Is transpupillary thermotherapy applicable to the treatment of age-related macular degeneration with pigment epithelial detachment?
The cause of pigment epithelial tears at the edge of a pigment epithelial detachment (PED) following transpupillary thermotherapy in eyes with associated age-related macular degeneration is unclear. We have treated 2 eyes which had a PED with TTT. Our findings suggest pigment epithelial tears are probably related to the shape of the PED and TTT should not applied to a balloon-shaped PED.


Neonatal status and hearing loss in high-risk infants.
Neurophysiologic and behavioral assessments of auditory function were performed on 224 very low birth weight (less than or equal to 1500 gm) infants requiring intensive care in the nursery. The subjects were studied prospectively from 36 weeks to 4 years of age, as available for follow-up. To classify them according to their neonatal status, we applied a principal components analysis to a number of variables representative of the extent of illness and of patient care in early postnatal life. The subjects were then divided into neonatal status quartiles and evaluated for hearing outcome. All those with sensorineural hearing loss fell exclusively into the lowest neonatal status quartile. Sensorineural hearing loss was statistically associated (1) with greater amounts of furosemide administration for longer durations and in combination with aminoglycoside antibiotics and (2) with more episodes of low pH, hypoxemia, or both, higher total bilirubin levels, and substantially lower neonatal status scores. Birth weight, gestational age, highest creatinine level, Apgar score, and aminoglycosides alone were not systematically related to hearing capacity. Subjects in the lowest neonatal status quartile also had a considerably higher incidence of middle ear disorders, characterized by elevated thresholds and prolonged auditory brain stem-response latencies reflective of conductive hearing loss. We conclude that protracted illness and its associated treatment, independently of specific diagnostic categories, constitute important risk factors for permanent hearing loss and for transient hearing loss in early life.


The structure of a tetrahydrofolate-sensing riboswitch reveals two ligand binding sites in a single aptamer.
Transport and biosynthesis of folate and its derivatives are frequently controlled by the tetrahydrofolate (THF) riboswitch in Firmicutes. We have solved the crystal structure of the THF riboswitch aptamer in complex with folinic acid, a THF analog. Uniquely, this structure reveals two molecules of folinic acid binding to a single structured domain. These two sites interact with ligand in a similar fashion, primarily through recognition of the reduced pterin moiety. 7-deazaguanine, a soluble analog of guanine, binds the riboswitch with nearly the same affinity as its natural effector. However, 7-deazaguanine effects transcriptional termination to a substantially lesser degree than folinic acid, suggesting that the cellular guanine pool does not act upon the THF riboswitch. Under physiological conditions the ligands display strong cooperative binding, with one of the two sites playing a greater role in eliciting the regulatory response, which suggests that the second site may play another functional role.


Alveolar Capillary Dysplasia as a Cause of Persistent Pulmonary Hypertension.
Persistent pulmonary hypertension (PPHN) in a term or late preterm has varied etiology. A late preterm neonate operated for esophageal atresia with tracheo-esophageal fistula was complicated by severe pulmonary hypertension and unable to be weaned off from respiratory support. The neonate expired by 15 weeks of life; diagnosis was made on postmortem lung biopsy. Alveolarcapillary dysplasia should be considered in a neonate with idiopathic refractory PPHN, if associated with anomalies.


Therapeutic plasma exchange in patients with thrombotic thrombocytopenic purpura: a retrospective multicenter study.
Thrombotic thrombocytopenic purpura (TTP) is a particular form of thrombotic microangiopathy typically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological abnormalities, and renal dysfunction. TTP requires a rapid diagnosis and an adapted management in emergency. Daily sessions of therapeutic plasma exchange (TPE) remain the basis of management of TTP. Also, TTP is a rare disease that is fatal if it is not treated. TPE has resulted in excellent remission and survival rates in TTP patients. We aimed to present our experience in 163 patients with TTP treated with TPE during the past 5years from 10 centers of Turkey. One hundered and sixty-three patients with TTP treated with TPE during the past 5years from 10 centers of Turkey were retrospectively evaluated. TPE was carried out 1-1.5times plasma volume. Fresh frozen plasma (FFP) was used as the replacement fluid. TPE was performed daily until normalization of serum lactate dehydrogenase (LDH) and recovery of the platelet count to >150×10(9)/dL. TPE was then slowly tapered. Clinical data, the number of TPE, other given therapy modalities, treatment outcomes, and TPE complications were recorded. Fifty-eight percent (95/163) of the patients were females. The median age of the patients was 42years (range; 16-82). The median age of male patients was significantly higher than female (53 vs. 34years; p<0.001). All patients had thrombocytopenia and microangiopathic hemolytic anemia. At the same time, 82.8% (135/163) of patients had neurological abnormalities, 78.5% (128/163) of patients had renal dysfunction, and 89% (145/163) of patients had fever. Also, 10.4% (17/163) of patients had three of the five criteria, 10.4% (17/163) of patients had four of the five criteria, and 6.1% (10/163) of patients had all of the five criteria. Primary TTP comprised of 85.9% (140/163) of the patients and secondary TTP comprised of 14.1% (23/163) of the patients. Malignancy was the most common cause in secondary TTP. The median number of TPE was 13 (range; 1-80). The number of TPE was significantly higher in complete response (CR) patients (median 15.0 vs. 3.5; p<0.001). CR was achieved in 85.3% (139/163) of the patients. Similar results were achieved with TPE in both primary and secondary TTP (85% vs. 87%, respectively; p=0.806). There was no advantage of TPE+prednisolone compared to TPE alone in terms of CR rates (82.1% vs. 76.7%; p=0.746). CR was not achieved in 14.7% (24/163) of the patients and these patients died of TTP related causes. There were no statistical differences in terms of mortality rate between patients with secondary and primary TTP [15% (21/140) vs. 13% (3/23); p=0.806]. But, we obtained significant statistical differences in terms of mortality rate between patients on TPE alone and TPE+prednisolone [14% (12/86) vs. 3% (2/67), p<0.001]. TPE is an effective treatment for TTP and is associated with high CR rate in both primary and secondary TTP. Thrombocytopenia together with microangiopathic hemolytic anemia is mandatory for the diagnosis of TTP and if these two criteria met in a patient, TPE should be performed immediately.


Polysubstance addiction patterns among 7,989 individuals with cocaine use disorder.
To characterize polysubstance addiction (PSA) patterns of cocaine use disorder (CoUD), we performed a latent class analysis (LCA) in 7,989 participants with a lifetime DSM-5 diagnosis of CoUD. This analysis identified three PSA subgroups among CoUD participants (i.e., low, 17%; intermediate, 38%; high, 45%). While these subgroups varied by age, sex, and racial-ethnic distribution (p < 0.001), there was no difference with respect to education or income (p > 0.05). After accounting for sex, age, and race-ethnicity, the CoUD subgroup with high PSA had higher odds of antisocial personality disorder (OR = 21.96 vs. 6.39, difference-p = 8.08✕10-6), agoraphobia (OR = 4.58 vs. 2.05, difference-p = 7.04✕10-4), mixed bipolar episode (OR = 10.36 vs. 2.61, difference-p = 7.04✕10-4), posttraumatic stress disorder (OR = 11.54 vs. 5.86, difference-p = 2.67✕10-4), antidepressant medication use (OR = 13.49 vs. 8.02, difference-p = 1.42✕10-4), and sexually transmitted diseases (OR = 5.92 vs. 3.38, difference-p = 1.81✕10-5) than the low-PSA CoUD subgroup. These findings underscore the importance of modeling PSA severity and comorbidities when examining the clinical, molecular, and neuroimaging correlates of CoUD.


Chemical restraint and analgesia for diagnostic and emergency procedures.
Diagnostic or emergency procedures are a necessity; however, the accompanying stress, discomfort, and pain must be considered and alleviated. The requirement for restraint and analgesia varies with the individual animal and its condition. Safe protocols are suggested for specific patient concerns. Recommendations for stabilization are included to reduce the detrimental effects of the drugs used. Alternatives are presented when feasible for animals in less critical condition. Technique of administration and dose adjustment is covered, as is drug selection.


Congenital deficiency of the extrinsic extensor mechanism of the hand.
In a 16-year-old girl, congenital extensor deficiency of the hand with absence of true clasping of the thumb was transmitted by an autosomal dominant mechanism of inheritance. The age of presentation was more advanced than usual. This case is the basis for proposing an hypothesis that the condition is a manifestation of a failure of innervation to develop in the extensor muscles of the forearm.


Short-term Intensive Lifestyle Therapy in a Worksite Setting Improves Cardiometabolic Health in People With Obesity.
The Pritikin Program, which provides intensive lifestyle therapy, has been shown to improve cardiometabolic outcomes when provided as a residential program. The purpose of the present study was to conduct a short-term, randomized, controlled trial to evaluate the feasibility and clinical efficacy of treatment with the Pritikin Program in an outpatient worksite setting. Cardiometabolic outcomes were evaluated in people with overweight/obesity and ≥2 metabolic abnormalities (high triglycerides, low high-density lipoprotein (HDL) cholesterol, high blood pressure, HbA1c > 5.7%), before and after they were randomized to 6 weeks of standard care (n = 26) or intensive lifestyle therapy, based on the Pritikin Program (n = 28). Participants in the lifestyle intervention group were provided all food as packed-out meals and participated in group nutrition, behavioral education, cooking classes, and exercise sessions 3 times per week at a worksite location. Compared with standard care, intensive lifestyle therapy decreased body weight (-5.0% vs -0.5%), HbA1c (-15.5% vs +2.3%), plasma total cholesterol (-9.8% vs +7.7%), low-density lipoprotein cholesterol (-10.3% vs +9.3%) and triglyceride (-21.7% vs +3.0%) concentrations, and systolic blood pressure (-7.0% vs 0%) (all P values < .02), and increased exercise tolerance (time to exhaustion walking on a treadmill by +23.7% vs +4.5%; P < .001). This study demonstrates the feasibility and clinical effectiveness of short-term, intensive outpatient lifestyle therapy in people with overweight/obesity and increased risk of coronary heart disease when all food is provided and the intervention is conducted at a convenient worksite setting.


Macrophage-mediated natural cytotoxicity against various target cells in vitro. II. Macrophages from rats of different ages.
Adherent, predominantly phagocytic mononuclear cells from various rat tissues express spontaneous cytoxicity against diverse target cells in vitro. The extent to which cytotoxicity was expressed by effector cells depended on the age of donors. Cytolytic effector-cell capacity was already fully developed a few days after birth, and persisted over many months, but was clearly reduced in senescence. Similarly, the ability to intensify natural cytotoxicity by peptone in vivo was already fully manifested in the newborn, but was significantly diminished in old rats.


Successful organoid-mediated generation of iPSC-derived CAR-T cells.
Artificial thymic organoids (ATOs) allow the selective differentiation of chimeric antigen receptor (CAR)-transduced human iPSCs into CAR-T cells. In this issue of Cell Stem Cell, Wang et al. now use ATOs to produce human CD19+ CAR-T cells that mimic conventional CAR-T cells and effectively control the progression of human CD19+ leukemia in an animal model.


Humoral response to SARS-CoV-2 and seasonal coronaviruses in COVID-19 patients.
We used enzyme-linked immunoassay methods to measure the prevalence and the levels of antibody responses to the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and four seasonal human coronaviruses (HCoV-OC43, HCoV-HKU1, HCoV 229E, and HCoV-NL63) in a cohort of 115 convalescent plasma donors infected with SARS-CoV-2 (1-61 days after symptom onset) compared to antibody levels in 114 individuals with no evidence of a recent infection with SARS-CoV-2. In the humoral response to the four seasonal coronaviruses, only HCoV-HKU1- and HCoV-229E-assays showed slightly elevated antibody levels in the COVID group compared to the control group. While in the COVID-group the levels of SARS-CoV-2 antibodies correlated significantly with disease severity, no association was found in the levels of antibodies against the seasonal coronaviruses. The most striking result in both groups was that the levels of antibodies against all tested coronaviruses, including the new SARS-CoV-2 showed a highly significant correlation with each other. There seems to be an individual predisposition to a weaker or stronger humoral immune response against all known seasonal human coronaviruses including the new SARS-CoV-2, which could lead to a definition of low and high responders against human coronaviruses with potential impact on the assessment of postinfection antibody levels and protection.


Upstream transcription factor 1 (USF1) polymorphisms associate with Alzheimer's disease-related neuropathological lesions: Tampere Autopsy Study.
The apolipoprotein E (APOE) gene associates with Alzheimer's disease (AD) and cholesterol levels. Upstream transcription factor 1 (USF1) regulates lipid metabolism genes, including APOE, and the AD Aβ-precursor protein. We investigated associations between 6 haplotype-tagging USF1 single-nucleotide polymorphisms (and haplotypes) and AD-related neuropathological lesions [senile plaques (SP), neurofibrillary tangles (NFT) ] in an autopsy series comprising 603 cases (ages 0-97, mean 62 years, 215 women) that died out-of-hospital. In age- and APOE-adjusted analyses, the minor G-allele of rs2774276, previously linked to elevated cholesterol, associated with late-stage burnt out SP among women and early non-neuritic SP among men. The G-allele of the previously unreported rs10908821 showed significant risk of having SP, especially neuritic and burnt out SP, among women but not men. USF1 haplotype GCGCAC carriers (risk alleles of rs2774276 and rs10908821) associated with SP risk, especially neuritic and late-stage burnt out SP, among women but not men. Younger CCGCAC carriers (risk allele of rs2774276 and protective of rs10908821) were more likely to have non-neuritic and diffuse SP. Conversely, USF1 CCGCAC haplotype carriers had lower NFT prevalence among 65+ year-olds. These results suggest USF1 has an independent but gender- and age-associated effect on AD-related brain lesion development.


Comparison between broth microdilution and agar disk diffusion methods for antimicrobial susceptibility testing of bovine mastitis pathogens.
In order to counter the antibiotic resistance phenomenon, a prudent and rational use of antimicrobials should be driven by an accurate clinical diagnosis and, when possible, by the isolation of the etiological agent followed by susceptibility testing, with the aim to select the most suitable molecule for therapy. Cow mastitis is considered the main cause of antibiotic use in the cattle breeding sector. The purpose of this study was to compare the broth microdilution (BMD) method performed with Sensititre Custom Plates and the agar disk diffusion (ADD) method in determining antimicrobial susceptibility of 215 isolates from bovine mastitis, including contagious pathogens (Staphylococcus aureus, Streptococcus agalactiae) and environmental (Streptococcus uberis, Streptococcus dysgalactiae, Enterococcus spp., Escherichia coli, Serratia marcescens, Klebsiella pneumoniae). We compared results of the following antimicrobials: amoxicillin/clavulanic acid, ampicillin, cefazolin, ceftiofur, enrofloxacin, erythromycin, kanamycin, oxacillin, penicillin, pirlimycin, rifampicin and trimethoprim/sulphonamides. We applied MIC breakpoints and zone diameter breakpoints as recommended by CLSI and EUCAST. MIC and disk diffusion diameters were compared for 1839 microorganism/antimicrobial combination and discrepancies between the two methods were classified as very major discrepancy (VMD), major discrepancy (MD) and minor discrepancy (MiD). The overall agreement between the two methods was found to be 80.7% with a Cohen's kappa coefficient of 0.397, thus indicating a fair concordance. BMD method and ADD method demonstrated a satisfactory agreement (89 to 100%) for S. aureus and S. marcescens and all antimicrobial agents tested. Low agreement was observed for S. uberis and rifampicin (20%), enrofloxacin (49%), penicillin (51%) and pirlimycin (52%), E. coli and ampicillin (20%), S. dysgalactiae and enrofloxacin (44%), S. agalactiae and rifampicin (25%). A possible explanation for the discrepancies detected could be found in the breakpoints used which, sometimes, are not specific for the tissue-matrix of isolation/animal species/pathogen agent. The majority of the discrepancies found were MiD and MD, revealing a higher restrictiveness of the BMD method, while VMD represented only 0.2% of the total observations, a comforting fact since this type of error may result in treatment failure.


Laser mirrors with variable reflected intensity and uniform phase shift: design process.
Optical coatings with circularly symmetric graded reflectance are used as laser mirrors in unstable resonators. A proper design of such coatings permits any maximum central reflectance to be obtained along with a null external reflectance. Different design approaches are discussed, and an optimized design that gives negligible distortion of the reflected and transmitted wave front is proposed. Coatings with super-Gaussian and step reflectance profiles are examined as two different solutions for improving laser beam quality.


Pulmonary hypertension in end-stage pulmonary sarcoidosis: therapeutic effect of sildenafil?
The objectives of this study were to assess the frequency and severity of pulmonary hypertension (PH) and the effect of sildenafil treatment in patients with recalcitrant pulmonary sarcoidosis. This investigation was a single-center, retrospective study of all patients (n = 25) with end-stage pulmonary sarcoidosis referred for lung transplantation. Hemodynamic measurements were evaluated by right-side cardiac catheterization in 24 of 25 patients. Sildenafil treatment for patients with sarcoidosis-associated PH was introduced in April 2004. The study group of 24 patients (16 men, 8 women) had a median age of 45 (range 35 to 58) years, and duration of sarcoidosis of 11 (range 2 to 38) years. Mean pulmonary arterial pressure (MPAP) was median 36 (range 18 to 73) mm Hg. PH (MPAP >25 mm Hg) was present in 19 of 24 patients (79%). Sildenafil was administered to 12 of 13 patients at a dose of 150 (range 75 to 225) mg/day for 4 (range 1 to 12) months. Sildenafil treatment was associated with reductions in MPAP of -8 mm Hg (CI -1 to -15 mm Hg), and PVR -4.9 Wood units (CI -7.2 to -2.6 Wood units). Cardiac output and cardiac index also increased during treatment (p = 0.01, respectively). There were no consistent changes in 6-minute walk distance. Patients with severe pulmonary sarcoidosis have a high prevalence of PH. Sildenafil treatment was associated with significant improvements in hemodynamic parameters.


An investigation into the incidence of auto-immune disorders in patients with localized morphoea.
Patients with localized morphoea have an increased incidence of auto-immune disorders, but this is not related to the age of onset, duration of disease nor the site or number of lesions. The patients have an increased incidence of tissue antibodies and these are more common when more than one lesion is present. The relatives of the patients have also been found to have an increased incidence of auto-immune disorders. These findings suggest an immunological basis for the disease and indicate that the patients should be investigated and followed up to detect the evidence of other auto-immune disorders.


Factors affecting the moisture permeability of lipid-based edible films: a review.
Moisture transfers inside food products could be controlled or limited by the use of edible films. These are usually based on hydrophobic substances such as lipids to improve barrier efficiency. Water permeability of films is affected by many factors, depending on both the nature of barrier components, the film structure (homogeneous, emulsion, multilayer, etc.), crystal type, shape, size and distribution of lipids, and thermodynamics such as temperature, vapor pressure, or the physical state of water in contact to the films. After a brief presentation of lipids and hydrophobic substances used as moisture barrier, cited in the scientific literature, this article reviews all of the parameters affecting barrier performances of edible films and coatings.


Tolerability to etoricoxib in patients with aspirin-exacerbated respiratory disease.
The use of selective cyclooxygenase (COX) 2 inhibitors as an alternative to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been suggested for patients with aspirin-exacerbated respiratory disease (AERD). To evaluate tolerability to etoricoxib, a second-generation COX-2 inhibitor with high in vitro selectivity for COX-2 in patients with AERD. We conducted a retrospective review of patients with suspected aspirin intolerance seen between October 2007 and April 2012. Single-blind, placebo-controlled oral challenges with increasing doses of aspirin and etoricoxib were performed on 3 different days. Of 262 patients with suspected aspirin intolerance, 248 underwent challenge testing with aspirin and 122 (49.2%) showed positive test results. In 104 of these aspirin-sensitive patients, etoricoxib was tested as an alternative drug and was tolerated in all but 3 (2.9%), who developed a positive asthmatic reaction. The highly selective COX-2 inhibitor etoricoxib was tolerated in most but not all patients tested. An oral provocation test is therefore recommended before prescribing etoricoxib for patients with AERD.


Strain-specific and outcome-specific efficacy of probiotics for the treatment of irritable bowel syndrome: A systematic review and meta-analysis.
Consistent guidance for choosing an appropriate probiotic for the treatment of irritable bowel syndrome is lacking. Literature databases searched included: PubMed, Google Scholar and NIH registry of clinical trials from inception to June 2021. Inclusion criteria: randomized controlled trials (RCTs) enrolling adult or pediatric IBS patients comparing probiotics against controls and ≥ 2 RCTs with common IBS outcome measures within each type of probiotic. Five common measures of IBS symptoms (changes in global Irritable Bowel Syndrome Severity Scoring System or IBS-SSS scores, frequency of global responders, changes in bloating or abdominal pain scores and frequency of abdominal pain relief) were used. This study was registered at Prospero (#CRD42018109169). We screened 521 studies and included 42 randomized controlled trials (45 treatment arms, N = 3856). Four probiotics demonstrated significant reduction in abdominal pain relief: B. coagulans MTCC5260 (RR= 4.9, 95% C.I. 3.3, 7.3), L. plantarum 299v (RR= 4.6, 95% CI 1.9, 11.0), S. boulardii CNCM I-745 (RR= 1.5, 95% C.I. 1.1, 2.1) and S. cerevisiae CNCM I-3856 (RR= 1.3, 95% C.I. 1.04, 1.6). Mild-moderate adverse events were reported in 51% of the trials, none were more associated with the probiotic compared to controls. Although the analysis of probiotic efficacy was limited by the diversity of IBS outcomes used in trials and lack of confirmatory trials for some strains, six single-strain probiotics and three different types of probiotic mixtures showed significant efficacy for at least one IBS outcome measure. These results might be relevant to clinical practice and policy.


Interactions between developmental processes, growth, and food selection in the larvae and juveniles of Rutilus rutilus (L.) (Cyprinidae).
The aim of this study was to assess the effects of developmental events, occurring in fish during the first weeks after hatching, on the quantity and quality of the ingested food and on growth. The investigation was carried out with the larvae and juveniles of Rutilus rutilus, the single cyprinid species occurring in an oligotrophic subalpine lake in Tirol, Austria. Comparison between availability of prey in the water and gut contents suggests that the selection of food by the young fish is strongly influenced by developmental processes. For example, the prevalence of indigestible phytoplankton in the gut of young larvae can be taken as a sign of the not yet fully developed sensory and locomotory capacities of the young fish (El-Fiky et al. 1987). Furthermore, quantitative and qualitative changes in the gut contents correlate strongly with changes in the form and relative length of the gut, but reflect only weakly the availability of prey in the water. In the Seefelder See population of R. rutilus the switch from a phytoplankton to a cladoceran dominated diet is accompanied by an increase in relative growth rate by nearly one order of magnitude (Wieser et al. 1988).


Pigmented corneal rings in neonates with liver disease.
We performed eye examinations in neonates to determine whether pigmented corneal rings were present in infants with hepatic disease, as in adults. None of 16 control infants had pigmented corneal rings, but 10 (71%) of 14 infants with cholestatic liver disease had such rings. Most rings could be seen without slit lamp by direct inspection of the cornea. Furthermore, the rings appeared to resolve over time. Liver dysfunction tended to be more severe in patients with corneal rings. We speculate that abnormal tissue accumulation of copper may be present in many infants with cholestatic liver disease. Ophthalmologic examination for pigmented corneal rings or determination of serum copper levels may need to be performed in patients at high risk with hepatic disease to monitor for excessive copper accumulation.


The neuroprotective role of rosiglitazone in advanced glycation end product treated human neural stem cells is PPARgamma-dependent.
Hyperglycemia is accompanied by an accelerated formation rate of advanced glycation end products (AGEs), which is associated with the pathogenesis of diabetic neuronal deficits. Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors and its ligands are known to control many physiological, pathological and inflammatory pathways. Weinvestigated the hypothesis that the PPARγ agonist (rosiglitazone) would abrogate AGEs-mediated neurotoxic effects on human neural stem cells (hNSCs), by whichAGEs may play a role in diabetic-related neuronal impairment. Here, we show that rosiglitazone treatment increases cell viability of hNSCs via downregulation of caspase 3 activity. These rescue effects were extended in our studies showingrosiglitazone-mediated activation of PPARγ reversed the expression levels of two neuroprotective factors (Bcl-2 and PGC1α) that were downregulated in hNSCs exposed to AGEs alone. The stimulation of mitochondrial function and anti-oxidative stress by rosiglitazone was associated with activation of the PGC1α pathway by up-regulation of mitochondrial (NRF-1 and Tfam) and oxidative defense (SOD1, SOD2 and Gpx1) genes. Moreover, rosiglitazone significantly normalized the inflammatory responses (TNF-α and IL-1β), NF-κB (p65), and inflammatory genes (iNOS and COX-2) in the hNSCs treated with AGEs. This neuroprotective effect of rosiglitazone was effectively blocked by PPARγ-specific antagonist (GW9662), demonstrating that the action of rosiglitazone was mediated by at PPARγ-dependent pathway. Collectively, these novel findings show AGEs induce neurotoxic effects in hNSCs, and provide important mechanistic insights that may explain the increased risk of neuronal impairment deficits in diabetic patients. More importantly, these data show rosiglitazone-mediated activation of PPARγ-dependent signaling is neuroprotective in AGE-treated hNSCs, and suggests PPARγ ligands may be useful in the therapeutic management of patients with neurodegenerative diseases.


Repetitive detection by immunoblotting of an integumental 25-kDa antigen in Ixodes ricinus and a corresponding 20-kDa antigen in Rhipicephalus appendiculatus with sera of pluriinfested mice and rabbits.
Mice were pluriinfested with nymphs and rabbits, with adult Ixodes ricinus. As determined by immunoblotting, greater than 50% of sera from these animals reacted against a tick antigen with a molecular weight of 25 kDa, which was detected in total extracts of partially fed I. ricinus females and in tick integumental extract. It was also found in engorged nymphs but was absent from larvae. Sera of I. ricinus-infested rabbits and mice or of rabbits infested with Rhipicephalus appendiculatus adults reacted with a 20-kDa antigen in total extracts of partially fed R. appendiculatus females and the integument of this species.


Jejunal adenocarcinoma after biliopancreatic diversion. Report of a case.
The effects of bariatric surgery on the development of gastrointestinal cancers remain ill defined. We present a case of jejunal adenocarcinoma developing 19 years after biliopancreatic diversion (BPD) procedure according to Scopinaro's technique. The patient developed a marked distension of the biliopancreatic limb caused by a jejunal mass, evolving towards the so called "duodenal blowout". Emergency jejunal resection of the biliopancreatic limb, with creation of a new end-to-side jejunal-ileal anastomosis was necessary. The histological examination resulted in a moderately-differentiated ulcerated adenocarcinoma, with reactive lymph nodes and tumor-free resection margins. Tumors of the gastrointestinal system can arise following malabsorptive operations for morbid obesity, and they may be difficult to diagnose, since the symptoms are often attributed to the anatomical-functional changes resulting from this type of surgery. The case reported herein suggests that there is a need for surveillance in patients complaining of digestive symptoms after malabsorptive bariatric surgery.


Americans with disabilities act: recent and pending u.s. Supreme court decisions and implications for spine professionals.
This article highlights recent and pending United States Supreme Court cases interpreting employment provisions of the Americans with Disabilities Act and discusses their implications for spine professionals. The implications include how Spine readers approach evaluations of employees and job applicants with disabilities and workplace accommodations in light of the recent decisions. The cases pending before the Supreme Court involve orthopedic impairments and the "reasonableness" of certain workplace accommodations. Increasingly, spine professionals will be called on to assist in the analysis of these issues. This article will familiarize Spine readers with the legal interpretations under the Americans with Disabilities Act of "disability," "mitigating measures," "qualified individual," and "reasonable accommodations." It illustrates the ways in which spine professionals may be called on to help interpret and apply qualification and safety standards under the Americans with Disabilities Act to assist individuals, employers, attorneys, and other stakeholders in the employment of people with disabilities.


Synergistic effect of folate-mediated targeting and verapamil-mediated P-gp inhibition with paclitaxel -polymer micelles to overcome multi-drug resistance.
Multidrug resistance (MDR) in tumor cells is a significant obstacle for successful cancer chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is a key factor contributing to the development of tumor drug resistance. Verapamil (VRP), a P-gp inhibitor, has been reported to be able to reverse completely the resistance caused by P-gp. For optimal synergy, the drug and inhibitor combination may need to be temporally colocalized in the tumor cells. Herein, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel (PTX), along with VRP, using DOMC-FA micelles to overcome tumor drug resistance. The floate-functionalized dual agent loaded micelles resulted in the similar cytotoxicity to PTX-loaded micelles/free VRP combination and co-administration of two single-agent loaded micelles, which was higher than that of PTX-loaded micelles. Enhanced therapeutic efficacy of dual agent micelles could be ascribe to increased accumulation of PTX in drug-resistant tumor cells. We suggest that the synergistic effect of folate receptor-mediated internalization and VRP-mediated overcoming MDR could be beneficial in treatment of MDR solid tumors by targeting delivery of micellar PTX into tumor cells. As a result, the difunctional micelle systems is a very promising approach to overcome tumor drug resistance.


Determination of active ingredients of Rhododendron dauricum L. by capillary electrophoresis with electrochemical detection.
High-performance capillary electrophoresis with electrochemical detection was employed to analyse active ingredients of Rhododendron dauricum L., an important crude herb frequently used in Chinese medicines. Farrerol, quercetin, syringic acid, vanillic acid, 4-hydroxybenzoic acid, protocatechuic acid are major important active ingredients. Operated in a wall-jet configuration, a 300-microm diameter carbon-disk electrode was used as the working electrode, which exhibits a good response at +950 mV (vs. saturated calomel electrodes) for six analytes. Under the optimum conditions, the analytes were baseline separated within 16 min in a borax buffer (pH 8.7). Notably, excellent linearity was obtained over two orders of magnitude with detection limits (S/N=3) ranged from 9 x 10(-7) to 3.0 x 10(-6) M for all analytes. This method was successfully used in the analysis of Rhododendron dauricum L. with relatively simple extraction procedures, and the assay results were satisfactory.


G2Vec: Distributed gene representations for identification of cancer prognostic genes.
Identification of cancer prognostic genes is important in that it can lead to accurate outcome prediction and better therapeutic trials for cancer patients. Many computational approaches have been proposed to achieve this goal; however, there is room for improvement. Recent developments in deep learning techniques can aid in the identification of better prognostic genes and more accurate outcome prediction, but one of the main problems in the adoption of deep learning for this purpose is that data from cancer patients have too many dimensions, while the number of samples is relatively small. In this study, we propose a novel network-based deep learning method to identify prognostic gene signatures via distributed gene representations generated by G2Vec, which is a modified Word2Vec model originally used for natural language processing. We applied the proposed method to five cancer types including liver cancer and showed that G2Vec outperformed extant feature selection methods, especially for small number of samples. Moreover, biomarkers identified by G2Vec was useful to find significant prognostic gene modules associated with hepatocellular carcinoma.


The "good enough" body size as judged by people of varying age and weight.
To examine the concept of the "good enough" body size acceptability across a wide range of ages and weight status. Subjects were 303 children, 427 adolescents, 261 young adults, and 326 middle-age adults who selected acceptable body sizes from an array of drawings representing their own age and gender. They also selected body sizes representing their own actual and ideal size. A large majority (87%) of subjects considered their own body size socially acceptable. This finding applied to both genders in all age groups and to underweight, normal weight, and overweight subjects. Even among obese subjects, 48% considered their own body size socially acceptable. For the large percentage of subjects who reported a discrepancy between their actual and ideal body sizes, most considered their own body size acceptable. This finding also applied to both genders in all age groups and to underweight, normal weight, and overweight subjects. Most male and female subjects across a wide range of ages and status considered their own body size to be within the range of socially acceptable body sizes even though, for many, it did not match their ideal. The implications of expanding body size research to include the conceptual framework of body size acceptability is discussed in terms of contributing to a paradigm of positive psychology.


Comparison of the offspring ultrasound thyroid volume in hypothyroid mothers treated with different levothyroxine doses: A cohort study.
We aimed to determine the volume of the thyroid gland in full-term neonates born to hypothyroid mothers as compared with full-term infants born to healthy mothers and to investigate the association between levothyroxine doses and the thyroid volume of neonates. This is single center prospective observational study of 245 full-term neonates (96 from hypothyroid and 149 from healthy mothers). Ultrasound examination in both longitudinal and transverse projections was used to calculate the thyroid volume applying the ellipsoid formula. Median (interquartile range) thyroid volume of newborns from hypothyroid mothers was significantly smaller compared to the control group with regard to the total thyroid volume and the left lobe (p < 0.05). We found no statistically significant difference for the right lobe (p > 0.05) and inverse correlation between the thyroid volume and levothyroxine doses taken by mothers. Results of the present study indicate that maternal thyroid hormone levels may interfere with the fetal hypothalamic-pituitary axis.


Targeted co-delivery of PD-L1 monoclonal antibody and sorafenib to circulating tumor cells via platelet-functionalized nanocarriers.
Circulating tumor cells (CTCs) can adsorb and activate platelets to form a microthrombus protective barrier around them, so that therapeutic drugs and immune cells cannot effectively kill CTCs. The platelet membrane (PM) bionic carrying drug system has the powerful ability of immune escape, and can circulate in the blood for a long time. we developed platelet membrane coated nanoparticles (PM HMSNs) to improve the precise delivery of drugs to tumor sites and to achieve more effective immunotherapy combined with chemotherapy strategy. Successfully prepared aPD-L1-PM-SO@HMSNs particles, whose diameter is 95-130 nm and presenting the same surface protein as PM. Laser confocal microscopy and flow cytometry experimental results showed that the fluorescence intensity of aPD-L1-PM-SO@HMSNs was greater than SO@HMSNs that are not coated by PM. Biodistribution studies in H22 tumor-bearing mice showed that due to the combined action of the active targeting effect and the EPR effect, the high accumulation of aPD-L1-PM-SO@HMSNs in the local tumor was more effective in inhibiting tumor growth than other groups of therapeutic agents. Platelet membrane biomimetic nanoparticles have a good targeted therapeutic effect, which can effectively avoid immune clearance and have little side effects. It provides a new direction and theoretical basis for further research on targeted therapy of CTCs in liver cancer.


A new species of Polana (Angusana) (Hemiptera: Cicadellidae: Gyponini): new record, key to males and description of the female terminalia of Polana exornata.
The subgenus Angusana is newly recorded from Brazil with description of a new species, Polana (Angusana) eliasi sp. nov. from State of Rondnia. Polana (Angusana) exornata is recorded from Costa Rica and the female terminalia is described and illustrated for the first time. A revised diagnosis and key to males of Angusana are provided.


Effects of dichloroacetate in patients with congestive heart failure.
Conventional approaches to management of congestive heart failure (CHF) rely on drugs that increase myocardial contractility or reduce ventricular afterload. These approaches often improve cardiac symptoms and survival, but may be associated with significant deleterious effects. An alternative approach is to enhance myocardial energy production. Dichloroacetate (DCA) stimulates pyruvate dehydrogenase activity and accelerates aerobic glucose, pyruvate, and lactate metabolism in myocardial cells. These alterations would be expected to improve myocardial function. The purpose of the investigation was to assess the efficacy of DCA in patients with left ventricular systolic dysfunction and to examine the mechanism by which improvement occurs. A total of 25 patients (16 men, 9 women; age range 31-72 years, mean 59) with CHF and ejection fraction < or = 40% received an intravenous infusion of 50 mg/kg DCA over 15 min. Indices of systolic and diastolic function were obtained by two-dimensional and Doppler echocardiography performed at baseline, 30 min, and 60 min following completion of DCA infusion. Baseline ventricular ejection fraction was 27.3 +/- 9.1%; 17 patients (68%) had nonischemic cardiomyopathy. Heart rate increased after DCA infusion from 73.9 +/- 14.5 to 79.2 +/- 14.9 beats/min at 60 min; p = 0.02. Left ventricular diastolic and systolic volumes increased at 30 min compared with baseline (248.7 +/- 98.1 vs. 259.6 +/- 99.6; p = 0.04, and 180.1 +/- 80.4 vs. 192.2 +/- 84.9; p = 0.002, respectively), but stroke volume (49.2 +/- 19.1 vs. 48.9 +/- 18.1; p = 0.9) and ejection fraction (27.3 +/- 9.1 vs. 25.7 +/- 9.8; p = 0.2) were unchanged. Indices of diastolic function were also unchanged. Dichloroacetate infusion in patients with CHF is not associated with improvement in noninvasively assessed left ventricular function.


Nalmefene: a review of its use in the treatment of alcohol dependence.
The opioid system modulator nalmefene (Selincro®) is approved in the EU for as-needed use to reduce alcohol consumption in alcohol-dependent adults with a high drinking risk level. This article reviews the efficacy and tolerability of as-needed oral nalmefene in the treatment of alcohol dependence, as well as summarizing its pharmacological properties. In two randomized, double-blind, multinational trials (ESENSE 1 and ESENSE 2), as-needed nalmefene significantly reduced the number of heavy drinking days (in both trials) and total alcohol consumption (in ESENSE 1) at month 6. In the randomized, double-blind, multinational SENSE trial, as-needed nalmefene significantly improved both of these endpoints at month 13, but not at month 6. As-needed nalmefene had a greater beneficial effect in the target population (i.e. alcohol-dependent patients with at least a high drinking risk level at screening and randomization), with post hoc analyses revealing significant reductions in both the number of heavy drinking days and total alcohol consumption at month 6 (in ESENSE 1 and ESENSE 2) and at month 13 (in SENSE). Oral nalmefene was generally well tolerated in patients with alcohol dependence, with the most commonly occurring adverse events including nausea, insomnia and dizziness. In conclusion, as-needed nalmefene provides an important new option for use in the treatment of alcohol dependence.


Glucagon increases contractility in ventricle but not in atrium of the rat heart.
This study evaluates the inotropic responses to glucagon in electrically driven isolated left and right atria as well as in right ventricular strips of rat heart. For comparison, the contractile effects resulting from stimulating beta-adrenoceptors with isoprenaline in atrial and ventricular tissues were also obtained. Glucagon (0.01-1 microM) produces a concentration-dependent positive inotropic effect in ventricular but not in atrial myocardium. Isoprenaline, however, increases contractility both in atrial and ventricular tissues. The nonselective phosphodiesterase (PDE) inhibitor 3-isobutylmethylxantine (IBMX, 10 microM) enhances the contractile effect of glucagon on ventricular myocardium. However, glucagon still failed to increase contractility in atrial myocardium in the presence of 10 microM, IBMX. Also, in left atria of rats pretreated with pertussis toxin, glucagon did not produce any positive inotropic effect, either alone or in the presence of 10 microM, IBMX. Western blotting analysis indicates that glucagon receptors expression is 5 times higher in ventricular than in atrial myocardium. Taken together, these results indicate that the lack of inotropic effect of glucagon in atrium is not due to Gi protein or PDEs activity but seems to be a consequence of a lower glucagon receptor density in this tissue.


Angiography of colonic Crohn's disease: the zoning sign revisited.
The zoning sign can be demonstrated in 50% of angiographies in colonic Crohn's disease and provides a reliable differential diagnostic aid against ulcerative colitis. The composition of the sign has been enlarged by the recognition of a zone C. The application of angiography in the radiologic diagnosis of inflammatory disease of the colon is discussed.


Study of the surface morphology of a cholesteryl tethering system for lipidic bilayers.
The immobilization of functional molecules embedded in lipidic membranes onto inorganic substrates is of great interest for numerous applications in the fields of biosensors and biomaterials. We report on the preparation and the morphological characterization of a tethering system for lipidic bilayers, which is based on cholesteryl derivatives deposited on hydrophilic surfaces by self-assembling and microcontact printing techniques. The investigation of the structural properties of the realized films by atomic, lateral, and surface potential microscopy allowed us to assess the high quality of the realized cholesteryl layers.


A case of transitional cell carcinoma of the bladder presenting with brain metastases.
A patient with brain metastases from transitional cell carcinoma of the bladder is presented. This patient had multiple intracranial metastases. The disease progressed very aggressively despite systemic chemotherapy and he died in a very short time. In a review of the literature it is noticed that the incidence of brain metastases from transitional cell carcinoma of the bladder has increased recently. This is probably because of the current complicated therapeutic approach to bladder carcinoma, including radical surgery and combination chemotherapy for high stage disease.


Association of endothelin-1 with normal tension glaucoma: clinical and fundamental studies.
Impaired ocular blood flow is suspected to be one of the causes of normal tension glaucoma (NTG). We investigated whether endothelin (ET), a potent and continuous vasoacting peptide which was discovered recently, is associated with NTG. Plasma ET-1 levels of 52 patients with NTG but without systemic vascular or circulatory disorders were measured by radioimmunoassay, and were found to be significantly higher than those of 10 normal controls. The patients with NTG in the initial stage of visual field loss (Kosaki's classification) showed higher plasma ET-1 levels than those in the middle stage. These facts suggest that elevated plasma levels of ET-1 are correlated with NTG and its stages. We then studied the effects of ET-1 on rabbit eyes. Intravenous administration of ET-1 (10(-10) mol/kg) induced reductions in both intraocular pressure (IOP) and blood flow in the optic nerve head during three hours' observation, although it affected systemic blood pressure slightly and transiently. Blood flow in the choroid also decreased, but recovered at 90 minutes. Intravitreal injection of ET-1 (10(-5) M, 0.1 ml) also caused reductions in IOP (for 14 days) and in blood flow in the optic nerve head (during three hours' observation). Prolongation of VEP-N1 latency was observed for 14 days. These results indicate that ET-1 may be associated with NTG, especially with blood flow in the optic nerve head.


Autoantibodies to crude human leucocyte interferon (IFN), native human IFN, recombinant human IFN-alpha 2b and human IFN-gamma in healthy blood donors.
Recently, naturally occurring antibodies to IFN-alpha were discovered in a few systemic lupus erythematosus (SLE) and cancer patients; however, in most patients monitored for anti-IFN antibodies before treatment, no antibodies were found. In an attempt to explain the 'IFN-blocking effect' that we observed in all serum samples we investigated 200 sera from healthy blood donors. We isolated the globulin fraction, and used rabbit anti-human IgG and IgM columns, protein A columns and T-gel affinity chromatography to isolate human IgG and IgM. All sample fractions were tested in a biological IFN neutralization assay by means of a sensitive MTT-assay. We found that normal human serum contained autoantibodies to crude human leucocyte IFN, native human fibroblast IFN, recombinant human leucocyte IFN-alpha 2b and recombinant human IFN-gamma, and that these naturally occurring antibodies were biologically active immunoglobulins of IgG and IgM type. These anti-IFN antibodies were also present in purified human normal immunoglobulin pools. We conclude that all humans have naturally occurring anti-interferon antibodies in their serum, and it is a tempting theory that human cytokines and lymphokines are, at least partly, regulated by immunoglobulins.


Inhibition of biliary phospholipid secretion by bilirubin in partially hepatectomized rats.
The effect of i.v. administration of bilirubin on biliary phospholipid secretion was studied in sham operated and two-thirds hepatectomized Wistar rats. Following bilirubin infusion at 260 nmol/100 g body wt/min, a maximal biliary bilirubin excretion was reached in the sham operated rats. No modifications of bile flow or bile acid secretion appeared, but biliary phospholipid secretion was significantly inhibited. At 12 and 24 h after hepatectomy, the maximal bilirubin excretion was markedly lowered but biliary phospholipid secretion still remained significantly inhibited. The infusion of taurocholate at 200 nmol/100 g body wt/min counteracted the impairment of phospholipid secretion, both in sham operated and hepatectomized animals. Bile acid secretions more than two-fold that of the controls were needed to reach half maximal biliary phospholipid secretion in bilirubin-infused animals, with or without the addition of taurocholate.


Affect asymmetry and comfort food consumption.
It is proposed that the emotional triggers of comfort food consumption can reliably be predicted by factors tied to affect asymmetry whereby negative affects dominate one's experience, decision making and behaviors in some instances while positive emotions prevail in others. Specifically, we relate three of these factors (age, gender, and culture) to differences in the emotional triggers of comfort food consumption and we further explore the possibility that the type of food eaten during comfort-seeking episodes can also be tied to affect asymmetry. Two hundred and seventy-seven participants completed a web-based survey conducted to assess the emotional antecedents and consequences of comfort food consumption. Consistent with expectations, results indicate that men's comfort food consumption was motivated by positive emotions whereas women's consumption was triggered by negative affects. Consumption of comfort foods alleviated women's negative emotions but also produced guilt. Positive affect was a particularly powerful trigger of comfort food consumption for older participants and for participants with French cultural background. Younger participants and participants with English background reported more intense negative emotions prior to consuming comfort foods. Foods high in sugar and fat content were more efficient in alleviating negative affects whereas low-calorie foods were more efficient in increasing positive emotions.


Splenogonadal fusion: A rare finding during routine orchiopexy.
Splenogonadal fusion remains a rare congenital anomaly, with limited reports in the literature. It is important to be aware of this benign condition as orchiectomy can result from confusion with malignant processes. We present a case of splenogonadal fusion in a 12-month-old healthy male with history of cryptorchidism found at the time of surgery.


Radiation therapy at the end of life in patients with incurable nonsmall cell lung cancer.
Receipt of chemotherapy at the end of life (EOL) is considered an indicator of poor quality of care for medical oncology. The objective of this study was to characterize the use of radiotherapy (RT) in patients with nonsmall cell lung cancer (NSCLC) during the same period. Treatment characteristics of patients with incurable NSCLC who received RT at the EOL, defined as within 14 days of death, were analyzed from the National Comprehensive Cancer Network NSCLC Outcomes Database. Among 1098 patients who died, 10% had received EOL RT. Patients who did and did not receive EOL RT were similar in terms of sex, race, comorbid disease, and Eastern Cooperative Oncology Group performance status. On multivariable logistic regression analysis, independent predictors of receiving EOL RT included stage IV disease (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.09-3.83) or multiorgan involvement (OR, 1.75; 95% CI, 1.08-2.84) at diagnosis, age <65 years at diagnosis (OR, 1.85; 95% CI, 1.21-2.83), and treating institution (OR, 1.24-5.94; P = .02). Nearly 50% of EOL RT recipients did not complete it, most commonly because of death or patient preference. In general, EOL RT was received infrequently, was delivered more commonly to younger patients with more advanced disease, and often was not completed as planned. There also was considerable variation in its use among National Comprehensive Cancer Network institutions. Next steps include expanding this research to other cancers and settings and investigating the clinical benefit of such treatment.


DFT investigation on the carbonate radical formation in the system containing carbon dioxide and hydroxyl free radical.
A density functional theory (DFT) study was performed to explore the reaction mechanisms of CO2-containing systems(CO2,HCO3-,H2CO3) with hydroxyl radical using UM06-2X/aug-cc-pVTZ for geometry optimization and UCCSD(T)-F12/cc-pVDZ-F12 for electronic energies, the effect of solvation is considered using the implicit solvent model with two explicit water molecule. The final transformation of hydroxyl radical into carbonate anion radical by reaction with CO2-containing system was studied. The energy barriers, Gibbs free energy, reaction enthalpy changes and reaction rate constants for reaction of CO2-containing systems by hydroxyl radical are calculated. The results show that the reaction of hydroxyl with HCO3- has the lowest energy barrier (5.6 kcal/mol) and maximum reaction rate constant (7.60 × 107dm3mol-1s-1). However, the reaction of hydroxyl radical with CO2 has the highest energy barrier (20.3 kcal/mol) and the minimum reaction rate constant (8.88 × 10-10 dm3mol-1s-1) respectively. The equilibrium constant and rate ratio were calculated by the concentration ratio and free energy of the two conformations of H2CO3 in aqueous solution. The results show that the cc conformation of carbonate has a little higher reaction energy barrier and a higher reaction rate than ct conformation. ∙HCO3 generated by the reaction of CO2 and H2CO3 with hydroxyl radical is further dissociated in aqueous solution to form carbonate radical anion. The calculated free energy of the dissociation process is -2.5 kcal/mol and pKa is -1.9, indicating that HCO3- is a strong acid. Therefore, hydroxyl radicals are spontaneously converted to carbonate radical anions in CO2-containing systems.


Measles, polio and tetanus toxoid antibody levels in Gambian children aged 3 to 4 years following routine vaccination.
A nation-wide cross-sectional survey of 816 children 3-4 years old was carried out in The Gambia between September 1990 and July 1991 to assess the seroprevalence of antibodies against 3 diseases included in the expanded programme on immunization: measles, poliomyelitis and tetanus. Among 689 children whose records were available, 94.5% were fully immunized. Measles vaccine was administered to 97% of the children and 91% of these had detectable antibodies at the time of the survey. Antibodies against type 1 and type 3 polioviruses, after up to 6 doses of oral polio vaccine, were present in 88.1% and 89.3% of the children respectively. Ninety-seven percent of the children who had received 4 doses of diphtheria-pertussis-tetanus vaccine (DPT) and 91% of those who received 3 doses had detectable tetanus toxoid antibodies at the age of 3-4 years. This study shows that serological responses to EPI vaccines given in infancy persist at very satisfactory levels throughout early childhood.


Effects of lactic acid bacteria fermented feed and three types of lactic acid bacteria (L. plantarum, L. acidophilus, B. animalis) on intestinal microbiota and T cell polarization (Th1, Th2, Th17, Treg) in the intestinal lymph nodes and spleens of rats.
In this study, we investigated the effects of Rubus coreanus-derived lactic acid bacteria (LAB) fermented feed (RC-LAB fermented feed) and three types of LAB (Lactobacillus plantarum, Lactobacillus acidophilus, Bifidobacterium animalis) on the expression of transcription factors and cytokines in Th1, Th2, Th17, and Treg cells in the intestinal lymph nodes and spleens of rats. In addition, the effect on intestinal microbiota composition and body weight was investigated. Five-week-old male rats were assigned to five treatments and eight replicates. The expression of transcription factors and cytokines of Th1, Th2, Th17, and Treg cells in the intestinal lymph nodes and spleens was analyzed using real-time reverse transcriptase polymerase chain reaction assays. Intestinal tract microbiota compositions were analyzed by next-generation sequencing and quantitative polymerase chain reaction assays. RC-LAB fermented feed and three types of LAB increased the expression of transcription factors and cytokines in Th1, Treg cells and Galectin-9, but decreased in Th2 and Th17 cells. In addition, the intestinal microbiota composition changed, the body weight and Firmicutes to Bacteroidetes (F/B) ratio decreased, and the relative abundance of LAB increased. LAB fermented feed and three types of LAB showed an immune modulation effect by inducing T cell polarization and increased LAB in the intestinal microbiota.


Infections after experimental cadaver bone marrow transplantation in beagle dogs. Transplantations with and without selective gastrointestinal decontamination.
Experimental transplantations of cadaver bone marrow (BMT) in beagle dogs were performed to evaluate the problems and potentials in a preclinical setting. The effectiveness of selective decontamination of the gut (SD) and gnotobiotic surveillance in preventing infections during longer aplastic periods was investigated. Three groups of dogs were compared. Group A: controls. Group B: dogs with BMT, without SD and irregular gnotobiotic surveillance. Group C: dogs with BMT, with SD and regular gnotobiotic surveillance. The intestinal colonization of normal healthy beagles shows similarities as well as dissimilarities to the human intestinal microflora. Aerobic potentially pathogenic organisms do not colonize the gut of healthy beagles under our keeping conditions. SD resulted in a significant decrease in infections with Escherichia coli and Plesiomonas. Infections with anaerobes, as well as bacterial infections of the respiratory tract were, however, not prevented. The intestinal colonization in dogs of group C with Clostridium difficile is another obvious effect of SD. The infections encountered during the study indicate the importance of the "take" for the clinical significance and outcome of intestinal colonization with potentially pathogenic organisms. In order to reduce the drug burden of BMT patients, we consider the elimination of routine SD after BMT not to be superior to gnotobiotic surveillance and germ-specific short term decontamination.


Matrix Metalloproteinase-14 as an Instigator of Fibrosis in Human Pterygium and Its Pharmacological Intervention.
There exists a paucity of information on the pathogenesis of pterygium, a benign ocular tumor that scars the cornea and can lead to vision loss. The main recourse for pterygium is surgery; however, recurrence is observed. Matrix metalloproteinases (MMPs) are involved in the pathology of pterygium. The determination of the specific MMP involved among the 24 human enzymes has not been established due to challenges in MMP profiling. We used an affinity resin that binds specifically to the active forms of MMPs in the complex mixture of the cellular proteome. The proteomics analysis identified active MMP-14 and three related metalloproteinases, ADAM9, ADAM10, and ADAM17, in human pterygia. Inhibition of MMP-14 with the small-molecule inhibitor (R)-ND-336 was assessed in cell migration and collagen contraction assays. (R)-ND-336 attenuated human conjunctiva fibroblast migration and mitigated collagen contraction, both activities required for the formation of pterygium. (R)-ND-336 holds the promise of a therapeutic recourse for pterygium as an orphan disease.


Atrial natriuretic factor decreases renal dopamine turnover and catabolism without modifying its release.
Atrial natriuretic factor (ANF) and dopamine (DA) are both important regulators of sodium and water transport across renal proximal tubules. Many evidences suggest that some of ANF inhibitory effects on sodium and water reabsorption are mediated by dopaminergic mechanisms. We have previously reported that ANF stimulates extraneuronal DA uptake in external renal cortex by activation of NPR-A receptors coupled to cGMP signal and PKG. Moreover, ANF enhanced DA-induced inhibition of Na(+)-K(+) ATPase activity. The aim of the present study was to evaluate if ANF could alter also renal DA release, catabolism and turn over. The results indicate that ANF did not affect basal secretion of the amine in external renal cortex or its KCl-induced release, but diminished DA turn over. Moreover, ANF diminished COMT and did not alter MAO activity. In conclusion, present results as well as previous findings show that ANF modifies DA metabolism in rat external renal cortex by enhancing DA uptake and decreasing COMT activity. All those effects, taken together, may favor DA accumulation into renal cells and increase its endogenous content and availability. This would permit D1 receptor recruitment and stimulation and in turn, Na(+), K(+)-ATPase activity over inhibition that results in decreased sodium reabsorption. Therefore, ANF and DA could act via a common pathway to enhance natriuresis and diuresis.


Analysis of the hyperpolarizing effect of catecholamines on canine cardiac Purkinje fibres.
1. The hyperpolarization induced by catecholamines on barium-depolarized (0.2-0.8 mM BaCl) canine cardiac Purkinje fibres, in vitro, was studied by use of conventional microelectrode recordings of transmembrane electrical potentials. 2. Noradrenaline, adrenaline and isoprenaline hyperpolarized Purkinje fibres in a concentration-dependent manner from a threshold concentration around 5 nM. The three catecholamines were shown to be approximately equipotent. Tachyphylaxis was observed when the interval between catecholamine applications was less than 15 min. 3. Atenolol (10 microM) blocked the hyperpolarization reversibly and theophylline (0.5 mM) potentiated it. 4. Tetrodotoxin (5 microM) did not affect the hyperpolarization induced by isoprenaline. Acetylcholine and histamine, up to 10 microM, were not effective in hyperpolarizing Purkinje fibres. 5. Low extracellular potassium concentrations (zero and 1 mM) did not affect the hyperpolarization, but high extracellular potassium concentrations (10-20 mM), markedly reduced the effect of isoprenaline (100 nM). 6. Reduction of the extracellular sodium concentration produced a roughly proportional reduction in the isoprenaline-induced hyperpolarization. The hyperpolarization was reversibly blocked in 34 mM sodium Tris-Tyrode solution. 7. The hyperpolarization was not reduced in Tyrode solution containing 0.6 mM calcium, but was drastically reduced in zero-calcium Tyrode solution. This effect was reversible. 8. Addition of verapamil (5-10 microM) diminished the hyperpolarization, in a concentration-dependent manner. This effect was partially reversed after washing. 9. Ouabain (0.7-1 microM) significantly reduced the isoprenaline-induced hyperpolarization, but 2,4-dinitrophenol (0.2 mM) did not affect it. 10. Caesium chloride (20 mM) abolished the hyperpolarization. The blockade was only partially reversed upon washing. 11. It is suggested that the hyperpolarization induced by a short exposure to catecholamines is mainly due to an increase in potassium permeability (PK). A mechanism involving calciumdependent potassium channels might underlie the increase in PK.


Early pregnancy hyperglycaemia as a significant predictor of large for gestational age neonates.
We aimed to determine the effect of early pregnancy hyperglycaemia on having a large for gestational age (LGA) neonate. A prospective cohort study was conducted among pregnant women in their first trimester. One-step plasma glucose (PG) evaluation procedure was performed to assess gestational diabetes mellitus (GDM) and diabetes mellitus (DM) in pregnancy as defined by the World Health Organization (WHO) criteria with International Association of Diabetes in Pregnancy Study Group (IADPSG) thresholds. The main outcome studied was large for gestational age neonates (LGA). A total of 2,709 participants were recruited with a mean age of 28 years (SD = 5.4) and a median gestational age (GA) of eight weeks (interquartile range [IQR] = 2). The prevalence of GDM in first trimester (T1) was 15.0% (95% confidence interval [CI] = 13.7-16.4). Previously undiagnosed DM was detected among 2.5% of the participants. Out of 2,285 live births with a median delivery GA of 38 weeks (IQR = 3), 7.0% were LGA neonates. The cumulative incidence of LGA neonates in women with GDM and DM was 11.1 and 15.5 per 100 women, respectively. The relative risk of having an LGA neonate among women with DM and GDM was 2.30 (95% CI = 1.23-4.28) and 1.80 (95% CI = 1.27-2.53), respectively. The attributable risk percentage of a LGA neonate for hyperglycaemia was 15.01%. T1 fasting PG was significantly correlated with both neonatal birth weight and birth weight centile. The proposed WHO criteria for hyperglycaemia in pregnancy are valid, even in T1, for predicting LGA neonates. The use of IADPSG threshold for Fasting PG, for risk assessment in early pregnancy in high-risk populations is recommended.


A general approach to proving the minimality of phylogenetic trees illustrated by an example with a set of 23 vertebrates.
We have recently described a method of building phylogenetic trees and have outlined an approach for proving whether a particular tree is optimal for the data used. In this paper we describe in detail the method of establishing lower bounds on the length of a minimal tree by partitioning the data set into subsets. All characters that could be involved in duplications in the data are paired with all other such characters. A matching algorithm is then used to obtain the pairing of characters that reveals the most duplications in the data. This matching may still not account for all nucleotide substitutions on the tree. The structure of the tree is then used to help select subsets of three or more characters until the lower bound found by partitioning is equal to the length of the tree. The tree must then be a minimal tree since no tree can exist with a length less than that of the lower bound. The method is demonstrated using a set of 23 vertebrate cytochrome c sequences with the criterion of minimizing the total number of nucleotide substitutions. There are 131130 7045768798 96033440625 topologically distinct trees that can be constructed from this data set. The method described in this paper does identify 144 minimal tree variants. The method is general in the sense that it can be used for other data and other criteria of length. It need not however always be possible to prove a treee minimal but the method will give an upper and lower bound on the length of minimal trees.


Influence of repeated liver regeneration on hepatic carcinogenesis by diethylnitrosamine in mice.
In mice given a single dose of diethylnitrosamine, a hepatonecrotic dose of carbon tetrachloride, 5 weeks after dosing with DEN and repeated 6 times at 4-weekly intervals, augmented the tumour yield in the livers. A single hepatonecrotic dose of CCl4 24 h before a single dose of DEN also increased the number of tumours produced. The effect of the repeated administration of CCl4 after the dose of DEN occurred in addition to, and was therefore independent of, the enhancing effect of a single dose of CCl4 before DEN. These results may be interpreted as implying (1) that the liver in the regenerative phase after a hepatonecrotic dose of CCl4 is more susceptible to an initiating action of DEN, i.e. produces more potential foci of tumour growth than in the normal liver and (2) that the repeated doses of CCl4 leading to repeated phases of regeneration, after the dose of DEN, provide a promoting stimulus.


Age-related decreases in the concentration of Met- and Leu-enkephalin and neurotensin in the basal ganglia of rats.
Previous studies using radioimmunoassay procedures have failed to show age-related changes in the concentration of Met- and Leu-enkephalin or neurotensin in rat basal ganglia. In contrast, using a combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) technique we now report considerable decreases in the levels of these neuropeptides in areas of basal ganglia of 22 months old-compared to 3 months-old male Wistar rats. The concentration of Met-enkephalin was greatly reduced in the striatum and nucleus accumbens, but not in substantia nigra, of old compared to young animals. There was a similarly large decrease in Leu-enkephalin content in striatum of old rats with less marked decreases occurring in both the nucleus accumbens and substantia nigra. Neurotensin levels in the striatum and substantia nigra were greatly reduced in old rats, with a less marked decrease in the nucleus accumbens.


Increased otoacoustic-emission amplitude secondary to cochlear lesions.
The measurements of transient evoked otoacoustic emissions and distortion-product otoacoustic emissions are being used increasingly, both as an objective hearing test clinically, and as a research tool to investigate the micromechanical aspects of cochlear function. We hypothesized that localized damage in the apical or middle cochlear turns may have an influence on the micromechanics and the function of adjacent, apparently normal cochlea. For that purpose, we used an animal model of localized apical and middle-turn cochlear lesions. Extent of damage was assessed by scanning electron microscopy and the function of the damaged cochlea by change in the otoacoustic emission (OAE) levels. We found that localized damage to the apical or middle turn may be accompanied by an increase in OAE measured from adjacent apparently normal cochlea. Explanations to this phenomenon are suggested, and possible clinical associations such as to Meniere's disease and to sudden hearing loss are reviewed.


Enzymatic properties, renaturation and metabolic role of mannitol-1-phosphate dehydrogenase from Escherichia coli.
Enzymatic properties, renaturation and metabolic role of mannitol-1-phosphate dehydrogenase from Escherichia coli. D-mannitol-1-phosphate dehydrogenase was purified to homogeneity from Escherichia coli, and its physicochemical and enzymatic properties were investigated. The molecular weight of the polypeptide chain is 45,000 as determined by polyacrylamide gel electrophoresis in denaturing conditions. High performance size exclusion chromatography gives an apparent molecular weight of 47,000 for the native enzyme, showing that D-mannitol-1-phosphate dehydrogenase is a monomeric NAD-dependent dehydrogenase. D-mannitol-1-phosphate dehydrogenase is rapidly denatured by 6 M guanidine hydrochloride. Non-superimposable transition curves for the loss of activity and the changes in fluorescence suggest the existence of a partially folded inactive intermediate. The protein can be fully renatured after complete unfolding, and the regain of both native fluorescence and activity occurs rapidly within a few seconds at pH 7.5 and 20 degrees C. Such a high rate of reactivation is unusual for a protein of this size. D-mannitol-1-phosphate dehydrogenase is specific for mannitol-1-phosphate (or fructose-6-phosphate) as a substrate and NAD+ (or NADH) as a cofactor. Zinc is not required for the activity. The affinity of D-mannitol-1-phosphate dehydrogenase for the reduced or oxidized form of its substrate or cofactor remains constant with pH. The affinity for NADH is 20-fold higher than for NAD+. The forward and reverse catalytic rate constants of the reaction: mannitol-1-phosphate + NAD+ in equilibrium fructose-6-phosphate + NADH have different pH dependences. The oxidation of mannitol-1-phosphate has an optimum pH of 9.5, while the reduction of fructose-6-phosphate has its maximum rate at pH 7.0. At pH values around neutrality the maximum rate of reduction of fructose-6-phosphate is much higher than that of oxidation of mannitol-1-phosphate. The enzymatic properties of isolated D-mannitol-1-phosphate dehydrogenase are discussed in relation to the role of this enzyme in the intracellular metabolism.


Artificial Intelligence: Exploring the Future of Innovation in Allergy Immunology.
Artificial intelligence (AI) has increasingly been used in healthcare. Given the capacity of AI to handle large data and complex relationships between variables, AI is well suited for applications in healthcare. Recently, AI has been applied to allergy research. In this article, we review how AI technologies have been utilized in basic science and clinical allergy research for asthma, atopic dermatitis, rhinology, adverse reactions to drugs and vaccines, food allergy, anaphylaxis, urticaria, and eosinophilic gastrointestinal disorders. We discuss barriers for AI adoption to improve the care of patients with atopic diseases. These studies demonstrate the utility of applying AI to the field of allergy to help investigators expand their understanding of disease pathogenesis, improve diagnostic accuracy, enable prediction for treatments and outcomes, and for drug discovery.


Scalp-recorded contingent negative variation (CNV) increases during experimentally induced sustained ischemic pain in humans.
Contingent negative variations (CNV) after acoustic stimuli (S1) followed by optical ones (S2) were recorded using electroencephalography in 22 healthy students both under control conditions and during ischemic pain to study the effects of sustained pain on CNV. Mean negative CNV-amplitudes and integrated areas below CNV were significantly larger during periods of ischemic pain than under control conditions (16.53 versus 13.11 microV, respectively (P=0.0028) and 8.318 versus 6.357 microV*s, respectively (P=0.00071)). We conclude that deep somatic pain augments CNV. Reduced CNV amplitudes occurring during migraine attacks, however, reflect other mechanisms which may mask the effects of migraine headache on CNV.


Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs).
Natural human immunity to the mycobacteria group, including Mycobacterium tuberculosis, Bacille Calmette-Guérin (BCG) or nontuberculous mycobacteria (NTM), and/or Salmonella species, relies on the functional IL-12/23-IFN-γ integrity of macrophages (monocyte/dendritic cell) connecting to T lymphocyte/NK cells. Patients with severe forms of primary immunodeficiency diseases (PIDs) have more profound immune defects involving this impaired circuit in patients with severe combined immunodeficiencies (SCID) including complete DiGeorge syndrome, X-linked hyper IgM syndrome (HIGM) (CD40L mutation), CD40 deficiency, immunodeficiency with or without anhidrotic ectodermal dysplasia (NEMO and IKBA mutations), chronic granulomatous disease (CGD) and hyper IgE recurrent infection syndromes (HIES). The patients with severe PIDs have broader diverse infections rather than mycobacterial infections. In contrast, patients with an isolated inborn error of the IL-12/23-IFN-γ pathway are exclusively prone to low-virulence mycobacterial infections and nontyphoid salmonella infections, known as Mendelian susceptibility to the mycobacterial disease (MSMD) phenotype. Restricted defective molecules in the circuit, including IFN-γR1, IFN-γR2, IL-12p40, IL-12R-β1, STAT-1, NEMO, IKBA and the recently discovered CYBB responsible for autophagocytic vacuole and proteolysis, and interferon regulatory factor 8 (IRF8) for dendritic cell immunodeficiency, have been identified in around 60% of patients with the MSMD phenotype. Among all of the patients with PIDs referred for investigation since 1985, we have identified four cases with the specific defect (IFNRG1 for three and IL12RB for one), presenting as both BCG-induced diseases and NTM infections, in addition to some patients with SCID, HIGM, CGD and HIES. Furthermore, manifestations in patients with autoantibodies to IFN-γ (autoAbs-IFN-γ), which is categorized as an anticytokine autoantibody syndrome, can resemble the relatively persistent MSMD phenotype lacking BCG-induced diseases.


Instrumentation and techniques for examination of the ear, nose, throat, and sinus.
Optimal and accurate management of any patient depends on a detailed history and thorough physical examination. The information garnered dictates the definitive management of the patient. Adequate examination of the head and neck, particularly the upper aerodigestive tract, presents a unique challenge because much of the area to be examined is not easily accessible to direct visualization. However, advances in medical technology have prompted the evolution of the instrumentation and the techniques used to examine this anatomic region. This evolution allows for a more informative assessment of the patient and a more comfortable experience.


Social Smoking Environment and Associations With Cardiac Rehabilitation Attendance.
Continued cigarette smoking after a major cardiac event predicts worse health outcomes and leads to reduced participation in cardiac rehabilitation (CR). Understanding which characteristics of current smokers are associated with CR attendance and smoking cessation will help improve care for these high-risk patients. We examined whether smoking among social connections was associated with CR participation and continued smoking in cardiac patients. Participants included 149 patients hospitalized with an acute cardiac event who self-reported smoking prior to the hospitalization and were eligible for outpatient CR. Participants completed a survey on their smoking habits prior to hospitalization and 3 mo later. Participants were dichotomized into two groups by the proportion of friends or family currently smoking ("None-Few" vs "Some-Most"). Sociodemographic, health, secondhand smoke exposure, and smoking measures were compared using t tests and χ2 tests (P < .05). ORs were calculated to compare self-reported rates of CR attendance and smoking cessation at 3-mo follow-up. Compared with the "None-Few" group, participants in the "Some-Most" group experienced more secondhand smoke exposure (P < .01) and were less likely to attend CR at follow-up (OR = 0.40; 95% CI, 0.17-0.93). Participants in the "Some-Most" group tended to be less likely to quit smoking, but this difference was not statistically significant. Social environments with more smokers predicted worse outpatient CR attendance. Clinicians should consider smoking within the social network of the patient as an important potential barrier to pro-health behavior change.


Cerebral Arteriovenous Malformations as Acquired Lesions: Case Reports and Review of the Literature.
Cerebral arteriovenous malformations (AVMs) are generally attributed to congenital lesions that arise from aberrant vasculogenesis between the fourth and eighth weeks of embryonic life. However, this dogma has been challenged by several recent observations, one of which is de novo formation of AVMs. Forty cases of de novo AVMs were published between 2000 and 2019, all of which involved a history of intracranial insult, such as vascular abnormalities or nonvascular conditions, prior to AVM diagnosis. We hereby present two unique operative cases of ruptured de novo AVMs in older adult patients. Case 1 is novel in the sense that the patient did not experience any kind of environmental trigger ("second hit") such as a previous intracranial insult, while Case 2 serves as the second report of a de novo AVM patient with a medical history of Bell's palsy. Although the exact mechanisms of AVM formation remain to be elucidated, it is likely to be a multifactorial process related to environmental and hemodynamic factors.


Asymptomatic Primary Hyperparathyroidism: Diagnostic Pitfalls and Surgical Intervention.
Primary hyperparathyroidism (PHPT) is a common disease, with a prevalence as high as 1 in 400 women and 1 in 1000 men, and most are asymptomatic. Patients with PHPT have hypercalcemia with inappropriately normal levels of parathyroid hormone. Parathyroidectomy is the only curative therapy, and the procedure has become more common and more safe. Among asymptomatic patients, parathyroidectomy halts the progression of disease, improves quality of life, and may decrease risk of fracture and adverse cardiovascular outcomes. Thus, surgery should be considered in all patients with asymptomatic PHPT who have minimal perioperative risk and sufficient life expectancy, regardless of chronologic age.


Spatial-temporal variations in the thermal growing degree-days and season under climate warming in China during 1960-2011.
Vegetation growth and phenology are largely regulated by base temperature (Tb) and thermal accumulation. Hence, the growing degree-days (GDD) and growing season (GS) calculated based on Tb have primary effects on terrestrial ecosystems, and could be changed by the significant warming during the last century. By choosing 0, 5, and 10 °C, three key Tb for vegetation growth, the GDD and GS in China during 1960-2011 were developed based on 536 meteorological stations with homogenized daily mean temperatures. Results show that both the GDD and GS showed positive sensitivity to the annual mean temperature. The start of the growing season (SOS) has advanced by 4.86-6.71 days, and the end of the growing season (EOS) has been delayed by 4.32-6.19 days, lengthening the GS by 10.76-11.02 days in China as a whole during 1960-2011, depending on the Tb chosen. Consistently, the GDD has totally increased 218.92-339.40 °C days during the 52 years, with trends more pronounced in those based on a lower Tb. The GDD increase was significant (Mann-Kendall test, p < 0.01) over China except for the north of Southwest China, while the significant GS extension only scattered over China. Whereas the extensions of GS0 and GS5 were dominated by the advance in SOS, the GS10 extension was closely linked to the delay in EOS. Regionally, the GS extension in the eastern monsoon zone and northwest arid/semi-arid zone was driven by the advance in SOS and delay in EOS, respectively. Moreover, each variation has a substantial acceleration mostly in 1987 or 1996, and a speed reduction or even a trend reversal in the early 2000s. Changes in the thermal growing degree-days and season are expected to have great implications for biological phenology, agricultural production, and terrestrial carbon cycle in the future.


Analytical evidence of amorphous microdomains within nitridosilicate and nitridoaluminosilicate single crystals.
Single crystals of new nitridosilicates and nitridoaluminosilicates with excellent R values in X-ray investigations were analysed quantitatively using 30 to 60 microm single-spot LA-ICP-MS. Significant discrepancies between expected and measured chemical composition could not be explained by the crystallographic data. High spatial resolution analysis using electron probe microanalysis (EPMA, 10 microm) leads to the discovery of inhomogeneities in the crystalline material. The application of standard single-spot LA-ICP-MS with a spatial resolution of 30 to 60 microm is not suitable for the analysis of these crystals as the existing inhomogeneities dominate and alter the determined concentrations. However, owing to the better detection capabilities, a scanning LA-ICP-MS procedure enables a more representative analysis of single crystals of Ca(5)Si(2)Al(2)N(8) than single-spot LA-ICP-MS as a result of a larger sampling volume. It is highly likely that these impurities consist of amorphous, vitreous phases as powder diffraction X-ray data indicates the existence of a significant fraction of an X-ray amorphous material besides crystalline silicates. These microdomains contain less aluminium, silicon and calcium or are nearly free of aluminium, which explains the detected discrepancies in the chemical composition.


Pathways to care and treatment delays in first and multi episode psychosis. Findings from a developing country.
In contrast to findings from the developed world where general practitioners and mental health professionals are central in first episode psychosis pathways, studies from Africa have found GPs to play a less prominent role with other help providers such as traditional healers being more important. We compared pathways to care, treatment delays and gender differences in patients with first versus multi episode psychosis. Private sector GPs were first contacts in first episode patients in as many as 38% of patients and were significantly more likely to be the first contact (odds ratio = 4.5, 95% CI = 1.38-14.67) and final referring agent (odds ratio = 6.8, 95% CI = 1.56-25.12) in first episode patients. Female multi episode patients were significantly more likely to make first contact with primary care practitioners whereas male multi episode patients were more likely to first come into contact with the police (P = 0.003) and be admitted compulsorily (P = 0.009). Only 5.6% (n = 4) of patients contacted traditional healers at some point in their pathway to care. Treatment delays and DUP in first episode patients were longer and reached a median of 4.5 versus 2.5 months in multi episode patients. Treatment discontinuation of antipsychotics occurred in 82% of multi episode patients. Despite significantly longer overall treatment delays in first episode patients the distribution of treatment delays in multi episode patients followed a similar pattern to DUP in first episode patients with a subgroup having very long delays. Pathways to care in this treatment setting correspond more to findings from first world and newly industrialized countries. A subgroup of multi episode patients had very long periods of untreated illness. Limitations include small sample size and the retrospective nature of data collection.


Tuberculoid cutaneous infection due to a niacin-positive Mycobacterium chelonei.
A case of cutaneous infection due to a niacin-positive Mycobacterium chelonei (previously called M. abscessus) on the dorsum of the hand of a professional cotton-classifier is reported from Hong Kong. The infection was probably directly acquired from handling contaminated raw cotton. The patient was successfully treated with combined anti-tuberculous drugs over a period of 1 year. Histologically, the skin lesion showed tuberculoid granulomas, in addition to abscesses.


Susceptibility of Anopheles gambiae and Anopheles stephensi to tropical isolates of Plasmodium falciparum.
The susceptibility of anopheline mosquito species to Plasmodium infection is known to be variable with some mosquitoes more permissive to infection than others. Little work, however, has been carried out investigating the susceptibility of major malaria vectors to geographically diverse tropical isolates of Plasmodium falciparum aside from examining the possibility of infection extending its range from tropical regions into more temperate zones. This study investigates the susceptibility of two major tropical mosquito hosts (Anopheles gambiae and Anopheles stephensi) to P. falciparum isolates of different tropical geographical origins. Cultured parasite isolates were fed via membrane feeders simultaneously to both mosquito species and the resulting mosquito infections were compared. Infection prevalence was variable with African parasites equally successful in both mosquito species, Thai parasites significantly more successful in An. stephensi, and PNG parasites largely unsuccessful in both species. Infection success of P. falciparum was variable according to geographical origin of both the parasite and the mosquito. Data presented raise the possibility that local adaptation of tropical parasites and mosquitoes has a role to play in limiting gene flow between allopatric parasite populations.


Focus on Health Literacy: Recommendations to Improve European Union Risk Management Plan Public Summaries.
The complexity of drug risk information often exceeds patients' abilities to understand and effectively act on it. The authors evaluated a layperson-focused European Union Risk Management Plan Public Summary and revised it to improve its understandability and usability by applying health literacy principles. The Suitability Assessment of Materials was used to test the appropriateness of the document for readers with low-to-average literacy levels. Two rounds of usability tests were conducted with American adults who had low to average education levels to identify areas of confusion. Revisions were made within perceived regulatory constraints. A number of health literacy principles can be applied to improve the understandability and usability of the document; however, the document contains many inherently complex concepts. The authors recommend that stakeholders reassess the intended use of the document by members of the public and rethink its scope and structure, with close involvement of patients and caregivers.


Mercury in soil and perennial plants in a mining-affected urban area from Northwestern Romania.
The mercury (Hg) concentrations were evaluated in soils and perennial plants sampled in four districts of Baia Mare city, a historical mining and ore processing center in Northwestern Romania. The results showed that the Hg concentration exceeded the guideline value of 1.0 mg kg(-1) dry weight (dw) established by the Romanian Legislation, in 24 % of the analyzed soil samples, while the median Hg concentration (0.70 mg kg(-1) dw) was lower than the guideline value. However, Hg content in soil was generally higher than typical values in soils from residential and agricultural areas of the cities all over the world. The median Hg concentration was 0.22 mg kg(-1) dw in the perennial plants, and exceeded the maximum level of Hg (0.10 mg kg(-1)) established by European Directive 2002/32/EC for plants used in animal feed in order to prevent its transfer and further accumulation in the higher levels of food chain. No significant correlations were found between soil Hg and other analyzed metals (Cd, Cu, Pb, Zn) resulted from the non-ferrous smelting activities, probably due to the different physicochemical properties, that led to different dispersion patterns.


Endogenous mu opioid systems and suckling in the neonatal rat.
Localized injections of the mu antagonist CTOP into intracisternal (i.c.) or intracerebroventricular (i.c.v.) sites altered the behavior of 1-day-old rat pups during continuous exposure to an artificial nipple. Blockade of mu opioid receptors by i.c. injection decreased oral responsiveness to the nipple, while blockade of receptors by i.c.v. injection of CTOP increased oral responsiveness. The injection of CTOP into the i.c. site produced a transient reduction in body weight gain in pups suckling from their mother, while injection into the i.c.v. site had no effect. When cesarean-delivered pups were tested prior to suckling, injection of CTOP into the i.c. site increased latency of the first nipple attachment and decreased total time attached to a surrogate nipple providing milk. Injection of CTOP into the i.c.v. site decreased latency to the first nipple attachment. The results indicate that there is a caudal population of opioid receptors that is involved in the initiation of suckling behavior and a rostral population that plays a role in decreasing responsiveness at the nipple.


Prescription opioid use and misuse among adolescents and young adults in the United States: A national survey study.
Prescription opioid misuse has become a leading cause of unintentional injury and death among adolescents and young adults in the United States. However, there is limited information on how adolescents and young adults obtain prescription opioids. There are also inadequate recent data on the prevalence of additional drug abuse among those misusing prescription opioids. In this study, we evaluated past-year prevalence of prescription opioid use and misuse, sources of prescription opioids, and additional substance use among adolescents and young adults. This was a retrospective analysis of the National Survey on Drug Use and Health (NSDUH) for the years 2015 and 2016. Prevalence of opioid use, misuse, use disorder, and additional substance use were calculated with 95% confidence intervals (CIs), stratified by age group and other demographic variables. Sources of prescription opioids were determined for respondents reporting opioid misuse. We calculated past-year prevalence of opioid use and misuse with or without use disorder, sources of prescription opioids, and prevalence of additional substance use. We included 27,857 adolescents (12-17 years of age) and 28,213 young adults (18-25 years of age) in our analyses, corresponding to 119.3 million individuals in the extrapolated national population. There were 15,143 respondents (27.5% [95% CI 27.0-28.0], corresponding to 32.8 million individuals) who used prescription opioids in the previous year, including 21.0% (95% CI 20.4-21.6) of adolescents and 32.2% (95% CI 31.4-33.0) of young adults. Significantly more females than males reported using any prescription opioid (30.3% versus 24.8%, P < 0.001), and non-Hispanic whites and blacks were more likely to have had any opioid use compared to Hispanics (28.9%, 28.1%, and 25.8%, respectively; P < 0.001). Opioid misuse was reported by 1,050 adolescents (3.8%; 95% CI 3.5-4.0) and 2,207 young adults (7.8%; 95% CI 7.3-8.2; P < 0.001). Male respondents using opioids were more likely to have opioid misuse without use disorder compared with females (23.2% versus 15.8%, respectively; P < 0.001), with similar prevalence by race/ethnicity. Among those misusing opioids, 55.7% obtained them from friends or relatives, 25.4% from the healthcare system, and 18.9% through other means. Obtaining opioids free from friends or relatives was the most common source for both adolescents (33.5%) and young adults (41.4%). Those with opioid misuse reported high prevalence of prior cocaine (35.5%), hallucinogen (49.4%), heroin (8.7%), and inhalant (30.4%) use. In addition, at least half had used tobacco (55.5%), alcohol (66.9%), or cannabis (49.9%) in the past month. Potential limitations of the study are that we cannot exclude selection bias in the study design or socially desirable reporting among participants, and that longitudinal data are not available for long-term follow-up of individuals. Results from this study suggest that the prevalence of prescription opioid use among adolescents and young adults in the US is high despite known risks for future opioid and other drug use disorders. Reported prescription opioid misuse is common among adolescents and young adults and often associated with additional substance abuse, underscoring the importance of drug and alcohol screening programs in this population. Prevention and treatment efforts should take into account that greater than half of youths misusing prescription opioids obtain these medications through friends and relatives.


The 5q- syndrome: biology and treatment.
The 5q- syndrome is a myelodsyplastic syndrome (MDS) characterized by symptomatic anemia and an indolent natural history with low transformation potential. Our understanding of the molecular pathogenesis of this disease has advanced considerably, paralleled by the delineation of the relevant targets underlying selective lenalidomide sensitivity. The context in which one treats the 5q- syndrome, and all lower risk MDS, is critical. The focus of treatment should remain the amelioration of refractory cytopenias. In the 5q- syndrome, lenalidomide is the treatment of choice for patients with symptomatic anemia as it relieves the burden of transfusion dependence and iron overload in the majority of cases. We discuss herein the current understanding of the biology of the 5q- syndrome, actions of efficacy of lenalidomide and strategies for clinical management.