Second malignant neoplasms in survivors of pediatric Hodgkin's lymphoma treated with low-dose radiation and chemotherapy.
Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation. Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires. One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis. Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.


[Diurnal profile of arterial pressure in healthy residents of northern regions].
Five-year observations yielded diurnal profiles of arterial pressure (AP) in practically healthy residents of the north of Tyumen region. Their analysis revealed the enhancement of AP variability in day- and nighttime (especially diastolic AP), elevated rise of morning AP in the absence of adequate decrease of nocturnal AP.


Racial distribution of alpha1-antitrypsin variants among junior high school students.
A survey of alpha1-antitrypsin phenotypes and serum trypsin inhibitory capacities was performed in 1,841 seventh grade junior high school students. Antitrypsin deficiency states were detected only in white subjects (3.04) per cent) and not in 461 subjects of other races or of Mexican origin. A screening level of serum trypsin inhibitory capacity at 75 per cent of normal or less included all of the deficient phenotypes, but phenotyping was necessary to eliminate a small percentage of normal and unimportant variant phenotypes from this group. It is suggested that future programs for detecting antitrypsin deficiency and for counseling students who are genetically prone to develop pulmonary emphysema be aimed primarily at white populations.


Summarizing and coding case records: can the task be delegated?
After several preliminary joint sessions a doctor and a nurse independently constructed summary cards for 100 alphabetically consecutive case records and coded them according to the classification of the Royal College of General Practitioners. The searches and codings were repeated after an interval of at least one month. The error rates of the doctor and the nurse were similar. The interobserver concordance for the ratings was acceptable for broad diagnostic categories, but was less good when strict criteria were applied. It is concluded that the task may be delegated.


Upregulation of long noncoding RNA Gadd45a is associated with sevoflurane-induced neurotoxicity in rat neural stem cells.
Emerging evidence has shown that long noncoding RNA (lncRNA) plays a crucial role in controlling neural stem cells' (NSCs) survival. However, the fundamental role of lncRNA underlying sevoflurane-induced neurotoxicity remains poorly elucidated. In the present study, we investigate the effect of sevoflurane-induced neurotoxicity in a concentration-dependent and duration-dependent manner. Furthermore, we assayed the differential profile of lncRNA in rat hippocampal NSCs following sevoflurane exposure, and identified lncRNA Gadd45a and the correlation between lncRNA Gadd45a and Gadd45a. We found that lncRNA Gadd45a and its nearby gene, Gadd45a, were significantly upregulated in NSCs exposed to sevoflurane. Notably, Gadd45a was enriched in the cell cycle-relative pathway including mitogen-activated protein kinases and P53 signaling, whereas lncRNA Gadd45a was positively correlated with Gadd45a. These results suggest lncRNA Gadd45a is associated with sevoflurane-induced toxicity, and thus shed light on a new key target for revealing the molecular mechanism of sevoflurane-induced toxicity.


Osteoblast recruitment routes in human cancellous bone remodeling.
It is commonly proposed that bone forming osteoblasts recruited during bone remodeling originate from bone marrow perivascular cells, bone remodeling compartment canopy cells, or bone lining cells. However, an assessment of osteoblast recruitment during adult human cancellous bone remodeling is lacking. We addressed this question by quantifying cell densities, cell proliferation, osteoblast differentiation markers, and capillaries in human iliac crest biopsy specimens. We found that recruitment occurs on both reversal and bone-forming surfaces, as shown by the cell density and osterix levels on these respective surfaces, and that bone formation occurs only above a given cell density. Canopies appeared an important source of osteoprogenitors, because (i) canopy cells proved to be more proliferative and less differentiated than bone surface cells, as shown by the inverse levels of Ki-67 and procollagen-3 N-terminal peptide versus osterix, and (ii) canopy cell densities, found to decline with age, and canopy-capillary contacts above eroded surfaces correlated positively with osteoblast density on bone-forming surfaces. Furthermore, we showed that bone remodeling compartment canopies arise from a mesenchymal envelope surrounding the red bone marrow, which is lifted and hypertrophied on initiation of bone resorption. This study, together with earlier reports, led to a model in which canopies and nearby capillaries are critical for reaching the osteoblast density required for bone formation.


NosR, a membrane-bound regulatory component necessary for expression of nitrous oxide reductase in denitrifying Pseudomonas stutzeri.
The regulatory element NosR was identified within the nos region of the denitrification gene cluster of Pseudomonas stutzeri ZoBell (ATCC 14405) and characterized. It is essential for expression of the N2O reductase encoded by nosZ immediately downstream of nosR. The nosR region was initially identified by Tn5 mutagenesis (W. G. Zumft, K. Döhler, and H. Körner, J. Bacteriol. 163:918-924, 1985). It consists of a single open reading frame of 2,172 nucleotides and has the coding capacity for an 81.9-kDa protein. The codon usage for nosR, with its high G + C content of 62.4 mol% and a preference for G or C at the third position, is characteristic for a Pseudomonas gene. Hydropathy analysis classified NosR as an integral membrane protein with at least seven membrane-spanning segments. No similarity to known bacterial regulator proteins was found in a data bank search. However, the C terminus of NosR shows sequence similarity to the cysteine clusters of several 2[4Fe-4S] bacterial ferrodoxins. A monocistronic mRNA for nosZ which allowed us to monitor NosR function was identified. Complementation of Nos- mutant MK418 (nosR::Tn5) with the nosR gene supplied in trans restored nosZ transcription and expression of a catalytically active N2O reductase. In addition to evidence of the requirement for NosR, indirect evidence for involvement of the transcriptional regulator Fnr is presented.


Electric and magnetic excitation of coherent magnetic plasmon waves in a one-dimensional meta-chain.
A one-dimensional diatomic meta-chain with equal-size holes and different-length slits is designed. Broadband coherent magnetic plasmon waves (MPW) are formed in such a system, excited by both the electric resonance in the slits and the magnetic resonance in the holes in a wide range of incidence angles (0°-40°) and broad frequency bands (200-230 THz). The dispersion properties of the MPW measured in our experiments agree with the theoretical calculation based on the Lagrange model. The coherent MPWs reported in this paper may have applications in subwavelength integrated nanocircuits.


Low prevalence of human papillomavirus infection of the cervix in renal transplant recipients.
An increased risk of anogenital tract malignancies has been noted among renal transplant recipients. A high prevalence of human papillomavirus (HPV) infection of the cervix in the female renal-transplant population has been assumed based on increasing evidence suggesting that HPV infection is the major risk factor for cervical intraepithelial neoplasia (CIN) and cervical cancer. It has been assumed that immunosuppression leads to either a reactivation of latent HPV or a reduction in the host's ability to contain a primary HPV infection, thereby increasing the risk of CIN and cervical cancer. The objective of this study was to evaluate the prevalence of human papillomavirus (HPV) infection in a population of iatrogenically immunosuppressed renal transplant recipients. Twenty-one women were recruited from the renal transplant clinic at Presbyterian Hospital and underwent a gynaecological examination which included colposcopy, a Papanicolaou smear, and a cervicovaginal lavage. Lavage samples were analysed for HPV DNA using L1 consensus primers and the polymerase chain reaction (PCR). No cases of cervical intraepithelial neoplasia (CIN) were detected in this cohort of 21 immuno-suppressed renal transplant recipients. HPV DNA was detected in only a single patient. Our data suggests that HPV infection is not highly prevalent among older, cytologically normal renal transplant recipients, particularly those who are currently monogamous or not presently sexually active. This study suggests that recent sexual behaviours are more important than past behaviours as a determinant of HPV status in transplant recipients, and also suggests that education concerning the avoidance of high-risk sexual behaviour is an important part of the care of the female renal transplant recipient. Our data is consistent with previous work suggesting that the incidence of CIN is declining in transplant recipients, and it also suggests that the prevalence of HPV infection may be declining as well.


Clinical and radiological correlates of apathy in multiple sclerosis.
Although apathy has been associated with fronto-striatal dysfunction in several neurological disorders, its clinical and magnetic resonance imaging (MRI) correlates have been poorly investigated in people with multiple sclerosis (PwMS). To evaluate clinical variables and investigate microstructural integrity of fronto-striatal grey matter (GM) and white matter (WM) structures using diffusion tensor imaging (DTI). A total of 123 PwMS (age: 40.25 ± 11.5; female: 60.9%; relapsing-remitting multiple sclerosis: 75.6%) were prospectively enrolled and underwent neurological and neuropsychological evaluation, including Expanded Disability Status Scale (EDSS), Apathy Evaluation Scale (AES-S), Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and brain 3T-MRI volumes of whole brain, frontal/prefrontal cortex (PFC) and subcortical regions were calculated. DTI-derived metrics were evaluated in the same GM regions and in connecting WM tracts. Apathetic PwMS (32.5%) showed lower education levels, higher HADS, MFIS scores and WM lesions volume than nonapathetic PwMS. Significant differences in DTI metrics were found in middle frontal, anterior cingulate and superior frontal PFC subregions and in caudate nuclei. Significant alterations were found in the right cingulum and left striatal-frontorbital tracts. Apathy in PwMS is associated with higher levels of physical disability, depression, anxiety and fatigue together with lower educational backgrounds. Microstructural damage within frontal cortex, caudate and fronto-striatal WM bundles is a significant pathological substrate of apathy in multiple sclerosis (MS).


Development of a multiple regression model to identify multi-family residential buildings with a high prevalence of sick building syndrome (SBS).
The aim was to develop a multiple logistic regression model to identify multi-family houses with an increase of sick building syndrome (SBS). In Stockholm, 609 multi-family buildings with 14,235 dwellings were selected by stratified random sampling. The response rate was 77%. Multiple logistic regression analysis was applied, adjusting for ownership of the building, building age and size, age, gender, and atopy. Females, subjects with allergy, those above 65 yr, and those in new buildings reported significantly more SBS. Subjects owning their own building reported less SBS, but the relationship between ownership and building age was strong. A regression model, including factors with a high explanatory value was developed. According to the model, 5% of all buildings built before 1961, 13% of those built 1976-1984, and 15% of those built 1985-1990 would have significantly more SBS than expected. In conclusion, SBS is related to personal factors, building age, and ownership of the building. To identify multi-family buildings with more SBS than expected, it is necessary to adjust for ownership and population characteristics.


Bivariate Causal Discovery and Its Applications to Gene Expression and Imaging Data Analysis.
The mainstream of research in genetics, epigenetics, and imaging data analysis focuses on statistical association or exploring statistical dependence between variables. Despite their significant progresses in genetic research, understanding the etiology and mechanism of complex phenotypes remains elusive. Using association analysis as a major analytical platform for the complex data analysis is a key issue that hampers the theoretic development of genomic science and its application in practice. Causal inference is an essential component for the discovery of mechanical relationships among complex phenotypes. Many researchers suggest making the transition from association to causation. Despite its fundamental role in science, engineering, and biomedicine, the traditional methods for causal inference require at least three variables. However, quantitative genetic analysis such as QTL, eQTL, mQTL, and genomic-imaging data analysis requires exploring the causal relationships between two variables. This paper will focus on bivariate causal discovery with continuous variables. We will introduce independence of cause and mechanism (ICM) as a basic principle for causal inference, algorithmic information theory and additive noise model (ANM) as major tools for bivariate causal discovery. Large-scale simulations will be performed to evaluate the feasibility of the ANM for bivariate causal discovery. To further evaluate their performance for causal inference, the ANM will be applied to the construction of gene regulatory networks. Also, the ANM will be applied to trait-imaging data analysis to illustrate three scenarios: presence of both causation and association, presence of association while absence of causation, and presence of causation, while lack of association between two variables. Telling cause from effect between two continuous variables from observational data is one of the fundamental and challenging problems in omics and imaging data analysis. Our preliminary simulations and real data analysis will show that the ANMs will be one of choice for bivariate causal discovery in genomic and imaging data analysis.


[Introduction of the anterior sagittal trans-ano-rectal approach (ASTRA) as a technical variation of the Passerini-Glazel clitoro-vaginoplasty: preliminary results].
A variant technique to the 1-stage clitorovaginoplasty in severely masculinized female pseudohermaphrodites is presented. The new variant consist of an anterior sagittal trans-ano-rectal approach (A.S.T.R.A.) with the patient placed in the prone position after that a clitoroplasty was performed by the Paserini-Glazel procedure. A.S.T.R.A. permit to perform the dissection between the vagina and the urethra, the suture of the vaginal stump and the anastomosis between the neo-introitus vaginalis and the vagina under direct vision. A.S.T.R.A. with a protective colostomy was performed in two patients with normal rectum. The anorectal sphinteric mechanism was divided in the anterior midline, and the rectum was opened just in the anterior rectal wall. This provided excellent exposure to urogenital sinus. The vagina was then easily and fully separated from the urogenital sinus, the vaginal stump sutured and the anastomosis between the mucocutaneous cylinder (neo-introitus vaginalis) and the vagina performed. The rectum, perineal body and the anterior sphinteric mechanism were reconstructed. The postoperative course was uneventful. The patients had normal fecal control after the colostomy closure. No urinary incontinence was encountered. An anterior sagittal midline incision provides excellent exposure to the urogenital sinus and assure the preservation of the anorectal innervation and the sphinteric mechanism.


Nurses' ethical challenges when providing care in nursing homes during the COVID-19 pandemic.
Background: Older, frail patients with multimorbidity are at an especially high risk for disease severity and death from COVID-19. The social restrictions proved challenging for the residents, their relatives, and the care staff. While these restrictions clearly impacted daily life in Norwegian nursing homes, knowledge about how the pandemic influenced nursing practice is sparse. Aim: The aim of the study was to illuminate ethical difficult situations experienced by Norwegian nurses working in nursing homes during the COVID-19 pandemic. Research design and participants: The research design involved semistructured individual interviews conducted with 15 nurses working in 8 nursing homes in 3 health regions in Norway, within both urban and rural areas. Ethical considerations: Oral and written information about the study was provided before the participants gave their written consent. The transcribed interviews were de-identified. The study was approved by the Norwegian Centre for Research Data. Findings: Four ethical difficult situations were identified: (a) turning the nursing home into a prison; (b) using medication to maintain peace and order; (c) being left alone with the responsibility; and (d) s. impact on decision-making. Conclusions: The nurses' ethical challenges were intertwined with external factors, such as national and local guidelines, and the nurses' own internalized factors, which were connected to their subjective professionality. This duality inflicted emotional distress and gave nurses few opportunities to perform nursing in a professionally sound and safe manner.


Chemical composition and in vitro biological activities of the essential oil of Vepris macrophylla (BAKER) I.VERD. endemic to Madagascar.
Vepris macrophylla is an evergreen tree occurring in sub-humid forest of Madagascar and traditionally used in the Island to treat several complaints as well as to prepare aromatic teas and alcoholic drinks. In the present work, the essential oil distilled from the leaves was analyzed for the first time by gas chromatography (GC-FID) and gas chromatography/mass spectrometry (GC/MS). The major compounds were citral (56.3%), i.e., mixture of neral (23.1%) and geranial (33.2%), citronellol (14.5%), and myrcene (8.3%). The essential oil exhibited antimicrobial activity against S. aureus, P. aeruginosa, and C. albicans as determined by vapor-diffusion assay, supporting the traditional use of the plant for preparing steam bath for the treatment of infectious diseases. The essential oil was evaluated for cytotoxic activity on human tumor cell lines by MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay, showing inhibitory effects comparable to those of cisplatin, notably on MDA-MB 231 (human breast adenocarcinoma) and HCT116 (human colon carcinoma) cell lines. Finally, the essential oil was also subjected to screening for its antioxidant activity and the free radical scavenging capacity.


Characterizing re-triage guidelines: A scoping review of states' rules and regulations.
State guidelines for re-triage, or emergency inter-facility transfer, have never been characterized across the United States. All 50 states' Department of Health and/or Trauma System websites were reviewed for publicly available re-triage guidelines within their rules and regulations. Communication was made via phone or email to state agencies or trauma advisory committees to obtain or confirm the absence of guidelines where public data was unavailable. Guideline criteria were abstracted and grouped into domains of Center for Disease Control Field Triage Criteria: pattern/anatomy of injury, vital signs, special populations, and mechanisms of injury. Re-triage criteria were summarized across states using median and interquartile ranges for continuous data and frequencies for categorical data. Demographic data of states with and without re-triage guidelines were compared using the Wilcoxon rank sum test. Re-triage guidelines were identified for 22 of 50 states (44%). Common anatomy of injury criteria included head trauma (91% of states with guidelines), spinal cord injury (82%), chest injury (77%), and pelvic injury (73%). Common vital signs criteria included Glasgow Coma Score (91% of states) ranging from 8 to 14, systolic blood pressure (36%) ranging from 90 to 100 mm Hg, and respiratory rate (23%) with all using 10 respirations/minute. Common special populations criteria included mechanical ventilation (73% of states), age (68%) ranging from <2 or >60 years, cardiac disease (59%), and pregnancy (55%). No significant demographic differences were found between states with versus without re-triage guidelines. A minority of US states have re-triage guidelines. Characterizing existing criteria can inform future guideline development.


Detection of speech landmarks: use of temporal information.
Studies by Shannon et al. [Science, 270, 303-304 (1995)], Van Tasell et al. [J. Acoust. Soc. Am. 82, 1152-1161 (1987)], and others show that human listeners can understand important aspects of the speech signal when spectral shape has been significantly degraded. These experiments suggest that temporal information is particularly important in human speech perception when the speech signal is heavily degraded. In this study, a system is developed that extracts linguistically relevant temporal information that can be used in the front end of an automatic speech recognition system. The parameters targeted include energy onset and offsets (computed using an adaptive algorithm) and measures of periodic and aperiodic content; together these are used to find abrupt acoustic events which signify landmarks. Overall detection rates for strongly robust events, robust events, and weak events in a portion of the TIMIT test database are 98.9%, 94.7%, and 52.1%, respectively. Error rates increase by less than 5% when the speech signals are spectrally impoverished. Use of the four temporal parameters as the front end of a hidden Markov model (HMM)-based system for the automatic recognition of the manner classes "sonorant," "fricative," "stop," and "silence" results in the same recognition accuracy achieved when the standard 39 cepstral-based parameters are used, 70.1%. The combination of the temporal parameters and cepstral parameters results in an accuracy of 74.8%.


Protective effect of kombucha on rats fed a hypercholesterolemic diet is mediated by its antioxidant activity.
Kombucha (KT) is claimed to have various beneficial effects on human health, but there is very little scientific evidence available in the literature. The present study investigates the effects of Camellia sinensis (GT) Linn. (Theaceae) and KT, two natural drinks, on cholesterol and antioxidant status using a hypercholesterolemia rat model. The present study compared the free-radical scavenging abilities and polyphenol levels of GT and KT. Wistar rats fed cholesterol-rich diets were given KT or GT (5 mL/kg body weight per day, po) for 16 weeks, then fasted overnight and sacrificed. The plasma lipid levels, thiobarbituric acid reactive substances (TBARS) and aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (GGT) serum levels, antioxidant activities of superoxide dismutase (SOD) and catalase (CAT), and creatinine and urea rats were examined. KT had a phenolic compound of 955 ± 0.75 mg GAE/g) followed, by GT (788.92 ± 0.02 mg GAE/g). The free radical scavenging activity of KT was higher than GT. Compared with GT, KT induced lowered serum levels of TC, TG, VLDL-C, and LDL-C by 26, 27, 28, and 36%, respectively, and increased the serum level of high-density lipoprotein cholesterol (HDL-C). KT induced a 55% decrease of TBARS level in liver and 44% in kidney, compared with those of rats fed a cholesterol-rich diet alone. Moreover, CAT and SOD activities were reduced by 29 and 33%, respectively, in liver and 31 and 35%, respectively, in kidney, after oral administration of KT, compared with those of HCD-fed rats. The findings revealed that KT administration induced attractive curative effects on hypercholesterolemic, particularly in terms of liver-kidney functions in rats. Its effect on humans needs to be studied further.


Cloning and Characterization of a Human Genomic Sequence that Alleviates Repeat-Induced Gene Silencing.
Plasmids bearing a mammalian replication initiation region (IR) and a nuclear matrix attachment region (MAR) are spontaneously amplified in transfected mammalian cells, and such amplification generates chromosomal homogeneously staining regions (HSRs) or extrachromosomal double minutes (DMs). This method provides a novel, efficient, and rapid way to establish cells that stably produce high levels of recombinant proteins. However, because IR/MAR plasmids are amplified as repeats, they are frequently targeted by repeat-induced gene silencing (RIGS), which silences a variety of repeated sequences in transgenes and the genome. To address this problem, we developed a novel screening system using the IR/MAR plasmid to isolate human genome sequences that alleviate RIGS. The screen identified a 3,271 bp sequence (B-3-31) that elevated transgene expression without affecting the amplification process. Neither non-B structure (i.e., the inverted repeats or bending) nor known epigenetic modifier elements such as MARs, insulators, UCOEs, or STARs could explain the anti-silencing activity of B-3-31. Instead, the activity was distributed throughout the entire B-3-31 sequence, which was extremely A/T-rich and CpG-poor. Because B-3-31 effectively and reproducibly alleviated RIGS of repeated genes, it could be used to increase recombinant protein production.


Palliative Care Research in the Asia Pacific Region: A Systematic Review and Bibliometric Analysis of Peer-Reviewed Publications.
Background: The state of palliative care research is closely linked to the development of palliative care services in a country or region. Objective: To systematically review the current state of palliative care research in the Asia Pacific region and analyze its relationship with the performance of each country in the region on the Economist Intelligence Unit's 2015 Quality of Death Index. Design: Systematic review and bibliographic analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol 2015 (PRISMA-P). Data Sources: The PubMed/MEDLINE, EMBASE, SCOPUS, CINAHL, and PsychiNFO databases were searched on February 4, 2018. Results: One thousand six hundred sixty-seven articles were reviewed. Eighteen out of 32 countries in the region published research. Around 74.15% (1236) of the articles were produced by high-income countries. Research output (articles per 1 m population) was closely linked to country performance on the Economist Intelligence Unit's 2015 Quality of Death Index (adjusted R2 = 0.85). Palliative care research in the region is overwhelmingly focused on cancer (80.13% of articles reviewed). The most common themes of research were "palliative care service (24.45%)" and "clinical" (15.38%). Conclusions: Palliative care research in the region is growing but remains largely centered on the high-income countries, with many low- and middle-income countries having little published research output. Much work is required to drive research in these countries to generate the evidence required for the development of palliative care services. The emphasis on cancer in research also indicates that the needs of patients suffering from noncancer-related diseases may be neglected.


Evaluation of a strategy for enrolling the families of critically ill patients in research using limited human resources.
Clinical trials of interventions aimed at the families of intensive care unit (ICU) patients have proliferated but recruitment for these trials can be challenging. To evaluate a strategy for recruiting families of patients currently being treated in an ICU using limited human resources and time-varying daily screening over 7 consecutive days. We screened the Johns Hopkins Hospital medical ICU census 7 days per week to identify eligible family members. We then made daily, in-person attempts to enroll eligible families during a time-varying 2-hour enrollment period until families declined participation, consented, or were no longer eligible. The primary outcome was the proportion of eligible patients for whom ≥1 family member was enrolled. Secondary outcomes included enrollment of legal healthcare proxies, the consent rate among families approached for enrollment, and success rates for recruiting at different times during the day and week. Among 284 eligible patients, 108 (38%, 95% CI 32%-44%) had ≥1 family member enrolled, and 75 (26%, 95% CI 21%-32%) had their legal healthcare proxy enrolled. Among 117 family members asked to participate, 108 (92%, 95% CI 86%-96%) were enrolled. Patients with versus without an enrolled proxy were more likely to be white (44% vs. 30%, P = .02), live in a zip code with a median income of ≥$100,000 (15% vs. 5%, P = .01), be mechanically ventilated (63% vs. 47%, P = .01), die in the ICU (19% vs. 9%, P = .03), and to have longer ICU stays (median 5.0 vs. 1.8 days, P<.001). Day of the week and time of day were not associated with family presence in the ICU or consent rate. Family members were recruited for more than one third of eligible patients, and >90% of approached consented to participate. There are important demographic differences between patients with vs without an enrolled family member.


Depressive symptoms before and after long-term CPAP therapy in patients with sleep apnea.
The outcome of depressive symptoms under CPAP therapy for OSA-hypopnea syndrome (OSAHS) has been poorly evaluated. In this multicenter, prospective cohort study, we evaluated the prevalence and correlates of persistent depressive symptoms after long-term CPAP therapy for OSAHS. This study included 300 patients with OSAHS and depressive symptoms (13-item, self-rated Pichot depression scale [QD2A] ≥ 7) at diagnosis. The primary dependent variable was persistent depressive symptoms after ≥ 1 year of CPAP therapy. Multivariate regression analyses were performed to determine variables independently associated with the persistence of depressive symptoms. After an average of 529 days (range, 365-1,569 days) of CPAP therapy, the mean (SD) QD2A score decreased from 9.2 (2.0) to 5.4 (4.0) (P < .0001), but 125 patients (41.7%) presented persistent depressive symptoms. The persistence of depressive symptoms was independently associated with persistent excessive daytime sleepiness (EDS) (OR, 2.72; 95% CI, 1.33-5.61), comorbid cardiovascular disease (OR, 1.76; 95% CI, 1.02-3.00), and female sex (OR, 1.53; 95% CI, 1.09-2.13). A positive linear trend was observed for the adjusted OR of persistent depressive symptoms with decreasing CPAP effect on the Epworth sleepiness scale (P < .0001). CPAP therapy does not resolve depressive symptoms in many patients with OSAHS. Persistent depressive symptoms are strongly associated with EDS. Active monitoring of depressive symptoms is needed in patients with OSAHS who are treated with CPAP. Interventional trials are required to evaluate the impact of antidepressants, cognitive behavioral therapy, or both on comorbid depression in patients with OSAHS.


Cipura paludosa extract prevents methyl mercury-induced neurotoxicity in mice.
Cipura paludosa (Iridaceae), a native plant widely distributed in the north of Brazil, is used in traditional medicine as an anti-inflammatory and analgesic agent, against tuberculosis and gonorrhoea and for regulation of menstrual flow. However, scientific studies on the pharmacological properties of C. paludosa are scarce. We have examined the potential protective effects of the ethanolic extract of C. paludosa against methyl mercury (MeHg)-induced neurotoxicity in adult mice. MeHg was diluted in drinking water (40 mg/l, freely available) and the ethanolic C. paludosa extract (CE) was diluted in a 150 mM NaCl solution and administered by gavage (10 and 100 mg/kg body weight, respectively, twice a day). Because treatment lasted for 14 days and each animal weighed around 40 g, the total dosage of plant extract given to each mouse was 5.6 and 56 g, respectively. After the treatment period, MeHg exposure induced a significant deficit in the motor coordination, which was evident by a reduction (90%) in the falling latency in the rotarod apparatus. Interestingly, this phenomenon was completely recovered to control levels by CE co-administration, independent of dosages. MeHg exposure inhibited cerebellar glutathione peroxidase (mean percentage inhibition of 42%) - an important enzyme involved in the detoxification of endogenous peroxides - and this effect was prevented by co-administration of CE. Conversely, MeHg exposure increased cerebellar glutathione reductase activity (mean percentage inhibition of 70%), and this phenomenon was not affected by C. paludosa co-administration. Neither MeHg nor CE changed the cerebellar glutathione levels. This study has shown for the first time, the in vivo protective effects of CE against MeHg-induced neurotoxicity. In addition, our findings encourage studies concerning the beneficial effects of C. paludosa on neurological conditions related to excitotoxicity and oxidative stress.


The effect of anatomical noise on perception of low contrast in intra-oral radiographs: an in vitro study.
Radiographic images suffer from varying amounts of noise. The most studied and discussed of these is random noise. However, recent research has shown that the projected anatomy contributes substantially to noise, especially when detecting low-contrast objects in the images. Our aim, therefore, was to evaluate the extent to which overprojected anatomical noise affects the detection of low-contrast objects in intra-oral images. Our study used four common sensor models. With each sensor, we took four series of images, three series with and one series without an anatomical phantom present. In each series, we exposed a low-contrast phantom at 18 different exposure times using a standardized method. 4 observers evaluated all 288 images. The low-contrast characteristics differed substantially when imaging low contrast on a homogeneous background compared with imaging low contrast when an anatomical phantom was present. For three of the sensors, optimal exposure times for low-contrast imaging were found, while the fourth sensor displayed a completely different behaviour. Calibrating the low-contrast properties of an imaging system using low-contrast objects on a homogeneous background is not recommended. On an anatomical background, low-contrast properties are completely different, and these will mimic the clinical situation much more closely, directing the operator how to best use the system. There is a clear demand for further research on this subject.


Recent Advances in the Management of Hormone-Sensitive Oligometastatic Prostate Cancer.
After primary treatment for prostate cancer with either radical prostatectomy or radiotherapy, a significant proportion of patients are at risk of developing metastases. In recent years, a deeper understanding of the underlying biology together with improved imaging techniques and the advent of new therapeutic options including metastases-directed therapies and new drugs have revolutionized the management of low-burden metastatic disease, also known as oligometastatic state. The purpose of this narrative review is to report the recent developments in the management of hormone-sensitive oligometastatic prostate cancer patients.


Expression of testicular phosphorylated proteins in types 1 and 2 diabetes mellitus in mice: An experimental study.
Types 1 and 2 diabetes mellitus (DM) are known to be the cause of sub/infertility. However, the comparisons of potential markers in spermatogenesis and steroidogenesis in DM males have never been elucidated. This study aimed to examine the expressions of tyrosine-phosphorylated and steroidogenic acute regulatory (StAR) proteins in testis of DM mice. Fifty-six male C57BL/6 mice were divided into four groups (n░=░14/ each): control of MLD-STZ (multiple low doses of streptozotocin), MLD-STZ, control of HFD-STZ (high-fat diet with STZ), and HFD-STZ. MLD-STZ mice (type 1 DM) were intraperitoneally (i.p.) injected with STZ at 40░mg/kg BW for five days. HFD-STZ mice (type 2 DM) received an HFD for 14 days and i.p.-induced by STZ at 85░mg/kg BW and fed with HFD. At the end of the experiment (days 36 and 72), the expressions of phosphorylated proteins and StAR were examined. Tyrosine phosphorylated proteins were localized in late spermatids, luminal fluid, and Leydig cells. The intensities of phosphorylated 110, 85, 72, 60, and 55░kDas were lower in the 36 day-DM mice. Although such intensities were present in both groups, only 85░kDa in the MLD-STZ mice was higher in HFD mice at 72 days. StAR expressions in both groups were decreased than that of the controls. Decreased expressions of StAR and tyrosine-phosphorylated proteins may be directly involved in low testosterone levels and impaired spermatogenesis. These findings support the notion that both DM types play a role in male infertility.


Mechanochemical coupling in spin-labeled, active, isometric muscle.
Observed effects of inorganic phosphate (P(i)) on active isometric muscle may provide the answer to one of the fundamental questions in muscle biophysics: how are the free energies of the chemical species in the myosin-catalyzed ATP hydrolysis (ATPase) reaction coupled to muscle force? Pate and Cooke (1989. Pflugers Arch. 414:73-81) showed that active, isometric muscle force varies logarithmically with [P(i)]. Here, by simultaneously measuring electron paramagnetic resonance and the force of spin-labeled muscle fibers, we show that, in active, isometric muscle, the fraction of myosin heads in any given biochemical state is independent of both [P(i)] and force. These direct observations of mechanochemical coupling in muscle are immediately described by a muscle equation of state containing muscle force as a state variable. These results challenge the conventional assumption mechanochemical coupling is localized to individual myosin heads in muscle.


Financial and family burden associated with cancer treatment in Ontario, Canada.
To determine the financial and family resources burden associated with the treatment of cancer. A questionnaire was developed to determine the direct monthly "out-of-pocket costs" (OOPC), the indirect costs, and the associated perceived family burden. A self-administered questionnaire using a quota sample from five cancer clinics in Ontario, Canada was given to 282 cancer patients (74 breast, 70 colorectal, 68 lung, and 70 prostate). Monthly OOPC were obtained for: drugs, home care, homemaking, complementary and alternative medicines, vitamins and supplements, family care, travel, parking, accommodations, devices, and others. The questionnaire asked if OOPC for treatment were a burden, and if others took time from work to provide caregiving. The mean monthly OOPC was $213, with an additional $372 related to imputed travel costs. For those patients who responded that the burden was "significant" (16.5%), their OOPC was $452. In the case of patients responding that their burden was "unmanageable" (3.9%), their OOPC was $544. The survey showed that 35.6% of patients required others to take time from work and this was higher in the under-65 category. The mean number of days lost from work in the previous 30 days for these caregivers was 7 days. These results suggest the financial burden is problematic for 20% of this sample. The caregivers' lost time from work influence this burden, and for 36% of this sample, it amounts to one third of their working days in any given month. Policies and programs to address these gaps are needed.


The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer.
Enhancer of zeste 2 (EZH2), a polycomb histone methyltransferase, is overexpressed in various cancers, including cervical cancer. Gene expression analysis revealed that increased expression of EZH2 is associated with cervical cancer progression, particularly the progression to invasive squamous cell carcinoma. Enhancer of zeste 2 is known to trimethylate lysine 27 on histone H3, leading to gene silencing that contributes to the progression of tumours into a more aggressive form of cancer. However, the specific molecular mechanisms by which EZH2 contributes to the development of cervical cancer remain largely unknown. Recently, an EZH2 inhibitor was reported to selectively inhibit trimethylated lysine 27 on histone H3 and to reactivate silenced genes in cancer cells. In this study, we found that GSK343 (a specific inhibitor of EZH2 methyltransferase) induces phenotypic reprogramming of cancer cells from mesenchymal to epithelial cells, reducing proliferation and cell motility and blocking the invasion of cervical cancer cell lines both in vitro and in vivo. Treatment with the EZH2 inhibitor led to increased levels of the epithelial marker E-cadherin and decreased levels of mesenchymal markers such as N-cadherin and vimentin. The observed reprogramming is associated with restrained cervical cancer progression and provides direct evidence in support of EZH2 as a therapeutic target.


[Informative value of adenosine deaminase and 2-deoxyadenosine deaminase in the diagnosis of tuberculous pleurisy].
Adenosine deaminase (ADA) and 2-deoxyadenosine deaminase (2-deoxyADA) activities were measured in pleural exudation of different origin in 373 patients (124 of these with serous tuberculous pleurisy and 75 with specific empyema). High diagnostic value of ADA activity in the presence of threshold value higher than 35 Units/liter was established: the sensitivity of the test in the diagnosis of tuberculous pleurisy and empyema was 94.4 and 93.3% respectively, specificity 93.0 and 89.5%, respectively. Judging by the coefficient of 2-deoxyADA/ADA, total ADA activity is determined by the activity of ADA-2 isoenzyme, while in tuberculous empyema by ADA-1. Additional use of this coefficient, requiring measurement of 2-deoxyADA activity, does not improve the efficiency of the diagnostic process, including measurement of total ADA activity in pleural exudate.


[Evaluation of cisplatin ototoxicity by the audiometric curve in retinoblastoma].
To evaluate hearing loss severity according to Brock's gradient and to compare it with the audiometric curve during cisplatin treatment in children with retinoblastoma. This was an observational retrospective and retrolective study. Twenty children with the diagnosis of retinoblastoma under cisplatin treatment were included. Audiometric testing was performed before treatment, after the second and fourth doses, and after the final dose. Decreased audition was observed in 100% of the cases. Ototoxicity can be observed with cumulative doses of 240 mg/m(2) and higher. No improvement in audition was observed and the audition loss progressed from high to medium frequencies; 15% of the patients showed a grade II loss of high frequencies at the end of the second dose. This level was observed in 95% of the cases at the end of treatment. Two years after completion of therapy, no patient showed auditory recovery. Area below the curve showed higher sensitivity to identify initial auditory loss. Evaluation of audition with Brock's gradient can be performed. The area under the curve is a useful method to identify minor changes in serial conventional audiometry.


Universal tag arrays in forensic SNP analysis.
Microarray-based single nucleotide polymorphism (SNP) genotyping enables simultaneous and rapid detection of a large number of markers and is thus an attractive method for forensic individual acid identification. This assay relies on a one-color detection system and minisequencing in solution before hybridization to universal tag arrays. The minisequencing reaction is based on incorporation of a fluorescent dideoxynucleotide to a primer containing a tag-sequence flanking the position to be interrogated. This one-color system detects C and T polymorphisms in separate reactions on multiple polymerase chain reaction targets with the fluorophore TAMRA coupled to the respective dideoxynucleotide. After incorporation, tagged primer sequences are hybridized through their complementary sequence on the array, and positive signals are detected by a confocal laser-scanner.


Psychiatric consultation of all suicide-attempt patients during a one year period in a tertiary hospital.
Many tertiary hospitals provide psychiatric services that treat diverse clinical situations. Most patients referred to these services following a serious suicide attempt have psychiatric diagnoses, but their unique characteristics and needs are not known. To examine the files of patients hospitalized in a tertiary hospital in Israel following a serious suicide attempt. Their mental conditions were determined and their unique demographic and clinical characteristics and needs compared to the other patients examined by the psychiatric service. The study focused on 49 consecutive patients admitted after performing a life-threatening suicide attempt. They were compared to 389 non-suicidal patients assessed by the same psychiatric service during one year. Nearly half the patients hospitalized following a serious suicide attempt had only an axis II diagnosis (personality disorder). Non-violent methods of suicide were used predominantly by females, and violent methods mainly by males. All suicide attempts by Muslims used violent methods, while less than half the attempts by Jews were violent. Compared to the non-suicidal patients, the suicide-attempters group was younger and had greater representation of Jewish females and Muslim males. Compared to the non-suicidal patients, these patients required more intense psychiatric care, earlier commencement of treatment in the course of hospitalization, more psychiatric visits and treatment hours, and more referrals for further care. Several risk factors appear to be associated with a need for more intense in-hospital care and a greater need for referral: male gender, religion, method of suicide attempt (violent vs. non-violent), and the existence of a psychiatric diagnosis. Suicide-attempt patients who are in need of hospitalization for further medical treatment have unique clinical characteristics and require more intense treatment provided by the Consultation-Liaison Unit.


[The adolescent and the hospital].
This article deals with the care and treatment of the adolescent in hospital. As a result of changes in society and alterations in the biological and psychological patterns of growth adolescents are being increasingly regarded as a distinct and separate group. In the authors' opinion medical care in the Netherlands is still not sufficiently adapted or geared to the needs of the adolescent. The authors propose that special facilities be created for adolescents in hospitals and out-patient departments, along the lines of those currently available in the U.S.A. The establishment of special adolescent units in children's hospitals and general hospitals requires considerable organisation and the recruitment of suitably qualified staff; in addition, medical students and nurses must be given factual and scientifically accurate information about adolescence during their training courses.


[Caseload profile in emergency services: sentinel events for monitoring primary health care].
The study's hypothesis was that certain disease entities treated in emergency services, based on the sentinel event concept, are related to flaws in primary care and can be used to develop an indicator for monitoring such care. Quantitative and qualitative data were used on previously selected occurrences treated in the emergency department. Using triangulation of methods, the differences were verified in the frequencies of these occurrences between the areas of patients' residence/ primary care units and the motivations leading them to seek the emergency department. Distribution of the frequency of these events varied from 30% to 42.8%, according to the area of residence/ primary care unit (Chi2 = 9.19 and p = 0.027). The interviews suggested the existence of causality between the reason stated for seeking the emergency service and the performance of the primary care units. (1) the frequency of the selected occurrences was influenced by the area of residence/ location of the primary care unit; (2) this influence results partially from the primary care performance; and (3) the study instrument is simple and can help local administrators monitor the daily performance of primary care services.


Reverse line blot hybridization assay for identification of medically important fungi from culture and clinical specimens.
We evaluated a combined panfungal PCR-reverse line blot (RLB) hybridization assay based on internal transcribed spacer 1 (ITS1) and ITS2 region polymorphisms to identify 159 Candida, Cryptococcus neoformans, and Aspergillus isolates (22 species). Its utility to identify fungal pathogens directly from 27 clinical specimens was also determined. ITS sequence analysis was performed to resolve discrepant identifications or where no RLB result was obtained. Species-specific ITS2- and ITS1-based probes correctly identified 155 of 159 isolates (98%) and 149 (93.7%) isolates, respectively. All strains were unambiguously differentiated with the exception of cross-reactivity between the Candida norvegensis probe and Candida haemulonii DNA product. Species identification of the pathogen was made for all 21 specimens (sensitivity of 100%) where species-specific probes were included in the RLB; however, there was no ITS2 probe-based hybridization signal for two specimens. Results were concordant with the culture results for 18 (85.7%) specimens. The assay was able to provide species identification in the absence of a culture result (two specimens) and to detect mixed infection (one specimen). The results indicate that the RLB assay is capable of reliably detecting yeasts and Aspergillus spp. in clinical specimens and that the incorporation of both ITS1- and ITS2-targeted probes is required for optimal sensitivity. The test has potential utility in the early diagnosis of invasive fungal infection, since "fungal" DNA was detected in all 27 specimens. Prior to incorporation of probes to detect other fungal species, ITS sequencing may be performed to achieve species identification.


A retrospective multicenter study on outcomes after midurethral polypropylene sling revision for voiding dysfunction.
: The purpose of this study was to determine outcomes of sling revision after midurethral sling (MUS) placement and whether timing of sling revision affected those outcomes. : This is a multicenter study including patients who underwent MUS placement and subsequent sling revision secondary to voiding dysfunction. Diagnostic outcomes before and after sling revision were compared for all sling revision patients with complete data. Logistic regression analyses were performed to determine if revision timing predicted voiding dysfunction and stress incontinence. : One hundred seventy-five patients who met the study criteria had complete data. Overall, 70% (133) of MUS were retropubic and 30% (56) were obturator slings. Midurethral sling revision was accomplished by cutting (54%), excision (29%), and pulling down on the mesh (18%). Stress urinary incontinence (SUI) resolved in 38%, urinary tract infections (UTIs) in 69%, and overactive bladder (OAB) in 75%. In comparison, 21% experienced de novo SUI; 18%, de novo UTIs; and 12%, de novo OAB symptoms after revision. Voiding dysfunction resolved in 80%, however 10% experienced new voiding dysfunction symptoms. Retropubic slings displayed more voiding dysfunction, higher de novo/worsened OAB, and more UTIs after revision than obturator slings. Sling revision timing did not predict persistent voiding dysfunction but did predict SUI with earlier revision (≤2 weeks) resulting in less postrevision SUI when compared to revisions at 15-90 days or greater than 90 days. The method of sling revision (cut, excised, pulled down) did not predict SUI, OAB, or obstructive voiding symptoms. : Sling revision resolves voiding dysfunction symptoms, UTIs and post-sling OAB symptoms in the majority of patients. Resolution of voiding dysfunction is independent of method and timing of revision; however earlier revision is associated with decreased postrevision SUI.


[Azotobacter chroococcum, a producer of a new antifungal antibiotic].
Strain 92 of Azotobacter chroococcum was obtained as result of natural selection. It produces an antibiotic active against phytopathogenic fungi. The antibiotic was isolated from the bacterial mass of the culture with ethanol extraction followed by column and thin-layer chromatography on silica gel. The pure antibiotic is a viscous oily substance of a yellowish colour, readily soluble in the majority of the organic solvents, not soluble in water, readily oxidized by air oxygen. The UV absorption spectrum of the antibiotic ethanol solution had bonds characteristic of the conjugated tetraene system. The presence of ketone and enol groups in the antibiotic molecule was shown with the colour reactions. It was confirmed by the data of the antibiotic IR spectrum investigation. According to the data of high resolution mass spectroscopy the empirical formula of the antibiotic is C20H30O4, the molecular weight is 334. It is suggested that the antibiotic is an ester of aliphatic tetraenic acid differing from the known antibiotics produced by Azotobacter.


Patients' interest in reading their medical record: relation with clinical and sociodemographic characteristics and patients' approach to health care.
Although opportunities for patients to review their medical records are increasing, nothing is known about which patients want to take advantage of those opportunities. The objective of this study was to determine the proportion and characteristics of patients who are very interested in examining their clinic medical record and the reasons for their interest. Cross-sectional, mailed survey (conducted in May 2001) to a random sample of 4500 adults who had a recent clinic visit. The response rate was 81%; 36% were very interested in reading their medical record (dependent variable). In multivariate logistic regression, the significantly related factors were seeking health information (finding the Internet very important for health information [adjusted odds ratio, 2.09], having a health newsletter subscription [adjusted odds ratio, 1.23], and using a health resource book in last month [adjusted odds ratio, 1.36]); being very concerned about errors in care (adjusted odds ratio, 2.52); and lacking trust in their physician (adjusted odds ratio, 1.55). Health status, use of health care, education, and income were not independently related to patients' interest. The most common reasons for patients wanting to look at their medical record were to see what their physician said about them (74%), to be more involved in their health care (74%), and to understand their condition better (72%). Patients' interest in reading their medical record is better predicted by their consumer approach to health care than it is by their clinical characteristics. Demographic characteristics of sex and race were related, while socioeconomic factors of education and income were not.


Pilicides regulate pili expression in E. coli without affecting the functional properties of the pilus rod.
The infectious ability of uropathogenic Escherichia coli relies on adhesive fibers, termed pili or fimbriae, that are expressed on the bacterial surface. Pili are multi-protein structures that are formed via a highly preserved assembly and secretion system called the chaperone-usher pathway. We have earlier reported that small synthetic compounds, referred to as pilicides, disrupt both type 1 and P pilus biogenesis in E. coli. In this study, we show that the pilicides do not affect the structure, dynamics or function of the pilus rod. This was demonstrated by first suppressing the expression of P pili in E. coli by pilicide treatment and, next, measuring the biophysical properties of the pilus rod. The reduced abundance of pili was assessed with hemagglutination, atomic force microscopy and Western immunoblot analysis. The biodynamic properties of the pili fibers were determined by optical tweezers force measurements on individual pili and were found to be intact. The presented results establish a potential use of pilicides as chemical tools to study important biological processes e.g. adhesion, pilus biogenesis and the role of pili in infections and biofilm formation.


Factors associated with tuberculin reactivity in two general hospitals in Mexico.
To identify risk factors associated with tuberculin reactivity in healthcare workers (HCWs). Cross-sectional survey of tuberculin reactivity (2 TU of purified protein derivative (PPD) RT23, using the Mantoux two-step test). Two general hospitals located in a region with a high prevalence of tuberculosis and high bacille Calmette-Guerin (BCG) coverage. Volunteer sample of HCWs. 605 HCWs were recruited: 71.2% female; mean age, 36.4 (standard deviation [SD], 8.2) years; 48.9% nurses, 10.4% physicians, 26.8% administrative personnel; mean time of employment, 10.9 (SD, 6.7) years. PPD reactivity (> or =10 mm) was found in 390 (64.5%). Multivariate analysis revealed an association of tuberculin reactivity with occupational exposure in the hospital: participation in autopsies (odds ratio [OR], 9.3; 95% confidence interval [CI95], 2.1-40.5; P=.003.), more than 1 year of employment (OR, 2.4; CI95, 1.1-5.0; P=.02), work in the emergency or radiology departments (OR, 2.0; CI95, 1.03-3.81; P=.04), being physicians or nurses (OR, 1.5; CI95, 1.04-2.11; P=.03), age (OR, 1.04; CI95, 1.02-1.07 per year of age; P<.001), and BCG scar (OR, 2.1; CI95, 1.2-3.4; P=.005). Although the studied population has a high baseline prevalence of tuberculosis infection and high coverage of BCG vaccination, nosocomial risk factors associated with PPD reactivity were identified as professional risks; strict early preventive measures must be implemented accordingly.


Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22.
Previous linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 Mb for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region.


An epigenome-wide association study in whole blood of measures of adiposity among Ghanaians: the RODAM study.
Epigenome-wide association studies (EWAS) have identified DNA methylation loci involved in adiposity. However, EWAS on adiposity in sub-Saharan Africans are lacking despite the high burden of adiposity among African populations. We undertook an EWAS for anthropometric indices of adiposity among Ghanaians aiming to identify DNA methylation loci that are significantly associated. The Illumina 450k DNA methylation array was used to profile DNA methylation in whole blood samples of 547 Ghanaians from the Research on Obesity and Diabetes among African Migrants (RODAM) study. Differentially methylated positions (DMPs) and differentially methylation regions (DMRs) were identified for BMI and obesity (BMI ≥ 30 kg/m2), as well as for waist circumference (WC) and abdominal obesity (WC ≥ 102 cm in men, ≥88 cm in women). All analyses were adjusted for age, sex, blood cell distribution estimates, technical covariates, recruitment site and population stratification. We also did a replication study of previously reported EWAS loci for anthropometric indices in other populations. We identified 18 DMPs for BMI and 23 for WC. For obesity and abdominal obesity, we identified three and one DMP, respectively. Fourteen DMPs overlapped between BMI and WC. DMP cg00574958 annotated to gene CPT1A was the only DMP associated with all outcomes analysed, attributing to 6.1 and 5.6% of variance in obesity and abdominal obesity, respectively. DMP cg07839457 (NLRC5) and cg20399616 (BCAT1) were significantly associated with BMI, obesity and with WC and had not been reported by previous EWAS on adiposity. This first EWAS for adiposity in Africans identified three epigenome-wide significant loci (CPT1A, NLRC5 and BCAT1) for both general adiposity and abdominal adiposity. The findings are a first step in understanding the role of DNA methylation in adiposity among sub-Saharan Africans. Studies on other sub-Saharan African populations as well as translational studies are needed to determine the role of these DNA methylation variants in the high burden of adiposity among sub-Saharan Africans.


Guanidine-resistant mutants of aphthovirus induce the synthesis of an altered nonstructural polypeptide, P34.
Extracts of cells infected with guanidine-resistant mutants of aphthovirus were examined for differences in virus-induced polypeptides by using electrofocusing. Four of 1 independent spontaneous mutants induced the synthesis of an altered nonstructural polypeptide, P34. The precursor of P34, P52, and a previously unmapped polypeptide, P20c, also carried these charge-change mutations. No mutations in other regions of the genome were detected, and the remaining six guanidine-resistant mutants appeared entirely normal by electrofocusing. However, when the P34 of one of the latter mutants was examined by tryptic peptide fingerprinting, it too differed from that of the guanidine-sensitive parent. The frequency of P34 alterations among guanidine-resistant mutants suggests that P34 is functionally involved in the antiviral action of guanidine.


The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis.
We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.


Preservation of a tooth related with central giant cell granuloma with non-invasive curettage: 7 years followed-up case report.
Central Giant Cell Granuloma (CGCG) is defined by the World Health Organization as an intraosseous lesion consisting of cellular fibrous tissue containing multiple foci of hemorrhage, aggregations of multinucleated giant cells, and occasionally trabeculae of woven bone. An 8-year-old patient presented with painless swelling and bleeding in his upper right canine region was referred to our clinic. Incisional biopsy was confirmed that this was a CGCG. The patient was treated with non-invasive curettage and secondary intention healing. Seven-year follow-up of the patient revealed a complete resolution of the lesion and uneventful eruption of the permanent canine tooth. In this case report, a successful long-term outcome of the conservative treatment of the CGCG was presented.


It's five o'clock somewhere: An examination of the association between happy hour drinking and negative consequences.
This study aims to understand which young adults' drinking behaviors change in the presence of happy hour specials, the ways in which they change, and whether a link exists between happy hour drinking behavior and negative outcomes. Using data collected from bar-going respondents (n = 1,423) within a print survey administered to a general college sample (n = 2,349), we identify significant differences in changes in happy hour behavior between demographic groups using χ(2) tests and determine whether this behavior is related to six negative alcohol-related outcomes using logistical and ordinary least squares regression models with a variety of controls, including age of onset and frequency of use. Women, students under 21, non-athletes, members of Greek-affiliated organizations, more affluent and unemployed students, and students living on campus were more likely to change their drinking behavior in the presence of happy hour specials. In general, the most robust predictors of negative events are gender, alcohol use frequency, age of alcohol use onset, and increasing drinking due to happy hours/bar specials. While it was linked to various negative and illegal behaviors, altered happy hour drinking was not associated with an increased likelihood of an alcohol-related arrest. This study lends support to the idea that alcohol price specials should be regulated in an effort to reduce high consumption and alcohol-related negative consequences. Future research into the relationship between happy hour drinking and negative outcomes is necessary and should examine the impact of happy hour advertisements, different types of specials, and the timing of happy hours.


What is the current clinico-radiological diagnostic accuracy for intracranial tumours?
To determine the diagnostic accuracy of routine clinico-radiological workup for a population-based selection of intracranial tumours. In this prospective cohort study, we included consecutive adult patients who underwent a primary surgical intervention for a suspected intracranial tumour between 2015 and 2019 at a single-neurosurgical centre. The treating team estimated the expected diagnosis prior to surgery using predefined groups. The expected diagnosis was compared to final histopathology and the accuracy of preoperative clinico-radiological diagnosis (sensitivity, specificity, positive and negative predictive values) was calculated. 392 patients were included in the data analysis, of whom 319 underwent a primary surgical resection and 73 were operated with a diagnostic biopsy only. The diagnostic accuracy varied between different tumour types. The overall sensitivity, specificity and diagnostic mismatch rate of clinico-radiological diagnosis was 85.8%, 97.7% and 4.0%, respectively. For gliomas (including differentiation between low-grade and high-grade gliomas), the same diagnostic accuracy measures were found to be 82.2%, 97.2% and 5.6%, respectively. The most common diagnostic mismatch was between low-grade gliomas, high-grade gliomas and metastases. Accuracy of 90.2% was achieved for differentiation between diffuse low-grade gliomas and high-grade gliomas. The current accuracy of a preoperative clinico-radiological diagnosis of brain tumours is high. Future non-invasive diagnostic methods need to outperform our results in order to add much value in a routine clinical setting in unselected patients.


Coupling to substrate adhesions drives the maturation of muscle stress fibers into myofibrils within cardiomyocytes.
Forces generated by heart muscle contraction must be balanced by adhesion to the extracellular matrix (ECM) and to other cells for proper heart function. Decades of data have suggested that cell-ECM adhesions are important for sarcomere assembly. However, the relationship between cell-ECM adhesions and sarcomeres assembling de novo remains untested. Sarcomeres arise from muscle stress fibers (MSFs) that are translocating on the top (dorsal) surface of cultured cardiomyocytes. Using an array of tools to modulate cell-ECM adhesion, we established a strong positive correlation between the extent of cell-ECM adhesion and sarcomere assembly. On the other hand, we found a strong negative correlation between the extent of cell-ECM adhesion and the rate of MSF translocation, a phenomenon also observed in nonmuscle cells. We further find a conserved network architecture that also exists in nonmuscle cells. Taken together, our results show that cell-ECM adhesions mediate coupling between the substrate and MSFs, allowing their maturation into sarcomere-containing myofibrils.


Evaluation of IgM ELISA using a sonicate and a lipopolysaccharide antigen for the serodiagnosis of melioidosis.
Melioidosis, caused by Burkholderia pseudomallei, has variable manifestations. The disease can present as an acute or a chronic form or localized or disseminated or can remain latent for many years. Acute septicaemic melioidosis has a high fatality rate when untreated and therefore, an early diagnosis is critical. Lack of testing facilities and of an awareness of the manifestations of the disease makes it likely that it is underreported in India. A sonicate and a lipopolysaccharide (LPS) antigen were evaluated by an IgM enzyme immunoassay in patients with culture-confirmed melioidosis (n = 29), fever of unknown origin (n = 214) and healthy controls (n = 109). Patients with melioidosis had significantly higher optical density values than both control categories, but the sensitivity of both tests was low (25% for sonicate, 62% for LPS). These data highlight the problems with serodiagnosis in endemic settings, where high cut-off values are required for specificity, and result in low sensitivity.


Postweaning diarrhea in swine: experimental model of enterotoxigenic Escherichia coli infection.
A reproducible model of postweaning colibacillosis was obtained by controlling management and environmental variables to simulate conditions often seen at weaning. Suckling pigs were exposed briefly to starter diet at 1 week of age, weaned at 3 weeks of age, held at an ambient temperature of 20 +/- 2 C, and again given the starter diet. One day after weaning, each pig was given 10(10) colony-forming units of enterotoxigenic Escherichia coli strain M1823B (O157:K88ac:H43-LT+ STb+) in broth containing 1.2% sodium bicarbonate via stomach tube. In vitro adhesion by strain M1823B to isolated intestinal branch borders was used to test pigs for susceptibility to K88. In this model, 3 syndromes were induced in susceptible pigs: (1) peracute fatal diarrhea; (2) moderate diarrhea, weight loss, and fecal shedding of the inoculum strain; and (3) no diarrhea, weight loss, and fecal shedding of the inoculum strain. Rotavirus particles were not found in fecal specimens of pigs with diarrhea. The K88-susceptible, noninoculated control pigs remained clinically normal. It was concluded that susceptibility to adhesion by K88+ enterotoxigenic Escherichia coli was a requirement for the production of disease in this model; inoculation with rotavirus was not necessary.


S1 nuclease protection mapping.
The use of S1 nuclease to map the start site of a transcription unit is a well-established technique. Based on the method of Berk and Sharp, it has undergone many refinements over the years. S1 nuclease mapping requires a relatively detailed knowledge of the gene structure and sequence data (or a very good restriction map) of the first exon and several hundred bases of upstream sequence. Although S1 nuclease mapping is mainly used to map transcription start sites accurately (to be described in this chapter), this method can also be used to map intron-exon junctions. Note that in order to identify a transcriptional start site unambiguously, S1 nuclease mapping should be used in conjunction with primer extension (Chapter 44).


Multi-level educational affiliations for a CE (clinical engineer) department.
Educational programs for clinical engineers and biomedical equipment technicians should provide students with an exposure to the clinical environment. Through alliances with educational institutions, hospitals can assist future engineers and technicians in obtaining a well-rounded education. These affiliations provide a hospital with engineering expertise for research projects, as well as a resource for the clinical engineering department. One hospital, Baystate Medical Center in Springfield, Massachusetts, has successfully developed internships for technician candidates in an Associate's degree program and for undergraduate and graduate engineering students through educational affiliations with three different academic institutions. The internships of the students intertwine, giving them a unique educational experience.


[Nonconvulsive status epilepticus of frontal origin. A case report].
Nonconvulsive status epilepticus (NCSE) of frontal origin is a form of partial status epilepticus which has rarely been well-documented. The inespecificity of the symptoms contribute frequently to its misinterpretation being the EEG the most useful tool to make an accurate diagnosis. We report a 53-year-old woman who suffered from two generalized tonic-clonic seizures secondary to a left frontal hematoma in 1994. Onset of treatment with carbamazepine was followed by a complete control of seizures. After remaining seizure-free during four years, antiepileptic therapy was discontinued. By June 1999, she presented with a prolonged confusional state having a generalized tonic-clonic seizure at the emergency room. At that moment, a computed tomography (CT) scan was normal. Generalized seizures were controlled with phenytoin, however, the patient remained confused having occasionally episodes of turning of the head and eyes to the right side. Ictal EEG examination showed recurrent bilateral frontopolar, frontocentral and frontotemporal epileptiform discharges with a left frontal focal onset. The diagnosis of NCSE of frontal origin was made. Despite several anticonvulsant combinations, confusional state remained unchanged and she was transferred to the intensive care unit for sedation with propofol and mydazolam. On the following days, she experienced a marked improvement and EEG showed a few frontal spikes and sharp waves but without evidence of electrographic status epilepticus. The patient was finally discharged and remains seizure-free on phenytoin therapy. Our clinical and EEG findings are in keeping with the diagnosis of NCSE of frontal origin. A severe confusional state was the most prominent symptom and EEG was essential for the diagnosis.


Clinical Significance of Two Real-Time PCR Assays for Chronic Hepatitis C Patients Receiving Protease Inhibitor-Based Therapy.
The aim of this study was to determine the efficacy of two hepatitis C virus (HCV) real-time PCR assays, the COBAS AmpliPrep/COBAS TaqMan HCV test (CAP/CTM) and the Abbott RealTime HCV test (ART), for predicting the clinical outcomes of patients infected with HCV who received telaprevir (TVR)-based triple therapy or daclatasvir/asunaprevir (DCV/ASV) dual therapy. The rapid virological response rates in patients receiving TVR-based triple therapy were 92% (23/25) and 40% (10/25) for CAP/CTM and ART, respectively. The false omission rate (FOR) of ART was 93.3% (14/15), indicating that CAP/CTM could accurately predict clinical outcome in the early phase. In an independent examination of 20 patients receiving TVR-based triple therapy who developed viral breakthrough or relapse, the times to HCV disappearance by ART were longer than by CAP/CTM, whereas the times to HCV reappearance were similar. In an independent experiment of WHO standard HCV RNA serially diluted in serum containing TVR, the analytical sensitivities of CAP/CTM and ART were similar. However, cell cultures transfected with HCV and grown in medium containing TVR demonstrated that ART detected HCV RNA for a longer time than CAP/CTM. Similar results were found for 42 patients receiving DCV/ASV dual therapy. The FOR of ART was 73.3% (11/15) at week 8 after initiation of therapy, indicating that ART at week 8 could not accurately predict the clinical outcome. In conclusion, although CAP/CTM and ART detected HCV RNA with comparable analytical sensitivity, CAP/CTM might be preferable for predicting the clinical outcomes of patients receiving protease inhibitor-based therapy.


Communication and effectiveness in a US nursing home quality-improvement collaborative.
In this study, we explored the relationship between changes in resident health outcomes, practitioner communication patterns, and practitioner perceptions of group effectiveness within a quality-improvement collaborative of nursing home clinicians. Survey and interview data were collected from nursing home clinicians participating in a quality-improvement collaborative. Quality-improvement outcomes were evaluated using US Federal and State minimum dataset measures. Models were specified evaluating the relationships between resident outcomes, staff perceptions of communication patterns, and staff perceptions of collaborative effectiveness. Interview data provided deeper understanding of the quantitative findings. Reductions in fall rates were highest in facilities where respondents experienced the highest levels of communication with collaborative members outside of scheduled meetings, and where respondents perceived that the collaborative kept them informed and provided new ideas. Clinicians observed that participation in a quality-improvement collaborative positively influenced the ability to share innovative ideas and expand the quality-improvement program within their nursing home. For practitioners, a high level of communication, both inside and outside of meetings, was key to making measurable gains in resident health outcomes.


Usefulness of a new gelatin glue sealant system for dural closure in a rat durotomy model.
Watertight dural closure is imperative after neurosurgical procedures, because inadequately treated leakage of cerebrospinal fluid (CSF) can have serious consequences. We used a rat durotomy model to test the usefulness of a new gelatin glue as a dural sealant in a rat model of transdural CSF leakage. All rats were randomly divided into one of the following three treatment groups: no application (control group: N = 18), application of fibrin glue (fibrin glue group: N = 18), and application of the new gelatin glue (new gelatin glue group: N = 18). The craniotomy side was re-opened, and CSF leakage was checked and recorded at 1, 7, and 28 days postoperatively. The new gelatin glue was adequate for stopping CSF leakage; no leakage was observed at postoperative days 1 or 7, and leakage was observed in only one rat at postoperative day 28. This result was statistically significant when compared to the control group (P = 0.002, P = 0.015, P = 0.015, respectively). The pathologic score of the new gelatin group was not different from that of the control or fibrin glue groups. We conclude that our new gelatin glue provides effective watertight closure 1, 7, and 28 days after operation in the rat durotomy model.


Rapid and Sensitive Assay of K-ras Mutations in Pancreatic Cancer by Electrochemical Detection with Ferrocenyl-naphthalene-diimide.
The DNA chip is a very powerful tool for genetic analysis. Conventional DNA chips that utilize fluorescence detection systems are very complicated, expensive and impractical, but the electrochemical array (ECA) chip is gaining popularity. To investigate the validity of the ECA chip, which utilizes ferrocenyl-naphthalene-diimide (FND), k-ras mutations in 20 pancreatic cancer tissues were examined. DNA was isolated from 20 pancreatic cancer tissues and subjected to a 2-stage polymerase chain reaction (PCR). The k-ras mutations were detected with the ECA chip. To verify the reliability of the ECA chip, the DNA was also analyzed by direct sequencing and the PCR-dependent preferential homoduplex formation assay (PCR-PHFA). The ECA chip could detect one mutation in a background of 1000 wild-type DNAs. K-ras mutations were identified in 17 out of 20 (85%) pancreatic cancer samples. Three mutations of codon 12 of k-ras, GTT, GAT and AGT, were detected. K-ras mutations were detected in 13 out of 20 (65%) samples by sequencing and in 17 out of 20 (85%) samples by PCR-PHFA. These findings were concordant with the ECA chip result. The FND-ECA chip is a sensitive, rapid and reliable method for screening point mutations in a variety of clinical samples.


A preliminary application of principal components and cluster analysis to internal tongue deformation patterns.
Complex patterns of muscle contractions create gross tongue motion during speech. It is of scientific and medical importance to better understand speech motor strategies and variations due to language or disorders. Dense patterns of tongue motion can be imaged using tagged magnetic resonance imaging, but characterisation of motion strategies is difficult using visualisation alone. This paper explores the use of principal component analysis for dimensionality reduction and cluster analysis for tongue motion categorisation. Velocity fields were acquired and analysed from midsagittal tongue slices during motion from /i/ to /u/ for eight datasets containing multiple languages and a glossectomy patient. The analyses were carried out on the tongue-only and tongue-plus-floor of the mouth regions. The results showed that both the analyses were sensitive to region size and that cluster analysis was harder to interpret. Both the analyses grouped the Japanese speaker with the glossectomy patient, which although explicable with biologically plausible reasons, highlights the limitations of extensive data reduction.


Mixed methods immigrant mental health research in Canada: a systematic review.
Canada is home to a growing immigrant population. However, immigrant mental health declines over time following arrival in Canada. Canada's Mental Health Strategy emphasizes the importance of research that gathers information from multiple sources of knowledge to identify the mental health challenges faced by diverse immigrant populations. Mixed methods research (MMR) is well suited for this task. However, a dearth of research exists on the application of MMR to the study of immigrant mental health. A systematic review of the published MMR literature in Canadian immigrant mental health was carried out. Overall, existing MMR studies failed to incorporate correct mixed methods terminology and fully integrate the quantitative and qualitative components of the research. A checklist of important elements to include in MMR studies is offered.


Chemistry of molecular growth processes in flames.
Chemical mechanisms of pyrolysis, growth, and oxidation processes in flames have traditionally been inferred from spatial profile measurements of species concentrations. Experimental investigations now include the detection of numerous minor species such as reactive radicals and intermediate hydrocarbons. In assessing a proposed mechanism important new constraints can be established when the detailed species profile data are combined with velocity and temperature measurements and analyzed to determine production and destruction rates for specific molecules. Recent results on hydrocarbon diffusion flames provide new information on the interplay between chemical and transport processes. These measurements have led to direct tests of proposed routes for the formation of aromatic hydrocarbons and the first, small soot particles. The inception chemistry of hydrocarbon growth reactions and initial particle formation is thought to control soot formation, flame radiation and energy transfer, and pollutant emission in combustion environments.


Academic research productivity of post-graduate students at Makerere University College of Health Sciences, Uganda, from 1996 to 2010: a retrospective review.
Research is a core business of universities globally, and is crucial in the scientific process as a precursor for knowledge uptake and use. We aimed to assess the academic productivity of post-graduate students in a university located in a low-income country. This is an observational retrospective documentary analysis using hand searching archives, Google Scholar and PubMed electronic databases. The setting is Makerere University College of Health Sciences, Uganda. Records of post-graduate students (Masters) enrolled from 1996 to 2010, and followed to 2016 for outcomes were analysed. The outcome measures were publications (primary), citations, electronic dissertations found online or conference abstracts (secondary). Descriptive and multivariable logistic regression analyses were performed using Stata 14.1. We found dissertations of 1172 Masters students over the 20-year period of study. While half (590, 50%) had completed clinical graduate disciplines (surgery, internal medicine, paediatrics, obstetrics and gynaecology), Master of Public Health was the single most popular course, with 393 students (31%). Manuscripts from 209 dissertations (18%; 95% CI, 16-20%) were published and approximately the same proportion was cited (196, 17%; 95% CI, 15-19%). Very few (4%) policy-related documents (technical reports and guidelines) cited these dissertations. Variables that remained statistically significant in the multivariable model were students' age at enrolment into the Masters programme (adjusted coefficient -0.12; 95% CI, -0.18 to -0.06; P < 0.001) and type of research design (adjusted coefficient 0.22; 0.03 to 0.40; P = 0.024). Cohort studies were more likely to be published compared to cross-sectional designs (adjusted coefficient 0.78; 95% CI, 0.2 to 1.36; P = 0.008). The productivity and use of post-graduate students' research conducted at the College of Health Sciences Makerere University is considerably low in terms of peer-reviewed publications and citations in policy-related documents. The need for effective strategies to reverse this 'waste' is urgent if the College, decision-makers, funders and the Ugandan public are to enjoy the 'return on investment' from post-graduate students research.


Canalization effect in the coagulation cascade and the interindividual variability of oral anticoagulant response. A simulation study.
Increasing the predictability and reducing the rate of side effects of oral anticoagulant treatment (OAT) requires further clarification of the cause of about 50% of the interindividual variability of OAT response that is currently unaccounted for. We explore numerically the hypothesis that the effect of the interindividual expression variability of coagulation proteins, which does not usually result in a variability of the coagulation times in untreated subjects, is unmasked by OAT. We developed a stochastic variant of the Hockin-Mann model of the tissue factor coagulation pathway, using literature data for the variability of coagulation protein levels in the blood of normal subjects. We simulated in vitro coagulation and estimated the Prothrombin Time and the INR across a model population. In a model of untreated subjects a "canalization effect" can be observed in that a coefficient of variation of up to 33% of each protein level results in a simulated INR of 1 with a clinically irrelevant dispersion of 0.12. When the mean and the standard deviation of vitamin-K dependent protein levels were reduced by 80%, corresponding to the usual Warfarin treatment intensity, the simulated INR was 2.98 ± 0.48, a clinically relevant dispersion, corresponding to a reduction of the canalization effect.Then we combined the Hockin-Mann stochastic model with our previously published model of population response to Warfarin, that takes into account the genetical and the phenotypical variability of Warfarin pharmacokinetics and pharmacodynamics. We used the combined model to evaluate the coagulation protein variability effect on the variability of the Warfarin dose required to reach an INR target of 2.5. The dose variance when removing the coagulation protein variability was 30% lower. The dose was mostly related to the pretreatment levels of factors VII, X, and the tissue factor pathway inhibitor (TFPI). It may be worth exploring in experimental studies whether the pretreatment levels of coagulation proteins, in particular VII, X and TFPI, are predictors of the individual warfarin dose, even though, maybe due to a canalization-type effect, their effect on the INR variance in untreated subjects appears low.


The role of aligned polymer fiber-based constructs in the bridging of long peripheral nerve gaps.
Peripheral nerve regeneration across long nerve gaps is clinically challenging. Autografts, the standard of therapy, are limited by availability and other complications. Here, using rigorous anatomical and functional measures, we report that aligned polymer fiber-based constructs present topographical cues that facilitate the regeneration of peripheral nerves across long nerve gaps. Significantly, aligned but not randomly oriented fibers elicit regeneration, establishing that topographical cues can influence endogenous nerve repair mechanisms in the absence of exogenous growth promoting proteins. Axons regenerated across a 17 mm nerve gap, reinnervated muscles, and reformed neuromuscular junctions. Electrophysiological and behavioral analyses revealed that aligned but not randomly oriented constructs facilitated both sensory and motor nerve regeneration, significantly improved functional outcomes. Additionally, a quantitative comparison of DRG outgrowth in vitro and nerve regeneration in vivo on aligned and randomly oriented fiber films clearly demonstrated the significant role of sub-micron scale topographical cues in stimulating endogenous nerve repair mechanisms.


[Ambulatory treatment of agitation in encephalopathies].
In a young patient with encephalopathy and major agitation, sultopride given in a daily dosage of two 400 mg tablets (associated with a corrector, trihexyphenidyl, CL drops nightly) ensured better vigilance, sedation of vociferations, agitation, and automutilation, and improvement of autonomy (particularly recovery of sphincter control). The excellent activity of sultopride was all the more noteworthy as many tranquilizers had failed previously.


A phosphorylation-sensitive anti-rhodopsin monoclonal antibody reveals light-induced phosphorylation of rhodopsin in the photoreceptor cell body.
Rho-1C5, a monoclonal antibody sensitive to phosphorylation of rhodopsin, bound to the retinal photoreceptor cell body region of dark-adapted but not light-adapted 8 to 13-day-old-rats. There was no cell body labeling visible either before or after this time, although the photoreceptor outer segments were labeled at all times from postnatal day 5 (PN5) onwards, in both light and dark adapted retinas. However, opsin was detectable in the photoreceptor cell body region from birth onwards using another rhodopsin antibody binding to a site unaffected by phosphorylation. Competitive inhibition radioimmunoassays also indicated light-dependent differences in Rho-1C5 binding at PN8 and adult. Biochemical studies showed light-dependent phosphorylation of rhodopsin at PN8, PN13 (just after eye opening) and adult. These data indicate that rhodopsin can be phosphorylated in a light-regulated manner early in development before eye opening and imply that photoactive chromophores can attach to opsin in the cell body as well as the outer segment.


Risk factors for Neisseria meningitidis carriage in a school during a community outbreak of meningococcal infection.
As part of the management of an outbreak of meningococcal infection, 119 school contacts of an index case were swabbed for nasopharyngeal carriage. In a cohort study, risk factors for Neisseria meningitidis carriage were ascertained by means of a questionnaire, completed by 114 (96%) of those swabbed. Twenty five (21%) cultures were identified as "neisseria positive'; of which there were 18 (15%) Neisseria meningitidis isolates, 2 (2%) Neisseria lactamica isolates and 5 (4%) showed contaminants only. Two (2%) carriers were identified as harbouring the implicated outbreak strain. Single variable analysis identified six statistically significant risk factors for meningococcal carriage; increasing age, female sex, manual social class, personal smoking, regular attendance at a discotheque and rhinorrhoea. Multivariate analysis, using logistic regression modelling, found that of these six variables only age, sex and social class remained statistically significant when the other factors were controlled for. Nevertheless the role of smoking, social events and respiratory/viral infections in nasopharyngeal carriage, and other plausible mechanisms whereby age, sex and social class might exert their effect, could usefully be investigated further.


Antioxidative effect of schisanhenol on human low density lipoprotein and its quantum chemical calculation.
To investigate the effect of schisanhenol (Sal) on copper ion-induced oxidative modulation of human low density lipoprotein (LDL). The antioxidative activity of eight schisandrins (DCL) on microsome lipid peroxidation induced by Vit C/NADPH system was first observed, and then, the effect of Sal on Cu2+-induced human LDL oxidation was studied. The generation of malondialdehyde (MDA), lipofuscin, reactive oxygen species (ROS), consumption of a-tocopherol as well as electrophoretic mobility of LDL were determined as criteria of LDL oxidation. Finally, the quantum chemical method was used to calculate the theoretical parameters of eight DCL for elucidating the difference of their antioxidant ability. Sal was shown to be the most active one among eight schizandrins in inhibiting microsome lipid oxidation induced by Vit C/NADPH. Sal 100, 50, and 10 micromol/L inhibited production of MDA, lipofuscin and ROS as well as the consumption of a-tocopherol in Cu2+-induced oxidation of human LDL in a dose-dependent manner. Sal also reduced electrophoretic mobility of the oxidized human LDL. Further study of quantum chemistry found that Sal was the strongest one among eight DCL to scavenge O2, R, RO and ROO radicals. Sal has antioxidative effect on human LDL oxidation. The mechanism of Sal against LDL oxidation may be through scavenging free radicals.


Fenfluramine in man: hypophagia associated with diminished serotonin turnover.
A double-blind trial of orally administered fenfluramine was conducted in 7 non-obese adults with various neurological disorders. Caloric intake and body weight fell significantly after 8 days of treatment although there was no definite change in appetite ratings. Average central turnover of serotonin, as estimated by the cerebrospinal fluid (CSF) accumulation of 5-hydroxyindoleacetic acid (5-HIAA) during probenecid loading, decreased by 66%. No significant change in homovanillic acid, the major dopamine product, was apparent. The results support the contention that the effect of fenfluramine on human dietary intake may be mediated by alterations in serotonergic rather than dopaminergic mechanisms.