potential of -80 mV resulted in a small initial inward current followed by a large outward current. Prolonged depolarizing voltage steps revealed inactivating and noninactivating components of outward current. Outward current was sensitive to the level of Ca2+ in the pipette and was increased by the calcium ionophore A23187; it was blocked by tetraethylammonium (TEA+), quinine, and 4-aminopyridine (4-AP). 4-AP blocked 70% of the outward current with a Ki of 7 x 10(-5) M, and part of the remaining current was abolished by Ni2+. Ni2+ caused a reduction in outward current by blocking IK(Ca) indirectly via decreasing Ca2+ entry through T-type Ca2+ channels. Separating Ni(2+)-sensitive from -insensitive outward conductance gives components that correspond notionally to IK(Ca) and IK(V), respectively. On this basis IK(Ca) represents approximately 28% of K+ outward current. Charybdotoxin blocked 26% of the outward conductance at very depolarized voltage steps as calculated from the slope of the current-voltage curve in this region. It is concluded that there are two major components to the outward current: IK(V), an inactivating voltage-sensitive K+ current, and IK(Ca), which is dependent on the entry of Ca2+ through T-type Ca2+ channels and comprises approximately a quarter of the total K+ outward current under the conditions described. Because of their relative voltage-activation properties, IK(Ca) will be the more important in terms of K+ transport and the secretion of aqueous humor by the ciliary epithelium.


Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors.
To perform a phase I clinical and pharmacologic study of ZD1694 (Tomudex, Alderley Park, United Kingdom), a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy. From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m2. Pharmacokinetic (PK) analysis was performed with the first two courses of treatment. There were 33 men and 28 women with a median age of 53 years (range, 21 to 73). Fifty-five patients (90%) had previously received chemotherapy. Reversible liver toxicity and dose-related gastrointestinal (GI) and bone marrow toxicity occurred at > or = 1.6 mg/m2. Liver function usually returned to normal with repeated treatment, but GI and bone marrow toxicities generally became more severe. No renal toxicity was observed. The maximum-tolerated dose (MTD) was 3.5 mg/m2, at which, in addition to antiproliferative toxicities, four of six patients (67%) developed severe malaise that consisted of anorexia, nausea, and asthenia, with rapidly decreasing performance status that limited re-treatment. Abnormal liver function was also seen in four patients (67%). At 3.0 mg/m2, grades III and IV diarrhea were seen in six of 23 patients (26%) and grade IV myelosuppression in two others. Liver toxicity was self-limiting and not associated with severe malaise. Two patients had a partial response to treatment. PK analysis showed that plasma elimination was triexponential, with pronounced variability in the mean terminal half-life (t1/2gamma) for a given dose ranging from 8.2 to 105 hours. There was a linear relationship between dose and both the area under the concentration-time curve (AUC) and maximum concentration (Cmax), but no clear association between these parameters and response or toxicity. The dose of ZD1694 recommended for phase II trials is 3.0 mg/m2.


FGF23-induced hypophosphatemia persists in Hyp mice deficient in the WNT coreceptor Lrp6.
Deregulated phosphate homeostasis can lead to a wide range of disorders, including myopathy, cardiac dysfunction, and skeletal abnormalities. Therefore, characterization of the molecular regulation of phosphate metabolism is of pathophysiological and clinical significance. Hyp mouse is the model for human X-linked hypophosphatemia which is due to mutations that inactivate the endopeptidases of the X chromosome (PHEX). PHEX inactivation leads to increased serum levels of fibroblast growth factor 23 (FGF23), a phosphaturic hormone that induces excessive renal phosphate excretion and severe hypophosphatemia. The expression of WNT signaling components is increased in Hyp mice. To determine the potential role of WNT signaling in FGF23-mediated hypophosphatemia, we cross-bred Hyp mice with mice deficient in the WNT coreceptor low-density lipoprotein receptor-related protein 6 (Lrp6) to generate Hyp and Lrp6 double mutant mice (Hyp/Lrp6). Like Hyp mice, Hyp/Lrp6 double mutants maintained high serum levels of FGF23, and accordingly exhibited hypophosphatemia to the same degree as the Hyp mice did, indicating that genetically reducing WNT signaling does not impact FGF23-induced phosphaturia. Moreover, similar to Hyp mice, the Hyp/Lrp6 double mutants also exhibited reduced mineralization of the bone, further supporting that reduced WNT signaling does not affect the chronic phosphate wasting caused by excess FGF23 in these mice. In further support of our finding, injection of bioactive FGF23 protein into Lrp6 mutant mice reduced serum phosphate levels to a similar degree as FGF23 injection into wild-type mice. Our in vivo studies provide genetic and pharmacological evidence for a WNT-independent function of FGF23 in the regulation of phosphate homeostasis.


The mycotoxin fumonisin B1 transiently activates nuclear factor-kappaB, tumor necrosis factor alpha and caspase 3 via protein kinase Calpha-dependent pathway in porcine renal epithelial cells.
Fumonisin B1 (FB1) is a toxic mycotoxin produced by Fusarium verticillioides, predominantly present in corn. The principal biochemical responses of FB1 involve disruption of sphingolipid metabolism from the inhibition of ceramide synthesis leading to accumulation of free sphingoid bases, particularly sphinganine. The ability of FB1 to modulate signal transduction pathways plays a role in its toxicity. We recently reported that FB1 selectively and transiently activates protein kinase Calpha (PKCalpha) in porcine renal epithelial cells (LLC-PK1). The aim of current study was to investigate the effect of PKCalpha activation by FB1 on NF-kappaB activation and subsequently on TNFalpha gene expression and caspase 3 induction in LLC-PK1 cells. FB1 (1 micromol/L for 5 min) transiently activated PKCalpha and increased nuclear translocation of NF-kappaB, followed by their down-regulation at later time points. Preincubating the cells with the PKC inhibitor, calphostin C, prevented the activation of NF-kappaB by FB1. TNFalpha mRNA expression was increased after 15 min exposure to FB1 or the PKC activator, phorbol 12-myristate 13-acetate. In addition, an increase in caspase 3 activity was observed after addition of FB1 for 1 h. Calphostin C prevented both the FB1-induced increase in TNFalpha expression and caspase 3 activation. In summary, we hereby demonstrate that the FB1 activation of NF-kappaB and sequential induction of TNFalpha expression resulting in the subsequent increase in caspase 3 activity are all dependent on PKCalpha stimulation in LLC-PK1 cells.


An esthetic approach to vertical root extrusion in a patient with an anterior open bite: report of case.
A previous attempt to locate the root canal system in the maxillary left central incisor with a bur created a perforating root defect at the level of the alveolar crest. The patient received root canal therapy. Next, vertical root extrusion was chosen to expose sound tooth structure apical to the defect so that a crown could be constructed. With an anterior open bite, the natural crown was left intact and it was possible to position the anchor bar in an incisal and lingual position, maintaining esthetics for the patient during both the extrusive and stabilization phases of treatment.


Serum protein electrophoretogram profile detected in apparently healthy cats infected with Leishmania infantum - Short communication.
The information about the clinical features of Leishmania infantum infection in cats is scarce. In this study, we evaluated the serum protein electrophoresis of samples from 19 infected but apparently healthy cats. To detect L. infantum infection, two serological tests, i.e. western blot (WB) and enzyme-linked immunosorbent assay (ELISA) as well as quantitative polymerase chain reaction (qPCR) on the blood samples were performed. Eventual infection by several selected bacterial and viral pathogens was also tested. All but one of the cats were found positive with WB. The WB-negative cat was positive by ELISA only. From the 18 WB-positive cats, only three were positive also by ELISA and eight with qPCR, including the only animal which was positive in all the three tests. No concomitant infections were detected in any of the cats. The main alteration of the proteinogram was characterised by an increase of the α-2 fraction. In the five cats with hypergammaglobulinaemia, the pattern detected was polyclonal. None of the cats were seropositive to any other pathogens tested. The presence of polyclonal gammopathy and elevation of the α-2 fraction could suggest the presence of active infection. In contrast, the only detection of an increase of the α-2 fraction alone with the presence of positive serological result could be associated by immune response activation against L. infantum.


Partially multiplexing sensor network exploiting low coherence interferometry.
A partially multiplexed fiber-optic-based sensor network based on low coherence interferometry is reported for which the scanning interferometer simultaneously sweeps the coherence-matched region of each sensor. The advantage of this approach is that the signal-to-noise ratio is maximized while the cross talk between sensors is minimized. The normal requirement that each sensor must be fabricated with a different length also does not apply. The concept is demonstrated by multiplexing two bulk optic Michelson interferometers. A resolution of ~ 50 nm with an operational range of 200 microm was achieved in the prototype system.


Caring for a family member with chronic mental illness.
The aim of the phenomenological study described in this article was to depict the lived world of caring for a family member with chronic mental illness. Through two individual in-depth interviews, 14 participants were asked to describe their experience of caring for a son, daughter, or parent affected by chronic mental illness. The main themes emerging from the study related to temporality, the need to "live each day as it comes" without being able to make long-term plans, and to relationality, the need to "look at the world through the other's window," always aware of how the world responds, not only to oneself but also to the person with mental illness.


Dural Reconstruction Using Laparoscopic Gastro-omental Free Flap in Refractory Cranial Infections.
Epidural abscesses and subdural empyema after craniotomy are potentially lethal complications in neurosurgery. Patients with recalcitrant cranial wound infections may be difficult to manage, and dural reconstruction in these patients is challenging. A total of 14 patients presented with recurrent intracranial infection after craniotomy. The symptoms and signs included persistent fever, despite prolonged systemic broad-spectrum antibiotic administration and repetitive debridement of the dural space. They underwent reconstruction with an omental free flap to cover the craniotomy defect. Microvascular anastomosis is usually performed between the gastroepiploic and superficial temporal vessels. Surgeries were performed in the chronic stages of infection, and the patients were reviewed and assessed for recurrence over the long-term postoperatively. The postoperative course was uneventful, and flap survival was excellent in all patients. The patients were discharged with no evidence of wound discharge, and there were no reports of infection recurrence, flap failure, or donor site morbidity. The use of vascularized free omentum flap was effective in cases involving intractable cranial wound infection.


Optimal assembly for high throughput shotgun sequencing.
We present a framework for the design of optimal assembly algorithms for shotgun sequencing under the criterion of complete reconstruction. We derive a lower bound on the read length and the coverage depth required for reconstruction in terms of the repeat statistics of the genome. Building on earlier works, we design a de Brujin graph based assembly algorithm which can achieve very close to the lower bound for repeat statistics of a wide range of sequenced genomes, including the GAGE datasets. The results are based on a set of necessary and sufficient conditions on the DNA sequence and the reads for reconstruction. The conditions can be viewed as the shotgun sequencing analogue of Ukkonen-Pevzner's necessary and sufficient conditions for Sequencing by Hybridization.


High IFN-γ Release and Impaired Capacity of Multi-Cytokine Secretion in IGRA Supernatants Are Associated with Active Tuberculosis.
Interferon gamma (IFN-γ) release assays (IGRAs) detect Mycobacterium tuberculosis (Mtb) infection regardless of the active (ATB) or latent (LTBI) forms of tuberculosis (TB). In this study, Mtb-specific T cell response against region of deletion 1 (RD1) antigens were explored by a microbead multiplex assay performed in T-SPOT TB assay (T-SPOT) supernatants from 35 patients with ATB and 115 patients with LTBI. T-SPOT is positive when over 7 IFN-γ secreting cells (SC)/250 000 peripheral blood mononuclear cells (PBMC) are enumerated. However, over 100 IFN-γ SC /250 000 PBMC were more frequently observed in the ATB group compared to the LTBI group. By contrast, lower cytokine concentrations and lower cytokine productions relative to IFN-γ secretion were observed for IL 4, IL-12, TNF-α, GM-CSF, Eotaxin and IFN-α when compared to LTBI. Thus, high IFN-γ release and low cytokine secretions in relation with IFN-γ production appeared as signatures of ATB, corroborating that multicytokine Mtb-specific response against RD1 antigens reflects host capacity to contain TB reactivation. In this way, testing cytokine profile in IGRA supernatants would be helpful to improve ATB screening strategy including immunologic tests.


The Rapid Reduction of Infection-Related Visits and Antibiotic Use Among People With Cystic Fibrosis After Starting Elexacaftor-Tezacaftor-Ivacaftor.
People with cystic fibrosis (CF) routinely suffer from recurrent sinopulmonary infections. Such infections require frequent courses of antimicrobials and often involve multidrug-resistant organisms. The goal of this study was to identify real-world evidence for the effectiveness of elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) in decreasing infection-related visits and antimicrobial use in people with CF. Using IBM MarketScan data, we identified 389 enrollees with CF who began taking ELX/TEZ/IVA before 1 December 2019 and were enrolled from 1 July 2019 to 14 March 2020. We also identified a comparison population who did not begin ELX/TEZ/IVA during the study period. We compared the following outcomes in the 15 weeks before and after medication initiation: total healthcare visits, inpatient visits, infection-related visits, and antimicrobial prescriptions. We analyzed outcomes using both a case-crossover analysis and a difference-in-differences analysis, to control for underlying trends. For the case-crossover analysis, ELX/TEZ/IVA initiation was associated with the following changes over a 15-week period: change in overall healthcare visit dates, -2.5 (95% confidence interval, -3.31 to -1.7); change in inpatient admissions, -0.16 (-.22 to -.10); change in infection-related visit dates, -0.62 (-.93 to -.31); and change in antibiotic prescriptions, -0.78 (-1.03 to -.54). Results from the difference-in-differences approach were similar. We show a rapid reduction in infection-related visits and antimicrobial use among people with CF after starting a therapy that was not explicitly designed to treat infections. Currently, there are >30 000 people living with CF in the United States alone. Given that this therapy is effective for approximately 90% of people with CF, the impact on respiratory infections and antimicrobial use may be substantial.


Review: A review on classical and atypical scrapie in caprine: Prion protein gene polymorphisms and their role in the disease.
Scrapie is a naturally occurring transmissible spongiform encephalopathy in sheep and goat. It has been known for ~250 years and is characterised by the accumulation of an abnormal isoform of a host-encoded prion protein that leads to progressive neurodegeneration and death. Scrapie is recognised in two forms, classical and atypical scrapie. The susceptibility to both types of scrapie is influenced by polymorphisms of the prion protein gene (PRNP). Sheep susceptibility or resistance to classical scrapie is strongly regulated by the polymorphisms at codons 136, 154 and 171 of the PRNP. The genetic role in atypical scrapie in sheep has been defined by polymorphisms at codons 141, 154 and 171, which are associated with different degrees of risk in the occurrence of the ovine disease. Progress has been achieved in the prevention of scrapie in sheep due to efficient genetic breeding programmes based on eradication and control of the disease. In Europe, the success of these programmes has been verified by applying eradication and genetic selection plans. In general terms, the ovine selection plans aim to eliminate and reduce the susceptible allele and to enrich the resistant allele ARR. During outbreaks all susceptible animals are slaughtered, only ARR/ARR resistant rams and sheep and semi-resistant females are preserved. In the occurrence of scrapie positive goats a complete cull of the flock (stamping out) is performed with great economic loss and severe risk of extinction for the endangered breeds. The ability to select scrapie-resistant animals allows to define new breeding strategies aimed to boost genetic progress while reducing costs during scrapie outbreaks. Allelic variants of PRNP can be protective for caprine scrapie, and the knowledge of their distribution in goats has become very important. Over the past few years, the integration of genetic information on goat populations could be used to make selection decisions, commonly referred to as genetic selection. The objective of this review was to summarise the main findings of polymorphisms of the caprine prion protein (PrP) gene and to discuss the possible application of goat breeding schemes integrating genetic selection, with their relative advantages and limitations.


Mouse hepatocyte growth factor activator inhibitor type 1 (HAI-1) and type 2 (HAI-2)/placental bikunin genes and their promoters.
Hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1) and type 2 (HAI-2) were recently discovered as specific inhibitors of HGF activator. Each of them contains two Kunitz-type serine protease inhibitor domains and a transmembrane domain, so that their overall structures are similar to each other. In this study, mouse genes encoding HAI-1 and HAI-2 were cloned by screening of a mouse genomic bacterial artificial chromosome library and by polymerase chain reaction of mouse genomic DNA, respectively. The genes (mHAI-1 and mHAI-2) were defined to consist of 11 and eight exons spanning 11 kbp and 9.5 kbp, respectively. Neither a TATA nor CAAT box was found in 5'-flanking regions of both genes and no apparent homologous portion was observed between mHAI-1 and mHAI-2 promoter regions. Promoter assay of mHAI-1 and human HAI-1 revealed that the potential binding sites of a complex of Egr-1-3 and Sp1, which was well-conserved between human (-42 to -58) and mouse (-44 to -57), might be a key portion of its transcriptional regulation to function as not only house-keeping but also early responsive genes.


Synergistic effect of optimizing light-emitting diode illumination quality and intensity to manipulate composition of fatty acid methyl esters from Nannochloropsis sp.
In the study, the relationship between the quality and intensity of LED illumination with FAMEs produced were investigated. Nannochloropsis sp. was cultivated for 14 days under different intensities of 100, 150 and 200 μmol photons m(-2) s(-1) of red, blue and mixed red blue LED. The findings revealed that suitable combination of LED wavelengths and intensity; (red LED: 150, blue: 100 and mixed red blue: 200 μmol photons m(-2) s(-1)) produced maximum biomass growth and lipid content. It was observed that the quality and intensity of LED significantly influenced the composition of FAMEs. FAMEs produced under blue LED has high degree of unsaturation (DU) and low cetane number while those under red LED has low DU but higher CN. The combination of red blue LED has produced FAMEs with high ignition and lubricating property and also good oxidation stability indicated by the DU and CN values which lies midway between the red and blue.


Nonreplicability of seasonal rhythm in REM sleep in a subtropical climate.
The present paper attempts to replicate Askenasy and Goldstein's (1995) findings of seasonality in rapid eye movement (REM) sleep measures in patients recorded in Israel. Analysis of sleep stage data of 706 nonselected male sleep apnea patients failed to find seasonality in REM sleep measures. In contrast, our data revealed stability of REM time with a maximum difference between seasons of 7.0 minutes. Age differences were found in sleep efficiency, true sleep time, and amount and percentage of REM sleep, with patients over 60 having a lower sleep efficiency, shorter true sleep, and REM sleep time than patients under 60. Rapid eye movement latency was also found to differ according to apnea severity, with patients who had > 40 apneas and hypopneas per hour of sleep having a longer latency than those with fewer apneas and hypopneas.


Effect of phacoemulsification surgery on intraocular pressure and function of bleb after trabeculectomy.
To evaluate the effect of phacoemulsification (PE) surgery on intraocular pressure (IOP) control and morphology of filtering bleb in eyes that have previously had trabeculectomy in the long-term. This retrospective study included 98 eyes of 93 patients who had undergone trabeculectomy first and then PE surgery. The IOP, morphology of bleb, the number of glaucoma medication of each patient before PE, and 1 day, 1 month, 3 months, 1 year, 2 years after PE, and at the last visit were recorded. The need for additional glaucoma medication or glaucoma surgery were noted. Surgical success was defined as 6 mmHg ≤ IOP ≤ 21 mm Hg at the 3rd month, 1st year, and 2nd year follow-up visit, without additional medication or surgery. Before PE the IOP was ≤ 21 mmHg in all of the eyes. At the last visit, the IOP was ≤ 21 mmHg in 6 eyes with fewer glaucoma medication, in 24 eyes with the same number, and in 36 eyes with more. There was an increase in the number of glaucoma medications on each visit (p < 0.05). There was a statistically significant difference in bleb morphologies between before PE and each visit after PE (p < 0.001). Surgical success after PE was obtained in 52 eyes, additional glaucoma medication was needed in 36 eyes, and additional surgical procedures were required in 14 eyes. Phacoemulsification surgery may increase the number of glaucoma medications and the mean IOP and also may reduce the function of bleb in eyes that underwent trabeculectomy.


Infant wariness toward strangers reconsidered: infants' and mothers' reactions to unfamiliar persons.
In this study, the interpretation of infants' responses to approaching strangers as "wariness" or "fear" was questioned by comparing infants' behaviors toward strangers with adults' behaviours toward strangers. 24 8-month-old infants and their mothers were observed in a standard laboratory situation. Both infants and mothers were approached by female strangers with a fast, 12-sec approach and a slow, 40-sec approach. Mothers' and infants' behaviors were coded at 4 distances during each approach. Behaviors coded were smile, alert face, quizzical look, frown, looks at mother/infant, looks at stranger, and averts gaze. Mothers showed significantly more behaviors typically labeled "wary" than did infants, particularly as the proximity of the stranger increased. These findings suggest that wary responses toward strangers are not unique to infants and may be more characteristic of the situation than of the developmental level of the individual.


Has fetal echocardiography improved the prognosis of congenital heart disease? Comparison of patients with hypoplastic left heart syndrome with and without prenatal diagnosis.
As prenatal diagnosis of congenital heart disease has gained in popularity, the questions of whether prenatal diagnosis of congenital heart disease is beneficial for the patient and whether fetal echocardiography has improved the prognosis of congenital heart disease are arising. We compared four patients with prenatally diagnosed hypoplastic left heart syndrome (HLHS) with 10 patients of non-prenatally diagnosed HLHS from the view points of (i) age at transfer to our Children's Hospital; (ii) whether the oxygen was inhaled during perinatal period; (iii) whether prostaglandin E1 was administered in the period of waiting before operation; (iv) whether the patient had ductal shock; (v) timing of operation; and (vi) surgical outcome. The timing of the transfer to our Children's Hospital was earlier in prenatally diagnosed group than in non-diagnosed group. Oxygen was not given to any of the patients in prenatally diagnosed group. In contrast, oxygen inhalation was given in two of 10 patients in the non-prenatally diagnosed group. Prostaglandin E1 was administrated in three of four patients in the prenatally diagnosed group and seven of 10 patients in the non-prenatally diagnosed group. In terms of ductal shock, none of the patients in prenatally diagnosed group had ductal shock. However, four of 10 patients had ductal shock in the non-prenatally diagnosed group. The median age at Norwood operation was 7 days in the prenatally diagnosed group; however, it was 19 days in non-prenatally diagnosed group. Surgical outcomes showed no significant changes between the two groups. Prenatal diagnosis of HLHS was surely beneficial for preventing ductal shock and for keeping the patients' preoperative condition good.


A single-center experience of the usefulness of caliceal-pelvic height in three different lithotripters.
Stone-free rates for lower caliceal stones after Extracorporeal Shockwave Lithotripsy (SWL) are persistently poor. As stone-free rates vary with lithotripter type, we have compared the applicability of caliceal-pelvic height (CPH) in the prediction of stone clearance in patients treated with three different lithotripters within one center. Four hundred seventy adult patients with solitary, radiopaque, lower caliceal stones of size 6 to 10 mm receiving primary SWL between January 1992 and June 2002 were identified. They were treated with one of three lithotriptors: the Wolf Piezolith 2300, the Dornier MPL 9000, and the Dornier Compact Delta. Pretreatment intravenous urograms were reviewed and CPH, the vertical distance from the lowermost point of the calix to the highest point of the lower lip of pelvis, was measured. The primary end-point was stone-free status after 3 months. Adjusted odds ratios (AORs) of different potential predictor variables for the overall results and individual machines were estimated using multiple logistic regression. In the overall analysis, stone size and machine type were the only predictors associated with stone clearance. While smaller stones had better clearance overall, the MPL 9000 appears to have the best performance, followed by the Piezolith 2300. However, after patients were stratified into different machine subgroups, CPH became a significant predictor of stone-free rate for the Piezolith 2300 (AOR = 0.960; 95% CI 0.925, 0.960; P = 0.031), but not the other two machines. CPH was only useful in the prediction of lower caliceal stone clearance for the Piezolith 2300. Therefore the usefulness of one anatomic factor to assess treatment using one lithotripter may not be extrapolated to other machines.


Bisphosphonates: atypical fractures?
A disturbing series of atypical hip fractures in patients receiving long-term bisphosphonate therapy was recently published. An unusual radiological pattern of cortical thickening was sometimes observed.


Significant modulation of the hepatic proteome induced by exposure to low temperature in Xenopus laevis.
The African clawed frog, Xenopus laevis, is an ectothermic vertebrate that can survive at low environmental temperatures. To gain insight into the molecular events induced by low body temperature, liver proteins were evaluated at the standard laboratory rearing temperature (22°C, control) and a low environmental temperature (5°C, cold exposure). Using nano-flow liquid chromatography coupled with tandem mass spectrometry, we identified 58 proteins that differed in abundance. A subsequent Gene Ontology analysis revealed that the tyrosine and phenylalanine catabolic processes were modulated by cold exposure, which resulted in decreases in hepatic tyrosine and phenylalanine, respectively. Similarly, levels of pyruvate kinase and enolase, which are involved in glycolysis and glycogen synthesis, were also decreased, whereas levels of glycogen phosphorylase, which participates in glycogenolysis, were increased. Therefore, we measured metabolites in the respective pathways and found that levels of hepatic glycogen and glucose were decreased. Although the liver was under oxidative stress because of iron accumulation caused by hepatic erythrocyte destruction, the hepatic NADPH/NADP ratio was not changed. Thus, glycogen is probably utilized mainly for NADPH supply rather than for energy or glucose production. In conclusion, X. laevis responds to low body temperature by modulating its hepatic proteome, which results in altered carbohydrate metabolism.


The effects of regular inhaled formoterol and budesonide on preformed Th-2 cytokines in mild asthmatics.
In a recent placebo-controlled study in mild atopic asthmatics, we observed a significant decrease in eosinophils in the bronchial submucosa, after 2 months oftreatment with inhaled formoterol and budesonide. Biopsy material from each treatment group; formoterol (24 microg bid), budesonide (400 microg b. i. d.) and placebo has been further assessed to investigatethe role of Th-2 cytokines by immunohistochemistry using Mabs to eosinophils as an index of inflammation, IL-4 and IL-5. Treatment with formoterol significantly reduced the number of eosinophils (EG2+) in the submucosa and epithelium, but this was not paralleled by changes in cytokine immunoreactivity In contrast, treatment with budesonide significantly reduced both the number of eosinophils (EG2+) and immunoreactivity for IL-4 and IL-5 in the submucosa. Thus, while budesonide has effects on cytokines involved in eosinophil recruitmentthis explanation does not apply tothe eosinopaenia observed with the long-acting beta2 adrenoreceptor agonist formoterol.


Application of ALOGPS to predict 1-octanol/water distribution coefficients, logP, and logD, of AstraZeneca in-house database.
The ALOGPS 2.1 was developed to predict 1-octanol/water partition coefficients, logP, and aqueous solubility of neutral compounds. An exclusive feature of this program is its ability to incorporate new user-provided data by means of self-learning properties of Associative Neural Networks. Using this feature, it calculated a similar performance, RMSE = 0.7 and mean average error 0.5, for 2569 neutral logP, and 8122 pH-dependent logD(7.4), distribution coefficients from the AstraZeneca "in-house" database. The high performance of the program for the logD(7.4) prediction looks surprising, because this property also depends on ionization constants pKa. Therefore, logD(7.4) is considered to be more difficult to predict than its neutral analog. We explain and illustrate this result and, moreover, discuss a possible application of the approach to calculate other pharmacokinetic and biological activities of chemicals important for drug development.


Molecular Epidemiology of Tuberculosis in British Columbia, Canada: A 10-Year Retrospective Study.
Understanding regional molecular epidemiology allows for the development of more efficient tuberculosis prevention strategies in low-incidence settings. We analyzed 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) genotyping for 2290 Mycobacterium tuberculosis clinical isolates collected in the province of British Columbia (BC), Canada, in 2005-2014. Laboratory data for each isolate were linked to case-level clinical and demographic data. These data were used to describe the molecular epidemiology of tuberculosis across the province. We detected >1500 distinct genotypes across the 4 major M. tuberculosis lineages, reflecting BC's diverse population. Disease site and clustering rates varied across lineages, and MIRU-VNTR was used to group the 2290 isolates into 189 clusters (2-70 isolates per cluster), with an overall clustering rate of 42.4% and an estimated local transmission rate of 34.1%. Risk factors for clustering varied between Canadian-born and foreign-born individuals; the former had increased odds (odds ratio, 7.8; 95% confidence interval [CI], 6.2-9.6) of belonging to a genotypic cluster, although nearly one-quarter of clusters included both Canadian- and foreign-born persons. Large clusters (≥10 cases) occurred more frequently within the M. tuberculosis Euro-American lineage, and individual-level risk factors associated with belonging to a large cluster included being Canadian born (adjusted odds ratio, 3.3; 95% CI, 2.3-4.8), residing in a rural area (2.3; 1.2-4.5), and illicit drug use (2.0; 1.2-3.4). Although tuberculosis in BC largely arises through reactivation of latent tuberculosis in foreign-born persons, locally transmitted infections occur in discrete populations with distinct disease and risk factor profiles, representing groups for targeted interventions.


Insecticidal, Antimalarial, and Antileishmanial Effects of Royal Jelly and Its Three Main Fatty Acids, trans-10-Hydroxy-2-decenoic Acid, 10-Hydroxydecanoic Acid, and Sebacic Acid.
Natural products and their derivatives as an inexpensive, accessible, and useful alternative medicine are broadly applied for the treatment of a wide range of diseases and infectious ones. The present study was designed to evaluate the insecticidal, antimalarial, antileishmanial, and cytotoxic effects of royal jelly and its three main fatty acids (trans-10-hydroxy-2-decenoic acid (10-H2DA), 10-hydroxydecanoic acid (10-HDAA), sebacic acid (1,10-decanedioic acid)). Insecticidal activity of RJ and 10-H2DA, 10-HDAA, and sebacic acid was performed against healthy 4th instar larvae at 25 ± 2°C. Antiplasmodial and antileishmanial effects of RJ and 10-H2DA, 10-HDAA, and sebacic acid were also performed against chloroquine-resistant Plasmodium falciparum K1-strain and Leishmania major amastigotes according to the Malstat method and macrophage model, respectively. In addition, the level of nitric oxide (NO) production in J774-A1 macrophages cells, plasma membrane permeability, and caspase-3-like activity and cytotoxicity effects of RJ and 10-H2DA, 10-HDAA, and sebacic acid against human embryonic kidney 293 (HEK239T cells) were evaluated. Considering the insecticidal activity, the results showed that the lethal concentration 50% value for RJ, 10-H2DA, 10-HDAA, and sebacic acid was 24.6, 31.4, 37.8, and 44.7 μg/mL μg/mL, respectively. RJ, 10-H2DA, 10-HDAA, and sebacic acid showed potent (P < 0.0001) antileishmanial effects with IC50 values ranging from 2.4 to 8.4 μg/mL. Various concentrations of RJ, 10-H2DA, 10-HDAA, and sebacic acid significantly (P < 0.05) increased the production of NO, plasma membrane permeability, and caspase-3-like activity level as a dose-dependent response. Considering the cytotoxicity, SIs > 10 of these compounds exhibited their specificity to parasites and safety against human HEK239T normal cells. The results of the present investigation revealed the promising insecticidal, antimalarial, and antileishmanial effects of RJ and its three main fatty acids (10-H2DA, 10-HDAA, and sebacic acid). However, more studies are required to confirm the mechanisms of action mode of these compounds as well as their efficacy in animal models and clinical settings.


Ultrasonic evaluation with second harmonic imaging and SonoVue in the assessment of cerebral perfusion in diabetic patients: a case-control study.
The purpose was to compare human brain tissue perfusion in diabetic patients and healthy subjects with second harmonic imaging ultrasound and SonoVue to test the hypothesis that brain tissue perfusion differences are present in these two groups of patients. In a prospective case-control study, second harmonic examinations performed in 20 patients with type II diabetes mellitus and in 20 matched control patients were compared. After administration of 2.5 ml of SonoVue, 60 time-triggered images were recorded. Time-intensity curves, including peak intensity and positive gradient normalized to the middle cerebral artery, were calculated to quantify ultrasound intensity in a region of interest. The Mann-Whitney U-test was used to reveal any differences between healthy and diabetic subjects. Mean peak intensity was 0.64+/-0.1 Au in healthy subjects and 0.53+/-0.09 Au in diabetic patients. Mean positive gradient was 0.04+/-0.007 Au/s in healthy subjects and 0.04+/-0.008 Au/s in diabetic patients. Peak intensity and positive gradient were significantly lower in diabetic patients than in healthy subjects (P<0.05). Ultrasound examination with second harmonic imaging and SonoVue administration is able to detect clinically silent, reduced cerebral perfusion in type II diabetic patients. Diabetic patients have reduced cerebral perfusion in comparison to healthy subjects.


Solid phase in vitro mutagenesis using plasmid DNA template.
Site-specific mutagenesis was accomplished using a solid support to generate single stranded vector and insert fragments which can be used to form gap-duplex plasmids through flanking, complementary double stranded regions. More than 80% mutants were obtained in both a single and a double primer approach. No special vectors or strains are needed and mismatch repair is avoided as the mutagenesis region is in a single stranded form when transformed into the Escherichia coli host cell. The fragments to be immobilized can be produced either by a polymerase chain reaction using general primers or by a site-specific restriction followed by a fill-in reaction. This novel method is rapid, simple and flexible and well suited for both manual and semi-automated in vitro mutagenesis protocols.


Effect of IFN-gamma and IFN-alpha on killing of human trophoblast by decidual LAK cells.
Human decidual large granular lymphocytes are capable of killing both normal trophoblast and choriocarcinoma cells after stimulation with recombinant interleukin-2 (rIL-2) in vitro. We now show that pre-treatment of normal trophoblast and JEG-3 choriocarcinoma cells with interferon-gamma (IFN-gamma) protects these target cells from killing by decidual effectors, although pre-treatment with interferon-alpha (IFN-alpha) had no such effect. In contrast, JAR choriocarcinoma cells were readily killed before and after exposure to both IFN-gamma and IFN-alpha. This protective effect might be due to upregulation of non-classical trophoblast HLA Class I molecules, as IFN-gamma but not IFN-alpha enhances Class I surface expression in both normal trophoblast and JEG-3 choriocarcinoma cells. JAR cells, however, are constitutively and inductively negative for Class I expression.


The contribution of hibernation to heart failure.
For many years the functional sequelae of chronic coronary artery disease (CAD) were considered irreversible. Evidence accrued over the past three decades proves that this concept is not necessarily true. Non-randomised studies demonstrated that coronary revascularisation (CR) confers symptomatic and prognostic benefits to patients with CAD and heart failure. Based on available studies, one can assume that the beneficial effect of CR in heart failure derives primarily from recovery of contractile function in 'hibernating myocardium' (HM), i.e., chronically dysfunctional, but viable, myocardium subtended by stenosed coronary arteries which recovers after CR. Cardiac imaging with echocardiography, single photon and positron emission tomography (PET) and magnetic resonance allows the identification of HM. These techniques have comparable predictive values in patients with moderate left ventricular impairment. PET studies have shown that resting myocardial blood flow is preserved in most cases of HM while its main feature is a severe impairment of coronary flow reserve. Thus, the pathophysiology of HM is more complex than initially postulated. Recent evidence that repetitive ischaemia in patients can be cumulative and lead to more severe and prolonged stunning, lends further support to the hypothesis that, at least initially, stunning and HM are two facets of the same coin.