Isotope effect evidence for the zinc hydroxide mechanism of carbonic anhydrase catalysis.
The carbon kinetic isotope effect on the enzymatic dehydration of HCO3- ion is k12/k13 = 1.011 and is independent, within experimental error, of the addition of sucrose, substitution of D2O for H2O, and substitution of enzyme-bound Zn2+ by Co2+. These results are consistent with a ping-pong mechanism in which proton transfer between enzyme and solvent is separated from HCO3- dehydration. For the dehydration half-reaction, diffusional processes are severalfold faster than dehydration, and the rate-determining step is the dehydration itself. The intrinsic isotope effect is approximately 1.011, indicating that hydration of CO2 occurs by reaction of zinc-bound OH-, rather than zinc-bound H2O.


Docosahexaenoic acid protects from amyloid and dendritic pathology in an Alzheimer's disease mouse model.
Genetic data argues that Alzheimer's disease (AD) can be initiated by aggregates of a 42 amino acid beta amyloid peptide (Abeta42). The Abeta aggregates, notably small oligomer species, cause a cascade of events including oxidative damage, inflammation, synaptic toxicity and accumulation of intraneuronal inclusions; notably neurofibrillary tangles. Cognitive deficits are likely to begin with a failure of synaptogenesis and synaptic plasticity with dendritic spine loss and dying back of dendritic arbor. This is followed by neuron loss in key areas involved in learning and memory. Significant prevention or delay of clinical onset may be achievable by modifying environmental risk factors that impact the underlying pathogenic pathways. Because low fish intake and low blood levels of the marine lipid, docosahexaenoic acid (DHA) have been associated with increased AD risk we have tested the impact of depleting or supplementing with dietary DHA on AD pathogenesis in transgenic mice bearing a mutant human gene known to cause AD in people. We reported that even with intervention late in life dietary DHA depletion dramatically enhanced oxidative damage and the loss of dendritic markers, while DHA supplementation markedly reduced Abeta42 accumulation and oxidative damage, corrected many synaptic deficits and improved cognitive function. Loss of brain DHA was exacerbated in mice expressing the mutant human AD transgene, this is consistent with evidence for increased oxidative attack on DHA oxidation in AD. Treatment with the curry spice extract curcumin, a polyphenolic antioxidant that inhibits AP aggregation, has been strongly protective in the same mouse model. Many Western diets are typically deficient in DHA and low in polyphenolic antioxidant intake. These and other data argue that increasing dietary intake of both DHA and polyphenolic antioxidants may be useful for AD prevention.


Clinical presentation and management of hypoparathyroidism.
The clinical manifestations of hypoparathyroidism are variable and can involve almost any organ system. The main clinical features of the hypoparathyroidism are typically signs or symptoms due to neuromuscular irritability owing to low serum calcium level. In addition to hypocalcemia, hyperphosphatemia can contribute to long-term complications, including extra-skeletal calcifications. Bone turnover markers are generally decreased, and bone mass density is usually normal-increased compared to age- and gender-matched controls. It is still unclear whether or not these bone features could have an impact on the risk of fracture. Impaired renal function is a common complication described in patients treated for hypoparathyroidism. Other complications include premature cataracts, seizures, basal ganglia calcifications, and cardiac arrhythmias. Lastly, some clinical studies have also reported a reduced quality of life of patients with hypoparathyroidism. Increased awareness of the clinical manifestations of this disease is important to improve its clinical management.


Interpretation and clinical significance of small monoclonal peaks in capillary electrophoresis.
Although the testing mechanism and interpretation criteria for capillary electrophoresis differ from those for gel-based electrophoresis, there are not that many reports on the efficacy of capillary electrophoresis. We performed a retrospective analysis, using the Laboratory Information System (LIS) to review a total of 163 capillary electrophoresis results from 117 different patients treated in our hospital between March and August 2012. Capillary electrophoresis was performed on capillary2 (Sebia, Lysse, France). Among the patients' group, 4 patients presented very small M-peaks in capillary electrophoresis. By using the zoom function in capillary electrophoresis, two of them were confirmed to have monoclonality, but the remaining two required reconfirmation in gel electrophoresis, leading to confirmation of a discrete monoclonal band. In this study, we found that small peaks in capillary electrophoresis accompanying a skewed K/L ratio deserve particular attention as they can grow into larger peaks within a few months. We suggest that any trivial M-peak in capillary electrophoresis should not be overlooked and that a combination of platform tests such as gel electrophoresis or FLC assay be implemented in order to confirm monoclonality.


Translation initiation in Escherichia coli: old and new questions.
We discuss the features of Escherichia coli mRNAs which determine where and how efficiently translation is initiated. We have shown that DNA fragments comprising 60-80 nucleotides that bracket the initiation codon of real genes generally promote translation when inserted within a foreign mRNA, while those not corresponding to an authentic gene start do not do so even if they include a Shine-Dalgarno-like element followed by AUG or GUG. Therefore, the information that pinpoints the correct start sites, while extending beyond the mere presence of these elements, remains essentially local. The possible nature of this information is discussed. Next, we point out that, in order to remain accessible, translational starts must escape long-range base-pairing within large mRNAs, and we argue that the tight coupling between translation and transcription plays an important role in achieving this. Finally, we discuss two intriguing situations in which the initiation frequency should be dependent upon the rate of translation elongation.


Insect P450 inhibitors and insecticides: challenges and opportunities.
P450 enzymes are encoded by a large number of genes in insects, often over a hundred. They play important roles in insecticide metabolism and resistance, and growing numbers of P450 enzymes are now known to catalyse important physiological reactions, such as hormone metabolism or cuticular hydrocarbon synthesis. Ways to inhibit P450 enzymes specifically or less specifically are well understood, as P450 inhibitors are found as drugs, as fungicides, as plant growth regulators and as insecticide synergists. Yet there are no P450 inhibitors as insecticides on the market. As new modes of action are constantly needed to support insecticide resistance management, P450 inhibitors should be considered because of their high potential for insect selectivity, their well-known mechanisms of action and the increasing ease of rational design and testing.


Effectiveness and Cost-benefit Evaluation of a Comprehensive Workers' Health Surveillance Program for Sustainable Employability of Meat Processing Workers.
Objective To evaluate the effectiveness of a comprehensive workers' health surveillance (WHS) program on aspects of sustainable employability and cost-benefit. Methods A cluster randomized stepped wedge trial was performed in a Dutch meat processing company from february 2012 until march 2015. In total 305 workers participated in the trial. Outcomes were retrieved during a WHS program, by multiple questionnaires, and from company registries. Primary outcomes were sickness absence, work ability, and productivity. Secondary outcomes were health, vitality, and psychosocial workload. Data were analyzed with linear and logistic multilevel models. Cost-benefit analyses from the employer's perspective were performed as well. Results Primary outcomes sickness absence (OR = 1.40), work ability (B = -0.63) and productivity (OR = 0.71) were better in the control condition. Secondary outcomes did not or minimally differ between conditions. Of the 12 secondary outcomes, the only outcome that scored better in the experimental condition was meaning of work (B = 0.18). Controlling for confounders did not or minimally change the results. However, our stepped wedge design did not enable adjustment for confounding in the last two periods of the trial. The WHS program resulted in higher costs for the employer on the short and middle term. Conclusions Primary outcomes did not improve after program implementation and secondary outcomes remained equal after implementation. The program was not cost-beneficial after 1-3 year follow-up. Main limitation that may have contributed to absence of positive effects may be program failure, because interventions were not deployed as intended.


Whole Liver Palliative Radiotherapy for Patients with Massive Liver Metastases.
The purpose of this retrospectively study was to examine the effectiveness and tolerability of a radiotherapy technique for the palliation of symptomatic liver metastases. Twenty-seven patients with liver metastases were enrolled and received targeted whole liver irradiation consisting of mean 1, 8 Gy in five to twelve fractions to a total mean dose 17 Gy. Symptoms at baseline were hepatic pain (26 patients), lost of weight (6), lack of appetite (2), and night sweats (1). Seventeen patients (63%) had failed previous treatment with chemotherapy and/or high-dose steroids. Individual symptom response rates were 100% at 4 weeks. Partial or complete global symptomatic responses were noted in 11 patients (40%) after 2 months. After 3 months, 8 patients (28%) reported loss of pain. The treatment was well tolerated with one patient (3%) experiencing grade 3 toxicity (one vomiting and one diarrhoea). Overall the median survival time was 4.9 months (range 1-14 months). One year survival was 39%. This is simple and well-tolerated treatment but to achieve good palliation effects we should carefully selected patients whose conventional treatment does not bring good analgesic control.


Continuity and change in children's social maladjustment: a developmental behavior genetic study.
Two developmental models were used to study genetic and environmental mechanisms underlying continuity and change in children's maladjustment. The transmission model assumed that successive levels of functioning were causally linked and that earlier experiences or prior genetic influences affected later maladjustment. The liability model related continuity in problem behavior to stable underlying environmental or genetic factors. The analyses pertained on average to 436 pairs of full siblings, 119 pairs of half siblings, and 122 pairs of cousins for whom maternal ratings of problem behaviors were available at ages 4-6, 6-8, and 8-10. Nonshared environmental influences appeared to be most important for changes in children's problem behaviors and did not have significant effects on age-to-age continuity. To represent the genetic and shared environmental mechanisms underlying stability in problem behavior, the authors preffered liability models without time specific effects.


Neospora caninum detected in feral rodents.
The role of rodents in the epidemiology of neosporosis was investigated by assaying brain tissue of feral mice (Mus musculus) and rats (Rattus norvegicus) for Neospora caninum. Both mouse and rat brain tissue were extracted for total DNA, and subjected to two different N. caninum-specific nested polymerase chain reaction (PCR) assays. A portion of brain tissue from the mice and rats were also assayed for N. caninum in gerbils or gamma-interferon gene knockout (KO) mice. Of the 105 feral mice tested, 10% were positive in the N. caninum-specific PCR assays. Of the 242 rats tested, 30% were positive in both assays. Although mice and rats had N. caninum by PCR testing, clinical signs of N. caninum infection were not observed nor were N. caninum parasites observed in gerbils or KO mice inoculated with the rodent brain tissue.


HDAC10 Is Positively Associated With PD-L1 Expression and Poor Prognosis in Patients With NSCLC.
Currently, non-small cell lung carcinoma (NSCLC) is a major worldwide health problem. Meanwhile accumulating evidence indicates that histone deacetylase (HDAC) activation could induce PD-L1 expression in various types of cancer, especially in myeloma and B-cell lymphomas. Therefore, we hypothesized that high-level expression of HDAC10 is associated with PD-L1 induction and poor prognosis in patients with NSCLC. In total 180 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection were enrolled from April 2004 to August 2009. The patients with integrated clinicopathological records were followed up. The expression level of HDAC10 and PD-L1 in tissue samples was determined by immunohistochemistry. We observed that HDAC10 expression in lung cancer tissue is significantly higher than that in corresponding para-cancer tissue. Moreover, HDAC10 expression positively correlated with the expression level of PD-L1 (r = 0.213, P < 0.05) in NSCLC patients. Subgroup, multivariate analysis showed that the expression level of HDAC10 can be an independent prognostic factor and high-level expression of HDAC10 indicated poor overall survival for pulmonary carcinoma (r = 0.540, P < 0.001). Our findings suggest that the expression level of HDAC10 is positively associated with PD-L1 expression and may predict the outcome of patients with NSCLC.


When to apply immune checkpoint inhibitor in patients with refractory advanced gastric cancer.
Background: Immune checkpoint inhibitors (ICIs) show clinical benefit in patients with refractory advanced gastric cancer (GC). The ICIs in routine clinical practice have been used in various treatment lines. Therefore, we investigated the timing for application of ICI in patients with refractory advanced GC. Methods: We analyzed 187 patients with refractory advanced or recurrent GC who received ICIS as a 3rd- or 4th-line treatment between September 2015 and October 2020. Clinical outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were evaluated. Results: Among 187 patients, 105 received ICIs as a 3rd-line treatment and 82 as a 4th line. The ORR for ICIs was 10.5% (11/105) in 3rd line and 8.5% (7/82) in 4th line. The DCR for ICIs was 36.2% (38/105) in 3rd-line treatment and 31.7% (26/82) in 4th line. There was no significant difference for ORR (P = 0.819) or DCR (P = 0.870). The median PFS and OS to ICIs was 1.4 months (95% CI, 1.1 to 1.8 months) and 4.4 months (95% CI, 1.6 to 7.2 months) in 3rd line and 1.8 months (95% CI, 1.4 to 2.3 months) and 2.8 months (95% CI, 2.2 to 3.4 months) in 4th line. The median PFS and OS to ICIs was not different between 3rd line and 4th line (P = 0.495 and P=0.208, respectively). There were also no significant difference for PFS and OS between PD-L1-positive tumors (CPS≥1) and PD-L1-negative tumors (P = 0.910 and P=0.931, respectively). Conclusions: ICIs showed similar clinical benefits in the 3rd-line and 4th-line settings. ICIs might be a reasonable approach for patients with refractory GC in the setting of 3rd-line or 4th-line treatment options.


Management of stage III colon cancer in the elderly: Practice patterns and outcomes in the general population.
Clinical trials have established surgical resection and adjuvant chemotherapy (ACT) as the standard management for stage III colon cancer; however, the extent to which these results apply to elderly patients in routine practice is unclear. This article describes the management and outcomes of elderly patients with stage III colon cancer. All cases of surgically resected colon cancer from 2002 to 2008 were identified with the population-based Ontario Cancer Registry. Pathology reports were obtained for a random sample (25% of all cases); those with stage III disease constituted the study population. The utilization of ACT, cancer-specific survival (CSS), and overall survival (OS) in elderly patients (≥70 years) and nonelderly patients (<70 years) were compared. The study population included 2920 patients, and 1521 (52%) were elderly. The 30- and 90-day mortality rates increased with advanced age: <70 years, 2% and 5%; 70 to 74 years, 3% and 7%; 75 to 79 years, 5% and 8%, and ≥80 years, 9% and 16% (P < .001). ACT was delivered to 48% of elderly patients and to 81% of younger patients (P < .001). Factors independently associated with ACT utilization among the elderly were a younger age (P < .001), male sex (P = .041), and no comorbidities (P = .001). Among elderly patients, ACT was associated with improved CSS (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.60-0.88) and OS (HR, 0.71; 95% CI, 0.60-0.83); however, the magnitude of the benefit was smaller for elderly patients than younger patients (HR for CSS, 0.53; 95% CI, 0.42-0.67; HR for OS 0.56; 95% CI, 0.45-0.69). Half of elderly patients with stage III colon cancer do not receive ACT. Although the effect size is smaller than that in younger patients, ACT is associated with improved long-term survival. Cancer 2017;123:2840-49. © 2017 American Cancer Society.


Multiple well-differentiated retroperitoneal liposarcomas with different patterns of appearance on computed tomography: A case report.
Primary retroperitoneal liposarcoma (PRPLS) is a rare soft tissue tumor with nonspecific clinical symptoms; it has different computed tomography (CT) image features according to pathological types. Some patients with a single tumor have been previously reported in the literature. We present an exceptional case of a PRPLS patient with multiple large tumors exhibiting different patterns of appearance on CT and confirmed as atypical lipomatous tumor/well-differentiated liposarcoma by postoperative pathology. A 64-year-old man presented with abdominal distension for 1 year. The patient was diagnosed with PRPLS based on physical examination, laparotomy, ultrasonography, CT scan, and surgery. Both of the tumors were completely resected through surgery and confirmed as atypical lipomatous tumor/well-differentiated liposarcoma by postoperative pathology. The postoperative course was uneventful without recurrence or metastasis, as demonstrated by abdominal-pelvic CT during an 18 mo follow-up. Multiple large Well-differentiated liposarcomas with different patterns of appearance on CT image can occur simultaneously in the same patient, to which more attention should be paid to make an effective differential diagnosis.


Bidirectional promoter of the mouse thymidylate synthase gene.
The promoter of the mouse thymidylate synthase (TS) gene lacks both a TATAA box and an initiator element and directs transcriptional initiation at multiple sites over a 90 nucleotide initiation window. Earlier studies defined an essential region near the 5' end of the initiation window that is required for promoter activity. The essential region contains possible binding sites for Sp1 and Ets transcription factors. In the present study we show that this essential region stimulates transcription with approximately equal strength in both directions. Transcription is initiated over a broad initiation window in the reverse direction. The same elements are important for the reverse promoter and for the normal TS promoter. Sequences upstream of the essential region partially suppress expression in the reverse direction. The TS 5' flanking region, in either the normal or inverted orientation, directs S phase-specific expression of a TS minigene. This raises the possibility that an upstream gene and the TS gene may be coordinately induced at the G1/S phase boundary by a common set of control elements.


Clinico-immunologic aspects of botulinum toxin type B treatment of cervical dystonia.
In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity of botulinum toxin type B (BTX-B) and correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit. Thus, the high antigenicity of BTX-B limits its long-term efficacy.


Darapladib for the treatment of cardiovascular disease.
Elevated levels of phospholipase A2 have been linked to atherosclerotic plaque progression, instability via promoting inflammation and subsequent acute coronary events. Epidemiological studies have demonstrated the correlation between elevated levels associated phospholipase A2 and cardiovascular events. Therefore, specific inhibition of lipoprotein-associated phospholipase A2 with darapladib has been tested as a therapeutic option for atherosclerosis. The aim of this profile is to review the physiologic aspects of lipoprotein-associated phospholipase A2 and to revisit the clinical evidence of darapladib as therapeutic option for atherosclerosis.


Respiratory Syncytial Virus Coinfections With Rhinovirus and Human Bocavirus in Hospitalized Children.
It is not clearly established if coinfections are more severe than single viral respiratory infections.The aim of the study was to study and to compare simple infections and viral coinfections of respiratory syncytial virus (RSV) in hospitalized children.From September 2005 to August 2013, a prospective study was conducted on children younger than 14 years of age, admitted with respiratory infection to the Pediatric Department of the Severo Ochoa Hospital, in Spain. Specimens of nasopharyngeal aspirate were taken for virological study by using polymerase chain reaction, and clinical data were recorded. Simple RSV infections were selected and compared with double infections of RSV with rhinovirus (RV) or with human bocavirus (HBoV).In this study, 2993 episodes corresponding to 2525 children were analyzed. At least 1 virus was detected in 77% (2312) of the episodes. Single infections (599 RSV, 513 RV, and 81 HBoV) were compared with 120 RSV-RV and 60 RSV-HBoV double infections. The RSV-RV coinfections had fever (63% vs 43%; P < 0.001) and hypoxia (70% vs 43%; P < 0.001) more often than RV infections. Hypoxia was similar between single or dual infections (71%). Bronchiolitis was more frequent in the RSV simple group (P < 0.001). Pediatric intensive care unit admission was more common in RSV simple or RSV-RV groups than in the RV monoinfection (P = 0.042).Hospitalization was longer for both RSV simple group and RSV-HBoV coinfection, lasting about 1 day (4.7 vs 3.8 days; P < 0.001) longer than in simple HBoV infections. There were no differences in PICU admission. RSV single group was of a younger age than the other groups.Coinfections between RSV-RV and RSV-HBoV are frequent. Overall viral coinfections do not present greater severity, but have mixed clinical features.


Is osmol gap an effective screen in accurate prediction of toxic volatiles?
A review of the literature was done to determine the number of studies published on the osmol gap. We wanted to examine whether these studies were able to establish a consensus on the formula to be used, the appropriate reference interval to be used and finally the performance of the osmol gap in its ability as a screening test for toxic volatile substance. Our study was disappointing since no published literature exists to allow the clinical laboratory to use the osmol gap based on evidenced based studies.


Utilizing shared frailty with the Cox proportional hazards regression: Post discharge survival analysis of CHF patients.
Understanding patients' survival probability as well as the factors affecting it constitute a significant concern for researchers and practitioners, in particular for patients with severe chronic illnesses such as congestive heart failure (CHF). CHF is a clinical syndrome characterized by comorbidities and adverse medical events. Risk stratification to identify patients most likely to die shortly after hospital discharge can improve the quality of care by better allocating organizational resources and personalized interventions. Probability assessment improves clinical decision-making, contributes to personalized care, and saves costs. Although one of the most informative indices is the time to an adverse event for each patient, commonly analyzed using survival analysis methods, these are often challenging to implement due to the complexity of the medical data. Numerous studies have used the Cox proportional hazards (PH) regression method to generate the survival distribution pattern and factors affecting survival. This model, although advantageous for survival analysis, assumes the homogeneity of the hazard ratio across patients and independence of the observations in terms of survival time. These assumptions are often violated in real-world data, especially when the dataset is composed of readmission data for chronically ill patients, since these recurring observations are inherently dependent. This study ran the Cox PH regression on a feature set selected by machine learning algorithms from a rich hospital dataset. The event modeled here was patient mortality within 90 days post-hospital discharge. The sample was composed of medical records of patients hospitalized in the Israeli Sheba Medical Center more than once, with CHF as the primary diagnosis. We modeled the survival of CHF patients using the Cox PH regression with and without the shared frailty correction that addresses the shortcomings of the Cox Model. The results of the two models of the Cox PH regression - with and without the shared frailty correction were compared. The results demonstrate that the shared frailty correction, which was statistically significant in our analysis, improved the performance of the basic Cox PH model. While this is the main contribution, we also show that this model outperforms two commonly used measures (ADHERE and EFFECT) for predicting early mortality of CHF patients. Thus, the results illustrate how applying advanced analytics can outperform traditional methods. An additional contribution is the feature set selected using machine-learning methods that is different from those used in the extant literature.


Incorporation of L-2,5-dihydrophenylalanine into cell proteins of Escherichia coli and sarcoma 180.
l-2,5-Dihydrophenylalanine is extensively incorporated as a phenylalanine analogue into cell proteins. Phenylalanine-requiring Escherichia coli ATCC 9723f and sarcoma 180 grow at normal rates initially with the analogue and maximally replace 65 and 33%, respectively, of phenylalanine in the peptide residues of their cell protein without death. With the analogue alone growth of E. coli becomes non-steady-state and asymptotically inhibited. In mixtures of the analogue and phenylalanine, growth eventually becomes steady state or logarithmic. The logarithmic rate is inversely proportional to the extent of incorporation of this analogue or of p-fluorophenylalanine, and the projected maximal replacement is the same as that obtained asymptotically with the analogue alone. Thus, the toxicities in steady-state and non-steady-state growth are closely related. Moreover, it is proposed that single salient protein defects may determine the extent of growth rate reduction.


Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group.
The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients. In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales. Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness. Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.


[A case of complete regression of hepatocellular carcinoma during administration of COX-2 inhibitor].
Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Inhibitors of COX-2 have proapoptotic and antiproliferative effects on malignant tumors and inhibit tumor invasion to the surrounding tissues. We report here a case of complete regression of advanced hepatocellular carcinoma (HCC) during COX-2 inhibitor administration. An eighty-year-old female was diagnosed as an advanced HCC, which was associated with HCV infection. She received COX-2 inhibitor for 3 months due to degenerative arthritis of both knees. Tumor enhancement on arterial phase CT completely disappeared without specific treatment for the HCC, and the tumor size decreased on the follow-up CT scan.


Two classes of cholesterol binding sites for the β2AR revealed by thermostability and NMR.
Cholesterol binding to G protein-coupled receptors (GPCRs) and modulation of their activities in membranes is a fundamental issue for understanding their function. Despite the identification of cholesterol binding sites in high-resolution x-ray structures of the ?2 adrenergic receptor (β2AR) and other GPCRs, the binding affinity of cholesterol for this receptor and exchange rates between the free and bound cholesterol remain unknown. In this study we report the existence of two classes of cholesterol binding sites in β2AR. By analyzing the β2AR unfolding temperature in lipidic cubic phase (LCP) as a function of cholesterol concentration we observed high-affinity cooperative binding of cholesterol with sub-nM affinity constant. In contrast, saturation transfer difference (STD) NMR experiments revealed the existence of a second class of cholesterol binding sites, in fast exchange on the STD NMR timescale. Titration of the STD signal as a function of cholesterol concentration provided a lower limit of 100 mM for their dissociation constant. However, these binding sites are specific for both cholesterol and β2AR, as shown with control experiments using ergosterol and a control membrane protein (KpOmpA). We postulate that this specificity is mediated by the high-affinity bound cholesterol molecules and propose the formation of transient cholesterol clusters around the high-affinity binding sites.


Pediatric nurses' pain management practice: barriers to change.
A qualitative, descriptive design was used to examine factors that influence pediatric nurses' pain management practices. Staff nurses from one pediatric unit (N = 16) at a community-based hospital attended from one to six discussion groups. Detailed content analysis of transcripts from each discussion group was conducted. Several themes emerged in the analysis. Some themes are based on the nurses clinical practice of pain assessment and management, while others reflect the organizational issues and changes staff experienced. Themes identified included: barriers/solutions to clinical practice change, organizational barriers to practice change, and staff commitment toward pain management. Staff attendance and commitment to participation in this research was commendable considering the external pressures they felt and expressed about job insecurity and poor unit morale. It seemed that their commitment to attend and participate was, in part, based on the value they placed upon clinical skills and knowledge. The opportunity to talk about the effects of organizational change, both individually and collectively, on their work environment was also considered beneficial.


Sex-biased transcriptomic response of the reproductive axis to stress.
Stress is a well-known cause of reproductive dysfunction in many species, including birds, rodents, and humans, though males and females may respond differently. A powerful way to investigate how stress affects reproduction is by examining its effects on a biological system essential for regulating reproduction, the hypothalamic-pituitary-gonadal (HPG) axis. Often this is done by observing how a stressor affects the amount of glucocorticoids, such as cortisol or corticosterone, circulating in the blood and their relationship with a handful of known HPG-producing reproductive hormones, like testosterone and estradiol. Until now, we have lacked a full understanding of how stress affects all genomic activity of the HPG axis and how this might differ between the sexes. We leveraged a highly replicated and sex-balanced experimental approach to test how male and female rock doves (Columba livia) respond to restraint stress at the level of their transcriptome. Females exhibit increased genomic responsiveness to stress at all levels of their HPG axis as compared to males, and these responsive genes are mostly unique to females. Reasons for this may be due to fluctuations in the female endocrine environment over the reproductive cycle and/or their evolutionary history, including parental investment and the potential for maternal effects. Direct links between genome to phenome cause and effect cannot be ascertained at this stage; however, the data we report provide a vital genomic foundation on which sex-specific reproductive dysfunction and adaptation in the face of stress can be further experimentally studied, as well as novel gene targets for genetic intervention and therapy investigations.


Functional limitation of recruitable collaterals in human subjects--ST segment deviation on intracoronary electrocardiogram during transient coronary occlusion induced by balloon inflation.
Three patients showed ST elevation on precordial electrocardiogram and ST depression on intracoronary electrocardiogram during angioplasty of the left anterior descending coronary arteries (LAD). While none of the patients had spontaneously visible collaterals, all showed transient recruitable collaterals to the LAD. No evident collaterals into the diagonal branches were observed. Possibly, if the intracoronary electrocardiogram represents the potential changes of the epicardial surface in the vicinity of the guidewire tip, then endocardial ischemia may have developed even though epicardial ischemia was not observed, due to relatively sufficient blood flow through the recruitable collaterals to the LAD. ST elevation on the precordial electrocardiogram may have represented epicardial and endocardial ischemia of the diagonal branches, where the recruitable collaterals could not protect against transmural ischemia. These phenomena suggests that the recruitable collaterals are functionally limited during acute coronary occlusion, even though the collaterals are well developed.


Radioprotective combination of α-tocopherol and ascorbic acid promotes apoptosis that is evident by release of low-molecular weight DNA fragments into circulation.
Genotoxic stresses, including irradiation, lead to the apoptosis of damaged cells and the release of DNA fragments into circulation. Both α-tocopherol acetate and ascorbic acid possess antioxidant and radioprotective properties. Interestingly, depending on a particular experimental system, the treatment with vitamins may demonstrate either apoptosis-promoting or apoptosis-suppressing effects. Adult Wistar male rats received total body irradiation with 2-100 Gy doses, while non-irradiated rats served as controls. Oral gavages with vitamins were administered either 10 min or 1 h before irradiation. Control groups were similarly treated with water. Blood samples were collected at 5 h post irradiation. The levels and the composition of circulating DNA were profiled. Chromosomal aberrations were assessed 24 h after irradiation. A substantial dose-dependent increase in circulating low-molecular weight (LMW) DNA levels was observed after whole body irradiation. An order-of-magnitude increase in the proportion of bone marrow cells with chromosomal abnormalities was observed after irradiation at 2 Gy. Single vitamin preparations were not protective, while the combination of α-tocopherol (10 mg/kg) and ascorbic acid (20 mg/kg) displayed a protective effect evident from marked decrease in chromosomal aberrations. In animals treated with a combination of the vitamins only, substantial increases in the release of LMW DNA were observed. Radioprotective combination of α-tocopherol and ascorbic acid promotes apoptosis that is evident by release of low-molecular weight DNA into circulation. We hypothesize that the pretreatment with vitamins provides radioprotection, at least in part, by aiding non-inflammatory, apoptotic elimination of most damaged cells. The microevolutionary nature of observed adaptive response provides mechanistic foundation for the phenomenon of hormesis.


The potential of native species as bioenergy crops on trace-element contaminated Mediterranean lands.
The establishment of energy crops could be an option for the management of degraded and contaminated lands, where they would not compete with food production for land use. Here, we aimed to explore the potential of certain native Mediterranean species for the revegetation of contaminated lands for energy production purposes. A field survey was conducted in a trace-element (TE) contaminated area from SW Spain, where the patterns of biomass production, TE accumulation and the calorific value of some thistle species were analyzed along a soil contamination gradient. In a greenhouse experiment the response of two thistle species (Cynara cardunculus and Silybum marianum) and the shrub Dittrichia viscosa to soil contamination was assessed, as well as the effects of these species on some soil microbial parameters involved in nutrient cycling (enzyme activities and arbuscular mycorrhizal colonization in roots). Silybum marianum was able to colonize highly contaminated soils. Its aboveground biomass accumulated Cd and had a relatively high calorific value; this value was similar in biomass obtained from both heavily and moderately contaminated soils. Greenhouse experiment confirmed that S. marianum biomass production and calorific value is scarcely affected by soil contamination. In addition, some soil enzyme activities were clearly enhanced in the S. marianum rhizosphere. Dittrichia viscosa is another promising species, given its capacity to produce a high biomass with appreciable calorific value in acid contaminated soils. Germination of both species was hampered in the acid contaminated soil, and therefore soil pH correction would have to be accomplished before establishing these species on extremely acid soils. Further assessment of the risk of transfer of Cd and other TE to the food chain would be needed to confirm the suitability of these species for the revegetation of contaminated lands with energy production purposes.


Research philosophy and Socrates: rediscovering the birth of phenomenology.
Socrates can, to some extent, be credited with an original conception of what is now seen as 20th century phenomenology 'invented' by Heidegger. With phenomenology becoming more recognised as important in understanding health care and all its complexities, this article by Victoria Vivilaki and Martin Johnson provides a theoretical evaluation of some of the terminology and the underpinning philosophy used in recent phenomenological studies.


The Psychohistory of Child Maltreatment Among Antebellum Slaveholders.
Examining the inner workings of the slaveholder family, including slave caretakers, this article probes the psychodynamics of slaveholder development to assess the extent of child abuse in the Old South. Childcare was haphazard and premised on paternal absence, maternal ambivalence, and the exigencies of slave surrogacy. Corporal punishment, sanctified by southern religion, was the rule. The likelihood of slave negligence and retaliatory attacks against slaveholder children are addressed. Childrearing practices such as swaddling, aunt adoption, and maternal incest are considered, as well as the possible usage of a West African cleansing ritual. The article classifies planter families within the Ambivalent Mode of parent-child relations and suggests the restaging of childhood trauma as the underlying dynamic in the march to civil war.


Methamphetamine Causes Photoreceptor Cell Damage Through Promoting Polarization of Macrophages and Inducing Inflammatory Response.
Classically activated macrophages (M1) are proinflammatory effectors and closely related to the progression of neurotoxicity. As a powerful psychostimulant and addictive drug, methamphetamine (Meth) abuse could result in long-lasting abnormalities in retina. This study investigated the effect of Meth at nontoxic concentration on macrophage activation state and its resultant toxicity to photoreceptor cells. Results showed that cytotoxicity was caused by Meth on 661 W cells after coculturing with RAW264.7 macrophage. RAW264.7 cells tended to switch to the M1 phenotype, releasing more proinflammatory cytokines after treatment with Meth. Meth could also upregulate the M1-related gene and protein expression. Our study demonstrated that Meth promoted macrophage polarization from M0 to M1 and induced inflammatory response, providing the scientific rationale for the photoreceptor cell damage caused by the Meth abuse.


Oral acyclovir after penetrating keratoplasty for herpes simplex keratitis.
To determine the efficacy of systemic acyclovir in decreasing complications and improving the outcome of penetrating keratoplasty for herpes simplex virus (HSV) keratitis. Retrospective study of 53 primary penetrating keratoplasties for HSV keratitis at an eye hospital from January 1, 1989, through December 31, 1996. Medical records were analyzed for history of HSV keratitis, preoperative neovascularization, and disease activity. Postoperative use of acyclovir, recurrence of HSV keratitis, rejection, uveitis or edema, and graft failure were evaluated. Twenty-four patients (mean +/- SD follow-up, 44.7 +/- 32.6 months) received no acyclovir and were compared with 20 patients, (mean +/- SD follow-up, 28.8 +/- 16.7 months), who received 400 mg acyclovir twice a day for at least 1 year. No patient in the acyclovir group had a recurrence of dendritic keratitis in the first year compared with 5 (21%) of the patients who did not receive acyclovir (P = .03). No patient had graft failure in the acyclovir group compared with 4 (17%) in the group without acyclovir after 1 year of follow-up (P = .06). Postoperative systemic acyclovir therapy after penetrating keratoplasty for HSV keratitis is associated with a reduced rate of recurrent HSV dendritic keratitis and possible graft failure at 1 year of follow-up.


The development of field-based measurement methods for radioactive fallout assessment.
An overview is provided on the development of field equipment, instrument systems, and methods of analyses that were used to assess the impact of radioactive fallout from atmospheric weapons tests. Included in this review are developments in fallout collection, aerosols measurements in surface air, and high-altitude sampling with aircraft and balloons. In addition, developments in radiation measurements are covered in such areas as survey and monitoring instruments, in situ gamma-ray spectrometry, and aerial measurement systems. The history of these developments and the interplay with the general advances in the field of radiation and radioactivity metrology are highlighted. An emphasis is given as to how the modifications and improvements in the instruments and methods over time led to their adaptation to present-day applications to radiation and radioactivity measurements.


Alcohol Use Disorder and Heavy Episodic Drinking in Rural Communities in Cambodia: Risk Factors and Community-Perceived Strategies.
Alcohol misuse is increasing in Southeast Asia. We investigated the extent of and risk factors for alcohol use disorder (AUD) and heavy episodic drinking (HED) in a rural community in Cambodia. We also attempted to explore the communities' perception of alcohol misuse and elicited potential community-based strategies to address the alcohol problem. A mixed-methods study design was used, combining a cross-sectional questionnaire survey with qualitative interviews (focus group discussions and key informant interviews). AUD and HED were measured using the AUDs Identification Test Alcohol Consumption questionnaire. The prevalence of AUD and HED was high: 25% and 31%, respectively. Male sex, younger age, and increasing income were significant risk factors. The communities were well aware of the harmful effects of alcohol, expressed the importance of implementing community-based measures, and proposed various community-led solutions. Evidence-based strategies that are culturally appropriate, accepted, and driven by communities are urgently needed.


Artificial Intelligence Auxiliary Algorithm for Wushu Routine Competition Decision Based on Feature Fusion.
The developments of modern science and technology have significantly promoted the progress of sports science. Advanced technological methods have been widely used in sports training, which has not only improved the scientific level of training but also promoted the continuous growth of sports technology and competition results. Competitive Wushu routine is an important part of Chinese Wushu. The development trend of competitive Wushu routine affects the development of the whole Wushu movement. To improve the training effect of the Wushu routine using artificial intelligence, this paper employed fuzzy information processing and feature extraction technology to analyze the visual features in the process of Wushu competition. The deep neural network-based region segmentation method was employed for implicit feature extraction to examine the shape, texture, and other image features of Wushu routines and improve the recognition performance. The proposed feature extraction model achieved the highest average accuracy of 93.98% accuracy as compared to other contemporary algorithms. Finally, the model was evaluated to validate the superior performance of the proposed method in improving the decision-making ability and effective instruction ability of the martial arts routine competition.


Oxyazapeptides: synthesis, structure determination, and conformational analysis.
Herein we report the synthesis, X-ray structure determination, and conformational analysis of a novel class of heteroatom-modified peptidomimetics, which we shall call "oxyazapeptides". Substituting the typical native N-C(α) bond with an O-N(α) bond creates a completely new, previously unknown family of peptidomimetics, which are hydrolytically stable and display very interesting conformational behavior. Force field calculations revealed that the barrier to rotation around the O-N(α) bond in oxyazapeptides is five times lower than that around the N-N(α) bond in azapeptides. Also, conformational analysis supported by X-ray suggests that the oxyaza moiety can effectively induce β-turns, which can make the newly discovered oxyazapeptide scaffold a useful tool for drug discovery and for design of biologics.


Secretory lysozyme of the human middle ear mucosa: immunocytochemical localization.
Lysozyme was demonstrated by an immunocytochemical technique in the biopsied mucosa obtained from the promontory of the fifteen patients who had chronic middle ear effusions. Lysozyme was localized in the mucigen granules of the secretory cells, as well as in the specific granules of the polymorphonuclear neutrophilic leukobytes (PMN) and macrophages. The specimens obtained from patients with mucous effusion showed numerous secretory cells that contained lysozyme, in sharp contrast to the serous type in which only a few secretory cells could be found. The present morphological finding was in agreement with the biochemical finding which demonstrated higher lysozyme level in mucous effusions than that of the serous type. It was concluded that human middle ear mucosa provided lysozyme and that its secretion was active in serous otitis media, particularly of mucoid type.


THE DISTRIBUTION AMONG POPULATIONS IN PHENOTYPIC VARIANCE WITH INBREEDING.
The effects of inbreeding on the phenotypic variance within populations were measured in a set of 30 bottlenecked lines derived from a single source population of Drosophila melanogaster. Inbred lines had significant variance among lines in the amount of phenotypic variance within lines, for thorax length, and sternopleural bristle scores. When significance levels were corrected on an experimentwide basis, no line had significant increases in phenotypic variance for sternopleural bristle counts, although two lines had significant increases in thorax length variance. These results demonstrate that inbred lines cannot be treated as necessarily more uniform than outbred lines and that results on changes in variance due to inbreeding should be treated with caution unless there has been sufficient replication. These results also demonstrate the validity of an important assumption of models of evolution by variance-mediated mechanisms, such as the variance-induced peak-shift model.


Minocycline Loaded Hybrid Composites Nanoparticles for Mesenchymal Stem Cells Differentiation into Osteogenesis.
Bone transplants are used to treat fractures and increase new tissue development in bone tissue engineering. Grafting of massive implantations showing slow curing rate and results in cell death for poor vascularization. The potentials of biocomposite scaffolds to mimic extracellular matrix (ECM) and including new biomaterials could produce a better substitute for new bone tissue formation. A purpose of this study is to analyze polycaprolactone/silk fibroin/hyaluronic acid/minocycline hydrochloride (PCL/SF/HA/MH) nanoparticles initiate human mesenchymal stem cells (MSCs) proliferation and differentiation into osteogenesis. Electrospraying technique was used to develop PCL, PCL/SF, PCL/SF/HA and PCL/SF/HA/MH hybrid biocomposite nanoparticles and characterization was analyzed by field emission scanning electron microscope (FESEM), contact angle and Fourier transform infrared spectroscopy (FT-IR). The obtained results proved that the particle diameter and water contact angle obtained around 0.54 ± 0.12 to 3.2 ± 0.18 µm and 43.93 ± 10.8° to 133.1 ± 12.4° respectively. The cell proliferation and cell-nanoparticle interactions analyzed using (3-(4,5-dimethyl thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt) MTS assay (Promega, Madison, WI, USA), FESEM for cell morphology and 5-Chloromethylfluorescein diacetate (CMFDA) dye for imaging live cells. Osteogenic differentiation was proved by expression of osteocalcin, alkaline phosphatase activity (ALP) and mineralization was confirmed by using alizarin red (ARS). The quantity of cells was considerably increased in PCL/SF/HA/MH nanoparticles when compare to all other biocomposite nanoparticles and the cell interaction was observed more on PCL/SF/HA/MH nanoparticles. The electrosprayed PCL/SF/HA/MH biocomposite nanoparticle significantly initiated increased cell proliferation, osteogenic differentiation and mineralization, which provide huge potential for bone tissue engineering.


The Odyssey of Dental Anxiety: From Prehistory to the Present. A Narrative Review.
Dental anxiety (DA) can be considered as a universal phenomenon with a high prevalence worldwide; DA and pain are also the main causes for medical emergencies in the dental office, so their prevention is an essential part of patient safety and overall quality of care. Being DA and its consequences closely related to the fight-or-flight reaction, it seems reasonable to argue that the odyssey of DA began way back in the distant past, and has since probably evolved in parallel with the development of fight-or-flight reactions, implicit memory and knowledge, and ultimately consciousness. Basic emotions are related to survival functions in an inseparable psychosomatic unity that enable an immediate response to critical situations rather than generating knowledge, which is why many anxious patients are unaware of the cause of their anxiety. Archeological findings suggest that humans have been surprisingly skillful and knowledgeable since prehistory. Neanderthals used medicinal plants; and relics of dental tools bear witness to a kind of Neolithic proto-dentistry. In the two millennia BC, Egyptian and Greek physicians used both plants (such as papaver somniferum) and incubation (a forerunner of modern hypnosis, e.g., in the sleep temples dedicated to Asclepius) in the attempt to provide some form of therapy and painless surgery, whereas modern scientific medicine strongly understated the role of subjectivity and mind-body approaches until recently. DA has a wide range of causes and its management is far from being a matter of identifying the ideal sedative drug. A patient's proper management must include assessing his/her dental anxiety, ensuring good communications, and providing information (iatrosedation), effective local anesthesia, hypnosis, and/or a wise use of sedative drugs where necessary. Any weak link in this chain can cause avoidable suffering, mistrust, and emergencies, as well as having lifelong psychological consequences. Iatrosedation and hypnosis are no less relevant than drugs and should be considered as primary tools for the management of DA. Unlike pharmacological sedation, they allow to help patients cope with the dental procedure and also overcome their anxiety: achieving the latter may enable them to face future dental care autonomously, whereas pharmacological sedation can only afford a transient respite.


Intraoperative ultrasonography of the pancreas: techniques and clinical applications.
Intraoperative ultrasound of the pancreas is a dynamic clinical diagnostic field providing crucial information to the surgeon at the time of exploration, and impacting on clinical management decisions and choices of surgical techniques. It is a rapid and effective technique for imaging the entire pancreas, differentiating normal from pathological processes, imaging the pancreatic and common bile ducts, and demonstrating the exact relationship between pathological processes of the pancreas and the adjacent arterial and venous structures, the common bile duct, and the duodenal wall. The demand for intraoperative ultrasound (IOUS) of the pancreas is expected to increase, particularly as management algorithms become accepted clinical practice, due to advances in intraoperative tumor ablation and radiotherapeutic techniques, as well as technical improvements in laparoscopic ultrasound methods and instrumentation. Not only is IOUS of the pancreas becoming a recognized modality for visualizing and characterizing solid and cystic lesions of the pancreas, but it also has superior lesion detection rates over other non-invasive preoperative imaging modalities. Provisional studies from our department suggest that data from IOUS significantly affects surgical decision making.


8-Hydroxylation of guanine bases in kidney and liver DNA of hamsters treated with estradiol: role of free radicals in estrogen-induced carcinogenesis.
The chronic administration of estradiol induces a high incidence (80-100%) of renal tumors in male Syrian hamsters. As part of our examination of a mechanism of carcinogenesis by free radicals generated during redox cycling of catecholestrogen metabolites, we assayed levels of 8-hydroxy-2'-deoxyguanosine (8-OHdGua), a marker product of hydroxy radical interaction with DNA, in livers and kidneys of hamsters treated with estradiol. Injections of 50 and 100 mg/kg estradiol doubled renal 8-OHdGua levels over controls [10.0 +/- 0.1 (SD) and 5.4 +/- 0.4 8-OHdGua/10(5) dGua, respectively] and raised hepatic 8-OHdGua levels almost 4-fold over control values, respectively. These changes were observed in kidney 4 h and in liver 1 or 2 h after treatment of hamsters with estradiol. Estradiol implants administered to hamsters for 3 days raised renal levels of 8-OHdGua by 50% over control values. Six days after 17 beta-estradiol implantation, 8-OHdGua levels returned to near-normal values. Liver DNA was not affected by estradiol implants. These data support a mechanism of estrogen-induced carcinogenesis by free radicals generated via redox cycling of catecholestrogen metabolites.


Fernblock® Upregulates NRF2 Antioxidant Pathway and Protects Keratinocytes from PM2.5-Induced Xenotoxic Stress.
Humans in modern industrial and postindustrial societies face sustained challenges from environmental pollutants, which can trigger tissue damage from xenotoxic stress through different mechanisms. Thus, the identification and characterization of compounds capable of conferring antioxidant effects and protection against these xenotoxins are warranted. Here, we report that the natural extract of Polypodium leucotomos named Fernblock®, known to reduce aging and oxidative stress induced by solar radiations, upregulates the NRF2 transcription factor and its downstream antioxidant targets, and this correlates with its ability to reduce inflammation, melanogenesis, and general cell damage in cultured keratinocytes upon exposure to an experimental model of fine pollutant particles (PM2.5). Our results provide evidence for a specific molecular mechanism underpinning the protective activity of Fernblock® against environmental pollutants and potentially other sources of oxidative stress and damage-induced aging.


[Evaluation of domestically made recalled nitinol alloy stent implantation for severe airway stenosis].
it is more difficult and carries more risks to place airway stent under local anaesthesia for the patient with severe airway stenosis. The technique and method of domestically made recalled nitinol alloy stent implantation for severe airway stenosis was explored and evaluated. by using bronchoscopy via larynx mask, trachea intubation, or rigid bronchoscope under general anaesthesia and mechanical ventilation, stents are placed in the airway of patients with severe airway stenosis for which had been difficult to performed under local anaesthesia. according to the various tracheobronchial lesions of patients, 42 stents were successfully placed in 40 patients, via larynx mask 23 cases, trachea intubation 11 cases, and rigid bronchoscope 6 cases under general anaesthesia and mechanical ventilation. No complications happened. The recalled nitinol alloy stents were placed in trachea 27 cases (membrane covered stent 9 cases), left primary bronchus 8 cases, right primary bronchus to medial segment 2 cases, trachea to left primary bronchus (wedge shaped stent) 5 cases respectively. The airway pressure decreased to normal level and other ventilator parameters also recovered after stents were placed. In most patients, the dyspnea index was improved immediately and the scores decreased from grades IV-V to grades 0-II, with higher scores indicating worse dyspnea. for patients with severe airway stenosis, it is safer, effective and more comfortable to place the stent via larynx mask, trachea intubation, or rigid bronchoscope under general anaesthesia and mechanical ventilation compared to local anaesthesia and is worth spread and popularization in the future.


A comprehensive multi-media program to prevent smoking among black students.
Much research has been done in developing and implementing smoking prevention programs; however, few studies have focused on urban Black populations. In November of 1989, a comprehensive prevention program was implemented to decrease the incidence of new smokers within the adolescent population in a Black community. The program combined a school-based curriculum with a comprehensive media intervention. All components of the program were financed by business leaders from the targeted community. There were two experimental conditions: one group participated in a school-based intervention and were prompted to participate in a multi-media intervention and the other group had access to the multi-media intervention; however, they were not prompted to participate. A key finding was that the rate of smoking decreased for all children involved in the intervention. The authors present a model that can be employed to prevent other high-risk behaviors within the Black population.


Molecular insight into nanoscale water films dewetting on modified silica surfaces.
In this work, molecular dynamics simulations are adopted to investigate the microscopic dewetting mechanism of nanoscale water films on methylated silica surfaces. The simulation results show that the dewetting process is divided into two stages: the appearance of dry patches and the quick contraction of the water film. First, the appearance of dry patches is due to the fluctuation in the film thickness originating from capillary wave instability. Second, for the fast contraction of water film, the unsaturated electrostatic and hydrogen bond interactions among water molecules are the driving forces, which induce the quick contraction of the water film. Finally, the effect of film thickness on water films dewetting is studied. Research results suggest that upon increasing the water film thickness from 6 to 8 Å, the final dewetting patterns experience separate droplets and striation-shaped structures, respectively. But upon further increasing the water film thickness, the water film is stable and there are no dry patches. The microscopic dewetting behaviors of water films on methylated silica surfaces discussed here are helpful in understanding many phenomena in scientific and industrial processes better.


The effect of ginseng on bile-pancreatic secretion in the rat. Increase in proteins and inhibition of total lipids and cholesterol secretion.
Ginseng is one of the most popular herbal remedies. Studies were performed in anaesthetized rats to examine the effect of ginseng on bile secretion. Male Sprague-Dawley rats were anaesthetized with intraperitoneal (i.p.) urethane (1.25 g kg(-1)) and equipped with biliary cannulas inserted into the bile duct through the sphincter of Oddi. Rats were treated with a single i.p. injection of ginseng at 25, 50 or 100 mg kg(-1) (1 ml(-1)) 30 min before bile collection; the control group received i.p. saline only at 1 ml(-1)volume. The effect of multiple doses of ginseng on bile volume and biliary composition was also studied. Ginseng was given in the higher dose of 100 mg kg(-1) (1 ml(-1), i.p.) every 12 hours for 2 days. Bile was collected in 15 min fractions for 90 min. Bile flow (bile-pancreatic juice), biliary excretion of total proteins, cholesterol and total lipids were measured. The single administration of different doses (25, 50 and 100 mg kg (-1)) of ginseng reduced basal bile secretion in a dose-dependent manner. Single-dose administration of ginseng at 100 mg kg(-1) caused 32.9% reduction in basal bile flow. Meanwhile, mean basal bile flow was reduced by 15.1% in rats treated with multiple doses of ginseng at 100 mg kg(-1) for two days. Biliary protein concentrations were significantly increased after single- or multiple-dose administration of ginseng, but protein output was only significantly increased (33%) in rats treated with ginseng (100 mg kg(-1)) twice a day for 2 days. Biliary total lipids and cholesterol concentration and outputs were significantly reduced after single or multiple administration of ginseng. In conclusion, administration of ginseng in the rat resulted in a reduction of bile flow and in bile secretion of total lipids and cholesterol, while it increased the secretion of proteins in a dose-dependent manner. The precise mechanisms underlying these effects remain to be elucidated. The findings indicate the need for clinical trials for the effect of this herb on bile composition and flow in man in view of a possible modulatory effect for the herb on gallstone formation.


Voltage-gated membrane currents in neurons involved in odor information processing in snail procerebrum.
The procerebrum (PC) of the snail brain is a critical region for odor discrimination and odor learning. The morphological organization and physiological function of the PC has been intensively investigated in several gastropod species; however, the presence and distribution of ion channels in bursting and non-bursting cells has not yet been described. Therefore, the aim of our study was to identify the different ion channels present in PC neurons. Based on whole cell patch-clamp and immunohistochemical experiments, we show that Na(+)-, Ca(2+)-, and K(+)-dependent voltage-gated channels are differentially localized and expressed in the cells of the PC. Different Na-channel subtypes are present in large (10-15 μm) and small (5-8 μm) diameter neurons, which are thought to correspond to the bursting and non-bursting cells, respectively. Here, we show that the bursting neurons possess fast sodium current (I NaT) and NaV1.9-like channels and the non-bursting neurons possess slow sodium current (I NaT) and NaV1.8-like channels in addition to the L-type Ca(-), KV4.3 (A-type K-channel) and KV2.1 channels. We suggest that the bursting and/or non-bursting character of the PC neurons is at least partly determined by the battery of ion-channels present and their cellular and subcellular compartmentalization.


Comparison of three protocols for breathing exercises during immersion in 38 degrees C water for chronic obstructive pulmonary disease.
Respiratory function test, arterial blood gas analysis, and ejection fraction were used to compare three protocols of breathing exercises during immersion in 38 degrees C water. Therapy was given for 2 mo to patients with stable chronic obstructive pulmonary disease. Protocol A consisted of a total exercise period of 20 min/wk (10 min/day, 2 days/wk) and was performed by 7 patients (5 cases of asthma and 2 cases of emphysema). Protocol B consisted of a total exercise period of 120 min/wk (20 min x 2 per day at 10:00 am and 3:00 pm, 3 days/wk) and was performed by 9 patients (6 asthmas and 3 emphysemas). Protocol C consisted of a total exercise period of 120 min/wk (20 min/day, 6 days/wk) and was performed by 8 patients (4 asthmas and 4 emphysemas). The ratio of forced expired volume in one second to forced vital capacity (FEV1.0%) was significantly increased in protocols B and C (P < 0.01). The ratio of forced vital capacity to the predicted normal value (%FVC) was not changed in any of the three protocols. A significant increase in peak flow was observed in protocols B and C (P < 0.05). The maximal expiratory flow at 25% (V25) was not changed in any of the three protocols. PaO2 was significantly increased and PacO2 was significantly decreased in protocol B (P < 0.01 and P < 0.05, respectively), whereas only PaCO2 was significantly decreased in protocol C (P < 0.05). Ejection fraction was increased in protocols B and C. These results suggest that exercise for a total period of 120 min/wk is preferable to that of 20 min/wk in COPD.


Optimizing experimental parameters for orbital mapping.
A new material characterization technique is emerging for the transmission electron microscope (TEM). Using electron energy-loss spectroscopy, real space mappings of the underlying electronic transitions in the sample, so called orbital maps, can be produced. Thus, unprecedented insight into the electronic orbitals responsible for most of the electrical, magnetic and optical properties of bulk materials can be gained. However, the incredibly demanding requirements on spatial as well as spectral resolution paired with the low signal-to-noise ratio severely limits the day-to-day use of this new technique. With the use of simulations, we strive to alleviate these challenges as much as possible by identifying optimal experimental parameters. In this manner, we investigate representative examples of a transition metal oxide, a material consisting entirely of light elements, and an interface between two different materials to find and compare acceptable ranges for sample thickness, acceleration voltage and electron dose for a scanning probe as well as for parallel illumination.


Single Site Fluorination of the GM4 Ganglioside Epitope Upregulates Oligodendrocyte Differentiation.
Relapsing multiple sclerosis is synonymous with demyelination, and thus, suppressing and or reversing this process is of paramount clinical significance. While insulating myelin sheath has a large lipid composition (ca. 70-80%), it also has a characteristically large composition of the sialosylgalactosylceramide gangliosde GM4 present. In this study, the effect of the carbohydrate epitope on oligodendrocyte differentiation is determined. While the native epitope had no impact on oligodendroglial cell viability, a single site OH → F substitution is the structural basis of a significant increase in ATP production that is optimal at 50 μg/mL. From a translational perspective, this subtle change increases the amount of MBP+ oligodendrocytes compared to the control studies and may open up novel therapeutic remyelination strategies.


Immunological protection against HPV16 E7-expressing human esophageal cancer cell challenge by a novel HPV16-E6/E7 fusion protein based-vaccine in a Hu-PBL-SCID mouse model.
Increasing evidence has suggested that infection with high-risk human papillomavirus (HPVs) is closely associated with esophageal squamous cell carcinoma (ESCC) in China. The E6 and E7 oncoproteins expressed in ESCC are considered as attractive tumor-specific antigen targets for immunotherapy. We have reported that the HPV16 mE6delta/mE7/TBhsp70delta fusion protein vaccination induced powerful anti-tumor immunity against TC-1 tumor cells in a C57BL/6 mouse model. In the present study, we further evaluate the protective efficacy of this fusion protein vaccine using an HPV E7-expressing human ESCC cell line (EC9706) and a Hu-PBL-SCID mouse model. We demonstrated that immunization with the fusion protein vaccine caused significant inhibition of tumor growth with the delay time to tumor detection (tests vs. controls, 16 d vs. 9 d, p<0.01) and much smaller tumor size (p<0.01) in vivo. The inhibitory rate was ca. 69.6%, and 25% of the fusion protein vaccinated-mice remained tumor free by the end of the experiment (42 d). Furthermore, the activated lymphocytes (CD8+) were capable of infiltrating into the tumor site, and much more apoptotic cells along with activation of caspase-3 were observed in the tumors from vaccinated-mice. Also, high expression levels of human IFN-gamma, TNF-alpha, granzyme B and perforin were detected in the tumors from vaccinated-mice. Therefore, we concluded that the HPV16 mE6delta/mE7/TBhsp70delta fusion protein vaccine is able to stimulate cellular-mediated immune response against E7-containing ESCC cells through CD8+-dependent CTL-induced apoptosis in Hu-PBL-SCID mice. These findings provide a scientific basis for HPV E7-expressing ESCC active immunotherapy.


High expression of PINK1 promotes proliferation and chemoresistance of NSCLC.
PTEN-induced putative kinase 1 (PINK1) was identified initially as a gene upregulated in cancer cells which regulates cellular processes of significance in cancer cell biology, including cell survival, stress resistance and the cell cycle. However, the expression and function of PINK1 in non-small cell lung cancer (NSCLC) has not been determined yet. We demonstrated high PINK1 expression in NSCLC tumor tissues and cell lines as assessed by western blot and immunohistochemistry (IHC) assays. In addition, IHC analysis revealed that PINK1 expression was associated with a more invasive tumor phenotype and poor prognosis. Furthermore, in vitro studies using upregulation and knockdown of PINK1 confirmed that PINK1 promoted cell proliferation of NSCLC, which might be through as the NF-κB pathway. Moreover, we also demonstrated that downregulation of PINK1 enhanced cisplatin (CDDP)-induced NSCLC cell apoptosis. Together, our findings indicate that PINK1 plays a significant role in NSCLC progression and chemoresistance, and highlights its potential role as a target in future anticancer therapies.


Study of radial potential fluctuations by using a gold neutral beam probe system.
A study of fluctuation is one of the main issues in fusion plasma researches. The potential and its fluctuation are measured by a gold neutral beam probe (GNBP) in the tandem mirror GAMMA10. Since there is no stable isotope ((197)Au approximately 100%), there are little measurement errors. GNBP system can measure the potential with about +/-30 V of error. The time and spatial resolutions are estimated to be about 3 micros and 5 mm, respectively. During the formation of axial confining potentials, the radial profiles of the potential and its fluctuation were successfully measured in GAMMA10. GNBP is a useful tool for the study of radial potential fluctuation directly in plasmas.


Biological activity and toxicity of the Chinese herb Magnolia officinalis Rehder & E. Wilson (Houpo) and its constituents.
Traditional Chinese herbal drugs have been used for thousands of years in Chinese pharmacopoeia. The bark of Magnolia officinalis Rehder & E. Wilson, known under the pinyin name "Houpo", has been traditionally used in Chinese and Japanese medicines for the treatment of anxiety, asthma, depression, gastrointestinal disorders, headache, and more. Moreover, Magnolia bark extract is a major constituent of currently marketed dietary supplements and cosmetic products. Much pharmacological activity has been reported for this herb and its major compounds, notably antioxidant, anti-inflammatory, antibiotic and antispasmodic effects. However, the mechanisms underlying this have not been elucidated and only a very few clinical trials have been published. In vitro and in vivo toxicity studies have also been published and indicate some intriguing features. The present review aims to summarize the literature on M. officinalis bark composition, utilisation, pharmacology, and safety.


A Spotty Liver of Pregnancy.
Herpes simplex virus (HSV) hepatitis by definition constitutes disseminated herpes simplex infection; it is rare, with only approximately 130 cases reported in the literature. Although HSV hepatitis typically occurs in immunocompromised hosts, pregnancy-especially the third trimester, has been identified as a risk factor for its development. This is likely because of the fact that humoral and cell-mediated immunity decrease throughout pregnancy and nadir in the third trimester with decreased T-cell counts and altered B/T lymphocyte ratios. Here, we report on a patient with HSV 2 hepatitis in a previously healthy 27-year-old woman in her 23rd week of pregnancy. She initially presented with nausea, vomiting, and abdominal pain and was found to have acute hepatocellular liver injury and a systemic inflammatory response syndrome. Broad-spectrum antibiotics and acyclovir were promptly initiated. Liver biopsy, serum DNA polymerase chain reaction (PCR) as well as a labial ulcer culture and PCR were all positive for HSV 2. The patient recovered completely; however, her fetus did not survive. Review of the literature emphasizes that presentation with disseminated HSV infection typically occurs in the third trimester of pregnancy. This report emphasizes that abdominal pain combined with fever and hepatic dysfunction in pregnancy should prompt immediate consideration of the diagnosis of HSV hepatitis. Furthermore, given the high mortality rate and effective treatment, empiric treatment with acyclovir should be considered early in all potential cases.


Mixed model approach for IBD-based QTL mapping in a complex oil palm pedigree.
Elaeis guineensis is the world's leading source of vegetable oil, and the demand is still increasing. Oil palm breeding would benefit from marker-assisted selection but genetic studies are scarce and inconclusive. This study aims to identify genetic bases of oil palm production using a pedigree-based approach that is innovative in plant genetics. A quantitative trait locus (QTL) mapping approach involving two-step variance component analysis was employed using phenotypic data on 30852 palms from crosses between more than 300 genotyped parents of two heterotic groups. Genome scans were performed at parental level by modeling QTL effects as random terms in linear mixed models with identity-by-descent (IBD) kinship matrices. Eighteen QTL regions controlling production traits were identified among a large genetically diversified sample from breeding program. QTL patterns depended on the genetic origin, with only one region shared between heterotic groups. Contrasting effects of QTLs on bunch number and weights reflected the close negative correlation between the two traits. The pedigree-based approach using data from ongoing breeding programs is a powerful, relevant and economic approach to map QTLs. Genetic determinisms contributing to heterotic effects have been identified and provide valuable information for orienting oil palm breeding strategies.


Exocellular phospholipase C activity from a Propionibacterium acnes strain isolated from a periodontal pocket.
The culture supernatant of a strain of Propionibacterium acnes was investigated for its phospholipase (PL) activity. The microorganism was isolated from a periodontal pocket of a patient with periodontal disease. Supernatants from cultures of this microorganism were used as a source to obtain enzymes. Proteins from the supernatants were concentrated, and their enzymatic activity was partially purified through molecular sieving. The procedure yielded two peaks of activity. This activity was shown to hydrolyze phosphatidyl choline (PC) and phosphatidyl ethanolamine (PE) and was effective in a pH range of 5 to 9, with an optimal activity at pH 7.0. Divalent cations were not required for activity of the enzymes. Analysis of the products obtained from the hydrolysis of PC labeled in the choline, phosphoryl, or acyl moieties and PE containing labeled oleic acid indicated that the supernatants' activity was mostly phospholipase C (PL-C). Phospholipase C can act synergistically with other factors to produce tissue damage, and hence may contribute to the pathogenesis of periodontal disease.


pH Scores in Hiatal Repair with Transoral Incisionless Fundoplication.
Transoral incisionless fundoplication is an alternative to traditional laparoscopic fundoplications. Recently, hiatal hernia repair combined with transoral incisionless fundoplication has become an accepted modification of the original procedure; however, outcomes information, particularly objective pH monitoring, has been sparse. We retrospectively review the subjective and objective outcomes of transoral incisionless fundoplication combined with hiatal hernia repair. Ninety-seven consecutive patients presenting for reflux evaluation were reviewed for outcomes after evaluation and treatment. Fifty-five patients proceeded to hiatal hernia repair with transoral incisionless fundoplication. Twenty-nine patients (53%) were found to have matched preoperative and postoperative validated surveys and pH evaluations. There were no serious complications. The mean followup was 296 days (SD, 117 days). The mean Gastroesophageal Reflux Disease Health Related Quality of Life score improved from 33.7 (SD, 22.0) to 9.07 (SD, 13.95), P < .001. The mean Reflux Symptom Index score improved from 20.32 (SD, 13) to 8.07 (SD, 9.77), P < .001. The mean pH score improved from 35.3 (SD, 2.27) to 10.9 (SD, 11.5), P < .001. Twenty-two of the 29 patients were judged to have an intact hiatal repair with transoral incisionless fundoplication (76%). Of the 22 patients with an intact hiatal repair and intact fundoplication, 21 (95%) had normalized their pH exposure. In this retrospective review, hiatal hernia repair combined with transoral incisionless fundoplication significantly improved outcomes in patients with gastroesophageal reflux disease in both subjective Gastroesophageal Reflux Disease Health Related Quality of Life and Reflux Symptom Index measurements as well as in objective pH scores.


The Vision of Blindness-Sight Versus Insight: A Case Report and Literature Review of Self-enucleation (Oedipism).
Self-enucleation or "Oedipism" is a rare ophthalmic and psychiatric emergency. Given the severity of its consequences, it requires proper medical management and that clinicians understand and be aware of the psychiatric presentation. Important clinical considerations include identification of various etiologies leading to self-enucleation, awareness of possible complications, and provision of appropriate care. We present a case of bilateral self-enucleation by a young male patient in the context of his first episode of psychosis and review the literature on this clinical entity. Ocular damage interferes significantly with activities of daily living and is associated with decreased quality of life so that identifying risk factors is of major importance to prevent this dangerous behavior.


Imaging biomarkers in Parkinson's disease and Parkinsonian syndromes: current and emerging concepts.
Two centuries ago in 1817, James Parkinson provided the first medical description of Parkinson's disease, later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants (also termed, Parkinson-plus syndromes). Today, Parkinson's disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 million. Conversely, atypical parkinsonian syndromes encompass a group of relatively heterogeneous disorders that may share some clinical features with Parkinson's disease, but are uncommon distinct clinicopathological diseases. Decades of scientific advancements have vastly improved our understanding of these disorders, including improvements in in vivo imaging for biomarker identification. Multimodal imaging for the visualization of structural and functional brain changes is especially important, as it allows a 'window' into the underlying pathophysiological abnormalities. In this article, we first present an overview of the cardinal clinical and neuropathological features of, 1) synucleinopathies: Parkinson's disease and other Lewy body spectrum disorders, as well as multiple system atrophy, and 2) tauopathies: progressive supranuclear palsy, and corticobasal degeneration. A comprehensive presentation of well-established and emerging imaging biomarkers for each disorder are then discussed. Biomarkers for the following imaging modalities are reviewed: 1) structural magnetic resonance imaging (MRI) using T1, T2, and susceptibility-weighted sequences for volumetric and voxel-based morphometric analyses, as well as MRI derived visual signatures, 2) diffusion tensor MRI for the assessment of white matter tract injury and microstructural integrity, 3) proton magnetic resonance spectroscopy for quantifying proton-containing brain metabolites, 4) single photon emission computed tomography for the evaluation of nigrostriatal integrity (as assessed by presynaptic dopamine transporters and postsynaptic dopamine D2 receptors), and cerebral perfusion, 5) positron emission tomography for gauging nigrostriatal functions, glucose metabolism, amyloid and tau molecular imaging, as well as neuroinflammation, 6) myocardial scintigraphy for dysautonomia, and 7) transcranial sonography for measuring substantia nigra and lentiform nucleus echogenicity. Imaging biomarkers, using the 'multimodal approach', may aid in making early, accurate and objective diagnostic decisions, highlight neuroanatomical and pathophysiological mechanisms, as well as assist in evaluating disease progression and therapeutic responses to drugs in clinical trials.


Surgical management of multiple neuraxial ependymomas. Case report.
A case is reported of a 13-year-old girl who required four operations in 4 years for the removal of multiple spinal, supratentorial and infratentorial ependymoma seedlings, and who remains well 2 1/2 years after the last operation. The place of radiotherapy and surgery are discussed.


Cranial transillumination norms of the premature infant.
Ninety-five infants from 26 to 42 weeks of gestational age were studied with a simple standardized cerebral transillumination technique utilizing a Chun gun fitted with a clear flexible disc to establish normal measurements and to test the hypothesis that transillumination is useful in differentiating "catch-up" growth from hydrocephalus. One group of infants were measured at birth; the other group were infants grown to similar gestational age and serially measured. Data from these groups were found to be similar. Transillumination was not found to be a useful technique for separating "catch-up" growth infants from the normal population, but was found to be potentially useful in separating the normal and "catch-up" population from children with hydrocephalus or serious anatomic abnormalities of the central nervous system.


Relative and combined roles of ethanol and protein malnutrition on muscle zinc, potassium, copper, iron, and magnesium.
The aim of the present study is to analyse the relative and combined effects of ethanol and protein malnutrition on muscle zinc, copper, iron, potassium, and magnesium in ethanol-fed rats. The study was performed in 32 animals divided into four groups, fed with the Lieber-DeCarli control, 36% ethanol, 2% protein, and 36% ethanol 2% protein containing diets, respectively. Right gastrocnemius muscle was removed 2 months later, and was studied both chemically and histochemical-morphometrically. Both muscle zinc and potassium, but not copper nor iron nor magnesium, were significantly decreased in the protein-deprived, ethanol-fed animals, the main effect of these variations being attributable to ethanol rather than to protein deprivation. However, coexisting protein deprivation aggravated the decrease in both muscle zinc and potassium. Both muscle zinc and potassium were significantly related to serum albumin, weight loss, and type IIb fibre atrophy; and muscle zinc, in addition, to the decrease in type IIb fibre proportion. Therefore, a decrease in muscle content of both elements is related to histochemical-morphometrical changes observed in alcoholic myopathy. In addition, both ethanol and protein deficiency exerted independent, highly significant effects both on type IIb fibre atrophy and proportion.


Herbal medicine on the rise: the case of 'awa.
There has been increasing interest in 'awa on several levels (e.g., cultural, medicinal, economic). The present article explores the issues surrounding 'awa use, highlights existing literature, places the discussion in its proper indigenous context, and sheds light on the tensions fueled by culturally inappropriate practice. In concluding the article, recommendations within a native context are put forth in four domains: (a) education, (b) research, (c) analysis and implementation of legal protections, and (d) economic development.


Comparison of double-ended transition state search methods.
While a variety of double-ended transition state search methods have been developed, their relative performance in characterizing complex multistep pathways between structurally disparate molecular conformations remains unclear. Three such methods (doubly-nudged elastic band, a string method, and a growing string method) are compared for a series of benchmarks ranging from permutational isomerizations of the seven-atom Lennard-Jones cluster (LJ(7)) to highly cooperative LJ(38) and LJ(75) rearrangements, and the folding pathways of two peptides. A database of short paths between LJ(13) local minima is used to explore the effects of parameters and suggest reasonable default values. Each double-ended method was employed within the framework of a missing connection network flow algorithm to construct more complicated multistep pathways. We find that in our implementation none of the three methods definitively outperforms the others, and that their relative effectiveness is strongly system and parameter dependent.


Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease.
Fabry disease (FD) is a rare metabolic disorder of glycosphingolipid storage caused by mutations in the GLA gene encoding lysosomal hydrolase α-galactosidase A (α-gal A). Recently, the diagnostic procedure for FD has advanced in several ways, through the development of a specific biomarker (lyso-Gb3) and the implementation of newborn screenings, which acted as a catalyst to augment general awareness of the disease. Heterologous over-expression of α-gal A variants and subsequent in vitro measurement of enzyme activity provided molecular data to elucidate the relationship between mutation, enzyme damage, lyso-Gb3 biomarker levels, and clinical phenotype. This knowledge is the foundation for improved counseling with regard to prognosis and therapeutic decisions. Herein, we resume the approach of in vitro characterization, with a further 73 mainly novel GLA gene mutations. Patient lyso-Gb3 data were available for most of the mutations. All mutations were tested for responsiveness to pharmacological chaperone treatment and phenotypic data for 61 hemizygous male and 116 heterozygous female patients carrying a mutation associated with ≥ 20% residual activity, formerly classified as "mild" variant, were collected in order to evaluate the pathogenicity. We conclude that a mild GLA variant is typically characterized by high residual enzyme activity and normal biomarker levels. We found evidence that these variants can still be classified as a distinctive, but milder, sub-type of FD.


Genomic features and regulatory roles of intermediate-sized non-coding RNAs in Arabidopsis.
Recent advances in genome-wide techniques allowed the identification of thousands of non-coding RNAs with various sizes in eukaryotes, some of which have further been shown to serve important functions in many biological processes. However, in model plant Arabidopsis, novel intermediate-sized ncRNAs (im-ncRNAs) (50~300 nt) have very limited information. By using a modified isolation strategy combined with deep-sequencing technology, we identified 838 im-ncRNAs in Arabidopsis globally. More than half (58%) are new ncRNA species, mostly evolutionary divergent. Interestingly, annotated protein-coding genes with 5'-UTR-derived novel im-ncRNAs tend to be highly expressed. For intergenic im-ncRNAs, their average abundances were comparable to mRNAs in seedlings, but subsets exhibited significantly lower expression in senescing leaves. Further, intergenic im-ncRNAs were regulated by similar genetic and epigenetic mechanisms to those of protein-coding genes, and some showed developmentally regulated expression patterns. Large-scale reverse genetic screening showed that the down-regulation of a number of im-ncRNAs resulted in either obvious molecular changes or abnormal developmental phenotypes in vivo, indicating the functional importance of im-ncRNAs in plant growth and development. Together, our results demonstrate that novel Arabidopsis im-ncRNAs are developmentally regulated and functional components discovered in the transcriptome.


Comparative study on the microbiota of colostrum and nipple skin from lactating mothers separated from their newborn at birth in China.
Increasing studies have found breast milk (BM) contains its own microbiota. However, the route through which microbes enter the BM is still unclear. In order to verify the entero-mammary pathway of BM, we designed a rigorous study that prevented oral bacteria from contaminating the breast and nipple skin (NS) during baby nursing. Thirty-one healthy, postpartum mothers living in southern China who were immediately separated from their newborn after delivery were enrolled in this study. Using an aseptic protocol for sampling, sterile water was used to wash the NS and was then collected. Then the first drop of BM was discarded and colostrum was collected manually. Amplicon sequencing was performed targeting the V3-V4 region of the bacterial 16S rRNA gene, and the differences between the microbiota of the colostrum and NS were analyzed. Additionally, the effects of environmental factors, such as the delivery mode and intrapartum antibiotic exposure, on the diversity of the colostrum microbiota were also analyzed. We found significant differences in the α diversity and richness between the BM and NS as evidenced by richness, Chao1, and Simpson indices. There were 170 operational taxonomic units (OTUs) shared by colostrum and NS, while 111 and 87 OTUs were unique, respectively, as well as a clear distinction in OTUs was observed by unifrac binary analysis between them. Linear discriminant analysis effect size analysis found that anaerobes, such as Bifidobacterium and Pantoea at the genus level and enterobacteria including Enterobacteriaceae at the family level, were predominant in the colostrum, while the predominant bacteria on the NS were Bacteroides, Staphylococcus, and Parabacteroides at the genus level. BM is colonized by bacteria prior to baby suckling, and the diversity of the colostrum microbiota differs from that of the NS. The predominant microbiota taxa in BM indicated that they were likely to be transferred to the breast through the intestinal tract. Our study provides direct evidence for the revolutionary active migration hypothesis. Additionally, factors like intrapartum antibiotic exposure did not significantly affect the diversity of the microbiota in the BM. Therefore, it is suggested that mothers continue to provide BM for their newborns during separation.


Surgical management of paediatric cerebral cavernomas.
Over the past 15 years (1981-1995) 24 children with cerebral cavernous angiomas have been treated surgically at the Section of Pediatric Neurosurgery of the Catholic University of Rome. The most common symptoms at presentation were epilepsy (13 children) and intracranial hypertension (9 children). None of these patients had a family history of cerebro-vascular malformations. Multiple lesions were detected in two subjects. In 19 cases, radiological signs of significant acute and subacute hemorrhage were present at the radiological examinations. The supratentorial compartment was the most frequent localization of the lesions, with only four cavernomas observed in the subtentorial space. The post-surgical results were good: only nine children had a persistence of the presurgical neurological signs, although ameliorated by the treatment; no patient showed a progression of pre-operative neurological signs, neither the onset of new deficits; only one child died, but his clinical conditions were very critical before surgery. Our results suggest that the youngest children present with evidence of significant hemorrhages more frequently than their older counterpart. In our series, the removal of cavernomas allowed to control the seizure disorders in all the case, thus suggesting that in this type of malformative lesion, lesionectomy alone may be sufficient to resolve epilepsy.


Errors on the WCST correlate with language proficiency scores in Spanish-English bilingual children.
This study examined the relationship between the degree of balance in bilinguals (i.e., degree to which an individual shows equivalence in their level of mastery of two languages) and performance on executive function tests. Twenty-four "more balanced" and 16 "less balanced" Spanish-English bilingual, third- and fourth-grade children completed the Wechsler Abbreviated Scale of Intelligence, the English and Spanish Bilingual Verbal Ability Test (BVAT) (an objective measure of English and Spanish language proficiency), and executive function tests (Wisconsin Card Sorting Test [WCST] and Stroop Test). Significant correlations were found between the degree of balance and error scores on the WCST, such that participants with more similar scores on both English and Spanish BVAT (i.e., the more-balanced group) scored lower on perseveration measures of the WCST than the less-balanced group. Between-group comparisons showed significantly fewer perseverative errors and perseverative responses on the WCST in the more-balanced group compared with the less-balanced group. Stroop Test scores did not reveal group differences. These findings support previous results documenting a "bilingual advantage" on executive function tests and provide support for the hypothesis that the degree of balance moderates the relationship between bilingualism and executive functions.