Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France.
To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP. We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression. By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies. Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large-fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing).


Primary melanoma of the female genital system: a report of 10 cases and review of the literature.
Primary melanoma of the female genital system are extremely rare (2-3%). A retrospective review was undertaken of patients with primary melanoma of the female genital system treated from 1990-2003 at Rostock University Hospital, Germany. Different treatments (sentinel node biopsy, inguinofemoral lymphadenectomy, en bloc resection, adjuvant Interferon-alpha-therapy, adjuvant chemotherapy) are discussed. The complicated classification is reduced to a clinical path for daily use (UICC stage and invasion depth of Breslow, Clark's level and Chung's level). We report on 10 patients, aged 26 to 76 years, with primary melanoma of the female genital tract. Seven women developed a vulvar melanoma and one woman a malignant melanoma of the cutaneous inguinal region, while another 2 women had an unusual primary location of the malignant melanoma, the cervico-vaginal region (n=1) and the left ovary (n = 1). Initial surgical modality did not influence long-term survival, but affected disease-free survival significantly.


Genetic analysis of products of conception using a HLPA/SNP-array strategy.
Fetal chromosomal abnormalities was the most frequent cause of miscarriage, and the traditional testing method G-banded karyotyping has limitations. Then high-throughput ligation-dependent probe amplification (HLPA) and single nucleotide polymorphism array (SNP-array) were introduced for genetic analysis on products of conception (POC). HLPA and SNP-array analysis were combined. POC samples were initially tested using HLPA, followed by SNP-array analysis on samples that were found to be normal by HLPA. Of the 326 POC samples tested, the overall abnormality rate was 54.6% (178/326), including 44.8% (146/326) chromosomal abnormalities identified by HLPA and 9.8% (32/326) additional chromosomal abnormalities further detected by SNP-array. The combination of HLPA and SNP-array analysis is an efficient and cost-effective strategy for genetic analysis of POC.


Neuroendocrine response to antipsychotics: effects of drug type and gender.
To study the influences of drug type and gender on the neuroendocrine response to neuroleptic treatment, we compared the endocrine actions of two neuroleptics with different receptor affinity profiles--a substituted benzamide, amisulpride, a selective D2-like dopamine antagonist; and a thioxanthene, flupenthixol, a mixed D1/D2-like antagonist also blocking serotonin, H1, and D1 receptors--on anterior pituitary hormone secretion in schizophrenic patients (DSM-III-R). Blood was withdrawn at 15-min intervals to assess basal secretion of prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH). Four hundred micrograms of thyrotropin-releasing hormone (TRH) was injected i.v. to investigate drug effects on TRH-stimulated secretion of prolactin, TSH, and GH. Prolactin plasma levels were markedly elevated in both treatment groups. In female, but not in male patients, this elevation was significantly more pronounced under amisulpride than under flupenthixol. The prolactin response to TRH was significantly blunted by amisulpride only in male subjects. While basal TSH secretion was significantly increased by both compounds, TRH-stimulated TSH secretion was elevated only in patients treated with amisulpride. Low basal prolactin levels predicted improvement of negative symptoms in patients treated with amisulpride. Amisulpride's more pronounced endocrine effects may be a reflection of its distinguished pharmacology and pharmacokinetics.


Characterization of microRNAs during Embryonic Skeletal Muscle Development in the Shan Ma Duck.
Poultry skeletal muscle provides high quality protein for humans. Study of the genetic mechanisms during duck skeletal muscle development contribute to future duck breeding and meat production. In the current study, three breast muscle samples from Shan Ma ducks at embryonic day 13 (E13) and E19 were collected, respectively. We detected microRNA (miRNA) expression using high throughput sequencing following bioinformatic analysis. qRT-PCR validated the reliability of sequencing results. We also identified target prediction results using the luciferase reporter assay. A total of 812 known miRNAs and 279 novel miRNAs were detected in six samples; as a result, 61 up-regulated and 48 down-regulated differentially expressed miRNAs were identified between E13 and E19 (|log2 fold change| ≥ 1 and p ≤ 0.05). Enrichment analysis showed that target genes of the differentially expressed miRNAs were enriched on many muscle development-related gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, especially mitogen-activated protein kinase (MAPK) signaling pathways. An interaction network was constructed using the target genes of the differentially expressed miRNAs. These results complement the current duck miRNA database and offer several miRNA candidates for future studies of skeletal muscle development in the duck.


Pentacyclic and hexacyclic cucurbitacins from Elaeocarpuspetiolatus.
Four undescribed cucurbitacins, designated as petiolaticins A-D, and four known cucurbitacins were isolated from the bark and leaves of Elaeocarpus petiolatus (Jack) Wall. Their chemical structures were elucidated based on detailed analyses of the NMR and MS data. The absolute configuration of petiolaticin A was also determined by X-ray diffraction analysis. Petiolaticin A represents a cucurbitacin derivative incorporating a 3,4-epoxyfuranyl-bearing side chain, while petiolaticin B possesses a furopyranyl unit fused to the tetracyclic cucurbitane core structure. Petiolaticins A, B, and D were evaluated in vitro against a panel of human breast, pancreatic, and colorectal cancer cell lines. Petiolaticin A exhibited the greatest cytotoxicity against the MDA-MB-468, MDA-MB-231, MCF-7, and SW48 cell lines (IC50 7.4, 9.2, 9.3, and 4.6 μM, respectively). Additionally, petiolaticin D, 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one, and 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one 3-O-β-D-glucopyranoside were tested for their ability to inhibit cell entry of a pseudotyped virus bearing the hemagglutinin envelope protein of a highly pathogenic avian influenza virus. Petiolaticin D showed the highest inhibition (44.3%), followed by 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one (21.0%), and 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one 3-O-β-D-glucopyranoside showed limited inhibition (9.0%). These preliminary biological assays have demonstrated that petiolaticins A and D possess anticancer and antiviral properties, respectively, which warrant for further investigations.


Recognition of virally transformed cells by lymphocytes from patients with prostatic cancer.
Data presented describe the first assay using human peripheral blood lymphocytes (PBL) against two unique virally transformed cell lines in vitro. Human cells transformed by a cytomegalovirus (CMV-Mj) isolated from normal human prostate tissue were used as target cells in microcytoxicity assays with lymphocytes from 100 patients. Three target cell types were used: control human embryonic lung cells (HEL), transformed HEL cells (CMV-Mj-HEL-2), and transformed HEL cells retrieved from tumors induced in athymic nude mice (CMV-Mj-HEL-2, T-1) by injection of CMV-Mj-HEL-2 cells. PBL preparations from 84% of all patients tested significantly killed CMV-Mj-HEL-2, T-1 cells. However, only PBL from patients with prostatic carcinoma were cytotoxic for CMV-Mj-HEL-2 cells significantly more often than for control HEL. The implications of this approach are discussed.


Extramedullary hematopoiesis with multiple tumor-simulating mediastinal masses in a patient with beta-thalassemia intermedia.
A patient with beta-thalassemia intermedia with massive extramedullary hematopoiesis in the mediastinum is presented. These masses, which simulate tumors, are usually asymptomatic only rarely causing spinal cord compression. The histologic examination showed that they consist of hematopoietic tissue. The importance of correct diagnosis without surgery is stressed.


Formulating a fully converged biorefining chain with zero wastewater generation by recycling stillage liquid to dry acid pretreatment operation.
Huge wastewater generation is the major challenge of biorefinery technology for production of cellulosic ethanol. This study designed and verified a method for completely recycling of wastewater stream (the stillage liquid from the beer column) in cellulosic ethanol production by dry biorefining processing. When the stillage liquid was directly recycled to dry acid pretreatment operation, ethanol production gradually reduced after two recycles primarily because the inorganic compounds accumulated by around 139%. To ultimately solve this technical barrier, the stillage liquid was evaporated and condensed into distillated water, then recycled to the pretreatment for complete dry biorefining process. This strategy supported a stable cellulosic ethanol production, and the overall mass and heat balance confirmed that only 65% of the lignin residue consumption was used for wastewater evaporation with 35% surplus for electricity generation. This study provided a fully converged biorefining process with a closed-loop wastewater recycling.


Feeding behaviors and weight loss outcomes over 64 months.
Maintenance of reduced body weight following intentional weight loss is often unsuccessful. Identification of behaviors associated with sustained reductions should aid in dietary weight management. This survey assessed associations between an array of appetitive indices and weight loss outcomes in a sample of 80 adults participating in an open-labeled, unsupervised weight management program over a 64-month period. Participants were divided into maintainers (weight loss >5 kg at Year 1, sustained reduction >75% at Month 64), rebounders (weight loss >5 kg at Year 1, <75% reduction at Month 64), and nonresponders (weight loss <5 kg at Year 1). Nonresponders spent significantly more time shopping for food weekly, tended to have the highest total exposure time to food and to eat with fewer people than the other groups. Maintainers reported higher mean hunger over the course of a day, tended to spend more time preparing food and consumed less energy from fat and foods that they rated as predominantly bitter. Rebounders had significantly lower dietary restraint scores and tended to have less control over the purchase and preparation of foods in their diet. Individuals with different long-term weight loss outcomes possess distinct feeding-related attributes that may provide a basis for improved intervention strategies.


Antibacterial peptides from Monochamus alternatus induced oxidative stress and reproductive defects in pine wood nematode through the ERK/MAPK signaling pathway.
Pine wilt disease is a devastating disease of pine caused by the pine wood nematode (PWN) Bursaphelenchus xylophilus. Long-term use of chemical nematicides leads to the development of resistance in nematodes and harms the environment. Evaluations for green environmental protection agents, identified the antibacterial peptide, MaltDef1, from Monochamus alternatus which had nematicidal effect. We studied its nematicidal activity and action against PWN. In this study, the antibacterial peptide S-defensin was synthesized from M. alternatus. The results showed that S-defensin caused mortality to the PWN, causing shrinkage, pore, cell membrane dissolution and muscle atrophy. In addition, PWN reproduction was also affected by S-defensin; it decreased in a concentration dependent manner with increasing treatment concentration. By contrast, reactive oxygen species (ROS) in vivo increased in a concentration-dependent manner. We applied transcriptome to analyze the changes in gene expressions in S-defensin treated PWN, and found that the most significantly enriched pathway was the ERK/MAPK signaling pathway. RNAi was used to validate the functions of four differential genes (Let-23, Let-60, Mek-2 and Lin-1) in this pathway. The results showed that knockdown of these genes significantly decreased the survival rate and reproductive yield of, and also increased ROS in PWN. The antibacterial peptide S-defensin had a significant inhibitory effect on the survival and reproduction of PWN, shown by cell membrane damage and intracellular biological oxidative stress via regulating the ERK/MAPK signaling pathway. This indicates that S-defensin has a target in B. xylophilus, against which new green target pesticides can be developed.


Acute reserpine treatment induces down regulation of D-1 dopamine receptor associated adenylyl cyclase activity in rat striatum.
Behavioural studies suggest a functional interaction between D-1 and D-2 systems in normal rat striatum to alter motor behaviour and which is disrupted by dopamine depletion induced by acute reserpine treatment. Consequently, we have investigated the effect of acute reserpine treatment on the biochemical interaction between D-1 and D-2 receptors present in rat striatal slices. Twenty-four hours following the administration of reserpine (5 mg/kg i.p.), striatal dopamine content was depleted by more than 73%; the density (B(max)) of D-1 receptor sites measured by the in vitro binding of [3H]SCH 23390 to striatal membranes was increased while the binding of [3H]spiperone to D-2 receptor sites was unaltered. Reserpine treatment had no effect on the affinity (Kd) of [3H]SCH 23390 or [3H]spiperone for D-1 and D-2 sites. Basal levels of cyclic AMP accumulation in striatal slices prepared from reserpine-treated rats were lower than those observed in control slices. In striatal slices prepared from normal rats, dopamine (10-320 microM) and the D-1 agonist SKF 38393 (0.1-3.2 microM) induced concentration-dependent increases in cyclic AMP accumulation. The D-1 antagonist SCH 23390 (10 microM) abolished the accumulation of cyclic AMP produced by dopamine or SKF 38393. The D-2 antagonist (+/-)-sulpiride (50 microM) enhanced the response to dopamine (10-320 microM) while the D-2 agonist quinpirole (10 microM) abolished the response to SKF 38393 (0.1-3.2 microM). However, 24 hr after reserpine treatment the ability of dopamine (10-320 microM) and SKF 38393 (0.1-3.2 microM) to elicit an increase in cyclic AMP accumulation was markedly reduced in striatal slices. SCH 23390 (10 microM) did not enhance the trend for an increase in cyclic AMP accumulation produced by dopamine. Also, quinpirole (10 microM) did not affect the response to SKF 38393 (0.1-3.2 microM) in striatal slices from reserpine pretreated rats. The data confirm the positive linkage between D-1 receptors and adenylyl cyclase and the inhibitory coupling to D-2 sites in striatal slices from normal, rats. Acute reserpine treatment appears to cause an uncoupling of D-1 receptors associated with adenylyl cyclase.


Drones delivering automated external defibrillators-Integrating unmanned aerial systems into the chain of survival: A simulation study in rural Germany.
Community first responders (CFR) improve survival in out-of-hospital cardiac arrest (OHCA) but are often hampered by limited availability of public access defibrillation. Unmanned aerial systems (UAS) delivering automated external defibrillators (AED) directly to an OHCA site could help overcome this. We evaluated the feasibility of integrating UAS into the chain of survival in rural Northeast Germany. This simulation study explored UAS-AED delivery combined with a smartphone-based CFR dispatch. Five OHCA locations (A-E) were randomly selected. We routed a flight corridor to each of these sites from a corresponding UAS base; 50 OHCA scenarios with 10 flights per corridor were scheduled. All steps were accurately simulated, from a bystander finding the patient, making an emergency call, conducting dispatcher-assisted cardiopulmonary resuscitation, and simultaneous CFR plus UAS deployment, to the bystander and CFR interacting with UAS and AED. This process was time-tracked and video-recorded until defibrillation. We performed 46 OHCA simulations. Missions were flown autonomously but needed pilot assistance during landing. Distances (km) and average time intervals from alert to defibrillation (td in min:sec ± SD) were 0.4 (6:02 ± 0:56), 2.29 (6:53 ± 0:19), 4.0 (8:54 ± 0:25), 7.43 (14:51 ± 1:055), and 9.79 (15:51 ± 1:16) for routes A to E, respectively. All participants were able to retrieve the AED within seconds after UAS landing and interacted safely with the UAS and AED. Integrating airborne AED delivery into the chain of survival appeared feasible and safe but remains an experimental technology. Linking this with CFR potentially improves the availability of early public-access defibrillation, particularly in rural regions.


Seen as core: a Delphi consensus study of essential elements of mental health nursing care in Ireland.
Continued ambiguity about the scope of mental health nursing is harmful to the discipline's identity and to patients' interests. Using a Delphi survey design, consensus was achieved on a set of 70 items representing core elements of mental health nursing among a sample of 150 mental health nurses working in Ireland. Items achieving consensus in Round 3 of the survey were composed of 28 clinical phenomena (framed as client problems), 18 direct and 12 indirect nursing interventions, and 12 nursing-sensitive outcomes of care. Mental health nurses accepted responsibility across a broad range of outcomes apart from those linked to physical care, the one domain of care rejected by participants. The findings portray mental health nursing as a psychosocial enterprise, encompassing both phenomenological and diagnosis-related elements.


Flexible, all-organic chemiresistor for detecting chemically aggressive vapors.
Chemiresistors made of thin films of single-walled carbon nanotube (CNT) bundles on cellulosics (paper and cloth) can detect aggressive oxidizing vapors such as nitrogen dioxide and chlorine at 250 and 500 ppb, respectively, at room temperature in ambient air without the aid of a vapor concentrator. Inkjet-printed films of CNTs on 100% acid-free paper are significantly more robust than dip-coated films on plastic substrates. Performance attributes include low sensor-to-sensor variation, spontaneous signal recovery, negligible baseline drift, and the ability to bend the sensors to a crease without loss of sensor performance.


Localizing the human brain response to olfactory stimulation: A meta-analytic approach.
The human sense of smell and the ability to detect and distinguish odors allows for the extraction of valuable information from the environment, thereby driving human behavior. Not only can the sense of smell help to monitor the safety of inhaled air, but it can also help to evaluate the edibility of food. Therefore, in an effort to further our understanding of the human sense of smell, the aim of this meta-analysis was to provide the scientific community with activation probability maps of the functional anatomy of the olfactory system, in addition to separate activation maps for specific odor categories (pleasant, food, and aversive odors). The activation likelihood estimation (ALE) method was utilized to quantify all relevant and available data to perform a formal statistical analysis on the inter-study concordance of various odor categories. A total of 81 studies (108 contrasts, 1053 foci) fulfilled our inclusion criteria. Significant ALE peaks were observed in all odor categories in brain areas typically associated with the functional neuroanatomy of olfaction including the piriform cortex, amygdala, insula, and orbitofrontal cortex, amongst others. Additional contrast analyses indicate clear differences in neural activation patterns between odor categories.


Ontology integration: experience with medical terminologies.
To build a common controlled vocabulary is a formidable challenge in medical informatics. Due to vast scale and multiplicity in interpretation of medical data, it is natural to face overlapping terminologies in the process of practicing medical informatics [A. Rector, Clinical terminology: why is it so hard? Methods Inf. Med. 38 (1999) 239-252]. A major concern lies in the integration of seemingly overlapping terminologies in the medical domain and this issue has not been well addressed. In this paper, we describe a novel approach for medical ontology integration that relies on the theory of Algorithmic Semantic Refinement we previously developed. Our approach simplifies the task of matching pairs of corresponding concepts derived from a pair of ontologies, which is vital to terminology mapping. A formal theory and algorithm for our approach have been devised and the application of this method to two medical terminologies has been developed. The result of our work is an integrated medical terminology and a methodology and implementation ready to use for other ontology integration tasks.


5-HTTLPR differentially predicts brain network responses to emotional faces.
The effects of the 5-HTTLPR polymorphism on neural responses to emotionally salient faces have been studied extensively, focusing on amygdala reactivity and amygdala-prefrontal interactions. Despite compelling evidence that emotional face paradigms engage a distributed network of brain regions involved in emotion, cognitive and visual processing, less is known about 5-HTTLPR effects on broader network responses. To address this, we evaluated 5-HTTLPR differences in the whole-brain response to an emotional faces paradigm including neutral, angry and fearful faces using functional magnetic resonance imaging in 76 healthy adults. We observed robust increased response to emotional faces in the amygdala, hippocampus, caudate, fusiform gyrus, superior temporal sulcus and lateral prefrontal and occipito-parietal cortices. We observed dissociation between 5-HTTLPR groups such that LA LA individuals had increased response to only angry faces, relative to neutral ones, but S' carriers had increased activity for both angry and fearful faces relative to neutral. Additionally, the response to angry faces was significantly greater in LA LA individuals compared to S' carriers and the response to fearful faces was significantly greater in S' carriers compared to LA LA individuals. These findings provide novel evidence for emotion-specific 5-HTTLPR effects on the response of a distributed set of brain regions including areas responsive to emotionally salient stimuli and critical components of the face-processing network. These findings provide additional insight into neurobiological mechanisms through which 5-HTTLPR genotype may affect personality and related risk for neuropsychiatric illness.


N2O and CH4 fluxes from intensively managed grassland: The importance of biological and environmental drivers vs. management.
Agriculture is the main contributor to anthropogenic nitrous oxide (N2O) and methane (CH4) emissions. Therefore, mitigation options are urgently needed. In contrast to carbon dioxide, eddy covariance measurements of N2O and CH4 fluxes are still scarce, and thus little is known how environmental and biotic drivers as well as management affect the net N2O and CH4 exchange in grasslands. Thus, we investigated the most important drivers of net ecosystem N2O and CH4 fluxes in a temperate grassland, and continued a N2O mitigation experiment (increased clover proportion vs. fertilization with slurry). Random forest gap-filling models were able to capture intermittent emission peaks, performing better for half-hourly N2O than for CH4 fluxes. The unfertilized clover parcel (parcel B) continued to show lower N2O emissions (4.4 and 2.7 kg N2O-N ha-1 yr-1) compared to the fertilized parcel (parcel A; 6.9 and 5.9 kg N2O-N ha-1 yr-1) for 2019 and 2020, respectively. Tier 1 nitrogen (N) emission factors of 2.6 % and 1.9 % were observed at the fertilized parcel during the study period. Lower soil N concentrations indicated a lower N leaching risk at the clover than at the fertilized parcel. Annual CH4 emissions (including periods with sheep grazing) were similar from both parcels, and ranged from 25 to 38.5 kg CH4-C ha-1. The most important drivers of both N2O and CH4 fluxes were lagged precipitation and water filled pore space, but also management (for N2O from parcel B; CH4 from parcel A). Biotic variables such as vegetation height and leaf area index were important predictors for the N2O exchange, while grazing temporarily increased CH4 emissions. Overall, reducing N fertilization and increasing the legume proportion were effective N2O reduction measures. In particular, adjusting N fertilization to plant N demands can help to avoid high N2O emissions from grasslands.


Preliminary study on miRNA in prostate cancer.
To screen for miRNAs differentially expressed in prostate cancer and prostate hyperplasia tissues and to validate their association with prostate cancer. Patients diagnosed by pathology in the Department of Urology of the First Affiliated Hospital of Xinjiang Medical University from October 2021 to June 2022 were selected, and their general clinical information, blood samples, and prostate tissue samples were collected. miRNA microarray technology was performed to obtain differentially expressed miRNAs in prostate cancer and hyperplasia tissues, and miRNAs to be studied were screened by microarray results and review of relevant literature. The detection of miRNA expression in the patients' blood and prostate tissue samples was measured. The miRNA-222-mimics were transfected into PC3 cells, and cell biology experiments such as CCK8, scratch, Transwell, and flow cytometry were performed to detect the effects of overexpressed miRNA-222 on the growth and proliferation, invasive ability, apoptotic ability, and metastatic ability of prostate cancer cells. The results of the miRNA microarray showed that there were many differentially expressed miRNAs in prostate cancer and hyperplasia tissues, and four miRNAs, miRNA-144, miRNA-222, miRNA-1248, and miRNA-3651 were finally selected as the subjects by reviewing relevant literature. The results showed that the expression of miRNA-222 in prostate cancer tissues was lower than that in prostate hyperplasia tissues (P < 0.05). The expression of miRNA-222, miRNA-1248, and miRNA-3651 in blood samples of prostate cancer patients was lower than that in prostate hyperplasia patients (P < 0.05). The analysis results indicated that the f/t ratio and the relative expression of miRNA-222 and miRNA-1248 were independent influences of prostate cancer (P < 0.05), in which overexpression of miRNA-222 decreased the proliferative, invasive, and metastatic abilities of PC3 cells and enhanced the level of apoptosis of cancer cells. Although there was no significant change in the overall incidence of prostate cancer in this study, significant changes occurred in the incidence of prostate cancer with different characteristics. In addition, the nomogram prediction model of prostate cancer-specific survival rate constructed based on four factors has a high reference value, which helps physicians to correctly assess the patient-specific survival rate and provides a reference basis for patient diagnosis and prognosis evaluation.


A pilot study evaluating the efficacy and toxicity of biweekly gemcitabine and pegylated liposomal doxorubicin in recurrent platinum-resistant epithelial ovarian cancer.
Both gemcitabine and pegylated liposomal doxorubicin (PLD) are antineoplastic drugs with clinical activity in patients with platinum-resistant ovarian cancer. The present study was designed to assess the efficacy and safety of biweekly scheduled gemcitabine and PLD combination therapy in such patients. Eighteen women with ovarian cancer that had recurred within 6 months after standard carboplatin and paclitaxel therapy were eligible for enrollment. Gemcitabine 2000 mg/m(2) and PLD 20 mg/m(2) were administered intravenously on days 1 and 15 of a 28-day cycle. Hematological toxicity was mild. No severe (grade III/IV) leucopenia/neutropenia or thrombocytopenia was observed. Severe anemia was seen in only 3 (17%) patients. Several other severe nonhematological adverse effects were well tolerated and easily managed. The overall response rate was 28% (5 of 18; 95% confidence interval [CI], 10%-54%) with 2 (11%) complete and 3 (17%) partial responses. The median overall survival time was 17 months (range, 1 to 25 months). The median survival for patients with clinical benefit including disease response or stabilization was 17 months (range, 3 to 26 months) compared to that of patients with progressive disease, which was 2 months (range, 1 to 11 months; P = 0.04). A biweekly schedule of gemcitabine combined with PLD is an active and safe chemotherapy regimen with acceptable and easily manageable toxicities in women with recurrent platinum-resistant ovarian cancer.


Circumferential Reconstruction of Subaxial Cervical and Cervicothoracic Spine by Simultaneously Combined Anterior-posterior Approaches in the Sitting Position.
To introduce and analyze the feasibility of a new surgical strategy for circumferential reconstruction of subaxial cervical and cervicothoracic spine by simultaneously combined anterior-posterior approach in the sitting position. A retrospective review was performed for seven patients who underwent the above surgical procedure between July 2011 and January 2015. Among the seven patients, there were six men and one woman, with an average age of 52 years (range, 36-79 years). Six patients were confirmed to have a lower subaxial cervical fracture and dislocation with a locked facet joint, and the other patient had an invasive tumor involving both anterior and posterior parts of vertebrae and lamina, detected by radiological examination. The levels involved for all patients were from C4 to T2 . According to American Spinal Injury Association (ASIA) classification, one case was class A, four were class B, and two were class D. The patients were restricted in the sitting position with traction and a halo in extension to immobilize the head during the operation. The simultaneously combined anterior-posterior operation for reduction, decompression or tumor resection and circumferential reconstruction was carried out. Both anterior and posterior procedures were successfully completed simultaneously in the sitting position in all cases. There were no perioperative complications. The average operative time was 175 ± 32 min (range, 120-240 min), and the mean blood loss was 430 ± 85 mL (range, 200-1100 mL). The patients were followed up for 35.8 months (range, 18-60 months). The symptom of neck pain improved distinctly and no evidence of implant failure was noted in any patients. Neurological status improvement was confirmed in six patients, who had suffered incomplete paralysis. The ASIA grade improved in five patients, and two cases had no change in grade. The "sitting position" simultaneously combined anterior-posterior approach is safe and is superior to the traditional prone position and supine position, and the surgical results are satisfactory.


Serial ultra-deep sequencing of circulating tumor DNA reveals the clonal evolution in non-small cell lung cancer patients treated with anti-PD1 immunotherapy.
Immune-therapy with anti-PD1 inhibitors, such as pembrolizumab, is revolutionizing the treatment of non-small cell lung cancers (NSCLC). However, identifying patients for the potential therapeutic response and predicting therapy resistance and early relapse remains a challenge. Between 2016 and 2018, 60 patients were treated with pembrolizumab, among who 12 NSCLC patients had both baseline (before treatment) and serial (on treatment) periodical circulating tumor DNA (ctDNA) samples. Those samples were sequenced on a 329 pan cancer-related gene panel. Analyses of tumor burden, blood tumor mutational burden (bTMB), maximum somatic allele frequency (MSAF), and tumor clonal structure were performed in association with clinical response. Candidate resistance mutations involved in relapse and metastases were further investigated. ctDNA was detected and mutational profiling was performed for each patient. Those with a high baseline bTMB level showed significantly improved progression-free survival (PFS) after pembrolizumab treatment. Tumor burden and therapeutic response significantly correlated with the MSAF instead of the bTMB. Clone analysis detected tumor progression about 2-4 months ahead of computed tomography (CT) scan. One mutation in gene PTCH1 (Protein patched homolog 1) and two acquired anti-PD1 candidate resistance mutations of gene B2M (β2 microglobulin) were identified in association with distant metastasis. The evolutionary tree of a representative patient was also described. This pilot study showed that MSAF could be another good indicator of therapeutic response, and clonal analysis could be clinically useful in monitoring clonal dynamics and detecting remote metastasis and early relapse.


Long-term safety and efficacy of risankizumab for the treatment of moderate-to-severe plaque psoriasis: Interim analysis of the LIMMitless open-label extension trial up to 5 years of follow-up.
Psoriasis is a chronic, inflammatory skin disease often requiring long-term therapy. To evaluate the long-term safety and efficacy of risankizumab in patients with psoriasis. LIMMitless is an ongoing phase 3, open-label extension study evaluating the long-term safety and efficacy of continuous risankizumab 150 mg every 12 weeks for adults with moderate-to-severe plaque psoriasis following multiple phase 2/3 base studies. This interim analysis assessed safety (ie, monitored treatment-emergent adverse events [TEAEs]) through 304 weeks. Efficacy assessments included determining the proportion of patients who achieved ≥90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90/100), static Physician's Global Assessment of clear/almost clear (sPGA 0/1), and Dermatology Life Quality Index of no effect on patient's life (DLQI 0/1) through 256 weeks. Among 897 patients randomized to risankizumab in the base studies, 706 were still ongoing at data cutoff. Rates of TEAEs, TEAEs leading to discontinuation, and TEAEs of safety interest were low. At week 256, 85.1%/52.3% of patients achieved PASI 90/100, respectively, 85.8% achieved sPGA 0/1, and 76.4% achieved DLQI 0/1. Open-label study with no placebo or active-comparator group. Long-term continuous risankizumab treatment for up to 5 years was well tolerated and demonstrated high and durable efficacy.


Significance of basolateral domain of polarized MDCK cells for Sendai virus-induced cell fusion.
Fusion (fusion from within) of polarized MDCK monolayer cells grown on porous membranes was examined after infection with Sendai viruses. Wild-type virus, that buds at the apical membrane domain, did not induce cell fusion even when the F glycoprotein expressed at the apical domain was activated with trypsin. On the other hand, a protease activation mutant, F1-R, with F protein in the activated form and that buds bipolarly at the apical and basolateral domains, caused syncytia formation in the absence of exogenous protease. Anti-Sendai virus antibodies added to the basolateral side, but not at the apical side, inhibited cell fusion induced by F1-R. In addition, T-9, a mutant with bipolar budding phenotype of F1-R but with an uncleavable F protein phenotype like wild-type virus, induced cell fusion exclusively when trypsin was added to the basolateral medium. By electron microscopy, cell-to-cell fusion was shown to occur at the lateral domain of the plasma membrane. These results indicate that in addition to proteolytic activation of the F protein, basolateral expression of Sendai virus envelope glycoproteins is required to induce cell fusion.


Getting to wellness: The potential of the athletic model of marginal gains for the treatment of bipolar disorder.
People with bipolar disorder frequently have persistent symptoms, continued problems functioning and comorbid medical conditions. We propose applying the athletic coaching concept of marginal gains to help patients address these challenges to achieve wellness. We review the concept of marginal gains and potential interventions to improve long-term outcomes for bipolar patients. Evidence exists to help bipolar patients with diet and exercise, gradual behavioral change, mobile applications and peer support. Marginal gains, small and doable improvements across a broad range of areas, have great potential to improve the lives of people with bipolar disorder.


Secretome-based screening of fusion partners and their application in recombinant protein secretion in Saccharomyces cerevisiae.
For the efficient production of heterologous proteins in the yeast Saccharomyces cerevisiae, we screened for a novel fusion partner from the yeast secretome. From twenty major proteins identified from the yeast secretome, we selected Scw4p, a cell wall protein with similarity to glucanase, and modified to develop a general fusion partner for the secretory expression of heterologous proteins in yeast. The optimal size of the SCW4 gene to act as an efficient fusion partner was determined by C-terminal truncation analysis; two of the variants, S1 (truncated at codon 115Q) and S2 (truncated at codon 142E), were further used for the secretion of heterologous proteins. When fused with S2, the secretion of three target proteins (hGH, exendin-4, and hPTH) significantly increased. Conserved O-glycosylation sites (Ser/Thr-rich domain) and hydrophilic sequences of S2 were deemed important for the function of S2 as a secretion fusion partner. Approximately 5 g/L of the S2-exendin-4 fusion protein was obtained from fed-batch fermentation. Intact target proteins were easily purified by affinity chromatography after in vitro processing of the fusion partner. This system may be of general application for the secretory production of heterologous proteins in S. cerevisiae. KEY POINTS : • Target proteins were efficiently secreted with their N-terminus fused to Scw4p. • O-glycosylation and hydrophilic stretches in Scw4p were important for protein secretion. • A variant of Scw4p (S2) was successfully applied for the secretory expression of heterologous proteins.


Psychotherapeutic change in children and adolescents who have been sexually abused: a model from participants' perspectives.
Change in psychotherapy research in cases of child sexual abuse (CSA) has mainly emerged from a symptomatologic view, which needs to be complemented by a subjective perspective of change. Thus, this article aim is to describe different outcomes and stages of change during psychotherapy in children and adolescents who have been sexually abused, from the subjective perspectives of those involved in the process. A longitudinal qualitative study was developed. Qualitative interviews were conducted at different moments of the psychotherapeutic process (at around 6 months of therapy, 12 months and at the end of therapy) with 28 children and adolescents aged 6 to 17, with their caregivers and therapists. All children and adolescents attended and then completed psychotherapy due to sexual abuse in natural settings, in public specialized centres in Santiago, Chile. Sexual abuse occurred mainly in an intrafamilial context or by acquaintances. Data analysis was conducted using narrative analysis. Three stages of therapy were identified: (1) settling into therapy, (2) approaching CSA and (3) healing from abuse. Three different outcomes of psychotherapeutic change were also identified: (1) protective and psychosocial changes, (2) changes related to diminishing the effects of abuse and (3) changes related to healing from abuse. Psychosocial characteristics of the cases and features of the therapeutic process are described in each group. The outcomes of change and the stages of therapy are interrelated in a dynamic and gradual process where change is linked with the case's psychosocial characteristics and the features of the therapeutic process. Results allowed the authors to situate the voices of the participants within a proposed model of psychotherapeutic change for CSA, with clinical practical implications.


Open-label treatment with citalopram in patients with irritable bowel syndrome: a pilot study.
This open-label pilot study investigated whether the selective serotonin reuptake inhibitor (SSRI) citalopram improves symptoms of irritable bowel syndrome (IBS), a functional gastrointestinal disorder with frequent psychiatric comorbidity. Fifteen patients meeting Rome I criteria for IBS were administered open-label citalopram (20-40 mg/day) for 12 weeks. The study was conducted from October 2000 to August 2001. Twelve (80%) of the 15 subjects reported a > or = 50% decrease in the presence of abdominal pain, 10 (67%) reported a > or = 50% reduction in the severity of the symptom, and 12 (80%) reported a > or = 50% reduction in the frequency of the symptom. Approximately one half of the patients met criteria for remission (> or = 70% improvement) of abdominal pain. Results of this pilot study suggest that large controlled trials are needed to further evaluate the efficacy of SSRIs such as citalopram for the treatment of IBS.


Progress in the management of retrorectal tumours.
Tumours in the retrorectal space are rare and pathologically heterogeneous. The roles of imaging and preoperative biopsy, nonoperative management and the indications for surgical resection are controversial. This study investigated a series of retrorectal tumours treated in a single institution with the aim of producing a modern improved management algorithm. A retrospective analysis was conducted of the management of all retrorectal lesions identified between 1998 and 2013 from a radiology database search. Patient demographics, presenting symptoms, imaging, biopsy, management and the results were recorded. Descriptive statistics were used and Kaplan-Meier survival analysis was performed. Sixty-nine patients with a confirmed retrorectal tumour were identified. The median age was 50 (36-67 interquartile range) and 42 (56%) were female. Twenty (29%) of the tumours were malignant: 4 of 41 cystic lesions were malignant (12.9%) vs. 16 of 28 solid (or heterogeneous) lesions (57.1%) (P < 0.0001). Imaging demonstrated a 95% sensitivity and 64% specificity for differentiating benign from malignant tumours. Magnetic resonance imaging (MRI) was significantly better at distinguishing between benign and malignant tumours than computed tomography (94% vs. 64%, P = 0.03). Percutaneous biopsy was performed in 16 patients and only 27 underwent resection. There was no evidence of local recurrence associated with biopsy. Solid lesions were associated with a nonsignificant decreased overall survival (P = 0.348). This study demonstrated that MRI should be the investigation of choice for retrorectal lesions. Biopsy of solid lesions is safe and useful for guiding neoadjuvant and surgical therapy. Cystic lesions without suspicious radiological features can be followed by serial imaging without resection.


Eye disease in kidney transplantation: Clinical challenges in a unique patient population.
Eye disease is common among kidney transplant recipients, and their management is challenging. Chronic kidney disease is associated with ocular complications, both independently and in the context of various systemic disorders. In addition, chronic immunosuppression predisposes kidney transplant recipients to an array of long-term ocular issues. This may be broadly categorized into infections, malignancies, and other immunosuppression-specific side effects. The interdependence of kidney disease, transplant pharmacotherapy, and ocular health, therefore, requires a multispecialty approach. Although the kidney transplant population has grown along with the burden of associated oculopathies, systematic guidelines targeting this patient group are lacking. This evidenced-based narrative review summarizes the pertinent issues that may present in the ophthalmic and optometric clinical settings, with emphasis on collaborative management and directions for future research.


ChlVPP chemotherapy in advanced Hodgkin's disease.
Between March 1978 and January 1987 54 patients with advanced Hodgkin's disease (HD) or relapse following radiotherapy (RT) for Hodgkin's disease have been treated with combination chemotherapy consisting of chlorambucil, vinblastine, procarbazine and prednisolone (ChlVPP). A subgroup of five patients with bulky mediastinal disease received mantle RT in addition to ChlVPP chemotherapy. Forty-two patients (77.8%) entered complete remission with 33 (61.0%) remaining in unmaintained remission and 44 (81.5%) alive at a median follow up of 51 months (range: 22-103). The treatment was generally well tolerated with minimal toxicity. ChlVPP is effective first-line treatment for Hodgkin's disease with results which may be comparable to those achieved for MOPP but with significantly less toxicity.


Dysfunctional gaze processing in bipolar disorder.
Gaze conveys emotional information, and humans present sensitivity to its direction from the earliest days of life. Bipolar disorder is a disease characterized by fluctuating states of emotional and cognitive dysregulation. To explore the role of attentional control on face processing in bipolar patients (BP) we used gaze direction as an emotion modulation parameter in a two-back Working Memory (WM) task while high-density EEG data were acquired. Since gaze direction influences emotional attributions to faces with neutral expressions as well, we presented neutral faces with direct and averted gaze. Nineteen euthymic BP and a sample of age- and gender-matched controls were examined. In BP we observed diminished P200 and augmented P300 evoked responses, differentially modulated by non-repeated or repeated faces, as well as by gaze direction. BP showed a reduced P200 amplitude, significantly stronger for faces with direct gaze than averted gaze. Source localization of P200 indicated decreased activity in sensory-motor regions and frontal areas suggestive of abnormal affective processing of neutral faces. The present study provides neurophysiological evidence for abnormal gaze processing in BP and suggests dysfunctional processing of direct eye contact as a prominent characteristic of bipolar disorder.


Versatile Biocatalytic C(sp3 )-H Oxyfunctionalization for the Site- Selective and Stereodivergent Synthesis of α- and β-Hydroxy Acids.
C(sp3 )-H oxyfunctionalization, the insertion of an O-atom into C(sp3 )-H bonds, streamlines the synthesis of complex molecules from easily accessible precursors and represents one of the most challenging tasks in organic chemistry with regard to site and stereoselectivity. Biocatalytic C(sp3 )-H oxyfunctionalization has the potential to overcome limitations inherent to small-molecule-mediated approaches by delivering catalyst-controlled selectivity. Through enzyme repurposing and activity profiling of natural variants, we have developed a subfamily of α-ketoglutarate-dependent iron dioxygenases that catalyze the site- and stereodivergent oxyfunctionalization of secondary and tertiary C(sp3 )-H bonds, providing concise synthetic routes towards four types of 92 α- and β-hydroxy acids with high efficiency and selectivity. This method provides a biocatalytic approach for the production of valuable but synthetically challenging chiral hydroxy acid building blocks.


Development of human embryonic stem cell therapies for age-related macular degeneration.
Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults and ultimately leads to the death of photoreceptor cells in the macular area of the neural retina. Currently, treatments are only available for patients with the wet form of AMD. In this review, we describe recent approaches to develop cell-based therapies for the treatment of AMD. Recent research has focused on replacing the retinal pigment epithelium (RPE), a monolayer of cells vital to photoreceptor cell health. We discuss the various methods used to differentiate and purify RPE from human embryonic stem cells (HESC), and describe the surgical approaches being used to transplant these cells in existing and forthcoming clinical trials.


High-Concentration L-Menthol Exhibits Counter-Irritancy to Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde.
The transient receptor potential cation channel subfamily M 8 (TRPM8) agonist L-menthol has been used traditionally for its topical counterirritant properties. Although the use of topical L-menthol for pain is casuistically established, evidence regarding its efficacy is negligible. This study aimed to characterize the effect of L-menthol as a counterirritant on cutaneous pain and hyperalgesia provoked by topical application of the transient receptor potential cation channel, subfamily A, member 1 (TRPA1) agonist trans-cinnamaldehyde (CA). In a randomized, double-blinded study CA was applied to a 3 × 3-cm area of the volar forearm evoking neurogenic inflammation, pain, mechanical, and thermal hyperalgesia in 14 healthy volunteers. In different sessions, 10% CA alone or 40% L-menthol applied simultaneously with 10% CA were administered for 20 minutes, throughout which the subjects rated the pain intensity on a visual analogue scale of 0 to 10. Extensive quantitative sensory testing was conducted and superficial blood flow (neurogenic inflammation) was recorded. Administration of CA evoked spontaneous pain, neurogenic inflammation, thermal hyperalgesia, and primary and secondary mechanical hyperalgesia. Coadministration of topical L-menthol reduced spontaneous pain intensity (P < .01), neurogenic inflammation (P < .01), primary mechanical hyperalgesia (P < .05), secondary mechanical hyperalgesia (P < .05), and heat hyperalgesia (P < .05), but not cold hyperalgesia. L-menthol exhibited inhibitory effects on simultaneously established pain, hypersensitivity, and neurogenic inflammation in a human TRPA1-induced pain model. Potent TRPM8 agonists could be useful as topical antihyperalgesics. The study and the trial protocol is registered and approved by the local research ethics committee under the jurisdiction of the Danish Medicines Agency number N-20130005. The protocol also is registered at Clinicaltrials.gov under NCT02653703. Drugs interacting with transient receptor potential channels are of great therapeutic potential. In the present study we established cutaneous pain and hyperalgesia using the TRPA1 agonist CA. Subsequently, we showed that the frequently used topical counterirritant and TRPM8 agonist, L-menthol, decreased evoked pain, hyperalgesia, and inflammation, indicating direct and indirect antinociceptive mechanisms.


Fos expression and task-related neuronal activity in rat cerebral cortex after instrumental learning.
Learning has been shown to induce changes in neuronal gene expression and to produce development of task-specific neuronal activity. The connection between these two features of neuronal plasticity remains of a great interest. To address this issue we compared distribution of c-Fos expressing and task-related neurons in the rat cerebral cortex following instrumental learning of appetitive lever-press task. The number of Fos-positive neurons was determined immunohistochemically in the retrosplenial and the motor cortex of naive ("control" group), newly trained ("acquisition" group) and overtrained ("performance" group) animals. A significant activation of c-Fos expression was observed in the neurons of the retrosplenial but not motor cortex in the "acquisition" group rats, as compared with the "control" and "performance" groups. In accordance with this c-Fos expression difference, the retrosplenial cortex of the trained animals contained significantly more neurons with lever-press-related activity than the motor cortex. Therefore, the two examined cortical areas showed a parallel between experience-dependent induction of c-Fos and development of task-related neuronal activity. These data support a notion that learning-induced activation of c-Fos is associated with long-term neurophysiological changes produced by training.


Acceptability and usability of smartphone-based brainwave entrainment technology used by individuals with chronic pain in a home setting.
Brainwave entrainment (BWE) using rhythmic visual or auditory stimulation has many potential clinical applications, including the management of chronic pain, where there is a pressing need for novel, safe and effective treatments. The aim of this study was to gain qualitative feedback on the acceptability and usability of a novel BWE smartphone application, to ensure it meets the needs and wishes of end users. Fifteen participants with chronic pain used the application at home for 4 weeks. Semi-structured telephone interviews were then carried out. A template analysis approach was used to interpret the findings, with an initial coding template structured around the constructs of a theoretical framework for assessing acceptability of healthcare interventions. Structured data analysis generated a final modified coding structure, capturing themes generated across participants' accounts. The four main themes were 'approach to trying out the app: affective attitude and ethicality', 'perceived effectiveness', 'opportunity costs and burden' and 'intervention coherence and self-efficacy'. All participants were willing to engage with the technology and welcomed it as an alternative approach to medications. Participants appreciated the simplicity of design and the ability to choose between visual or auditory stimulation. All the participants felt confident in using the application. The findings demonstrate preliminary support for the acceptability and usability of the BWE application. This is the first qualitative study of BWE to systematically assess these issues.


Muscarinic interactions of bisindolylmaleimide analogues.
We have used radioligand binding studies to determine the affinities of seven bisindolylmaleimide analogues, six of which are selective inhibitors of protein kinase C, at human muscarinic M1-M4 receptors. The compounds were most potent at M1 receptors, and Ro-31-8220 was the most potent analogue, with a Kd of 0.6 microM at M1 receptors. The weakest compounds, bisindolylmaleimide IV and bisindolylmaleimide V, had Kd values of 100 microM. If it is necessary to use protein kinase C inhibitors at concentrations of 10 microM or more in studies involving muscarinic receptors then bisindolylmaleimide IV may be the most appropriate inhibitor to use.


Evaluation of four-dimensional computed tomography-based intensity-modulated and respiratory-gated radiotherapy techniques for pancreatic carcinoma.
To compare conformal radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and respiration-gated radiotherapy (RGRT) planning techniques for pancreatic cancer. All target volumes were determined using four-dimensional computed tomography scans (4D CT). The pancreatic tumor and enlarged regional lymph nodes were contoured on all 10 phases of a planning 4D CT scan for 10 patients, and the planning target volumes (PTV(all phases)) were generated. Three consecutive respiratory phases for RGRT delivery in both inspiration and expiration were identified, and the corresponding PTVs (PTV(inspiration) and PTV(expiration)) and organ at risk volumes created. Treatment plans using CRT and IMRT, with and without RGRT, were created for each PTV. Compared with the CRT plans, IMRT significantly reduced the mean volume of right kidney exposed to 20 Gy from 27.7% +/- 17.7% to 16.0% +/- 18.2% (standard deviation) (p < 0.01), but this was not achieved for the left kidney (11.1% +/- 14.2% to 5.7% +/- 6.5%; p = 0.1). The IMRT plans also reduced the mean gastric, hepatic, and small bowel doses (p < 0.01). No additional reductions in the dose to the kidneys or other organs at risk were seen when RGRT plans were combined with either CRT or IMRT, and the findings for RGRT in end-expiration and end-inspiration were similar. 4D CT-based IMRT plans for pancreatic tumors significantly reduced the radiation doses to the right kidney, liver, stomach, and small bowel compared with CRT plans. The additional dosimetric benefits from RGRT appear limited in this setting.


[Information quality and health risks in Spanish-language retail websites for Chinese herbal medicine].
The growing use of purchase online via Internet retailers favours the access to potentially toxic natural products. It also contributes to the quick dissemination of the claims made by the retailers on efficacy and safety, these claims being not always based upon reliable information. Here, we have conducted an online search to find Spanish-language retail websites for Chinese herbal medicine and we have analysed them for the quality of product information and the potential health risks. i) Online search in Google España to find Spanish-language retail websites for Chinese herbal medicine in which we analysed both the claims regarding possible health benefits and adequate safe use indications ii) Identification of potentially toxic herbs in the websites iii) Quantification of Chinese herbal medicines withdrawn by the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). 1) Only one third of the 30 Spanish-language retail websites found which sell Chinese herbal medicine observe the law, given that the other websites include illegal Western disease claims as marketing tools, 2) Five websites provide some safety information, 3) Two websites offer potentially toxic herbs and 4) Chinese herbal medicine adulterated with sibutramine, silfenafil or their analogues make a considerable percentage of the total products withdrawn by the AEMPS. Online health seekers should be warned about misinformation on retail websites for Chinese herbal medicine and directed to a Spanish government Web site for guidance in safely navigating the Internet for buying Chinese herbal medicine.


MyoD protein expression in Xenopus embryos closely follows a mesoderm induction-dependent amplification of MyoD transcription and is synchronous across the future somite axis.
The MyoD-related genes code for key regulators of skeletal muscle commitment and differentiation. In this study, expression of MyoD protein has been examined during Xenopus development. Protein is first detected in presumptive mesoderm at early gastrulation, directly following a dramatic increase in MyoD transcription that occurs in response to mesoderm induction. The pattern of expression resembles the muscle fate map at this time. Protein accumulates synchronously along the future somite axis, with no evidence of a spatial regulation which would explain the anterior/posterior wave of myogenic differentiation that follows MyoD expression. During gastrulation, the highest levels of MyoD are in cells next to the developing notochord, suggesting a role for the notochord in induction or maintenance of MyoD expression. After muscle differentiation, MyoD protein is degraded with a half-life of several hours, leading to very low expression in mature somites. These studies support a role for MyoD in induction of muscle mesoderm, but also point to the multi-layered regulation of these events.


Blind colour separation of H&E stained histological images by linearly transforming the colour space.
Blind source separation methods aim to split information into the original sources. In histology, each dye component attempts to specifically characterize different microscopic structures. In the case of the hematoxylin-eosin stain, universally used for routine examination, quantitative analysis may often require the inspection of different morphological signatures related mainly to nuclei patterns, but also to stroma distribution. Stain separation is usually a preprocessing operation that is transversal to different applications. This paper presents a novel colour separation method that finds the hematoxylin and eosin clusters by projecting the whole (r,g,b) space to a folded surface connecting the distributions of a series of [(r-b),g] planes that divide the cloud of H&E tones. The proposed method produces density maps closer to those obtained with the colour mixing matrices set by an expert, when comparing with the density maps obtained using nonnegative matrix factorization (NMF), independent component analysis (ICA) and a state-of-the-art method. The method has outperformed three baseline methods, NMF, Macenko and ICA, in about 8%, 12% and 52% for the eosin component, whereas this was about 4%, 8% and 26% for the hematoxylin component.


Intra-host Symbiont Diversity and Extended Symbiont Maintenance in Photosymbiotic Acantharea (Clade F).
Photosymbiotic protists contribute to surface primary production in low-nutrient, open-ocean ecosystems and constitute model systems for studying plastid acquisition via endosymbiosis. Little is known, however, about host-symbiont dynamics in these important relationships, and whether these symbioses are mutualistic is debated. In this study, we applied single-cell sequencing methods and advanced fluorescent microscopy to investigate host-symbiont dynamics in clade F acantharians, a major group of photosymbiotic protists in oligotrophic subtropical gyres. We amplified the 18S rRNA gene from single acantharian hosts and environmental samples to assess intra-host symbiont diversity and to determine whether intra-host symbiont community composition directly reflects the available symbiont community in the surrounding environment. Our results demonstrate that clade F acantharians simultaneously host multiple species from the haptophyte genera Phaeocystis and Chrysochromulina. The intra-host symbiont community composition was distinct from the external free-living symbiont community, suggesting that these acantharians maintain symbionts for extended periods of time. After selectively staining digestive organelles, fluorescent confocal microscopy showed that symbionts were not being systematically digested, which is consistent with extended symbiont maintenance within hosts. Extended maintenance within hosts may benefit symbionts through protection from grazing or viral lysis, and therefore could enhance dispersal, provided that symbionts retain reproductive capacity. The evidence for extended symbiont maintenance therefore allows that Phaeocystis could glean some advantage from the symbiosis and leaves the possibility of mutualism.


Rapid screening assay of congenital adrenal hyperplasia by measuring 17 alpha-hydroxyprogesterone with high-performance liquid chromatography/electrospray ionization tandem mass spectrometry from dried blood spots.
A rapid, simple, and specific method was developed for the diagnosis of congenital adrenal hyperplasia (CAH) from dried blood spots on newborn screening cards based on high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI-MS/MS). The usefulness of 17 alpha-hydroxyprogesterone (17 OH-P) determination on dried filter-paper blood samples from patients with CAH caused by 21-hydroxylase deficiency was evaluated. The LC/MS/MS detection of 17 OH-P was rapid, <4 min. The intra- and interday accuracy and precision of the method were <7%. Our procedure maintained good linearities (R(2) > 0.992) and recovery rate (>83%). We used this new method to directly determine the 17 OH-P levels in dried blood specimens from abnormal children of various ages, with a detection limit of 20 ng/ml (approximately 240 pg), to avoid the time-consuming derivatization steps required by the gas-chromatography/mass spectrometry (GC/MS) method. Four dried filter-paper blood samples of CAH patients (three girls and one boy, 1-14 years old) were all quantified in an LC/MS/MS study and revealed high 17 OH-P levels (>90 ng/ml). After treatment, all of the elevated 17 OH-P levels either decreased or disappeared. Compared with CAH patients, 17 OH-P was nearly undetectable (<20 ng/ml) in the normal infants by LC/MS/MS. This LC/MS/MS assay is not only useful for both diagnosis and monitoring of treatment of CAH in all other age groups, it also can be used as a screening test for CAH infants. In this study, we provided the first data on 17 OH-P in dried blood specimens affected with CAH using HPLC/ESI-MS/MS.


Orally acquired cyclic dinucleotides drive dSTING-dependent antiviral immunity in enterocytes.
Enteric pathogens overcome barrier immunity within the intestinal environment that includes the endogenous flora. The microbiota produces diverse ligands, and the full spectrum of microbial products that are sensed by the epithelium and prime protective immunity is unknown. Using Drosophila, we find that the gut presents a high barrier to infection, which is partially due to signals from the microbiota, as loss of the microbiota enhances oral viral infection. We report cyclic dinucleotide (CDN) feeding is sufficient to protect microbiota-deficient flies from enhanced oral infection, suggesting that bacterial-derived CDNs induce immunity. Mechanistically, we find CDN protection is dSTING- and dTBK1-dependent, leading to NF-kB-dependent gene expression. Furthermore, we identify the apical nucleoside transporter, CNT2, as required for oral CDN protection. Altogether, our studies define a role for bacterial products in priming immune defenses in the gut.


Atrial fibrillation in two adolescents.
Idiopathic atrial fibrillation (AF) in adolescents is extremely rare and has usually been associated with structural heart disease. We present two cases of symptomatic AF in adolescents without any identifiable etiology. No definitive guidelines are available for management of such patients.


Erysipelothrix endocarditis with previous cutaneous lesion: report of a case and review of the literature.
This report describes the first documented case of Erysipelothrix rhusiopathiae endocarditis in Latin America. The patient was a 51-years-old male, moderate alcoholic, with a previous history of aortic failure. He was used to fishing and cooking as a hobby and had his left hand wounded by a fish-bone. The disease began with erysipeloid form and developed to septicemia and endocarditis. He was treated with antibiotics and surgery for aortic valve replacement. There are only 46 cases of E. rhusiopathiae endocarditis reported to date. The authors wonder if several other cases might go unreported for lack of microbiological laboratorial diagnosis.


Relationship between repression-sensitization and word frequency estimates for pleasant and unpleasant words.
College students (45 females and 12 males) estimated the frequency of pleasant and unpleasant English words. 28 subjects estimated how often they, personally, had seen the words (Personal condition), and 29 subjects estimated how often a "language expert" had encountered the words (Kucera-Francis condition). Byrne's Repression-Sensitization scores were obtained for all subjects. In both conditions repressors judged pleasant words to be more frequent, and sensitizers judged unpleasant words to be more frequent (p less than .01). The results may clarify some contradictions in the literature on frequency estimation and may help to explain the relationship between repression-sensitization and perceptual defense/vigilance.


Phospholipid composition of human erythrocyte spectrin.
Human erythrocyte spectrin, which has been extracted at low ionic strength and precipitated at pH 5.1, contains 0.025 mumoles phospholipid/mg protein. The composition of the spectrin-phospholipids differs from that of the erythrocyte membrane. A remarkable similarity was found between the composition of the "available" phospholipids of the inner leaflet of the membrane bilayer and the spectrin-associated phospholipids. Rebinding studies with 125I-labeled spectrin show that the labeled spectrin binds preferentially to the cytoplasmic side of the membrane and that this binding is influenced by protein perturbations.


Diacylglycerol kinase ζ interacts with sphingomyelin synthase 1 and sphingomyelin synthase-related protein via different regions.
We previously reported that diacylglycerol (DG) kinase (DGK) δ interacts with DG-generating sphingomyelin synthase (SMS)-related protein (SMSr), but not SMS1 or SMS2, via their sterile α motif domains (SAMDs). However, it remains unclear whether other DGK isozymes interact with SMSs. Here, we found that DGKζ, which does not contain SAMD, interacts with SMSr and SMS1, but not SMS2. Deletion mutant analyses demonstrated that SAMD in the N-terminal cytosolic region of SMSr binds to the N-terminal half catalytic domain of DGKζ. However, the C-terminal cytosolic region of SMS1 interacts with the catalytic domain of DGKζ. Taken together, these results indicate that DGKζ associates with SMSr and SMS1 in different manners and suggest that they compose new DG signaling pathways.


Epidermal growth factor receptor signaling is partially responsible for the increased matrix metalloproteinase-1 expression in ocular epithelial cells after UVB radiation.
Pterygia are inflammatory, invasive, and proliferative lesions of the human ocular surface in which the matrix metalloproteinase (MMP) collagenase-1 (MMP-1) is highly expressed. Pterygia development may involve MMP-1 activity against interstitial fibrillar collagen, an abundant extracellular matrix component of the cornea, and its induction by ultraviolet light (UVB). We examined the pathways responsible for enhanced expression of MMP-1 in pterygium epithelial cells after UVB exposure and/or treatment with chemical inhibitors of mitogen-activated protein kinases or epidermal growth factor receptor. The induction of MMP-1 by UVB was comparable to that mediated by heparin-binding epidermal growth factor-like growth factor and epidermal growth factor. The epidermal growth factor receptor inhibitor PD153035 partially blocked the UVB-mediated induction of MMP-1 and totally abrogated its production after stimulation with either heparin-binding epidermal growth factor-like growth factor or epidermal growth factor. UVB exposure enhanced the phosphorylated form of ERK1/2 in a time-dependent manner whereas the ERK1/2 inhibitor PD98059 decreased this induction by at least fivefold. Transcripts for c-jun and c-fos were detected as early as 2 hours after UVB exposure and were suppressed by PD98059. The identification of a specific intracellular signaling pathway responsible for the enhanced production of a key enzyme that denatures intact fibrillar collagen has important implications for understanding the pathophysiology and future therapy for pterygia.


Attenuation of maitotoxin-induced cytotoxicity in rat aortic smooth muscle cells by inhibitors of Na+/Ca2+ exchange, and calpain activation.
The highly potent marine toxin maitotoxin (MTX) evoked an increase in cytosolic Ca(2+) levels in fura-2 loaded rat aortic smooth muscle cells, which was dependent on extracellular Ca(2+). This increase was almost fully inhibited by KB-R7943, a potent selective inhibitor of the reverse mode of the Na(+)/Ca(2+) exchanger (NCX). Cell viability was assessed using ethidium bromide uptake and the alamarBlue cytotoxicity assay. In both assays MTX-induced toxicity was attenuated by KB-R7943, as well as by MDL 28170, a membrane permeable calpain inhibitor. Maitotoxin-evoked contractions of rat aortic strip preparations in vitro, which persist following washout of the toxin, were relaxed by subsequent addition of KB-R7943 or MDL 28170, either in the presence of, or following washout of MTX. These results suggest that MTX targets the Na(+)/Ca(2+) exchanger and causes it to operate in reverse mode (Na(+) efflux/Ca(2+) influx), thus leading to calpain activation, NCX cleavage, secondary Ca(2+) overload and cell death.


Gas cluster ion beam SEM for imaging of large tissue samples with 10 nm isotropic resolution.
We demonstrate gas cluster ion beam scanning electron microscopy (SEM), in which wide-area ion milling is performed on a series of thick tissue sections. This three-dimensional electron microscopy technique acquires datasets with <10 nm isotropic resolution of each section, and these can then be stitched together to span the sectioned volume. Incorporating gas cluster ion beam SEM into existing single-beam and multibeam SEM workflows should be straightforward, increasing reliability while improving z resolution by a factor of three or more.


Prevalence and correlates of posttraumatic stress disorder among Kuwaiti military men according to level of involvement in the first Gulf War.
First, to compare the prevalence and intensity of posttraumatic stress disorder (PTSD) among Kuwaiti military men, divided into four groups (50 subjects each) according to degree of exposure to war trauma: (1) the retired (retired before the invasion); (2) an active-in-the-army group (AIA) (involved in duties at the rear only); (3) an in-battle (IB) group (involved in combat); and (4) prisoners of war (POWs-captured during combat). Second, to compare the severity of impact of event, comorbid depression, and anxiety among the groups. Third, to evaluate the contribution of self-esteem and locus of control (LOC). Subjects were interviewed once, 6 years after the war, using: the Clinician Administered PTSD Scale; the Impact of Event Scale (IES); the Hopkins Symptom Checklist-25; the Internal-External LOC; and The Self-Esteem Scale. Subjects were aged 24-71 years (mean 37.9). Sixty-three subjects (31.5%) fulfilled criteria for PTSD, with the rate significantly higher among the POWs (48%) than the retired (24%) and IB (22%), reflecting the severity of IES. Avoidance symptoms were the most pronounced. Self-esteem was significantly lowest among the POWs and those with PTSD. External LOC was associated with PTSD, anxiety, and depression. Self-esteem was the only covariate of PTSD scores. LOC was a significant covariate for anxiety. The characteristics of PTSD in these veterans showed similarity with those from elsewhere. The prominence of self-esteem and avoidance symptoms implies that they should be part of focus for interventions. Focus on LOC should be from the perspective of anxiety.


Corneal collagen cross-linking (CXL) in thin corneas.
Corneal collagen cross-linking (CXL) is a therapeutic procedure aiming at increasing the corneal stiffness in the keratoconus eyes by induction of cross-links within the extracellular matrix. It is achieved by ultraviolet-A (370 nm) irradiation of the cornea after saturation with the photosensitizer riboflavin. In the conventional CXL protocol, a minimum de-epithelialized corneal thickness of 400 μm is recommended to avoid potential irradiation damage to the corneal endothelium. In advanced keratoconus, however, stromal thickness is often lower than 400 μm, which limits the application of CXL in that category. Efforts have been undertaken to modify the conventional CXL procedure to be applicable in thin corneas. The current review discusses different techniques employed to achieve this end and their results. The overall safety and efficacy of the modified CXL protocols are good, as most of them managed to halt the progression of keratectasia without postoperative complications. However, the evidence of safety and efficacy in the use of modified CXL protocols is still limited to few studies with few patients involved. Controlled studies with long-term follow-up are required to confirm the safety and efficacy of the modified protocols.


Is Grey Level a Suitable Alternative to Low-Contrast Penetration as a Serial Measure of Sensitivity in Computerised Ultrasound Quality Assurance?
The aim of this study was to test the hypothesis that grey levels are a suitable alternative measure of sensitivity in ultrasound imaging quality assurance, as there are several caveats in the use of penetration depth. In a primary cohort of nine probes, where measurements had been made for 6 to 34 mo, both penetration depth and mean grey level fell below tolerance for six probes; both penetration depth and mean grey level remained within tolerance for three probes. In a secondary cohort where a measurement programme had been in place for a shorter period, grey level and/or penetration depth fell below tolerance in 15 of 66 probes; the sensitivity and specificity of at least 10% loss of grey level in predicting >5% loss in penetration depth were 91% and 93%, respectively. A loss of grey level accompanies a loss of penetration and provides a suitable alternative measure of sensitivity.


Left Main Coronary Artery to Superior Vena Cava Fistula Unmasked by Endarteritis.
Coronary artery fistulas are rare vascular malformations that can present with a broad range of symptoms. We present a case of a left main coronary artery to superior vena cava fistula that was discovered during a work-up for sepsis. A multidisciplinary approach is crucial for successful management of these vascular malformations. (Level of Difficulty: Beginner.).


Molecular or pharmacologic inhibition of the CD14 signaling pathway protects against burn-related myocardial inflammation and dysfunction.
Signaling through toll-like receptor 4 (TLR4) plays an obligate role in burn-related myocardial dysfunction. We hypothesized that signaling through CD14, a cellular receptor for endotoxin that lacks a transmembrane domain but is coupled to TLR4, also plays a role in postburn myocardial inflammation and dysfunction. Burn covering 40% total body surface area (or sham burn for controls) was produced in wild-type (WT) and CD14 knockout (KO) as well as vehicle-treated and geldanamycin-treated WT mice (1 microg/g body weight) to inhibit CD14 signaling. Groups included (1) WT shams, (2) CD14 KO sham, (3) WT burns, (4) CD14 KO burns, (5) vehicle-treated WT shams, (6) geldanamycin-treated WT shams, (7) vehicle-treated WT burns, and (8) geldanamycin-treated WT burns. Twenty-four hours after burn, cardiac function (Langendorff) and cardiomyocyte secretion of inflammatory cytokines TNF-alpha, IL-1 beta, and IL-6 (in pg/mL; 5 x 10(4) myocytes) were studied in all groups. Relative to sham WT controls, burn trauma in increased cardiac myocyte secretion of inflammatory cytokines (TNF-alpha, IL-1 beta, and IL-6 rose from 59 +/- 10 to 171 +/- 8; 6 +/- 0.2 to 78 +/- 1; and 88 +/- 3 to 170 +/- 12 pg/mL, respectively; P < 0.05) and produced robust cardiac contractile dysfunction (left ventricular pressure and +dP/dt fell from 105 +/- 4 to 73 +/- 5 mmHg and 2,400 +/- 73 to 1,803 +/- 90 mmHg/s; P < 0.05). Inability to signal through the CD14/TLR4 pathway (induced by CD14/KO or inhibition of CD14 expression by administration of geldanamycin) attenuated TNF-alpha, IL-1 beta, and IL-6 production in response to burn injury and improved postburn myocardial contractile function. Our data suggest that signaling through the CD14 pathway plays an obligate role in cardiac inflammation/dysfunction which occurs after major burn injury.


Experimental study of iron effect on the liver function.
The effect of iron on the liver function was studied in rats. A total of 40 rats were divided into four groups. Group 1 was given iron; Group 2, carbon tetrachloride; Group 3, a combination of iron and carbon tetrachloride; and Group 4 was the control. The changes in liver function were evaluated by using hepatobiliary and liver scintigraphy as the index of hepatocyte function and reticuloendothelial system function, respectively. Determination of liver CT number and a histological study were made at the same time. The administration of iron activated the reticuloendothelial system function per unit of liver weight. However, because of the decrease in liver weight, the total reticuloendothelial system function did not change at all. In the group given iron and carbon tetrachloride, liver cirrhosis and siderosis in the reticuloendothelial system occurred. Dysfunction in the reticuloendothelial system was more severe in this group than in the group given carbon tetrachloride only, by hepatocyte dysfunction was more mild. It is doubtful that the administration of iron after liver dysfunction had developed, which caused acceleration of fibrosis and reduction of liver blood flow, led to the enhancement of the reticuloendothelial system dysfunction.


Encephalocraniocutaneous lipomatosis: a case with unilateral odontomas and review of the literature.
We report a 7-year-old boy with the typical features of encephalocraniocutaneous lipomatosis (ECCL) including unilateral skin, eye, bone, and asymptomatic central nervous system involvement. The presenting sign were numerous ipsilateral odontomas which have been described in only two previous patients so far. We reviewed all 32 cases reported to date and focus on the dermatological hallmark of the condition, namely a fatty tissue naevus of the scalp for which the term naevus psiloliparus was recently coined. Sporadic occurrence, patchy type of organ involvement and roughly balanced sex ratio in ECCL are compatible with the concept of a lethal autosomal mutation only surviving in a mosaic state. In children presenting with a congenital smooth hairless lesion on the scalp, the diagnosis of naevus psiloliparus should be considered and other signs of encephalocraniocutaneous lipomatosis should be looked for.


Application of metabolome data in functional genomics: a conceptual strategy.
A gene with yet unknown physiological function can be studied by changing its expression level followed by analysis of the resulting phenotype. This type of functional genomics study can be complicated by the occurrence of 'silent mutations', the phenotypes of which are not easily observable in terms of metabolic fluxes (e.g., the growth rate). Nevertheless, genetic alteration may give rise to significant yet complicated changes in the metabolome. We propose here a conceptual functional genomics strategy based on microbial metabolome data, which identifies changes in in vivo enzyme activities in the mutants. These predicted changes are used to formulate hypotheses to infer unknown gene functions. The required metabolome data can be obtained solely from high-throughput mass spectrometry analysis, which provides the following in vivo information: (1) the metabolite concentrations in the reference and the mutant strain; (2) the metabolic fluxes in both strains and (3) the enzyme kinetic parameters of the reference strain. We demonstrate in silico that changes in enzyme activities can be accurately predicted by this approach, even in 'silent mutants'.


Assessment and classification of mechanical strength components of human femur trabecular bone using texture analysis and neural network.
In this work the mechanical strength components of human femur trabecular bone are analyzed and classified using planar radiographic images and neural network. The mechanical strength regions such as Primary Compressive, Primary Tensile, Secondary Tensile and Ward Triangle in femur trabecular bone images (N = 100) are delineated by semi-automatic image processing procedure. First and higher order texture parameters and parameters such as apparent mineralization and total area associated with the strength regions are derived for normal and abnormal images. The statistically derived significant parameters corresponding to the primary strength regions are fed to the neural network for training and validation. The classifications are carried out using feed forward network that is trained with standard back propagation algorithm. Results demonstrate that the apparent mineralization of normal samples is always high as (71%) compared to abnormal samples (64%). Entropy shows a high value (7.3) for normal samples and variation between the mean intensity and apparent mineralization for the primary strength zone is statistically significant (p < 0.0005). The classified outputs are validated by sensitivity and specificity measurements and are found to be 66.66% and 80% respectively. Further it appears that it is possible to differentiate normal and abnormal samples from the conventional radiographic images. As trabecular architecture in the human femur is an important factor contributing to bone strength, the procedure adopted here could be a useful supplement to the clinical observations for bone loss and fracture risk.


Gallbladder volvulus, a rare cause of acute abdomen, a case report.
The gallbladder volvulus is a rare surgical emergency and its defined as the rotation of the gallbladder on its mesentery along the axis of the cystic duct and cystic artery. Definitive diagnosis is usually made during surgery and a delay in treatment may result in a high mortality due to rupture of gall bladder and bile peritonitis. We report the case of an 88-year-old woman who presented with an acute torsion of gall bladder, which was treated promptly after admission by laparoscopic cholecystectomy. Acute torsion of gall bladder is a rare disease. Its pathogenesis is not well known but postulated to be multifactorial. Two anatomic variants that predispose to gall bladder torsion have been described. Clinical presentation is not specific, with symptoms and biologic signs that mimic acute cholecystitis. This condition should be suspected in elderly women with uncertain diagnosis of acute cholecystitis or acute abdominal pain of unknown origin. Gallbladder volvulus is a rare life-threatening surgical emergency that requires emergency surgical treatment. Out- come is often favorable when early diagnosis and surgery are made.


Validation study of new clinical scoring - "Apollo Clinical Scoring system" for bladder pain syndrome/interstitial cystitis and comparison of outcome with standard "O'Leary-Sant score".
Validation of the recently published newer clinical scoring system for bladder pain syndrome/interstitial cystitis and comparison of the results with the pre-existing standard O'Leary-Sant score. The symptoms are our primary guide to disease severity analysis, treatment, and response monitoring. The combined ICSI/ICPI (O'Leary-Sant Interstitial Cystitis Symptom and Problem Index) consist of a four-item symptom and problem index focusing on urgency, frequency, nocturia, and pain. A new scale, assigning more weight to pain and nocturia and adding the domains of sexual dysfunction and psychological impact, has been published by one of the authors (El Khoudary et al. J Women's Health 2002. 18:1361-1368; 7). This is a prospective study conducted to validate a newer clinical scoring system, namedht e 'Apollo Clinical Scoring' (ACS) system for patients with bladder pain syndrome/ interstitial cystitis (BPS/IC), and to compare its outcome with the simultaneously applied standard O'Leary-Sant (OLS) score. Thirty-five patients of BPS/IC diagnosed using the ESSIC definition were enrolled in the study and followed for 6 months. Intraclass correlation coefficient (ICC) for test-retest reliability, and Cronbach's α for measure of internal consistency, were applied to both scoring systems. Intraclass correlation coefficient for ACS was 0.715 and for OLS was 0.689. Cronbach's α for ACS was 0.736 and for OLS was 0.698. The present study suggests that the recently devised Apollo Clinical Scoring (ACS) system for patients of BPS/IC is internally consistent and a reliable scoring system. When compared with OLS in parallel setting, the newer ACS appeared to be marginally better.


[Abdominal actinomycosis mimicking an abdominal tumor. Case report in Senegal].
The purpose of this report is to describe a case of abdominal actinomycosis (Actinomyces israelii) with a pseudo-tumoral appearance in a 57-year-old Senegalese woman.


[HIV and dentistry. Part 7. The HIV positive dentist or student].
What should a dentist or dental student do when he happens to be HIV-seropositive? Should he or she disclose the disease to the patients or, in case of a student, to the university? Does he has to give up his practice or perhaps not even open one? Apparently, the legal regulations differ in various parts of the world. In the Netherlands dentists are advised to take their own responsibility in this matter.


Cranial magnetic resonance imaging findings of nutritional vitamin B12 deficiency in 15 hypotonic infants.
Nutritional vitamin B(12) deficieny is common among infants in the developing and underdeveloped countries. There is limited information concerning neuroimaging findings in infants with vitamin B(12) deficiency in the literature. The aim of this study is to evaluate the cranial magnetic resonance imaging (MRI) changes and clinical characteristics of hypotonic infants due to vitamin B(12) deficiency. A total of 15 infants with neuroradiologic investigations were diagnosed with nutritional B(12) vitamin deficiency. Cranial MRI was performed on all infants. Five infants were female (33%) and the mean age of infants was 12.3 ± 5.5 months. Hypotonia and neurodevelopmental retardation were present in all patients. MRI demonstrated thinning of the corpus callosum in 6 (40%), cortical atrophy in 5 (33.3%), large sylvian fissures in 5 (33.3%), ventricular dilatation in 3 (20%), asymetric large lateral ventricle in 2 (13.3%) and delayed in myelination in 2 (13.3%) patients. Four infants had normal MRI findings. Because of the importance of vitamin B(12) in the development of the brain, MRI findings may be detected and useful in infants with vitamin B(12) deficiency.


Preparation and characterization of gelatin-hydroxyapatite composite microspheres for hard tissue repair.
Gelatin-hydroxyapatite composite microspheres composed of 21% gelatin (G) and 79% hydroxyapatite (HA) with uniform morphology and controllable size were synthesized from a mixed solution of Ca(NO3)2, NH4H2PO4 and gelatin by a wet-chemical method. Material analyses such as X-ray diffraction (XRD), scanning/transmission electron microscopy examination (SEM/TEM) and inductively coupled plasma-mass spectroscopy (ICP-MS) were used to characterize G-HA microspheres by analyzing their crystalline phase, microstructure, morphology and composition. HA crystals precipitate along G fibers to form nano-rods with diameters of 6-10nm and tangle into porous microspheres after blending. The cell culture indicates that G-HA composite microspheres without any toxicity could enhance the proliferation and differentiation of osteoblast-like cells. In a rat calvarial defect model, G-HA bioactive scaffolds were compared with fibrin glue (F) and Osteoset® Bone Graft Substitute (OS) for their capacity of regenerating bone. Four weeks post-implantation, new bone, mineralization, and expanded blood vessel area were found in G-HA scaffolds, indicating greater osteoconductivity and bioactivity than F and OS.


How much change in pain score does really matter to patients?
The goal of this study was to determine the minimal change in pain score recognized by patients as meaningful known as minimal clinically important difference (MCID). Pain was recordedupon admission, 30 and 60 min later and patients were asked todescribe the extent of pain change on a 5-point Likert scale ranging from "much better" to "much worse". Patients reported their pain by two common pain scales comprising numeric rating scale (NRS) and visual analog scale (VAS). We used receiver operating characteristiccurve to assess the accuracy of pain scales. We then calculated the mean change in pain scores among patients who reported their pain change as "a little better" or "a little worse" and also analyzed regression to evaluate the MCID. A total of 150 patients and 253 pain changes were recruited. The MCID ± SD (95% CI) was 1.65 ± 1.58 (1.32-1.97) for NRS and 16.55 ± 17.53 (12.96-20.15) for VAS. The area under the curve by NRS and VAS were 0.86 and 0.89. For linear regression, the line slope and the y-intercept were 17.56 and 1.88, for VAS; these values were 1.73 and 0.31 for NRS, respectively. Recognizing the extent of change in pain score that really matters to patients is crucial for the evaluation of treatment effect. Patients perceived a change of 1.65 points on NRS and 16.55 on VAS in their pain severity as meaningful. This value was not different whether the pain was perceived alleviated or aggravated.


"The Competitive Season and Off-Season": Preliminary Research concerning the Sport-Specific Performance, Stress, and Sleep in Elite Male Adolescent Basketball Athletes.
Through scholastic sports programs, adolescent athletes compete to represent their communities. However, few studies investigate the changes in physiological and mental profiles during varied sport periodization among this population. Therefore, the purpose of this study was to compare the changes in sports performance and stress-related biomarkers between the competitive season (CS) and off-season (OS) in elite adolescent basketball players. Nine elite Division I male basketball players (age: 15-18 years. old) participated in this study. Basketball-specific performance, salivary dehydroepiandrosterone sulfate (DHEA-S)/cortisol levels, mood state, and sleep quality were all accessed during the CS and OS periods. The training load during OS was 26.0% lower than CS (p = 0.001). Muscle mass, aerobic capacity, 10 m sprint, and Abalakov jump (AJ) power during OS were greater than that during CS (+2.2-9.8%, p < 0.05), but planned agility was greater during CS (p = 0.003). The salivary DHEA-S/cortisol was greater during CS than during OS (p = 0.039). The overall mood state and sleep quality did not differ between periods, but the POMS-tension was higher during CS (p = 0.005). The present study demonstrates that muscle mass, aerobic capacity, peak AJ power, and 10 m sprint performance, but not planned agility, were greater during OS compared to CS among elite adolescent basketball players. Furthermore, the stress-related responses reflected by the D/C ratio and mood tension were relatively lower during the OS in these athletes. Thus, this study suggests that coaches and sport science professionals should closely monitor athletes' training states across varied training/competition periods to better react to modifying training or recovery plans.


Estimation of genetical parameters for a quantitative trait subject to major gene influences.
Both regression and correlation estimates of genetical variance and heritability for a quantitative trait influenced by a major gene can be obtained from the error variance-covariance matrix of MANOVA using relative-relative phenotype pairs as factors. The method is illustrated with parent-offspring data on red cell acid phosphatase phenotypes and serum acid phosphatase activity.


Preclinical activity of a new platinum analogue, lobaplatin, in cisplatin-sensitive and -resistant human testicular, ovarian, and gastric carcinoma cell lines.
Lobaplatin [1,2-diamminomethylcyclobutane-platinum(II) lactate] is a new platinum compound with interesting preclinical activity and apparently no nephro- or neurotoxicity that is currently undergoing clinical phase II studies. Little is known about the cross-resistance between cisplatin and lobaplatin. The activity of this new compound in comparison with cisplatin and carboplatin was evaluated in cisplatin-sensitive and cisplatin-resistant human testicular, gastric, and ovarian carcinoma cell lines using 96 h continuous drug exposure in a sulforhodamine-B assay. In three cisplatin-sensitive testicular carcinoma cell lines, lobaplatin and cisplatin showed comparable antitumor activity. The 50% growth-inhibitory concentrations (IC50 values) determined for cisplatin ranged from 0.1 to 0.4 microM, and those found for lobaplatin ranged from 0.25 to 0.5 microM. Carboplatin showed markedly lower cytotoxicity in all cell lines tested. Lobaplatin was not cross-resistant to cisplatin in a 10-fold cisplatin-resistant testicular carcinoma cell line and showed only weak cross-resistance in a 20-fold cisplatin-resistant ovarian carcinoma cell line. In contrast, complete cross-resistance between cisplatin and lobaplatin occurred in two cisplatin-resistant human gastric carcinoma cell lines, which were 3.3- and 9-fold resistant to cisplatin and 3.1- and 6.5-fold resistant to lobaplatin, respectively. Furthermore, lobaplatin showed significant activity against cisplatin-resistant human ovarian and testicular carcinoma xenografts in vivo. These data indicate a high level of activity for lobaplatin at clinically achievable concentrations in ug-sensitive testicular, ovarian, and gastric carcinoma cell lines and a lack of complete cross-resistance to cisplatin. Further clinical development of lobaplatin is clearly warranted.