Structural insights into the substrate selectivity of α-oxoamine synthases from marine Vibrio sp. QWI-06.
Pyridoxal phosphate (PLP)-dependent α-oxoamine synthases are generally believed to be responsible for offloading and elongating polyketides or catalyzing the condensation of amino acids and acyl-CoA thioester substrates, such as serine into sphingolipids and cysteate into sulfonolipids. Previously, we discovered vitroprocines, which are tyrosine- and phenylalanine-polyketide derivatives, as potential new antibiotics from the genus Vibrio. Using bioinformatics analysis, we identified putative genes of PLP-dependent enzyme from marine Vibrio sp. QWI-06, implying a capability to produce amino-polyketide derivatives. One of these genes was cloned, and the recombinant protein, termed Vibrio sp. QWI-06 α-oxoamine synthases-1 (VsAOS1), was overexpressed for structural and biochemical characterization. The crystal structure of the dimeric VsAOS1 was determined at 1.8-Å resolution in the presence of L-glycine. The electron density map indicated a glycine molecule occupying the pyridoxal binding site in one monomer, suggesting a snapshot of the initiation process upon the loading of amino acid substrate. In mass spectrometry analysis, VsAOS1 strictly acted to condense L-glycine with C12 or C16 acyl-CoA, including unsaturated acyl analog. Furthermore, a single residue replacement of VsAOS1 (G243S) allowed the enzyme to generate sphingoid derivative when L-serine and lauroyl-CoA were used as substrates. Our data elucidate the mechanism of substrate binding and selectivity by the VsAOS1 and provide a thorough understanding of the molecular basis for the amino acid preference of AOS members.


Stimulation of tyrosine phosphorylation after ligation of beta7 and beta1 integrins on human B cells.
B lymphocytes express several members of the integrin family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. In addition to beta1 integrins, predominantly alpha4 beta1, mature B cells also express alpha4 beta7, which is a receptor for vascular cell adhesion molecule-1 and fibronectin, and is also involved in the homing of B cells to mucosal sites through binding to a third ligand, mucosal address in cell adhesion molecule-1. Here we describe that crosslinking of alpha4 beta7 integrins on B cell lines and normal tonsillar B cells, induces tyrosine phosphorylation of multiple substrates of 105-130 kD, indicating that beta7 integrin plays a role as signaling molecule in B cells. This pattern of phosphorylated proteins was very similar to that induced following ligation of alpha4 beta1. Interestingly, ligation of alpha5 beta1 or alpha6 beta1 also stimulated the 105-125 kD group of phosphorylated proteins, whereas ligation of beta2 integrins did not. The focal adhesion tyrosine kinase p125FAK was identified as one of these substrates. Beta1 or beta7 mediated tyrosine phosphorylations were markedly decreased when the microfilament assembly was inhibited by cytochalasin B. These results suggest that intracellular signals initiated by different integrins in B cells may converge, to similar cytoskeleton-dependent tyrosine phosphorylated proteins.


Can the deployment of community health workers for the delivery of HIV services represent an effective and sustainable response to health workforce shortages? Results of a multicountry study.
In countries severely affected by HIV/AIDS, shortages of health workers present a major obstacle to scaling up HIV services. Adopting a task shifting approach for the deployment of community health workers (CHWs) represents one strategy for rapid expansion of the health workforce. This study aimed to evaluate the contribution of CHWs with a focus on identifying the critical elements of an enabling environment that can ensure they provide quality services in a manner that is sustainable. The method of work included a collection of primary data in five countries: Brazil, Ethiopia, Malawi, Namibia, and Uganda. The findings show that delegation of specific tasks to cadres of CHWs with limited training can increase access to HIV services, particularly in rural areas and among underserved communities, and can improve the quality of care for HIV. There is also evidence that CHWs can make a significant contribution to the delivery of a wide range of other health services. The findings also show that certain conditions must be observed if CHWs are to contribute to well-functioning and sustainable service delivery. These conditions involve adequate systems integration with significant attention to: political will and commitment; collaborative planning; definition of scope of practice; selection and educational requirements; registration, licensure and certification; recruitment and deployment; adequate and sustainable remuneration; mentoring and supervision including referral system; career path and continuous education; performance evaluation; supply of equipment and commodities. The study concludes that, where there is the necessary support, the potential contribution of CHWs can be optimized and represents a valuable addition to the urgent expansion of human resources for health, and to universal coverage of HIV services.


The economic disease burden of measles in Japan and a benefit cost analysis of vaccination, a retrospective study.
During 1999-2003, Japan experienced a series of measles epidemics, and in Action Plans to Control Measles and the Future Problems, it was proposed that infants be immunized soon after their one-year birthday.In this study, we attempted to estimate the nationwide economic disease burden of measles based on clinical data and the economic effectiveness of this proposal using the benefit cost ratio. Our survey target was measles patients treated at Chiba-Nishi general hospital from January 1999 to September 2001. Two hundred ninety-one cases were extracted from the database. The survey team composed of 3 pediatricians and 1 physician from Chiba-Nishi general hospital examined patient files and obtained additional information by telephone interview.We analyzed data based on a static model, which assumed that the number of measles patients would be zero after 100% coverage of single-antigen measles vaccine.Costs were defined as the direct cost for measles treatment, vaccination and transportation and the indirect cost of workdays lost due to the nursing of patients, hospital visits for vaccination or nursing due to adverse reactions. Benefits were defined as savings on direct and indirect costs. Based on these definitions, we estimated the nationwide costs of treatment and vaccination. Using our static model, the nationwide total cost for measles treatment was estimated to be US$ 404 million, while the vaccination cost was US$165 million. The benefit cost ratio of the base case was 2.48 and ranged from 2.21 to 4.97 with sensitivity analysis. Although the model has some limitations, we conclude that the policy of immunizing infants soon after their one-year birthday is economically effective.


Extensive conservation of sex chromosome organization between cat and human revealed by parallel radiation hybrid mapping.
A radiation hybrid (RH)-derived physical map of 25 markers on the feline X chromosome (including 19 Type I coding loci and 6 Type II microsatellite markers) was compared to homologous marker order on the human and mouse X chromosome maps. Complete conservation of synteny and marker order was observed between feline and human X chromosomes, whereas the same markers identified a minimum of seven rearranged syntenic segments between mouse and cat/human X chromosome marker order. Within the blocks, the feline, human, and mouse marker order was strongly conserved. Similarly, Y chromosome locus order was remarkably conserved between cat and human Y chromosomes, with only one marker (SMCY) position rearranged between the species. Tight linkage and a conserved gene order for a segment encoding three genes, DFFRY-DBY-UTY in human, mouse, and cat Y chromosomes, coupled with demonstrated deletion effects of these genes on reproductive impairment in both human and mouse, implicates the region as critical for Y-mediated sperm production.


[Fearfulness in animals--a zoological and forensic problem].
The recognition and the assessment of anxiety and fear in animals is discussed regarding zoological, forensic and ethical aspects. Following some definitions it is shown that fear, anxiety and other emotions are generally assessed by analogous reasoning and "Du-Evidenz". This causes scientific and forensic problems which are discussed. Towards a more adequate assessment of emotions in animals a zoological approach based on integrated ethological and stress-physiological theories and methods is proposed.


The band shifts in MoS2(0001) and WSe2(0001) induced by palladium adsorption.
The band structures of the transition metal dichalcogenides (TMD's) 2H-MoS2(0001) and 2H-WSe2(0001), before and after palladium adsorption, were investigated through angle-resolved photoemission. Palladium adsorption on 2H-MoS2(0001) is seen to result in very different band shifts than seen for palladium on 2H-WSe2(0001). The angle resolved photoemission results of palladium adsorbed on WSe2(0001) indicate that palladium accepts electron density from substrate. The resulting band shift will lead to a decrease in the barriers to the hole injection. The opposite band shifts occur upon palladium adsorption between 2H-MoS2(0001). The overall trend is consistent with the deposition of other metals deposited on TMD's, except that for palladium adsorption on MoS2(0001), there is an increase in the MoS2(0001) substrate band gap with palladium adsorption, as is evident from the combination of photoemission and inverse photoemission.


ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties.
Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein expressed in approximately 40-75% of breast cancers. GPNMB/OA promotes the migration, invasion and metastasis of breast cancer cells; it is commonly expressed in basal/triple-negative breast tumors and is associated with shorter recurrence-free and overall survival times in patients with breast cancer. Thus, GPNMB/OA represents an attractive target for therapeutic intervention in breast cancer; however, little is known about the functions of GPNMB/OA within the primary tumor microenvironment. We have employed mouse and human breast cancer cells to investigate the effects of GPNMB/OA on tumor growth and angiogenesis. GPNMB/OA-expressing tumors display elevated endothelial recruitment and reduced apoptosis when compared to vector control-derived tumors. Primary human breast cancers characterized by high vascular density also display elevated levels of GPNMB/OA when compared to those with low vascular density. Using immunoblot and ELISA assays, we demonstrate the GPNMB/OA ectodomain is shed from the surface of breast cancer cells. Transient siRNA-mediated knockdown studies of known sheddases identified ADAM10 as the protease responsible for GPNMB/OA processing. Finally, we demonstrate that the shed extracellular domain (ECD) of GPNMB/OA can promote endothelial migration in vitro. GPNMB/OA expression promotes tumor growth, which is associated with enhanced endothelial recruitment. We identify ADAM10 as a sheddase capable of releasing the GPNMB/OA ectodomain from the surface of breast cancer cells, which induces endothelial cell migration. Thus, ectodomain shedding may serve as a novel mechanism by which GPNMB/OA promotes angiogenesis in breast cancer.


Platelet activation during coronary angioplasty in humans.
Previous studies have indicated that balloon angioplasty is associated with local platelet activation. In addition, different contrast media have different effects on thrombus formation during angioplasty in humans. We hypothesized that coronary angioplasty in humans is associated with activation of platelets to specific platelet agonists and that this activation may be differently modified by different angiographic contrast agents. We studied 25 patients referred for angioplasty of the left anterior descending or circumflex coronary arteries. All patients were pretreated with aspirin and received heparin. Blood samples for assessment of platelet aggregation to serotonin, ADP, epinephrine, and collagen were obtained from the coronary sinus before any contrast injection, after initial diagnostic contrast injections, and after three balloon inflations. Patients were randomized to receive iopamidol, diatrizoate, or ioxaglate. Contrast alone was not associated with altered platelet aggregation. However, balloon angioplasty was consistently associated with increased platelet aggregation to serotonin but not to ADP, epinephrine, or collagen. These effects were similar with the three contrast agents studied except that the use of iopamidol was associated with increased platelet responsiveness to all concentrations of ADP after balloon dilation. Coronary angioplasty in humans was associated with increased platelet aggregation in blood drawn from the coronary sinus. This effect was primarily seen when serotonin was used as an agonist.


Ischaemic colitis associated with psychotropic drugs.
Two cases of patients with ischaemic colitis requiring operative treatment are presented. Both had received a commonly used psychotropic drug in large dosage before the acute episode. Evidence is produced which may link the drugs used with the condition of ischaemic colitis.


Nursing Considerations for Patients With HIV in Critical Care Settings.
Infection with HIV is a chronic condition that requires daily medication to suppress viral replication. With appropriate treatment, people living with HIV have a life expectancy approaching that of the general population. However, they are at increased risk for comorbidities including cardiovascular disease, renal disease, type 2 diabetes, neurologic conditions, and cancers, often with worse outcomes than in patients without HIV. When they are admitted to critical care settings, care considerations, particularly regarding antiretroviral therapy, must be addressed. Antiretroviral therapy is critical for successful management of HIV infection and should be continued when possible during intensive care unit stays. However, many antiretroviral regimens result in drug-drug interactions, adverse drug-related events, and secondary complications such as insulin resistance and prolonged QT intervals. Critical care nurses have unique opportunities to provide safe, unbiased, and compassionate care that promotes health for a population of people who have a history of being stigmatized.


High prevalence anti-Trypanosoma cruzi antibodies, among blood donors in the State of Puebla, a non-endemic area of Mexico.
Blood transfusion is the second most common transmission route of Chagas disease in many Latin American countries. In Mexico, the prevalence of Chagas disease and impact of transfusion of Trypanosoma cruzi-contaminated blood is not clear. We determined the seropositivity to T. cruzi in a representative random sample, of 2,140 blood donors (1,423 men and 647 women, aged 19-65 years), from a non-endemic state of almost 5 millions of inhabitants by the indirect hemagglutination (IHA) and enzyme linked immunosorbent assay (ELISA) tests using one autochthonous antigen from T. cruzi parasites, which were genetically characterized like TBAR/ME/1997/RyC-V1 (T. cruzi I) isolated from a Triatoma barberi specimen collected in the same locality. The seropositivity was up to 8.5% and 9% with IHA and ELISA tests, respectively, and up to 7.7% using both tests in common. We found high seroprevalence in a non-endemic area of Mexico, comparable to endemic countries where the disease occurs, e.g. Brazil (0.7%), Bolivia (13.7%) and Argentina (3.5%). The highest values observed in samples from urban areas, associated to continuous rural emigration and the absence of control in blood donors, suggest unsuspected high risk of transmission of T. cruzi, higher than those reported for infections by blood e.g. hepatitis (0.1%) and AIDS (0.1%) in the same region.


Association between Triglyceride to HDL-C Ratio (TG/HDL-C) and Insulin Resistance in Chinese Patients with Newly Diagnosed Type 2 Diabetes Mellitus.
To explore the association between the triglyceride to HDL-C ratio (TG/HDL-C) and insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus. Patients with newly diagnosed type 2 diabetes mellitus (272 men and 288 women) were enrolled and divided into three groups according to TG/HDL-C tertiles. Insulin resistance was defined by homeostatic model assessment of insulin resistance (HOMA-IR). Demographic information and clinical characteristics were obtained. Spearman's correlation was used to estimate the association between TG/HDL-C and other variables. Multiple logistic regression analyses were adopted to obtain probabilities of insulin resistance. A receiver operating characteristic analysis was conducted to evaluate the ability of TG/HDL-C to discriminate insulin resistance. TG/HDL-C was associated with insulin resistance in Chinese patients with newly diagnosed T2DM (Spearman's correlation coefficient = 0.21, P < 0.01). Patients in the higher tertiles of TG/HDL-C had significantly higher HOMA-IR values than patients in the lower tertiles [T1: 2.68(1.74-3.70); T2: 2.96(2.29-4.56); T3: 3.09(2.30-4.99)]. Multiple logistic regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR, and patients in the higher TG/HDL-C tertile had a higher OR than those in the lower TG/HDL-C tertile, after adjusting for multiple covariates including indices for central obesity [T1: 1; T2: 4.02(1.86-8.71); T3: 4.30(1.99-9.29)]. Following stratification of waist circumference into quartiles, the effect of TG/HDL-C on insulin resistance remained significant irrespective of waist circumference. TG/HDL-C was associated with insulin resistance independent of waist circumference. Whether it could be a surrogate marker for insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus still needs to be confirmed by more researches.


Incidental teaching of mentally retarded students within a token system.
Six mentally retarded students were taught to name sight words during the token-exchange periods of a token-reinforcement system. Words appeared on 25% of the tokens, and a student was given two opportunities to name a word written on a token before the token could be exchanged. Sequential teaching of new sets of sight words via a multiple-baseline design was used to evaluate the procedure. Five of the 6 students acquired sight-word vocabularies. The data support the contention that token-exchange periods may be used for educational purposes.


[A case of lung cancer in an elderly patient with malignant pleural effusion and pneumothorax treated with carboplatin, pemetrexed, and bevacizumab].
We report a case of an elderly patient with non-squamous non-small cell lung cancer who was successfully treated with chemotherapy using carboplatin(CBDCA), pemetrexed(PEM), and bevacizumab(Bev). The patient was an 84-year-old man who presented with a chief complaint of dyspnea. The right lung was completely collapsed due to malignant pleural effusion, and the mediastinum was shifted to the left. Right thoracic drainage was performed, but this was complicated by pneumothorax and a thoracotomy was performed. An absorbent tissue reinforcing agent was attached to the site of the air leakage and fibrin glue was applied. After discharge, the patient was administered 500mg/m / 2 PEM plus 15 mg/kg Bev for the first course of chemotherapy and experienced no serious side effects. CBDCA(area under the curve[AUC]4)was added from the second course. After the administration of seven courses, pleural effusion had almost disappeared and the primary tumor in the upper right lobe was observed to have shrunk. Administration of PEM+Bev was continued thereafter. The right pleural effusion was well controlled for up to 12 months(14 courses)from the start of the administration of chemotherapy, and shrinkage of the primary tumor was maintained. The side effects were mild and chemotherapy was administered safely. After the administration of 16 courses, a left malignant pleural effusion was observed, and the patient died 15 months after the initiation of chemotherapy.


Ovarian hormones through Wnt signalling regulate the growth of human and mouse ovarian cancer initiating lesions.
Ovarian cancer (OC) is the most deadly gynaecological disease largely because the majority of patients are asymptomatic and diagnosed at later stages when cancer has spread to other vital organs. Therefore, the initial stages of this disease are poorly characterised. Women with BRCA1/2 mutations have a genetic predisposition for developing OC, but not all of these women develop the disease. Epidemiological findings show that lifestyle factors such as contraceptive use and pregnancy, a progesterone dominant state, decrease the risk of getting OC. How ovarian hormones modify the risk of OC is currently unclear. Our study identifies activated Wnt signalling to be a marker for precursor lesions of OC and successfully develops a mouse model that mimics the earliest events in pathogenesis of OC by constitutively activating βcatenin. Using this model and human OC cells, we show that oestrogen promotes and progesterone suppresses the growth of OC cells.


The effects of cue level, hypnotizability, and state instruction on responses to leading questions.
Two sessions were conducted in which independent groups of 86 high- and 85 low-susceptible subjects, responding individually under waking or hypnotic instruction, answered high- and low-cued leading questions about a video event that depicted shooting at an airport. The two sessions were separated by 1 week, and the same questions were asked in both sessions. It was predicted that highly susceptible subjects responding under hypnotic instruction would show the most evidence of accepting false information via strongly cued leading questions. Results showed general effects for leading questions and level of susceptibility but no firm support for the involvement of hypnosis. Data are discussed in terms of both the linguistic and social factors that appear to have operated on subjects in the study, results overall highlight the strong influence of level of susceptibility on subjects' acceptance of false information.


Drug Permeability: From the Blood-Brain Barrier to the Peripheral Nerve Barriers.
Drug delivery into the peripheral nerves and nerve roots has important implications for effective local anesthesia and treatment of peripheral neuropathies and chronic neuropathic pain. Similar to drugs that need to cross the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) to gain access to the central nervous system (CNS), drugs must cross the peripheral nerve barriers (PNB), formed by the perineurium and blood-nerve barrier (BNB) to modulate peripheral axons. Despite significant progress made to develop effective strategies to enhance BBB permeability in therapeutic drug design, efforts to enhance drug permeability and retention in peripheral nerves and nerve roots are relatively understudied. Guided by knowledge describing structural, molecular and functional similarities between restrictive neural barriers in the CNS and peripheral nervous system (PNS), we hypothesize that certain CNS drug delivery strategies are adaptable for peripheral nerve drug delivery. In this review, we describe the molecular, structural and functional similarities and differences between the BBB and PNB, summarize and compare existing CNS and peripheral nerve drug delivery strategies, and discuss the potential application of selected CNS delivery strategies to improve efficacious drug entry for peripheral nerve disorders.


Screening investigations in small-for-gestational-age near-term and term infants.
The aims of this study are to examine how frequently near-term and term small-for-gestational-age (SGA) infants were investigated in our clinical practice, whether being born less than the third centile for weight increased the yield of positive investigations, and whether there were additional characteristics in infants with positive investigations. This retrospective cohort study was compiled using a database of a large maternity network, using the search near term and term gestational age (greater than or equal to 35 weeks) over a span of 4 years. SGA babies were further filtered into less than the tenth centile and third centile. Out of a population of 30,461 infants in the study period, 3437 (11.3%) SGA infants were identified. Four hundred fifteen SGA infants (12.1%) underwent screening investigations, of which 49 infants (11.8%) yielded a positive investigation. 27.2% of karyotypes, 12.8% of cranial ultrasounds and 0.4% of urine CMV tests showed positive results in < 10th centile group. Being born less than the third centile for weight did not increase the yield of positive investigations. Most infants with positive investigations had an additional maternal or neonatal characteristic or risk factor present. SGA babies without additional maternal or neonatal characteristics have a poor yield on neonatal screening investigations. Additional characteristics may be considered while deciding whether a SGA infant needs screening investigation. What is Known: • Small-for-gestational-age (SGA) infants have an increased risk of short- and long-term complications. • Whilst the causes for SGA are multifactorial, there has been a tendency to undertake screening investigations like Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes group of viruses (TORCH) screening and cranial ultrasounds in the neonatal period. What is New: • Comprehensive study investigating the rates of screening in near-term and term SGA population. • The yield of screening tests for near-term and term SGA infants without additional antenatal and postnatal characteristics is low.


Helicobacter pylori in Pediatric Patients.
Helicobacter pylori causes one of the most common chronic bacterial infections. Clinical manifestations include asymptomatic chronic gastritis, gastric and duodenal ulcers, adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma in adults. In children, most H pylori infections are asymptomatic despite being associated with microscopic gastric inflammation, and children rarely develop complications associated with infection. Due to rising resistance and lack of symptomatic improvement in the absence of peptic ulcer disease, testing and eradication therapy are recommended only for the subset of patients in whom there is a high suspicion of peptic ulcer disease. Studies do not support the role of H pylori infection in functional disorders such as recurrent abdominal pain. A variety of diagnostic modalities exist; therefore, it is important to understand the appropriate approach to diagnosing H pylori infection. The joint European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines were updated in 2016. Antibiotic and proton pump inhibitor weight-based dosing guidelines have changed to prevent ineffective treatment from increasing antimicrobial resistance. Treatment can also be guided by antibiotic sensitivities obtained from H pylori culture. Patients should be tested again after treatment to confirm eradication.


Campylobacter jejuni from Canine and Bovine Cases of Campylobacteriosis Express High Antimicrobial Resistance Rates against (Fluoro)quinolones and Tetracyclines.
Campylobacter (C.) spp. from poultry is the main source of foodborne human campylobacteriosis, but diseased pets and cattle shedding Campylobacter spp. may contribute sporadically as a source of human infection. As fluoroquinolones are one of the drugs of choice for the treatment of severe human campylobacteriosis, the resistance rates of C. jejuni and C. coli from poultry against antibiotics, including fluoroquinolones, are monitored within the European program on antimicrobial resistance (AMR) in livestock. However, much less is published on the AMR rates of C.jejuni and C. coli from pets and cattle. Therefore, C. jejuni and C. coli isolated from diseased animals were tested phenotypically for AMR, and associated AMR genes or mutations were identified by whole genome sequencing. High rates of resistance to (fluoro)quinolones (41%) and tetracyclines (61.1%) were found in C. jejuni (n = 29/66). (Fluoro)quinolone resistance was associated with the known point mutation in the quinolone resistance-determining region (QRDR) of gyrA, and tetracycline resistance was mostly caused by the tet(O) gene. These high rates of resistance, especially to critically important antibiotics in C. jejuni and C. coli, are worrisome not only in veterinary medicine. Efforts to preserve the efficacy of important antimicrobial treatment options in human and veterinary medicine have to be strengthened in the future.


Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults.
Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.


[Microsurgical treatment of trigeminal neuralgia. Results and prognostic factors of microsurgical vascular decompression].
The authors have reviewed 100 cases of trigeminal neuralgia operated upon at the cerebello-pontine angle using microsurgical techniques, i.e. 20% of their total series of 513 patients with tic douloureux, 413 of them having been submitted to percutaneous R.F.--thermocoagulation. In 10 of the above 100 patients, a tumour or an angioma have been found and with its removal a total relief of pain has been obtained. In all but three of the other 90 patients, a neurovascular conflict has been revealed. In 17 of them a selective section of the trigeminal root had to be performed, as its cross-compression could not be eliminated. A total cure was achieved in all but three cases in which the result was only partial. In 70 patients a microvascular decompression (MVD) was performed and in 68 of them a follow-up of 1 to 5 years has been analyzed. In 82.4% the results were excellent. Further 7.3% thought to be benefited by the operation; although they still had some pain, they were well controlled by medical treatment. In 10.3% an unsatisfactory improvement, failure or recurrence were noted. Then a critical study of the whole material has been made in search for the causes of unsatisfactory results and for the possibilities of making the efficacity of MVD ascertained in a higher percentage of patients. The results of this study lead to definite conclusions, a part of which is quoted below: Some of clinical findings showed to be of paramount importance for the prognosis. The most evident has been a highly significant difference in the percentage of a total cure in patients with attacks of tic douloureux only (94.5%) and in those with the same type of attacks, but associated with permanent pain (58.3%). The analysis of the operative findings and of the details of the surgical procedure indicated to a necessity of restitution of the normal shape and course of the trigeminal root from the petrous ridge up to the entry-zone and of an adequate root protection (for instance with Dacron), after the Vth nerve had been detached from the conflicting vessel. A correlation of the above findings with the angiographic ones has been made. A measurable method has been used to make available data which could be informative as to the presence of a conflict, as well as to its anatomical cause. But this still needs a further critical elaboration.


[The differentiation of viruses of the tick-borne encephalitis complex by means of RNA-DNA hybridization].
Nucleic acid spot hybridization with cloned cDNA of tick-borne encephalitis (TBE) virus, strain Sofjin, was used to differentiate strains of TBE and other flaviviruses. The cDNA probe reacted with strains of TBE and flaviviruses of TBE subgroup with the exception of Powassan virus. The probe did not react with viruses of Japanese encephalitis and Gendue subgroups. The viruses of TBE subgroup and some strains of TBE virus were differentiated from TBE strain Sofjin by thermal stability of RNA-DNA hybrids. Negishi and Louping ill viruses were found to be most closely related to TBE strain Sofjin among viruses of the TBE subgroup.


Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation.
Peroxynitrite plays a critical role in vascular pathophysiology by increasing arginase activity and decreasing endothelial nitric oxide synthase (eNOS) activity. Therefore, the aims of this study were to investigate whether arginase inhibition and L-arginine supplement could restore peroxynitrite-induced endothelial dysfunction and determine the involved mechanism. Human umbilical vein endothelial cells (HUVECs) were treated with SIN-1, a peroxynitrite generator, and arginase activity, nitrite/nitrate production, and expression levels of proteins were measured. eNOS activation was evaluated via Western blot and dimer blot analysis. We also tested nitric oxide (NO) and reactive oxygen species (ROS) production and performed a vascular tension assay. SIN-1 treatment increased arginase activity in a time- and dose-dependent manner and reciprocally decreased nitrite/nitrate production that was prevented by peroxynitrite scavenger in HUVECs. Furthermore, SIN-1 induced an increase in the expression level of arginase I and II, though not in eNOS protein. The decreased eNOS phosphorylation at Ser1177 and the increased at Thr495 by SIN-1 were restored with arginase inhibitor and L-arginine. The changed eNOS phosphorylation was consistent in the stability of eNOS dimers. SIN-1 decreased NO production and increased ROS generation in the aortic endothelium, all of which was reversed by arginase inhibitor or L-arginine. N(G)-Nitro-L-arginine methyl ester (L-NAME) prevented SIN-1-induced ROS generation. In the vascular tension assay, SIN-1 enhanced vasoconstrictor responses to U46619 and attenuated vasorelaxant responses to acetylcholine that were reversed by arginase inhibition. These findings may explain the beneficial effect of arginase inhibition and L-arginine supplement on endothelial dysfunction under redox imbalance-dependent pathophysiological conditions.


Mitochondrial DNA mutations in disease and ageing.
The chronological accumulation of mitochondrial DNA mutations has been proposed as a potential mechanism in the physiological processes of ageing and age-related disease. We discuss the evidence behind this theory and relate some of the ageing mitochondrial changes to mitochondrial DNA disorders. In particular, we describe the aggregation of cytochrome c oxidase-deficient cells in both skeletal muscle and the CNS in normal ageing as seen in the mitochondrial DNA disorders. These mitochondrial enzyme-deficient cells have been shown to occur in significant quantities in both muscle and CNS in patients with mitochondrial DNA disorders. In both ageing and mtDNA disorder muscle these cytochrome c-deficient fibres contain high levels of a single mutant strain of mitochondrial DNA. Whether these mutations are a primary or secondary event in the physiology of ageing remains to be determined.


Combination of blocking agents and suppressing agents in cancer prevention.
The design of the present study was based on the premise that if blocking agents and suppressing agents are targeted at different phases of chemical carcinogenesis, a greater chemopreventive effect would be achieved by using the combination treatment compared to the single-agent treatment. The dimethylbenz[a]anthracene (DMBA)-induced mammary tumor model in rats was used to test this hypothesis, with the blocking agent given before DMBA only and the blocking agent given after DMBA until the end of the experiment. A total of three sets of combination treatment were carried out; diallyl sulfide/Se-methylselenocysteine, ellagic acid/selenomethionine, and diallyl sulfide/quercetin. In all three cases, the combination regimen was much more effective than the single-agent treatment in tumor suppression. It should be noted that only naturally occurring inhibitors were selected for these experiments. The impact of minor dietary anutrients in cancer chemoprevention is also discussed.


Neural activity and neurotransmission regulate the maturation of the innervation field of cortical GABAergic interneurons in an age-dependent manner.
Neural activity guides the patterning of neuron synaptic territory in the developing nervous system. Evidence supporting this hypothesis comes from numerous studies on projection neurons in neuromuscular and visual systems. It is unknown whether the innervation field of GABAergic interneurons, which forms local dense innervations, follows similar rules. Cortical basket cells innervate hundreds of pyramidal cell somata and proximal dendrites. Thanks to this connectivity pattern, they can tightly control neural excitability and synchronization. Here we show that reducing excitation, and thus neurotransmitter release, in mouse cortical single basket cells in slice cultures decreases the number of innervated cells without changing the pattern of perisomatic innervation, both at the peak and after the proliferation phase of perisomatic synapse formation. Conversely, suppressing neurotransmitter release in single basket cells can have completely opposite effects depending on the developmental stage. Our results reveal a remarkably specific and age-dependent role of neural activity and neurotransmission levels in the establishment of the synaptic territory of cortical GABAergic cells.


[Acute pulmonary thromboembolism during the surgery for bilateral lower extremity fracture].
A 50-year-old woman underwent open reduction and internal fixation for bilateral lower extremity fracture under general anesthesia. During the surgery, arterial oxygen saturation and expired CO2 concentration dropped suddenly when the left limb was fixed. Immediately, we performed aspiration of the pulmonary thrombus and inserted a temporary infra-vena cava filter followed by heparinization. Ten days later, we carried out the surgery on the right limb uneventfully. The major cause of APTE is deep vein thrombosis (DVT), which is extremely common during perioperative period. Therefore, we must perform antithrombotic therapy for the patient at high risk for DVT.


[Brain abscess developed five years after splenectomy in a patient with idiopathic thrombocytopenic purpura].
The increased susceptibility to infection following splenectomy has been well documented. We report here, a case of brain abscess developed five years after splenectomy in a patient with idiopathic thrombocytopenic purpura (ITP). A 65-year-old woman was admitted to our hospital because of fever, mental disorientation, and weakness in August, 1999. She had been followed with diagnoses of essential hypertension and type 2 diabetes mellitus (DM) since 1988. The patient was diagnosed as having ITP in 1992, and then underwent splenectomy in 1994. Monoclonal gammopathy of undetermined significance (MGUS) of IgG, lambda type was found in February 1999. Though high grade fever persisted after admission, blood cultures were negative. Antibiotics were given without a satisfactory effect. Right hemiparesis and worsening of consciousness developed subsequently. Contrast enhanced cranial computed tomography (CT) disclosed a ringed enhanced low density mass in the left parieto-occipital lobe compatible with a diagnosis of brain abscess. Surgical drainage was performed and 20 ml of pus was obtained. No primary infectious focus of the brain abscess was detected with intensive examinations.


Cochlear implantation in far-advanced otosclerosis: hearing results and complications.
Severe forms of otosclerosis known as far-advanced otosclerosis (FAO) can lead to severe to profound sensorineural hearing loss and can justify cochlear implantation. Because of the pathophysiology of otosclerosis, patients implanted for FAO may experience an increased rate of complications, such as facial nerve stimulation or electrode dislocation, and may have poorer hearing outcomes than expected. This retrospective study aimed to compare cochlear implantation hearing outcomes, surgical difficulties and complications in FAO patients versus non-FAO patients. Moreover, we evaluated whether high resolution computed tomography (CT scan) findings were predictive of perioperative problems, complications and hearing outcomes. FAO patients were diagnosed based on medical history, examination and CT scan. Thirty-five ears from FAO patients were compared to 38 control ears. Audiometric results were assessed at least 12 months after implantation by pure tone average, speech reception threshold, monosyllabic and disyllabic word recognition score (WRS) and Central Institute for the Deaf (CID) sentences test. Complications and surgical difficulties were compiled. CT scan findings were categorised within 3 grades of otosclerotic extension. No significant difference was found between FAO and non-FAO hearing outcomes, except that monosyllabic WRS were lower for FAO patients, especially those who underwent previous stapedotomy. Facial nerve symptomatology occurred in 8.6% of FAO patients; among these, one required explantation-reimplantation surgery. 86% of FAO implanted patients had retrofenestral extension on CT. These were associated with poorer disyllabic WRS (51% vs 68%, p < 0.05) than those with only fenestral involvement. Although not significant, high grade of severity on CT tended to be associated with surgical difficulties and complications. Cochlear implantation in FAO patients is an effective treatment technique. Though the overall complication rate is low, it tends to be higher in cases of severe extension on CT. Patient counselling should be adjusted accordingly.


A comparative clinical study of Solcoseryl Eye-Gel and Cysteine Eye-Gel 2.4% in the treatment of foreign-body injuries of the cornea.
Solcoseryl, a protein-free haemodialysate, promotes tissue regeneration and improves utilization of oxygen in the cell. In a randomized, double-blind, clinical study, Solcoseryl Eye-Gel was compared with Cysteine Eye-Gel in the treatment of foreign-body injuries of the cornea in a total of 99 eyes. In order to facilitate objective evaluation of the effects of the treatment, the area of the lesion before the start of treatment and on the following day was determined by means of slit-lamp photographs. Healing of the lesion and relative reduction of the area of the wound were observed much more frequently in the group treated with Solcoseryl Eye-Gel than in the reference group. Maculae corneae after the end of the treatment were significantly less frequent under Solcoseryl Eye-Gel than under Cysteine Eye-Gel. Teh tolerability of the test preparation was good; an itching sensation was reported in only 2 cases. Under Cysteine Eye-Gel, on the other hand, a burning sensation was reported by a number of patients and very fine deposits in the epithelium were also observed in a few cases. Thus complete closure of the epithelium over the lesion after 1 day was observed much more frequently in the group of patients treated with Solcoseryl Eye-Gel than in the reference group (63 vs. 53%).


Ly-6G+CCR2- myeloid cells rather than Ly-6ChighCCR2+ monocytes are required for the control of bacterial infection in the central nervous system.
Myeloid cell recruitment is a characteristic feature of bacterial meningitis. However, the cellular mechanisms important for the control of Streptococcus pneumoniae infection remain largely undefined. Previous pharmacological or genetic studies broadly depleted many myeloid cell types within the meninges, which did not allow defining the function of specific myeloid subsets. Herein we show that besides CD11b(+)Ly-6G(+)CCR2(-) granulocytes, also CD11b(+)Ly-6C(high)CCR2(+) but not Ly-6C(low)CCR2(-) monocytes were recruited in high numbers to the brain as early as 12 h after bacterial challenge. Surprisingly, CD11b(+)Ly-6C(high)CCR2(+) inflammatory monocytes modulated local CXCL2 and IL-1beta production within the meninges but did not provide protection against bacterial infection. Consistent with these results, CCR2 deficiency strongly impaired monocyte recruitment to the infected brains but was redundant for disease pathogenesis. In contrast, specific depletion of polymorphonuclear granulocytes caused elevated local bacterial titer within the brains, led to an aggravated clinical course, and enhanced mortality. These findings demonstrate that Ly-6C(high)CCR2(+) inflammatory monocytes play a redundant role for the host defense during bacterial meningitis and that predominantly CD11b(+)Ly-6G(+)CCR2(-) myeloid cells are involved in the restriction of the extracellular bacteria.


[Anesthetic equipment: fresh gas delivery systems. II. Electronic systems].
To analyse the design, functioning, benefits and drawbacks of electronic fresh gas delivery units (FGDUs) included in anaesthetic machines marketed in France in 1999. Articles were obtained from a Medline review (1980-1999; search terms: anaesthetic machine, flowmeter, vaporizer), textbooks and personal files; specific data were also provided by manufacturers. The articles were analysed in considering the differences between mechanical and electronic FGDUs. Four anaesthetic machines out of 11 are equipped with electronic FGDUs. In comparison to mechanical units, they include the following benefits: wide range of accurate gas flow, especially in the low flow range, with analog and digital display; intermittent delivery of each gas, which is essential for automated gas delivery and quantitative anaesthesia or target controlled (FET vapor) inhalational anaesthesia; facilitated oxygen ratio control; possibility to print the gas and vapor flows on the automated anaesthetic record; interruption of gas flow when the main switch of the machine is set to off; and absence of risk for retropollution. Three FGDUs out of four are adapted for gas delivery to an accessory (ancillary) anaesthetic circuit. However, only one of them delivers a gas flow up to 30 L.min-1. The specificity of the ADU AS/3 (Datex-Ohmeda) is the bypass vaporizer included in the FGDU with an exchangeable vaporizing chamber (cassette). The specificity of the Julian (Dräger) is the delivery of fresh gas limited to the expiratory phase during mechanical ventilation. The specificity of the the FGDU from Kion (Siemens) is the possibility to act as an open circuit ventilator, similar to a Servoventilator. The specificity of the PhysioFlex is an FGDU included in the circle circuit, each gas and liquid anaesthetic being directly injected into the circuit. Data from the French medical device surveillance commission indicate that the main failures occur in the power supply device and the microprocessor.


Health-Led Interventions in the Early Years to Enhance Infant and Maternal Mental Health: A Review of Reviews.
Increasing recognition of the importance of maternal mental health and early parenting in optimising the later mental health of the child has given rise to new ways of working during the perinatal period. The objective of this review is to identify effective health-led interventions to support parents, parenting and the parent-infant relationship during the perinatal period,1 and beyond. A systematic search of key electronic databases was undertaken to identify secondary and primary sources of data addressing the research question. Twenty-four reviews addressed the effectiveness of interventions delivered during the postnatal period in promoting closeness and sensitive parenting, infant sensory and perceptual capabilities, and positive parenting, and in addressing infant regulatory problems, maternal mental health problems, and parent-infant relationship problems. A number of methods of working are recommended as part of a model of progressive-universalism beginning ante-natally and continuing through the first two post-natal years, and beyond. The implications for universal, targeted and specialist healthcare services are explored, alongside the role and contribution of CAMHS practitioners.


Theoretical and experimental considerations on the enthalpic relaxation of organic glasses using differential scanning calorimetry.
The enthalpy relaxation of amorphous salicin, used as model organic glass of pharmaceutical relevance, was investigated using a combination of DSC measurements and theoretical simulations. The combined approach makes it possible to discern between the effect of the glass forming properties of the material and the effects of the thermal history and experimental conditions. The approach also facilitates an unambiguous definition of the time scale of the experiment, such that objective comparison among relaxation time and glass transition temperature values can be made. The simulation provides accurate predictions of the DSC profiles obtained under a wide variety of experimental conditions. The effects of annealing time and the heating/cooling rate on the enthalpy recovery were explained by tracking the evolution of relaxation times as a function of temperature and time. The combined experimental and simulation approach also makes it possible to systematically explore the effect of specific glass forming properties, such as fragility and nonexponentiality, on the relaxation and associated thermal behavior of molecular organic glasses of pharmaceutical interest. To fully characterize these materials, it is necessary to go beyond the onset T(g) and include the early stages of the glass transition.


Kinetics of the AHL regulatory system in a model biofilm system: how many bacteria constitute a "quorum"?
Acylated homoserine lactones (AHLs) regulate a wide variety of phenotypes in Gram-negative bacteria. Most research suggests that AHL-mediated phenotypes are not expressed in populations until late logarithmic phase or stationary phase. Here, we model how the concentration of AHLs inside bacterial cells and in a biofilm changes over time as a function of population growth rate, diffusion of AHLs and the rate of autoinduction. Our theoretical results show that the concentration of AHLs inside a single bacterium (and by implication induction of a phenotype) has a non-trivial behaviour over time, and often exhibits a rapid increase early in population growth. This rapid increase is followed by a plateau, followed by another rise in the concentration of AHLs, to a second plateau. High concentrations of AHLs inside the bacterial cell early in population growth are positively affected by slow diffusion rates out of the cell and the biofilm, slow bacterial growth rates and fast autoinduction. In contrast, fast growth rates, slow autoinduction rates and high diffusion rates result in a high concentration plateau in stationary phase. More generally, the density-dependent nature of AHL regulation can be viewed as a trade-off between factors that dilute intracellular concentrations of AHLs (diffusion out of the cell, cell division), and those that increase concentrations (a slowing or restriction of diffusion or growth, or autoinduction). These results suggest that expression of AHL-mediated phenotypes can occur at relatively low cell densities and low external/environmental AHL concentrations.


Nuclear magnetism and electronic order in 13C nanotubes.
Single wall carbon nanotubes grown entirely from 13C form an ideal system to study the effect of electron interaction on nuclear magnetism in one dimension. If the electrons are in the metallic, Luttinger liquid regime, we show that even a very weak hyperfine coupling to the 13C nuclear spins has a striking effect: The system is driven into an ordered phase, which combines electron and nuclear degrees of freedom, and which persists up into the millikelvin range. In this phase the conductance is reduced by a universal factor of 2, allowing for detection by standard transport experiments.


[The plasma level of an inactive moiety of B-type natriuretic peptide precursor as a predictor of cardiac function during operations under extracorporeal circulation].
Ventricular cardiomyocytes secrete brain natriuretuc peptide (BNP) and an inactive moiety of its precursor (nt-proBNP). It is recommended the blood level of the latter should be monitored to ascertain the severity of myocardial lesion. This investigation was undertaken to study the diagnostic and prognostic value of a substantial increase in blood nt-proBNP levels (600 pg/ml or more) in patients operated on under extracorporeal circulation. Thirty-eight patients operated on for coronary heart disease were examined. Before surgery, the plasma concentration of nt-proBNP had been determined by electrochemiluminescence (Elescys, Roche). According to plasma nt-proBNP levels, the patients were divided into 2 groups: 1) 24 patients with nt-proBNP levels of less than 600 pg/ml; 2) 14 patients with its levels of 600 pg/ml or more. Group 1 patients showed signs of diastolic dysfunction of the right ventricle: the lower ratio of its early to atrial filling linear velocity integrals and the increased end-diastolic volume index. In the postperfusion period, nt-proBNP is a significant independent predictor of left ventricular function. The patients with the baseline nt-proBNP levels of above 600 pg/ml were found to have decreases in ejection fraction of the left ventricle and in its pump ratio along with elevated pulmonary wedge pressure.


Natural Causes of Sudden Young Adult Deaths in Forensic Autopsies.
Objective The aim of this study is to define epidemiologic differences and the most common pathologies that cause nontraumatic sudden, natural death in people in the age group of 18-35 years. Identifying causes of sudden death in this age group is important for determining approaches for prevention. Methods We performed a descriptive statistical methodology, analysis, and interpretation using demographic and autopsy data of sudden deaths. A total of 4034 autopsies were reviewed and 66 cases of sudden death were included in this study. Results We identified 58 (87.9%) subjects in whom the adjudicated cause of death was of potential cardiac etiology. The most common cause of sudden young adult death was ischemic heart disease associated with the atherosclerotic coronary artery (n=24, 36.3%), followed by ischemic heart disease associated with nonatherosclerotic coronary artery disease and dissecting aortic aneurysm. Conclusion We put forth that the main cause of sudden young adult death was cardiac (87.9%) in origin. Of these cardiac causes, ischemic etiology associated with atherosclerosis was the main reason for sudden young adult deaths. In order to reduce the incidence of sudden young adult deaths, major efforts should be directed to prevent atherosclerosis in this age group.


Two-dimensional electronic Stark spectroscopy of a photosynthetic dimer.
Stark spectroscopy, which measures changes in the linear absorption of a sample in the presence of an external DC electric field, is a powerful experimental tool for probing the existence of charge-transfer (CT) states in photosynthetic systems. CT states often have small transition dipole moments, making them insensitive to other spectroscopic methods, but are particularly sensitive to Stark spectroscopy due to their large permanent dipole moment. In a previous study, we demonstrated a new experimental method, two-dimensional electronic Stark spectroscopy (2DESS), which combines two-dimensional electronic spectroscopy (2DES) and Stark spectroscopy. In order to understand how the presence of CT states manifest in 2DESS, here, we perform computational modeling and calculations of 2DESS as well as 2DES and Stark spectra, studying a photosynthetic dimer inspired by the photosystem II reaction center. We identify specific cases where qualitatively different sets of system parameters produce similar Stark and 2DES spectra but significantly different 2DESS spectra, showing the potential for 2DESS to aid in identifying CT states and their coupling to excitonic states.


Long-lived reciprocal regulation of antigen-specific IgE and IgG2a responses in mice treated with glutaraldehyde-polymerized ovalbumin.
Previously, we discovered that administration of high Mr glutaraldehyde-polymerized ovalbumin (OA) to C57BL/6 mice prior to immunization with OA in A1(OH)3 adjuvant resulted in induction of an interferon-gamma (IFN-gamma) dependent, split tolerance in which maximal OA-specific IgE responses were 1-3% of those observed in saline-treated OA-[A1(OH)3] immunized controls. Concomitantly, these mice exhibited up to 10(3)-fold increases in OA-specific IgG2a synthesis. In this report we examine the longevity and resilience of these reciprocal effects on IgE inhibition/IgG2a enhancement over extended periods of time and following multiple re-exposures to the sensitizing allergen. The data indicate that the T-cell mediated changes in responsiveness which are induced upon exposure to glutaraldehyde-modified protein allergen, but not unmodified allergen, are (i) extremely long-lived (greater than 350 days); (ii) resistant to at least five re-immunizations with OA in A1(OH)3 adjuvant; and (iii) antigen-specific. The results are consistent with a virtually permanent shift in the OA-specific T-cell repertoire in vivo from one dominated by Th2-like patterns of cytokine synthesis (IL-4) to one dominated by Th1-like (IFN-gamma) cytokine production.


Detection of segmental aneuploidy and mosaicism in the human preimplantation embryo: technical considerations and limitations.
Whole-chromosome aneuploidy screening has become a common practice to improve outcomes and decrease embryonic transfer order in patients undergoing treatment for infertility through in vitro fertilization. Despite implementation of this powerful technology, a significant percentage of euploid embryos fail to result in successful deliveries. As technology has evolved, detection of subchromosomal imbalances and embryonic mosaicism has become possible, and these serve as potential explanations for euploid embryo transfer failures. Cases involving a parent with a balanced translocation provide a unique opportunity to characterize the capabilities and limitations of detecting segmental imbalances with a variety chromosome screening platforms. Adaptation of these methods to de novo imbalances now represent an ongoing challenge in the field of preimplantation genetic screening as additional factors including mosaicism, clinical predictive value, and distinguishing true imbalances from technical artifacts must be more carefully considered.


Photobacterium gaetbulicola sp. nov., a lipolytic bacterium isolated from a tidal flat sediment.
A Gram-negative, motile, non-spore-forming and lipolytic bacterial strain, designated Gung47(T), was isolated from a tidal flat on the west coast of Korea. Strain Gung47(T) grew optimally at 30 °C and with 2-5 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain Gung47(T) belonged to the genus Photobacterium. Strain Gung47(T) exhibited 98.1 % 16S rRNA gene sequence similarity with Photobacterium rosenbergii LMG 22223(T) and 94.3-96.3 % similarity with other type strains of species of the genus Photobacterium. Strain Gung47(T) exhibited 47 % DNA-DNA relatedness to P. rosenbergii LMG 22223(T). Strain Gung47(T) contained Q-8 as the predominant ubiquinone and C(16 : 1)ω7c and/or iso-C(15 : 0) 2-OH, C(16 : 0) and C(18 : 1)ω7c as the major fatty acids. In this study, two closely related type strains, P. rosenbergii LMG 22223(T) and Photobacterium halotolerans LMG 22194(T), were also found to have Q-8 as the predominant ubiquinone. The DNA G+C content of strain Gung47(T) was 50.6 mol%. The differential phenotypic properties together with the phylogenetic and genetic distinctiveness of strain Gung47(T) demonstrated that this strain is distinguishable from recognized Photobacterium species. Therefore, strain Gung47(T) is considered to represent a novel species of the genus Photobacterium, for which the name Photobacterium gaetbulicola sp. nov. is proposed. The type strain is Gung47(T) (=KCTC 22804(T) =CCUG 58399(T)).


Urinary sCD25 as a biomarker of lupus nephritis disease activity.
T cells play an important role in the pathogenesis of lupus nephritis (LN). We studied the role of urinary soluble CD25 (sCD25) as a biomarker of LN disease activity in a cross-sectional and longitudinal study. Patients with systemic lupus erythematosus were classified as active LN (AN), inactive disease (ID) and active non-renal (ANR) based on disease activity and renal involvement at the time of enrolment. Urine and serum samples were collected at baseline from all patients and at 3-monthly follow-up from patients with AN. SLE disease activity index (SLEDAI) was used for disease activity assessment at all visits. sCD25 was measured by ELISA and normalized to urinary creatinine excretion and is expressed as pg/mg. Urine samples from 10 healthy individuals (HC) served as controls. There were 119 patients (111 females, median age 27 years, 57 AN, 43 ID, 19 ANR). Median SLEDAI was 18, 2 and 8 in AN, ID and ANR groups, respectively. Median renal SLEDAI in AN was 8. Mean (±SD) urinary sCD25 in the AN, ID, ANR and HC groups at baseline was 741.1 (±794.9), 407.8 (±511.1), 735.4 (±667.7) and 250.9 (±122.2) pg/mg respectively (p = 0.019). Mean (±SD) serum sCD25 in AN, ID and ANR was 8285.25 (±5922.2), 6044 (±3501.92) and 6568.72 (±4333.62) pg/ml, respectively. Urinary sCD25 correlated with SLEDAI (r = 0.22; p = 0.015) but did not correlate with serum sCD25 or proteinuria. Urinary sCD25 compares well with traditional markers of disease activity in differentiating active from inactive renal disease. On follow-up mean urinary sCD25 decreased to 470.0 (±449.6; p < 0.05) at 3 months, 496.7 (±465.8; p = 0.006) at 6 months, 471.9 (±303.2; p = 0.041) at 9 months and 358.6 (±496.9; p = 0.007) at 12 months from baseline value of 741.1 (±794.9). In four patients who either had relapse, persistent disease activity or developed chronic kidney disease, urinary sCD25 showed rise preceding traditional abnormalities on urine examination. Urinary sCD25 is a good biomarker for follow-up of LN. It may also have the potential to predict poor response and relapse.


Ischemic stroke in a 7-month-old infant with antiphospholipid antibody and homozygous C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism.
Prothrombotic risk factors in children with ischemic stroke have been increasingly recognized with recent developments in technology. Extensive evaluation including a detailed family history is required to identify various inherited or acquired prothrombotic conditions. We report a 7-month-old male who presented with right hemiparesis. Acute cerebral infarction in the area supplied by the left lenticulostriate artery was confirmed through magnetic resonance imaging. De novo synthesis of antiphospholipid antibodies and homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism were identified as presumed prothrombotic risk factors. His twin sister and mother were also positive for antiphospholipid antibodies. Multiple risk factors for ischemic stroke should be considered, particularly in the perinatal and infancy period. This case also underlines the rare familial occurrence of antiphospholipid antibodies and its relationship to ischemic stroke in infancy.


Photosensitization reactions in vitro and in vivo.
This review of Photochemistry and Photobiology summarizes articles published in 2010, and highlights progress in the area of photosensitization. The synthesis of conjugated photosensitizers is an area of interest where increasing water solubility has been a goal. Targeting infrared sensitizer absorption has been another goal, and relates to the practical need of deep tissue absorption of light. Photodynamic techniques for inactivating microbes and destroying tumors have been particularly successful. Biologically, singlet oxygen [(1)O(2)((1)Δ(g))] is an integral species in many of these reactions, although photosensitized oxidations tuned to electron and hydrogen transfer (Type I) give rise to other reactive species, such as superoxide and hydrogen peroxide. How photoprotection against yellowing, oxygenation and degradation occurs was also an area of topical interest.


Regulation of epithelial sodium channels by the ubiquitin-proteasome proteolytic pathway.
Amiloride-sensitive epithelial Na+ channels (ENaC) play a crucial role in Na+ transport and fluid reabsorption in the kidney, lung, and colon. The magnitude of ENaC-mediated Na+ transport in epithelial cells depends on the average open probability of the channels and the number of channels on the apical surface of epithelial cells. The number of channels in the apical membrane, in turn, depends on a balance between the rate of ENaC insertion and the rate of removal from the apical membrane. ENaC is made up of three homologous subunits: alpha, beta, and gamma. The COOH-terminal domain of all three subunits is intracellular and contains a proline-rich motif (PPxY). Mutations or deletion of this PPxY motif in the beta- and gamma-subunits prevent the binding of one isoform of a specific ubiquitin ligase, neural precursor cell-expressed, developmentally downregulated protein (Nedd4-2), to the channel in vitro and in transfected cell systems, thereby impeding ubiquitin conjugation of the channel subunits. Ubiquitin conjugation would seem to imply that ENaC turnover is determined by the ubiquitin-proteasome system, but when Madin-Darby canine kidney cells are transfected with ENaC, ubiquitin conjugation apparently leads to lysosomal degradation. However, in untransfected renal cells (A6) expressing endogenous ENaC, ENaC is indeed degraded by the ubiquitin-proteasome system. Nonetheless, in both transfected and untransfected cells, the rate of ENaC degradation is apparently controlled by Nedd4-2 activity. In this review, we discuss the role of the ubiquitin conjugation and the alternative degradative pathways (lysosomal or proteasomal) in regulating the rate of ENaC turnover in untransfected renal cells and compare this regulation to that of transfected cell systems.


Evidence of lowered plasma membrane potential in different cell types in primary hypertension.
Basal electric potential in the plasma membrane of synaptosomes and platelets as well as the membrane potential in erythrocytes is lower in spontaneously hypertensive rats than in normotensive animals. Similar potential alterations have been found in platelets and erythrocytes of essential hypertensive patients. The reduction of the basal component of the transmembrane potential in synaptosomes and platelets in primary hypertension is partially or entirely compensated by an increase of its electrogenic component as a result of an enhanced activity of Na+K(+)-ATPase. In erythrocytes of patients with renal hypertension and in Cushing's syndrome no alterations of membrane potential are observed.


Identification of non-tuberculous mycobacteria isolated from clinical specimens at a tertiary care hospital: a cross-sectional study.
Non-tuberculous mycobacteria (NTM) are opportunistic pathogens in immuno-compromised patients. They are also increasingly recognized as pathogens in immuno-competent individuals. Globally, an increase in NTM isolation is being reported with a varied geographic prevalence of different species around the world. There is lack of data on species distribution of these organisms from Pakistan. Treatment options differ according to the species isolated and its susceptibility profile. Knowledge of local species variation would help targeted therapy. This study was performed to determine frequencies of different NTM species isolated from various clinical specimens submitted at a tertiary care hospital laboratory. NTM isolated from 25955 clinical specimens over a period of two years (2010 to 2011) were included. All NTM were identified using conventional tests. Drug susceptibility testing (DST) was performed by broth microdilution and interpreted according to Clinical and Laboratory Standards Institute's document M24-A2. A total of 104 NTM were included in the study. Of these, 76% (54/71) rapidly growing mycobacteria (RGM) and 57.6% (19/33) slow growing mycobacteria (SGM) could be further identified. Mycobacterium fortuitum (21/54) was the commonest NTM identified among RGM followed by M. mucogenicum (12/54) and M. smegmatis (11/54). Among SGM, M. avium complex (MAC) was the most frequent (14/19). Clinical significance could be assessed in a limited number (52/104) of NTM isolates and MAC appeared to be the commonest significant NTM. Three extra-pulmonary cases were found to be healthcare associated infections. DST results for RGM showed susceptibility to amikacin (100%), clarithromycin (100%, except M. fortuitum where it is not reportable), linezolid (90%) and moxifloxacin (75%). Whereas SGM were susceptible to clarithromycin (100%), linezolid (58.8%) and moxifloxacin (64.7%). This is the first study reporting NTM species and their clinical significance isolated from clinical specimens from Pakistan. Isolation of NTM from clinical specimens should prompt to evaluate their clinical significance.


Topological Transition of Superconductivity in Dirac Semimetal Nanowire Josephson Junctions.
We report the topological transition by gate control in a Cd_{3}As_{2} Dirac semimetal nanowire Josephson junction with diameter of about 64 nm. In the electron branch, the quantum confinement effect enforces the surface band into a series of gapped subbands and thus nontopological states. In the hole branch, however, because the hole mean free path is smaller than the nanowire perimeter, the quantum confinement effect is inoperative and the topological property maintained. The superconductivity is enhanced by gate tuning from electron to hole conduction, manifested by a larger critical supercurrent and a larger critical magnetic field, which is attributed to the topological transition from gapped surface subbands to a gapless surface band. The gate-controlled topological transition of superconductivity should be valuable for manipulation of Majorana zero modes, providing a platform for future compatible and scalable design of topological qubits.


Experimental and theoretical investigation of the stability of Pt-3d-Pt(111) bimetallic surfaces under oxygen environment.
The stability of the Pt-3d-Pt(111) (3d = Ti, V, Cr, Mn, Fe, Co, or Ni) bimetallic surface structures in the presence of adsorbed oxygen has been investigated by means of density functional theory (DFT). The dissociative binding energies of oxygen on Pt-3d-Pt(111) (i.e., subsurface 3d monolayer) and 3d-Pt-Pt(111) (i.e., surface 3d monolayer) were calculated. All of the Pt-3d-Pt(111) surfaces were found to have weaker oxygen binding energies than pure Pt(111) whereas all of the 3d-Pt-Pt(111) surfaces were found to have stronger oxygen binding energies than pure Pt(111). The total heat of reaction was calculated for the segregation for 3d metal atoms from Pt-3d-Pt(111) to 3d-Pt-Pt(111) when exposed to a half monolayer of oxygen. All of the Pt-3d-Pt(111) subsurface structures were predicted to be thermodynamically unstable with adsorbed oxygen. In addition, the segregation of subsurface Ni and Co to the surfaces of Pt-Ni-Pt(111) and Pt-Co-Pt(111) was investigated experimentally using Auger electron spectroscopy (AES) and high-resolution electron energy loss spectroscopy (HREELS). AES and HREELS confirmed the trend predicted by DFT modeling and showed that both the Pt-Ni-Pt(111) and Pt-Co-Pt(111) surface structures were unstable in the presence of adsorbed oxygen. The activation barrier of the segregation of surbsurface Ni and Co atoms was determined to be 15 +/- 2 and 7 +/- 1 kcal/mol, respectively. These results are further discussed for their implication in the design and selection of cathode bimetallic electrocatalysts for the oxygen reduction reaction (ORR) in polymer electrode membrane (PEM) fuel cells.


Building an RNA-Based Toggle Switch Using Inhibitory RNA Aptamers.
Synthetic RNA systems offer unique advantages such as faster response, increased specificity, and programmability compared to conventional protein-based networks. Here, we demonstrate an in vitro RNA-based toggle switch using RNA aptamers capable of inhibiting the transcriptional activity of T7 or SP6 RNA polymerases. The activities of both polymerases are monitored simultaneously by using Broccoli and malachite green light-up aptamer systems. In our toggle switch, a T7 promoter drives the expression of SP6 inhibitory aptamers, and an SP6 promoter expresses T7 inhibitory aptamers. We show that the two distinct states originating from the mutual inhibition of aptamers can be toggled by adding DNA sequences to sequester the RNA inhibitory aptamers. Finally, we assessed our RNA-based toggle switch in degrading conditions by introducing controlled degradation of RNAs using a mix of RNases. Our results demonstrate that the RNA-based toggle switch could be used as a control element for nucleic acid networks in synthetic biology applications.


Pediatric Gastroenterology in Cuba: Evolution and Challenges.
INTRODUCTION The professional practice of pediatric gastroenterology arose in Cuba as an expression of the specialty's development internationally and Cuba's new strategies in public health, and in response to national needs for health care expertise in digestive diseases of infants, older children and adolescents. OBJECTIVES Describe the history of pediatric gastroenterology's development in Cuba since its inception at the National Gastroenterology Institute in the early 1970s, its contributions, and efforts to extend it to pediatric hospitals throughout Cuba. EVIDENCE ACQUISITION This is a historical review based on document analysis. Institutional sources from the National Gastroenterology Institute and Ministry of Public Health were reviewed, as well as international and national literature on the history of pediatric gastroenterology and unpublished texts since its emergence in 1972. DEVELOPMENT Although pediatric gastroenterology has not been formally recognized as a medical specialty in Cuba, there have been important achievements in establishing a network of specialized health care services for digestive diseases of children and adolescents. Gastrointestinal endoscopy and other auxiliary diagnostic modalities have been introduced for children and play a major role in clinical trials and research. This article describes the international context that promoted the specialty's development in Cuba. Reference is made to specialized training from its initial stages in 1972, its consolidation as an emerging discipline in Cuban medicine, and its diffusion in Latin American and Caribbean countries. Professional development and specialized training to meet health human resource needs in pediatric hospitals are described, as well as Cuban participation in the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition. National and international milestones, publications, awards and recognitions that indicate advances despite difficulties are also presented. CONCLUSIONS Since 1972, there have been major strides in the development of pediatric gastroenterology practice in Cuba. The establishment of a national network of specialized services in pediatric hospitals throughout Cuba has provided quality health care for digestive diseases of childhood. Pediatric gastroenterology's development and achievements in healthcare and research are such that it deserves official recognition as a medical specialty Cuba. KEYWORDS Pediatric gastroenterology, history of medicine, national health system, service network, hepatology, children, adolescents, Cuba.


Effect of Postmortem Degradation on the Preservation of Viral Particles and Rabies Antigens in Mice Brains. Light and Electron Microscopic Study.
Rabies diagnosis is mainly made on fresh brain tissue postmortem by means of the direct immunofluorescence test. However, in some cases, it is not possible to use this technique, given that the affected nervous tissue goes through a postmortem degradation process, due to problems in the handling and transport of the samples. For this reason, the preservation in time of the rabies virus inclusions was assessed, as well as the immunoreactivity and the ultrastructure of viral particles in tissue with postmortem degradation. Brains of mice inoculated with rabies virus and control mice were processed for conventional histology, immunohistochemistry, electron microscopy, and immunoelectron microscopy in different postmortem times. In the processed tissues for hematoxylin and eosin, the presence of eosinophilic inclusions was not observed beyond 12 h postmortem. Surprisingly, the immunoreactivity of the viral antigens increased with time, at least until 30 h postmortem. It was possible to easily recognize the viral particles by means of conventional electron microscopy until 12 h postmortem. Immunoelectron microscopy allowed us to identify the presence of viral antigens disseminated in the neuronal cytoplasm until 30 h postmortem, but immunoreactive viral particles were not observed. The rabies infection did not cause histological or ultrastructural alterations different from those in the control group as a result of the postmortem degradation. In conclusion, the immunohistochemistry is a reliable test for rabies diagnosis in samples with postmortem degradation and that have been fixed with aldehydes.


Priorities of consumers, providers, and family members in the treatment of schizophrenia.
This study explored the extent and nature of agreement on outcome and service priorities between consumers, their providers, and their family members as well as providers' and family members' awareness of consumers' priorities. Interviews were conducted with members of 60 stakeholder sets that included a person with schizophrenia, one of his or her mental health care providers, and one of his or her family members. Each member of the set ranked seven outcomes and nine services in order of importance and rated the relative importance of each. Family members and providers also ranked the outcomes and services in the order in which they believed the consumer would rank them. Magnitude-estimation-preference-weight ratios and Kendall's rank-order correlation were used to evaluate pairwise (consumer and provider, consumer and family member, and family member and provider) and within-set agreement. Pairwise and within-set agreement was low. In general, no more than a third of the pairs agreed on outcome priorities, and no more than half agreed on service priorities. In about half of the 60 sets, none of the three pairs agreed on outcome priorities. Awareness of consumers' priorities was limited. Family members' and providers' estimates of consumers' outcome priorities were more similar to their own preferences than to consumers'. Low rates of agreement were also noted for providers' estimates of consumers' service priorities. Within-set agreement was lower than agreement by type of stakeholder. Current goal-setting in nonresearch clinical settings is generating neither consensus nor a shared understanding of consumers' priorities. Priorities vary widely among consumers, among providers, and among family members.


Evaluation of the latent tuberculosis screening and treatment strategy for asylum seekers in Stockholm, Sweden 2015-2018: a record linkage study of the care cascade.
About 90% of active tuberculosis (TB) cases in Sweden are foreign born and are mainly due to latent TB infection (LTBI) reactivation. The aim of this study was to assess the current migrant LTBI screening programme with regards to test results and completion of the care cascade. A retrospective cohort of all 14173 individuals attending a health examination was established for the Stockholm Region 2015-2018 through record-linkage of data extracted from the Swedish Migration Authority and medical records. Screening results, referrals to specialist care and treatment initiation were ascertained through automated data extraction for the entire cohort. Detailed cascade steps, including treatment completion, were analysed through manual data extraction for a subsample of all persons referred to specialist care in the period 2016-2017. Of 5470 patients screened with an interferon-gamma release assay (IGRA), 1364 (25%) were positive, of whom 358 (26%) initiated LTBI treatment. An increased trend in IGRA-positivity was seen for increased age and TB-incidence in country of origin. Among the IGRA positive patients, 604 (44%) were referred to specialist care. Lower age was the main referral predictor. In the subsample of 443 patients referred to specialist care in 2016-2017, 386 (87%) were invited, of whom 366 (95%) attended. Of 251 patients (69%) recommended for LTBI treatment, 244 (97%) started such treatment and of those 221 (91%) completed it. The low attrition in patient-dependent cascade steps shows that the voluntary approach works well. Low LTBI treatment attainment is due to the current conservative local treatment policy, which means the vast majority are IGRA-tested without an intention to treat for LTBI.


Who should donate blood? Policy decisions on donor deferral criteria should protect recipients and be fair to donors.
An important element in the development of voluntary blood donation schemes throughout the world has been the attention given to minimising the risk to recipients of donated blood, primarily the risk of transfusion transmitted infections. In response to the appearance of human immunodeficiency virus (HIV) in the 1980s a range of national policies emerged that excluded populations at high risk of contracting HIV from donating blood, with a particular focus on men who have sex with men (MSM), the primary reason being the protection of recipients of donated blood. Recently some countries, including the UK, have revised their policies, informed by advances in screening tests, epidemiological evidence of transmission rates and an increasing concern about unfair discrimination of specific groups in society. Policy makers face a difficult task of balancing safety of recipients; an adequate blood supply for those who require transfusion; and societal/legal obligations to treat everyone fairly. Given that no transfusion is risk free, the question is what degree of risk is acceptable in order to meet the needs of recipients and society. Decisions about acceptance of risk are complex and policy makers who set acceptable risk levels must provide ethically justifiable reasons for their decisions. We suggest it is possible to provide a set of reasons that stakeholders could agree are relevant based on careful evaluation of the evidence of all relevant risks and explicit acknowledgement of other morally relevant values. We describe using such a process in the Safety of Blood Tissue and Organs (SaBTO) review of donor deferral criteria related to sexual behaviour.


Elucidating the early signal transduction pathways leading to fetal brain injury in preterm birth.
Adverse neurologic outcome, including cerebral palsy, is a significant contributor to long-term morbidity in preterm neonates. However, the mechanisms leading to brain injury in the setting of a preterm birth are poorly understood. In the last decade, there has been a growing body of evidence correlating infection or inflammation with preterm birth. The presence of intrauterine inflammation significantly increases the risk for adverse neurologic outcome in the neonate. These studies were performed to elucidate the early signal transduction pathways activated in the fetal brain that may result in long-term neurologic injury. Using our mouse model of localized intrauterine inflammation, the activation of TH1/TH2 pathways in the placenta, fetus corpus, fetal liver, and fetal brain was investigated. Additional studies determined whether activation of TH1/TH2 pathways could promote cell death and alter glial development. Real-time PCR studies demonstrated that a robust TH1/TH2 response occurs rapidly in the fetal brain after exposure to intrauterine inflammation. The cytokine response in the fetus and placenta was not significantly correlated with the response in the fetal brain. Along with an immune response, cell death pathways were activated early in the fetal brain in response to intrauterine LPS. Implicating TH1/TH2 and cell death pathways in permanent brain injury are our findings of an increase in GFAP mRNA and protein as well as a loss of pro-oligodendrocytes. With increased understanding of the mechanisms by which inflammation promotes brain injury in the preterm neonate, identification of potential targets to limit adverse neonatal outcomes becomes possible.


WNK signalling pathways in blood pressure regulation.
Hypertension (high blood pressure) is a major public health problem affecting more than a billion people worldwide with complications, including stroke, heart failure and kidney failure. The regulation of blood pressure is multifactorial reflecting genetic susceptibility, in utero environment and external factors such as obesity and salt intake. In keeping with Arthur Guyton's hypothesis, the kidney plays a key role in blood pressure control and data from clinical studies; physiology and genetics have shown that hypertension is driven a failure of the kidney to excrete excess salt at normal levels of blood pressure. There is a number of rare Mendelian blood pressure syndromes, which have shed light on the molecular mechanisms involved in dysregulated ion transport in the distal kidney. One in particular is Familial hyperkalemic hypertension (FHHt), an autosomal dominant monogenic form of hypertension characterised by high blood pressure, hyperkalemia, hyperchloremic metabolic acidosis, and hypercalciuria. The clinical signs of FHHt are treated by low doses of thiazide diuretic, and it mirrors Gitelman syndrome which features the inverse phenotype of hypotension, hypokalemic metabolic alkalosis, and hypocalciuria. Gitelman syndrome is caused by loss of function mutations in the thiazide-sensitive Na/Cl cotransporter (NCC); however, FHHt patients do not have mutations in the SCL12A3 locus encoding NCC. Instead, mutations have been identified in genes that have revealed a key signalling pathway that regulates NCC and several other key transporters and ion channels in the kidney that are critical for BP regulation. This is the WNK kinase signalling pathway that is the subject of this review.


Clinical experience with the triple test for Down's syndrome screening.
The introduction of maternal serological screening for chromosome disorders in pregnancy in women aged over 30 years at the estimated date of delivery was monitored in two hospitals. The test used involved measurement of three substances in maternal serum combined with maternal age (the triple test). This is the first report of such screening applied to an unselected antenatal clinic population. Test uptake was high but there was no overall increase in amniocentesis numbers because the increase in younger mothers was compensated for by a decrease in older women who previously, without serological testing, might have gone directly to amniocentesis. It is anticipated that widespread introduction of such testing will lead to improved detection of Down's syndrome as predicted from retrospective studies.


[Is age a limiting factor for carotid surgery?].
To evaluate the role of carotid surgery in elderly patients 75 years and older, we reviewed 912 carotid endarterectomies performed on 806 patients between 1987 and 1990. There were 151 patients (19% of the whole series) aged 75 years and older (160 endarterectomies, group A), including 29 octogenarians, vs 655 patients under 75 years of age (group B). There were more women in the elderly age group (44%) than in the younger one (38%). Symptoms, risk factors, operative outcome and follow up data of the two groups were compared. The risk profile was similar for the two age groups, with exception for coronary heart disease, less frequent in the older patient group (25% had previous infarction vs 44%). Indication for carotid endarterectomy was different in the two age groups: 41% of group A underwent prophylactic thrombendarterectomy for high degree stenosis, while only 30% of group B had asymptomatic carotid disease. In group A, 6% of the patients had carotid endarterectomy after recovering from a mild stroke, vs 2% in group B. Angiography revealed bilateral carotid disease in 59% of the group A patients (including 15% with contralateral occlusion) vs 40% in group B. Operative mortality was 1.5% for the younger age group vs 2.5% for the older age group. The cause of death was cardiac in 60%. A follow up is available for all patients who benefited carotid endarterectomy since 1976, including 180 patients aged 75 years or older.(ABSTRACT TRUNCATED AT 250 WORDS)


Women with female infertility seeking medically assisted reproduction are not at increased risk of developing multiple sclerosis.
Is female infertility among women seeking medically assisted reproduction (MAR) associated with prevalent as well as incident multiple sclerosis (MS)? Women with a record of female infertility did not have an increased risk of developing MS compared with apparent fertile women; however, the prevalence of MS was slightly higher among women undergoing MAR compared with women who had a child without MAR, but this was not related to origin of infertility (i.e. male versus female factor infertility). Women with MS have fewer children compared with women without MS. Persons with MS more often have other coexisting autoimmune disorders including hypothyroidism compared with the general population. Thyroid dysfunction is associated with ovarian cause of infertility, miscarriage and ovarian failure. Conversely, women with endometriosis, that is highly associated with infertility, also more often have other coexisting autoimmune diseases including MS and hypothyroidism compared with the general population. However, whether the low fertility rate among women with MS is due to a genetically predisposition to other autoimmune and endocrine disorders that leads to reduced fertility, or an active choice of the woman, disease-related pathology or treatment-specific effect on endocrine and/or ovarian function, is not completely understood. A register-based cohort study of a total of 310 357 women from 1996 to 2018. A cross-sectional design was used for analysing prevalence of MS, whereas a cohort design with up to 24 years of follow-up was used for analysing incidence of MS. Three cohorts were included in the study (i) 55 404 women with a female infertility diagnosis registered in the Danish IVF register; (ii) 25 096 women with only male factor infertility recorded in the IVF register and thus no female infertility diagnosis and (iii) 229 857 age- and calendar-matched women with a record of first child birth in the Danish Medical Birth Register (DMBR) and no record ever in the IVF register. The prevalence and incidence of MS in the female infertility cohort were compared with the two control cohorts of apparent fertile women using log-binomial regression and Cox proportional hazard regression, respectively. The crude prevalence of having MS per 1000 persons was 3.2 for women who had undergone MAR treatment regardless of origin of infertility (i.e. male versus female factor infertility) and 2.3 for fertile DMBR controls. The age, calendar and educational level adjusted prevalence ratio of having a diagnosis of MS at the first MAR treatment was 1.27 (95% CI 1.07-1.52) for infertile women compared with fertile DMBR controls, and 1.00 (95% CI 0.77-1.31) for comparison to women with a male partner with infertility who had also undergone MAR treatment. We found no association between incident MS and female infertility compared with either of the control groups of fertile women. The cohort of infertile women is highly selected on the basis of their choice of having fertility treatment and thus does not include women with unestablished infertility or women who, for some reason, have chosen not to have MAR treatment. Additionally, due to the nature of the observational study design, we cannot exclude the possibility of unmeasured and/or residual confounding. Our results suggest that women with MS may undergo MAR treatment more often than women without MS due to more awareness about the possibility of MAR treatments, sexual dysfunction related to MS disease, but also need for timing of the pregnancy to avoid an unnecessary long time period without disease modifying therapy-especially of high efficacy-and hence a wish to conceive quickly. These findings are important for clinicians dealing with women with MS of childbearing age. The authors received no financial support for the study. T.I.K. has served on a scientific advisory board for Novartis and has received support for congress participation from Biogen. M.M. has served on scientific advisory boards for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie and Alexion. She has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi and Genzyme and has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck and Novartis. The remaining authors declare no conflict of interest. N/A.


Study of delayed development of the upper first molars.
The present study was undertaken to analyze the status of formation of the upper first molar in individuals suspected as having delayed eruption of the upper first molar. The subjects of this study were 51 patients presenting to orthodontic specialists with delayed eruption of the upper first molars. The 95 teeth of these 51 patients were observed. The investigation of the tooth development status included evaluation of the tooth development stage on panoramic radiographs according to the method of Moorrees et al. The upper first molars that showed delayed development were at the stage of initial cleft formation, reflecting a delay by 2.09 years in boys and 2.84 years in girls. In most cases, the delayed eruption was bilateral, and the development stage of the subject teeth did not differ between right and left sides. The plot of the developmental stage of the subject teeth (Y-axis) against the calendar age of the subjects (X-axis) showing delayed upper first molar development was fitted to the logistic curve. The tooth development was at the stage of initial cleft formation was delayed 2.5 years or more, according to these curves.


Neuroprotective effect of apolipoprotein E against ischemia.
Apolipoprotein E (APOE) deficiency has been shown to worsen neuronal injuries after cerebral ischemia. However, the molecular mechanism underlying the protective effect of APOE remains uncertain, even though several mechanisms including excitotoxicity, free radicals, and apoptosis have been cited as causes of selective neuronal vulnerability in cerebral ischemia. In the present study, we compared the vulnerability of cultured neurons prepared from APOE-knockout mice upon exposure to glutamate, hydrogen peroxide, and staurosporine. No significant difference in cell viability was observed after exposure to glutamate or staurosporine between APOE-deficient and wild-type mice. However, exposure to hydrogen peroxide significantly increased the level of cell death in APOE-deficient mice compared with that in wild-type mice. In the adult mice, after transient forebrain ischemia for 12 min, APOE-deficient mice showed more neuronal death than wild-type mice. Pretreatment of APOE-deficient mice with vitamin E for 2 months markedly reduced neuronal death caused by ischemia. The results suggested that APOE exerted the neuroprotective effect against ischemia through its antioxidant action, but not through mitigation of glutamate toxicity or blocking of apoptosis.