Genotype and allele frequencies of polymorphic CYP2E1 in the Turkish population.
Cytochrome P4502E1 (CYP2E1) gene shows genetic polymorphisms that vary markedly in frequency among different ethnic and racial groups. We studied the genotype distributions and allele frequencies of three CYP2E1 polymorphisms: CYP2E1*5B (RsaI/PstI RFLP, C-1053T/G-1293C SNP, rs2031920 /rs3813867), CYP2E1*6 (DraI RFLP, T7632A SNP, rs6413432), and CYP2E1*7B (DdeI RFLP, G-71T SNP, rs6413420) by PCR/RFLP technique in a sample of 206 healthy subjects representing Turkish population. CYP2E1*5B polymorphism analysis yielded the genotype distribution as 96.12% for *1A/*1A (c1/c1), and 3.88% for *1A/*5B (c1/c2). The genotype frequencies for CYP2E1*6 polymorphism were found as 83.98% for *1A/*1A (T/T), 15.53% for *1A/*6 (T/A) and 0.49% for *6/*6 (A/A). For CYP2E1*7B (G-71T) polymorphism, the genotype frequencies were determined to be 86.89% for *1A/*1A (G/G), 12.62% for *1A/*7B (G/T) and 0.49% for *7B/*7B (T/T). Accordingly, the allele frequencies for *5B, *6 and *7B were 1.94, 8.25, and 6.80%, respectively. The genotype distributions of CYP2E1*5B and *6 in Turkish population were similar to those in other Caucasian populations, while differed significantly from East Asian populations. Recently, a novel and functionally important CYP2E1*7B polymorphism was identified in the promoter region. There have been few studies and limited data on CYP2E1*7B polymorphism frequency in the world and, so far, no information has been available for Turkish population. The genotype frequencies of CYP2E1*7B in Turkish population were found to be similar to those of other Caucasian populations. Population studies like this could be useful in assessing the susceptibility of different populations to chemical-induced diseases, including several types of cancer.


Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood.
In 1993, a randomized controlled trial in Minnesota showed, after 13 years of follow-up, that annual fecal occult blood testing was effective in reducing colorectal cancer mortality by at least 33%. Biennial screening (i.e., every 2 years) resulted in only a 6% mortality reduction. Two European trials (in England and in Denmark) subsequently showed statistically significant 15% and 18% mortality reductions with biennial screening. Herein, we provide updated results-through 18 years of follow-up--from the Minnesota trial that address the apparent inconsistent findings among the trials regarding biennial screening. From 1976 through 1977, a total of 46551 study subjects, aged 50-80 years, were recruited and randomly assigned to an annual screen, a biennial screen, or a control group. A screen consisted of six guaiac-impregnated fecal occult blood tests (Hemoccult) prepared in pairs from each of three consecutive fecal samples. Participants with at least one of the six tests that were positive were invited for a diagnostic examination that included colonoscopy. All participants were followed annually to ascertain incident colorectal cancers and deaths. The numbers of deaths from all causes were similar among the three study groups. Cumulative 18-year colorectal cancer mortality was 33% lower in the annual group than in the control group (rate ratio, 0.67; 95% confidence interval [CI] = 0.51-0.83). The biennial group had a 21% lower colorectal cancer mortality rate than the control group (rate ratio, 0.79; 95% CI = 0.62-0.97). A marked reduction was also noted in the incidence of Dukes' stage D cancers in both screened groups in comparison with the control group. The results from this study, together with the other two published randomized trials of fecal occult blood screening, are consistent in demonstrating a substantial, statistically significant reduction in colorectal cancer mortality from biennial screening.


Using the Disease State Fingerprint Tool for Differential Diagnosis of Frontotemporal Dementia and Alzheimer's Disease.
Disease State Index (DSI) and its visualization, Disease State Fingerprint (DSF), form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD) and Alzheimer's disease (AD). The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases. We utilized data from neuropsychological tests, volumetric magnetic resonance imaging, single-photon emission tomography, cerebrospinal fluid biomarkers and the APOE genotype. The DSI classification results were calculated with a combination of leave-one-out cross-validation and bootstrapping. A DSF visualization of a FTD patient is presented as an example. The DSI distinguishes controls from FTD (area under the receiver-operator curve, AUC = 0.99) and AD (AUC = 1.00) very well and achieves a good differential diagnosis between AD and FTD (AUC = 0.89). In subsamples of autopsy-confirmed cases (AUC = 0.97) and clinically diagnosed cases (AUC = 0.94), differential diagnosis of AD and FTD performs very well. DSI is a promising computer-assisted biomarker approach for aiding in the diagnostic process of dementing diseases. Here, DSI separates controls from dementia and differentiates between AD and FTD.


Effects of genotype, environment, and their interactions on honey bee health in Europe.
There are several reports of honey bee populations in Europe which survive without treatment for Varroa. However, when evaluated outside their native area, higher survival and resistance traits were not observed in colonies of a survivor population. Varroa infestation is strongly influenced by environmental factors, probably affecting threshold levels on a European scale. In a Europe-wide experiment colonies of local origin survived significantly longer than colonies of non-local origin, clearly indicating the presence of genotype-environment interactions. Transmission by Varroa selects for virulent strains of DWV, but it is currently unknown how these may interact with different genotypes of bees. The distribution of Nosema ceranae is significantly affected by environment, but there is at least one Nosema-resistant population.


Impact of recent antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic humans.
To test the hypothesis that glycemic thresholds for hypoglycemic cognitive dysfunction, like those for neuroendocrine responses to and symptoms of hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia, 16 healthy young adult subjects (7 women and 9 men) were studied on two separate occasions in random sequence, once with hyperinsulinemic hypoglycemia (2.6 +/- 0.1 mmol/l, 47 +/- 1 mg/dl) and once with otherwise identical hyperinsulinemic euglycemia (4.8 +/- 0.1 mmol/l, 86 +/- 5 mg/dl) between 1430 and 1630. Neuroendocrine, symptomatic, and cognitive responses to hyperinsulinemic stepped hypoglycemic (4.7, 4.2, 3.6, 3.0, 2.8, 2.5, and 2.2 mmol/l; 85, 75, 65, 55, 50, 45, and 40 mg/dl) clamps were quantitated the following morning on both occasions. Cognitive function tests included measures of information processing (Serial Addition), attention (Stroop Arrow Word), pattern recognition and memory (Delayed Non-Match to Sample), and declarative memory (Paragraph Recall). As expected, plasma glucagon (P = 0.0094), epinephrine (P = 0.0063), and pancreatic polypeptide (P = 0.0046) responses to stepped hypoglycemia were reduced significantly, and symptomatic responses tended to be reduced after afternoon hypoglycemia. Performance on the cognitive function tests deteriorated (P < 0.0001) during stepped hypoglycemic clamps, but there were no significant overall effects of antecedent hypoglycemia on hypoglycemic cognitive dysfunction. Although deterioration was reduced (P < 0.05) from the 2.8 mmol/l (50 mg/dl) to the 2.5 mmol/l (45 mg/dl) steps on the Serial Addition and Delayed Non-Match to Sample tasks after afternoon hypoglycemia, comparable differences were not found on the Stroop Arrow Word or Paragraph Recall tasks. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, unlike those for neuroendocrine responses to and symptoms of hypoglycemia, do not seem to shift to substantially lower plasma glucose concentrations after recent antecedent hypoglycemia in nondiabetic humans.


Child neglect: outcomes in high-risk urban preschoolers.
Limited longitudinal research has been conducted on the impact of neglect on children's health and well-being. There is a need to consider the impact of specific subtypes of neglect on children's functioning. In addition, there is interest in examining the cumulative effect of experiencing >1 subtype of neglect. To examine the individual and cumulative relationships among physical, psychological, and environmental neglect and children's behavior and development at age 3, and the impact on changes in children's behavior and development between ages 3 and 5. One hundred thirty-six children and their primary caregivers participating in a prospective longitudinal study of children's development and maltreatment were assessed when the children were aged 3 and 5 years. The children were recruited from primary care clinics because of failure to thrive, risk for human immunodeficiency virus, or as a comparison group. Evaluations were conducted in laboratory and home settings using observations, maternal self-report, and standardized testing of the children. Scores on physical, psychological, and environmental neglect were combined into a Cumulative Neglect Index. Regression analyses were run to examine the association of specific subtypes of neglect and of cumulative neglect with children's functioning at age 3, controlling for group, sociodemographic risk, and maternal depression. The analyses were repeated examining the impact on child outcomes at age 5, controlling for the above 3 variables as well as the children's cognitive development and behavior at age 3. Of the subtypes of neglect at age 3, only psychological neglect was significantly associated with increased internalizing and externalizing behavior problems at age 3; the Cumulative Neglect Index was associated with internalizing problems. None of the neglect subtypes or cumulative neglect were predictive of changes in children's behavior and development between ages 3 and 5. Cognitive development of the entire sample was impaired at age 5, averaging 0.85 standard deviations below the norm, and their average externalizing behavior score was significantly problematic with an average of 0.60 standard deviations above the norm. In the context of poverty where many preschool children have poor cognitive development and increased behavior problems, psychological neglect is significantly related to reported behavior problems. Children who experienced multiple types of neglect had increased internalizing problems. Neglect did not explain changes in children's behavior or development between ages 3 and 5. There is a need for pediatricians to identify and address child neglect, particularly psychological neglect, as early as possible. Pediatricians should also screen for maternal depression.


Global insights into acetic acid resistance mechanisms and genetic stability of Acetobacter pasteurianus strains by comparative genomics.
Acetobacter pasteurianus (Ap) CICC 20001 and CGMCC 1.41 are two acetic acid bacteria strains that, because of their strong abilities to produce and tolerate high concentrations of acetic acid, have been widely used to brew vinegar in China. To globally understand the fermentation characteristics, acid-tolerant mechanisms and genetic stabilities, their genomes were sequenced. Genomic comparisons with 9 other sequenced Ap strains revealed that their chromosomes were evolutionarily conserved, whereas the plasmids were unique compared with other Ap strains. Analysis of the acid-tolerant metabolic pathway at the genomic level indicated that the metabolism of some amino acids and the known mechanisms of acetic acid tolerance, might collaboratively contribute to acetic acid resistance in Ap strains. The balance of instability factors and stability factors in the genomes of Ap CICC 20001 and CGMCC 1.41 strains might be the basis for their genetic stability, consistent with their stable industrial performances. These observations provide important insights into the acid resistance mechanism and the genetic stability of Ap strains and lay a foundation for future genetic manipulation and engineering of these two strains.


Diarrheal disease among HIV-infected adults in Karnataka, India: evaluation of risk factors and etiology.
The objectives of this study were to evaluate characteristics associated with diarrhea, the effect of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis on diarrhea, the response to treatment with ciprofloxacin and tinidazole (Cipro-TZ), and presence of enteric pathogens. Adults infected with human immunodeficiency virus with and without diarrhea served as cases and controls, respectively. Participants provided a medical history and underwent a physical examination. Blood was collected for CD4 cell counts and stool for culture. Cases were treated with Cipro-TZ. Factors associated with a risk of diarrhea included crowded living and no toilet (all P < 0.05). Protective variables (P < 0.05) included a CD4 count greater than 200 cells/mm(3) and TMP/SMX prophylaxis. Cases were more likely to have a pathogen identified (P = 0.05). Eighty-six percent of the cases responded to treatment. Important risk factors for diarrhea were identified. Protection by TMP/SMX reinforces the importance of prophylaxis. These data suggest that treatment with an antibiotic and anti-parasitic medication may be effective.


Fulminant amoebic colitis: a clinicopathological study of 30 cases.
To review the clinical and pathological factors associated with fulminant amoebic colitis (FAC) requiring colonic resection and its outcome. We retrospectively identified adult patients admitted to our centre between June 2007 and December 2011 with FAC who underwent colonic resection and were diagnosed with amoebic colitis based on the presence of trophozoites on histological examination. The clinical details were extracted from the medical notes and correlated with the pathological findings. Thirty patients (18 men and 12 women) met the inclusion criteria. Their mean age was 50.1 years (range 21-89). The most frequent symptoms were abdominal pain, vomiting and fever. More than half the patients (16/30) had underlying conditions associated with immunosuppression including diabetes mellitus and tuberculosis. Pathological investigation of colonic resections showed predominantly right-sided involvement with geographic colonic ulcers covered with a creamy-white pseudomembrane, perforations, gangrenous changes, amoeboma and lesions mimicking inflammatory bowel disease. All showed basophilic dirty necrosis with abundant nuclear debris and amoebic trophozoites on histological examination. 21/30 patients (70%) had involvement beyond the caecum. 17/30 patients (57%) died. Those with involvement beyond the caecum were more likely to die (15/21, 71.4%) than those with less extensive disease. FAC presents as acute abdomen and can mimic appendicitis, ischaemic bowel disease, tuberculosis and malignancy. Comorbidities causing immunosuppression frequently associated. Mortality remains high despite surgery, so FAC should be suspected in every case of acute abdomen with colonic perforation if associated with typical gross and microscopic findings and a history of stay in an endemic area.


Maximizing contrast to noise with inductively coupled implanted coils.
Magnetic resonance (MR) microscopy with inductively coupled implanted coils has been used previously to follow loss and return of intra-medullary contrast as a result of nephrotoxic acute tubular necrosis with 117 microns resolution over a 2000 microns thick slice. The purpose of the current study was to further investigate the capabilities of in vivo MR microscopy by combining the implanted coil imaging technique with spin echo pulse sequence optimization done through signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) modeling. These models included consideration of the effects of T2* and sampling time on signal-to-noise and contrast-to-noise ratios. They were initially tested with GdCl3 and agar gel phantoms constructed to the relaxation time and spin density specifications of the intra-medullary junction which bridges the outer and inner stripe of the outer medulla. In vivo microscopy was performed using single turn radiofrequency (RF) coils that were surgically implanted around the left kidney of two rats and inductively coupled to an external "birdcage" body coil. The models revealed maximum CNR per unit imaging time at a TR of 800 msec. A TE of 16 msec proved to be the best compromise between loss of transverse magnetization and decreased bandwidth. These CNR predictions were supported by the gel phantom and in vivo data. Maximizing the CNR in the current study enabled us to improve the resolution of in vivo MR microscopy to 78 microns over a 1000 microns slice with an SNR of 40 and a CNR of eight in a total imaging time of 54 minutes.


Organ donation, awareness, attitudes and beliefs among post graduate medical students.
Organ transplantation is the most preferred treatment modality for patients with end-stage organ disease. There is an inadequate supply of cadaver organs commensurate with need. Health-care professionals are the critical link in augmenting public awareness about organ donation. Their attitudes and beliefs can influence the public opinion. This study aims at understanding the awareness, attitudes, and beliefs among the medical postgraduate students. A total of 123 post-graduates of a medical college hospital in South India participated in the study. A specially de-signed questionnaire was used in assessment. Data were statistically analyzed using SPSS Windows version 10.0. The mean age of the postgraduate students was 28.32 + or - 3.5 years, 54% were males, 62% belonged to Christian religion, 69% were single, 77% were from nuclear families, 87% had urban background, and 54% were from upper socioeconomic strata. About 97% said they were aware of organ donation through media, 23 understood the concept of "cadaver" as "brain-death" and 93% were able to distinguish between brain-death and persistent vegetative state. Eighty-nine percent wished to donate their organs, 77% did not believe in body disfigurement and 87% did not believe in rebirth without the donated organs, if they pledged their organs. Sixty-nine percent were willing to donate the organs of their family members. Eighty percent were willing to receive organs from family and cadaver, 40% were willing to donate a child's organs, 95% did not believe that organ donation is against their religion, 87% disagreed with the notion that doctors would not impart adequate care if they were pledged organ donors and 79% agreed that doctors would not declare death prematurely, if they had pledged their organs during life. There was a statistically significant correlation between attitudes, beliefs and demographics. In conclusion, the concept of brain-death was clearly understood by only a small number of medical postgraduate students. They however, had positive attitudes and beliefs towards organ donation.


Myristoylated and nonmyristoylated pools of sea urchin sperm flagellar creatine kinase exist side-by-side: myristoylation is necessary for efficient lipid association.
In sperm of the sea urchin Strongylocentrotus purpuratus, a functional phosphocreatine shuttle, that requires the existence of mitochondrial and cytosolic creatine kinase (CK) isoforms in distinct locations, is essential for sperm motility. S. purpuratus sperm have an unusually large, 145 kDa CK isoform, present exclusively in the sperm tail (TCK), that is enriched in flagellum membrane preparations. Purified TCK contains two very similar proteins, designated TCKI and TCKII, of which only TCKII associates readily with liposomes and detergent micelles in vitro. Here we demonstrate by gas chromatography/mass spectrometry combined with selective ion monitoring that ions diagnostic for the presence of myristoylglycine in proteins are found in TCKII, but not TCKI. By contrast, TCKI, but not TCKII, served in vitro as a substrate for recombinant, polyhistidine-tagged N-myristoyltransferase and was myristoylated to high stoichiometries (0.58 +/- 0.14 pmol of myristate/pmol of TCK), in the presence of myristoyl-CoA, on glycine in amide linkage. In vitro myristoylated TCKI associated with phosphatidylcholine (PC)/phosphatidylserine (PS) (75:25) liposomes and Triton X-100 detergent micelles in gel filtration assays and with PC/PS liposomes in a centrifugation assay in the same manner as did TCKII. In gel filtration experiments, TCKI required at least 25-fold higher PC/PS liposome concentrations than TCKII to obtain 50% association. A partition coefficient of 0.8 x 10(5) M(-1) was determined for TCKII with PC/PS (75:25) liposomes in the centrifugation assay. Thus, myristoylated and nonmyristoylated forms of TCK exist side-by-side in the sea urchin flagellum, and myristoylation is essential for efficient liposome association of TCK.


Computer-assisted diagnosis for early stage pleural mesothelioma: towards automated detection and quantitative assessment of pleural thickening from thoracic CT images.
Pleural thickenings as biomarker of exposure to asbestos may evolve into malignant pleural mesothelioma. For its early stage, pleurectomy with perioperative treatment can reduce morbidity and mortality. The diagnosis is based on a visual investigation of CT images, which is a time-consuming and subjective procedure. Our aim is to develop an automatic image processing approach to detect and quantitatively assess pleural thickenings. We first segment the lung areas, and identify the pleural contours. A convexity model is then used together with a Hounsfield unit threshold to detect pleural thickenings. The assessment of the detected pleural thickenings is based on a spline-based model of the healthy pleura. Tests were carried out on 14 data sets from three patients. In all cases, pleural contours were reliably identified, and pleural thickenings detected. PC-based Computation times were 85 min for a data set of 716 slices, 35 min for 401 slices, and 4 min for 75 slices, resulting in an average computation time of about 5.2 s per slice. Visualizations of pleurae and detected thickenings were provided. Results obtained so far indicate that our approach is able to assist physicians in the tedious task of finding and quantifying pleural thickenings in CT data. In the next step, our system will undergo an evaluation in a clinical test setting using routine CT data to quantify its performance.


A new technique for placement of nasoenteral feeding tubes using external magnetic guidance.
To evaluate a new technique in which a hand-held external magnet is used to maneuver nasoenteral feeding tubes through the pylorus and into the duodenum. Prospective case series. Critical care units and medical and surgical wards of a university-affiliated community hospital. Thirty-five patients were entered into the study after the attending physician requested assistance in tube placement. A standard 12-Fr, 114-cm flexible nasoenteral feeding tube was modified by inserting a small magnet into the distal tip. The tube was inserted per nares into the stomach, using traditional technique. Next, an external magnet was placed over the right upper abdominal quadrant, at the midclavicular line to attract the tube tip along the lesser curvature of the stomach, through the pyloric sphincter, and into the duodenum. Portable abdominal radiography performed immediately after the procedure confirmed the anatomic location of the tube tip. Forty-two intubations were performed in 35 patients (in seven patients, the tube had to be reinserted due to inadvertent removal or surgery). In 37 (88%) of 42 intubations, the tube was passed through the pyloric sphincter and into the duodenum on the first attempt. The mean procedure time was 15 +/- 9 mins (range 10 to 45). There were no complications related to the procedure during the study period. This report describes a novel technique of enteral feeding tube placement, using external magnetic guidance. Transpyloric placement was achieved in 88% of cases. This reliable and convenient bedside method for rapid placement of the tube into the duodenum allows prompt and safe initiation of enteral nutrition.


Task-dependent posterior cingulate activation in mild cognitive impairment.
Neuroimaging research has demonstrated that the posterior cingulate cortex (PCC) is functionally compromised in individuals diagnosed with amnestic mild cognitive impairment (MCI), a major risk factor for the development of Alzheimer's disease (AD). In functional MRI studies with healthy participants, this same region is active during self-appraisal (requiring retrieval of semantic knowledge about the self) as well as episodic recognition of previously learned information. Administering both types of tasks to people with MCI may reveal important information on the role of the PCC in recollection. This study investigated fMRI activation in the PCC in individuals with MCI and matched controls across two tasks. The first task was a visual episodic recognition task. The second task was an autobiographical self-appraisal task in which subjects rated themselves on a set of trait adjectives. Results of a conjunction analysis revealed the PCC as the sole region commonly active during both tasks in the healthy older adults. Furthermore, additional analysis revealed an interaction in the PCC, indicating a task-dependent response in the MCI group. MCI participants showed PCC activation during self-appraisal, but not episodic retrieval. This result suggests in MCI that the PCC shows functional degradation during episodic retrieval; however, the PCC's role in retrieval and evaluation of highly elaborated information regarding the self is more well-preserved.


Ultrasound imaging for the rheumatologist. I. Ultrasonography of the shoulder.
Ultrasonography (US) has proved to be a useful diagnostic tool in patients with shoulder pain and/or limited range of motion. It allows careful assessment of a wide range of changes involving many different anatomic structures of the shoulder girdle, such as the rotator cuff tendons (tendonitis, tendon tears and calcific deposits), the long head of the biceps tendon (tenosynovitis, tendonitis, tears, rupture and displacement), the bursae (bursitis), the soft tissues of the gleno-humeral (synovial proliferation, joint effusion) and acromioclavicular joints (synovial proliferation and joint effusion). In addition, it is also a reliable tool in the evaluation of bony profiles detecting the presence of erosions and osteophytes. The use of high quality equipment and the application of a standard scanning protocol are mandatory for reliable US assessment of shoulder pathology.


Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group.
Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.


Protein-energy malnutrition as a risk factor for increased morbidity in long-term hemodialysis patients.
This prospective nonintervention single-center study was undertaken to investigate the role of protein-energy malnutrition (PEM) as a risk factor for morbidity in patients on long-term hemodialysis. Thirty-seven patients from the renal unit of Tygerberg Hospital, Tygerberg, South Africa, were studied for a mean period of 26 months. Morbidity was the main outcome and was defined as the number of hospitalizations and days of hospitalization per patient per year. Investigations included 4-monthly determinations of interdialytic protein catabolic rate (PCR), dietary intake of protein and energy, blood levels of albumin and urea, lymphocyte count, adequacy of dialysis (Kt/V), body weight, intradialytic weight loss, fat mass (FM), fat-free mass (FFM), body mass index (BMI), and bone-free arm muscle area (BF-AMA). A PEM composite score was derived from postdialysis serum albumin, BF-AMA, FM, FFM, and BMI. All-cause morbidity as defined by number of hospitalizations (see text for other definitions of morbidity) showed a significant correlation with the mean and baseline PEM score (P <.01), and a negative correlation with predialysis and postdialysis serum albumin (P <.05) and age (P <.05). There was no significant relationship with PCR, percentage intradialytic weight loss, Kt/V, reuse of dialyzer, period on maintenance hemodialysis, sex, race, and type of dialyzer membrane. When "only infection-related" morbidity was considered, the factors that showed a significant correlation were the mean (P <. 001) and baseline PEM score (P <.01), and percentage intradialytic weight loss (P <.01). There was no significant deterioration in the nutritional status of patients followed up for at least 24 months. It is concluded that infection-related morbidity was associated most strongly with the PEM score and the percentage intradialytic weight loss. The results suggest that PEM is one of the important contributing factors to morbidity, possibly via an effect on the immune system and infection.


Psychological distress in cardiac rehabilitation participants.
Limited data are available on the psychosocial characteristics of patients entering cardiac rehabilitation (CR). We characterized the psychological and clinical profiles of men and women entering CR to determine which, if any, characteristic identifies persons at high risk for psychological distress. The records of 417 patients enrolled in phase II CR between January 2001 and December 2004 were analyzed. One hundred forty-eight of these patients underwent a comprehensive Symptom Checklist-90 psychological survey. The analysis focused on measures of depression, anxiety, hostility, somatization, and a global severity index. Mean age of the patients was 60.6 years and 20.9% of them were women. More than one-third had a score of 90th percentile or more in at least 1 psychological category, and 23% had a score of 90th percentile or more in 3 or more categories. Approximately 20% and 36% of patients scoring in the 90th percentile or more and 98th percentile or more of depressive symptoms, respectively, had a history of depression. There was no difference in Symptom Checklist-90 scores by gender, age, education, work status, type of coronary event, metabolic syndrome, tobacco use, cerebrovascular disease, peripheral vascular disease, or diabetes. There was no relationship between psychological symptoms and indication for CR, although a trend of more somatic symptoms was seen in those who underwent an acute coronary syndrome and did not receive revascularization. Considering the prevalence of psychological distress in CR patients and the lack of clinical identifiers, routine assessment could help identify those who are at increased risk of noncompliance and may benefit from psychological and/or pharmacological intervention.


Relationships between seafood consumption during pregnancy and childhood and neurocognitive development: Two systematic reviews.
Abundant data are now available to evaluate relationships between seafood consumption in pregnancy and childhood and neurocognitive development. We conducted two systematic reviews utilizing methodologies detailed by the Dietary Guidelines for Americans Scientific Advisory Committee 2020-2025. After reviewing 44 publications on 106,237 mother-offspring pairs and 25,960 children, our technical expert committee developed two conclusion statements that included the following: "Moderate and consistent evidence indicates that consumption of a wide range of amounts and types of commercially available seafood during pregnancy is associated with improved neurocognitive development of offspring as compared to eating no seafood. Overall, benefits to neurocognitive development began at the lowest amounts of seafood consumed (∼4 oz/wk) and continued through the highest amounts, above 12 oz/wk, some range up to >100 oz/wk.", "This evidence does not meet the criteria for "strong evidence" only due to a paucity of randomized controlled trials that may not be ethical or feasible to conduct for pregnancy" and "Moderate and consistent evidence indicates that consumption of >4 oz/wk and likely >12 oz/wk of seafood during childhood has beneficial associations with neurocognitive outcomes." No net adverse neurocognitive outcomes were reported among offspring at the highest ranges of seafood intakes despite associated increases in mercury exposures. Data are insufficient for conclusive statements regarding lactation, optimal amounts, categories or specific species characterized by mercury content and neurocognitive development; although there is some evidence that dark/oily seafood may be more beneficial. Research was conducted in healthy women and children and is generalizable to US populations. Assessment of seafood as a whole food integrates inherently integrates any adverse effects from neurotoxicants, if any, and benefits to neurocognition from omega-3 fats, as well as other nutrients critical to optimal neurological development. Understanding of the effects of seafood consumption on neurocognition can have significant public health implications.


Determination of the Oswestry Disability Index score equivalent to a "satisfactory symptom state" in patients undergoing surgery for degenerative disorders of the lumbar spine-a Spine Tango registry-based study.
The achievement of a given change score on a valid outcome instrument is commonly used to indicate whether a clinically relevant change has occurred after spine surgery. However, the achievement of such a change score can be dependent on baseline values and does not necessarily indicate whether the patient is satisfied with the current state. The achievement of an absolute score equivalent to a patient acceptable symptom state (PASS) may be a more stringent measure to indicate treatment success. This study aimed to estimate the score on the Oswestry Disability Index (ODI, version 2.1a; 0-100) corresponding to a PASS in patients who had undergone surgery for degenerative disorders of the lumbar spine. This is a cross-sectional study of diagnostic accuracy using follow-up data from an international spine surgery registry. The sample includes 1,288 patients with degenerative lumbar spine disorders who had undergone elective spine surgery, registered in the EUROSPINE Spine Tango Spine Surgery Registry. The main outcome measure was the ODI (version 2.1a). Surgical data and data from the ODI and Core Outcome Measures Index (COMI) were included to determine the ODI threshold equivalent to PASS at 1 year (±1.5 months; n=780) and 2 years (±2 months; n=508) postoperatively. The symptom-specific well-being item of the COMI was used as the external criterion in the receiver operating characteristic (ROC) analysis to determine the ODI threshold equivalent to PASS. Separate sensitivity analyses were performed based on the different definitions of an "acceptable state" and for subgroups of patients. JF is a copyright holder of the ODI. The ODI threshold for PASS was 22, irrespective of the time of follow-up (area under the curve [AUC]: 0.89 [sensitivity {Se}: 78.3%, specificity {Sp}: 82.1%] and AUC: 0.91 [Se: 80.7%, Sp: 85.6] for the 1- and 2-year follow-ups, respectively). Sensitivity analyses showed that the absolute ODI-22 threshold for the two follow-up time-points were robust. A stricter definition of PASS resulted in lower ODI thresholds, varying from 16 (AUC=0.89; Se: 80.2%, Sp: 82.0%) to 18 (AUC=0.90; Se: 82.4%, Sp: 80.4%) depending on the time of follow-up. An ODI score ≤22 indicates the achievement of an acceptable symptom state and can hence be used as a criterion of treatment success alongside the commonly used change score measures. At the individual level, the threshold could be used to indicate whether or not a patient with a lumbar spine disorder is a "responder" after elective surgery.


Scarless wound repair: a human fetal skin model.
Animal studies demonstrate that the fetus heals cutaneous wounds by reformation of normal tissue architecture without scar formation. We have developed a new model to study human fetal skin wound healing. Grafts of human fetal skin placed onto athymic mice retain the morphologic features of normal development, although they differentiate at an accelerated rate when placed cutaneously compared to subcutaneously. Full-thickness skin grafts from human fetuses at 15 (n = 12), 17 (n = 11), 18 (n = 25), 19 (n = 20) and 22 (n = 13) weeks gestational age were placed onto athymic (nu/nu) mice in 2 locations: (1) cutaneously onto a fascial bed and thereby exposed to air or (2) subcutaneously in a pocket under the murine panniculus carnosus. Linear incisions were made in each graft 7 days after transplantation. Grafts were harvested at 7, 14 and 21 days postwounding and analyzed histologically for scar formation. By hematoxylin & eosin and Mallory's trichrome stains, complete epidermal and dermal graft wound healing without scar formation was demonstrated in the subcutaneous grafts at each gestational age studied. In contrast, scar was seen at all time points in the cutaneous grafts in both the incisional wound and at the interface of the fetal human skin graft and adult mouse skin, regardless of fetal skin gestational age.(ABSTRACT TRUNCATED AT 250 WORDS)


CDKN2A deletion is a frequent event associated with poor outcome in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).
Nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) remains a diagnosis encompassing a heterogenous group of PTCL cases not fitting criteria for more homogeneous subtypes. They are characterized by a poor clinical outcome when treated with anthracycline-containing regimens. A better understanding of their biology could improve prognostic stratification and foster the development of novel therapeutic approaches. Recent targeted and whole exome sequencing studies have shown recurrent copy number abnormalities (CNAs) with prognostic significance. Here, investigating 5 formalin-fixed, paraffin embedded cases of PTCL-NOS by whole genome sequencing (WGS), we found a high prevalence of structural variants and complex events, such as chromothripsis likely responsible for the observed CNAs. Among them, CDKN2A and PTEN deletions emerged as the most frequent aberration, as confirmed in a final cohort of 143 patients with nodal PTCL. The incidence of CDKN2A and PTEN deletions among PTCL-NOS was 46% and 26%, respectively. Furthermore, we found that co-occurrence of CDKN2A and PTEN deletions is an event associated with PTCL-NOS with absolute specificity. In contrast, these deletions were rare and never co-occurred in angioimmunoblastic and anaplastic lymphomas. CDKN2A deletion was associated with shorter overall survival in multivariate analysis corrected by age, IPI, transplant eligibility and GATA3 expression (adjusted HR =2.53; 95% CI 1.006-6.3; p=0.048). These data suggest that CDKN2A deletions may be relevant for refining the prognosis of PTCL-NOS and their significance should be evaluated in prospective trials.


Analyzing micro-RNA expression using microarrays.
The discovery of micro-RNAs (miRNAs) and the growing appreciation of the importance of micro-RNAs in the regulation of gene expression are driving increasing interest in miRNA expression profiling. Early studies have suggested prominent roles for these genetically encoded regulatory molecules in a variety of normal biological processes and diseases, particularly cancer. However, the field of miRNA expression profiling is in its infancy. Several factors, including the small size, the unknown but limited number of miRNAs, and the tissue-to-tissue and tissue-to-disease state variability in miRNA expression, make the adaptation of microarray technology to the evaluation of miRNA expression nontrivial. This chapter describes the unique features of miRNA microarray experiments and analysis and provides a case study demonstrating our approach to miRNA expression analysis.


Novel Immunomodulatory Flagellin-Like Protein FlaC in Campylobacter jejuni and Other Campylobacterales.
The human diarrheal pathogens Campylobacter jejuni and Campylobacter coli interfere with host innate immune signaling by different means, and their flagellins, FlaA and FlaB, have a low intrinsic property to activate the innate immune receptor Toll-like receptor 5 (TLR5). We have investigated here the hypothesis that the unusual secreted, flagellin-like molecule FlaC present in C. jejuni, C. coli, and other Campylobacterales might activate cells via TLR5 and interact with TLR5. FlaC shows striking sequence identity in its D1 domains to TLR5-activating flagellins of other bacteria, such as Salmonella, but not to nonstimulating Campylobacter flagellins. We overexpressed and purified FlaC and tested its immunostimulatory properties on cells of human and chicken origin. Treatment of cells with highly purified FlaC resulted in p38 activation. FlaC directly interacted with TLR5. Preincubation with FlaC decreased the responsiveness of chicken and human macrophage-like cells toward the bacterial TLR4 agonist lipopolysaccharide (LPS), suggesting that FlaC mediates cross-tolerance. C. jejuni flaC mutants induced an increase of cell responses in comparison to those of the wild type, which was suppressed by genetic complementation. Supplementing excess purified FlaC likewise reduced the cellular response to C. jejuni. In vivo, the administration of ultrapure FlaC led to a decrease in cecal interleukin 1β (IL-1β) expression and a significant change of the cecal microbiota in chickens. We propose that Campylobacter spp. have evolved a novel type of secreted immunostimulatory flagellin-like effector in order to specifically modulate host responses, for example toward other pattern recognition receptor (PRR) ligands, such as LPS. IMPORTANCE Flagellins not only are important for bacterial motility but are major bacterial proteins that can modulate host responses via Toll-like receptor 5 (TLR5) or other pattern recognition receptors. Campylobacterales colonizing the intestinal tracts of different host species harbor a gene coding for an unusual flagellin, FlaC, that is not involved in motility but is secreted and possesses a chimeric amino acid sequence composed of TLR5-activating and non-TLR5-activating flagellin sequences. Campylobacter jejuni FlaC activates cells to increase in cytokine expression in chicken and human cells, promotes cross-tolerance to TLR4 ligands, and alters chicken cecal microbiota. We propose that FlaC is a secreted effector flagellin that has specifically evolved to modulate the immune response in the intestinal tract in the presence of the resident microbiota and may contribute to bacterial persistence. The results also strengthen the role of the flagellar type III apparatus as a functional secretion system for bacterial effector proteins.


Suppression of RANTES in children with Plasmodium falciparum malaria.
Severe malarial anemia (MA) is the primary manifestation of severe malaria among children in areas of holoendemic Plasmodium falciparum transmission. Although overproduction of inflammatory-derived cytokines are implicated in the immunopathogenesis of severe MA, chemokines such as regulated on activation, normal T-cell expressed and secreted (RANTES, CCL5) are largely unexplored in childhood malaria. We found that RANTES is decreased during severe MA (p<0.01), and associated with suppression of erythropoiesis (p<0.05) and malaria-induced thrombocytopenia (p<0.05). These findings suggest that thrombocytopenia may be a source of reduced RANTES which may contribute, at least in part, to suppression of erythropoiesis in children with malarial anemia.


A generalized mechanism for perception of pitch patterns.
Surviving in a complex and changeable environment relies on the ability to extract probable recurring patterns. Here we report a neurophysiological mechanism for rapid probabilistic learning of a new system of music. Participants listened to different combinations of tones from a previously unheard system of pitches based on the Bohlen-Pierce scale, with chord progressions that form 3:1 ratios in frequency, notably different from 2:1 frequency ratios in existing musical systems. Event-related brain potentials elicited by improbable sounds in the new music system showed emergence over a 1 h period of physiological signatures known to index sound expectation in standard Western music. These indices of expectation learning were eliminated when sound patterns were played equiprobably, and covaried with individual behavioral differences in learning. These results demonstrate that humans use a generalized probability-based perceptual learning mechanism to process novel sound patterns in music.


Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10.
A major goal of HIV research is to develop vaccines reproducibly eliciting broadly neutralizing Abs (bNAbs); however, this has proved to be challenging. One suggested explanation for this difficulty is that epitopes seen by bNAbs mimic self, leading to immune tolerance. We generated knock-in mice expressing bNAb 4E10, which recognizes the membrane proximal external region of gp41. Unlike b12 knock-in mice, described in the companion article (Ota et al. 2013. J. Immunol. 191: 3179-3185), 4E10HL mice were found to undergo profound negative selection of B cells, indicating that 4E10 is, to a physiologically significant extent, autoreactive. Negative selection occurred by various mechanisms, including receptor editing, clonal deletion, and receptor downregulation. Despite significant deletion, small amounts of IgM and IgG anti-gp41 were found in the sera of 4E10HL mice. On a Rag1⁻/⁻ background, 4E10HL mice had virtually no serum Ig of any kind. These results are consistent with a model in which B cells with 4E10 specificity are counterselected, raising the question of how 4E10 was generated in the patient from whom it was isolated. This represents the second example of a membrane proximal external region-directed bNAb that is apparently autoreactive in a physiological setting. The relative conservation in HIV of the 4E10 epitope might reflect the fact that it is under less intense immunological selection as a result of B cell self-tolerance. The safety and desirability of targeting this epitope by a vaccine is discussed in light of the newly described bNAb 10E8.


Thrombin induces epithelial-mesenchymal transition and collagen production by retinal pigment epithelial cells via autocrine PDGF-receptor signaling.
De-differentiation of RPE cells into mesenchymal cells (epithelial-mesenchymal transition; EMT) and associated collagen production contributes to development of proliferative vitreoretinopathy (PVR). In patients with PVR, intraocular coagulation cascade activation occurs and may play an important initiating role. Therefore, we examined the effect of the coagulation proteins factor Xa and thrombin on EMT and collagen production by RPE cells. Retinal pigment epithelial cells were stimulated with factor Xa or thrombin and the effect on zonula occludens (ZO)-1, α-smooth muscle actin (α-SMA), collagen, and platelet-derived growth factor (PDGF)-B were determined by real-time quantitative-polymerase chain reaction (RQ-PCR), immunofluorescence microscopy, and HPLC and ELISA for collagen and PDGF-BB in culture supernatants, respectively. PDGF-receptor activation was determined by phosphorylation analysis and inhibition studies using the PDGF-receptor tyrosine kinase inhibitor AG1296. Thrombin reduced ZO-1 gene expression (P < 0.05) and enhanced expression of the genes encoding α-SMA and the pro-alpha1 chain of collagen type-1 (P < 0.05), indicating EMT. Also, ZO-1 protein expression declined on thrombin stimulation, whereas production of α-SMA and collagen increased. In contrast to thrombin, factor Xa hardly stimulated EMT by RPE. Thrombin clearly induced PDGF-BB production and PDGF-Rβ chain phosphorylation in RPE. Moreover, AG1296 significantly blocked the effect of thrombin on EMT and collagen production. Our findings demonstrate that thrombin is a potent inducer of EMT by RPE via autocrine activation of PDGF-receptor signaling. Coagulation cascade-induced EMT of RPE may thus contribute to the formation of fibrotic retinal membranes in PVR and should be considered as treatment target in PVR.


Usefulness of fusion images of unenhanced and contrast-enhanced arterial phase cone-beam CT in the detection of viable hepatocellular carcinoma during transarterial chemoembolization.
We aimed to evaluate the diagnostic efficacy of fusion imaging of unenhanced and arterial phase contrast-enhanced cone-beam computed tomography (CBCT) by comparing with multidetector computed tomography (MDCT) in detection of viable hepatocellular carcinoma (HCC) in patients who have been previously treated with transarterial chemoembolization (TACE). In this retrospective study, a total of 173 tumors in 33 known HCC patients (21 men, 12 women; mean age, 64±7.6 years; mean tumor size, 2.15±1.70 cm) who had been previously treated with TACE and underwent additional session of TACE were included. The sensitivity and positive predictive values of preprocedural MDCT and fusion CBCT for detection of viable tumor were analyzed with follow-up MDCT images performed 3-4 weeks after TACE, as reference standard. A total of 141 remote and 32 marginal viable tumors were included. The sensitivities for detection of remote, marginal, and total viable tumors were 80.9%, 68.8%, and 78.6% for MDCT and 96.5%, 96.9%, and 96.5% for fusion CBCT, respectively. The positive predictive values for detection of remote, marginal, and total viable tumors were 95.0%, 78.6%, and 95.8% for MDCT, and 97.1%, 88.6%, and 97.7% for fusion CBCT, respectively. Fusion CBCT showed statistically higher sensitivity and positive predictive value for detection of viable tumors (P < 0.001). The diagnostic performance of fusion imaging of unenhanced and contrast-enhanced arterial phase CBCT was superior to MDCT for detection of viable HCCs.


Enterobacteriaceae Sepsis Outcome Programme annual report, 2013.
The Australian Group on Antimicrobial Resistance performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric Gram-negative pathogens. The 2013 survey focussed for the first time on blood stream infections. Four thousand nine hundred and fifty-eight Enterobacteriaceae species were tested using commercial automated methods (Vitek® 2, BioMérieux; Phoenix™, BD). The results were analysed using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (January 2014). Of the key resistances, non-susceptibility to the third-generation cephalosporin, ceftriaxone, was found in 7.5%/7.5% (CLSI/EUCAST criteria respectively) of Escherichia coli; 6.3%/6.3% of Klebsiella pneumoniae, and 7.4%/7.4% of K. oxytoca. Non-susceptibility rates to ciprofloxacin were 10.3%/11.3% for E. coli, 4.6%/7.5% for K. pneumoniae, 0.6%/0.6% for K. oxytoca, and 3.6%/6.1% in Enterobacter cloacae. Resistance rates to piperacillin-tazobactam were 3.1%/6.2%, 4.2%/7.0%, 11.9% /12.6%, and 17.3% /22.2% for the same 4 species respectively. Fourteen isolates were shown to harbour a carbapenemase gene, 9 blaIMP, 3 blaKPC, and 2 blaNDM.


Expression of a prostate-associated protein, human glandular kallikrein (hK2), in breast tumours and in normal breast secretions.
The recent demonstration of human glandular kallikrein (hK2) expression in a breast carcinoma cell line has suggested that this putatively prostate-restricted, steroid hormone-regulated protease may also be expressed in breast epithelium in vivo and secreted into the mammary duct system. Given that the only substrate yet identified for hK2 activity is the precursor of prostate-specific antigen (PSA), the expression of which in breast carcinomas may be associated with favourable prognosis, our purpose was to examine the expression pattern of both hK2 and PSA in breast tumour tissues. Cytosolic extracts of 336 primary breast carcinomas prepared for routine oestrogen receptor (ER) and progesterone receptor (PR) analysis, as well as 31 nipple aspirates from six women with non-diseased mammary glands, were assayed for hK2 and PSA using immunofluorometric assays developed by the authors. In the tumour extracts, measurable hK2 and PSA concentrations were detected in 53% and 73% of cases respectively, and were positively correlated to each other (r = 0.59, P = 0.0001). Higher concentrations of PSA and hK2 were found in tumours expressing steroid hormone receptors (P = 0.0001 for PSA and P = 0.0001 for hK2, by Wilcoxon tests for both ER and PR), and both PSA (r = 0.25, P = 0.0001) and hK2 (r = 0.22, P = 0.0001) correlated directly with PR levels. A negative correlation between patient age and PSA (r = -0.12, P = 0.03) was also found. Both proteins were present in nipple aspirate fluid at relatively high concentrations which were positively correlated (r = 0.53, P = 0.002). The molecular weights of the immunoreactive species quantified by the hK2 and PSA assays were established by high-performance liquid chromatography (HPLC) and were consistent with the known molecular weights of hK2 and PSA. Together these data provide the first evidence, to our knowledge, that both malignant breast tissue and normal breast secretion contain measurable quantities of hK2, and that the degree of hK2 expression or secretion is directly proportional to the expression of PSA and steroid hormone receptors. hK2 expression may therefore be a marker of steroid hormone action in breast tissue.


Phase I/II Trial Evaluating Carbon Ion Radiotherapy for Salvaging Treatment of Locally Recurrent Nasopharyngeal Carcinoma.
Radiation therapy is the mainstay strategy for the treatment of nasopharyngeal cancer (NPC). Intensity-modulated X-ray therapy (IMXT) alone is the current standard for stage I and II NPC. For stage III and IV A/B diseases, concurrent chemotherapy should be provided in addition to IMXT. However, optimal treatment for locally recurrent NPC after previous definitive dose of radiotherapy is lacking. Various techniques including brachytherapy, IMXT, stereotactic radiosurgery or radiotherapy (SRS or SBRT) have been used in the management of locally recurrent NPC. Due to the inherent limitation of these techniques, i.e., limited range of irradiation or over-irradiation to surrounding normal tissues, moderate efficacy has been observed at the cost of severe toxicities. Carbon ion radiotherapy (CIRT) offers potential physical and biological advantages over photon and proton radiotherapy. Due to the inverted dose profile of particle beams and their greater energy deposition within the Bragg peak, precise dose delivery to the target volume(s) without exposing the surrounding organs at risk to extra doses is possible. In addition, CIRT provides an increased relative biological effectiveness (RBE) as compared to photon and proton radiotherapy. Such advantages may translate to improved outcomes after irradiation in terms of disease control in radio-resistant and previously treated, recurrent malignancies. It is therefore reasonable to postulate that recurrent NPC after high-dose radiotherapy could be more resistant to re-irradiation using photons. Reports on the treatment of radio-resistant malignancies in the head and neck region such as melanoma, sarcoma, and adenoid cystic carcinoma (ACC) have demonstrated superior local control rates from CIRT as compared to photon irradiation. Thus patients with recurrent NPC are likely to benefit from the enhanced biological effectiveness of carbon ions. As effective retreatment strategy is lacking for locally recurrent NPC, carbon ion radiation therapy offers an ideal alternate to conventional X-ray irradiation. The recommended dose of re-irradiation using CIRT for locally recurrent NPC will be determined in the dose-escalating phase (Phase I) of the study. Efficacy in terms of local progression-free survival (LPFS) and overall survival (OS) will be studied in the second phase of the study. Increasing doses of CIRT using raster scanning technology from 55GyE (22×2.5 GyE) to 65 GyE (26× 2.5 GyE) will be delivered in the Phase I part of the study. The primary endpoint of the Phase I part of the study is acute and sub-acute toxicities; the primary endpoint in the Phase II part is local progression-free survival and overall survival. Using the historical 2-year OS rate of 50% in locally recurrent NPC patients treated with photon or proton, we hypothesize that CIRT can improve the 2-year OS rate to 70%. The utilization of conventional radiation techniques including IMXT, brachytherapy, or stereotactic radiation therapy provides moderate efficacy in the treatment of locally recurrent NPC due to the limitations in dose distribution and biological effectiveness. Improved outcome in terms of treatment-induced toxicity, LC, LPFS, and OS are expected using CIRT due to the physical and biological characteristics of carbon ion beam. However, the recommended dose of CIRT used in re-irradiation for the local NPC focus remain to be determined. The recommended dose as well as the efficacy of CIRT in the treatment of locally recurrent NPC will be evaluated in the present trial.


[Perceptions and use of collective health by surgeon dentists egress from Federal University of Goiás].
The present time is demanding for the dentists the challenge of reviewing the conception of health attention. The Brazilian National Curriculum Guidance (DCN) suggests changes in graduation, strengthening SUS. The aim of this study was to know the perceptions and uses of the collective health knowledge in the daily practice of the dentists graduated at the Federal University of Goiás in the years of 2000, 2001 and 2002. It was used the methodology of triangulation overlapping technique. Results indicated that 83.3% of the graduated are working as dentists. After graduation, 68.1% attended post graduation courses, specialization. They have doubts about collective health actions in spite of saying that practice them. This indicates that the terminology of collective health still remain unclear. Those who work in the public health system accomplished more actions in the field. They related, as difficulties, the lack of complementary material and little valorization by the population of this kind of activity. The most remembered item was health promotion (100%) and the most used in the practice were education and prevention (60%). The practices during the practical stages were considered very important. It is necessary to be clearer during the course about the collective health practices and deeper curriculum integration.


Hierarchical structures of amorphous solids characterized by persistent homology.
This article proposes a topological method that extracts hierarchical structures of various amorphous solids. The method is based on the persistence diagram (PD), a mathematical tool for capturing shapes of multiscale data. The input to the PDs is given by an atomic configuration and the output is expressed as 2D histograms. Then, specific distributions such as curves and islands in the PDs identify meaningful shape characteristics of the atomic configuration. Although the method can be applied to a wide variety of disordered systems, it is applied here to silica glass, the Lennard-Jones system, and Cu-Zr metallic glass as standard examples of continuous random network and random packing structures. In silica glass, the method classified the atomic rings as short-range and medium-range orders and unveiled hierarchical ring structures among them. These detailed geometric characterizations clarified a real space origin of the first sharp diffraction peak and also indicated that PDs contain information on elastic response. Even in the Lennard-Jones system and Cu-Zr metallic glass, the hierarchical structures in the atomic configurations were derived in a similar way using PDs, although the glass structures and properties substantially differ from silica glass. These results suggest that the PDs provide a unified method that extracts greater depth of geometric information in amorphous solids than conventional methods.


Anaesthesia ventilators.
Anaesthesia ventilators are an integral part of all modern anaesthesia workstations. Automatic ventilators in the operating rooms, which were very simple with few modes of ventilation when introduced, have become very sophisticated with many advanced ventilation modes. Several systems of classification of anaesthesia ventilators exist based upon various parameters. Modern anaesthesia ventilators have either a double circuit, bellow design or a single circuit piston configuration. In the bellows ventilators, ascending bellows design is safer than descending bellows. Piston ventilators have the advantage of delivering accurate tidal volume. They work with electricity as their driving force and do not require a driving gas. To enable improved patient safety, several modifications were done in circle system with the different types of anaesthesia ventilators. Fresh gas decoupling is a modification done in piston ventilators and in descending bellows ventilator to reduce th incidence of ventilator induced volutrauma. In addition to the conventional volume control mode, modern anaesthesia ventilators also provide newer modes of ventilation such as synchronised intermittent mandatory ventilation, pressure-control ventilation and pressure-support ventilation (PSV). PSV mode is particularly useful for patients maintained on spontaneous respiration with laryngeal mask airway. Along with the innumerable benefits provided by these machines, there are various inherent hazards associated with the use of the ventilators in the operating room. To use these workstations safely, it is important for every Anaesthesiologist to have a basic understanding of the mechanics of these ventilators and breathing circuits.


Host-pathogen interactions during entry and actin-based movement of Listeria monocytogenes.
Listeria monocytogenes is a pathogenic bacterium that induces its own uptake into mammalian cells, and spreads from one cell to another by an actin-based motility process. Entry into host cells involves the bacterial surface proteins InlA (internalin) and InlB. The receptor for InlA is the cell adhesion molecule E-cadherin. InlB-mediated entry requires activation of the host protein phosphoinositide (PI) 3-kinase, probably in response to engagement of a receptor. Actin-based movement of L. monocytogenes is mediated by the bacterial surface protein ActA. The N-terminal region of this protein is necessary and sufficient for polymerization of host cell actin. Other host proteins involved in bacterial motility include profilin, Vasodilator-Stimulated Phosphoprotein (VASP), the Arp2/Arp3 complex, and cofilin. Studies of entry and intracellular movement of L. monocytogenes could lead to a better understanding of receptor-ligand signaling and dynamics of actin polymerization in mammalian cells.


Shedding Light on Living Cells.
An overview of the optical methods available to modulate the cellular activity in cell cultures and biological tissues is presented, with a focus on the use of exogenous functional materials that absorb electromagnetic radiation and transduce it into a secondary stimulus for cell excitation, with high temporal and spatial resolution. Both organic and inorganic materials are critically evaluated, for in vitro and in vivo applications. Finally, as a direct practical application of optical-stimulation techniques, the most recent results in the realization of artificial visual implants are discussed.


Persistently high estimates of late night, indoor exposure to malaria vectors despite high coverage of insecticide treated nets.
It has been speculated that widespread and sustained use of insecticide treated bed nets (ITNs) for over 10 years in Asembo, western Kenya, may have selected for changes in the location (indoor versus outdoor) and time (from late night to earlier in the evening) of biting of the predominant species of human malaria vectors (Anopheles funestus, Anopheles gambiae sensu stricto, and Anopheles arabiensis). Mosquitoes were collected by human landing catches over a six week period in June and July, 2011, indoors and outdoors from 17 h to 07 h, in 75 villages in Asembo, western Kenya. Collections were separated by hour of the night, and mosquitoes were identified to species and tested for sporozoite infection with Plasmodium falciparum. A subset was dissected to determine parity. Human behavior (time going to bed and rising, time spent indoors and outdoors) was quantified by cross-sectional survey. Data from past studies of a similar design and in nearby settings, but conducted before the ITN scale up commenced in the early 2000s, were compared with those from the present study. Of 1,960 Anopheles mosquitoes collected in 2011, 1,267 (64.6%) were morphologically identified as An. funestus, 663 (33.8%) as An. gambiae sensu lato (An. gambiae s.s. and An. arabiensis combined), and 30 (1.5%) as other anophelines. Of the 663 An. gambiae s.l. collected, 385 were successfully tested by PCR among which 235 (61.0%) were identified as An. gambiae s.s. while 150 (39.0%) were identified as An. arabiensis. Compared with data collected before the scale-up of ITNs, daily entomological inoculation rates (EIRs) were consistently lower for An. gambiae s.l. (indoor EIR = 0.432 in 1985-1988, 0.458 in 1989-1990, 0.023 in 2011), and An. arabiensis specifically (indoor EIR = 0.532 in 1989-1990, 0.039 in 2009, 0.006 in 2011) but not An. funestus (indoor EIR = 0.029 in 1985-1988, 0.147 in 1989-1990, 0.010 in 2009 and 0.103 in 2011). Sporozoite rates were lowest in 2009 but rose again in 2011. Compared with data collected before the scale-up of ITNs, An. arabiensis and An. funestus were more likely to bite outdoors and/or early in the evening (p < 0.001 for all comparisons). However, when estimates of human exposure that would occur indoors (πi) or while asleep (πs) in the absence of an ITN were generated based on human behavioral patterns, the changes were modest with >90% of exposure of non-ITN users to mosquito bites occurring while people were indoors in all years. The proportion of bites occurring among non-ITN users while they were asleep was ≥90% for all species except for An. arabiensis. For this species, 97% of bites occurred while people were asleep in 1989-1990 while in 2009 and 2011, 80% and 84% of bites occurred while people were asleep for those not using ITNs. Assuming ITNs prevent a theoretical maximum of 93.7% of bites, it was estimated that 64-77% of bites would have occurred among persons using nets while they were asleep in 1989-1990, while 20-52% of bites would have occurred among persons using nets while they were asleep in 2009 and 2011. This study found no evidence to support the contention that populations of Anopheles vectors of malaria in Asembo, western Kenya, are exhibiting departures from the well-known pattern of late night, indoor biting characteristic of these typically highly anthropophilic species. While outdoor, early evening transmission likely does occur in western Kenya, the majority of transmission still occurs indoors, late at night. Therefore, malaria control interventions such as ITNs that aim to reduce indoor biting by mosquitoes should continue to be prioritized.


Ethnicity, control appraisal, coping, and adjustment to chronic pain among black and white Americans.
To identify similarities and differences among non-Hispanic black and white patients in pain appraisal, beliefs about pain, and ways of coping with pain. We also examined the association between these factors (i.e., appraisals, beliefs, coping) and patient perception or subjective experience of their functioning in each ethnic group. Cross-sectional survey of patients with chronic pain at pretreatment assessment. Integrated pain management program at a Veterans Affairs Medical Center in Texas. A total of 128 non-Hispanic black Americans and 354 non-Hispanic white Americans completed self-report measures of pain appraisal, coping, and adjustment that included the Multidimensional Pain Inventory, Survey of Pain Attitudes, Coping Strategies Questionnaire, and Chronic Pain Coping Inventory. Although the analyses indicated many similarities between the two groups concerning pain-related beliefs and coping, the black patients reported lower perceived control over pain, more external pain-coping strategies, and a stronger belief that others should be solicitous when they experience pain. The black patients also reported significantly higher levels of depression and disability, even after controlling for pain severity. Regression analyses revealed that the coping and appraisal factors predicting physical and psychological functioning were the same for both white and black patients, with ethnicity accounting for a nonsignificant amount of the total variance. The current findings suggest similarities as well as differences between non-Hispanic black and white patients in the ways they view and cope with pain. However, the association between psychological factors (attitudes and beliefs, coping responses) and adjustment to chronic pain was comparable for both ethnic groups. If replicated, the findings suggest that specific tailoring of cognitive behavioral therapies to different racial/ethnic groups may not be needed to maximize treatment outcome.


Immigrant residential segregation in U.S. metropolitan areas, 1990-2000.
This paper examines the extent of spatial assimilation among immigrants of different racial and ethnic origins. We use restricted data from the 1990 and 2000 censuses to calculate the levels of dissimilarity by race and Hispanic origin, nativity, and year of entry, and then run multivariate models to examine these relationships. The findings provide broad support for spatial assimilation theory. Foreign-born Hispanics, Asians, and blacks are more segregated from native-born non-Hispanic whites than are the U.S.-born of these groups. The patterns for Hispanics and Asians can be explained by the average characteristics of the foreign-born that are generally associated with higher levels of segregation, such as lower levels of income, English language ability, and home ownership. We also find that immigrants who have been in the United States for longer periods are generally less segregated than new arrivals, and once again, much of this difference can be attributed to the characteristics of immigrants. However, patterns also vary across groups. Levels of segregation are much higher for black immigrants than for Asian, Hispanic, and white immigrants. In addition, because black immigrants are, on average, of higher socioeconomic status than native-born blacks, such characteristics do not help explain their very high levels of segregation.


Estradiol and body weight during temporally targeted food restriction: Central pathways and peripheral metabolic factors.
We used temporally-targeted food restriction (TTFR), in which ovariectomized rats had chow only for 2 h/day, to test the hypothesis that estradiol benzoate (EB) suppresses feeding and decreases body weight during brief (4 day) TTFR, as it does during ad libitum feeding. All rats lost weight during TTFR, but the loss was greater with EB treatment. However, OIL and EB-treated rats ate comparable amounts of chow during TTFR. We next investigated central nervous system pathways and peripheral hormonal and metabolic changes that accompany the effects of TTFR to determine the mechanism for this effect. Immunolabeling for fos in the nucleus of the solitary tract, the terminal site of vagal afferents from the gastrointestinal tract, was increased when rats on TTFR had access to chow for 1 h on the test day, indicating neuronal activation associated with consumption of the meal. However, fos immunolabeling was not affected by EB treatment, nor were numbers of the α subtype of estrogen receptors. TTFR had the expected effects on carbohydrate and lipid metabolites and metabolic hormones, with only slight differences in plasma glucose, triglycerides, and free fatty acids attributable to EB treatment. Interestingly, plasma corticosterone levels were greater in EB-treated rats on TTFR, and increased further after eating. Given that corticosterone affects metabolism, these findings suggest that elevated corticosterone may explain the persistence of EB-induced differences in body weight during TTFR despite the lack of effect on food intake.


Reducing Magnesium within Seawater Used in Mineral Processing to Improve Water Recovery and Rheological Properties When Dewatering Clay-Based Tailings.
In areas where access to water for mineral processing is limited, the direct use of seawater in processing has been considered as an alternative to the expense of its desalination. However, efficient flotation of copper sulfides from non-valuable phases is best achieved at a pH > 10.5, and raising the pH of seawater leads to magnesium precipitates that adversely affect subsequent tailings dewatering. Seawater pre-treatment with lime can precipitate the majority of magnesium present, with these solids then being removed by filtration. To understand how such treatment may aid tailings dewatering, treated seawater (TSw) was mixed with raw seawater (Rsw) at different ratios, analyzing the impact on the flocculated settling rate, aggregate size as measured by focused beam reflectance measurement (FBRM), and vane yield stress for two synthetic clay-based tailings. A higher proportion of Tsw (10 mg/L Mg2+) led to larger aggregates and higher settling rates at a fixed dosage, with FBRM suggesting that higher calcium concentrations in Tsw may also favor fines coagulation. The yield stress of concentrated suspensions formed after flocculation decreased with higher proportions of Tsw, a consequence of lower flocculant demand and the reduced presence of precipitates; while the latter is a minor phase by mass, their high impact on rheology reflects a small particle size. Reducing magnesium concentrations in seawater in advance of use in processing offers advantages in the water return from thickening and subsequent underflow transport. However, this may not require complete removal, with blending Tsw and Rsw an option to obtain acceptable industrial performance.


Blood pressure measurement in research.
The aim of this paper is to summarize the issues raised during a consensus conference on the role of different blood pressure (BP) monitoring techniques in research, including pathophysiological studies, clinical outcome trials and clinical pharmacology trials. This review includes the contribution of the participants in a task force at the Eighth Consensus Conference on Ambulatory BP Monitoring (October 28-31, 2001, Sendai, Japan) and the results of a discussion open to all conference participants. Individual contributions have been summarized together with the points raised during the subsequent discussion, and the main statements are also presented in a table format. (1) BP monitoring in pathophysiological studies. The essential role played by continuous BP monitoring in this field had been acknowledged, and further development of non-invasive beat-by-beat monitoring techniques has been advocated. (2) BP monitoring in clinical trials. In clinical trials automated ambulatory BP monitoring (ABPM) and self BP measurements (SBPM) at home share similar advantages, with specific features that make these approaches not alternative solutions but rather approaches able to complement each other. A few examples of application of ABPM and SBPM in clinical trials include the Treatment of Hypertension according to Home or Office Blood Pressure (THOP) trial and the Trial of Preventing Hypertension (TROPHY). (3) Use of ABPM in clinical pharmacology studies. Use of ABPM is now an established routine, aimed at describing the 24-h effect of new antihypertensive drugs. An example of these applications that was discussed in the conference is the use of ABPM in the evaluation of a new long-acting calcium channel blocker (Barnidipine) (J-MUBA study). (4) Specific models for the analysis of BP fluctuations. The features characterizing the chronobiological approach to description of 24-h BP profiles and its limitations (mainly consisting of the high risk of data over-modelling) are discussed. Also the possible occurrence of a circaseptan (approximately with a 7-day period) rhythm in BP has been addressed, although repeated performance of 24-h ABPM over a week obviously faces a number of practical problems. (5) Progress in technology: BP monitoring and telemedicine. The possibility to implement an interactive telemonitoring system of home SBPM values and the perspectives for a clinical application of this technology in the Hypertension Objective treatment based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) trial is discussed.


Kynurenine 3-Monooxygenase Inhibition during Acute Simian Immunodeficiency Virus Infection Lowers PD-1 Expression and Improves Post-Combination Antiretroviral Therapy CD4+ T Cell Counts and Body Weight.
The kynurenine pathway (KP) is a key regulator of many important physiological processes and plays a harmful role in cancer, many neurologic conditions, and chronic viral infections. In HIV infection, KP activity is consistently associated with reduced CD4 T cell counts and elevated levels of T cell activation and viral load; it also independently predicts mortality and morbidity from non-AIDS events. Kynurenine 3-monooxygenase (KMO) is a therapeutically important target in the KP. Using the nonhuman primate model of SIV infection in rhesus macaques, we investigated whether KMO inhibition could slow the course of disease progression. We used a KMO inhibitor, CHDI-340246, to perturb the KP during early acute infection and followed the animals for 1 y to assess clinical outcomes and immune phenotype and function during pre-combination antiretroviral therapy acute infection and combination antiretroviral therapy-treated chronic infection. Inhibition of KMO in acute SIV infection disrupted the KP and prevented SIV-induced increases in downstream metabolites, improving clinical outcome as measured by both increased CD4+ T cell counts and body weight. KMO inhibition increased naive T cell frequency and lowered PD-1 expression in naive and memory T cell subsets. Importantly, early PD-1 expression during acute SIV infection predicted clinical outcomes of body weight and CD4+ T cell counts. Our data indicate that KMO inhibition in early acute SIV infection provides clinical benefit and suggest a rationale for testing KMO inhibition as an adjunctive treatment in SIV/HIV infection to slow the progression of the disease and improve immune reconstitution.


Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children.
Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).


Iodine-129 in waterfowl muscle from a radioactive leaching pond complex in southeastern Idaho.
Waterfowl were collected at radioactive leaching ponds, an adjacent sewage lagoon on the Idaho National Engineering Laboratory ( INEL ) and on nearby control areas to determine 129I / 127I (stable isotope) atom ratios in muscle tissue. Iodine-129/127 atom ratios in muscle tissue averaged about 1.6 X 10(-6) for wild waterfowl from the leaching pond, 1.6 X 10(-6) for waterfowl from the sewage pond, and 1.3 X 10(-6) for control samples. A group of wing-clipped waterfowl placed on the ponds for 2-156 days had average 129I / 127I atom ratios in muscle of 6.0 X 10(-6). Iodine-129/127 atom ratios in muscle were statistically higher (P less than 0.05) in the wing-clipped waterfowl than in control, sewage lagoon and wild waterfowl samples because of the extended period of time they spent on the ponds. Internal lifetime whole-body dose from 129I was estimated to be 1.0 X 10(-5) mrad for waterfowl from control areas and 3.0 X 10(-5) mrad for leaching pond waterfowl. The lifetime thyroid dose commitment to man consuming a wild duck from the leaching ponds was 1.3 X 10(-4) mrem. Liquid effluents disposed in the radioactive leaching ponds do not appear to cause an appreciable increase in 129I / 127I atom ratios in tissues of waterfowl using the ponds.


Can Personality Type Explain Heterogeneity in Probability Distortions?
There are two regularities we have learned from experimental studies of choice under risk. The first is that the majority of people weigh objective probabilities non-linearly. The second regularity, although less commonly acknowledged, is that there is a large amount of heterogeneity in how people distort probabilities. Despite of this, little effort has been made to identify the source of heterogeneity. In this paper, we explore the possibility that personality type is linked to probability distortions. Using validated psychological questionnaires, we clustered participants into distinct personality types: motivated, impulsive, and affective. We found that the motivated viewed gambling more attractive, whereas the impulsive were the most capable of discriminating non-extreme probabilities. Our results suggest that the observed heterogeneity in probability distortions may be explained by personality profiles, which can be elicited though standard psychological questionnaires.


Effect of fluoride varnish and chlorhexidine-thymol varnish on mutans streptococci levels in human dental plaque: a double-blinded randomized controlled trial.
Recent systematic reviews on clinical trials comparing the efficacy of chlorhexidine and fluoride varnish found that the evidence was inconclusive and further well-conducted randomized controlled clinical trials were advocated. To compare the effect of fluoride varnish (F) and Chlorhexidine-thymol varnish (CHX/T) with intensive application regimen on mutans streptococci (MS) levels in human dental plaque. Seventy-five subjects between 6 and 10 years of age were allocated into three groups: Group 1-F varnish (n = 29); Group 2-CHX/T varnish(n = 29); Group 3-placebo varnish (n = 17) by stratified block randomization. After baseline plaque samples were obtained, varnish application was applied and repeated at an interval of 3 days in each group. Plaque samples were repeated at 48 h, 1 month, and 3 months. The samples were spread over mitis-salivarius-bacitracin (MSB) culture media, and the colony-forming units per ml (CFU) were measured. In both Groups 1 and 2, Wilcoxon matched-pairs signed-rank test revealed significant differences in log CFU values of MS between baseline and 48 h, baseline and 1 month but no significant difference between baseline and 3 months. An intergroup comparison at different time intervals showed that the difference between three groups was statistically insignificant. F varnish and CHX/T varnish, with an intensive regimen application have equivocal effect on MS levels in dental plaque.


Precocene-I inhibits juvenile hormone biosynthesis, ovarian activation, aggression and alters sterility signal production in bumble bee (Bombus terrestris) workers.
Juvenile hormone (JH) is an important regulator of development and physiology in insects. While in many insect species, including bumble bees, JH functions as gonadotropin in adults, in some highly eusocial insects its role has shifted to regulate social behavior including division of labor, dominance and aggression. Studying JH functions across social insect species is important for understanding the evolution of sociality; however, these studies have been limited because of the inability to reduce JH levels without surgically removing its glandular source, the corpora allata. Precocene is known to inhibit JH biosynthesis in several non-social insects, but has been poorly studied in social insects. Here, we tested whether precocene-I can effectively reduce JH levels in Bombus terrestris workers, and examined its effects on their physiology and behavior. Precocene-I treatment of three-worker groups decreased JH titer and ovarian activation, irrespective of the bees' dominance rank within the group, and was remedied by JH replacement therapy. Precocene-I also decreased aggressiveness and increased ester-sterility signal production; these changes were rank-dependent, and affected mainly the most reproductive and the least aggressive workers, respectively, and could not be remedied by JH replacement therapy. These results clearly confirm the role of JH as a gonadotropin and mediator of aggression in B. terrestris, and indicate that JH effects are associated with worker dominance rank. The ability to chemically reduce JH titer provides us with a non-intrusive method to probe the evolutionary changes associated with JH and the hormonal mechanisms that are associated with reproduction and behavior in social insects.


Composition, acquisition, and distribution of the Vi exopolysaccharide-encoding Salmonella enterica pathogenicity island SPI-7.
Vi capsular polysaccharide production is encoded by the viaB locus, which has a limited distribution in Salmonella enterica serovars. In S. enterica serovar Typhi, viaB is encoded on a 134-kb pathogenicity island known as SPI-7 that is located between partially duplicated tRNA(pheU) sites. Functional and bioinformatic analysis suggests that SPI-7 has a mosaic structure and may have evolved as a consequence of several independent insertion events. Analysis of viaB-associated DNA in Vi-positive S. enterica serovar Paratyphi C and S. enterica serovar Dublin isolates revealed the presence of similar SPI-7 islands. In S. enterica serovars Paratyphi C and Dublin, the SopE bacteriophage and a 15-kb fragment adjacent to the intact tRNA(pheU) site were absent. In S. enterica serovar Paratyphi C only, a region encoding a type IV pilus involved in the adherence of S. enterica serovar Typhi to host cells was missing. The remainder of the SPI-7 islands investigated exhibited over 99% DNA sequence identity in the three serovars. Of 30 other Salmonella serovars examined, 24 contained no insertions at the equivalent tRNA(pheU) site, 2 had a 3.7-kb insertion, and 4 showed sequence variation at the tRNA(pheU)-phoN junction, which was not analyzed further. Sequence analysis of the SPI-7 region from S. enterica serovar Typhi strain CT18 revealed significant synteny with clusters of genes from a variety of saprophytic bacteria and phytobacteria, including Pseudomonas aeruginosa and Xanthomonas axonopodis pv. citri. This analysis suggested that SPI-7 may be a mobile element, such as a conjugative transposon or an integrated plasmid remnant.


Recurrent irritable hip in childhood.
Between 1989 and 1992 we admitted 426 children with an irritable hip, 363 (85.2%) once and 63 (14.8%) on 143 occasions. We assessed the records retrospectively to determine whether the groups differed and in particular whether recurrence was followed by pathological sequelae. We identified no feature which distinguished between them at either presentation. The use of bone isotope scans was greatly increased in recurrent cases, without clinical benefit. No relationship between recurrence and subsequent abnormality was identified, with 22 (42%) of the recurrences taking place in the opposite hip. The only difference was a higher incidence of 'psychosocial factors' recorded in the notes of children who presented on more than two occasions. The incidence of recurrent irritable hip is larger than previously indicated and in the presence of normal radiographs and low-grade clinical signs, more detailed investigation on subsequent admission is unlikely to be helpful.


Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics.
Previous reports concerning the effects of gender and age on steady-state plasma concentrations of clozapine and its major metabolites, norclozapine and clozapine-N-oxide, have been controversial. Since the frequency distribution of the plasma levels is asymmetrical and skewed to the right, the statistical methods (such as analysis of variance and regression analysis) used earlier are actually inappropriate for analyzing the effects of the variables on the concentrations and might contribute to the inconsistent results. The goal of the present study, with befitting statistics, is to measure the potential effect of dose, gender, age, and body weight on plasma levels of clozapine and its 2 major metabolites. We retrospectively analyzed data from a therapeutic drug monitoring study for steady-state plasma clozapine, norclozapine, and clozapine-N-oxide levels that was conducted in a large group of Chinese schizophrenic inpatients (male:female ratio = 83:79; age range, 33.8 +/- 9.3 years). The daily doses of clozapine had ranged from 100 to 900 mg, with a mean +/- SD value of 379.5 +/- 142.2 mg. Plasma concentrations had been measured using high-performance liquid chromatography with ultraviolet detection. Multiple linear regression was adopted to quantify the effects of various factors on the plasma levels. The natural logarithm of the plasma level was used as the dependent variable to overcome the skewness problem. After adjusting the effects of gender, age, and body weight by multiple linear regression, each 1-mg increment in the daily dose could raise the clozapine level by 0.31%, norclozapine by 0.27%, and clozapine-N-oxide by 0.16%. Female patients had 34.9% higher clozapine levels and 36.3% higher norclozapine, with other variables being controlled. No sex differences were demonstrated for clozapine-N-oxide levels. Each 1-year increment in age would elevate the clozapine level by 1.1%, norclozapine by 1.0%, and clozapine-N-oxide by 1.0%. Body weight could not influence the levels of these compounds. The present results suggest that women possess higher plasma levels (about one third higher) of clozapine and norclozapine, but not the N-oxide metabolite. Each addition of 1 year in age elevated clozapine and either metabolite's levels by about 1%. Furthermore, every 1-mg increase in the daily dose raised clozapine and norclozapine concentrations by approximately 0.3%. These findings could assist clinicians in optimizing clozapine dosing strategies.


Relationship between pedal force asymmetry and performance in cycling time trial.
It remains unclear if cyclists with better performance have less asymmetry. Therefore, this study aimed at assessing the relationship between cycling time trial performance and bilateral asymmetries in pedal forces. Ten cyclists/triathletes performed an incremental cycling test to exhaustion to measure maximal oxygen uptake and power output. In a second session, bilateral pedal forces were acquired during a 4-km cycling time trial on the stationary cycle ergometer. Resultant and effective forces were computed along with the index of effectiveness at 500 m sections of the time trial using instrumented pedals. Intra-limb variability and the asymmetry index were calculated for each force variable. Multivariate analysis assessed bilateral differences in pedal forces accounting for power output, pedalling cadence and oxygen uptake of each cyclist. Force variables did not change throughout the test (effective - P=0.98, resultant - P=0.90 and index of effectiveness - P=0.99) with larger force applied by the dominant limb (11-21%). The relationship between asymmetries and performances was strong for the effective force (r=-0.72) but weak for the resultant force (r = 0.01) and for the index of effectiveness (r=-0.29). Substantial asymmetries were observed for the effective force (36-54%), resultant force (11-21%) and for the index of effectiveness (21-32%) at greater range than intra-limb variability (effective force =8-22%, resultant force =5-10% and index of effectiveness =1-3%). Larger asymmetries in effective force were related to better performances during the 4-km time trial with low intra-limb variability for force measures suggesting consistence in asymmetries for individual cyclists.


Northern European adolescent attitudes toward dating violence.
A focus group methodology was used to examine attitudes toward dating violence among 86 adolescents (aged 12-17) from four northern European countries (England, Sweden, Germany, and Belgium). Four superordinate themes were identified from thematic analyses: gender identities, television as the educator, perceived acceptability of dating violence, and the decision to seek help/tell someone. Although violence in relationships was generally not condoned, when violence was used by females, was unintended (despite its consequences), or was in retaliation for infidelity, violence was perceived as acceptable. Adolescents indicated that their views were stereotypical and based solely on stereotypical television portrayals of violence in relationships. Stereotypical beliefs and portrayals generate barriers for victimized males to seek help because of fear of embarrassment.