Consequences of delay in screening, monitoring, and treatment of angiomyolipoma and tuberous sclerosis: A case report .
Tuberous sclerosis complex (TSC) is a multisystem disorder that results in tumor growth in various organs. TSC can affect the kidneys in the form of renal angiomyolipomas and cysts that can lead to chronic kidney disease. A 38-year-old woman was referred to Kennedy Krieger Institute for comprehensive TSC management. Before referral, the patient had gone most of her life without a definite diagnosis of TSC despite visually-prominent signs such as forehead plaques, facial angiofibromas, and ungual fibromas. Eventually, complications of the disease led to the patient requiring hemodialysis at age 34 and a complete bilateral nephrectomy at age 36. However, the patient was not diagnosed with TSC until an evaluation at the National Institutes of Health at age 37. After becoming a patient at our clinic, a multidisciplinary approach was taken to provide comprehensive care by including various disciplines such as nephrology, neurology, pulmonology, ophthalmology, dentistry, dermatology, and cardiology. TSC consensus recommendations aid in diagnosis, monitoring, and treatment of TSC and its associated manifestations, including those involving the kidneys. Our case underscores the importance of early identification of TSC to prevent future complications and promotes use of a multidisciplinary team to provide comprehensive care. .


Mechanisms underlying insect freeze tolerance.
Freeze tolerance - the ability to survive internal ice formation - has evolved repeatedly in insects, facilitating survival in environments with low temperatures and/or high risk of freezing. Surviving internal ice formation poses several challenges because freezing can cause cellular dehydration and mechanical damage, and restricts the opportunity to metabolise and respond to environmental challenges. While freeze-tolerant insects accumulate many potentially protective molecules, there is no apparent 'magic bullet' - a molecule or class of molecules that appears to be necessary or sufficient to support this cold-tolerance strategy. In addition, the mechanisms underlying freeze tolerance have been minimally explored. Herein, we frame freeze tolerance as the ability to survive a process: freeze-tolerant insects must withstand the challenges associated with cooling (low temperatures), freezing (internal ice formation), and thawing. To do so, we hypothesise that freeze-tolerant insects control the quality and quantity of ice, prevent or repair damage to cells and macromolecules, manage biochemical processes while frozen/thawing, and restore physiological processes post-thaw. Many of the molecules that can facilitate freeze tolerance are also accumulated by other cold- and desiccation-tolerant insects. We suggest that, when freezing offered a physiological advantage, freeze tolerance evolved in insects that were already adapted to low temperatures or desiccation, or in insects that could withstand small amounts of internal ice formation. Although freeze tolerance is a complex cold-tolerance strategy that has evolved multiple times, we suggest that a process-focused approach (in combination with appropriate techniques and model organisms) will facilitate hypothesis-driven research to understand better how insects survive internal ice formation.


Synaptosomal GABA release as influenced by valerian root extract--involvement of the GABA carrier.
The effect of an aqueous extract obtained from the roots of Valeriana officinalis was investigated on the uptake and release of GABA in synaptosomes isolated from rat brain cortex. Aqueous extract of valerian inhibited the uptake and stimulated the release of [3H]GABA, either in the absence or in the presence of K+ depolarization. The release was Na(+)-dependent and independent of the presence of Ca2+ in the external medium. It is concluded that valerian extract releases [3H]GABA by reversal of the GABA carrier, which is Na(+)-dependent and Ca(2+)-independent. This increase in [3H]GABA release appears to be independent from Na(+)-K(+)-ATPase activity and the membrane potential.


Protocol of a natural experiment to evaluate a supermarket intervention to improve food purchasing and dietary behaviours of women (WRAPPED study) in England: a prospective matched controlled cluster design.
Poor diet is a leading risk factor for non-communicable diseases and costs the National Health Service £5.8 billion annually. Product placement strategies used extensively in food outlets, like supermarkets, can influence customers' preferences. Policy-makers, including the UK Government, are considering legislation to ensure placement strategies promote healthier food purchasing and dietary habits. High-quality scientific evidence is needed to inform future policy action. This study will assess whether healthier placement strategies in supermarkets improve household purchasing patterns and the diets of more than one household member. This natural experiment, with a prospective matched controlled cluster design, is set in discount supermarkets across England. The primary objective is to investigate whether enhanced placement of fresh fruit and vegetables improves household-level purchasing of these products after 6 months. Secondary objectives will examine: (1) differences in intervention effects on purchasing by level of educational attainment, (2) intervention effects on the dietary quality of women and their young children, (3) intervention effects on store-level sales of fruit and vegetables and (4) cost-effectiveness of the intervention from individual, retailer and societal perspectives. Up to 810 intervention and 810 control participants will be recruited from 18 intervention and 18 matched control stores. Eligible participants will be women aged 18-45 years, who hold a loyalty card and shop in a study store. Each control store will be matched to an intervention store on: (1) sales profile, (2) neighbourhood deprivation and (3) customer profile. A detailed process evaluation will assess intervention implementation, mechanisms of impact and, social and environmental contexts. Ethical approval was obtained from the University of Southampton, Faculty of Medicine Ethics Committee (ID 20986.A5). Primary, secondary and process evaluation results will be submitted for publication in peer-reviewed scientific journals and shared with policy-makers. NCT03573973; Pre-results.


Osteoporosis and osteopenia: implications for periodontal and implant therapy.
How does low bone mineral density alter treatment decisions? Osteoporosis and osteopenia are major health care issues that may impact on periodontal and implant therapy. Because of the prevalence of osteoporosis, understanding its etiology and the current treatment regimens for patients with low bone mineral density is essential for dental professionals. Millions of patients are now taking medications for the treatment of osteoporosis, and periodontists should be aware of the many medication options that are prescribed. The most frequently prescribed drugs are the bisphosphonates. It is important to be aware that bisphosphonates are not all the same, and patient responses to treatment may vary depending on which bisphosphonates they are taking. Due to recent concerns about bisphosphonate-induced osteonecrosis of the jaw, this paper provides guidance to help the clinician regarding decision-making about preventive and interventional dental treatment when their patient has been prescribed a bisphosphonate. An understanding of current bisphosphonates, their uses, their structural differences and their intended actions helps to improve clinical decision-making. Current knowledge regarding the effects of osteoporosis/osteopenia on periodontal diseases and alveolar bone loss is inconclusive. It is certainly clear that bisphosphonates are not indicated as an adjunctive treatment as part of periodontal therapy because of the risk of osteonecrosis. Regarding implant placement, there are no convincing data that dental implant placement is contraindicated in the osteoporotic patient. However, patients should understand the small risk of compromised bone healing following implant placement if the patient has been taking bisphosphonates. Due to the risks of osteonecrosis, dental clinicians should work closely with their medical colleagues prior to the physician prescribing oral bisphosphonates. Ideally, optimal periodontal and dental health should be established before the patient commences bisphosphonate therapy.


Bone turnover and bone collagen maturation in osteoporosis: effects of antiresorptive therapies.
Bone collagen maturation may be important for anti-fracture efficacy as the reduction in risk is only partly explained by a concomitant increase in BMD during anti-resorptive therapy. Different treatments caused diverse profiles in bone collagen degradation products, which may have implications for bone quality. The aim of the present study was to evaluate the effect of different anti-resorptive treatments on bone collagen maturation measured as the ratio between the degradation products of newly synthesized and mature isomerized C-telopeptides of type I collagen. Participants were from cohorts of healthy postmenopausal women participating in double blind, placebo-controlled 2-year studies of alendronate, ibandronate, intranasal hormone replacement therapy (HRT), oral HRT, transdermal HRT, or raloxifene (n = 427). The non-isomerized alphaalphaCTX and isomerized betabetaCTX were measured in urine samples obtained at baseline, and after 6, 12, and 24 months of therapy. Bone collagen maturation measured as the ratio between alphaalphaCTX and betabetaCTX showed that bisphosphonate treatment induced a collagen profile consistent with an older matrix with a 52% (alendronate) and 38% (ibandronate) reduction in the ratio between the two CTX isoforms vs. 3% and 15% with HRT or raloxifene, respectively. Anti-resorptive treatments had different effects on the endogenous profile of bone collagen maturation. Whether that effect on bone collagen has an impact on bone strength independent on the treatment-dependent effect on BMD should be investigated.


Volumetric display using rotating prism sheets arranged in a symmetrical configuration.
A volumetric display that creates a distortion-free three-dimensional (3D) image in midair is described. The proposed system consists of rotating prism sheets used as an optical scanner and a dihedral corner reflector array (DCRA), which is a distortion-free imaging element. Two prism sheets are arranged in a symmetrical configuration to reduce an unnatural motion parallax caused by optical aberrations. A cross-section of the 3D image is formed by the DCRA in midair and moved by the rotating prism sheets to create a 3D displayable space. A 3D volume image was displayed without image distortion or unnatural motion parallax.


Simultaneous quantitative susceptibility mapping and Flutemetamol-PET suggests local correlation of iron and β-amyloid as an indicator of cognitive performance at high age.
The accumulation of β-amyloid plaques is a hallmark of Alzheimer's disease (AD), and recently published data suggest that increased brain iron burden may reflect pathologies that synergistically contribute to the development of cognitive dysfunction. While preclinical disease stages are considered most promising for therapeutic intervention, the link between emerging AD-pathology and earliest clinical symptoms remains largely unclear. In the current study we therefore investigated local correlations between iron and β-amyloid plaques, and their possible association with cognitive performance in healthy older adults. 116 older adults (mean age 75 ± 7.4 years) received neuropsychological testing to calculate a composite cognitive score of performance in episodic memory, executive functioning, attention, language and communication. All participants were scanned on a combined PET-MRI instrument and were administered T1-sequences for anatomical mapping, quantitative susceptibility mapping (QSM) for assessing iron, and 18F-Flutemetamol-PET for estimating β-amyloid plaque load. Biological parametric mapping (BPM) was used to generate masks indicating voxels with significant (p < 0.05) correlation between susceptibility and 18F-Flutemetamol-SUVR. We found a bilateral pattern of clusters characterized by a statistical relationship between magnetic susceptibility and 18F-Flutemetamol-SUVR, indicating local correlations between iron and β-amyloid plaque deposition. For two bilateral clusters, located in the frontal and temporal cortex, significant relationships (p<0.05) between local β-amyloid and the composite cognitive performance score could be observed. No relationship between whole-cortex β-amyloid plaque load and cognitive performance was observable. Our data suggest that the local correlation of β-amyloid plaque load and iron deposition may provide relevant information regarding cognitive performance of healthy older adults. Further studies are needed to clarify pathological correlates of the local interaction of β-amyloid, iron and other causes of altered magnetic susceptibility.


Allometry of maximum vertical force production during hovering flight of neotropical orchid bees (Apidae: Euglossini).
The ability of orchid bees to generate vertical forces was evaluated using a load-lifting method that imposed asymptotically increasing loads during ascending flight, ultimately eliciting maximum forces while hovering. Among 11 orchid bee species varying by approximately an order of magnitude in body mass, the capacity to produce vertical forces expressed relative either to body weight or to flight muscle weight declined linearly with increased body mass. Allometric analysis of log-transformed data, by contrast, found maximum vertical force to scale isometrically with body mass, but also to exhibit a slightly negative allometry with respect to flight muscle mass. Maximum stroke amplitude at limiting loads averaged 140 degrees and was remarkably constant among species, a result consistent with anatomical constraints of the hymenopteran thorax on wing motions. By contrast, wing-beat frequencies during maximum performance declined with increasing body mass. Repeated lifting by individual bees reduced performance only when the number of consecutive lifts exceeded 15. Variation in linear mass density of the lifted load did not systematically alter performance estimates, although measurements on one species in two consecutive years at different thermal environments yielded significant differences in estimates of maximum force production. These findings suggest an adverse scaling of vertical force production at greater body mass even if flight muscle mass scales isometrically.


Evolution and replication of tobacco ringspot virus satellite RNA mutants.
The replication properties of linker insertion-deletion mutants of tobacco ringspot virus satellite RNA have been studied by amplification in plants infected with the helper virus. Sequence analysis of the cDNAs corresponding to the replicated forms shows that only one of the original mutated molecules replicates unaltered, and in general new variants accumulate. Depending on the location of the original mutation three types of sequence modifications were observed: (i) deletion of the mutated region followed by sequence duplication, (ii) sequence duplication and deletion outside of the mutated region and (iii) limited rearrangements at the site of mutation. The mutant that replicates without sequence changes accumulates linear multimeric forms suggesting that self-cleavage is affected although the sequence alteration does not involve the hammerhead catalytic domain. Alternative RNA conformations are likely to play a role in the origin of this phenotype and in the formation of sequence duplications. These results demonstrate the great structural flexibility of this satellite RNA.


A balloon-assisted facialplasty technique.
An ongoing goal of aesthetic surgery is a reduction in complications and an improvement in reproducibility and speed. Balloon dissector devices have been used in other areas of surgery to achieve these goals. This report presents early clinical experience using a balloon dissector to elevate the skin flap in facialplasty. The first step in the technique is the creation of a tunnel from a small preauricular incision toward the oral commissure using scissors dissection. The balloon device is inserted into this tunnel and inflated. Unrolling the device elevates the skin flap in the cheek and neck area. Retroauricular dissection and final adjustment of flap size and shape is completed sharply. Subsequent superficial musculoaponeurotic system flap development, skin redraping, and closure is performed in a conventional fashion after customary facialplasty incisions are made. Comparison of complications, postoperative drainage, and time required for dissection and for hemostasis was made between a balloon-dissected side and a conventionally dissected side in 10 patients undergoing facialplasty. Ten additional patients were treated with balloon dissection bilaterally. Patients ranged in age from 45 to 73 years. Mean balloon dissection time was 1.4 minutes (range, 0.75-4 minutes). This produced an even flap thickness in the correct plane with few if any bleeding points. Mean total dissection time on the balloon side was significantly shorter-13.6 minutes-compared with 27.8 minutes (p < 0.003) on the conventional side. Mean difference in time to hemostasis between conventional and balloon sides was 3.8 minutes (p < 0.001). Mean total postoperative drainage (all drains removed at 24 hours) was 13.8 cc on the balloon side and 18.8 cc on the conventional side (not significant, p=0.08). Less ecchymosis and swelling was observed on the balloon side compared with the scissors-dissected side. There were no skin losses, hematomas, infections, or nerve injuries on either side. Appearance of skin redraping was comparable on each side in all patients. Balloon dissection represents a promising alternative means of creating rapid, reproducible skin flap elevation in facialplasty, and is associated with a minimum of bleeding, ecchymosis, and swelling.


Organisational and occupational risk factors associated with work related injuries among public hospital employees in Costa Rica.
To explore the relation between occupational and organisational factors and work related injuries (WRI) among public hospital employees in Costa Rica. A cross-sectional survey was conducted among a stratified random sample of 1000 employees from 10 of the 29 public hospitals in Costa Rica. A previously validated, self-administered questionnaire which included occupational and organisational factors and sociodemographic variables was used. From the final eligible sample (n = 859), a total of 842 (response rate 98%) questionnaires were returned; 475 workers were analysed after excluding not-at-risk workers and incomplete questionnaires. WRI were computed for the past six months. Workers exposed to chemicals (RR = 1.36) and physical hazards (RR = 1.26) had higher WRI rate ratios than non-exposed workers. Employees reporting job tasks that interfered with safety practices (RR = 1.46), and a lack of safety training (RR = 1.41) had higher WRI rate ratios than their counterparts. Low levels of safety climate (RR = 1.51) and safety practices (RR = 1.27) were individually associated with an increased risk of WRI. Also, when evaluated jointly, low levels of both safety climate and safety practices showed the highest association with WRI (RR = 1.92). When evaluated independently, most of the occupational exposures and organisational factors investigated were significantly correlated with an increased injury risk. As expected, some of these associations disappeared when evaluated jointly. Exposure to chemical and physical hazards, lack of safety training, and low levels of safety climate and safety practices remained significant risk factors for WRI. These results will be important to consider in developing future prevention interventions in this setting.


Critical Casimir force in the presence of random local adsorption preference.
We study the critical Casimir force for a film geometry in the Ising universality class. We employ a homogeneous adsorption preference on one of the confining surfaces, while the opposing surface exhibits quenched random disorder, leading to a random local adsorption preference. Disorder is characterized by a parameter p, which measures, on average, the portion of the surface that prefers one component, so that p=0,1 correspond to homogeneous adsorption preference. By means of Monte Carlo simulations of an improved Hamiltonian and finite-size scaling analysis, we determine the critical Casimir force. We show that by tuning the disorder parameter p, the system exhibits a crossover between an attractive and a repulsive force. At p=1/2, disorder allows to effectively realize Dirichlet boundary conditions, which are generically not accessible in classical fluids. Our results are relevant for the experimental realizations of the critical Casimir force in binary liquid mixtures.


Contagious Bovine and Caprine Pleuropneumonia: a research community's recommendations for the development of better vaccines.
Contagious bovine pleuropneumonia (CBPP) and contagious caprine pleuropneumonia (CCPP) are major infectious diseases of ruminants caused by mycoplasmas in Africa and Asia. In contrast with the limited pathology in the respiratory tract of humans infected with mycoplasmas, CBPP and CCPP are devastating diseases associated with high morbidity and mortality. Beyond their obvious impact on animal health, CBPP and CCPP negatively impact the livelihood and wellbeing of a substantial proportion of livestock-dependent people affecting their culture, economy, trade and nutrition. The causative agents of CBPP and CCPP are Mycoplasma mycoides subspecies mycoides and Mycoplasma capricolum subspecies capripneumoniae, respectively, which have been eradicated in most of the developed world. The current vaccines used for disease control consist of a live attenuated CBPP vaccine and a bacterin vaccine for CCPP, which were developed in the 1960s and 1980s, respectively. Both of these vaccines have many limitations, so better vaccines are urgently needed to improve disease control. In this article the research community prioritized biomedical research needs related to challenge models, rational vaccine design and protective immune responses. Therefore, we scrutinized the current vaccines as well as the challenge-, pathogenicity- and immunity models. We highlight research gaps and provide recommendations towards developing safer and more efficacious vaccines against CBPP and CCPP.


[The chronic form of the Budd-Chiari syndrome].
A rare chronic course of Budd-Chiari syndrome associated with thrombosis of the portal vein was observed in a 30-year-old male patient suffering from postmyocarditic cardiosclerosis. At the age of 24 the patient had infectious allergic myocarditis, was hospitalized and rehospitalized for circulatory insufficiency. Upon 3 years since the disease onset the patient was admitted to a hematological department for progressive enlargement of the spleen. The diagnosis on discharge was idiopathic myelofibrosis with portal hypertension. The treatment included prednisolone, blood transfusions, myelosan. In 1987 the patient presented with enlarged liver and spleen, ascites, gastric and esophageal varicosis, augmenting hepatic insufficiency clinically evaluated as hepatic cirrhosis. Postmortem examination revealed macrofocal cardiosclerosis, splenomegaly, ascites, portal varicosis, enlarged nutmeg liver with smooth surface. Microscopically there was phlebosclerosis and phlebothrombosis varying in duration and involving predominantly medial branches of the hepatic and portal veins, liver fibrosis. The findings provided evidence for the final diagnosis of Budd-Chiari syndrome running an uncommon chronic course.


Female brain size and parental care in carnivores.
Comparative studies indicate that species differences in mammalian brain size relate to body size, ecology, and life-history traits. Previous analyses failed to show intrasexual or behavioral patterns of brain size in mammals. Across the terrestrial Carnivora, I find to the contrary. Differences in female, but not male, brain size associate with a fundamental ecological and evolutionary characteristic of female behavior. Other factors equal, females that provide the sole parental care have larger brains than those of biparental or communal species. For females, more parental investment accompanies larger brains. Future comparative studies of mammalian brain size must recognize that some patterns arise independently in the two sexes.


Knowledge and attitude of medical science students toward hepatitis B and C infections.
The present survey aimed to determine the knowledge level and attitude of medical students in Guilan University toward Hepatitis B and C viruses' infections. In a cross-sectional survey, the knowledge and attitude of 424 medical science undergraduate students of nursing, midwifery, operating room technician, laboratory, anesthesiology and radiology in Guilan University of Medical Sciences toward Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections were investigated using a standardized questionnaire. The mean (SD) knowledge level of the medical students toward HBV and HCV were 17 ± 5 from 28 and 10.58 ± 6.7 from 29 questions respectively. Females, nursing students, forth year students, those who worked in hospital and those who had needle stick injuries (NSI) history showed significantly higher knowledge scores toward HBV (P< 0.05). Married students, anesthesiology students, those who were in their fourth year of study, and those who worked in hospital had significantly higher mean knowledge scores toward HCV (P< 0.05). Also students' attitude toward HBV and HCV was positively correlated with their mean knowledge level (r=0.14, p=0.004), (r=0.18, p=0.0001). Education on the nature, symptoms, transmission, prevention and treatment of HBV and HCV infections may increase the willingness of health care workers to care for infected persons.


[The hygiene of using agrochemicals in a greenhouse with different technologies for growing vegetables].
Basing on the results of complex physiological and hygienic studies, the author provides a comparative analysis of female green-house workers' labour conditions at different stages and techniques of green-house vegetable processing. There was desirability of the overall norming in using agrochemical substances in green-houses, particularly when intensive agrotechnical technologies are used.


Metabolic Consequences of Supplemented Methionine in a Clinical Context.
The central position of methionine (Met) in protein metabolism indicates the importance of this essential amino acid for growth and maintenance of lean body mass. Therefore, Met might be a tempting candidate for supplementation. However, because Met is also the precursor of homocysteine (Hcy), a deficient intake of B vitamins or excessive intake of Met may result in hyperhomocysteinemia (HHcy), which is a risk factor for cardiovascular disease. This review discusses the evidence generated in preclinical and clinical studies on the importance and potentially harmful effects of Met supplementation and elaborates on potential clinical applications of supplemental Met with reference to clinical studies performed over the past 20 y. Recently acquired knowledge about the NOAEL (no observed adverse effect level) of 46.3 mg · kg-1 · d-1 and the LOAEL (lowest observed adverse effect level) of 91 mg · kg-1 · d-1 of supplemented Met will guide the design of future studies to further establish the role of Met as a potential (safe) candidate for nutritional supplementation in clinical applications.


Speakers of different languages remember visual scenes differently.
Language can have a powerful effect on how people experience events. Here, we examine how the languages people speak guide attention and influence what they remember from a visual scene. When hearing a word, listeners activate other similar-sounding words before settling on the correct target. We tested whether this linguistic coactivation during a visual search task changes memory for objects. Bilinguals and monolinguals remembered English competitor words that overlapped phonologically with a spoken English target better than control objects without name overlap. High Spanish proficiency also enhanced memory for Spanish competitors that overlapped across languages. We conclude that linguistic diversity partly accounts for differences in higher cognitive functions such as memory, with multilinguals providing a fertile ground for studying the interaction between language and cognition.


D-Arg0-Bradykinin-Arg-Arg, a Latent Vasoactive Bradykinin B2 Receptor Agonist Metabolically Activated by Carboxypeptidases.
We previously reported hypotensive and vasodilator effects from C-terminally extended bradykinin (BK) sequences that behave as B2 receptor (B2R) agonists activated by vascular or plasma peptidases. D-Arg0-BK-Arg-Arg (r-BK-RR) is a novel prodrug peptide hypothetically activated by two catalytic cycles of Arg-carboxypeptidases (CPs) to release the direct agonist D-Arg0-BK. N-terminally extending the BK sequence with D-Arg0 in the latter peptide was meant to block the second kinin inactivation pathway in importance, aminopeptidase P. The affinity of r-BK and r-BK-RR for recombinant B2R was assessed using a [3H]BK binding displacement assay. Their pharmacology was evaluated in human isolated umbilical vein, a contractile bioassay for the B2R, in a morphological assay involving the endocytosis of B2R-green fusion protein (GFP) and in anesthetized rats instrumented to record hemodynamic responses to bolus intravenous injection of both peptides. r-BK exhibited an affinity equal to that of BK for the rat B2R, while r-BK-RR was 61-fold less potent. In the vein and the B2R-GFP internalization assay, r-BK was a direct agonist unaffected by the blockade of angiotensin converting enzyme (ACE) with enalaprilat, or Arg-CPs with Plummer's inhibitor. However, the in vitro effects of r-BK-RR were reduced by these inhibitors, more so by enalaprilat. In anesthetized rats, r-BK and r-BK-RR were equipotent hypotensive agents and their effects were inhibited by icatibant (a B2R antagonist). The hypotensive effects of r-BK were potentiated by enalaprilat, but not influenced by the Arg-CPs inhibitor, which is consistent with a minor role of Arg-CPs in the metabolism of r-BK. However, in rats pretreated with both enalaprilat and Plummer's inhibitor, the hypotensive responses and the duration of the hypotensive episode to r-BK were significantly potentiated. The hypotensive responses to r-BK-RR were not affected by enalaprilat, but were reduced by pre-treatment with the Arg-CPs inhibitor alone or combined with enalaprilat. Therefore, in vivo, Arg-CPs activity is dominant over ACE to regenerate the B2R agonist r-BK from r-BK-RR, a prodrug activator of the B2R. A B2R agonist activated only at the level of the microcirculation by resident peptidases could be developed as an intravenously infused drug for ischemic diseases.


Experience-Dependent Counselor-Client Brain Synchronization during Psychological Counseling.
The role of the counselor's experience in building an alliance with the clients remains controversial. Recently, the expanding nascent studies on interpersonal brain synchronization (IBS) using functional near-infrared spectroscopy (fNIRS) on human subjects have hinted at the possible neural substrates underlying the relationship qualities between the counselor-client dyads. Our study assessed the clients' self-report working alliance (WA) as well as simultaneously measured IBS by fNIRS in 14 experienced versus 16 novice counselor-client dyads during the first integrative-orientation psychological counseling session. We observed that synchronous brain activity patterns were elicited from the right temporo-parietal junction (rTPJ) across counselor-client dyads. Furthermore, such IBS, together with alliance quality, was especially evident when counselors had more psychotherapy experience. Time-lagged counselor-client brain synchronization might co-vary with the alliance (goal component) when the client's brain activity preceded that of the counselor. These findings favor the notion that the IBS between counselor-client associated with the WA is an experience-dependent phenomenon, suggesting that a potential adaptive mechanism is embedded in psychological counseling.


Reference values for lung function: past, present and future.
Reliable interpretation of pulmonary function results relies on the availability of appropriate reference data to help distinguish between health and disease and to assess the severity and nature of any functional impairment. The overwhelming number of published reference equations, with at least 15 published for spirometry alone in the past 3 yrs, complicates the selection of an appropriate reference. The use of inappropriate reference equations and misinterpretation, even when potentially appropriate equations are used, can lead to serious errors in both under and over diagnosis, with its associated burden in terms of financial and human costs. Further misdiagnosis occurs when fixed cut-offs, such as 80% predicted forced expiratory volume in 1 s (FEV(1)) or 0.70 FEV(1)/forced vital capacity, are used; particularly in young children and elderly adults. While per cent predicted has historically been used to interpret lung function results, z-scores are more appropriate as they take into account the predicted value, as well as the between-subject variability of measurements. We aim to highlight some of the main issues in selecting and using reference equations and discuss how recent developments may improve interpretation of pulmonary function results.


Utility of knowledge, attitude, and practice survey, and prevalence of dental caries among 11- to 13-year-old children in an urban community in India.
The school oral health education program is believed to be a cost-effective method for promoting oral health. The KAP (knowledge-attitude-practice) model of oral health education is often the foundation of most health education programs. To assess the existing knowledge, attitude, and oral health care practices among 11- to 13-year-old children and the association of knowledge with attitude, oral health care practices, and dental caries prevalence. Cross-sectional design, involving 858 children studying in class seven at various schools in the city of Mangalore, India. The children were selected using stratified random sampling method. Prevalence of dental caries was determined using decayed, missing, and filled permanent teeth (DMFT) index. A self-administered questionnaire on self-care practices in oral health, knowledge, and attitude toward oral health care was filled by children. The association of different variables with knowledge was analyzed using binary logistic regression analysis. The dental caries prevalence was 59.4%, and 54.5% had low knowledge. They lacked knowledge regarding use of fluoridated toothpaste and did not use them. Children with low knowledge had significantly higher odds of having DMFT ≥ 1, not using fluoridated toothpaste, and being afraid of going to the dentist due to possible pain. There was no association of other oral health care practices and attitudes with knowledge. Oral health care practices and attitudes are not fully explained by knowledge, and other models of health education need to be considered.


Hopelessness in the myocardial infarction patient.
Events that cause hopelessness following a myocardial infarction may include coronary heart disease, reality-based misperceptions, lack of future goals and lack of relatedness to others. The susceptibility to hopelessness will depend on how successful the patient has been in accepting previous cardiac-related problems. Once hopelessness occurs, the patient may perceive the future to be limited. Hopelessness centers around seven components: physiological, cognitive, temporal, affective, behavioral, affiliative and contextual loss of hope. This article outlines how hopeless patients may distort their immediate environment and future goals. Methods of identifying hopelessness and intervening with appropriate nursing interventions, which will assist with the management of hopelessness, are described.


High cholinesterase predicts tolerance to sorafenib treatment and improved prognosis in patients with transarterial chemoembolization refractory intermediate stage hepatocellular carcinoma.
Although sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC), the predictive factors sorafenib tolerance in intermediate-stage HCC cannot be accurately determined. The aim of the current study was to identify the predictive characteristics for the continuation of sorafenib treatment (≥400 mg) in patients with transarterial chemoembolization (TACE)-refractory intermediate HCC and to identify candidates for second-line sorafenib treatment. A total of 33 TACE-refractory intermediate patients with HCC that were treated with sorafenib, and who had reached progressive disease (PD), were analyzed in the present retrospective study. Of 33 patients, 6 patients (18.1%) were able to continue sorafenib treatment (≥400 mg) until PD, however, a total of 27 patients (71.9%) were unable to continue treatment (<400 mg). The current study compared the baseline characteristics parameters to sorafenib ≥400 mg and <400 mg using a logistic regression model. The overall survival (OS) of patients receiving sorafenib ≥400 mg treatment was significantly increased compared with patients receiving sorafenib treatment <400 mg [554.5 days (228-674) vs. 219 days (134-369); P=0.0315). A univariate analysis was performed and indicated that Age (<75 years; P=0.021), total cholesterol (>180 mg/dl; P=0.026) and cholinesterase (ChE; ≥220 U/l; P=0.024) were significant factors, and a multivariate analysis indicated that ChE (≥220 U/l) was a significant prognostic factor (HR: 11.9; 95% CI: 1.19-118.0; P=0.004). Both progression-free survival [279 (204-403) vs. 117.5 (63-197) days; P=0.0136] and OS [470 (277-679) vs. 171.5 (80-236) days; P=0.0004] were significantly increased in patients with ChE levels ≥220 U/l compared with patients exhibiting ChE levels <220 U/l. Baseline high value of ChE in intermediate-stage HCC predicts the ability to continue sorafenib treatment at ≥400 mg.


Spatial structure of genetic variation and primary succession in the pioneer tree species Antirhea borbonica on La Réunion.
In habitats where colonization and extinction are recurrent, the distribution of gene frequencies among patches of suitable habitat may reflect the age structure of different populations. In this study, we quantify population genetic structure for a pioneer tree species, Antirhea borbonica, in a chrono-sequence of primary succession on the lava flows of the Piton de La Fournaise volcano (La Réunion). Using microsatellite loci and amplified fragment length polymorphism (AFLP) markers, we quantified genetic variation within and among populations for early- and late-succession populations in a landscape where extinction and recolonization are recurrent (the 'Grand Brûlé') and for late-succession populations in a more stable landscape. This study produced three main results. First, we detected no evidence that founder events increase genetic differentiation among colonizing populations; F(ST) values among early- and among late-succession populations were similar. Second, we found no evidence for isolation by distance; genetic distance was not correlated with spatial distance within and among populations. Third, F(IS) values are consistently high in all populations, despite the fact that A. borbonica populations are functionally close to dioecy and thus expected to have an outcrossing mating system. Multiple colonization events from different sources may limit differentiation among young populations and spatial isolation may enhance differentiation among late-succession populations. Ecological processes acting during colonization may create the conditions for spatial aggregation within pioneer populations, and thus contribute to the high F(IS) values.


Management of older hypertensive patients: is there a difference in approach?
Hypertension is the most common reason Americans visit a physician. Recent analyses from the Framingham Heart Study and others have shown that there will be 70 million hypertensive Americans by the year 2020 and that the overwhelming majority of hypertensives will be 65 years of age or older (what we used to call elderly). The lifetime risk of Americans who live to age 85 years of becoming hypertensive is approximately 90% for both men and women. These individuals, even if they develop an elevated blood pressure late in life, are at significantly increased risk of the many medical complications attributable to hypertension (coronary artery disease, strokes, heart failure, chronic renal disease, and more). Older hypertensives are more likely to have an elevated systolic blood pressure and a low diastolic blood pressure, both of which are related to a loss of article compliance and have an increase in left ventricular mass and a decrease in peripheral resistance. We now have a substantial body of evidence from well done clinical trials that older hypertensives benefit as much or more than younger patients from antihypertensive therapy, so there is no longer any justification for withholding medication from any hypertensive patient whose competing risk or other medical problems are not a contraindication to treatment. These same studies, and practice-based analyses, have shown that the major barrier to reaching blood pressure goal is our failure to reduce systolic blood pressure to <140 mm Hg in most patients and to <130 mm Hg in diabetics and those with renal failure. The basis for all antihypertensive therapy, especially in older people, is thiazide diuretics with either angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, or calcium entry blockers as appropriate add-on treatment. The choice of the second agent depends on other factors, such as comorbidity, lifestyle, and affordability. We must be more aggressive in getting the message out that older hypertensives benefit from treatment and we must overcome the clinical inertia that seems to be a factor in the decision of many physicians not to treat an older patient. No older person should suffer a preventable, life-threatening event or become confined to a wheel chair if attention to lifestyle issues and a few pills a day could avoid that outcome.


Serum human glandular kallikrein 2 (hK2) for distinguishing stage and grade of prostate cancer.
Human glandular kallikrein (hK2) has been shown to add important information regarding the early detection and staging of prostate cancer. Preliminary analysis pointed out that hK2 may discriminate between pT2 and pT3 tumors, and that hK2 may predict Gleason grade 4/5 cancer volume, better than prostate-specific antigen (PSA) or percent free PSA (%fPSA). We investigated the role of hK2 serum values for predicting pathological stage, grade and Gleason score. Prostate-specific antigen, free PSA and hK2 were measured on 222 untreated prostate cancer patients who had received radical prostatectomy at the Charité Hospital, Berlin, Germany. Pathological work up revealed pT2-cancer in 111 patients and pT3-cancer in 111 patients. Grade 2 was found in 118 patients whereas grade 3 tumors were found in 104 patients. For pT2 and pT3 patients, the %fPSA (P=0.006), the ratios hK2/fPSA (P=0.08) and hK2xtPSA/fPSA (P=0.002) were all significant different whereas hK2 (P=0.143) and PSA (P=0.1) did not differ. Between grade 2 and grade 3 tumors, the hK2 alone (P=0.27), the %fPSA (P=0.13), the ratios hK2/fPSA (P=0.94) and hK2xtPSA/fPSA (P=0.12) did not separate, whereas PSA (P=0.039) showed a difference. The same relationships were found between the two groups in Gleason score<7 and >or=7. Neither the hK2 ratio, nor % fPSA was different. Human glandular kallikrein was not different between pT2 and pT3, nor between G2 versus G3 or Gleason scores<7 and >or=7 prostate cancer. Together with %fPSA, hK2 may only help to distinguish preoperatively between pT2 and pT3 prostate cancer but cannot add further information.


Prostaglandin E(2)-mediated activation of HIV-1 long terminal repeat transcription in human T cells necessitates CCAAT/enhancer binding protein (C/EBP) binding sites in addition to cooperative interactions between C/EBPbeta and cyclic adenosine 5'-monophosphate response element binding protein.
Previous work indicates that treatment of human T cells with PGE(2) results in an increase of HIV-1 long terminal repeat (LTR) transcriptional activity. The noticed PGE(2)-mediated activation of virus gene activity required the participation of specific intracellular second messengers such as calcium and two transcription factors, i.e., NF-kappaB and CREB. We report in this work that the nuclear transcription factor CCAAT/enhancer binding protein (C/EBP) is also important for PGE(2)-dependent up-regulation of HIV-1 LTR-driven gene activity. The implication of C/EBP was shown by using a trans-dominant negative inhibitor of C/EBP (i.e., liver-enriched transcriptional inhibitory protein) and several molecular constructs carrying site-directed mutations in the C/EBP binding sites located within the HIV-1 LTR. Mutated HIV-1 LTR constructs also revealed the involvement of the two most proximal C/EBP binding sites. Data from cotransfection experiments with vectors coding for dominant negative mutants and gel mobility shift assays indicated that PGE(2)-mediated induction of HIV-1 LTR activity results from a cooperative interaction between C/EBPbeta and CREB, two members of the basic leucine zipper family of transcription factors. Altogether these findings indicate that treatment of human T cells with PGE(2) induces HIV-1 LTR activity through a complex interplay between C/EBPbeta and CREB. Such a combinatorial regulation may represent a mechanism that permits a fine regulation of HIV-1 expression by PGE(2) in human T cells.


Oxidative stress and inflammation: essential partners in alcoholic liver disease.
Alcoholic liver disease (ALD) is a multifaceted disease that is characterized by hepatic steatosis or fat deposition and hepatitis or inflammation. Over the past decade, multiple lines of evidence have emerged on the mechanisms associated with ALD. The key mechanisms identified so far are sensitization to gut-derived endotoxin/lipopolysaccharide resulting in proinflammatory cytokine production and cellular stress due to oxidative processes, contributing to the development and progression of disease. While oxidative stress and inflammatory responses are studied independently in ALD, mechanisms linking these two processes play a major role in pathogenesis of disease. Here we review major players of oxidative stress and inflammation and highlight signaling intermediates regulated by oxidative stress that provokes proinflammatory responses in alcoholic liver disease.


[Perception features of emotional intonation of short pseudowords].
Reaction time and recognition accuracy of speech emotional intonations in short meaningless words that differed only in one phoneme with background noise and without it were studied in 49 adults of 20-79 years old. The results were compared with the same parameters of emotional intonations in intelligent speech utterances under similar conditions. Perception of emotional intonations at different linguistic levels (phonological and lexico-semantic) was found to have both common features and certain peculiarities. Recognition characteristics of emotional intonations depending on gender and age of listeners appeared to be invariant with regard to linguistic levels of speech stimuli. Phonemic composition of pseudowords was found to influence the emotional perception, especially against the background noise. The most significant stimuli acoustic characteristic responsible for the perception of speech emotional prosody in short meaningless words under the two experimental conditions, i.e. with and without background noise, was the fundamental frequency variation.


Long-Term Efficacy of Subcutaneous C1 Inhibitor in Pediatric Patients with Hereditary Angioedema.
Background: Hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency is characterized by recurrent attacks of edema of the skin and mucosal tissues. Symptoms usually present during childhood (mean age at first attack, 10 years). Earlier symptom onset may predict a more severe disease course. Subcutaneous (SC) C1INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. We analyzed the long-term efficacy of C1INH (SC) in subjects ≤17 years old treated in an open-label extension (OLE) of the pivotal phase III Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1 Inhibitor Replacement Therapy (COMPACT) trial. Methods: Eligible subjects (age ≥6 years, with ≥4 attacks over 2 consecutive months before entry into the OLE or placebo-controlled COMPACT trial) were treated with C1INH (SC) 40 or 60 IU/kg twice weekly for 52-140 weeks. Subgroup analyses by age (≤17 vs. >17 years) were performed for key efficacy endpoints. Results: Ten subjects were ≤17 years old [mean (range) age, 13.3 (8-16) years, 3 subjects <12 years old; exposure range, 51-133 weeks]. All 10 pediatric subjects experienced ≥50% reduction (mean, 93%) in number of attacks versus the prestudy period, with a 97% reduction in the median number of attacks/month (0.11). All subjects had <1 attack/4-week period and 4 had <1 attack/year (1 subject was attack free). No subject discontinued treatment due to a treatment-related adverse event. Conclusions: Data from pediatric subjects treated with C1INH (SC) for up to 2.55 years and adult subjects revealed similar efficacy. C1INH (SC) is effective and well tolerated as long-term prophylaxis in children, adolescents, and adults with HAE.


Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells.
Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients.


Value of hospital resources for effective pressure injury prevention: a cost-effectiveness analysis.
Hospital-acquired pressure injuries are localised skin injuries that cause significant mortality and are costly. Nursing best practices prevent pressure injuries, including time-consuming, complex tasks that lack payment incentives. The Braden Scale is an evidence-based stratification tool nurses use daily to assess pressure-injury risk. Our objective was to analyse the cost-utility of performing repeated risk-assessment for pressure-injury prevention in all patients or high-risk groups. Cost-utility analysis using Markov modelling from US societal and healthcare sector perspectives within a 1-year time horizon. Patient-level longitudinal data on 34 787 encounters from an academic hospital electronic health record (EHR) between 2011 and 2014, including daily Braden scores. Supervised machine learning simulated age-adjusted transition probabilities between risk levels and pressure injuries. Hospitalised adults with Braden scores classified into five risk levels: very high risk (6-9), high risk (10-11), moderate risk (12-14), at-risk (15-18), minimal risk (19-23). Standard care, repeated risk assessment in all risk levels or only repeated risk assessment in high-risk strata based on machine-learning simulations. Costs (2016 $US) of pressure-injury treatment and prevention, and quality-adjusted life years (QALYs) related to pressure injuries were weighted by transition probabilities to calculate the incremental cost-effectiveness ratio (ICER) at $100 000/QALY willingness-to-pay. Univariate and probabilistic sensitivity analyses tested model uncertainty. Simulating prevention for all patients yielded greater QALYs at higher cost from societal and healthcare sector perspectives, equating to ICERs of $2000/QALY and $2142/QALY, respectively. Risk-stratified follow-up in patients with Braden scores <15 dominated standard care. Prevention for all patients was cost-effective in >99% of probabilistic simulations. Our analysis using EHR data maintains that pressure-injury prevention for all inpatients is cost-effective. Hospitals should invest in nursing compliance with international prevention guidelines.


Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.
Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.


[Adrenoleukodystrophy and adrenomyeloneuropathy--clinical spectrum, pathobiochemical aspects, diagnosis and therapy].
Adrenoleukodystrophy (ALD) is characterized by adrenal cortical insufficiency and progressive demyelination of the central nervous system with lethal outcome in childhood. Adrenomyeloneuropathy (AMN) represents a clinical variant of ALD with later manifestation during adolescence. The neurological symptoms of this form are slowly progressive spastic paraparesis and peripheral neuropathy. Other intermediate forms, which might be classified as adrenoleukomyeloneuropathy (ALMN), possibly represent an overlap of the two conditions. Heterozygote carriers of the X-linked disease may also show neurological symptoms, such as spastic paraparesis and peripheral neuropathy. Biochemically, all these X-linked forms of ALD/AMN are characterized by an accumulation of very-long-chain fatty acids in various tissues and body fluids indicating an impaired peroxisomal metabolism. In this study two families with ALD are presented. The two forms of ALD and AMN were observed in different members of the families including a heterozygote female carrier with neurological symptoms. The different clinical syndromes, the biochemical and genetic basis, and new therapeutical strategies are discussed.


Vascular vasopressin receptors in renal hypertensive rats.
We investigated the plasma concentration of [Arg8]-vasopressin (AVP), the density of AVP-binding sites on membranes from the mesenteric vascular bed, and the pressor response to AVP of the perfused mesenteric vasculature in vitro from one-kidney, one-clip (1K, 1C) and two-kidney, one-clip (2K, 1C) Goldblatt hypertensive rats. The plasma concentration of AVP was increased in 1K, 1C hypertensive rats. The density of AVP-binding sites was similar in sham-operated normotensive, in 2K, 1C hypertensive, and in uninephrectomized rats but was significantly decreased in 1K, 1C hypertensive rats (P less than 0.05). The binding affinity of AVP was similar in all experimental groups. Vasoconstrictor response to AVP was increased in 2K, 1C hypertensive rats (27% higher than sham-operated normotensive rats, P less than 0.05). Responses in 1K, 1C hypertensive rats were similar to those of uninephrectomized rats. Our results indicate that together with an increased concentration of AVP in plasma the number of vascular AVP-binding sites is decreased in 1K, 1C hypertensive rats, whereas both are unaltered in 2K, 1C hypertensive rats. Vascular AVP receptors appear to be regulated inversely to plasma AVP concentrations. Pressor responsiveness to AVP is normal in 1K, 1C hypertensive rats and exaggerated in 2K, 1C hypertensive rats. Increased vascular responsiveness to AVP may occur independently of the regulation of AVP receptors and may contribute to elevation of blood pressure in renal hypertension in the rat.


A simulated comparison of lung tumor target verification using stereoscopic tomosynthesis or radiography.
Mobile lung tumors are increasingly being treated with ablative radiotherapy, for which precise motion management is essential. In-room stereoscopic radiography systems are able to guide ablative radiotherapy for stationary cranial lesions but not optimally for lung tumors unless fiducial markers are inserted. We propose augmenting stereoscopic radiographic systems with multiple small x-ray sources to provide the capability of imaging with stereoscopic, single frame tomosynthesis. In single frame tomosynthesis, nine x-ray sources are placed in a 3 × 3 configuration and energized simultaneously. The beams from these sources are collimated so that they converge on the tumor and then diverge to illuminate nine non-overlapping sectors on the detector. These nine sector images are averaged together and filtered to create the tomosynthesis effect. Single frame tomosynthesis is intended to be an alternative imaging mode for existing stereoscopic systems with a field of view that is three times smaller and a temporal resolution equal to the frame rate of the detector. We simulated stereoscopic tomosynthesis and radiography using Monte Carlo techniques on 60 patients with early-stage lung cancer from the NSCLC-Radiomics dataset. Two board-certified radiation oncologists reviewed these simulated images and rated them on a 4-point scale (1: tumor not visible; 2: tumor visible but inadequate for motion management; 3: tumor visible and adequate for motion management; 4: tumor visibility excellent). Each tumor was independently presented four times (two viewing angles from radiography and two viewing angles from tomosynthesis) in a blinded fashion over two reading sessions. The fraction of tumors that were rated as adequate or excellent for motion management (scores 3 or 4) from at least one viewing angle was 53% using radiography and 90% using tomosynthesis. From both viewing angles, the corresponding fractions were 7% for radiography and 48% for tomosynthesis. Readers agreed exactly on 62% of images and within 1 point on 98% of images. The acquisition technique was estimated to be 75 mAs at 120 kVp per treatment fraction assuming one verification image per breath, approximately one order of magnitude less than a standard dose cone beam CT. Stereoscopic tomosynthesis may provide a noninvasive, low dose, intrafraction motion verification technique for lung tumors treated by ablative radiotherapy. The system architecture is compatible with real-time video capture at 30 frames per second. Simulations suggest that most, but not all, lung tumors can be adequately visualized from at least one viewing angle.


Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan.
Clozapine is generally recommended to be prescribed in a divided dosing regimen based on its relatively short plasma half-life. However, there has been little evidence to support the superiority of divided dosing of clozapine over once-daily dosing. To our knowledge, there have been no studies examining differences in actual plasma concentrations or adverse effects between the 2 dosing strategies of clozapine. We aimed to compare actual plasma concentrations of clozapine between once-daily and divided dosing regimens, and to examine the relationships of these regimens with psychiatric symptoms and adverse effects of clozapine. We analyzed data from 108 participants of a previous study conducted in 2 hospitals in Japan. A population pharmacokinetic model was used to estimate the peak and trough plasma concentrations of clozapine based on actual plasma concentrations. We evaluated psychiatric symptoms with the Brief Evaluation of Psychosis Symptom Domains and adverse effects of clozapine with the Glasgow Antipsychotic Side-effects Scale for Clozapine. The estimated peak and trough plasma concentrations of clozapine did not differ significantly between once-daily and divided dosing regimens. There were no significant differences in psychiatric symptoms except for depression/anxiety or subjective adverse effects of clozapine between the 2 dosing strategies. Our findings tentatively support the feasibility and clinical utility of once-daily dosing of clozapine in clinical practice. Further studies are needed to replicate these findings and determine causality between dosing strategies and clinical outcomes.


Formation of concatemeric DNA as an intermediate in the replication of bacteriophage T1 DNA molecules.
The structure of intracellular DNA extracted from phage T1 infected cells was analysed by sedimentation through sucrose gradients. DNA labelled with 3H-dThd during a short pulse given at any time during T1 DNA synthesis sedimented in neutral gradients as a broad heterogeneous band with a large fraction of the label sedimenting more rapidly than mature T1 DNA molecules. Rapidly-sedimenting label was also observed when pulse-labelled DNA was denatured and analysed on alkaline sucrose gradients. Electron microscopy of intracellular T1 DNA revealed linear molecules of variable length the longest of which were three to four times the mature genome length. The distribution of lengths derived from electron microscopy are consistent with the molecular length distributions calculated from the sedimentation coefficients. We conclude that the rapidly-sedimenting DNA is in the form of concatemers consisting of linear tandem repeats of the T1 genome. The concatemeric form of replicating T1 DNA is a precursor of progeny T1 genomes since in pulse-chase experiments it was converted efficiently into mature, infectious T1 phage particles. The identification of this concatemeric form of T1 DNA provides supporting evidence for the model proposed by Gill & MacHattie (1976) to account for the formation of the very limited number of cyclic permutations of gene sequence found for mature T1 DNA molecules.


Utilization of ultrasound sensors for anti-collision systems of powered wheelchairs.
Anti-collision systems have been developed for use with powered wheelchairs in order to enable people with cognitive or physical impairments to safely operate a powered wheelchair. Anti-collision systems consist of sensors that have the ability to detect objects near the wheelchair and a computer that can stop the chair if a collision is determined to be likely. This investigation considered the suitability of using ultrasound sensors in such a system when encountering objects typically found within a home or a long-term care facility. An ultrasound sensor's ability to detect an object was dependent on the object's size, shape, specularity, reflectivity, and sound absorption characteristics. Ultrasound sensors, by themselves, were found to be unsuitable for anti-collision systems due to an inability to detect objects commonly encountered in the target environment (the home or long-term care facility) without increasing the complexity of the system to such a degree that it would be prohibitive to deploy this technology to the public.


Danggui Buxue decoction ameliorates lipid metabolic defects involved in the initiation of diabetic atherosclerosis; identification of active compounds.
To determine the constituent compounds of Danggui buxue decoction (DBD) involved and the potential mechanisms mediating its effects, with specific reference to lipids playing a role in the initiation of diabetic atherosclerosis. Liquid chromatography-tandem mass spectrometry was used to identify and quantify the absorbed bioactive compounds (ABCs) present in DBD. Goto-Kakizaki (GK) rats were randomly allocated to a diabetes atherosclerosis (DA) group, a DBD group, and an ABC group (10 per group), which were all high-fat diet-fed. The treated rats were administered DBD (4 g/kg) or ABCs (in amounts equal to those present in DBD) once daily for 28 d, and a control group of Wistar rats were administered vehicle. Body mass gain, fasting blood glucose, and homeostasis assessment of insulin resistance (HOMA- IR) were measured. Serum triglyceride (TG), cholesterol (CHOL), high density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL- C) and tumor necrosis factor-α (TNF-α) concentrations were determined. Hematoxylin and eosin staining and microscopy were used to characterize the abdominal aorta and the expression of lipogenic genes was quantified in this vessel. Seven ABCs were identified in rat serum: ferulic acid, formononetin, calycosin, astragaloside, caffeic acid, ligustilide, and butyphthalide. DBD significantly reduced HOMA-IR, the serum concentrations of TG, CHOL, and LDL-C, and the expression of the lipogenic genes monocyte chemotactic protein 1, Fas, intercellular adhesion molecule 1, and Cd36 in aorta; and significantly increased the mRNA expression of Scd1 in aorta. DBD affects lipid metabolism in the early stage of atherosclerosis in diabetic GK rats, with the mechanism likely involving the regulation of lipid metabolic genes in vessels. The contribution of ABCs to the effect of DBD on lipid metabolism was 24%-101%.


Postnatal testosterone levels and disorder relevant behavior in the second year of life.
The objective of the current study was to investigate the relationship between testosterone collected at 3-4 months of age and sex-linked disorder-relevant behaviors in the second year of life. Eighty-four children participated at 3-4 (when salivary testosterone levels were obtained and second to fourth digit ratios were measured) and 18-24 months of age (when behavioral ratings of aggression and verbal ability were coded from two 8-min play sessions). Parents also completed the Brief Infant-Toddler Social and Emotional Assessment, and the four subscales (Internalizing, Externalizing, Dysregulation, and Autism Spectrum Disorder) were used to indicate child specific problems. Greater postnatal testosterone levels in early infancy were predictive of more male-typical behaviors in the second year of life (i.e., more autism spectrum behaviors, less time vocalizing, and more Internalizing Problems). These results support the hypothesis that early infancy may be another critical period for the development of gender-linked behavior.


Effect of the Use of Intranasal Spray of Essential Oils in Patients with Perennial Allergic Rhinitis: A Prospective Study.
Among allergic rhinitis (AR) symptoms, nasal obstruction particularly affects the quality of life. Antihistamines and intranasal corticosteroids are the most frequently prescribed symptomatic drugs, but their efficacy is often incomplete. Essential oils (EO) have shown an anti-inflammatory effect and potential in treating patients with AR. The aim of this study was to evaluate the effectiveness of a hypertonic EO-based nasal spray on perennial AR (PAR) symptoms. This prospective, open-label, non-randomized, multicentric trial included 43 patients with PAR sensitized to mites, not controlled for more than a year. All were treated with Puressentiel® Respiratory-Decongestant Nasal Spray for 30 days. Their usual treatment remained unchanged during the study period. Before and after treatment, each participant filled out a rhinitis questionnaire, the Allergic Rhinitis Control Test (ARCT). A nasal inspiratory peak flow (NIPF) was performed. The mean ARCT was 16.4 and 20.5 at D0 and D30, respectively (p < 0.001); the mean increase between D0 and D30 was 4.1 (p < 0.001). The proportion of patients with controlled rhinitis after 30 days of treatment was 69.8 versus 14% before treatment (p < 0.001). The mean NIPF was 86.5 L/min and 105.1 L/min at D0 and D30, respectively (p < 0.001); the mean increase between D0 and D30 was 18.5 L/min. A hypertonic EO-based nasal spray could be a new and natural option in the management of PAR. It could also be used as an add-on therapy when nasal symptoms are not fully controlled.


Comparison of the Vidas system and two recent fully automated assays for diagnosis and follow-up of toxoplasmosis in pregnant women and newborns.
Serological testing to detect toxoplasmosis is of major importance to avoid the possible effects of the disease in newborns. This study assessed anti-Toxoplasma IgG and IgM with the Vidas (bioMérieux), Architect (Abbott), and Liaison (DiaSorin) systems in 631 sera from pregnant women and newborns as well as anti-Toxoplasma IgG avidity with these three systems on 54 sera from pregnant women with positive IgG and IgM. The IgG and IgM results were in agreement in, respectively, 95.2% and 98.3% (Vidas versus Architect) and 96.9% and 95.3% (Vidas versus Liaison) of the samples. Specificities were excellent for all the assays, while Vidas sensitivities ranged (depending on the classification of gray zone results) from 93.8 to 98.4% for IgG (Architect, 84.4 to 93.8%; Liaison, 93.8%) and from 81.8 to 90.9% for IgM (Architect, 63.6%; Liaison, 81.8 to 90.9%). In seroconversion sequences, IgMs were generally detected simultaneously by the three assays, while Architect was the earliest assay to detect IgG. In noninfected children, maternally transmitted IgGs were detected for a longer time with Architect than with the other systems. IgMs were positive in only one infected child with the Vidas and Liaison systems. Significantly more sera were classified in the high-avidity category with Vidas than with Architect. This evaluation shows similar performances for Vidas and more recent systems. The Vidas system adequately detects toxoplasmosis in pregnant women and newborns. This system fits the needs of laboratories working on small routine series for first-line testing as well as expert laboratories, due to a high specificity and a powerful avidity test.


Direct ceramic coating of calcium phosphate doped with strontium via reactive growing integration layer method on α-Ti alloy.
A strontium (Sr)-doped hydroxyapatite-like coating was deposited on α-Ti alloy via the growing integration layer (GIL) method at various applied voltages. We added 0.03 M strontium hydroxide (Sr(OH)2·8H2O) to a solution containing calcium acetate and sodium dihydrogen phosphate to produce Sr-doped hydroxyapatite (Sr-HA) coatings. The scanning electron microscope (SEM) images of these coatings showed that all various features, such as average pore size, coating thickness, micro-hardness, and roughness, were similar to those of HA. As the voltage increased from 250 to 300 V, the amount of micro cracks decreased, and there were eliminated at 350 V. The SEM images also showed that the Sr-HA coatings were closely integrated with the alloy: without any gaps between the oxide layers and the alloy. In addition, energy-dispersive X-ray spectroscopy verified the Sr integration from the bottom up. X-ray diffraction patterns confirmed Sr-HA formation instead of calcium phosphate, even at the lowest voltage of 250 V. The value of Ecorr increased by 6.6% after raising the voltage from 250 to 350 V. The electrochemical impedance spectroscopy analysis confirmed that the adequate corrosion resistance of Sr-HA coatings, especially at the highest voltage of 350 V. In addition, the GIL treatment increased the layer resistance measured by Rp/Rc. Optimally, the GIL method used the highest voltage of 350 V to produce higher quality of Sr-HA-rich coatings.


Focal adhesion kinase: from in vitro studies to functional analyses in vivo.
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that has been shown to have key roles in cell migration, proliferation and survival. FAK activity can be stimulated in response to several types of extracellular ligands, including components of the extracellular matrix and growth factors, suggesting that FAK is an important integrator of multiple cues in the extracellular milieu. Recently, major progress has been made in understanding the molecular mechanisms regulating FAK activity. In particular, several novel proteins have been identified that can bind to FAK and inhibit its activity and associated cellular functions, including cell motility and invasion. Consistent with its critical functions in signal transduction, FAK also plays a pivotal role in mouse development. The inactivation of FAK in mice results in embryonic lethality around E8.5; this early embryonic lethal phenotype limits the use of the FAK total knockout mouse model for studying FAK function in later embryonic development stages and in adult mice. To overcome this problem, three independent groups created FAK/flox mice and generated several different FAK tissue-specific knockout mice models. Here we summarize the progress that has been made regarding the regulation of FAK-mediated signaling events in cell-based systems and also highlight the in vivo functions of FAK in a number of terminally differentiated cell lineages, including vascular endothelial cells, cardiomyocytes, neuronal cells, keratinocytes and several cancerous cell types.


Is preoperative neutrophil-to-lymphocyte ratio a red flag which can predict high-risk pathological characteristics in renal cell carcinoma?
Renal cell carcinoma (RCC) is known to invoke both immunological and inflammatory responses. While the neutrophils mediate the tumor-induced inflammatory response, the lymphocytes bring about the various immunological events associated with it. The neutrophil-to-lymphocyte ratio (NLR) is a simple indicator of this dual response. We investigated the association between preoperative NLR and histopathological prognostic variables of RCC intending to find out whether it can be of value as a red flag capable of alerting the clinician as to the biological character of the tumor under consideration. Preoperative NLR and clinicopathological variables, namely histological subtype, nuclear grade, staging, lymphovascular invasion, capsular invasion, tumor necrosis, renal sinus invasion, and sarcomatoid differentiation of 60 patients who underwent radical or partial nephrectomy, were analyzed to detect the association between the two. We found that mean preoperative NLR was significantly higher in clear-cell carcinomas (3.25 ± 0.29) when compared with nonclear-cell carcinomas (2.25 ± 0.63). There was a linear trend of NLR rise as the stage of the disease advanced. A significant rise in preoperative NLR was noted in tumors with various high-risk histopathological features such as tumor size, capsular invasion, tumor necrosis, and sarcomatoid differentiation. Preoperative measurement of NLR is a simple test which may provide an early clue of high-risk pathological features of renal cell cancer.


Quantitative sensory testing in patients with postthoracotomy pain syndrome: Part 2: variability in thermal threshold assessments.
Quantitative sensory testing is a reference method for characterization of postsurgical neuropathic components. Correct interpretation of data requires detailed information concerning the validity of the testing methods. The objective of the study was to assess the test-retest variability of thermal thresholds in patients (n = 14) with the postthoracotomy pain syndrome. Sensory mapping with a metal roller (25°C) on the surgical side delineated an area with cool sensory dysfunction. In this area and in a contralateral area, 4 prespecified sites (2.6 cm) were outlined, in addition to the maximum pain site on the surgical side. In these total 9 sites, warmth detection threshold, cool detection threshold, and heat pain threshold were assessed. Comparisons of thermal test-retest assessments did not demonstrate any significant intraside differences. The SDs of the thermal assessments in nonpain sites and in the maximum pain site ranged from 1.9 to 2.5°C and 3.5 to 6.9°C, respectively. The estimated within-patient and between-patient variances were 5% to 28% and 72% to 95%, respectively, of the total variances. Although a generally poor test-retest agreement was demonstrated, the much lower within-patient than between-patient variances facilitated estimations of highly statistical significant, within-patient differences in thermal thresholds. In patients with postthoracotomy pain syndrome, several statistical methods indicated an excessively high variability in thermal thresholds, questioning the use of single quantitative sensory testing in assessments to characterize patients with chronic pain states.


Exposure to physical and psychosocial stressors in relation to symptoms of common mental disorders among European professional football referees: a prospective cohort study.
The study aim was to explore the association of physical and psychosocial stressors (severe injuries, surgeries, recent life events, social support) with one-season onset of symptoms of common mental disorders (CMDs) among European professional football referees. An observational prospective cohort study over a follow-up period of one season (2015-2016) was conducted among professional football referees from Belgium, Finland, France, Germany, Norway, Russia, Scotland and Sweden. Based on physical and psychosocial stressors as well as symptoms of CMD, an electronic questionnaire in English and French was set up and distributed by eight football federations involved. The prevalence of symptoms of CMD ranged from 5.9% for distress to 19.2% for eating disorders. A higher number of severe injuries and a lower degree of satisfaction about social support were significantly related to the occurrence of symptoms of CMD with an OR of 2.63 and an OR of 1.10, respectively. A higher number of severe injuries and a lower degree on satisfaction about social support were found to be significantly associated with the onset of symptoms of CMD among European professional football referees. Referees suffering from severe injuries were nearly three times more likely to report symptoms of anxiety and depression. Referees who reported a low satisfaction of social support were significantly more likely to report symptoms of eating disorder.


Psychometric validation of the Ostomy Skin Tool 2.0.
Peristomal skin complications (PSCs) pose a major challenge for people living with an ostomy. To avoid severe PSCs, it is important that people with an ostomy check their peristomal skin condition on a regular basis and seek professional help when needed. To validate a new ostomy skin tool (OST 2.0) that will make regular assessment of the peristomal skin easier. Seventy subjects participating in a clinical trial were eligible for the analysis and data used for the validation. Item-level correlation with anchors, inter-item correlations, convergent validity of domains, test-retest reliability, anchor- and distribution-based methods for assessment of meaningful change were all part of the psychometric validation of the tool. A final tool was established including six patient reported outcome items and automatic assessment of the discolored peristomal area. Follow-up with cognitive debriefing interviews assured that the concepts were considered relevant for people with an ostomy. The OST 2.0 demonstrated evidence supporting its reliability and validity as an outcome measure to capture both visible and non-visible peristomal skin complications.


[Induction of aGVHD after allogeneic hematopoietic stem cell transplantation for refractory or relapsed acute leukemia].
Patients with refractory or relapsed acute leukemia after allogeneic hematopoietic stem cell transplantation had a poor prognosis with high death rate due to relapse or transplant-related mortality (TRM). The purpose of this paper was to clarify the role of inducing acute graft-versus-host disease (aGVHD) during transplantation in preventing relapse. Thirty adult patients with refractory or relapsed leukemia were acute lymphoblastic leukemia (n=16), acute myelogenous leukemia (n=10), and acute mixed leukemia (n=4). They were in first complete remission (n=4), second complete remission (n=9), partly remission (n=12), and non-response (n=5) at the time of transplantation. Patients underwent allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from HLA-identical siblings (n=21), mismatched siblings donors (n=3), and allogeneic bone marrow transplantation (n=5) or allo-PBSCT (n=1) from unrelated HLA matched donors. All patients received myeloablative regimens for eliminating residual leukemic cell. For aGVHD prophylaxis the patients with HLA-identical siblings donors received cyclosporine (CSA) alone, and the patients with mismatched siblings or unrelated donors received CSA, methotrexate, mycophenolate mofetil, and low-dose ATG. For inducing aGVHD after transplantation, patients were scheduled to be quickly reduced the maintenance dose of CSA at 20% to 30% off every week or treated with pre-emptive donor leukocyte infusion if there was no appearance of aGVHD at +30 days to 60 days after transplantation. After a median follow-up of 18.1 months, there were 24/30 (80%) patients developed aGVHD (grade 3 or 4 had 4/30, 13.3%). There were 11/19 (57.9%) patients developed chronic GVHD (cGVHD), with 3/19 (15.8%) had extensive cGVHD. Eighteen patients are alive with disease-free survival (18/30, 60%) and 12 patients have died of relapse (5/28, 17.9%) and TRM (7/30, 23.3%). Induction of aGVHD after transplantation is feasible and effective to prevent relapse in patients with refractory or relapsed acute leukemia.


Automated identification of patients with a diagnosis of binge eating disorder from narrative electronic health records.
Binge eating disorder (BED) does not have an International Classification of Diseases, 9th or 10th edition code, but is included under 'eating disorder not otherwise specified' (EDNOS). This historical cohort study identified patients with clinician-diagnosed BED from electronic health records (EHR) in the Department of Veterans Affairs between 2000 and 2011 using natural language processing (NLP) and compared their characteristics to patients identified by EDNOS diagnosis codes. NLP identified 1487 BED patients with classification accuracy of 91.8% and sensitivity of 96.2% compared to human review. After applying study inclusion criteria, 525 patients had NLP-identified BED only, 1354 had EDNOS only, and 68 had both BED and EDNOS. Patient characteristics were similar between the groups. This is the first study to use NLP as a method to identify BED patients from EHR data and will allow further epidemiological study of patients with BED in systems with adequate clinical notes.


Identification of tau protein regions required for process formation in PC12 cells.
Tau is a neuronal microtubule-associated protein that is required for the development and maintenance of neuronal cell polarity. It promotes microtubule assembly in vitro and we have recently reported that a specific tau region, which spans amino acid residues 154-172 of human fetal tau, is not required for growth of existing microtubules, but is required for nucleation of new microtubules. These residues also confer stronger microtubule binding activity in 3T3 cells. The aim of this study was to investigate the functional organization of tau in relation to its role in promoting process formation in a neuronal model system. We transfected undifferentiated PC12 cells with vectors expressing tau fragments and treated the expressing cells with cytochalasin B to allow process extension. We found that deletion of amino acid residues 154-172 greatly reduced the percentage of transfected cells bearing processes compared to that of cells transfected with full-length tau or with an amino-terminally deleted tau fragment containing residues 154-172. These differences do not appear to result from a quantitative difference in protein expression, as shown by immunoblot analysis of transfected cells. We also observed that while the presence of tau fragments increases acetylation of microtubules, the pattern of acetylation in cells transfected with the fragment missing residues 154-172 is less extensive, suggesting that it does not result in the same level of stabilization as the longer tau fragments. Taxol promoted process outgrowth in cells treated with cytochalasin and restored process outgrowth to cells transfected with the tau fragment lacking this activity. Therefore, process formation involves primarily the stabilization and nucleation of microtubules. We conclude that the residues necessary for conferring microtubule nucleation activity of tau in vitro are important for process formation in vivo. It is likely that these residues influence the binding affinity and therefore the stabilization activity of tau.


Personalized Goal for Dyspnea and Clinical Response in Advanced Cancer Patients.
The clinical response after comprehensive symptom management is difficult to determine in terms of a clinically important difference. Moreover, therapies should try to reach the threshold perceived by the individual patient for the determination of a favorable response to a treatment. The Edmonton Symptom Assessment Score (ESAS) was measured at admission (T0), and seven days after starting palliative care (T7). Patient Global Impression and Goal Response after one week of palliative care and its relation with the Personalized Dyspnea Goal were measured at T7. Patients admitted to palliative care units underwent a comprehensive symptom assessment by a specialist palliative care team. At T0, patients were asked about their Personalized Dyspnea Intensity Goal on ESAS. One week later (T7), after a comprehensive palliative care treatment, Personalized Dyspnea Intensity Goals were measured again. Patients were considered to have achieved a Patient Dyspnea Goal Response if dyspnea intensity (measured at T7) was equal or less than their expected Personalized Dyspnea Intensity Goal. At the same interval (T7), Patient Global Impression (improvement or deterioration) was measured. 279 patients were analyzed in this study. The mean Personalized Dyspnea Intensity Goal at T0 and T7 were 0.97 (SD 1.3), and 0.71 (SD 2.1), respectively. 263 patients (94.2%) indicated a Personalized Dyspnea Intensity Goal of ≤3 as a target at T0. Patients perceived a bit better, a better improvement, and a much better improvement with a mean decrease in dyspnea intensity of -2.1, -3.5, and -4.3 points on the dyspnea intensity scale, respectively. In 60 patients (21.5%), dyspnea intensity did not change, and in 4.7%, dyspnea intensity worsened. Patients perceived a Minimal Clinically Important Difference (little worse) with a mean increase in dyspnea intensity of 0.10, and they perceived a worse with a mean increase of 1.7 points. Higher dyspnea intensity at T0 and lower dyspnea intensity at T7 were independently related to Patient Global Impression. At T7, 93 (33.3%) patients achieved their Personalized Goal Response, based on Personalized Dyspnea Intensity. Patient Dyspnea Goal Response was associated with Memorial Delirium Assessment Scale score and Personalized Dyspnea Intensity Goal at T0, and inversely associated with dyspnea intensity at T0 and T7, and lower Karnofsky level. For Patient Dyspnea Goal Response, no significant differences among categories of dyspnea intensity were found (P>0.05). Patient Dyspnea Goal Response and Patient Global Impression seem to be relevant for evaluating the effects of a comprehensive management of symptoms, including dyspnea, assisting decision making process. Some factors may be implicated in determining the individual target and clinical response. A personalized symptom goal may translate in terms of therapeutic intervention, according to the achievement of the patients' expectations. High values of dyspnea intensity, a lower Karnofsky level, as well as high level of Dyspnea Intensity Goal (that is less patients' expectations) favor the achievement of the target.


Clinical crown height (length)--a review of published measurements.
Clinical crown height is an objective measure of the position of the gingival margin which could be used in determining the 'normal' position of the gingival margin. The aim of this study was to do a systematic review of published clinical crown heights in the human permanent dentition to compare the measurements and to see if a clear trend with age exists. An on-line literature search was done using the key words clinical crown height (or) clinical crown length. From January 1975 to August 2000, 11 published papers have listed measurements; three of these report on all tooth types, the remainder on anterior teeth. All studies used the same measuring technique but age group reporting differed as did the tooth types measured. Measurements from the 10 acceptable studies of the clinical crown height of the same teeth are comparable at similar ages, so published values are reasonable estimates of 'normality' for diagnosis. There is a statistically significant increase in clinical crown height of central and lateral incisors with age that slows as age increases.


Oblique saccadic eye movements of primates.
The objective of these experiments was to determine whether the trajectories of the horizontal and vertical components of oblique saccades in primates were coupled. Human and monkey eye movements were recorded during a visual tracking task that jumped a small visible target spot to different locations on a tangent screen. For oblique saccades larger than ca. 3 deg, there was coupling between the horizontal and vertical components so that the duration of the smaller component was longer ("stretched") than would have been expected from its amplitude-duration relationship. The duration of a stretched component of an oblique saccade was linearly related to the vector amplitude of the eye movement but not to the amplitude of the stretched component. Stretched components of oblique saccades had lower peak and average velocities than would have occurred with pure horizontal or vertical saccades of the same size. Decreased component velocity was not caused by low-velocity eye movement components inserted at the beginning or end of the saccade, but was a function of the saccade's direction and component amplitude. For any saccade, there was a linear relationship between peak and average component velocity. We compared the discharge of monkey abducens neurons with the characteristics of the on-direction horizontal components of oblique saccades. The burst duration of an abducens neuron was lengthened when the horizontal component of an oblique saccade was stretched. Intraburst firing frequency was also decreased in correspondence with a decrease in horizontal component velocity. For an oblique saccade, the duration of the neuron's burst was correlated with the duration of the horizontal component and with the vector amplitude of the saccade, but was not correlated with the amplitude of the horizontal component itself. The duration of the smaller component of an oblique saccade was proportional but not always equal to the duration of the larger component. Usually, the smaller component began later and ended earlier than the larger component. These results show that the horizontal and vertical components of oblique saccades are coupled centrally so that the velocity of the smaller component is decreased and its duration is increased. For oblique saccades, larger than ca. 3 deg, amplitude-duration and amplitude-velocity relationships based on pure horizontal or vertical saccade data are not applicable. These findings are discussed in relation to three recently proposed models of coupled saccadic burst generators.


Effective immunity to dental caries: protection of gnotobiotic rats by local immunization with a ribosomal preparation from Streptococcus mutans.
A ribosomal preparation from Streptococcus mutans 6715 was characterized for its ability to induce an immune response in gnotobiotic rats which was protective against S. mutans-induced dental caries. Animals injected in the salivary gland region with the S. mutans ribosomal vaccine developed significantly higher (P less than 0.01) salivary IgA and serum IgG antibody activities against whole S. mutans cells and ribosomal preparations than nonimmunized rats. Vaccinated animals had significantly lower (67%; P less than 0.01) levels of S. mutans adherent to their molar surfaces than the control rats after infection with the homologous, cariogenic S. mutans. The immunized animals had significantly fewer (P less than 0.01) carious lesions on their buccal, sulcal, and proximal molar surfaces than the nonimmunized rats following challenge with the virulent organism. Animals injected with the ribosomal preparation developed salivary IgA and IgG antibodies with specificities to various cell surface-associated antigens such as lipoteichoic acid and glucosyltransferase, suggesting that the observed protection may be due to antibodies against cell surface contaminants of the ribosomal vaccine. These results are the first demonstration that a ribosomal preparation from S. mutans protected rats from caries formation after challenge with the homologous, virulent S. mutans.


The training and integration of village health workers.
This article describes the selection, training, activities, and supervision of village health workers (VHWs) in a rural area of Haiti. The aim is to provide an overview of work that may serve as a useful example to others engaged or wishing to engage in VHW programs. The account describes selection and training of the VHWs, relationships established between themselves and with other health team members, operation of the VHW program, and development of community pharmacies by the VHWs in their homes.


Regulation of embryonic haematopoietic multipotency by EZH1.
All haematopoietic cell lineages that circulate in the blood of adult mammals derive from multipotent haematopoietic stem cells (HSCs). By contrast, in the blood of mammalian embryos, lineage-restricted progenitors arise first, independently of HSCs, which only emerge later in gestation. As best defined in the mouse, 'primitive' progenitors first appear in the yolk sac at 7.5 days post-coitum. Subsequently, erythroid-myeloid progenitors that express fetal haemoglobin, as well as fetal lymphoid progenitors, develop in the yolk sac and the embryo proper, but these cells lack HSC potential. Ultimately, 'definitive' HSCs with long-term, multilineage potential and the ability to engraft irradiated adults emerge at 10.5 days post-coitum from arterial endothelium in the aorta-gonad-mesonephros and other haemogenic vasculature. The molecular mechanisms of this reverse progression of haematopoietic ontogeny remain unexplained. We hypothesized that the definitive haematopoietic program might be actively repressed in early embryogenesis through epigenetic silencing, and that alleviating this repression would elicit multipotency in otherwise lineage-restricted haematopoietic progenitors. Here we show that reduced expression of the Polycomb group protein EZH1 enhances multi-lymphoid output from human pluripotent stem cells. In addition, Ezh1 deficiency in mouse embryos results in precocious emergence of functional definitive HSCs in vivo. Thus, we identify EZH1 as a repressor of haematopoietic multipotency in the early mammalian embryo.


FABP1 and FABP2 as markers of diabetic nephropathy.
Background: Diabetes mellitus is the leading cause of diabetic nephropathy and a major public health issue worldwide. Approximately 20-30% of patients with type 2 diabetes mellitus (T2DM) have renal impairment. Fatty acid-binding protein 1 (FABP1) is expressed in renal proximal tubule cells and released into urine in response to hypoxia caused by decreased peritubular capillary blood flow, and FABP2 is responsible for the transport of free fatty acids in the intestinal endothelium cells. There is increasing evidence that FABP1 and FABP 2 play a role in the development and progression of chronic kidney disease. The aim of this study was to investigate the relation of circulating FABP1 and FABP2 levels to nephropathy in patients with T2DM. Methods: For this study, 268 subjects with T2DM who were enrolled in a disease management program were stratified according to urinary microalbumin and serum creatinine measurements. The plasma FABP1 and FABP2 concentrations were examined by enzyme-linked immunosorbent assay. Demographic and potential metabolic confounding factors were analyzed with logistic regression to calculate the effects of FABP1 and FABP2 levels on diabetic nephropathy. Results: The FABP1 and FABP2 levels increased in parallel with the advancement of diabetic nephropathy. Increasing concentrations of FABP1 and FABP2 were independently and significantly associated with diabetic nephropathy. Multiple logistic regression analysis revealed FABP1 and FABP2 as an independent association factor for diabetic nephropathy, even after full adjustment of known biomarkers. Furthermore, receiver operating characteristic curve analysis showed that a FABP1 level of >33.8 ng/mL and a FABP2 level of >2.8 ng/mL were associated with diabetic nephropathy. Conclusion: Our results suggest that FABP1 and FABP2 may be novel biomarkers of diabetic nephropathy.