Factors that influence parents' experiences with results disclosure after newborn screening identifies genetic carrier status for cystic fibrosis or sickle cell hemoglobinopathy.
Newborn screening (NBS) identifies genetic carriers for sickle cell hemoglobinopathy and cystic fibrosis. We aimed to identify factors during initial NBS carrier results disclosure by primary care providers (PCPs) that influenced parents' experiences and reactions. Open-ended responses from telephone interviews with 270 parents of carriers were analyzed using mixed-methods. Conventional content analysis identified influential factors; chi-square tests analyzed relationships between factors and parent-reported reactions. Parents reported positive (35%) or negative (31%) reactions to results disclosure. Parents' experiences were influenced by specific factors: content messages (72%), PCP traits (47%), and aspects of the setting (30%). Including at least one of five specific content messages was associated (p<0.05) with positive parental reactions; omitting at least one of four specific content messages was associated (p<0.05) with negative parental reactions. Parents reported positive reactions when PCPs avoided jargon or were perceived as calm. Parents reported negative reactions to jargon usage and results disclosure by voicemail. Parents identified aspects of PCP communication which influenced their reactions and results disclosure experiences. Our findings suggest ways PCPs may improve communication of carrier results. PCPs should provide specific content messages and consider how their actions, characteristics, and setting can influence parental reactions.


Determination of glycyrrhizin and glycyrrhetinic acid in traditional Chinese medicinal preparations by capillary electrophoresis.
A simple, rapid, accurate and reproducible capillary electrophoretic method was developed for the assay of glycyrrhizin and glycyrrhetinic acid in traditional Chinese medicinal preparations. The buffer solution used in this method was acetonitrile and 0.02 M sodium dihydrogen-phosphate solution adjusted to pH 7.5 with 0.05 M sodium hydroxide. The linear calibration range was 0.04-2.00 mg/ml (r = 0.9988) for glycyrrhizin and 0.007-0.35 mg/ml (r = 0.9985) for glycyrrhetinic acid and recoveries were 98.1-101.3% for glycyrrhizin and 98.5-101.4% for glycyrrhetinic acid. The relative standard deviations were 1.02% (n = 6) for glycyrrhizin and 0.91% (n = 6) for glycyrrhetinic acid. The content of these two acids in Glycyrrhizae Radix and Glycyrrhizae Radix-containing Chinese medicinal preparations was successfully determined within 10 min.


Methyl jasmonate mediates upregulation of bacoside A production in shoot cultures of Bacopa monnieri.
Methyl jasmonate (MJ) enhances the production of a range of secondary metabolites including triterpenoid saponins in a variety of plant species. Here, it enhanced production of bacoside A, a valuable triterpenoid saponin having nootropic therapeutic activity in in vitro shoot cultures of Bacopa monnieri, the only known source of bacoside A. The highest yield was with 50 μM MJ giving 4.4 mg bacoside A/g dry wt; an 1.8-fold increase (compared to control) after 1 week.


Long-term outcome of flexible onabotulinum toxin A treatment in facial dystonia.
The purpose of this study was to assess the long-term outcome of onabotulinum used to treat facial dystonia and compare a flexible and fixed treatment regimen. This was a retrospective comparative study looking at benign essential blepharospasm (BEB), hemifacial spasm (HFS) and aberrant facial nerve regeneration synkinesis (AFR) treatment with onabotulinum toxin A (Botox®) over a minimum of 10 years. Fifty-one patients were recruited into the study, with each dystonia subgroup having 17 patients. Blepharospasm disability score (BDS), subjective improvement score (SIS), duration of maximal effect (DME) and complications were recorded at each visit. The mean age was 63 years and gender predominately female. Thirty-seven patients underwent flexible treatment intervals compared to 14 fixed treatment intervals, averaging 3.4 and 4 per annum, respectively. Mean BDS significantly improved from 6 to 3 at last review across all 3 groups, with the highest effect on BEB. BDS improvement was greater in flexible intervals. SIS remained similar for all three conditions during follow-up, but in those undergoing flexible intervals, SIS increased by a small margin compared to fixed interval. Mean DME was 10.5 weeks across all dystonias, but increased progressively only in the flexible interval group. Complications included ptosis (30%), dry eye (14%) and lagophthalmos (8%). Flexible onabotulinum provided better long-term relief on BDS for facial dystonia than a fixed regimen. Flexible interval treatment may also provide better patient satisfaction and longer DME compared to fixed treatment. Both have similar complication rates. With flexible treatment however, fewer injections were required over 10 years, leading to cost saving.


A novel guided surgery system with a sleeveless open frame structure: a retrospective clinical study on 38 partially edentulous patients with 1 year of follow-up.
This retrospective clinical study aims to present results of experience with a novel guided surgery system with a sleeveless, open-frame structure, in which the surgical handpiece (not the drills used for preparation) is guided. This study was based on an evaluation of the records of partially edentulous patients who had been treated with a sleeveless open-frame guided surgery system (TWIN-Guide®, 2Ingis, Brussels, Belgium), between January 2015 and December 2017. Inclusion criteria were patients with good systemic/oral health and a minimum follow-up of 1 year. Exclusion criteria were patients who had been treated without a guide, or with a guide with sleeves, patients with systemic/oral diseases and who did not have a follow-up of 1 year. The main outcomes were surgical (fit and stability of the surgical guide, duration of the intervention, implant stability, and any intra-operative or immediate post-operative complication), biologic, and prosthetic. Thirty-eight patients (24 males, 14 females; mean age 56.5 ± 14.0 years) were included in the study. These patients had been treated with 110 implants inserted by means of 40 sleeveless, open-frame guides. With regard to fit and stability, 34 guides were excellent, 4 acceptable, and 2 inadequate for use. The mean duration of the intervention was 23.7 (± 6.7) minutes. Immediately after placement, 2 fixtures were not stable and had to be removed. Two patients experienced pain/swelling after surgery. The 108 surviving implants were restored with 36 single crowns and 32 fixed partial prostheses (24 two-unit and 8 three-unit bridges); these restorations survived until the 1-year follow-up, with a low incidence of biologic and prosthetic complications. Within the limits of this study, this novel guided surgery system with sleeveless, open frame-structure guides seems to be clinically reliable; further studies on a larger sample of patients are needed to confirm these outcomes.


Beneficial effect of octreotide treatment in acute pancreatitis in rats.
Octreotide treatment contributes to the regulation of tumor necrosis factor (TNF) production in sodium taurocholate-induced acute necrotizing pancreatitis in rats. Owing to its complex effect, octreotide can partially ameliorate the deleterious consequences of acute necrotizing pancreatitis. Elevated TNF and interleukin-6 (IL-6) levels in the peritoneal fluid may be considered a consequence of the activation of peritoneal macrophages. The effects of octreotide on exocrine pancreatic function have been investigated in numerous studies, but little attention has been paid to its influence on cytokine production in acute pancreatitis. Acute pancreatitis was induced by the retrograde injection of taurocholic acid into the pancreatic duct in male Wistar rats. Serum amylase activity, wet pancreatic weight/body weight (pw/bw) ratio, and TNF and IL-6 levels were measured. Four micrograms/kg of octreotide was administered subcutaneously at the time of induction of pancreatitis and 24 or 48 h later. Rats were sacrificed 6, 24, 48, or 72 h after the operation. The serum amylase level and pancreatic weight to body weight ratio were decreased significantly in the octreotide-treated group. The serum TNF level was decreased significantly in the octreotide-treated group as compared with the control group at 6, 24, and 48 h (0.6 +/- 1.5, 2.0 +/- 3.3, and 0 vs 50 +/- 15.5, 37.5 +/- 18.4, and 13.1 +/- 12.5 U/mL, respectively). The ascites TNF level was decreased to 0 in the octreotide-treated group and was elevated in the control group at 72 h (28.0 +/- 49.0 U/mL). IL-6 production in ascites was extremely high in both groups at 6 h (80,000 +/- 43,817 pg/mL and 58,500 +/- 33,335 pg/mL), but the difference was not significant.


Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells.
Papillary thyroid carcinomas are characterized by rearrangements of the RET receptor tyrosine kinase generating RET/PTC oncogenes. Here we show that osteopontin (OPN), a secreted glycoprotein, is a major RET/PTC-induced transcriptional target in PC Cl 3 thyroid follicular cells. OPN upregulation depended on the integrity of the RET/PTC kinase and tyrosines Y1015 and Y1062, two major RET/PTC autophosphorylation sites. RET/PTC also induced a strong overexpression of CD44, a cell surface signalling receptor for OPN. Upregulation of CD44 was dependent on RET/PTC Y1062, as well. Constitutive OPN overexpression or treatment with exogenous recombinant OPN sharply increased proliferation, Matrigel invasion and spreading in collagen gels of RET/PTC-transformed PC Cl 3 cells. These effects were impaired by the treatment of PC Cl 3-RET/PTC cells with OPN- and CD44-locking antibodies. Thus, RET/PTC signalling triggers an autocrine loop involving OPN and CD44 that sustains proliferation and invasion of transfomed PC Cl 3 thyrocytes.


Comparison of molecular and immunological typing of isolates of Rice yellow mottle virus.
Isolates of Rice yellow mottle virus (RYMV) were typed at the molecular level through the sequences of the open reading frame (ORF) 4 (coding for the coat protein) and ORF1 (coding for the movement protein), and serologically by means of polyclonal and monoclonal antibodies. The overall patterns of diversity shown by molecular and serological analyses were similar: East-African isolates differed from West-African ones, and the West-African isolates from forest differed from the savannah ones. Each major strain had a different serological profile. However, molecular typing was more discriminating than immunological typing since several sequence variants belonged to the same serotype. In rare instances, there were explainable discrepancies between molecular and serological typing. Two amino acids at positions 115 (alanine vs threonine) and 191 (valine vs threonine) consistently discriminated between the major serotypes. These positions were located in antigenic sites as revealed by Spot-scan method and were recognised by discriminating monoclonal antibodies. One shared epitope, lying within a conserved region, may be responsible for the cross-reactivity between RYMV isolates. A rationale for the correlation between molecular and immunological typing of RYMV and other sobemoviruses is proposed.


Role of NF-κB in the pathogenesis of psoriasis elucidated by its staining in skin biopsy specimens.
NF-κB is a transcription factor belonging to the Re1 family, and it regulates the activity of a large number of proinflammatory genes. Its role in psoriasis, which is a prototype chronic inflammatory disease, is therefore expected to be considerable. It has been found that many of the triggering factors for psoriasis initiate inflammation by activation of NF-κB. Skin biopsies of 74 psoriatic cases were studied for the grade of NF-κB staining. They were then correlated with the histopathological indices of severity, especially epidermal hyperplasia and inflammatory infiltrate. Epidermal nuclear positivity for NF-κB correlated with the grade of epidermal hyperplasia (P = 0.043). There was a significant correlation between grade of basal cell positivity of NF-κB and inflammatory infiltrate (P = 0.004). Lymphocyte staining showed a strong correlation with epidermal and basal cell staining pattern for NF-κB (P = 0.004 and 0.003, respectively). There was, however, no correlation of lymphocyte staining with any histopathological parameter. There was also a peculiar propensity for NF-κB to show a positive nuclear stain at the tips of dermal papillae. The study has demonstrated that translocation of NF-κB in the epidermis and basal cells is responsible for two of the key pathological features of psoriasis, epidermal hyperplasia, and inflammation. We have postulated that translocation of NF-κB in lymphocytes, in psoriatic skin leads to NF-κB translocation in the epidermis and basal cells. NF-κB is therefore likely to be one of the key molecules in the pathogenesis of psoriasis.


Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.
Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.


A simplified radioimmunoassay for melatonin and its application to biological fluids. Preliminary observations on the half-life of plasma melatonin in man.
A simplified and rapid radioimmunoassay (RIA) for melatonin is presented. Melatonin is extracted from seru, plasma or urine and RIA is performed by using [3H]melatonin as the tracer. The standard curve covers the range 0.2--4.3 nmol/l. By increasing the sample volume the range can be extended to 0.06 nmol/l. The intra-assay variability is 7% (relative standard deviation = rsd) and the inter-assay variability is 10% (rsd). The recovery of melatonin added to calf serum is 96%. The long term variability of the assay (43 assays on aliquots of one serum sample during 6 months) is 13.5% (rsd). The serum levels in man after one oral dose of 430 mumol melatonin have been measured. The peak value, 620 nmol/l, was noted after 0.5 h and the melatonin concentration was still above the normal range at 24 h (2.1 nmol/l).


Precision technologies for the management of reproduction in dairy cows.
Precision livestock farming (PLF) utilizes information and communication technology (ICT) to continuously monitor, control, and enhance the productivity, reproduction, health, welfare, and environmental impact of livestock. Technological advancements have facilitated the seamless flow of information from animals to humans, enabling practical decision-making processes concerning health, reproduction management, and calving surveillance. With the increasing population of livestock per farm, it has become impractical for farmers to individually track every animal within these large groups. Historically, cattle management decisions heavily relied on human observation, judgment, and experience. However, it is impossible for a single individual to gather reliable audio-visual monitoring data round the clock. Presently, dairy cows exhibit subtler indicators of estrus, resulting in a substantial chance of missing an estrus cycle. Furthermore, calving complications sometimes go unnoticed on farms, resulting in a higher number of culled cattle. In addition, an increasing number of crossbred cows experience delayed return to estrus after calving due to low body condition scores (BCS). The decline in BCS during the dry period is associated with a reduced likelihood of pregnancy following the first and second postpartum inseminations. Precision technologies enable the monitoring and tracking of an individual cow's physiological behavior and reproductive parameters, thereby optimizing management practices and farm performance. Despite the exploration of various technologies, there are still some common challenges that need to be addressed, including battery lifespan, transmission range, specificity and sensitivity, storage capacity, and economic affordability. Nonetheless, the demand for these tools from farmers and researchers is growing, and the implementation of PLF in grazing systems can yield positive outcomes in terms of animal reproductive welfare and labor optimization. This review primarily focuses on the different aspects of reproduction management in dairy using sensors, automated cameras, and various computer software.


Ten-year outcome after aortic valve replacement with the freestyle stentless bioprosthesis.
Stentless aortic bioprostheses offer excellent hemodynamics and potentially improved durability compared with other bioprostheses. The present report describes the clinical and hemodynamic outcomes for the Freestyle aortic root bioprosthesis in a large, multicenter cohort prospectively followed up for 10 years. A total of 725 patients at 8 centers in North America (668 [92%] aged more than 60 years) were followed up prospectively after aortic valve replacement with the Freestyle stentless bioprosthesis. Implant technique was subcoronary in 509, total root in 178, and root inclusion in 38. Follow-up was 4,488 patient-years (mean 6.2 years/patient). For subcoronary, full root, and root inclusion groups, 10-year actuarial freedom from structural valve deterioration was 97.0% +/- 2.2%, 96.0% +/- 4.5%, and 90.9% +/- 11.2%, respectively; and actuarial freedom from reoperation was 91.7% +/- 3.5%, 92.3% +/- 6.0%, and 92.0% +/- 10.7%, respectively. Mean pressure gradient at 10 years was 8.9 +/- 7.9 mm Hg for subcoronary, 7.0 +/- 4.1 mm Hg for full root, and 10.0 +/- 11.1 mm Hg for root inclusion groups; effective orifice area was 1.6 +/- 0.5 cm2, 1.6 +/- 0.6 cm2, and 1.7 +/- 0.5 cm2, respectively. Fredom from moderate or more aortic regurgitation at 10 years was good for all three implant groups, but slightly higher for full root (97.7% +/- 1.6%) compared with subcoronary (87.2% +/- 2.8%) patients (p < 0.005). The Freestyle stentless aortic root bioprosthesis is a versatile option for aortic valve replacement. Measures of clinical outcomes and prosthesis durability remain excellent through 10 years.


Hypoglycemic activity of Abutilon indicum leaf extracts in rats.
Alcohol and water extracts of Abutilon indicum leaves (400 mg/kg, p.o.) showed significant hypoglycemic effect in normal rats 4 h after administration (23.10% and 26.95%, respectively).


Annual cycle of hypoxia off the Changjiang (Yangtze River) Estuary.
The annual cycle of hypoxia off the Changjiang Estuary, China, was assessed from data acquired during nine cruises in 2006-2007. Hypoxia began to develop in late spring and early summer, reached its maximum in August, weakened in the autumn and finally disappeared in the winter. Hypoxia first developed south-east of the Changjiang Estuary in June, appeared in the east and north-east in July, and spread both south and north of the Changjiang Estuary in August. By September, it had started to recede in the north-east, and had dissipated in the southern part of the studied area by winter. The geographical displacement of the hypoxic zone was controlled by both seasonal changes in regional water column stratification and variations of the northward extension of the Taiwan Warm Current toward the Changjiang Estuary.


Studies on mammalian chromosome replication. III. Organization and replication of diplochromosomes.
The process of DNA synthesis in normal and endoreduplicating mammalian cells are very similar. Both types of chromosomes are replicated in defined units termed chromosomal replicons, and in the same sequences along their lengths. The sister chromosomes of the diplochromosomes are replicated synchronously in identical patterns. The present observations suggest that organization and sequences of chromosome replication are genetically programmed.


Frequency of the arylsulphatase A pseudodeficiency allele in the Spanish population.
Pseudodeficiency in arylsulphatase A (ASA) is a relatively frequent condition in healthy individuals. It produces a reduction in enzyme activity similar to that found in metachromatic leukodystrophy (MLD). Unambiguous discrimination between the two conditions cannot be achieved through conventional enzyme activity assays. A PCR method has been developed which detects the pseudodeficiency (pd) allele using a single pair of primers encompassing the mutation site and hair follicles as the source of DNA. The frequency of this allele in the Spanish population has been evaluated and correlations between different genotypes and ASA activity levels have been established. Ten out of 55 individuals were heterozygous for the ASA pd allele, while two were homozygous. The allele frequency was thus 12.7%.


Clinical outcomes of gemtuzumab ozogamicin for relapsed acute myeloid leukemia: single-institution experience.
We retrospectively evaluated the clinical efficacy and toxicity of gemtuzumab ozogamicin (GO) in patients with relapsed acute myeloid leukemia (AML). Nineteen patients (median 70 years) received GO (9 mg/m2, days 1 and 15) as salvage therapy in our institution between 2006 and 2017. The primary endpoint was the response rate. The secondary endpoint was the occurrence of adverse events. Thirteen patients had de novo AML, and 6 patients had secondary AML. Most of the patients had received salvage treatments more than once prior to GO. Six patients responded to the treatment (31.6%) with 3 complete remissions (15.8%). Five patients had stable disease, and 8 patients did not show any response. GO was more efficacious among the patients with fewer numbers of prior salvage treatments. CD33 positivity of leukemic cells was higher in responders than in nonresponders. Peripheral WT1 mRNA levels mostly decreased over time in the responders. The adverse event most commonly seen was febrile neutropenia (84%). No patient presented with veno-occlusive disease. Three patients died by day 30 (mortality rate 15.8%), one due to acute respiratory distress syndrome and the other two due to sepsis. GO remains an effective salvage treatment.


A novel M163L mutation in connexin 26 causing cell death and associated with autosomal dominant hearing loss.
Mutations in GJB2 gene (encoding connexin 26) are the most common cause of hereditary non-syndromic sensorineural hearing loss (NSSHL) in different populations. The majority of GJB2 mutations are recessive, but a few dominant mutations have been associated with hearing loss either isolated or associated with skin disease. We describe a novel dominant pathogenic GJB2 mutation, identified in a Portuguese family affected with bilateral mild/moderate high-frequency NSSHL. In vitro functional studies demonstrate that the mutant protein (p.M163L) has defective trafficking to the plasma membrane and is associated with increased cell death.


Factors explaining the intention to give blood among the general population.
The aim of this study was to identify factors explaining the intention to donate blood. A random sample of 4000 respondents drawn from the general population received a questionnaire by mail. This questionnaire assessed variables as defined by the most prominent social cognitive theories. Overall, the respondents expressed a neutral mean level of intention to give blood in the next 6 months (2.84 on a five-point scale); 56.2% had never given blood in the past. The variables explaining 74% of the variance of intention were: perceived behavioural control (beta = 0.39; P < 0.001); factors facilitating taking action (beta = 0.25; P < 0.001); anticipated regret (beta = 0.16; P < 0.001); moral norm (beta = 0.11; P < 0.001); attitude (beta = 0.08; P < 0.01); level of education (beta = -0.03; P < 0.05); and past experience in giving blood (beta = 0.09; P < 0.001). Nonetheless, the predictive power of perceived behavioural control and moral norm was higher among the ever donors (both at P < 0.01) compared to the never donors, whereas the reverse was observed for attitude (P < 0.05). People's intentions are mainly determined by perceived barriers and obstacles regarding blood donations. This suggests that promotional strategies should focus on the elimination of barriers to action as well as the development of a higher perception of control. Also, messages should be adapted to the targeted population, based on their previous blood donation behaviour (i.e. never donors vs. ever donors).


RETRACTED: Comparison of efficacy and side effects of Fixed-dose combination of Aclidinium/Formoterol and Monotherapy of Aclidinium or Formoterol in COPD: A meta-analysis.
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Application of clinical bioinformatics in lung cancer-specific biomarkers.
The fact that lung cancer is a heterogeneous disease suggests that there is a high likelihood that effective lung cancer biomarkers will need to address patient-specific molecular defects, clinical characters, and aspects of the tumor microenvironment. In this transition, clinical bioinformatics tools and resources are the most appropriate means to improve the analysis, as major biological databases are now containing clinical data alongside genomics, proteomics, and other biological data. Clinical bioinformatics comprises a series of concepts and approaches that have been used successfully both to delineate novel biological mechanisms and to drive translational advances in individualized healthcare. In this article, we outline several of emerging clinical bioinformatics-based strategies as they apply specifically to lung cancer.


Body composition and overweight prevalence in 1704 schoolchildren from 7 American Indian communities.
Nationwide data on obesity prevalence in American Indian communities are limited. We describe the body composition and anthropometric characteristics of schoolchildren from 7 American Indian communities enrolled in the Pathways study, a randomized field trial evaluating a program for the primary prevention of obesity. A total of 1704 children in 41 schools were enrolled in the study. Basic anthropometric measurements included weight, height, and triceps and subscapular skinfold thicknesses. Percentage body fat was estimated from bioelectrical impedance and anthropometric variables with the use of an equation developed and validated for this population. The children's mean (+/- SD) age was 7.6 +/- 0.6 y, and their mean weight and height were 32.1 +/- 8.9 kg and 129.8 +/- 6.3 cm, respectively. Mean body mass index (BMI; in kg/m(2)) was 18.8 +/- 3.9, and mean percentage body fat was 32.6 +/- 6.8%. With the use of current Centers for Disease Control and Prevention reference values, 30.5% of girls and 26.8% of boys were above the 95th percentiles for BMI-for-age, and 21% of girls and 19.6% of boys were between the 85th and 95th percentiles. Although there was a wide range in BMI across study sites and for both sexes, the percentage of children with a BMI above the 95th percentile was consistently higher than the national averages in all communities studied and in both girls and boys. Overweight can be documented in a substantial number of American Indian children by the time they reach elementary school. Despite differences in the prevalence of overweight observed among communities, rates are uniformly high relative to national all-race averages.


Clinical and radiological outcomes of robotic-assisted unicompartmental knee arthroplasty: Early lessons from the first 100 consecutive knees in 85 patients.
Robotic-assisted unicompartmental knee arthroplasty (UKA) is associated with improved component positioning and comparable short- and mid-term implant survivorship with manual UKA. This study aims to evaluate clinical and radiological outcomes following robotic-assisted UKA as well as any potential learning-curves associated with the introduction of such new technology. Prospective study of patients undergoing robotic-assisted UKA. Outcome measures were patient-reported outcome measures (PROMs) including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Society Score (KSS) and Oxford Knee Score (OKS), complications, implant survivorship, component positioning and learning curve. Eighty-five patients comprising 100 knees were recruited and followed up for 21.0 ± 4.3 months. At two years, there were significant and sustained improvements in PROMs and 100% implant survivorship rate. A high degree of implant accuracy was achieved with the robotic system. A cumulative learning curve of 20 cases was noted. Robotic-assisted UKA achieves excellent implant accuracy and clinical outcomes in the short-term. Long-term follow up is needed to evaluate this relationship.


Predictors of polysubstance use in patients with severe alcohol use disorder: the role of reward craving.
Different craving typologies (i.e., reward, relief, obsessive) have been identified in alcohol use disorder (AUD) but have been less investigated in specific populations like AUD patients with polysubstance use (PSU). The role of dysfunctional personality traits and reward pathways has been reported in both AUD and PSU. We hypothesized that patients with AUD-PSU might show a prevalent reward craving, alongside specific sociodemographic, clinical, and personality features, and aimed at investigating differences in 423 severe AUD outpatients with and without PSU. One hundred fifteen patients (27.1% of the sample, 67% males, 42 ± 11.6 years old) displayed PSU. Sociodemographic, clinical features and psychopathological/personality dimensions were assessed through: Craving Typologies Questionnaire (CTQ); Obsessive-Compulsive Drinking Scale (OCDS); UPPS-P Impulsive Behavior Scale (S-UPPS-P); Difficulties in Emotion Regulation Scale (DERS). A binomial logistic regression explored factors associated with PSU. We found higher CTQ 'reward' scores (p < 0.001) in AUD-PSU patients, and a significant association between reward craving and PSU through logistic regression (OR:1.13; p = 0.005). Earlier AUD onset (p < 0.001), greater rates of binge drinking (p = 0.029), more legal problems (p = 0.015), but no significantly higher S-UPPS-S and DERS scores, were detected in AUD-PSU patients. Reward craving was associated with increased risk for PSU in severe AUD patients. Given AUD-PSU participants greater severity and detrimental treatment responses imputed to PSU, identifying prevalent craving types among risk factors for PSU in AUD may help to implement therapeutic strategies. Addressing neurobiological and behavioral mechanisms through combined psychotherapies, pharmacological and neuromodulation treatments could support tailored interventions with better long-term outcome.


Isolation and evaluation of the efficacy of bacteriophages against multidrug-resistant (MDR), methicillin-resistant (MRSA) and biofilm-producing strains of Staphylococcus aureus recovered from bovine mastitis.
Staphylococcus aureus (S. aureus) is one of the major causes of bovine mastitis with significant economic losses around the worldwide. The emergence of multidrug-resistant (MDR), methicillin-resistant (MRSA) and biofilm-producing strains of S. aureus challenges the treatment strategies based on the antibiotic application. Today, alternative or combinational treatment options such as bacteriophage application has received much attention. The goal of the present study was to focus on isolation and evaluation of the efficacy of bacteriophages with specific lytic activity against S. aureus strains with low cure rates (MDR, MRSA and biofilm-producing strains). In the present study, two phages belonging to the Podoviridae family with specific lytic activity against S. aureus were isolated from the sewage of dairy farms and designated as Staphylococcus phage M8 and Staphylococcus phage B4. Latent period and burst size for Staphylococcus phage M8 (70 min, 72 PFU/cell) and Staphylococcus phage B4 (30 min, 447 PFU/cell) were also defined. Our results revealed the susceptibility of MDR (4/20; 20%), MRSA (4/13; 30.8%) and biofilm-producing (1/10; 10%) strains to Staphylococcus phage M8. Moreover, one biofilm-producing strain (1/10; 10%) was susceptible to Staphylococcus phage B4. Furthermore, both phages kept their lytic activity in milk. They reduced the S. aureus population by about 3 logs in cultured milk after 8 h of incubation. In conclusion, it seems that both phages had the potential to serve as biological control agents alone or in combination with other agents such as antibiotics against infections induced by S. aureus. However, further studies are needed to investigate the efficacy of these phages in vivo.


Are we missing diagnostic opportunities in cases of carcinoid tumours of the appendix?
Carcinoid tumour of appendix is an uncommon condition that can potentially give rise to a variation in management. We aimed to assess the occurrence and mode of presentation of carcinoid tumour of appendix, and any variation of its management. All appendicectomies that took place at North Middlesex University Hospital, London between 1995 and 2005 were considered for study. A total of 1941 appendicectomies took place. Sixteen (0.82%) patients had carcinoid tumours. The mean age of patients with carcinoid tumour (41.8 years) was significantly higher than those with non-carcinoid pathology (27.7 years) (p = 0.001). The incidence of female patients was higher than the male amongst the carcinoid tumour group (female/male ratio 2.2). None of the carcinoid tumours were identified at operation. Eight patients as well as their general practitioners (53.3%) were unaware of the diagnosis. Multidisciplinary team involvement or specialty referral took place in three cases (20%). One patient (6.6%) required right hemicolectomy. Three patients (20%) were followed-up in inconsistent manner. Carcinoid tumour of the appendix remains an incidental diagnosis. Patients with carcinoids were significantly older than non-carcinoid conditions. There was a trend of increased occurrence of carcinoids amongst the females. Re-operation rate was low. There was a wide variation in involving the multidisciplinary team, conveying the diagnosis to patients as well as their general practitioners, and follow-ups. This can be perceived as a missed opportunity of selective screening of synchronous and metachronous lesions, raises clinical governance issues and has medicolegal implications.


Vascularized bone flaps in oromandibular reconstruction. A comparative anatomic study of bone stock from various donor sites to assess suitability for enosseous dental implants.
To identify donor sites from which vascularized bone may be harvested capable of accepting osseointegrated implants of the minimum dimensions required to ensure long-term implant stability. An anatomic study of the most commonly employed donor sites for vascularized bone in oromandibular reconstruction was conducted on 28 cadavers. Academic tertiary referral center. Twenty-eight freshly embalmed, adult white cadavers (16 male, 12 female) were dissected. The ipsilateral fibula, iliac crest, radius, and lateral border of the scapula were harvested and multiply sectioned at predetermined sites. Implantability was determined for each section based on measurements of height, width, and cross-sectional area utilizing computer planimetry. The iliac crest was the most consistently implantable donor site, followed by the scapula, fibula, and radius (83%, 78%, 67%, and 21% of sections from each donor site satisfying the criteria for implantability). Consistent regional differences in implantability were encountered at each donor site except the scapula. Following ablation of oromandibular malignant neoplasms, restoration of stable retentive dentition is a prerequisite to a successful functional oral rehabilitation. This is best achieved with enosseous implants, capable of supporting a stable dental prosthesis, placed directly into vascularized bone flaps at the time of mandibular reconstruction. The implications of the results obtained in this study for gender, donor site selection, and orientation of the vascularized bone flap are discussed.


Soil enzymatic activities and microbial community structure with different application rates of Cd and Pb.
This study focused on the changes of soil microbial diversity and potential inhibitory effects of heavy metals on soil enzymatic activities at different application rates of Cd and/or Pb. The soil used for experiments was collected from Beijing and classified as endoaquepts. Pots containing 500 g of the soil with different Cd and/or Pb application rates were incubated for a period of 0, 2, 9, 12 weeks in a glasshouse and the soil samples were analyzed for individual enzymes, including catalase, alkaline phosphatase and dehydrogenase, and the changes of microbial community structure. Results showed that heavy metals slightly inhibited the enzymatic activities in all the samples spiked with heavy metals. The extent of inhibition increased significantly with increasing level of heavy metals, and varied with the incubation periods. The soil bacterial community structure, as determined by polymerase chain reaction-denaturing gradient gel electrophoresis techniques, was different in the contaminated samples as compared to the control. The highest community change was observed in the samples amended with high level of Cd. Positive correlations were observed among the three enzymatic activities, but negative correlations were found between the amounts of the heavy metals and the enzymatic activities.


X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60.
This study describes the ophthalmic findings in two unrelated white families with X-linked retinitis pigmentosa (XLRP) caused by a missense mutation in the retinitis pigmentosa GTPase regulator (RPGR) gene. Genetic screening and clinical correlation. Thirty-six families with XLRP seen by the authors were screened for a possible mutation in the RPGR gene to identify three affected hemizygotes with retinitis pigmentosa and four heterozygote carriers in one family and one hemizygote and one carrier in a second family. All nine patients underwent a routine ocular examination, including slit-lamp biomicroscopy and a dilated fundus examination. Goldmann visual field kinetic perimetry, static threshold perimetry, and electroretinography also were obtained. The DNA screening was performed on the three affected male patients and four obligate carriers examined from one family and the two examined patients, plus an additional male and obligate carrier, from the second family to determine the presence of any causative mutation in the RPGR gene. Findings on fundus examination, static threshold and kinetic perimetry, and electroretinography testing were the main outcome measures. A G-->T nucleotide change at position 238 in exon 3 of the RPGR gene resulting in a putative substitute of Gly-->Val at codon 60 was shown to segregate with RP in affected males and the carrier state in female heterozygotes in these two families. The ophthalmologic findings in hemizygotes as well as the carriers in this family were within the spectrum of findings characteristically noted in XLRP families. A tapetal-like reflex was not observed in any of the five female carriers. Psychophysical and electrophysiologic testing on the carriers indicated that cone and rod functions were impaired equivalently. When present in the carriers, visual field restriction was most apparent in, or limited to, the superotemporal quadrant, which corresponded to the retinal pigmentary changes that tended to occur in the inferonasal retina. A mutation in exon 3 of the RPGR gene, which would result in a putative glycine to valine substitution at codon 60, is associated with a severe clinical phenotype in male patients and a patchy retinopathy without a tapetal-like reflex in carrier females. In these families, heterozygote carriers showed equivalent impairment of their cone and rod function.


Brain arteriovenous malformation modeling, pathogenesis, and novel therapeutic targets.
Patients harboring brain arteriovenous malformation (bAVM) are at life-threatening risk of rupture and intracranial hemorrhage (ICH). The pathogenesis of bAVM has not been completely understood. Current treatment options are invasive, and ≈ 20 % of patients are not offered interventional therapy because of excessive treatment risk. There are no specific medical therapies to treat bAVMs. The lack of validated animal models has been an obstacle for testing hypotheses of bAVM pathogenesis and testing new therapies. In this review, we summarize bAVM model development and bAVM pathogenesis and potential therapeutic targets that have been identified during model development.


Blueberry extract decreases oxidative stress and improves functional parameters in lungs from rats with pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a condition characterized by an increased resistance of pulmonary vasculature, culminating in an increase in pulmonary pressure. This process involves disturbances in lung redox homeostasis, causing progressive right heart failure. In this context, the use of natural antioxidants, such as those found in blueberries, may represent a therapeutic approach. The aim of this study was to evaluate the effect of blueberry extract (BB) on functional parameters and oxidative stress levels in rat lungs with induced PAH. Forty-eight male Wistar rats (weighing 200 ± 20 g) were randomized into five groups: control, monocrotaline, monocrotaline + BB 50, monocrotaline + BB 100, and monocrotaline + BB 200. PAH was induced by the administration of monocrotaline (60 mg/kg, intraperitoneal). Rats were treated with BB at doses of 50, 100, and 200 mg/kg via gavage for 5 wk (2 wk before monocrotaline and 3 wk after monocrotaline injection). At day 35, rats were submitted to echocardiography and catheterization. They were then sacrificed and lungs were harvested for biochemical analyses. BB increased the E/A ratio of blood flow across the tricuspid valve and tricuspid annular phase systolic excursion, as wells as decreased the mean pulmonary artery pressure of animals compared with the PAH group. Moreover, BB decreased total reactive species concentration and lipid oxidation, reduced activity of nicotinamide adenine dinucleotide phosphate oxidase and expression of xanthine oxidase, increased the activity of superoxide dismutase and restored sulfhydryl content in the animal lungs compared with those in the PAH group. Additionally, BB restored expression of the antioxidant transcriptional factor Nrf2 in the lungs of the animal subjects. Finally, BB normalized the endothelin receptor (ETA/ETB) expression ratio in the animal lungs, which were increased in the PAH group. Intervention with BB mitigated functional PAH outcomes through improvement of the pulmonary redox state. Our results provide a basis for future research on natural antioxidant interventions as a novel treatment strategy in PAH.


[Comparative study on the efficacy of cefuroxime, amoxycillin/clavulanic acid and fosfomycin in prophylaxis of nosocomial infections in oncologic patients after surgical operations].
Rational antibiotic prophylaxis and antibacterial therapy of nosocomial infections is an actual problem in surgery. Improvement of antimicrobial chemotherapy and prophylaxis of nosocomial infections is of special importance in urgent cases in oncologic units. Data on the design of rational schemes for antibacterial prophylaxis of nosocomial infections developing during the postoperative period in patients with cancer of the urinary bladder as one of the unfavourable complications of the main disease treatment are presented. The use of fosfomycin in the schemes of the antibiotic prophylaxis was shown to be more efficient vs. the use of the traditional beta-lactam antibiotics.


Metabolically healthy obesity: is there a link with polyunsaturated fatty acid intake and status?
The aim of this study was to compare dietary intake and status of polyunsaturated fatty acids (PUFA) in plasma and erythrocyte phospholipids metabolically healthy and unhealthy, and obese and nonobese persons. Metabolic health status in 171 participants was defined according to criteria for metabolic syndrome. Obese and nonobese metabolically unhealthy persons (MUHO and MUHNO) had higher energy intake of n-6 PUFA (7.82 ± 1.03 and 7.49 ± 0.86) and lower intake of n-3 PUFA (0.60 ± 0.12 and 0.62 ± 0.11) compared to obese and nonobese metabolically healthy persons (MHO and MHNO) (5.92 ± 0.63 and 5.72 ± 0.67; 1.20 ± 0.07 and 1.22 ± 0.09, respectively) and a higher n-6/n-3 PUFA ratio. The plasma level of n-6 PUFA was lower in the MUHO and MUHNO groups (38.49 ± 3.71 and 38.53 ± 2.19) compared to MHNO (40.90 ± 2.43), while n-3 PUFA status was lower in obese than in nonobese persons (3.58 ± 0.79 and 3.50 ± 1.02 vs. 4.21 ± 0.80 and 4.06 ± 1.15). The MHO group had a higher eicosapentaenoic/arachidonic acid ratio and estimated desaturase (SCD16, D6D) and elongase activity in plasma phospholipids compared to MHNO. The low intake of n-3 PUFA is directly associated with metabolic risk factors. These results indicated that obesity is closely associated with low levels of n-3 PUFA in plasma phospholipids, suggesting that dietary modifications including n-3 PUFA supplementation appear to be suitable therapeutic strategy in obese persons.


Smoking Status at Diagnosis and Colorectal Cancer Prognosis According to Tumor Lymphocytic Reaction.
Smoking has been associated with worse colorectal cancer patient survival and may potentially suppress the immune response in the tumor microenvironment. We hypothesized that the prognostic association of smoking behavior at colorectal cancer diagnosis might differ by lymphocytic reaction patterns in cancer tissue. Using 1474 colon and rectal cancer patients within 2 large prospective cohort studies (Nurses' Health Study and Health Professionals Follow-up Study), we characterized 4 patterns of histopathologic lymphocytic reaction, including tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral lymphocytic reaction, and Crohn's-like lymphoid reaction. Using covariate data of 4420 incident colorectal cancer patients in total, an inverse probability weighted multivariable Cox proportional hazards regression model was conducted to adjust for selection bias due to tissue availability and potential confounders, including tumor differentiation, disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. The prognostic association of smoking status at diagnosis differed by TIL status. Compared with never smokers, the multivariable-adjusted colorectal cancer-specific mortality hazard ratio for current smokers was 1.50 (95% confidence interval = 1.10 to 2.06) in tumors with negative or low TIL and 0.43 (95% confidence interval = 0.16 to 1.12) in tumors with intermediate or high TIL (2-sided P interaction = .009). No statistically significant interactions were observed in the other patterns of lymphocytic reaction. The association of smoking status at diagnosis with colorectal cancer mortality may be stronger for carcinomas with negative or low TIL, suggesting a potential interplay of smoking and lymphocytic reaction in the colorectal cancer microenvironment.


Gonadal hormones in schizophrenia and mood disorders.
There are gender-related differences in the prevalence, course and treatment response characteristics of schizophrenia and mood disorders. Gonadal steroids exert potent effects on mood, cognition and behavior, and there is little doubt that androgens are crucial for differentiating to each gender. Serum level of total testosterone, free testosterone, estradiol and sex hormone binding globulin was measured in 69 medication-free men with either schizophrenia (n=29) or bipolar I disorder, manic episode (n=18) or major depressive disorder (n=22). There was a statistically significant difference in free testosterone level between mania and schizophrenia groups (p<0.05). The higher free testosterone level in the mania group compared to the schizophrenia group found in this study supports further investigation of a potential difference in the hypothalamic-pituitary-gonadal axis between patients with schizophrenia and bipolar I disorder, manic.


Interlocked Intramedullary Nail Without Fluoroscopy.
Surgical Implant Generation Network (SIGN) was founded 15 years ago to create equality of fracture care throughout the world. This is done by education and supply of the appropriate implants and instruments to implement the education. SIGN implants have been used in 150,000 long bone fractures in developing countries. The same implants and instruments are used to provide intramedullary nail interlocking screw fixation in the tibia, femur, and humerus. The design of SIGN implants and the surgical technique are described.


Anthropogenic activities influence the mobilization of trace metals and oxyanions in coastal sediment porewaters.
The biogeochemical cycle of trace metals and oxyanions in marine sediments is mainly controlled by early diagenesis of organic material, but anthropogenic activities such as dumping of dredged sludge or shipyard activities can strongly perturb these natural processes. Therefore, the impact of dumping of dredged sludge, shipyard activities such as blasting of boat hulls and the mixing of polluted Scheldt estuary water with less polluted coastal water on the mobilization of trace metals and oxyanions in the sediments was studied in the pre- and post-bloom period (March and October) in Belgian Coastal Zone (BCZ). Vertical profiles of total and labile dissolved trace element concentrations, dissolved sulfide, pH and redox potential were assessed in sediment porewaters. Generally, total and labile dissolved element profiles in the porewaters are well correlated, showing higher concentrations in March when the redox potential is lower and sulfide concentrations higher. Low pH levels were documented together with high amounts of Fe and associated elements in March at the dumping station. At the coastal station in the vicinity of the shipyards, sediment porewaters are enriched in dissolved Zn while at the mouth of the Scheldt estuary the highest dissolved Cu levels were found. Theoretical calculations with Visual MINTEQ confirm the increased Fe and associated element concentrations in March (lower pH) and the lower metal concentrations in October (lower Eh). R values, ratio of labile dissolved to total dissolved concentrations, reflect the potential of the solid sediment phase to supply labile elements to the porewater. They were lowest for Cu and highest for V. This study showed that anthropogenic activities in the BCZ such as dumping of dredged sludge and blasting of boat hulls have a serious impact on the levels, distribution and bioavailability of contaminants in the sediments, which may form a real threat to the benthic ecosystem.


Better than average? When can we say that subsampling of items is better than statistical summary representations?
Myczek and Simons (2008) have described a computational model that subsamples a few items from a set with high accuracy, showing that this approach can do as well as, or better than, a model that captures statistical representations of the set. Although this is an intriguing existence proof, some caution should be taken before we consider their approach as a model for human behavior. In particular, I propose that such simulation-based research should be based on a more expanded range of phenomena and that it should include more accurate representations of errors in judgments.


A biophysical and computational study unraveling the molecular interaction mechanism of a new Janus kinase inhibitor Tofacitinib with bovine serum albumin.
The interaction of a recently certified kinase inhibitor Tofacitinib (TFB) with bovine serum albumin (BSA) has been studied, by spectroscopic and molecular docking studies. Spectrofluorimetric measurements at 3 different temperatures (288, 298, and 310 K) showed that TFB quench the intrinsic fluorescence of BSA upon forming a nonfluorescent complex. The intrinsic fluorescence data showed that TFB binds to BSA with binding constant (Kb ) of approximately 104 M-1 , affirming a significant affinity of TFB with BSA. The decrease in Stern-Volmer quenching constant with increasing temperature exhibited the static mechanism of quenching. Negative value of ΔG (-6.94 ± 0.32 kcal·mol-1 ), ΔH (-7.87 ± 0.52 kcal·mol-1 ), and ΔS (-3.14 ± 0.42 cal·mol-1 ·K-1 ) at all 3 temperatures declared the reaction between BSA and TFB to be spontaneous and exothermic. Far-UV circular dichroism spectroscopy results demonstrated an increase in helical content of BSA in the presence of TFB. Moreover, dynamic light scattering measurements showed that TFB resulted into a decrease in the hydrodynamic radii (from 3.6 ± 0.053 to 2.9 ± 0.02 nm) of BSA. Molecular docking studies confirmed that TFB binds near site II on BSA, hydrogen bonding, and hydrophobic interaction were involved in the BSA-TFB complex formation. The present study characterizing the BSA-TFB interaction could be significant towards gaining an insight into the drug pharmacokinetics and pharmacodynamics and also in the direction of rational drug designing with better competence, against emerging immune-mediated diseases, ie, alopecia and rheumatoid arthritis.


Paroxysmal dysarthria and ataxia in multiple sclerosis and corresponding magnetic resonance imaging findings.
Paroxysmal dysarthria (PD) and paroxysmal dysarthria-ataxia (PDA) syndromes are uncommon symptoms of the neurological dysfunction in multiple sclerosis (MS). We describe two patients who had clinically definite MS presented with symptomatic PD and PDA syndromes, respectively, related to demyelinating lesions. In one patient, the PD symptom was the initial manifestation of an acute episode. In the other patient, the episode of dysarthria was accompanied by ataxia disorders. Both patients had midbrain lesions at or below the level of the right red nucleus on magnetic resonance imaging (MRI), confirming that this area is critically involved. Both responded well to carbamazepine (CBZ).


Childhood socioeconomic position and blood pressure dipping in early adulthood: a longitudinal study.
The experience of low socioeconomic position in childhood may increase risk for adult cardiovascular disease above and beyond the effects of current socioeconomic position. One limitation of most previous research is that childhood socioeconomic position was assessed retrospectively. Measures of ambulatory blood pressure, heart rate, and heart rate variability were obtained from 110 young men (22 years) who were enrolled in a long-term study of child development at age 6. Men who had lower childhood socioeconomic position had smaller decreases in systolic blood pressure (SBP) during sleep independent of current education, daytime SBP, and body mass index (BMI). They also displayed smaller decreases in low-frequency heart rate variability during sleep. Twenty-four-hour SBP was negatively associated with childhood socioeconomic position independent of current education and BMI. While the mechanisms are unclear, childhood socioeconomic position may influence blood pressure in early adulthood independent of current life circumstances.


LncRNA UCA1 inhibits proliferation and promotes apoptosis of cervical cancer cells by regulating β-catenin/TCF-4.
The aim of this study was to explore the regulatory effect of long non-coding ribonucleic acid (lncRNA) urothelial carcinoma antigen 1 (UCA1) on the proliferation and apoptosis of HeLa cells and to elucidate its potential regulatory mechanism. HeLa cells were cultured in vitro and randomly divided into three groups, including blank control group (Control group), lncRNA UCA1 negative control (NC) group, and lncRNA UCA1 interference group [lncRNA UCA1 small interfering RNA (siRNA) group]. The expression level of lncRNA UCA1 in HeLa cells was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Methyl thiazolyl tetrazolium (MTT) assay was performed to determine the effect of lncRNA UCA1 on the proliferation of HeLa cells. The effect of lncRNA UCA1 on the apoptosis of HeLa cells was determined via Hoechst 33258 staining assay and flow cytometry. In addition, qRT-PCR and Western blotting were employed to measure the messenger RNA (mRNA) and protein expression levels of β-catenin and TCF-4 in HeLa cells, respectively. There were no statistically significant differences in the proliferation and apoptosis of HeLa cells as well as the mRNA and protein levels of β-catenin and TCF-4 in HeLa cells between Control group and lncRNA UCA1 NC group (p>0.05). In comparison with lncRNA UCA1 NC group, lncRNA UCA1 siRNA group exhibited overtly reduced proliferation, enhanced apoptosis rate of HeLa cells and down-regulated mRNA and protein levels of β-catenin and TCF-4 in HeLa cells (p<0.05). LncRNA UCA1 inhibits proliferation and promotes the apoptosis of HeLa cells. Furthermore, its mechanism of action may be related to the inhibition on the β-catenin/TCF-4 signaling pathway.


ZRX1, the first EGFR inhibitor-capecitabine based combi-molecule, requires carboxylesterase-mediated hydrolysis for optimal activity.
Capecitabine, an orally available prodrug of 5-FU, requires activation by carboxylesterase (CES) enzymes present in the liver to generate 5'-deoxy-5-flurocytidine ribose (5'-DFCR). The deamination of the latter by cytidine deaminase gives 5'-deoxy-5-fluorouridine ribose (5'-DFUR). Finally, the conversion of 5'-DFUR to the cytotoxic drug 5-FU, occurs primarily in the tumour and is catalyzed by thymidine phosphorylase (TP). Accordingly, it was surmised that events associated with an increase of TP levels should enhance the potency of capecitabine and its metabolites. EGFR inhibition was found to be one such event. The observed synergy between gefitinib and 5'-DFUR has inspired the design of single molecules capable of acting as prodrugs of both an EGFR inhibitor and 5-FU. Here, we report on the synthesis and characterization of one such molecule, ZRX1, that consists of an acetylated 5'-DFCR moiety linked to a quinazoline inhibitor of EGFR through an alkyl dicarbamate spacer that requires CES activation to generate the two active metabolites. Our results showed that ZRX1 was ineffective as an intact molecule. However, when CES was present, ZRX1 induced an increase in EGFR inhibition, TP expression, DNA damage and apoptosis. ZRX1 was, at least, 3-fold more potent than capecitabine and 5'-DFUR and recapitulated the effects of the combination treatments. LC-MS analysis showed that in the presence of CES, ZRX1 is metabolized into a mixture of bioactive quinazoline derivatives and 5'-DFCR derived metabolites. Our results in toto, suggest that capecitabine-based EGFR targeting combi-molecules of the same type than ZRX1, have the potential to induce stronger growth inhibitory potency than capecitabine, 5'-DFUR or single EGFR inhibitors and equivalent potency when compared with combinations of EGFR inhibitors + 5'-DFUR.


Outpatient blind percutaneous liver biopsy in infants and children: is it safe?
We aim to investigate the safety of outpatient blind percutaneous liver biopsy (BPLB) in infants and children with chronic liver disease (CLD). BPLB was performed as an outpatient procedure using the aspiration Menghini technique in 80 infants and children, aged 2 months to 14 yrs, for diagnosis of their CLD. Patients were divided into three groups: Group 1 (<1 year), group 2 (1-6 yrs), and group 3 (6-14 yrs). The vital signs were closely monitored 1 hr before biopsy, and then 1, 2, 6, and 24 hrs after biopsy. Twenty-four hours pre- and post-biopsy complete blood counts, liver enzymes, prothrombin time (PT), and abdominal ultrasonography, searching for a biopsy-induced hematoma, were done for all patients. No mortality or major morbidities were encountered after BPLB. The rate of minor complications was 17.5% including irritability or "pain" requiring analgesia in 10%, mild fever in 5%, and drowsiness for >6 hrs due to oversedation in 2.5%. There was a statistically significant rise in the 1-hr post-biopsy mean heart and respiratory rates, but the rise was non-significant at 6 and 24 hrs except for group 2 where heart rate and respiratory rates significantly dropped at 24 hrs. No statistically significant difference was noted between the mean pre-biopsy and the 1, 6, and 24-hrs post-biopsy values of blood pressure in all groups. The 24-hrs post-biopsy mean hemoglobin and hematocrit showed a significant decrease, while the 24-hrs post-biopsy mean total leucocyte and platelet counts showed non-significant changes. The 24-hrs post-biopsy mean liver enzymes were non-significantly changed except the 24-hrs post-biopsy mean PT which was found to be significantly prolonged, for a yet unknown reason(s). Outpatient BPLB performed by the Menghini technique is safe and well tolerated even in infants and young children. Frequent, close monitoring of patients is strongly recommended to achieve optimal patient safety and avoid potential complications.


Analysis of sampling strategies to substantiate freedom from disease in large areas.
In this paper, we deal with the strategies of surveys to substantiate freedom from disease for a certain territory. Infection might not be distributed homogeneously. So, a relatively high within-herd prevalence might be observed while the herd-level prevalence is lower. For this situation, we compare various two-stage sample strategies. The calculation of appropriate sample sizes becomes quite complicated. The theoretical generalization of the hypergeometric distribution by Cameron and Baldock [Prev. Vet. Med. 24 (1998) 1] introduces a simple way to evaluate multi-stage sample sizes while regarding real-test properties. We demonstrate the theoretical foundations of these calculations. These principles open up the possibility of optimizing costs or other relevant variables, by choosing the appropriate sample strategy (each of which ensures the same alpha-level for the first stage). In addition, we evaluate the statistical power of the complete strategies under consideration.Furthermore, we apply our theoretical results to a data example of Brucella melitensis. We used the herd-size situation in Germany, characterized by many small sheep holdings and only a few large ones. The consequences of real-test properties on sample sizes and on the applicability of several strategies are discussed.


The social vulnerability metric (SVM) as a new tool for public health.
To derive and validate a new ecological measure of the social determinants of health (SDoH), calculable at the zip code or county level. The most recent releases of secondary, publicly available data were collected from national U.S. health agencies as well as state and city public health departments. The Social Vulnerability Metric (SVM) was constructed from U.S. zip-code level measures (2018) from survey data using multidimensional Item Response Theory and validated using outcomes including all-cause mortality (2016), COVID-19 vaccination (2021), and emergency department visits for asthma (2018). The SVM was also compared with the existing Centers for Disease Control and Prevention's Social Vulnerability Index (SVI) to determine convergent validity and differential predictive validity. The data were collected directly from published files available to the public online from national U.S. health agencies as well as state and city public health departments. The correlation between SVM scores and national age-adjusted county all-cause mortality was r = 0.68. This correlation demonstrated the SVM's robust validity and outperformed the SVI with an almost four-fold increase in explained variance (46% vs. 12%). The SVM was also highly correlated (r ≥ 0.60) to zip-code level health outcomes for the state of California and city of Chicago. The SVM offers a measurement tool improving upon the performance of existing SDoH composite measures and has broad applicability to public health that may help in directing future policies and interventions. The SVM provides a single measure of SDoH that better quantifies associations with health outcomes.


Primary neuroblastoma of the maxillary sinus.
Although neuroblastoma is the most common of extracranial solid tumors of childhood and infancy, we report the first case of an isolated neuroblastoma of a paranasal sinus. A 15-year-old girl with a right maxillary sinus mass was asymptomatic except for persistent epiphora. Computed tomography and magnetic resonance imaging scans showed that the mass extended into the nasal cavity, encroached on the lamina papyracea, and obstructed the nasofrontal duct. An extensive workup revealed no evidence of systemic disease. The patient underwent right craniofacial resection. Immunohistochemistry and electronmicroscopic findings were consistent with conventional neuroblastoma. Fluorescence in situ hybridization analysis was performed with probes selected to demonstrate genetic alterations associated with neuroblastoma. Studies revealed deletion of chromosome arm 1p, gain of chromosome 17, and normal N-myc gene copy number. In summary, the tumor exhibited morphologic features and genetic alterations more consistent with those of neuroblastoma than with those of esthesioneuroblastoma.


Investigating the relationship between satisfaction of basic psychological needs, general health, and some background variables in the Iranian older adults: a cross-sectional study.
Promoting the health and mental health (MH) of the older adults making up a large part of the world's population in the coming years can provide the necessary conditions for their health and well-being of them. This study aimed to investigate the relationship between the satisfaction of basic psychological needs (BPNs), general health (GH), and some variables in Iranian older adults. The present descriptive-correlational study was conducted on 780 older adults from Sarpol-e Zahab (Kermanshah) in 2019 including the study by multi-stage cluster random sampling. The data collection tool was BPNs satisfaction and GH questionnaire and a researcher-made questionnaire of individual and background information. Was used for data analysis using the SPSS version 16 program and descriptive statistics and tests Pearson correlation coefficient, chi-square test, independent-sample T-test, and multivariate linear regression. In the present study, participating a total of 780 older adult men aged 73.0 ± 29.32 years. There was a significant relationship between the satisfaction of BPNs and GH (p < 0.001). Also, 41% of the older adults were in poor GH and 30% were high in BPNs. Multiple logistic regression showed that the BPNs, age, income satisfaction, weather, and war zone were strong predictors of GH. the adjusted R2 value of 0.55 shows that the model described 55% of changes in the GH score. According to the findings of the study on the relationship between the satisfaction of BPNs and GH, providing insurance, social and economic support by developing health policies, creating supportive health environments, strengthening community action, and developing individual skills in the older adults can help improve their MH and that of the community.


Effects of size on predation risk, behavioural response to fish, and cost of reduced feeding in larval Ischnura verticalis (Coenagrionidae: Odonata).
We used laboratory studies to examine the role of predation risk and cost of anti-predator behaviour in determining the behavioural response of several larval instars of Ischnura verticalis to a fish predator (Lepomis gibbosus). Smaller larvae were less susceptible to fish predation than larger larvae. Smaller larvae depressed movement to a greater degree in the presence of fish than did larger larvae; large larvae were generally less active than small larvae regardless of fish presence. Reduced feeding resulted in smaller larvae suffering more in terms of reduced growth than did large larvae. In general, our results tend to support the hypothesis that individuals that suffer high costs of anti-predator behaviour but little risk of predation may only exhibit anti-predator behaviours in the presence of predators, whereas individuals with a higher risk of predation and a lower cost of anti-predator behaviour may evolve anti-predator mechanisms that are in effect even in the absence of predators.


Childbearing Decisions in Residency: A Multicenter Survey of Female Residents.
To characterize how female residents make decisions about childbearing, factors associated with the decision to delay childbearing, and satisfaction with these decisions. In 2017, the authors sent a voluntary, anonymous survey to 1,537 female residents enrolled across 78 graduate medical education programs, consisting of 25 unique specialties, at 6 U.S. academic medical centers. Survey items included personal, partner, and institutional characteristics, whether the respondent was delaying childbearing during residency, and the respondent's satisfaction with this decision. The survey response rate was 52% (n = 804). Among the 447 (56%) respondents who were married or partnered, 274 (61%) were delaying childbearing. Residents delaying childbearing were significantly more likely to be younger (P < .001), not currently a parent (P < .001), in a specialty with an uncontrollable lifestyle (P = .001), or in a large program (P = .004). Among self-reported reasons for delaying childbearing, which were not mutually exclusive, the majority cited a busy work schedule (n = 255; 93%) and desire not to extend residency training (n = 145; 53%). Many cited lack of access to childcare (n = 126; 46%), financial concerns (n = 116; 42%), fear of burdening colleagues (n = 96; 35%), and concern for pregnancy complications (n = 74; 27%). Only 38% (n = 103) of respondents delaying childbearing were satisfied with this decision, with satisfaction decreasing with increasing age. Decisions to delay childbearing are more common in certain specialties, and many residents who delay childbearing are not satisfied with that decision. These findings suggest that greater attention is needed overall, and particularly in certain specialties, to promote policies and cultures that both anticipate and normalize parenthood in residency, thus minimizing the conflict between biological and professional choices for female residents.


In Vitro Generation of Human Neutrophilic Myeloid-Derived Suppressor Cells.
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells of myeloid origin. MDSC are functionally defined by their capacity to suppress T, NK, and B cell responses and henceforth altering the disease outcome in various pathological conditions. MDSC are further subdivided into three distinct subsets: monocytic (M-) MDSC, neutrophilic or polymorphonuclear (PMN-) MDSC, and early-stage (e-) MDSC. However, since surface markers utilized to define MDSC are expressed on other myeloid cells too, it is mandatory to functionally assess the suppressive activity for characterizing these cells. Here, we provide a protocol for generation of PMN-MDSC in vitro from freshly isolated human peripheral blood mononuclear cells. These MDSC can be used further to perform functional assays to determine their immunosuppressive potential or test their activities in various biological conditions, for instance in infection and cancer.


Laparoscopic treatment of biliary hepatic cysts: short- and medium-term results.
The aim of this study was to evaluate the postoperative morbidity and, in the medium-term results, the incidence of relapses in the laparoscopic treatment of non-parasitic hepatic cysts (NPHC) and polycystic liver disease (PCLD). From 1999 to 2003, 12 patients with NPHC and 3 patients with PCLD with few large cysts in the anterior hepatic segments underwent laparoscopic fenestration and deroofing. There were no conversions and no mortality; the mean operative time was 55 min for NPHC and 120 min for PCLD. Postoperative morbidity comprised two patients with bronchopneumonic infiltrations and in one patient with PCLD ascites resolved spontaneously. All the patients experienced resolution of the symptomatology. Follow-up was carried out from 3 to 38 months (mean 18 months). There was no relapse of the disease. The preoperative selection of patients is fundamental to program the surgical treatment. Laparoscopy can be considered a safe and efficacious treatment for NPHC and PCLD.


What role can bispecific antibodies play in cancer targeting? A hypothesis.
Monoclonal antibodies (mAbs) are currently among the best remedies in the treatment of cancer disorders. Almost 12 anti-cancer therapeutic mAbs have been approved for clinical applications. Although mAbs have been found to target specific antigens, numerous impediments are emerged in cancer therapy by mAbs because of expression of a low level of the same antigens on the surface of normal cells. To exterminate tumor cells specifically, the current paper puts forward a novel strategy to target cancer cells more selectively by bispecific monoclonal antibody (bsmAb), which has an affinity against the tumor-specific antigens. Translocations in genes and chromosomes are known triggers for the development of human cancers. The mutations in gene profile could create novel tumor-specific proteins and receptors which could be detected using bsmAbs.


Effects of chronic right ventricular pressure overload on myocardial glucose and free fatty acid metabolism in the conscious rat.
The aim was to investigate the effects of chronic right ventricular pressure overload on myocardial glucose and free fatty acid metabolism in the right ventricular free wall, ventricular septum, and left ventricular free wall. Using a glucose analogue, 14C-2-deoxyglucose (14C-DG), and a fatty acid analogue, 14C-beta methylheptadecanoic acid (14C-BMHDA), quantitative autoradiography was performed in conscious rats with 4 week pulmonary artery constriction. In rats with chronic pulmonary artery constriction, right ventricular peak systolic pressure and right ventricular weight to body weight ratio increased by 88% and 127%, respectively, compared with sham operated rats (P < 0.01 for each). In the right ventricular free wall, 14C-DG deposition increased but 14C-BMHDA accumulation did not differ in the chronic pulmonary artery constricted rats compared with sham operated rats [212(SEM 27), n = 6 v 101(15) nCi.g-1, n = 4, P < 0.01, and 406(40), n = 6, v 333(48) nCi.g-1, n = 4, NS, respectively]. In sham operated rats, 14C-DG and 14C-BMHDA deposition did not differ between the ventricular septum and the left ventricular free wall. In contrast, 14C-DG and 14C-BMHDA accumulations were lower in the ventricular septum compared with the left ventricular free wall wall in chronic pulmonary artery constricted rats. Myocardial blood flow assessed by 14C-iodoantipyrine was homogeneously distributed throughout both ventricles. Chronic right ventricular pressure overload increases myocardial glucose uptake and/or its phosphorylation in the right ventricular free wall, and alters the regional profiles of substrate use in the ventricular septum and left ventricular free wall despite the homogeneous blood flow distribution. The results of the acute right ventricular pressure overload study, in which only right ventricular 14C-BMHDA deposition was increased compared with controls, suggest that the findings obtained from chronic pulmonary artery constricted rats cannot be explained by increased right ventricular pressure alone.


Clinical-radiological, histological and genetic analyses in a lung transplant recipient with Mounier-Kuhn syndrome and end-stage chronic obstructive pulmonary disease.
The Mounier-Kuhn syndrome (MKS) is a rare disease characterized by a pathological dilation of the trachea and the bronchial system. The etiology of the disorder remains elusive, but genetic alterations and degradation of elastic fibers are thought to be involved in the pathogenesis. No causative treatment is available although transplantation is an option for end-stage disease. Here, we describe a patient suffering from MKS who received a double lung transplant at our department. Since a familial clustering of MKS is discussed in the literature, we performed a chromosomal analysis and an array-comparative genomic hybridization (CGH) to search for genetic abnormalities. At the time of transplantation, we collected samples from the bronchi and performed hematoxylin and eosin (HE), Elastic von-Gieson (EVG) and immunohistochemical stains of the explanted MKS bronchus, a control bronchus and of the inflammatory infiltrates. Specimens of main bronchi from the donor lung harvested for transplant served as control. Bronchial smears were taken from both main bronchi of the recipient for microbiological cultures. No genetic alterations could be found in chromosomal analysis and in array-CGH. Histological analysis revealed a strong reduction of elastic fibers in the submucosal connective tissue and a diffuse inflammatory infiltrate, mainly comprised of CD4+ cells. In addition, immunohistochemistry showed increased matrix metalloproteinases (MMPs) protein expression of MMP-1, 2, 3 and 9. Based on our findings, we hypothesize that MKS is a chronic inflammatory disease characterized by an MMP-mediated degradation of submucosal elastic fibers.


N-methyl-D-aspartate glutamate receptor mediates spontaneous and angiotensin II-stimulated ovine fetal swallowing.
In adult rats, N-methyl-D-aspartate (NMDA) receptors have been implicated in the central control of body fluid homeostasis, as intracerebroventricular (ICV) injection of NMDA receptor antagonists suppresses stimulated drinking behavior. Fetal swallowing occurs at a significantly higher rate as compared to adult drinking, contributing to amniotic fluid volume regulation and fetal gastrointestinal development. The aim of present study was to determine the role of central NMDA receptors in the modulation of fetal swallowing activity. Eight time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and ICV catheters, electrocorticogram (ECoG), and esophageal electromyogram electrodes and studied at 130 +/- 1 days' gestation. Following an initial 2-hour baseline period (time 2 h), the NMDA receptor antagonist, dizocipline (1 mg), was injected ICV. At time 4 h, the dose of dizocipline was repeated, together with angiotensin II (AngII, 6.4 microg). Fetal swallowing was monitored for 2 hours after each injection. Four of these fetuses also received an identical control study (on an alternate day) in which dizocipline was replaced with artificial cerebrospinal fluid (aCSF). ICV dizocipline injection nearly abolished spontaneous fetal swallowing activities (0.6 +/- 0.1 to 0.2 +/- 0.1 swallows/min; P < .001). ICV AngII in the presence of dizocipline did not demonstrate a dipsogenic effect on fetal swallowing (0.1 +/- 0.1; P < .001). In the control study, ICV injection of aCSF did not change fetal swallowing activity (1.0 +/- 0.1 swallows/min), while ICV AngII resulted in a significant increase in fetal swallowing (2.0 +/- 0.1 swallows/min; P < .001). This study demonstrates that central NMDA-glutamate receptor-mediated activity contributes to the high rate of spontaneous and AngII-stimulated fetal swallowing. We speculate that reduced NMDA receptor expression within the forebrain dipsogenic neurons may account for observed differences in drinking activities between the fetus/neonate and the adult.


Cytochemistry of the acute leukaemias.
The use of the Romanowsky staining technique, Sudan Black B, the periodic acid-Schiff reaction and methods for revealing peroxidase, acid and alkaline phosphatases and butyrate, acetate or chloroacetate esterases for identifying and discriminating subvarieties of acute leukaemia at the light microscope level is reviewed and the results of their application in a recent study of the first 720 cases admitted to the Medical Research Council's 8th Acute Myeloid Leukaemia trial summarized. The distribution of varieties of acute myeloid leukaemia and the relevance of age and cytochemical findings to clinical prognosis is presented. Identification of the predominant primitive cell - myeloblast, promyelocyte, monoblast, and others - appears to have little prognostic significance. In fact, the presence of periodic acid-Schiff positive erythroblasts is a bad prognostic sign. The association of certain cytochemical findings with the 15;17 translocation and acute promyelocytic leukaemia, especially the patterns of esterase positivity in Auer rods and the Sudan Black, peroxidase, periodic acid-Schiff and esterase findings characteristic of the 8;21 translocation are illustrated. Cytochemical features helpful in distinguishing acute megakaryoblastic leukaemia, notably the periodic acid-Schiff reaction, differential esterase reactivities and 5'-nucleotidase, are discussed and illustrated. Brief reference is made to the cytochemical differentiation of lymphoblastic leukaemias. Details of a technical method for the demonstration of 5'-nucleotidase are given.


Mutations in TAP genes are common in cervical carcinomas.
To determine whether squamous cervical cancers exhibit mutations or deletions in MHC class I genes or transport-associated protein (TAP) genes. Polymerase chain reaction based protocols were used to examine HLA class I and TAP genes in a panel of cervical tumours, using DNA from corresponding blood samples as controls. SSP-PCR protocols were similarly used for examination of all TAP alleles in tumour and blood samples. In a series of cervical carcinomas, 7 of 27 (26%) exhibited mutations in HLA-A genes, while 12 of 23 (52%) exhibited mutations in TAP genes. HLA gene mutations were detected in 2 of 14 CIN2-3 lesions, and TAP gene mutations in none of 14, a frequency significantly less than observed in the cervical carcinoma samples (P<0.01). The TAP 2A/2B heterozygous genotype was observed with increased frequency in patients with cervical cancer compared to population controls (P<0.02). These data suggest that TAP genes may be relevant to evolution of cervical cancer from precursor lesions.


A systematic approach for identifying and presenting mechanistic evidence in human health assessments.
Clear documentation of literature search and presentation methodologies can improve transparency in chemical hazard assessments. We sought to improve clarity for the scientific support for cancer mechanisms of action using a systematic approach to literature retrieval, selection, and presentation of studies. The general question was "What are the mechanisms by which a chemical may cause carcinogenicity in the target tissue?". Di(2-ethylhexyl)phthalate was used as a case study chemical with a complex database of >3000 publications. Relevant mechanistic events were identified from published reviews. The PubMed search strategy included relevant synonyms and wildcards for DEHP and its metabolites, mechanistic events, and species of interest. Tiered exclusion/inclusion criteria for study pertinence were defined, and applied to the retrieved literature. Manual curation was conducted for mechanistic events with large literature databases. Literature trees documented identification and selection of the literature evidence. The selected studies were summarized in evidence tables accompanied by succinct narratives. Primary publications were deposited into the Health and Environmental Research Online (http://hero.epa.gov/) database and identified by pertinence criteria and key terms to permit organized retrieval. This approach contributes to human health assessment by effectively managing a large volume of literature, improving transparency, and facilitating subsequent synthesis of information across studies.


Metastatic renal cell carcinoma to the bladder 12 years after radical nephrectomy.
We report, herein, a case of metastatic renal cell carcinoma of the urinary bladder. A 76-year-old man presented to our hospital. He had undergone right radical nephrectomy at 64 years of age. Cystoscopy revealed a solitary, spherical tumor 1.5 cm in size protruding into the urinary bladder. Transurethral resection was performed and the pathological diagnosis of the lesion was clear cell carcinoma. The patient is alive 12 months after recurrence to the bladder, under the administration of interleukin-2.


Multiplex PCR assay for differentiation of Helicobacter felis, H. bizzozeronii, and H. salomonis.
Helicobacter felis, Helicobacter bizzozeronii, and Helicobacter salomonis are frequently found in the gastric mucous membrane of dogs and cats. These large spiral organisms are phylogenetically highly related to each other. Their fastidious nature makes it difficult to cultivate them in vitro, hampering traditional identification methods. We describe here a multiplex PCR test based on the tRNA intergenic spacers and on the urease gene, combined with capillary electrophoresis, that allows discrimination of these three species. In combination with previously described 16S ribosomal DNA-based primers specific for the nonculturable "Candidatus Helicobacter suis," our procedure was shown to be very useful in determining the species identity of "Helicobacter heilmannii"-like organisms observed in human stomachs and will facilitate research concerning their possible zoonotic importance.


Secukinumab efficacy in reducing the severity and the psychosocial impact of moderate-to-severe psoriasis as assessed by the Simplified Psoriasis Index: results from the IPSI-PSO study.
The utility of the Simplified Psoriasis Index (SPI), a recently developed multidomain tool for assessing psoriasis, was investigated in a study assessing response to secukinumab. In an open-label, multicentre study involving 17 French centres, patients with moderate-to-severe plaque psoriasis received secukinumab 300 mg subcutaneously once weekly from baseline to W4, then every 4 weeks until W48. Dermatologist-scored SPI psoriasis severity (proSPI-s) was compared with Psoriasis Area and Severity Index (PASI). Patient self-assessed severity (saSPI-s) and psychosocial impact (SPI-p) were compared with PASI and Dermatology Life Quality Index (DLQI), respectively. We included 120 patients (69.2% male; mean age 45.9 years; mean duration of psoriasis 21.6 years). Mean baseline scores were as follows: proSPI-s 24.9, saSPI-s 23.5, PASI 23.1, SPI-p 8.2 and DLQI 13.6. Severity scores achieved by 16 weeks (proSPI-s 2.3, saSPI-s 2.2 and PASI 2.2) were maintained to W52. Reductions in mean psychosocial impact scores were maintained to W52 (SPI-p and DLQI, respectively, 2.1 and 1.5 at W16; 1.5 and 1.9 at W52). Decrease of PASI scores in response to secukinumab was closely correlated with proSPI-s, supporting the latter's suitability for assessing response to therapy. Although the correlation between PASI and saSPI-s was slightly weaker, patients were able to complete a valid assessment of their psoriasis independently, and thus potentially remotely. With the added benefit of psychosocial impact assessment (SPI-p), SPI provides a valid tool enabling patients to assess their own psoriasis, remotely if necessary.


Sonographic lenticulostriate vasculopathy in infancy with tic and other neuropsychiatric disorders developed after 7 to 9 years of follow-up.
On gray-scale transfontanel sonography, the small arteries supplying the basal ganglia are indistinct from the brain parenchyma in normal infants. Bright linear 'branched candlestick' stripes in these regions, suggesting sonographic lenticulostriate vasculopathy, were reported in more than 200 infants in the English literature; including 34 our own patients. To identify its long-term outcome, a prospective study was accomplished on our 34 infants with sonographic lenticulostriate vasculopathy which included 13 cryptogenic cases and 21 with distinct etiologies. At the age of 7 to 9 years in the cryptogenic group, 7 in 13 patients developed tics, attention deficits, hyperactivity, and/or obsession/compulsion; while in the symptomatic group only 2 of 21 patients had tics. The rate of mortality (33% vs. 0%), developmental delay (24% vs. 8%), mental retardation (24% vs. 0%), and neurologic deficits (29% vs. 0%) were significantly higher in the symptomatic group than the cryptogenic group. Comparatively, the occurrence rate of attention deficit-hyperactivity disorder (10% vs. 54%), tics (10% vs. 38%), and obsessive-compulsive disorder (5% vs. 13%) were significantly lower in the symptomatic group than the cryptogenic group. The rates of these neuropsychiatric disorders were 10% in the symptomatic group and 54% in the cryptogenic group. We concluded that idiopathic sonographic lenticulostriate vasculopathy in infancy may predict development of neuropsychiatric disorders later in childhood.


Potential noradrenergic regulation of serotonergic neurons in the median raphe nucleus.
Pharmacological and morphological evidence suggests that the functional activity of serotonergic neurons may be regulated by catecholamines. We have attempted to reveal a potential pathway by which this interaction might occur. Rats received bilateral knife cut lesions of the ventral noradrenergic bundle which severed the A-1 and A-2 cell body contributions to this projection. Controls received a sham lesion into the cerebellum. Two weeks later all animals were sacrificed, and norepinephrine and serotonin levels were measured in discrete nuclei of the brain. Lesion placement was confirmed histofluorometrically. Serotonin levels in the median raphe nucleus were significantly reduced by 40%, but levels of serotonin were unaffected in the dorsal raphe nucleus and 8 serotonergic terminal regions. The lesions did not affect levels of norepinephrine in the locus coeruleus, cingulate cortex, or habenula. This study suggests that a noradrenergic projection to the median raphe nucleus from the A-1 and A-2 cell body groups may modulate serotonergic neuronal function.


Change in nickel levels in the saliva of patients with fixed orthodontic appliances.
Nickel-titanium (NiTi) alloys are used frequently in orthodontics. Nickel release thus poses a problem on account of the biological effects it may have. The aim of our paper is to evaluate levels of nickel released into saliva by fixed orthodontic appliances. To this end, we performed an in vivo study on 16 patients (eight boys, eight girls). Nickel levels in saliva were evaluated by mass spectrometry before appliance placement, just after placement, and 8 weeks after placement. Results showed a significant increase in nickel levels just after NiTi archwire insertion. However, the difference was non-significant 8 weeks later. Certain studies concur with ours, showing appreciable changes in concentration, but with no significant difference. Others, though, have shown a statistically significant difference. In conclusion, orthodontic appliances release nickel ions mainly at the start of orthodontic treatment.


The electrocardiography of AV universal DDD pacemakers.
The interpretation of DDD pacemaker electrocardiograms may be performed using basic techniques and by applying the fundamental principles of noncompetitive pulse generator sensing, timing, and pacing characteristics. Precise knowledge of individual model specifications and programmable parameters is mandatory if physicians are to avoid the consequences of misinterpretation. Manufacturers must provide adequate information regarding their DDD models, and the medical community should develop more sophisticated surveillance methods for following these pacemakers.


TonB-Dependent Receptors Affect the Spontaneous Oxytetracycline Resistance Evolution in Aeromonas hydrophila.
It is well known that most microbial populations develop their intrinsic antibiotics resistance at low concentrations in antibiotics environments, but the factors influencing spontaneous resistance are still largely unknown. In this study, Aeromonas hydrophila strains with different resistance levels to oxytetracycline (OXY) were induced by sublethal antibiotic selection pressure, and differential expression of proteins was compared among them using iTRAQ-based quantitative proteomics. Our following bioinformatic analysis showed that energy metabolism-related proteins were downregulated, while several iron-related proteins were upregulated in high OXY-resistant strains. To further investigate the role of spontaneous OXY resistance evolution, four TonB-dependent receptor-coded genes were deleted, and their OXY susceptibility capabilities and antibiotic evolutionary assays were performed, respectively. Our results showed that the deletion of these genes did not affect the susceptibility to OXY, but showed different evolution rates in the spontaneous OXY evolution compared with wild-type strain, especially for AHA_0971 and AHA_4251. Therefore, this study indicates the important role of TonB-dependent receptor proteins during the bacterial antibiotics resistance evolution and may provide a new prophylactic strategy against the development of antibiotic resistance.


Research in complex diseases.
Many diseases that have a substantial effect on health have a complex pathogenesis. Examples are atherosclerosis, diabetes mellitus, and rheumatoid arthritis. Here, we discuss a hierarchy of goals of research in complex diseases, and introduce a stepwise approach for the development of disease models, paying specific attention to the position of genetic factors and stochastic variables in these models.


Dynamic Opposition of Clustered Proteins Stabilizes Cortical Polarity in the C. elegans Zygote.
Dynamic maintenance of cell polarity is essential for development and physiology. Here we combine experiments and modeling to elucidate mechanisms that maintain cortical polarity in the C. elegans zygote. We show that polarity is dynamically stabilized by two coupled cross-inhibitory feedback loops: one involves the oligomeric scaffold PAR-3 and the kinase PAR-1, and the other involves CDC-42 and its putative GAP CHIN-1. PAR-3 and CDC-42 are both required locally to recruit PAR-6/PKC-3, which inhibits PAR-1 (shown previously) and inhibits local growth/accumulation of CHIN-1 clusters. Conversely, PAR-1 inhibits local accumulation of PAR-3 oligomers, while CHIN-1 inhibits CDC-42 (shown previously), such that either PAR-1 or CHIN-1 can prevent recruitment of PAR-6/PKC-3, but loss of both causes complete loss of polarity. Ultrasensitive dependence of CHIN-1 cluster growth on PAR-6/PKC-3 endows this core circuit with bistable dynamics, while transport of CHIN-1 clusters by cortical flow can stabilize the AP boundary against diffusive spread of PAR-6/PKC-3.


Clinical impact of first-line bevacizumab plus chemotherapy in metastatic colorectal cancer of mucinous histology: a multicenter, retrospective analysis on 685 patients.
In metastatic colorectal cancer (MCRC), mucinous histology has been associated with poor response rate and prognosis. We investigated whether bevacizumab combined with different chemotherapy regimens may have an impact on clinical outcomes of MCRC patients with mucinous histology. 685 MCRC patients were classified in mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (NMC) and were treated with first-line bevacizumab plus fluoropyrimidine (FP)-based, oxaliplatin (OXA)-based, irinotecan (IRI)-based, or FOLFOXIRI. Ninety-four (13.7%) patients had MC. With a median follow-up of 50 months, MC patients had a median overall survival (OS) of 28.2 months compared with 27.7 months for the NMC group [hazard ratio (HR) = 0.92; 95% confidence interval (CI) 0.70-1.19, P = 0.530]. The overall response rates for MC and NMC were 41.5% (95% CI 31.5-51.4) and 62.4% (95% CI 58.4-66.3), respectively (Chi-square test, P <0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, age, resection of the primary tumour, and number of metastatic sites were found to be associated with poorer OS, but not mucinous histology. Compared with NMC, MCRC patients with mucinous histology treated with bevacizumab plus chemotherapy had comparable OS despite lower overall response rate.