HIV infection and host genetic mutation among injecting drug-users of northeastern states of India.
A community-based cross-sectional study was conducted among injecting drug-users (IDUs) of the northeastern states of India to understand the host genetic factors that confer resistance to HIV infection. The study aimed at assessing the existence and magnitude of genetic mutations of chemokine receptors, such as CCR2-64I, CCR-5 D-32, and SDF-1-3'A, that are known to confer resistance to HIV infection and progression of disease in some set-ups. In total, 711 IDUs from Manipur, Mizoram, Nagaland, and Meghalaya were sampled for the study. The selected participants were interviewed to study their sociodemography, risk behaviours, and risk perceptions after obtaining their verbal informed consent. The interview was followed by collection of about 5 mL of blood samples by an unlinked anonymous method for studying genetic mutation and HIV infection. All the blood samples were transported to and processed at the clinical medicine laboratory of the National Institute of Cholera & Enteric Diseases, Kolkata, India. The genetic mutations were detected by polymerase chain reaction (PCR) and the restriction fragment length polymorphism (RFLP) assay techniques. The study revealed that 328 (46.1%) IDUs were aged 20-29 years, 305 (42.9%) were aged 30-39 years, and only two (0.3%) were aged above 49 years. The rate of HIV seropositivity varied widely among the IDUs living in different northeastern states that ranged from 4.5% to 61%. There was not a single IDU with CCR5 homozygous mutation. Mutated genes of CCR2-64I and SDF-1-3'A were detected in the frequencies of 49% and 23% respectively in them. The rate of HIV seropositivity in IDUs having CCR2 mutant gene was 27% (n=94) and without mutation was 27% (n=98). Similarly, HIV seropositivity in IDUs with and without SDF1 mutation was 28% (n=46) and 27% (n=146) respectively. Both the differences were not statistically significant. A CCR5 homozygous mutation is known to be the most prominent marker that confers resistance against HIV infection. The absence of CCRS mutant gene in this population suggests that they do not have any additional protection against HIV infection. Analysis also revealed that, although mutation of CCR2 and SDF1 was present in this population, it did not confer any additional resistance against HIV. This indicates that the IDUs of northeastern India are not additionally protected against HIV infection through genetic mutation and are, therefore, vulnerable to acquire HIV infection due to high-risk behaviour and other related factors.


Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.
Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.


Cytochemistry of the functional domains of the nucleus in normal and in pathologic conditions.
By means of ultrastructural cytochemistry significant advances have been made in understanding the functional roles of many nuclear domains. This review gives schematic information about the main nuclear domains involved in replication, transcription, processing and transport of the transcripts in normal and in pathologic conditions. Particular attention is paid to a functional domain that appears to be involved in signal transduction. Data are reported on the intranuclear specific localization of key elements of the polyphosphoinositide signal transduction system in different cell types including human osteosarcoma cell lines. Compared with the compartmentalization of the cytoplasm, the nucleus has long been considered as relatively unstructured. On the other hand, fundamental nuclear functions, such as DNA replication and RNA transcription, can be molecularly characterized also in cell-free systems, suggesting that supramolecular organization is not so strictly required as for other cell functions occurring within intact cytoplasmic organelles. Nevertheless, a stringent organization is required for packing about 200 cm of DNA in the about 30 micron 3 of the nucleus. In the absence of membrane-delimited organelles, the nuclear organization is based on functional compartments, or domains, whose spatial localization involves the nuclear matrix, which shares many properties with the cytoskeleton. The nuclear domains are defined as structural compartments, not necessarily stable but dynamically variable, which perform specific metabolic functions through the partitioning of molecular complexes. Their identification has been made possible in the last few years by the development of specific nuclear probes for confocal and electron microscope immunocytochemistry. Therefore, the complex network of structures and enzymatic functions that make up the nucleus is in several cases yielding to molecular analysis, but a large part remains unknown (Strouboulis and Wolffe, 1996; Laemmli and Tjian, 1996). Rapid advances in understanding the functional role of the nuclear domains have been made recently: in particular, of the nuclear envelope, of the nucleolus, and of RNA splicing. In other cases, e.g. the precise localization of the nuclear domains involved in signal transduction, much remains to be clarified (Forbes and Johnson, 1997). It is conceivable that in the near future unexpected new nuclear domains will come to light and new nuclear functions may emerge, especially in field of post-transcriptional processing and transport of RNAs, and in the relationships between the nucleo-skeleton and enzymic fixed sites involved in replication, transcription and signal transduction. The aim of this review is to provide information about the morphological characteristics, the associated functions and the molecular composition of the main nuclear domains found to date. To simplify the exposition, the main data on each nuclear domain are reported in Tables, together with the principal references on the subject. Figures refer to original findings on some aspects of nuclear domain organization.


Apparent diffusion coefficient of the superior cerebellar peduncle differentiates progressive supranuclear palsy from Parkinson's disease.
The early diagnosis of progressive supranuclear palsy (PSP) may be challenging, because of clinical overlapping features with Parkinson's disease (PD) and other parkinsonian syndromes such as the Parkinsonian variant of multiple system atrophy (MSA-P). Conventional MRI can help in differentiating parkinsonian disorders but its diagnostic accuracy is still unsatisfactory. On the basis of the pathological demonstration of superior cerebellar peduncle (SCP) atrophy in patients with PSP, we assessed the SCP apparent diffusion coefficient (ADC) values in patients with PSP, PD, and MSA-P in order to evaluate its differential diagnostic value in vivo. Twenty-eight patients with PSP (14 with possible-PSP and 14 with probable-PSP), 15 PD, 15 MSA-P, and 16 healthy subjects were studied by using diffusion weighted imaging (DWI). ADC was calculated in regions of interest defined in the left and right SCP by two clinically blinded operators. Intrarater (r = 0.98, P < 0.001) and interrater reliability (r = 0.97; P < 0.001) for SCP measurements were high. Patients with PSP had higher SCP rADC values (median 0.98 x 10(-3)mm(2)/s) than patients with PD (median 0.79 x 10(-3) mm(2)/s, P < 0.001), MSA-P (median 0.79 x 10(-3) mm(2)/s, P < 0.001), and healthy controls (median 0.80 x 10(-3) mm(2)/s, P < 0.001). DWI discriminated patients with PSP from PD and healthy subjects on the basis of SCP rADC individual values (100% sensitivity and specificity) and from patients with MSA-P (96.4% sensitivity and 93.3% specificity). The higher values of rADC in SCP of patients with PSP correspond with the in vivo microstructural feature of atrophy detected postmortem and provide an additional support for early discrimination between PSP and other neurodegenerative parkinsonisms.


Actual conditions of the mixing of antineoplastic drugs for injection in hospitals in Osaka Prefecture, Japan.
We conducted a questionnaire survey in order to grasp the actual conditions under which antineoplastic drugs are mixed for injection in hospitals. Questionnaires were sent to all 155 hospitals with 100 or more beds for general patients in Osaka Prefecture, Japan. The response rate was 69.0%. Mixing of antineoplastic drugs was done in 81.3% of the hospitals. The questionnaire was answered by doctors in 17.2% of the hospitals with antineoplastic drugs, nurses in 11.5%, and pharmacists in 70.1%. Mixing of antineoplastic drugs was done by doctors in 58.6% of the hospitals, nurses in 44.8%, and pharmacists in 63.2% (multiple answers). Occupational exposure to antineoplastic drugs was recognized in 97.7% of the hospitals. The mean frequency of the mixing operation was 8.8 d per month per worker. The mean number of antineoplastic drugs handled was 7.4 types. Guidelines for the safe handling of antineoplastic drugs were used in 52.8% of the hospitals and a biological safety cabinet was available in 57.4%. Gloves, mask, gown and goggles were used in 82.7, 69.0, 62.1 and 36.8% of the hospitals, respectively, but no personal protective equipment was used in 10.1%. The safety precautions of the hospitals in which the number of beds was small tended to be fewer than those of the hospitals in which the number of beds was large. Used vials and ampoules were disposed of as clinical, infectious or exclusive antineoplastic drug waste by 74.7% of the hospitals. Safety measures for handling the excrement of patients treated with antineoplastic drugs were performed in 8.0% of the hospitals. In 43.7% of the hospitals, the responders had experienced accidents during antineoplastic drug preparation, such as drugs adhering to hands or eyes, drug leakage, accidental injection and cutting by ampoules. Because of the adverse effects of antineoplastic drugs, all hospitals in which the healthcare workers handle them should promote safety precautions.


Specificity and efficiency of tamoxifen-mediated Cre induction is equivalent regardless of age.
Temporally controlling Cre recombination through tamoxifen (Tam) induction has many advantages for biomedical research. Most studies report early post-natal/juvenile (<2 m.o.) Tam induction, but age-related neurodegeneration and aging studies can require Cre induction in older mice (>12 m.o.). While anecdotally reported as problematic, there are no published comparisons of Tam-mediated Cre induction at early and late ages. Here, microglial-specific Cx3cr1creERT2 mice were crossed to a floxed NuTRAP reporter to compare Cre induction at early (3-6 m.o.) and late (20 m.o.) ages. Specificity and efficiency of microglial labeling at 21-22 m.o. were identical in mice induced with Tam at early and late ages. Age-related microglial translatomic changes were also similar regardless of Tam induction age. Each Cre and flox mouse line should be independently validated, however, these findings demonstrate that Tam-mediated Cre induction can be performed even into older mouse ages and should be generalizable to other inducible Cre models.


Race, Calcineurin Inhibitor Exposure, and Renal Function After Solid Organ Transplantation.
Calcineurin-inhibitor (CNI)-induced nephrotoxicity frequently complicates transplantation. African-Americans are at a greater risk of renal failure than the general population. We investigated whether race was an effect modifier of the relationship between CNI exposure and kidney function after nonrenal solid organ transplantation. This is a retrospective cohort study of 1609 patients who underwent initial nonrenal solid organ transplantation between January 2000 and June 2012. A central repository administrative database was queried electronically for demographics, comorbidities, and serial levels of tacrolimus, cyclosporine, and serum creatinine. Predictors of interest were total drug exposure of tacrolimus and cyclosporine (area under the concentration-time curve) and self-reported race. The outcome of interest was cumulative change in estimated glomerular filtration rate (GFR). There were 1109 patients treated with tacrolimus (271 African-Americans) and 500 patients treated with cyclosporine (113 African Americans). A decline in GFR over time was seen with total tacrolimus exposure (-1.3 mL/min/1.73 m(2) for every 5 ng/mL·year increase in tacrolimus) and total cyclosporine exposure (-1.1 mL/min/1.73 m(2) for every 50 ng/mL·year increase in cyclosporine). However, total CNI exposure effect on estimated GFR changes did not vary by race (P interaction was 0.9 for tacrolimus and 0.6 for cyclosporine). Total CNI exposure is associated with worsening kidney function among patients with nonrenal solid organ transplantation. However, African-American patients are not more vulnerable to chronic CNI-induced nephrotoxicity when compared to white patients.


Exploring expected reward and efficacy in enhancing cognitive control in patients with depression.
Depression is associated with impairments in cognitive control. Considering the lack of mechanistic models accounting for cognitive control deficits in depression, the expected value of control (EVC) theory offers a mechanistic view for allocating cognitive control emphasizing motivational components (efficacy, value). Efficacy refers to the possibility that an effort leads to a special outcome and reward refers to the value (amount) associated with the outcome. This study aimed to examine the role of the EVC in depression. This study used a within-between-subject design. Participants with depression (n = 36) and healthy controls (n = 31) completed a clinical diagnostic interview, the Beck Depression Inventory-II, the General Health Questionnaire-12, and a computer-based incentivized Stroop Color-Word Paradigm in which levels of efficacy (high vs. low) and the amount of rewards (high vs. low) were presented as cues before target stimuli. We found significant interaction effects of group × efficacy and efficacy × reward in terms of reaction time in the Stroop Paradigm. Follow-up analyses indicated the Depressed group were significantly slower than Controls on high efficacy trials, but the two groups did not differ significantly on low efficacy trials. Additionally, on high efficacy trials, reward did not influence performance, but on low efficacy trials, high reward improved performance in both groups. Lack of neurological measures and eye tracking techniques. Overall, our findings suggest that reward and efficacy may jointly improve cognitive control allocation and highlight the need for further research examining EVC theory as a mechanistic account of cognitive control deficits in depression.


The leaky pipeline: factors associated with early decline in interest in premedical studies among underrepresented minority undergraduate students.
To determine the causes among underrepresented racial and ethnic minority groups (URM) of a decline in interest during the undergraduate years in pursuing a career in medicine. From fall 2002 through 2007, the authors conducted a longitudinal study of 362 incoming Stanford freshmen (23% URM) who indicated on a freshman survey that they hoped to become physicians. Using a 10-point scale of interest, the authors measured the change in students' levels of interest in continuing premedical studies between the beginning of freshman year and the end of sophomore year. Follow-up interviews were conducted with 68 participants, approximately half of whom had experienced decreases in interest in continuing as premeds, and half of whom who had experienced increases in interest. URM students showed a larger decline in interest than did non-URM students; women showed a larger decline than did men, independent of race or ethnicity. The authors found no association between scholastic ability as measured by SAT scores and changes in level of interest. The principal reason given by students for their loss of interest in continuing as premeds was a negative experience in one or more chemistry courses. Students also identified problems in the university's undergraduate advising system as a contributor. Largely because of negative experiences with chemistry classes, URM students and women show a disproportionate decline in interest in continuing in premedical studies, with the result that fewer apply to medical school.


Clinical applicability of a methacholine inhalational challenge.
Cough, dyspnea, and chest pain are symptoms common to many cardiopulmonary diseases. A comprehensive evaluation, including a history, physical examination, ECG, chest roentgenogram, and pulmonary function studies, will often yield a specific diagnosis. However, when these symptoms are intermittent, as they often are in patients with bronchial asthma, the diagnosis may not be apparent. If asthma is thought to be a diagnostic possibility, a bronchial inhalation challenge should be used to demonstrate bronchial hyperreactivity, the hallmark of asthma. The methacholine chloride inhalation challenge is a simple and useful laboratory test to diagnose bronchial hyperreactivity. We describe eight patients with a variety of clinical symptoms to demonstrate the usefulness of this test. Patients with unexplained respiratory symptoms should be considered for bronchial inhalation challenge before proceeding to more invasive diagnostic procedures.


Temporal strength changes from resistance exercise and albuterol on unloaded muscle.
To assess unloaded knee extensor temporal strength changes, healthy subjects without asthma performed 40 continuous days of unilateral limb suspension, whereby their left leg refrained from normal weight-bearing and ambulatory activity. During the 40-day period, subjects performed resistance exercise (REX) with their unloaded leg on an inertial resistance ergometer and, as part of a double-blind design, consumed the maximal oral therapeutic dosage of albuterol (i.e., 16 mg.d) or a placebo (i.e., lactose) with no crossover. Workout data were partitioned into 4 10-day periods that ran consecutively. Dependent strength variables included concentric total work, eccentric total work, concentric average power (CAP), and eccentric average power (EAP). Dependent variables were analyzed with 5 (time) x 2 (group) x 2 (gender) mixed factorial analyses of variance and the Tukey honestly significant difference test. Concentric total work, CAP, and EAP each demonstrated a time-group-gender (p < 0.05) interaction. Female REX-placebo subjects had the greatest percentage of unloaded knee extensor strength loss. However, female REX-albuterol subjects fared best throughout the 40-day period and incurred significant unloaded knee extensor strength gains. Differences in strength changes between male and female REX-albuterol subjects was likely due to the higher relative dosage administered to the latter, as body mass showed a gender (i.e., men > women) effect. Future research may elucidate the ideal dose-response relationship for REX-albuterol treatment for use aboard manned space flights and in other disuse models. Coaches and practitioners should carefully examine their sport-governing bodies' rules on albuterol administration and give the drug only if an athlete's health warrants such treatment.


Mockup design of personal health diary app for patients with chronic kidney disease.
Health self-management is important in the care of patients with chronic kidney disease. It is possible to improve the efficiency of patient self-management through the use of mobile technology and related software. This study is divided into three stages: 1. analysis of need: through observation, interview and content analysis of the chronic kidney disease health management manual; 2. design of system prototype: establish interface and system function; 3. prototype evaluation: evaluate whether the prototype designed by this study meets user needs. The system prototype includes: daily record, laboratory examination results, trend graphs, information search, sharing, communications and settings. Prototyping is done with Pencil Project for interface design and linking. The prototype is then exported in PDF format for mock-up simulation. Evaluation results: overall score was 4.01±0.60 leaning towards "agree", the highest score was ease of use (4.25±0.6), followed by easy to learn (4.15±0.68), acceptance (4.01±0.61), reliability (3.87±0.6) and functionality (3.83±0.49). The results show positive attitude towards the system.


Contemporary clinical research of traditional Chinese medicines for chronic hepatitis B in China: an analytical review.
Chronic hepatitis B (CHB) is major global health problem. In China, where about 120,000,000 persons are chronically infected, CHB has been treated for centuries with traditional Chinese medicines (TCMs). This review summarizes and meta-analyzes the results of randomized controlled trials (RCTs) of TCM formulations reported in China in 1998-2008 for treatment of CHB. RCTs comparing either TCM formulations alone or in combination with interferon (IFN) or lamivudine (LAM) versus IFN or LAM were included. Chinese electronic databases were searched. The methodological quality of RCTs was assessed using the Jadad scale. TCMs had a greater beneficial effect (P = 0.0003) than IFN and a slightly better effect (P = 0.01) than LAM on the normalization of serum alanine aminotransferase. TCMs had a similar beneficial effect when compared with IFN or LAM for CHB on antiviral activity as evidenced by the loss of serum hepatitis B e antigen and hepatitis B virus (HBV) DNA. TCMs enhanced IFN and LAM antiviral activities and improvements of liver function. The quality of many studies was poor; reports often lacked information regarding methods of randomization or blinding and adverse events. Some TCMs seem effective as alternative remedies for patients with CHB, suggesting that further study of TCMs in the treatment of CHB is warranted, both in preclinical models of HBV infection and in higher quality RCTs worldwide.


Diagnostic accuracy of probe-based confocal laser endomicroscopy and narrow band imaging for small colorectal polyps: a feasibility study.
Probe-based confocal laser endomicroscopy (pCLE) allows real-time in-vivo microscopic imaging of tissue. Narrow band imaging (NBI) can also classify colorectal lesions. Both systems may allow accurate optical diagnosis of small (6-9 mm) and diminutive (1-5 mm) polyps without histopathology. This study assesses the accuracy of pCLE and NBI for prediction of histology. Participants underwent high-definition colonoscopy. The surface pit pattern of all polyps (1-9 mm) was determined in vivo using NBI. Confocal videos were obtained after administration of IV fluorescein. Recorded videos were subsequently analyzed offline, blinded to endoscopic characteristics, and histopathology. Confocal images were classified as neoplastic and non-neoplastic according to the Miami classification system. A total of 130 polyps (58 neoplastic, 72 non-neoplastic, mean size 4.6 mm) from 65 patients were assessed. Assuming histopathology as gold standard, pCLE had higher sensitivity than NBI (86% vs. 64%, P=0.008), with lower specificity (78% vs. 92%, p=0.027) and similar overall accuracy (82% vs. 79%, P=0.59). When 65 high-confidence cases were analyzed (polyps diagnosed identically with pCLE and NBI and with high-quality confocal videos), sensitivity and specificity were 94 and 97%. pCLE demonstrated higher sensitivity in predicting histology of small polyps compared with NBI, whereas NBI had higher specificity. When used in combination, the accuracy of pCLE and NBI was extremely high, approaching the accuracy of histopathology. Together, they may reduce the need for histological examination. However, further studies are warranted to evaluate the role of these techniques, especially in the population-based colon cancer screening.


Design of a randomized, placebo-controlled study evaluating efficacy and safety of a cancer preventative vaccine in dogs.
Preventative anti-cancer vaccination strategies have long been hampered by the challenge of targeting the diverse array of potential tumor antigens, with successes to date limited to cancers with viral etiologies. Identification and vaccination against frameshift neoantigens conserved across multiple species and tumor histologies is a potential cancer preventative strategy currently being investigated. Companion dogs spontaneously develop cancers at a similar incidence to those in people and are a complementary comparative patient population for the development of novel anti-cancer therapeutics. In addition to an intact immune system with tumors that arise in an autochthonous tumor microenvironment, dogs also have a shorter lifespan and temporally compressed tumor natural history as compared to humans, which allows for more rapid evaluation of safety, immunogenicity, and efficacy of cancer vaccination strategies. Here we describe the study protocol for the Vaccination Against Canine Cancer Study (VACCS), the largest interventional cancer clinical trial conducted in companion dogs to date. In addition to safety and immunogenicity, the primary endpoint of VACCS is the cumulative incidence (CI) of dogs developing malignant neoplasia of any type at the end of the study period. Secondary endpoints include changes in incidence of specific tumor types, survival times following neoplasia diagnosis, and all-cause mortality.


Impact of Phacoemulsification Combined with XEN Gel Stent Implantation on Corneal Endothelial Cell Density: 2-Year Results.
Corneal integrity has long been a preoccupation of glaucoma surgeons considering glaucoma drainage device surgery or antimetabolite-enhanced trabeculectomy. Despite having demonstrated a good safety profile and significant intraocular pressure-lowering capacities, the impact of XEN gel stents on endothelial density was never specifically investigated. The purpose of this study is to assess the effect of XEN gel stents on central endothelial cell density (ECD) over 24 months. To achieve this, we compared the effect on ECD of combined XEN surgery with that of a standard phacoemulsification procedure. This was an investigator-initiated, retrospective study, conducted at a single tertiary glaucoma center. Patients with primary or secondary open-angle glaucoma who underwent XEN implantation combined with phacoemulsification between January 2015 and June 2016 were retrospectively enrolled. Patients who had undergone standalone phacoemulsification over the same period of time were enrolled to form the control group of this comparative study. The primary outcome measure was the ECD. Patients who had undergone standalone XEN implantation and patients for whom both a baseline and 24-month ECD could not be obtained were excluded from the analysis. Percentages of ECD reductions were calculated for each studied eye, and the mean of ECD reductions was calculated for each group as well as for subgroups. Thirty-two eyes of 23 patients (mean age=76.0±7.9 y, 60% female) underwent standalone phacoemulsification (n=15) or combined XEN surgery (n=17) and had an ECD both at baseline and 24-month postoperatively. Mean baseline ECDs were 2568±491 versus 2379±335 cells/mm, respectively (P=0.21). In the combined XEN surgery group, 58.8% of eyes (n=10) required at least 1 mitomycin C (MMC)-enhanced needling revision to maintain their target intraocular pressure. In the standalone phacoemulsification group, ECD decreased by a mean 14.5%, from 2567.7±491.2 to 2196.1±591.9 cell/mm (P=0.072). In the combined XEN surgery group, ECD decreased by a mean 14.3%, from 2378.8±334.7 to 2039.6±451.1 cell/mm (P=0.018). The difference in percentage reduction of ECD between the 2 groups was not statistically significant (P=0.226). Within the combined XEN surgery group, the ECD decreased by a mean of 15.4% in patients who did not undergo needling revisions and by 13.1% in patients who underwent the MMC-augmented procedure (P=0.485). In the 3 patients who underwent >1 needling revision, a 21.3% reduction in ECD was observed, but the difference was not statistically significant (P=0.653). Neither the time of the first needling (P=0.452), the patients' age (P=0.285), or sex (P=0.308) was statistically associated with ECD loss. The present study demonstrated that the XEN gel implant combined with phacoemulsification produces 24-month ECD loss of a similar magnitude to that observed following standalone phacoemulsification. MMC-augmented needling revisions do not appear to have an impact on ECD.


Self-regulatory processes in goal striving during excellent distance-running performances: A qualitative study.
Goal setting can improve endurance performance, yet how endurance performers maintain goal striving and bring it to a successful close has received limited attention. In this study, we investigated the self-regulatory processes employed by long-distance runners during goal striving in excellent competitive performances. Through in-depth, event-focused interviews, we explored 21 long-distance runners' experiences of goal striving in excellent competitive performances (M = 77.43 h post-race). Furthermore, we recruited 10 additional participants with relevant experiences (runner n = 7, coach n = 2; sport psychologist n = 1) for external member-reflection interviews. Through our matrix analysis, we interpreted that by contrasting their current and future goal status periodically throughout their excellent performances, using a process called mental contrasting with implementation intentions (MCII), this helped the runners to make decisions about whether to persist with a goal, or disengage from a goal and reengage with an alternative. Furthermore, our findings depict how these goal decisions unfolded when runners perceived they were behind, equalling, or exceeding their goal(s). We also illustrate how goal revision was used as an adaptive process to maximise performance, and to avert or manage action crises. Our findings extend theoretical understandings of goal striving and the self-regulatory processes endurance performers employ to attain and/or adapt their goals. Psychological support provided for athletes should go beyond simply setting goals, but also include training on mental frameworks such as MCII to manage goal-striving challenges and decisional conflict encountered during performances.


[Placenta accreta--prenatal diagnosis, treatment].
Placenta accreta is a potentially life threatening obstetric condition that requires a multidisciplinary management. Placenta praevia and previous Cesarean section are the two most important known risk factors for placenta accreta. This study presents two patients having both of the foremention risk factors diagnosed ultrasonographically with placenta accreta in the second trimester. Ultrasound findings considered suggestive of placenta accreta are: presence of placental lacunae (vascular spaces), loss of the hyperehoic uterine serosa-bladder wall interface, loss of the retroplacental hypoechoic clear space, hypervascularity of the interface between the uterine wall and the bladder wall/isthmico-cervical zone, presence of placenta praevia, either anterior or posterior, overlying the uterine scar. Both of the cases with suspected placenta accreta ended successfully by planned preterm Cesarean hysterectomy with the placenta left in situ. Placenta accreta is a significant cause of maternal morbidity and mortality and the most common reason for urgent postpartum hysterectomy.


Firework-related Ocular Injuries During Festival Season: A Hospitalbased Study in a Tertiary Eye Care Center of Nepal.
Firework-related ocular injuries are an important cause of preventable ocular injuries and are common during the festival season. Despite the strict legislation in Nepal, the use of a firework is still commonly used during Tihar and Chaath festivals. To evaluate demographic distribution, mode, causative firework, type of fireworks-related ocular injuries, and visual outcome at a tertiary eye hospital in Eastern Nepal. This is a hospital-based prospective interventional study. All the patients with firework-related injuries who attended the emergency and outpatient department of SCEH, Lahan, during or within 1 month of the festival season (Tihar and Chaath puja) were included in this study. Total of 65 eyes were included. The left eye was involved in 49.1%, 82.5% were males. Mean age of the patients was 15.3±14.7 years (range 5yr - 75yr). Children less than 16 years were predominantly involved (77.2%). Firecrackers (56.1%) were the most common type of fireworks causing injury. The closed globe injuries were more (78.5%) compared to open globe injuries (21.5%). Surgical management was done in 50.9% of cases. Following management visual acuity of most patients improved. Only 8 eyes (12.3%) had visual acuity less than 3/60 after management compared to 28 eyes (43.1%) at the time of presentation. Firework related ocular injuries are important causes of preventable blindness. A combined approach of public awareness about the possible dangers, preventive measures, early treatment by trained primary ophthalmic care, and implementation of strict legislations are essential to reduce blindness due to this preventable cause.


The use of a cationic liposome formulation (DOTAP) mixed with a recombinant tumor-associated antigen to induce immune responses and protective immunity in mice.
The cationic liposome DOTAP is a well-known transfection reagent. It has been manufactured and approved for clinical use, is readily available, and can be easily used as an adjuvant. These characteristics prompted us to investigate the effectiveness of DOTAP as an adjuvant to induce immune responses and protective immunity in mice using baculovirus-derived carcinoembryonic antigen (bV-CEA) as a model antigen. Two routes of administration and a dose-response study of bV-CEA were used in BALB/c mice to define the magnitude of the immune response as well as the most effective route of immunization. The results demonstrate differences in antibody titers, immunoglobulin (Ig)G isotype, and T-cell responses between the intravenous (i.v.) or subcutaneous (s.c.) route of immunization. The titer of the anti-CEA antibodies induced by the s.c. immunization was greater than the response by i.v. immunization. The s.c. route enhanced the IgG2a/2b isotype, whereas i.v. immunization elicited primarily IgG1. T-cell proliferation responses and cytokine production paralleled the humoral response (i.e., production was higher in the s.c. immunized animals). No differences in immunological responses were seen using either 25 or 10 microg of bV-CEA three times. An amount of 25 microg of bV-CEA/DOTAP given by s.c. immunization was sufficient in protecting mice from the transplant of syngeneic tumor cells transduced with the human CEA gene. We conclude that the cationic liposome DOTAP may be a useful immunoadjuvant for active anti-tumor immunotherapy in future clinical trials. This study will help to define the most effective way to use such an adjuvant.


[Study on fluorescence spectra of the four heterocyclic compounds in solution].
The fluorescence spectra of the four compounds have been studied. Geometric configurations of the four compounds have been optimized by semi-empirical method RHF/AM1 of quantum chemistry. There is no imaginary frequency in vibrational analysis. Their fluorescence spectra have also been calculated by RHF/CIS. The results of calculation in solution are better agreement with experimental values than in gas phase.


Changes in Diarrheal Disease and Treatment Among Brazilian Children from 1986 to 1996.
We examined changes in diarrhea prevalence and treatment in Brazil between 1986 and 1996. Over this 10-year period there was a small decline in diarrhea prevalence but treatment with oral rehydration therapy (ORT) increased greatly. Deaths due to dehydration were thus averted, although the costly burden of morbidity remained high. The decline in diarrhea prevalence was largely due to changes in the effects of several key covariates, such as breastfeeding, with only a modest role played by socioeconomic change, infrastructure improvements, and other behavioral factors. ORT treatment of diarrhea was essentially unrelated to child and family characteristics, suggesting that the large increase was due to the success of public health efforts to promote its use widely. Our results suggest that the most effective policies for reducing diarrhea prevalence are likely to be further increases in education and the promotion of breastfeeding. Persistent disparities in diarrhea prevalence mean that policies to prevent the disease should be targeted at disadvantaged socioeconomic groups.


Downregulation of major histocompatibility complex class I molecules by Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins.
The T-cell-mediated immune response plays a central role in the defense against intracellular pathogens. To avoid this immune response, viruses have evolved elaborate mechanisms that target and modulate many different aspects of the host's immune system. A target common to many of these viruses is the major histocompatibility complex (MHC) class I molecules. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes K3 and K5 zinc finger membrane proteins which remove MHC class I molecules from the cell surface. K3 and K5 exhibit 40% amino acid identity to each other and localize primarily near the plasma membrane. While K3 and K5 dramatically downregulated class I molecules, they displayed different specificities in downregulation of HLA allotypes. K5 significantly downregulated HLA-A and -B and downregulated HLA-C only weakly, but not HLA-E, whereas K3 downregulated all four HLA allotypes. This selective downregulation of HLA allotypes by K5 was partly due to differences in amino acid sequences in their transmembrane regions. Biochemical analyses demonstrated that while K3 and K5 did not affect expression and intracellular transport of class I molecules, their expression induced rapid endocytosis of the molecules. These results demonstrate that KSHV has evolved a novel immune evasion mechanism by harboring similar but distinct genes, K3 and K5, which target MHC class I molecules in different ways.


A reappraisal, based on (31)P NMR, of the direct coordination of a metal ion with the phosphoryl oxygen at the cleavage site of a hammerhead ribozyme.
It has been generally accepted, on the basis of kinetic studies with phosphorothioate-containing substrates and analyses by NMR spectroscopy, that a divalent metal ion interacts directly with the pro-Rp oxygen at the cleavage site in reactions catalyzed by hammerhead ribozymes. However, results of our recent kinetic studies (Zhou, D.-M.; Kumar, P. K. R.; Zhang. L. H.; Taira, K. J. Am. Chem. Soc. 1996, 118, 8969-8970. Yoshinari, K.; Taira, K. Nucleic Acids Res. 2000, 28, 1730-1742) demonstrated that a Cd(2+) ion does not interact with the sulfur atom at the Rp position of the scissile phosphate (P1.1) in the ground state or in the transition state. Therefore, in the present study, we attempted to determine by (31)P NMR spectroscopy whether a Cd(2+) ion binds to the P1.1 phosphorothioate at the cleavage site in solution. In the case of the R32-S11S (ribozyme-substrate) complex, neither the Rp- nor the Sp-phosphorothioate signal from the S11S substrate at the cleavage site was perturbed (the change was less than 0.1 ppm) upon the addition of Cd(2+) ions (19 equiv) at pH 5.9 and 8.5. By contrast, we detected the significant perturbation of the P9 phosphorothioate signal from another known metal-binding site (the A9/G10.1 metal-binding motif). The Rp-phosphorothioate signal from A9/G10.1 was shifted by about 10 ppm in the higher field direction upon the addition of Cd(2+) ions. These observations support the results of our kinetic analysis and indicate that a Cd(2+) ion interacts with the sulfur atom of the phosphorothioate at the A9/G10.1 site (P9) but that a Cd(2+) ion does not interact with the sulfur atom at the Rp- or at the Sp-position of the scissile phosphate (P1.1) in the ground state.


Parkinson's disease-related visual hallucinations unresponsive to atypical antipsychotics treated with cholinesterase inhibitors: a case series.
I report here clinical effects of cholinesterase inhibitors (rivastigmine and donepezil) on visual hallucinations emerging in the course of Parkinson's disease (PD) and clinically unresponsive to antipsychotics. Five patients with PD (with or without dementia) complicated by visual hallucinations and unresponsive to atypical antipsychotics were offered a 12-week, open-label trial of a cholinesterase inhibitor. All 5 subjects completed the trial with no major adverse effects and, of note, no discontinuations due to adverse events. Visual hallucinations resolved in 4 subjects and were markedly diminished in one person. Neither changes in UPDRS scores nor exaggeration of subjective complaints about extrapyramidal symptoms were noted during treatment. Cholinesterase inhibitors might represent a useful alternative to antipsychotics for patients with PD accompanied by visual hallucinations even in the absence of dementia. One must, however, not forget that their use with this indication remains experimental and safety measures as well as accurate clinical surveillance are of crucial importance.


Divergent warning patterns contribute to assortative mating between incipient Heliconius species.
Theoretical models suggest that traits under divergent ecological selection, which also contribute to assortative mating, will facilitate speciation with gene flow. Evidence for these so-called "magic traits" now exists across a range of taxa. However, their importance during speciation will depend on the extent to which they contribute to reproductive isolation. Addressing this requires experiments to determine the exact cues involved as well as estimates of assortative mating in the wild. Heliconius butterflies are well known for their diversity of bright warning color patterns, and their amenability to experimental manipulation has provided an excellent opportunity to test their role in reproductive isolation. Here, we reveal that divergent color patterns contribute to mate recognition between the incipient species Heliconius himera and H. erato, a taxon pair for which assortative mating by color pattern has been demonstrated among wild individuals: First, we demonstrate that males are more likely to attempt to mate conspecific females; second, we show that males are more likely to approach pinned females that share their own warning pattern. These data are valuable as these taxa likely represent the early stages of speciation, but unusually also allow comparisons with rates of interbreeding between divergent ecologically relevant phenotypes measured in the wild.


Effect of small-quantity lipid-based nutrient supplements on growth, psychomotor development, iron status, and morbidity among 6- to 12-mo-old infants in South Africa: a randomized controlled trial.
Evidence on the effect of small-quantity lipid-based nutrient supplements (SQ-LNSs) on early child growth and development is mixed. This study assessed the effect of daily consumption of 2 different SQ-LNS formulations on linear growth (primary outcome), psychomotor development, iron status (secondary outcomes), and morbidity in infants from age 6 to 12 mo within the context of a maize-based complementary diet. Infants (n = 750) were randomly assigned to receive SQ-LNS, SQ-LNS-plus, or no supplement. Both SQ-LNS products contained micronutrients and essential fatty acids. SQ-LNS-plus contained, in addition, docosahexaenoic acid, arachidonic acid (important for brain and eye development), lysine (limiting amino acid in maize), phytase (enhances iron absorption), and other nutrients. Infants' weight and length were measured bimonthly. At age 6 and 12 mo, psychomotor development using the Kilifi Developmental Inventory and South African Parent Rating Scale and hemoglobin, plasma ferritin, C-reactive protein, and α1-acid glycoprotein were assessed. WHO Motor Milestone outcomes, adherence, and morbidity were monitored weekly through home visits. Primary analysis was by intention-to-treat, comparing each SQ-LNS group with the control. SQ-LNS-plus had a positive effect on length-for-age zscore at age 8 mo (mean difference: 0.11; 95% CI: 0.01, 0.22; P = 0.032) and 10 mo (0.16; 95% CI: 0.04, 0.27; P = 0.008) but not at 12 mo (0.09; 95% CI: -0.02, 0.21; P = 0.115), locomotor development score (2.05; 95% CI: 0.72, 3.38; P = 0.003), and Parent Rating Score (1.10; 95% CI: 0.14, 2.07; P = 0.025), but no effect for weight-for-age zscore. Both SQ-LNS (P = 0.027) and SQ-LNS-plus (P = 0.005) improved hemoglobin concentration and reduced the risk of anemia, iron deficiency, and iron-deficiency anemia. Both SQ-LNS products reduced longitudinal prevalence of fever, coughing, and wheezing but increased incidence and longitudinal prevalence of diarrhea, vomiting, and rash/sores. Point-of-use fortification with SQ-LNS-plus showed an early transient effect on linear growth and improved locomotor development. Both SQ-LNS products had positive impacts on anemia and iron status. This trial was registered at clinicaltrials.gov as NCT01845610.


Apoptosis update: to be, or not to be, and how to arrange the latter. Meeting review.
It has become accepted that cell death is an essential mechanism for the maintenance of an animal's health. But how do cells know when they should die, and how do they do it? A recent conference titled "Programmed Cell Death" was held by the American Association For Cancer Research in Bolton Landing, New York state, USA, on October 19-23, 1996, which focused on the signals that push a cell towards its own self-destruction, and also on the biochemical tools used by these cells in making this ultimate sacrifice. The molecular vocabulary of programmed cell death is only recently being deciphered. At the heart of programmed cell death exists at least one intrinsic program for committing cell suicide, although it is still unclear if there is only one [3]. If only one program exists, it probably contains multiple branches, overlapping pathways, and redundant molecular interactions. One item is clear, however: there exist many mechanisms for inducing cells to suicide.


On the programmed/non-programmed aging controversy.
The programmed vs. non-programmed aging controversy has now existed in some form for at least 150 years. For much of the XX century, it was almost universally believed that evolution theory prohibited programmed (adaptive) aging in mammals and there was little direct experimental or observational evidence favoring it. More recently, multiple new evolutionary mechanics concepts that support programmed aging and steadily increasing direct evidence favoring it overwhelmingly support the existence of programmed aging in humans and other organisms. This issue is important because the different theories suggest very different mechanisms for the aging process that in turn suggest very different paths toward treating and preventing age-related diseases.


Evaluation of osteopontin as a potential biomarker for central nervous system embryonal tumors.
Osteopontin (OPN) is a protein linked to tumor growth, progression and metastasis of cancers. However, its role in the progression of central nervous system (CNS) embryonal tumors such as atypical teratoid/rhabdoid tumor (AT/RT), medulloblastoma (MB) and primitive neuroepithelial tumors (PNET) remains elusive. In this study, we investigated the value of OPN staining in differential diagnosis of AT/RT from MB and PNET, and assessed the correlation between OPN expression and patients' prognosis. This retrospective study was conducted on tissue sections obtained from children cases with CNS embryonal tumors treated in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine from 2006 to 2012 by immunohistochemistry (IHC). 49 cases were collected (11 AT/RTs, 25 MBs, and 13 PNETs), with a median follow-up time of 28.9 months. OPN expression in AT/RT was significantly higher than MB and PNET with the positive rates of 100, 32, and 23 %, respectively (P < 0.01). The specificity and sensitivity of OPN staining in diagnosing AT/RT are 97.4 and 90.9 %, respectively, as judged by strong OPN IHC staining level (+++). Patients who had positive OPN staining have increased risks of poorer median overall survival (hazard risk 5.54, 95 % CI 1.87-16.38) and tumor progression (hazard risk 14.47, 95 % CI 4.47-46.85). OPN is a valuable biomarker to aid in the differential diagnosis between AT/RT and MB/PNET. Moreover, OPN is a potential novel prognostic marker for CNS embryonal tumors.


Biomechanical Comparison of Bicortical, Unicortical, and Unicortical Far-Cortex-Abutting Screw Fixations in Plated Comminuted Midshaft Clavicle Fractures.
The objective of this study was to assess the biomechanical properties of bicortical locking screws, unicortical locking screws, and unicortical far-cortex-abutting locking screw fixation in a cadaver model of comminuted midshaft clavicle fractures stabilized with a locking plate placed on the superior surface of the clavicle. Nine pairs of adult fresh-frozen cadaver clavicles were allocated into 3 groups for either bicortical, unicortical, or unicortical far-cortex-abutting locking plate fixation. After a 1-cm osteotomy to simulate a comminuted fracture and instrumentation with an 8-hole locking plate placed on the superior surface of the clavicle, the specimens were mounted in a custom dual-gimbal fixture in a materials-testing system and tested in axial compression, torsional, and torsional load to failure. Axial stiffness and axial osteotomy site stiffness did not demonstrate differences between constructs. In cyclical torsion, both the bicortical and the unicortical far-cortex-abutting constructs were significantly stiffer than the unicortical construct. For torsional failure stiffness, both the bicortical and the unicortical far-cortex-abutting constructs were significantly stiffer than the unicortical construct. There was no difference between bicortical and unicortical far-cortex-abutting for torsional failure stiffness. The bicortical construct exhibited significantly higher peak failure torque compared with the unicortical construct. Unicortical far-cortex-abutting locking screw fixation provides comparable mechanical properties under axial and torsional loads to bicortical fixation, without penetrating the far cortex. Unicortical far-cortex-abutting locking screw fixation obviates far cortex penetration, and thereby protects nearby anatomical structures, may ease symptomatic implant removal, alleviates refracture risk, and eases conversion to bicortical fixation in the case of revision surgery.


Use of the immunodiffusion test in the serodiagnosis of aspergillosis.
The diagnostic value of an immunodiffusion (ID) test with standardized precipitinogens derived from five Aspergillus species was determined with sera from 60 proven and 12 suspected cases of aspergillosis. The data demonstrated that the greatest number of aspergillosis cases were detected by the concurrent use of A. fumigatus and A. niger precipitinogens. With these precipitinogens, the ID test permitted the serodiagnosis of aspergillosis in 82% of the 60 proven cases and in 83% of the 12 suspected cases. The presence of one or more precipitins was indicative of aspergilloma, of allergic bronchopulmonary aspergillosis, or of invasive aspergillosis. Precipitins were detected in 93% of the sera from patients with aspergilloma, in 50% of the sera from patients with allergic bronchopulmonary aspergillosis, and in 88% of the sera from patients with invasive aspergillosis. Although the presence of one or two precipitin bands could indicate any form of aspergillosis, the presence of three or four was strong evidence of either aspergilloma or invasive aspergillosis. The ID test was found to be 100% specific in an evaluation of its effectiveness with 65 sera from individuals with other systemic mycotic infections, bacterial or neoplastic diseases, and from apparently normal humans. In diagnosed cases of aspergillosis, the examination of serial serum specimens provided information about the clinical course of the disease. A reduction in the number of precipitin bands and significant titer changes were noted as the patients responded to therapy.


[Obesity prevalence in Europe].
The prevalence of obesity is increasing in an alarming way, while that of other risk factors (hyperlipaemia, arterial hypertension.) are tending to diminish. Amongst all of the factors involved in its development, two are outstanding because of their potential for modification: an excessive calorie intake and a sedentary life style, in spite of the recommendations in favour of regularly practising physical exercise. The principal problem in studying the prevalence of obesity is the scarcity of studies that analyse it in a global form. In 1989 the first results of the MONICA project of the WHO were published, with the observation that the prevalence was higher for men than for women, and that it was greater in the Mediterranean countries and the east of Europe, in comparison with the north and centre-west. In 1997 a study was carried out by the Institute of European Food Studies (IEFS) in which 15,239 individuals participated proceeding from representative samples of the 15 Member States of the European Union. Its results showed that the higher prevalence of obesity was to be found in the United Kingdom (12%), followed by Spain (11%), while it was lower in Italy, France and Sweden (7%). By sex, the prevalence of obesity is somewhat greater amongst women, while overweightedness was greater amongst men. In Spain the distribution of overweightedness and obesity amongst the different socio-economic groups is similar to that of other regions, with the percentage of obesity being highest amongst the elderly, subjects of a lower socio-economic level and the inhabitants of the north and north-west of Spain.


Cardiovascular diseases and the nitric oxide pathway.
Fifteen years after its discovery, NO has fully reached an established position in physiology, medicine and therapeutics. It is difficult to find a biological function or a pathological condition where NO does not play a relevant role. Discoveries in the NO field have historically evolved from cardiovascular research, although its influences have already covered nearly all the medical specialties. This review analyzes, step by step, the pathway through which NO is synthesized in the cells of the cardiovascular system and the main physiological and pathological routes it undergoes once it is released. We focus on various diseases affecting the cardiovascular system (atherosclerosis, hypertension, diabetes mellitus and septic shock). We describe in detail those steps of the NO pathway in which anomalies have been detected and may account for the pathophysiology of these diseases. In atherosclerosis, hypertension and diabetes mellitus, the endothelial form of NOS is upregulated, but is very sensitive to environmental conditions, such as substrate or cofactor deficiencies or increases in LDL or glucose. In this situation NOS synthesizes superoxide anion instead of NO leading to oxidative and nitrosative stress. In diabetes mellitus and, very importantly, in septic shock, the inducible form of NOS is highly upregulated. Overproduction of NO appears to underlie the hypotension and tissue damage of septicemia and the destruction of beta-cells in diabetes mellitus. New knowledge of the role of NO in these diseases has started to influence therapeutic design. We also review the current status of research on NO-based therapies.


Two-dimensional echocardiography for diagnosing acute ascending aortic dissection.
The diagnosis of type A aortic dissection (involving the ascending aorta) can be made with two-dimensional echocardiography, but surgeons usually demand angiographic confirmation. Between January 1983 and February 1984, 10 patients presented at St. Michael's Hospital in Toronto with type A aortic dissection. Six patients underwent two-dimensional echocardiography early in their evaluation. A positive diagnosis was made in four, based upon visualization of an intimal flap or a false lumen. In the other two patients, the findings of an enlarged ascending aorta and pericardial effusion were suggestive but not diagnostic. Three patients survived operation and are alive and well (follow-up ranging from 3 to 5 months). One patient died while awaiting surgery, one died during aortography and one died during operation. All echocardiographic and angiographic findings were confirmed at surgery or at autopsy. It is concluded that two-dimensional echocardiography can diagnose ascending aortic dissection quickly, accurately, easily and without risk to the patient. In selected cases the presence of a false lumen or of an intimal flap makes it possible to proceed with operation without delay or the potential hazards of aortography.


Adsorption of dihalogen molecules on pristine graphene surface: Monte Carlo and molecular dynamics simulation studies.
Weak interactions of graphene surface with reactive molecular impurities are the subject of many studies since noncovalent functionalization of surface via molecular doping is a powerful tool for tuning the electronic properties of graphene layers. In this work, the adsorption of diatomic halogen gas molecules, F2, Cl2, Br2, I2 onto bilayer and multilayer pristine graphene surfaces were studied comparatively by Monte Carlo (MC) and molecular dynamics (MD) simulation techniques in canonical ensemble. The adsorption sites, adsorption capacity, coverage factors, adsorption isotherms, and adsorption kinetics were investigated and the adsorption energies were calculated for all adsorbates. Graphene was modeled as a two-dimensional layer of 200 carbon atoms in a honeycomb arrangement. The COMPASS force field was used in the simulations. The adsorption isotherms were obtained and fitted to Langmuir model. The kinetics of adsorption was studied and found to be first order. Both the monolayer and the multilayer adsorption of halogen molecules showed that van der Waals volumes of halogen molecules and also their polarizabilities display a competitive role in the saturation capacity and the strength of surface interactions.


[Effect of lipids on the binding of calmodulin with cyclic nucleotide phosphodiesterase].
The effects of various lipids on calmodulin interaction with Ca-dependent phosphodiesterase were investigated. Palmitic, myristic and stearic acids increased the enzyme activity; the degree of the enzyme activation by calmodulin was decreased thereby. Oleic acid produced a weak activating effect on phosphodiesterase but completely blocked calmodulin action. The effects of the fatty acids under study were reversible, the activation constant was equal to 10(-4)-5 X 10(-4) M. In the presence of Ca2+ phosphoinositides and fatty acids changed the fluorescence intensity of dansyl-labelled calmodulin; in the absence of Ca2+ the lipids did not affect protein fluorescence. The lipids had no influence on the protein affinity for Ca2+. During chromatography of phosphodiesterase on calmodulin-Sepharose the enzyme was eluted from the column both in the presence of EGTA and palmitic acid. It was concluded that fatty acids prevent the formation of the calmodulin - phosphodiesterase complex. This effects may both be due to the lipid binding to the enzyme and to calmodulin.


Heat shock and thermotolerance in plant and animal embryogenesis.
Although the strategies of early embryogenesis differ greatly among multicellular eukaryotes, there are certain parallels in structure, form, and function that cross even kingdom lines: the extreme heat sensitivity of zygotes and very early embryos, followed by the acquisition of thermotolerance during subsequent development, is one such parallel. The heat sensitivity may be so extreme that even moderate increases in temperature result in lethality (generally associated with the earliest phases of embryogenesis), or the effects may be less severe, resulting in defects in development but not in lethality. Mechanistically, and molecularly, these two forms of thermosensitivity appear to have different origins. On the one hand, outright lethality appears to result from an inability to induce heat shock genes and proteins; on the other hand, heat-induced developmental defects appear to result from an alteration in expression of non-heat shock genes and from a delay in the overall developmental program that generally accompanies the cell's response to heat shock. This review is focused on the developmental regulation of the heat shock response during early embryogenesis and on the impact of this regulation on the development of both animal and plant embryos. The two basic issues that we address here are (i) the expression of heat shock genes in the absence of heat shock during embryogenesis and (ii) the expression (or lack of expression) of heat shock genes after deliberate exposure of the embryos to heat shock and the consequences of this expression on its subsequent survival and development.


Loss of heterozygosity studies and deletion mapping identify two putative chromosome 14q tumor suppressor loci in renal oncocytomas.
Renal oncocytoma is considered to be a benign tumor that shares some phenotypic features with chromophobe renal cell carcinoma (RCC). Recently, we described high frequencies of allelic loss at 1p, 2p, 6p, 10p, 13q, 14q, 17p, and 21q, which correlate significantly with the chromophobe subtype of RCC. To investigate the genetic relationship between these two entities, we examined 12 oncocytomas for loss of heterozygosity (LOH) at these regions. In addition, we included markers for 3p, 5q, 7q, 11p, and 22q. The only chromosomal region showing similarly high frequencies of allelic loss for both subtypes was 14q. Therefore, a genetic relationship between renal oncocytoma and chromophobe RCC seems questionable. Eight of 12 oncocytomas (67%) showed LOH at 14q, a frequency that was significantly higher (P < 0.001, chi(2) test) than the frequencies of LOH in all other regions. To define regions potentially harboring novel tumor suppressor genes, we performed multifluorescence microsatellite analysis with 13 markers spanning 14q. Interstitial deletions at different regions of 14q were detected, with the highest frequencies at D14S258 (14q23-24.3) and D14S292 (14q32.1-32.2). 14q LOH might be associated with advanced-stage RCCs or other tumors, but it does not seem to indicate progression in oncocytomas. Its role in pathogenesis of renal oncocytomas remains to be clarified. Here, we provide evidence for two distinct tumor suppressor gene loci at 14q in renal oncocytoma, which will be useful for further fine-mapping studies of these critical regions.


Exploiting Differences in Heme Biosynthesis between Bacterial Species to Screen for Novel Antimicrobials.
The final three steps of heme biogenesis exhibit notable differences between di- and mono-derm bacteria. The former employs the protoporphyrin-dependent (PPD) pathway, while the latter utilizes the more recently uncovered coproporphyrin-dependent (CPD) pathway. In order to devise a rapid screen for potential inhibitors that differentiate the two pathways, the genes associated with the protoporphyrin pathway in an Escherichia coli YFP strain were replaced with those for the CPD pathway from Staphylococcus aureus (SA) through a sliding modular gene replacement recombineering strategy to generate the E. coli strain Sa-CPD-YFP. Potential inhibitors that differentially target the pathways were identified by screening compound libraries against the YFP-producing Sa-CPD-YFP strain in comparison to a CFP-producing E. coli strain. Using a mixed strain assay, inhibitors targeting either the CPD or PPD heme pathways were identified through a decrease in one fluorescent signal but not the other. An initial screen identified both azole and prodigiosin-derived compounds that were shown to specifically target the CPD pathway and which led to the accumulation of coproheme, indicating that the main target of inhibition would appear to be the coproheme decarboxylase (ChdC) enzyme. In silico modeling highlighted that these inhibitors are able to bind within the active site of ChdC.


Advance Care Planning Among Older Adults with Cognitive Impairment.
In this study, we used data from the Health and Retirement Study (HRS) to investigate factors associated with older adults' engagement with advance care planning (ACP) across varying levels of cognitive functioning status. Our analysis used a sample of 17,698 participants in the HRS 2014 survey. Survey descriptive procedures (Proc SurveyMeans, Proc SurveyFreq) and logistic regression procedures (Proc SurveyLogistic) were used. Race, ethnicity, level of cognition, education, age, and number of chronic diseases consistently predicted ACP. Participants with lower levels of cognition were less likely to have a living will and durable power of attorney for healthcare (DPOAH). African American and Hispanic participants, younger participants, and those with lower cognition and education levels were less likely to engage in ACP. Marital status and loneliness predicted ACP engagement. Some results varied across the cognition cohorts. Our results indicated that sociodemographic status, together with health and cognitive status, has a significant role in predicting ACP. The results can provide valuable insights on ACP for older adults with or at risk of Alzheimer's disease and related dementia and other cognitive impairments, caregivers, families, and healthcare providers.


Neurological features and outcome in COVID-19: dementia can predict severe disease.
The COVID-19 pandemic has infected more than 22 million people worldwide. Although much has been learned about COVID-19, we do not know much about its neurological features and their outcome. This observational study was conducted on the patients of Imam Hossein Hospital, and 361 adult patients (214 males) with confirmed diagnosis of COVID-19 from March 5, 2020 to April 3, 2020, were enrolled. Data was gathered on age, sex, comorbidities, initial symptoms, symptoms during the disease course, neurological symptoms, and outcome. The mean age of the patients was 61.90 ± 16.76 years. The most common initial symptoms were cough, fever, and dyspnea. In 21 patients (5.8%), the initial symptom was neurological. History of dementia was associated with severe COVID-19 disease (odds ratio = 1.28). During the course of the disease, 186 patients (51.52%) had at least one neurological symptom, the most common being headache (109 [30.2%]), followed by anosmia/ageusia (69, [19.1%]), and dizziness (54, [15%]). Also, 31 patients had neurological complications (8.58%). Anosmia, ageusia, dizziness, and headache were associated with favorable outcome (P < 0.001), while altered mental status and hemiparesis were associated with poor outcome. The mortality rate of patients who had neurological complications was more than twice than that of patients without neurological complication (P = 0.008). Almost half of the patients experienced at least one neurological symptom, which may be the initial presentation of COVID-19. Dementia appears to be associated with severe COVID-19. Mortality was higher in patients with neurological complications, and these patients needed more intensive care.


Keeping Secrets or Educating Others: A Dyadic Analysis of Group Entitativity's Influence on Spouses' Label Management Connected to AATD.
In 1963, Goffman argued that forming a group based on shared stigma may provide benefits. However, there is no empirical research on whether perception that a separate, unique, coherent group exists (i.e., group entitativity) influences coping, such as educating others or secrecy, for the stigmatized individual or his or her spouse. Further, little is known about how spouses influence each other in terms of promoting the education of others about a stigmatizing condition, especially when it comes to the role of believing that stigma-based groups, to which they may both belong, exist. This study provides a step toward bridging this gap in the research by applying the label management model in efforts to understand coping for couples in which one spouse is diagnosed with genetic mutations leading to alpha-1 antitrypsin deficiency (AATD). This study included 50 married couples in which one spouse is diagnosed with genetic mutations leading to alpha-1 antitrypsin deficiency (AATD). We found that group entitativity related to those with AATD counterbalanced the influence of genetic stigma on spouses' intentions to keep the diagnosis secret or to educate others about it. Intrapersonal and interpersonal influences appeared among spouses. Attention is needed on the power of creating groups for stigmatized persons and their relatives. Indeed, people live within a dynamic world of group entities, and multiple social identities including spousal and familial. While attention has been paid to the diffusion of stigmas to loved ones, less has been paid to the uplift of group entities for them.


Is measurement of non-HDL cholesterol an effective way to identify the metabolic syndrome?
The metabolic syndrome (MetS) has been shown to predict coronary heart disease (CHD). Non-high-density lipoprotein cholesterol (non-HDL-C) is also known to predict CHD, and recent evidence indicated non-HDL-C was able to predict MetS in adolescents. The study aim was to determine whether non-HDL-C serves as a useful metabolic marker for MetS in adults. Fasting non-HDL-C measurements were obtained in 366 non-diabetic adults not on lipid-lowering therapy. In addition to traditional non-HDL-C cut-points based on Adult Treatment Panel III guidelines, receiver-operating characteristic curve analysis was used to identify an optimal cut-point for predicting MetS. A secondary goal was to assess the relationship between non-HDL-C and insulin resistance, defined as the upper tertile of steady-state plasma glucose concentrations measured during the insulin suppression test. Prevalence of MetS was 40% among participants. Those with MetS had higher mean non-HDL-C (4.17 ± 1.0 vs 3.70 ± 0.85 mmol/L, p < 0.001), and the upper vs lower tertile of non-HDL-C concentrations was associated with 1.8-fold increased odds of MetS (p < 0.05). Traditional non-HDL-C cut-points ≥ 4.14 and ≥ 4.92 mmol/L demonstrated respective sensitivities 46% and 24% (specificities 72% and 89%) for identifying MetS. The optimal non-HDL-C cut-point ≥ 4.45 mmol/L had sensitivity 39% (specificity 82%). Comparable results were observed when non-HDL-C was used to identify insulin resistance. While MetS was associated with increased non-HDL-C, an effective non-HDL-C threshold to predict MetS in adults was not identified. Dyslipidemic nuances may explain why non-HDL-C may be less useful as a metabolic marker for MetS and/or insulin resistance than for CHD.


Rarity of encephalopathy associated with autoimmune thyroiditis: a case series from Mayo Clinic from 1950 to 1996.
Corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis (also called Hashimoto's encephalopathy) is a rare, life-threatening, treatable, and possibly autoimmune condition. We identified nine patients (with the diagnosis made after 1979) who had relapsing encephalopathy compatible with previous reports of Hashimoto's encephalopathy and no other identifiable cause of encephalopathy at Mayo Clinic Rochester. Of these nine patients, three were clinically hypothyroid, four were subclinically hypothyroid, and two were euthyroid. Thyroid antibodies were positive in eight of eight patients in whom these measurements were made. Electroencephalographic abnormalities were identified in eight of the nine patients (89%). Magnetic resonance imaging (MRI) abnormalities considered etiologically related to encephalopathy were present in three patients (33%). An increased protein concentration was noted on cerebrospinal fluid examination in seven patients (78%). Of the six patients who received high-dose glucocorticoid therapy, 5 (83%) had improvement of neurologic symptoms. In conclusion, encephalopathy associated with autoimmune thyroiditis is rare but important to recognize because it may be responsive to high-dose glucocorticoid therapy. We believe that this condition is not caused by thyroid dysfunction or antithyroid antibodies but represents an association of an uncommon autoimmune encephalopathy with a common autoimmune thyroid disease. The term Hashimoto's encephalopathy is a misnomer and should not be used.


Increased Nigral SLC6A3 Activity in Schizophrenia Patients: Findings From the Toronto-McLean Cohorts.
SLC6A3, which encodes the primary regulator of extracellular dopamine (DA) concentration, the DA transporter, has been implicated in schizophrenia (SCZ). However, the details of its genetic effect on risk remain largely unknown. The purpose of this candidate gene study was to identify a specificSLC6A3activity associated with SCZ by using functional genetic approaches. We first examined gene activity in DA neurons isolated from case-control postmortem nigral tissue and found that the averageSLC6A3mRNA level in controls was only 0.37-fold of that in cases (P= .0034). To understand this expression difference, we examined the association of 10 genetic markers, mostly located in the promoter region, with SCZ in 1717 subjects collected from Toronto and McLean cohorts, including 881 controls and 836 cases and identified the 5' promoter SNP rs1478435 as having a significant association signal (uncorrectedPvalue: .00462; adjustedPvalue: .0319) in unrelated Caucasians. Allele T was over-represented in controls (OR = .75); T-carrier controls had decreased mRNA levels in nigral DA neurons, contributing to the reduced activity in the controls. In vitro functional analysis confirmed that T carriers displayed attenuated enhancement of promoter activity. These findings collectively suggest that increased nigralSLC6A3activity may be a risk factor for SCZ, and may help to explain high rates of comorbidity with substance abuse.


Scene analysis by integrating primitive segmentation and associative memory.
Scene analysis is a major aspect of perception and continues to challenge machine perception. This paper addresses the scene-analysis problem by integrating a primitive segmentation stage with a model of associative memory. The model is a multistage system that consists of an initial primitive segmentation stage, a multimodule associative memory, and a short-term memory (STM) layer. Primitive segmentation is performed by a locally excitatory globally inhibitory oscillator network (LEGION), which segments the input scene into multiple parts that correspond to groups of synchronous oscillations. Each segment triggers memory recall and multiple recalled patterns then interact with one another in the STM layer. The STM layer projects to the LEGION network, giving rise to memory-based grouping and segmentation. The system achieves scene analysis entirely in phase space, which provides a unifying mechanism for both bottom-up analysis and top-down analysis. The model is evaluated with a systematic set of three-dimensional (3-D) line drawing objects, which are arranged in an arbitrary fashion to compose input scenes that allow object occlusion. Memory-based organization is responsible for a significant improvement in performance. A number of issues are discussed, including input-anchored alignment, top-down organization, and the role of STM in producing context sensitivity of memory recall.


Long-Term Evolution of Email Networks: Statistical Regularities, Predictability and Stability of Social Behaviors.
In social networks, individuals constantly drop ties and replace them by new ones in a highly unpredictable fashion. This highly dynamical nature of social ties has important implications for processes such as the spread of information or of epidemics. Several studies have demonstrated the influence of a number of factors on the intricate microscopic process of tie replacement, but the macroscopic long-term effects of such changes remain largely unexplored. Here we investigate whether, despite the inherent randomness at the microscopic level, there are macroscopic statistical regularities in the long-term evolution of social networks. In particular, we analyze the email network of a large organization with over 1,000 individuals throughout four consecutive years. We find that, although the evolution of individual ties is highly unpredictable, the macro-evolution of social communication networks follows well-defined statistical patterns, characterized by exponentially decaying log-variations of the weight of social ties and of individuals' social strength. At the same time, we find that individuals have social signatures and communication strategies that are remarkably stable over the scale of several years.


A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjects.
Hypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycemic or lipid-lowering drugs. The aim of these three studies was to investigate the pharmacokinetics, safety and tolerability of aliskiren, a direct renin inhibitor for the treatment of hypertension, co-administered with the glucose-lowering agents metformin or pioglitazone or the lipid-lowering agent fenofibrate in healthy volunteers. In three open-label, multiple-dose studies, healthy volunteers (ages 18 to 45 years) received once-daily treatment with either metformin 1000 mg (n = 22), pioglitazone 45 mg (n = 30) or fenofibrate 200 mg (n = 21) and aliskiren 300 mg, administered alone or co-administered in a two-period study design. Blood samples were taken frequently on the last day of each treatment period to determine plasma drug concentrations. Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration- time curve during the dose interval (AUC(tau)) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (C(max)) by 29% (GMR 0.71; 90% CI 0.56, 0.89) but these changes were not considered clinically relevant. Co-administration of aliskiren with fenofibrate had no effect on aliskiren AUC (GMR 1.05; 90% CI 0.96, 1.16) or C(max) (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUC(tau) (GMR 1.05; 90% CI 0.98, 1.13) or C(max) (GMR 1.01; 90% CI 0.84, 1.20). All other AUC and C(max) GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglita-zone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25. Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.


Droplet Chondrules: Jetting on high-velocity collision of small meteoritie particles may have produced droplet chondrules.
I have proposed that droplet chondrules were formed by jetting during collision of meteoritic particles with diameters ranging in order of magnitude from 0.5 mm to 20 cm. This conclusion, based on a dynamic model for the collision process, supports the hypotheses of Wasson (2) (based on geochemical considerations) and Whipple (35) and Cameron (36) (based on dynamic model considerations) that chondrules were formed from objects less than 1 m in radius. In this model, the formation of chondrules is viewed as a textural, but not substantial chemical, change in the material of the early solar system. Droplets of melt produced by jetting are mixtures of material derived from two parent grains. Jets are probably not appreciably fractionated (except in volatile elements) either in the short duration of the shock events (several microseconds) or in subsequent cooling. This model for the formation of droplet chondrules implies that they were formed at a time in the history of the solar system when particle sizes were small. The most likely time for this condition is early in the process of accretion of nebular dust to planetary matter. Since velocities less than approximately 1.5 km/sec are required for the agglomeration and accretion of particles (37), the relatively higher velocities indicated for droplet chondrule-forming collisions indicate an early high-velocity destructive epoch amidst the general trend toward accretion of material.


Forecasting the effect of the Amethyst initiative on college drinking.
A number of college presidents have endorsed the Amethyst Initiative, a call to consider lowering the minimum legal drinking age (MLDA). Our objective is to forecast the effect of the Amethyst Initiative on college drinking. A system model of college drinking simulates MLDA changes through (i) a decrease in heavy episodic drinking (HED) because of the lower likelihood of students drinking in unsupervised settings where they model irresponsible drinking (misperception), and (ii) an increase in overall drinking among currently underage students because of increased social availability of alcohol (wetness). For the proportion of HEDs on campus, effects of large decreases in misperception of responsible drinking behavior were more than offset by modest increases in wetness. For the effect of lowering the MLDA, it appears that increases in social availability of alcohol have a stronger impact on drinking behavior than decreases in misperceptions.


[Animal experiments of neuroma treatment with histoacryl].
A neuroma arises due to uncoordinated growth of axis cylinders in proliferated granulation tissue. An intact perineurial tube prevents further growth of the funiculi. Animal experiments were designed to close the perineurial tube such that it was impervious to water. Earlier experiments with purse string suture of the perineurial tube or closure with Histoacryl were not always successful. After severance of the sciatic nerve of the rat and shortening of the axons, the epineurial tube was plugged with Histoacryl blue and closed so that it was impervious to water. The preparations were checked optically and histologically. The results were promising, so that this technique was applied clinically.


Transport and Catabolism of Pentitols by Listeria monocytogenes.
Transposon insertion into Listeria monocytogenes lmo2665, which encodes an EIIC of the phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS), was found to prevent D-arabitol utilization. We confirm this result with a deletion mutant and show that Lmo2665 is also required for D-xylitol utilization. We therefore called this protein EIICAxl. Both pentitols are probably catabolized via the pentose phosphate pathway (PPP) because lmo2665 belongs to an operon, which encodes the three PTSAxl components, two sugar-P dehydrogenases, and most PPP enzymes. The two dehydrogenases oxidize the pentitol-phosphates produced during PTS-catalyzed transport to the PPP intermediate xylulose-5-P. L. monocytogenes contains another PTS, which exhibits significant sequence identity to PTSAxl. Its genes are also part of an operon encoding PPP enzymes. Deletion of the EIIC-encoding gene (lmo0508) affected neither D-arabitol nor D-xylitol utilization, although D-arabitol induces the expression of this operon. Both operons are controlled by MtlR/LicR-type transcription activators (Lmo2668 and Lmo0501, respectively). Phosphorylation of Lmo0501 by the soluble PTSAxl components probably explains why D-arabitol also induces the second pentitol operon. Listerial virulence genes are submitted to strong repression by PTS sugars, such as glucose. However, D-arabitol inhibited virulence gene expression only at high concentrations, probably owing to its less efficient utilization compared to glucose.


Defining the role of adjuvant radiotherapy for malignant pleural mesothelioma: a propensity-matched landmark analysis of the National Cancer Database.
Multimodality therapy may prolong survival among resectable malignant pleural mesothelioma (MPM). However, the role of adjuvant radiation remains controversial. We explored a large nationwide database to determine whether adjuvant radiation is associated with improved survival. The National Cancer Database (NCDB) was queried to identify patients with MPM who received cancer-directed surgery between 2004-2013. Adjuvant radiation included intensity modulated radiation therapy or conformal 3D radiation. Propensity matching was performed with a 150-day landmark to address survivorship bias. Cox regression was used with an interaction term between pathologic stage and radiation. A total of 2,846 patients were identified as having undergone cancer-directed surgery for MPM; among whom 213 (7%) received adjuvant radiation. Adjuvant radiation was associated with improved survival among those who were stage I-II (P=0.024), but not stage III or IV (P=0.890 and P=0.183, respectively). After propensity matching, adjuvant radiation was associated with improved survival for those who were stage I-II [hazard ratio (HR) 0.52, P=0.035], whereas no similar effect was observed for those who were stage III or IV (P=0.190 and P=0.562, respectively). Multivariable regression revealed that sarcomatoid histology (HR 1.80, P=0.018) and stage IV disease (HR 1.65, P=0.033) were also associated with worse survival. Adjuvant radiation was associated with improved survival among those with pathologic stage I-II MPM. No survival advantage was observed for those with pathologic stage III or stage IV MPM, however. Our results justify the need for further prospective trials to investigate the utility of adjuvant radiotherapy among those with MPM.


[The CT-stereotaxic biopsy of brain tumors].
CT-stereotaxic biopsy is a modern method for the diagnosis of intracranial tumors. The histological diagnosis established by means of it makes it possible to choose the most rational tactics of treatment and determine more exactly the indications and contraindications for the operation. The examination was conducted on 219 patients with various brain tumors. Authentic histological information was obtained in 84% of cases, 4 patients died, a stable neurological defect developed in another 2 patients. Some methodical procedures for increasing the informativeness and reducing the risk of complications are discussed. An important component is rapid examination of part of the bioptic material by means of smears for intraoperative appraisal of its representativeness and correction of biopsy targets. Among 73 cases in which smears were examined only in 9 the findings were in disagreement with the data of the traditional histologic study, only in the degree of tumor differentiation in all of them. Stereotaxic biopsy is most expedient in situations in which the tactics and main method of treatment are determined to a greater degree by the histological structure rather than by the localization and the patient's general condition. Such cases account for one fourth of all cases of intracerebral tumors.


Enhancement of Neural Stem Cell Proliferation in Rats with Spinal Cord Injury by a Combination of Repetitive Transcranial Magnetic Stimulation (rTMS) and Human Umbilical Cord Blood Mesenchymal Stem Cells (hUCB-MSCs).
BACKGROUND This study was designed to explore the combined effects of repetitive transcranial magnetic stimulation (rTMS) and human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) transplantation on neural stem cell proliferation in rats with spinal cord injury (SCI). MATERIAL AND METHODS SCI was induced in 90 rats by laminectomy at T10. Fifteen rats each were treated with 0.5 Hz rTMS or 10 Hz rTMS or underwent hUCB-MSC transplantation; 15 each were treated with 0.5 Hz rTMS+hUCB-MSCs or 10 Hz rTMS+hUCB-MSCs; and 15 were untreated (control group). The Basso, Beattie, and Bresnahan (BBB) scores and motor evoked potentials (MEPs) were measured, and all rats underwent biotin dextran-amine (BDA) tracing of the corticospinal tract (CST). The levels of expression of neural stem cell proliferation related proteins, including BrdU, nestin, Tuj1, Ng2+ and GFAP, were measured, and the levels of bFGF and EGF determined by Western blotting. RESULTS BBB scores and MEPs were increased after rTMS and hUCB-MSC transplantation, while histologically determined SCI-induced neuron apoptosis was attenuated. The numbers of BDA-positive fibers and Brdu-, nestin- and Tuj1-positive cells were markedly increased and the numbers of Ng2+- and GFAP-positive cells were markedly decreased following treatment with rTMS alone or rTMS plus hUCB-MSC transplantation. The levels of expression of bFGF and EGF were significantly upregulated following rTMS treatment and hUCB-MSC transplantation. Higher performance was observed after combined treatment with rTMS and hUCB-MSC transplantation than after either alone. CONCLUSIONS The combination of rTMS treatment and hUCB-MSC transplantation could attenuate SCI-induced neural stem cell apoptosis and motor dysfunction in rats.


Patient, hospital, and general practitioner characteristics associated with non-attendance: a cohort study.
Studies examining characteristics of non-attendance at hospital outpatients have given inconsistent results. We examined a cohort of 1972 referrals from 26 general practitioners, with complete follow-up. Five factors were found to be significantly associated with non-attendance: male sex, younger age, longer interval between referral and appointment, higher Jarman score and patients of a high-referring general practitioner. Targeting of strategies to reduce non-attendance is possible using these results.


Monitoring the exposure of rats to 2-acetylaminofluorene by the estimation of mutagenic activity in excreta, sister-chromatid exchanges in peripheral blood cells and DNA adducts in peripheral blood, liver and spleen.
The sensitivity of various methods suitable for biomonitoring the exposure to genotoxicants was compared in an animal model. The results were related to the presence of genotoxic effects in the target organ. Groups of male Wistar rats were given one oral dose of 0, 0.1, 10 or 200 mg 2-acetylaminofluorene (2-AAF)/5 ml dimethyl sulphoxide/kg body weight. Peripheral blood cells, excreta, liver and spleen were collected at different time intervals after dosing. Mutagenicity in urine and extracts of faeces was determined using the Ames test with Salmonella typhimurium TA98 with and without S9 and with and without beta-glucuronidase. Genotoxic effects were studied by measuring DNA-adduct formation in lymphocytes, liver and spleen, and sister-chromatid exchanges (SCEs) in lymphocytes. DNA adducts were measured with immunochemical techniques and postlabelling methods. Mutagenicity in urine and faeces, collected during the first 24 h after treatment, was detected at 2-AAF doses of 1 mg/kg b.w. and higher. At these doses DNA adducts also became apparent in the liver, the main target organ for tumour induction by 2-AAF. The adduct detected appeared to be the N-(deoxyguanosin-8-yl)-2-AAF adduct. There was no evidence of the presence of any other types of DNA adducts. At doses of 1 and 10 mg/kg b.w. no mutagenicity was detected in excreta collected during the second and third day after dosing. The DNA-adduct level in liver cells of the 1 mg/kg b.w. group was maximal 24 h after dosing. At 200 mg/kg b.w. a delay in excretion of mutagenicity with urine and faeces was seen and at 10 and 200 mg/kg b.w. the amount of DNA adducts continued to increase with time after dosing. At 24 and 48 h after treatment with 10 mg, the adduct levels were of the same order of magnitude as those found after the 20-fold higher dose. This points to overloading of the metabolizing system which in combination with the enterohepatic circulation, may lead to an increased retention of 2-AAF in the body. A slightly increased incidence of SCEs of doubtful significance was seen in lymphocytes, but only at the very high dose of 200 mg/kg b.w. No DNA adducts could be detected in blood lymphocytes or spleen cells at any of the dose levels applied, either with the immunochemical or with the postlabelling method.(ABSTRACT TRUNCATED AT 400 WORDS)


Association of the Addition of Oral Antibiotics to Mechanical Bowel Preparation for Left Colon and Rectal Cancer Resections With Reduction of Surgical Site Infections.
Surgical site infections (SSIs) after colorectal surgery remain a significant complication, particularly for patients with cancer, because they can delay the administration of adjuvant therapy. A combination of oral antibiotics and mechanical bowel preparation (MBP) is a potential, yet controversial, SSI prevention strategy. To determine the association of the addition of oral antibiotics to MBP with preventing SSIs in left colon and rectal cancer resections and its association with the timely administration of adjuvant therapy. A retrospective review was performed of 89 patients undergoing left colon and rectal cancer resections from October 1, 2013, to December 31, 2016, at a single institution. A bowel regimen of oral antibiotics and MBP (neomycin sulfate, metronidazole hydrochloride, and magnesium citrate) was implemented August 1, 2015. Patients receiving MBP and oral antibiotics and those undergoing MBP without oral antibiotics were compared using univariate analysis. Multivariable logistic regression controlling for factors that may affect SSIs was used to evaluate the association between use of oral antibiotics and MBP and the occurrence of SSIs. Surgical site infections within 30 days of the index procedure and time to adjuvant therapy. Of the 89 patients (5 women and 84 men; mean [SD] age, 65.3 [9.2] years) in the study, 49 underwent surgery with MBP but without oral antibiotics and 40 underwent surgery with MBP and oral antibiotics. The patients who received oral antibiotics and MBP were younger than those who received only MBP (mean [SD] age, 62.6 [9.1] vs 67.5 [8.8] years; P = .01), but these 2 cohorts of patients were otherwise similar in baseline demographic, clinical, and cancer characteristics. Surgical approach (minimally invasive vs open) and case type were similarly distributed; however, the median operative time of patients who received oral antibiotics and MBP was longer than that of patients who received MBP only (391 minutes [interquartile range, 302-550 minutes] vs 348 minutes [interquartile range, 248-425 minutes]; P = .03). The overall SSI rate was lower for patients who received oral antibiotics and MBP than for patients who received MBP only (3 [8%] vs 13 [27%]; P = .03), with no deep or organ space SSIs or anastomotic leaks in patients who received oral antibiotics and MBP compared with 9 organ space SSIs (18%; P = .004) and 5 anastomotic leaks (10%; P = .06) in patients who received MBP only. Despite this finding, there was no difference in median days to adjuvant therapy between the 2 cohorts (60 days [interquartile range, 46-73 days] for patients who received MBP only vs 72 days [interquartile range, 59-85 days] for patients who received oral antibiotics and MBP; P = .13). Oral antibiotics and MBP (odds ratio, 0.11; 95% CI, 0.02-0.86; P = .04) and minimally invasive surgery (odds ratio, 0.22; 95% CI, 0.05-0.89; P = .03) were independently associated with reduced odds of SSIs. The combination of oral antibiotics and MBP is associated with a significant decrease in the rate of SSIs and should be considered for patients undergoing elective left colon and rectal cancer resections.


Cytotoxic activity of styryl lactones and their derivatives.
Many studies that have been conducted to establish the cytotoxic potency of styryl lactones for several tumor cell lines is described. Extensive examination of the activity of more than 50 cytotoxic styryl lactones isolated/synthesized belonging to the genus goniothalamus representing future generation of antitumor drugs is described for the first time at the molecular level. Goniopypyrone (39) is the most cytotoxic compound followed by altholactone (+)-1 (10(-5) to 10(-7) molar for IC(50)). Enantiomer (-)-1 and three stereocongeners 2-4 did not exhibit any significant increase in cytotoxicity. Cytotoxicity of semisynthetically derived products 5-11 is discussed recognising 11-nitro altho-lactone (+)-5 as a promising lead compound. Eight membered styryl lactones 12a - 12e are substrates with important cytotoxicity explained by the inhibition of the mammalian mitochondrial respiratory chain complex I. Among C(7)-C(8) functionalised styryl lactones gonio diol (25) is the most active being selectively cytotoxic against A549 tumour cells. Goniofufurone (42) and several of its derivatives including one carbon homologues 43-50 were reported to be inactive.


Motor neuron disease--a review.
It is now clear that patients with MND are best managed using a multi-disciplinary approach conforming to evidence-based guidelines. Whilst scientific advances into the aetiology of MND have been of great importance in both the understanding of this and other neurodegenerative disease, they have only recently led to therapy directed at disease progression. The management of patients with MND remains largely supportive but it is hoped that the future may hold better prospects for those with the disease.