Genome scans reveal candidate domestication and improvement genes in cultivated sunflower, as well as post-domestication introgression with wild relatives.
The development of modern crops typically involves both selection and hybridization, but to date most studies have focused on the former. In the present study, we explore how both processes, and their interactions, have molded the genome of the cultivated sunflower (Helianthus annuus), a globally important oilseed. To identify genes targeted by selection during the domestication and improvement of sunflower, and to detect post-domestication hybridization with wild species, we analyzed transcriptome sequences of 80 genotypes, including wild, landrace, and modern lines of H. annuus, as well as two cross-compatible wild relatives, Helianthus argophyllus and Helianthus petiolaris. Outlier analyses identified 122 and 15 candidate genes associated with domestication and improvement, respectively. As in several previous studies, genes putatively involved in oil biosynthesis were the most extreme outliers. Additionally, several promising associations were observed with previously mapped quantitative trait loci (QTLs), such as branching. Admixture analyses revealed that all the modern cultivar genomes we examined contained one or more introgressions from wild populations, with every chromosome having evidence of introgression in at least one modern line. Cumulatively, introgressions cover c. 10% of the cultivated sunflower genome. Surprisingly, introgressions do not avoid candidate domestication genes, probably because of the reintroduction of branching.


Aldosterone blockade in chronic kidney disease: can it improve outcome?
The purpose of this review is to explain the rationale and limitations for use of mineralocorticoid receptor blockers (MRBs) for the treatment of chronic kidney disease (CKD) and its complications. Recent studies in animal models of CKD demonstrate that blockade of the mineralocorticoid receptor using spironolactone or eplerenone decreases inflammation, oxidative stress, proteinuria and glomerular and tubular injury. Patients with CKD are at very high risk for progression of kidney disease and major cardiovascular events. Recent studies in patients with CKD demonstrate that administration of low doses of MRBs added onto an angiotensin-converting enzyme inhibitor-based regimen reduces proteinuria--a risk marker for both progressive kidney disease and cardiovascular events. However, incident hyperkalemia, an unwanted side effect, dampened enthusiasm for this approach. There are no large-scale, long-term outcome trials examining whether MRB can slow progression of kidney disease or prevent cardiovascular events. At this time it is unknown whether mineralocorticoid receptor blockade can improve outcomes in patients with CKD. To move this field forward and determine whether these agents can improve the lives of patients with kidney disease, novel strategies to prevent or ameliorate hyperkalemia are needed.


All-trans-retinoic acid-mediated cytoprotection in LLC-PK1 renal epithelial cells is coupled to p-ERK activation in a ROS-independent manner.
Although all-trans-retinoic acid (ATRA) provides protection against a variety of conditions in vivo, particularly ischemia, the molecular mechanisms underpinning these effects remain unclear. The present studies were designed to assess potential mechanisms by which ATRA affords cytoprotection against renal toxicants in LLC-PK1 cells. Pretreatment of LLC-PK1 cells with ATRA (25 μM) for 24 h afforded cytoprotection against oncotic cell death induced by p-aminophenol (PAP), 2-(glutathion-S-yl)hydroquinone (MGHQ), and iodoacetamide but not against apoptotic cell death induced by cisplatin. Inhibition of protein synthesis with cycloheximide blunted ATRA protection, indicating essential cell survival pathways must be engaged before toxicant exposure to provide cytoprotection. Interestingly, ATRA did not prevent the PAP-induced generation of reactive oxygen species (ROS) nor did it alter glutathione levels. Moreover, ATRA had no significant effect on Nrf2 protein expression, and the Nrf2 inducers sulforaphane and MG132 did not influence ATRA cytoprotection, suggesting cytoprotective pathways beyond those that influence ROS levels contribute to ATRA protection. In contrast, ATRA rapidly (15 min) induced levels of the cellular stress kinases p-ERK and p-AKT at concentrations of ATRA (10 and 25 μM) required for cytoprotection. Consistent with a role for p-ERK in ATRA-mediated cytoprotection, inhibition of p-ERK with PD98059 reduced the ability of ATRA to afford protection against PAP toxicity. Collectively, these data suggest that p-ERK and its downstream targets, independent of ROS and antioxidant signaling, are important contributors to the cytoprotective effects of ATRA against oncotic cell death.


High diversity of hemotropic mycoplasmas in Iberian wild carnivores.
Two-hundred and thirty-one wild carnivores belonging to 10 species of in Spain were analyzed for the presence of DNA of hemotropic mycoplasmas (hemoplasmas) by means of a universal real-time PCR targeting a 16S rRNA gene fragment. Positive reactions were found for wolf (Canis lupus: 6/37), fox (Vulpes vulpes: 1/41), Eurasian badger (Meles meles: 49/85), pine marten (Martes martes: 11/23), stone marten (Martes foina: 6/9), least weasel (Mustela nivalis: 4/4), European wildcat (Felis s. silvestris: 1/2) and common genet (Genetta genetta: 7/27). Sixty-four readable sequences were obtained, resulting in 14 nucleotide sequence types (ntST). The highest diversity was detected in badger (6 ntST) and pine marten (5 ntST). The sequencing of a fragment of the RNase P gene showed that all positive reactions in wolves corresponded to Mycoplasma haemocanis. Three ntST showed an identity between 98-100% with Candidatus M. haemominutum, C. M. turicensis and C. M. haematoparvum, respectively. Four ntST were closely related to C. M. haemomeles and/or diverse genotypes reported from raccoons (Procyon lotor) in the USA. One ntST from a badger showed only 88% similarity to the closest published sequence and was phylogenetically unrelated to any other hemoplasma sequence reported. Three ntST were 99-100% similar to two different sequences reported in Spanish bats. This study confirms the widespread nature and the high genetic diversity of hemoplasma infection in carnivores. Wild carnivores might be natural hosts of some hemoplasmas infecting dogs and cats.


Acquired Fanconi syndrome with proximal tubular cytoplasmic fibrillary inclusions of λ light chain restriction.
Light chain proximal tubulopathy is a rarely reported entity associated with plasma cell dyscrasia that classically manifests as acquired Fanconi syndrome and is characterized by the presence of κ-restricted crystals in the proximal tubular cytoplasm. We herein present a case of multiple myeloma with Fanconi syndrome and acute kidney injury due to light chain proximal tubulopathy with light chain cast nephropathy. Prominent phagolysosomes and numerous irregularly shaped inclusions with a fibrillary matrix in the cytoplasm of the proximal tubules were identified on electron microscopy. A monotypic light chain of the λ type was detected in the distal tubular casts, proximal tubular cytoplasmic lysosomes and fibrillary inclusions on immunofluorescence and immune electron microscopy. This case underscores the importance of conducting careful ultrastructural investigations and immunocytologic examinations of light chains for detecting and diagnosing light chain proximal tubulopathy.


Construction and characterization of a temperature-sensitive human immunodeficiency virus type 1 reverse transcriptase mutant.
A temperature-sensitive (ts) human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) mutant was generated by charged-cluster-to-alanine mutagenesis. The mutant virus, containing three charged residues within the RT finger domain changed to alanine (K64A, K66A, and D67A), replicated normally at 34.5 but not 39.5 degrees C. Quantitating virus particle production by p24 antigen capture or virion-associated RT activity and virus infectivity by the MAGI cell assay, we found that (i) mutant virions produced at the permissive temperature were indistinguishable from wild-type virus in assays performed at the nonpermissive temperature, suggesting that the ts mutation did not impair early steps in the virus replication cycle and that the mutant RT enzyme was not ts; and (ii) virus particle production in cells transfected with the ts mutant at the nonpermissive temperature was comparable to that of wild-type virus. However, the particle-associated RT activity and infectivity of mutant virions produced at the nonpermissive temperature were greatly reduced when assays were conducted at the permissive temperature. These results are consistent with an irreversible ts event affecting RT that occurs during virus particle production. Radioimmunoprecipitation analyses revealed that both p66 and p51 RT subunits were absent from mutant virions generated at 39.5 degrees C. The presence of normal levels of HIV-1 integrase in mutant particles produced at the nonpermissive temperature was inconsistent with defective Gag-Pol synthesis or Gag-Pol incorporation into progeny virions. Furthermore, wild-type levels of the mutant Pr160(gag-pol) were detected in virions produced at the nonpermissive temperature when the HIV-1 protease was inactivated by site-specific mutagenesis. Taken together, these results are most consistent with a ts defect affecting the degradation or aberrant processing of the mutated RT during its processing/maturation within nascent particles.


Implementation of the patient-centered medical home in the Veterans Health Administration: associations with patient satisfaction, quality of care, staff burnout, and hospital and emergency department use.
In 2010, the Veterans Health Administration (VHA) began implementing the patient-centered medical home (PCMH) model. The Patient Aligned Care Team (PACT) initiative aims to improve health outcomes through team-based care, improved access, and care management. To track progress and evaluate outcomes at all VHA primary care clinics, we developed and validated a method to assess PCMH implementation. To create an index that measures the extent of PCMH implementation, describe variation in implementation, and examine the association between the implementation index and key outcomes. We conducted an observational study using data on more than 5.6 million veterans who received care at 913 VHA hospital-based and community-based primary care clinics and 5404 primary care staff from (1) VHA clinical and administrative databases, (2) a national patient survey administered to a weighted random sample of veterans who received outpatient care from June 1 to December 31, 2012, and (3) a survey of all VHA primary care staff in June 2012. Composite scores were constructed for 8 core domains of PACT: access, continuity, care coordination, comprehensiveness, self-management support, patient-centered care and communication, shared decision making, and team-based care. Patient satisfaction, rates of hospitalization and emergency department use, quality of care, and staff burnout. Fifty-three items were included in the PACT Implementation Progress Index (Pi2). Compared with the 87 clinics in the lowest decile of the Pi2, the 77 sites in the top decile exhibited significantly higher patient satisfaction (9.33 vs 7.53; P < .001), higher performance on 41 of 48 measures of clinical quality, lower staff burnout (Maslach Burnout Inventory emotional exhaustion subscale, 2.29 vs 2.80; P = .02), lower hospitalization rates for ambulatory care-sensitive conditions (4.42 vs 3.68 quarterly admissions for veterans 65 years or older per 1000 patients; P < .001), and lower emergency department use (188 vs 245 visits per 1000 patients; P < .001). The extent of PCMH implementation, as measured by the Pi2, was highly associated with important outcomes for both patients and providers. This measure will be used to track the effectiveness of implementing PACT over time and to elucidate the correlates of desired health outcomes.


[Clinical and metabolic effects of biological active food additives--phospholipids--in patients with cardiovascular diseases].
Uses of new phospholipid-containing food supplement 'Tonus' in patients with ischemic heart disease, hyperlipoproteinemia or hypertension during 4 weeks promoted positive changes clinical symptoms of diseases against a background of lowering of serum cholesterol, triglycerides and increasing of HDLP-cholesterol and improving liver function.


Fascicular shifting: a novel technique to overcome large nerve defects.
OBJECTIVE Over the last decade, a number of authors have investigated the utility of different biological and synthetic matrices as alternatives to conventional nerve grafts. However, the autologous nerve graft remains the gold standard, even though it often involves using a pure sensory nerve to reconstruct a mixed or even a pure motor nerve. Furthermore, limited donor sites often necessitate a significant mismatch of needed nerve tissue, especially for large proximal nerve defects such as brachial plexus lesions. Here, the authors present a new technique that overcomes these problems: the fascicular shift procedure (FSP). A fascicular group of the nerve distal to the injury is harvested in a sufficient length to bridge the nerve defect. METHODS The method of fascicular shifting was tested at the sciatic nerve in 45 Lewis rats. In the experimental group, a 15-mm nerve defect was created and reconstructed with a fascicular group that was harvested directly distal to the gap. This group was compared with 1 negative control group (defect without reconstruction) and 3 positive control groups (sensory, motor, and mixed graft). After 12 weeks of nerve regeneration, outcome was evaluated using retrograde labeling, histomorphometric analysis, and muscle force analysis. RESULTS All reconstructed groups showed successful regeneration with various levels of function. The negative control group showed minimal force measurements that were of no functional value. The fascicular shift provided sufficient guidance to overcome nerve defects, had higher (p < 0.1) motor neuron counts (1958.75 ± 657.21) than the sensory graft (1263.50 ± 538.90), and was equal to motor grafts (1490.43 ± 794.80) and mixed grafts (1720.00 ± 866.421). This tendency of improved motor regeneration was confirmed in all analyses. The mixed graft group was compared with the experimental group to investigate the influence of the potential damage induced by the fascicular shift distal to the repair site. However, none of the analyses revealed an impairment of nerve regeneration for both the tibial and common peroneal index muscles. CONCLUSIONS This study demonstrates that harvesting a transplant from the nerve segment distal to the injury site offers a mixed graft without causing additional donor-site morbidity. These grafts perform statistically better than a standard sensory graft in terms of motor recovery. The fascicular shift presents a novel method to reconstruct large proximal nerve defects, making it immensely attractive in brachial plexus reconstruction.


Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study.
The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy. In total, 35 children (14 males, 21 females; median age 11y, SD 3.4y, range 8-23y) were examined by static Humphrey perimetry, Goldmann kinetic perimetry, or Octopus perimetry. The aetiologies of infantile spasms identified were tuberous sclerosis (n=10), other symptomatic causes (n=3), or cryptogenic (n=22). Typical vigabatrin-attributed VFDs were found in 11 out of 32 (34%) children: in one out of 11 children (9%) who received vigabatrin for <1 year (group 1), in three out of 10 children (30%) who received vigabatrin for 12 to 24 months (group 2), and in seven out of 11 children (63%) who received vigabatrin treatment for longer than 2 years (group 3). VFDs were mild in five and severe in six children. Patients with tuberous sclerosis were at higher risk of VFDs (six out of 10 children). The mean cumulative doses of vigabatrin were 140.5, 758.8, and 2712g in group 1, 2, and 3, respectively. VFDs were found in 34% of the cohort of children in this study. The rate of VFD increased from 9% to 63% as duration of treatment increased. The results of this study showed that the risk-benefit ratio should always be considered when using vigabatrin.


ATP, beta-gamma-methylene-ATP, and adenosine inhibit non-cholinergic non-adrenergic transmission in rat urinary bladder.
ATP and adenosine caused a dose-dependent and reversible inhibition of the atropine-resistant contraction response to transmural nerve stimulation in the rat urinary bladder. Both purines also inhibited contraction responses to acetylcholine and direct muscle stimulation, indicating a postjunctional effect on the transmission. It seems as ATP per se inhibits the excitatory transmission, because the stable ATP-analogue beta-gamma-methylene-ATP was inhibitory as well, and because exogenous adenosine deaminase annulled the inhibition by adenosine but not that by ATP or beta-gamma-methylene-ATP. Blockade of purine inactivation enhanced the inhibitory action of ATP and adenosine, and by itself inhibited the transmission. These results are consistent with the possibility that endogenous purines may modulate non-cholinergic non-adrenergic excitatory transmission in the rat urinary bladder.


Surgery during pregnancy.
The anatomic and physiologic changes of pregnancy complicate a woman's response to elective or emergency surgical intervention. Alterations related to perioperative positioning, fluid volume replacement, effects of medicinal and anesthetic agents, and maternal/fetal assessment are discussed. Emotional and ethical/legal concerns are considered. A postoperative assessment guideline is presented.


The maturation of speech structure in psychosis is resistant to formal education.
Discourse varies widely with age, level of education, and psychiatric state. Word graphs have been recently shown to provide behavioral markers of formal thought disorders in psychosis (e.g., disorganized flow of ideas) and to track literacy acquisition in children with typical development. Here we report that a graph-theoretical computational analysis of verbal reports from subjects spanning 6 decades of age and 2 decades of education reveals asymptotic changes over time that depend more on education than age. In typical subjects, short-range recurrence and lexical diversity stabilize after elementary school, whereas graph size and long-range recurrence only steady after high school. Short-range recurrence decreases towards random levels, while lexical diversity, long-range recurrence, and graph size increase away from near-randomness towards a plateau in educated adults. Subjects with psychosis do not show similar dynamics, presenting at adulthood a children-like discourse structure. Typical subjects increase the range of word recurrence over school years, but the same feature in subjects with psychosis resists education.


A 212-nt long RNA structure in the Tobacco necrosis virus-D RNA genome is resistant to Xrn degradation.
Plus-strand RNA viruses can accumulate viral RNA degradation products during infections. Some of these decay intermediates are generated by the cytosolic 5'-to-3' exoribonuclease Xrn1 (mammals and yeast) or Xrn4 (plants) and are formed when the enzyme stalls on substrate RNAs upon encountering inhibitory RNA structures. Many Xrn-generated RNAs correspond to 3'-terminal segments within the 3'-UTR of viral genomes and perform important functions during infections. Here we have investigated a 3'-terminal small viral RNA (svRNA) generated by Xrn during infections with Tobacco necrosis virus-D (family Tombusviridae). Our results indicate that (i) unlike known stalling RNA structures that are compact and modular, the TNV-D structure encompasses the entire 212 nt of the svRNA and is not functionally transposable, (ii) at least two tertiary interactions within the RNA structure are required for effective Xrn blocking and (iii) most of the svRNA generated in infections is derived from viral polymerase-generated subgenomic mRNA1. In vitro and in vivo analyses allowed for inferences on roles for the svRNA. Our findings provide a new and distinct addition to the growing list of Xrn-resistant viral RNAs and stalling structures found associated with different plant and animal RNA viruses.


Population pharmacokinetic model of cefepime for critically ill adults: a comparative assessment of eGFR equations.
Cefepime exhibits highly variable pharmacokinetics in critically ill patients. The purpose of this study was to develop and qualify a population pharmacokinetic model for use in the critically ill and investigate the impact of various estimated glomerular filtration rate (eGFR) equations using creatinine, cystatin C, or both on model parameters. This was a prospective study of critically ill adults hospitalized at an academic medical center treated with intravenous cefepime. Individuals with acute kidney injury or on kidney replacement therapy or extracorporeal membrane oxygenation were excluded. A nonlinear mixed-effects population pharmacokinetic model was developed using data collected from 2018 to 2022. The 120 included individuals contributed 379 serum samples for analysis. A two-compartment pharmacokinetic model with first-order elimination best described the data. The population mean parameters (standard error) in the final model were 7.84 (0.24) L/h for CL1 and 15.6 (1.45) L for V1. Q was fixed at 7.09 L/h and V2 was fixed at 10.6 L, due to low observed interindividual variation in these parameters. The final model included weight as a covariate for volume of distribution and the eGFRcr-cysC (mL/min) as a predictor of drug clearance. In summary, a population pharmacokinetic model for cefepime was created for critically ill adults. The study demonstrated the importance of cystatin C to prediction of cefepime clearance. Cefepime dosing models which use an eGFR equation inclusive of cystatin C are likely to exhibit improved accuracy and precision compared to dosing models which incorporate an eGFR equation with only creatinine.


White collar-1, a DNA binding transcription factor and a light sensor.
Blue light regulates many physiological processes in fungi, but their photoreceptors are not known. In Neurospora crassa, all light responses depend on the Per-Arnt-Sim (PAS) domain-containing transcription factor white collar-1 (wc-1). By removing the WC-1 light, oxygen, or voltage domain, a specialized PAS domain that binds flavin mononucleotide in plant phototropins, we show that light responses are abolished, including light entrainment of the circadian clock. However, the WC-1-mediated dark activation of frq remains normal in this mutant, and the circadian clock can be entrained by temperature. Furthermore, we demonstrate that the purified Neurospora WC-1-WC-2 protein complex is associated with stoichiometric amounts of the chromophore flavin-adenine dinucleotide. Together, these observations suggest that WC-1 is the blue-light photoreceptor for the circadian clock and other light responses in Neurospora.


The effects of the opioid pharmacotherapies methadone, LAAM and buprenorphine, alone and in combination with alcohol, on simulated driving.
While methadone is currently the primary pharmacotherapy used in the treatment of heroin dependence in Australia, levo-alpha-acetyl-methodol (LAAM) and buprenorphine are new pharmacotherapies that are being examined as alternatives to methadone maintenance treatment. The aim of this research is to consider the effects of the methadone, buprenorphine and LAAM, as used in maintenance pharmacotherapy for heroin dependence, upon simulated driving. Clients stabilised in methadone, LAAM and buprenorphine treatment programs for 3 months, and a control group of non-drug-using participants, took part in this study which involved operating a driving simulator over a 75 min period. All participants attended one session without alcohol and one session with alcohol at around the 0.05% blood alcohol level. Simulated driving skill was measured through standard deviations of lateral position, speed and steering wheel angle, and reaction time to a subsidiary task was also measured. While alcohol impaired all measures of driving performance, there were no differences in driving skills across the four participant groups. These findings suggest that typical community standards around driving safety should be applied to clients stabilised in methadone, LAAM and buprenorphine treatment. The findings are important in terms of the widespread implementation of these treatment options in Victoria given that a large proportion of pharmacotherapy clients drive.


Characterisation of the transient mechanical response and the electromyographical activation of lower leg muscles in whole body vibration training.
The aim of this study is to characterise the transient mechanical response and the neuromuscular activation of lower limb muscles in subjects undergoing Whole Body Vibration (WBV) at different frequencies while holding two static postures, with focus on muscles involved in shaping postural responses. Twenty-five participants underwent WBV at 15, 20, 25 and 30 Hz while in hack squat or on fore feet. Surface electromyography and soft tissue accelerations were collected from Gastrocnemius Lateralis (GL), Soleus (SOL) and Tibialis Anterior (TA) muscles. Estimated displacement at muscle bellies revealed a pattern never highlighted before that differed across frequencies and postures (p < 0.001). After stimulation starts, muscle oscillation peaks, drops and further stabilises, suggesting the occurrence of a neuromuscular activation to reduce the vibration-induced oscillation. The oscillation attenuation at the SOL muscle correlated with its increased activation (rho = 0.29, p < 0.001). Furthermore, only specific WBV settings led to a significant increase in muscle contraction: WBV-induced activation of SOL and GL was maximal in fore-feet (p < 0.05) and in response to higher frequencies (30 Hz vs 15 Hz, p < 0.001). The analysis of the mechanical dynamics of lower leg muscles highlights a resonant response to WBVs, that for the SOL correlates to the increased muscle activation. Despite differing across frequencies and postures, this resonant behaviour seems to discourage the use of dynamic exercises on vibrating platforms. As for the most efficient WBV combination, calf muscle response to WBVs is maximised if those muscles are already pre-contracted and the stimulation frequencies are in the 25-30 Hz range.


Interim PET-CT in the management of diffuse large B-cell lymphoma.
Once the diagnosis of diffuse large B-cell lymphoma has been established, physicians and patients would like to know if a given treatment regimen is likely to succeed-if the patient can be cured or if at least a durable remission is achievable. This desire has lead to efforts to use interim positron emission tomography (PET) scanning as part of risk-adapted therapeutic clinical trials. In general, these studies use a variable number of doxorubicin-based induction cycles with rituximab, followed by the interim PET. If the test is negative, treatment is continued, but if it is positive, therapy is changed to treatment that concludes with autologous stem cell transplantation. Results of studies for interim PET have yielded mixed and confusing results, with high negative predictive value but positive predictive value ranging from 20%-80%. To use interim PET scanning effectively, clinicians need simple (positive or negative) criteria that are easy to interpret, reproducible, and have a high positive and negative predictive value so that we can be certain that by not changing therapy if the test is positive, we are not doing the patient a disservice.


Bile Salt and FGF19 Signaling in the Early Phase of Human Liver Regeneration.
The involvement of bile salt-fibroblast growth factor 19 (FGF19) signaling in human liver regeneration (LR) is not well studied. Therefore, we studied aspects of bile salt-FGF19 signaling shortly after liver resection in patients. We compared plasma bile salt and FGF19 levels in arterial, portal and hepatic venous blood, calculated venous-arterial differences (ΔVA), and determined hepatic transcript levels on two intra-operative time points: before (< 1 hour) and immediately after (> 2-3 hours) liver resection (i.e., following surgery). Postoperative bile salt and FGF19 levels were assessed on days 1, 2, and 3. LR was studied by computed tomography (CT)-liver volumetry. Following surgery, the liver, arterial, and portal bile salt levels were elevated (P < 0.05). Furthermore, an increased amount of bile salts was released in portal blood and extracted by the remnant liver (P < 0.05). Postoperatively, bile salt levels were elevated from day 1 onward (P < 0.001). For FGF19, intra-operative or postoperative changes of ΔVA or plasma levels were not observed. The bile salt-homeostatic regulator farnesoid X receptor (FXR) was markedly up-regulated following surgery (P < 0.001). Cell-cycle re-entry priming factors (interleukin 6 [IL-6], signal transducer and activator of transcription 3 [STAT3], and cJUN) were up-regulated following surgery and were positively correlated with FXR expression (P < 0.05). Postoperative hyperbilirubinemia was preceded by postsurgery low FXR and high Na+/Taurocholate cotransporting polypeptide (NTCP) expression in the remnant liver coupled with higher liver bile salt content (P < 0.05). Finally, bile salt levels on postoperative day 1 were an independent predictor of LR (P < 0.05). Conclusion: Systemic, portal, and liver bile salt levels are rapidly elevated after liver resection. Postoperative bile salts were positively associated with liver volume gain. In the studied time frame, FGF19 levels remained unaltered, suggesting that FGF19 plays a minor role in human LR. These findings indicate a more relevant role of bile salts in human LR.


Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood.
In Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC) time trends in the prevalence of rhinoconjunctivitis symptoms were analysed. Cross-sectional questionnaire surveys with identical protocols and questionnaires were completed a mean of 7 yr apart in two age groups comprising 498,083 children. In the 13- to 14-yr age group 106 centres in 56 countries participated, and in the 6- to 7-yr age group 66 centres in 37 countries participated. A slight worldwide increase in rhinoconjunctivitis prevalence was observed, but the variations were large among the centres and there was no consistent regional pattern. Prevalence increases in the older children exceeding 1% per year were recorded in 13 centres, including 3 of 9 centres in Africa, 2 of 15 in Asia-Pacific, 1 of 8 in India, 3 of 15 in Latin America, 3 of 9 in Eastern Europe and 1 of 34 in Western and Northern Europe. Decreasing rhinoconjunctivititis prevalence of similar magnitude was only seen in four centres. The changes were less pronounced in the 6- to 7-yr-old children and only in one centre did any change exceed 1% per year. The decrease in highest prevalence rates in ISAAC Phase I suggests that the prevalence has peaked in those regions. An increase was recorded in several centres, mostly in low and mid-income countries. The increases were more pronounced in the older age group, suggesting that environmental influences on the development of allergy may not be limited to early childhood.


Health risks associated with unpasteurized goats' and ewes' milk on retail sale in England and Wales. A PHLS Dairy Products Working Group Study.
A pilot study to determine the microbiological quality of unpasteurized milk from goats and ewes sampled from farm shops, health food shops, and other retail premises found that 47%, (47/100) of goats' and 50% (13/26) of ewes' milk samples failed the standards prescribed by the Dairy Products (Hygiene) Regulations 1995. In addition, Staphylococcus aureus, haemolytic streptococci or enterococci, were present in excess of 10(2) c.f.u./ml in 9 (7 %) 2 (2 %) and 19 (15%) samples, respectively. Salmonella, campylobacter, verocytotoxin-producing Escherichia coli O157:H7 and Listeria monocytogenes were not detected in the samples. At the time of purchase approximately half of the milk samples (58 %) were frozen, the rest were liquid. Farm outlets sold predominantly liquid milk, other retail premises sold a frozen product. The microbiological quality of goats' and ewes' milk, whether frozen or liquid, was not significantly different. Milk sold from farm shops was of lower quality than that from health food shops and other retail premises. In this pilot study most producers (92 %) supplied, and most retailers (76 %) sold unpasteurized goats' and ewes' milk that contained unacceptable levels of indicator organisms. The study was carried out during the winter when goats' milk production is reduced. The results indicate the need for a full representative study of unpasteurized goats' and ewes' milk on retail sale throughout the year.


Emergency endoscopy.
The need for emergency endoscopy is a matter of debate. The time interval for emergency procedures remains to be defined. Most authors propose a time span of 24 h as emergency time, while some define a period of 72 h (especially in acute pancreatitis). Several studies have shown a possible benefit for a select group of patients. Four main indications are established for emergency endoscopy: acute gastrointestinal bleeding (variceal and nonvariceal), acute biliary pancreatitis and acute cholangitis. In the case of upper gastrointestinal bleeding, emergency endoscopy enables exact diagnosis and appropriate therapy, and provides important prognostic information. There is some evidence that emergent endoscopic injection therapy improves clinical outcome and reduces mortality in patients with acute ulcer bleeding. Patients do not benefit if endoscopy is performed only as a diagnostic procedure. Controversial results were published recently for emergency endoscopy in acute biliary pancreatitis. There is good evidence that emergency endoscopic retrograde cholangiopancreatography is helpful in patients with severe pancreatitis and stone impaction if performed within the first 24 h after onset of symptoms. However, emergency endoscopic retrograde cholangiopancreatography is not beneficial for patients with mild pancreatitis if performed later than 72 h (or 24 h) after onset of symptoms. There is a limited number of well established evidence-based indications for emergency endoscopy. Some other indications are still a matter of debate, and controversial opinions have been published.


Diurnal variations in the effects of an unsaturated-fat-containing diet on fatty acid and cholesterol synthesis in rat hepatocytes.
Rats were fed ad libitum on either a standard high-carbohydrate diet, or a standard diet supplemented with 15% corn oil. Hepatocytes were prepared either during the light phase (L2-hepatocytes) or during the dark phase (D6-hepatocytes) of the diurnal cycle. In hepatocytes from rats fed on the fat-containing diet, fatty acid synthesis (lipogenesis) was suppressed to a much greater extent at D6 than at L2. The magnitude of the increase in plasma-free fatty acid concentration was similar at the two times of day. The rate of cholesterol synthesis was also significantly suppressed in the D6- but not in the L2-hepatocytes. This differential inhibition resulted in the abolition of the normal diurnal rhythm of cholesterogenesis. The initial activity of 3-hydroxy-3-methylglutaryl-CoA reductase in hepatocytes was also suppressed by corn-oil feeding at D6 but not at L2. In D6-hepatocytes, the inhibitory effect of the high-fat diet on the conversion of lactate into cholesterol and fatty acids was greater than that on total carbon flux into these substances for all endogenous sources. Despite this, under these conditions a high concentration of lactate and pyruvate resulted in a several-fold stimulation of total carbon flux into fatty acids. In hepatocytes prepared at L2, fat-feeding had little effect on the degree of stimulation of lipogenesis by insulin or inhibition by glucagon. However, at D6, fat-feeding blunted the response of lipogenesis to both these hormones.


A study of upper extremity training for patients with stroke using a virtual environment system.
[Purpose] A virtual environment (VE) system was designed to facilitate the retraining of motor control by feedback of movement trajectory to patients with neurological impairments, such as stroke victims or those with an acquired brain injury. In this study, we quantitatively assessed motion trajectory of the upper extremity during VE in order to further understand the effect of paralyzed upper extremity movement in VE for each patient as well as the functional clinical evaluations. [Subjects and Methods] Six patients with stroke were participated in this study. The VE system consisted of a computer, an electromagnetic motion tracking device, which monitored and displayed patient movement on the computer, and the VE software, which provided the tools for creating training scenes. This system was used to facilitate motor relearning of the upper extremity for six patients with stroke. [Results] The results showed there were improvements in variability and accuracy of the arm movement in motion trajectory. In addition, the scores of clinical evaluations improved, and VE did not hinder motor relearning of the upper extremity, which is necessary for activities of daily living. [Conclusion] This VE system might be effective at facilitating motor relearning of the upper extremity for stroke patients.


Allostimulatory capacity of conditionally immortalized proximal tubule cell lines for bioartificial kidney application.
Novel renal replacement therapies, such as a bioartificial kidney (BAK), are needed to improve current hemodialysis treatment of end-stage renal disease (ESRD) patients. As BAK applications may reveal safety concerns, we assessed the alloimmunization and related safety aspects of readily available conditionally immortalized human proximal tubule epithelial cell (ciPTEC) lines to be used in BAK. Two ciPTEC lines, originally derived from urine and kidney tissue, were characterized for the expression and secretion of relevant molecules involved in alloimmunization and inflammatory responses, such as HLA class-I, HLA-DR, CD40, CD80, CD86, as wells as soluble HLA class I and proinflammatory cytokines (IL-6, IL-8 and TNF-α). A lack of direct immunogenic effect of ciPTEC was shown in co-culture experiments with peripheral blood mononuclear cells (PBMC), after appropriate stimulation of ciPTEC. Tight epithelial cell monolayer formation on polyethersulfone flat membranes was confirmed by zonula occludens-1 (ZO-1) expression in the ciPTEC tight junctions, and by restricted inulin-FITC diffusion. Co-culture with (activated) PBMC did not jeopardize the transepithelial barrier function of ciPTEC. In conclusion, the absence of allostimulatory effects and the stability of ciPTEC monolayers show that these unique cells could represent a safe option for BAK engineering application.


Magmatic gas composition reveals the source depth of slug-driven strombolian explosive activity.
Strombolian-type eruptive activity, common at many volcanoes, consists of regular explosions driven by the bursting of gas slugs that rise faster than surrounding magma. Explosion quakes associated with this activity are usually localized at shallow depth; however, where and how slugs actually form remain poorly constrained. We used spectroscopic measurements performed during both quiescent degassing and explosions on Stromboli volcano (Italy) to demonstrate that gas slugs originate from as deep as the volcano-crust interface (approximately 3 kilometers), where both structural discontinuities and differential bubble-rise speed can promote slug coalescence. The observed decoupling between deep slug genesis and shallow (approximately 250-meter) explosion quakes may be a common feature of strombolian activity, determined by the geometry of plumbing systems.


Ethics and research among persons with disabilities in long-term care.
In this article, I reveal the arguments used to gain ethics approval to do research among persons with disabilities in adult residential care in New Brunswick and the specific ways I planned to act in their best interests. I also discuss the unexpected dilemmas encountered in the field and my efforts to resolve them. These dilemmas included determining the capacity of the persons in care to assent to be interviewed, addressing the propensity for acquiescence, dealing with anonymity and confidentiality issues, finding the optimum contexts for interviews, preparing participants for when I would leave the field, negotiating full disclosure as the mother of an adult with disabilities in long-term care, and ensuring that no persons under the auspices of the Office of the Public Trustee in New Brunswick participated in this research. I conclude that specific efforts should continue to be made to include persons with disabilities in future research.


Antibacterial activity of the essential oil from Rosmarinus officinalis and its major components against oral pathogens.
The essential oil of Rosmarinus officinalis L. (rosemary) was obtained by hydro-distillation and analysed by gas chromatography-mass spectrometry. Sixty-two constituents were identified, representing 98.06% of the total oil content. Oxygenated monoterpenes were the predominant components. The rosemary oil was characterized as having prominent (> 5%) contents of camphor (18.9%), verbenone (11.3%), a-pinene (9.6%), beta-myrcene (8.6%), 1,8-cineole (8.0%), and beta-caryophyllene (5.1%). The antimicrobial activity of the oil as well as of its major constituents was tested against the following microorganisms: Streptococcus mutans, Streptococcus mitis, Streptococcus sanguinis, Streptococcus salivarius, Streptococcus sobrinus, and Enterococcus faecalis, which are potentially responsible for the formation of dental caries in humans. The microdilution method was used for determination of the minimum inhibitory concentration (MIC) during evaluation of the antibacterial activity. The essential oil displayed low activity against the selected microorganisms. In the present study, the pure major compounds were more active than the essential oil. Among all the microorganisms tested, the pathogen S. mitis was the most susceptible and E. faecalis was the most resistant to the evaluated samples. This is the first report on antimicrobial activity of the major components of rosemary oil against oral pathogens.


Changing patterns in the workload of a district HIV/AIDS counselling unit 1987-90.
To describe the changing workload of an HIV/AIDS counselling unit between 1987 and 1990. Retrospective examination of data collected by the HIV/AIDS counselling unit between 1987-90 on the number of counselling sessions with patients, family members and staff. An HIV/AIDS counselling unit established in 1987 in a London teaching hospital. Number of new referrals to the HIV/AIDS counselling unit and the number of follow-up sessions. Number of counselling sessions with family members, hospital staff and people making telephone contact with the unit. New referrals to the HIV/AIDS counselling unit increased from 117 (1987-88) to 926 (1989-90). Follow-up appointments increased from 403 to 2016 in the same period. Telephone counselling sessions increased five-fold, and counselling sessions with family members nearly ten-fold over the three year period. Staff consultations doubled. The increase in the HIV/AIDS counselling unit's workload may be partly attributable to the rising incidence of AIDS in the community, reflecting earlier patterns of HIV infection. In addition, new HIV/AIDS services were developed in the hospital between 1987 and 1990. These included the establishment of a same-day HIV test and result clinic; integrated management of patients with HIV/AIDS, with an emphasis on early intervention in HIV infection; specialist services for families, antenatal clinic attenders and others affected by HIV; and the appointment of a designated HIV/AIDS consultant. New approaches to counselling and training health care providers in counselling skills will assume increasing importance in meeting future demand for HIV/AIDS counselling.


Hemodynamic effects of isoflurane in the newborn piglet: comparison with halothane.
To better understand the mechanism of hypotension and bradycardia that may occur in newborn infants during isoflurane anesthesia, we studied the hemodynamic changes in the major determinants of cardiac output in 15 newborn piglets given 0.5, 1.0, and 1.3 minimal alveolar concentrations (MAC) of isoflurane and in nine sham-instrumented, age-matched control animals. Cardiac output did not differ from the baseline reading or the control group at any isoflurane dose. Mean aortic pressure (MAP) decreased 23-45% in a dose-related manner. Total peripheral resistance index (TPRI) decreased 29% at 0.5 MAC, but did not decline further at higher concentrations. Because the decrease in MAP was offset by a similar reduction in TPRI, cardiac output did not change. Heart rate decreased significantly at 1.3 MAC (-19%). Contractility was depressed at all concentrations: left ventricular dP/dT decreased progressively at 0.5 and 1.0 MAC, and echocardiographic shortening fraction decreased significantly at 1.0 MAC. Left ventricular end-diastolic pressure was not affected. Eight of twelve animals who had bradycardia while breathing isoflurane were atrially paced at their baseline heart rate. Because pacing did not restore MAP, TPRI, and LV dP/dT/DP40 (a contractile index independent of preload and afterload) to control values, bradycardia was not primarily responsible for depression of these variables. At equipotent concentrations, isoflurane reduced MAP and TPRI more than, and cardiac output less than, halothane did in previous studies in this laboratory. Heart rate and dP/dT were decreased to a similar extent by both agents. Blood, heart, and brainstem isoflurane LD:MAC ratios were 2.04, 2.00, and 2.84, respectively, indicating a relatively low margin of safety for isoflurane in young piglets.


Viral load and a locus on chromosome 11 affect the late clinical disease caused by Theiler's virus.
Theiler's virus causes a persistent infection and a demyelinating disease of mice which is a model for multiple sclerosis. Susceptibility to viral persistence maps to several loci, including the interferon gamma locus. Inactivating the gene coding for the interferon gamma receptor makes 129/Sv mice susceptible to persistent infection and clinical disease, whereas inactivating the interferon gamma gene makes C57BL/6 mice susceptible to persistent infection but not to clinical disease. This difference in phenotype is due to the difference in genetic background. Clinical disease depends on high viral load and Tmevd5, a locus on chromosome 11. These results have consequences for the identification of viruses which might be implicated in multiple sclerosis.


The role of theory in increasing adherence to prescribed practice.
The purpose of this article is to apply theoretical frameworks to adherence behaviour and to guide the development of an intervention to increase adherence to prescribed home programmes. Delivering an effective intervention requires establishing one that is evidence based and of adequate dosage. Two-thirds of patients who receive home exercise prescriptions do not adhere to their home programme, which may contribute to their physiotherapy's being ineffective. The mediating concepts of self-efficacy (SE) and outcome expectations (OE) are common to the five relevant theories used to explain adherence to exercise: the health belief model, protection motivation theory, theory of reasoned action, theory of planned behaviour, and social cognitive theory. Few intervention studies with any theoretical underpinning have examined adherence to exercise. Even fewer have been designed to affect and measure change in the theoretical mediators of SE and OE in patient populations. Physiotherapists must consider increasing adherence as a component of effective physiotherapy. Ongoing research is needed to increase our understanding of adherence to prescribed home programmes and to design interventions to affect theoretical mediators for increasing adherence.


Blister-like supraclinoid internal carotid artery pseudoaneurysm in a 15-year-old male: case report and review of the literature.
With an incidence of less than 1-3 per million, pediatric aneurysms are rare clinical entities. A traumatic etiology is implicated in a large proportion of these cases, leading to the formation of both 'false' and 'true' aneurysms. These occur most often in the distal circulation, but have also been described in the supraclinoid distal internal carotid artery (ICA). Blood blister aneurysms are also found in this location; however, they have not been described in the pediatric population. We report the case of a 15-year-old male who presented following cranial trauma with diffuse basal subarachnoid hemorrhage and limited additional intracranial pathology. Computed tomography angiography demonstrated a small, 2-mm blister-like aneurysm arising from the dorsal surface of the left supraclinoid ICA at a non-branching site. Despite early endovascular treatment with Guglielmi detachable coils, the lesion continued to grow over subsequent studies, necessitating open surgical clipping. At the time of surgery, gross pathology of the native ICA was observed, raising the possibility of a preexisting blood-blister aneurysm. We review the epidemiology, pathophysiology and diagnostic considerations of these lesions. The endovascular and surgical management of these complex non-branching supraclinoid ICA aneurysms is also discussed.


Differential mechanisms of resistance to sublethal systemic Aspergillus fumigatus infection in immunocompetent BALB/c and C57BL/6 mice.
Studies of systemic and pulmonary Aspergillus fumigatus infection demonstrated differential susceptibility of inbred mice of various genetic background to lethal outcome, with an opposite pattern of Th1 cytokine interferon-γ (IFN-γ) and Th2 cytokine interleukin-4 (IL-4) in susceptible vs resistant mice. We have shown recently reciprocal IFN-γ and IL-4 expression in spleens of Th1-prone C57BL/6 mice in sublethal systemic aspergillosis. In this study, resistance to systemic (i.v.) A. fumigatus infection was investigated in Th2-prone BALB/c mice by survival rate at different fungal inocula, efficiency of reduction of visceral organ and spleen fungal burden at sublethal conidia dose and splenic immune response to this dose and compared to C57BL/6 mice. No strain differences in survival were noted at three A. fumigatus doses, with similar extent and dynamics of fungal eradication from all organs following sublethal conidia dose injection. Progressive decrease in spleen fungal burden was associated with different dynamics and quality of changes in spleen activity of BALB/c and C57BL/6 mice. Increased spleen mass and cellularity was noted in both strains, with higher values in BALB/c mice at some time points what might be ascribed to peripheral blood cell recruitment, as well as hematopoietic activity and red pulp upgrowth. Infection tipped the balance towards pro-inflammatory antifungal splenic response by a highly increasing IFN-γ and without changing the IL-4 expression in BALB/c mice, in contrast to down-regulating anti-inflammatory (IL-4) and a moderately increasing IFN-γ response in C57BL/6 mice. Jointly, stimulation of IL-17 expression noted in both strains provided an optimal inflammatory milieu in the spleen of infected mice that might have contributed to efficient removal of conidia.


Three-dimensional digital stereophotogrammetry: a reliable and valid technique for measuring scar surface area.
The surface area of scars is an important outcome parameter in scar assessment. It is often used to quantify the extent of scar features, such as pigmentation disturbances, hypertrophy, and contracture. Currently available techniques for measuring the surface area are known to be cumbersome or do not meet the basic clinimetric criteria (i.e., reliability and validity). Three-dimensional stereophotogrammetry is a technique that may improve the quality of surface area measurements. The aim of this study was to investigate the reliability and validity of three-dimensional stereophotogrammetry for measuring scar surface area. In a cross-sectional study, two independent clinicians photographed and measured 50 scar areas of 32 patients using a handheld stereographic camera, to assess reliability. Subsequently, using planimetry, the scar surface was traced on a transparent sheet (considered the accepted standard) to assess validity. Three-dimensional stereophotogrammetry showed good reliability, with an intraclass correlation coefficient of 0.99 and a coefficient of variation of 6.8 percent. To visualize the differences between the two observers, data were plotted and the limits of agreement were calculated at 0 ± 0.19 × mean surface area. Also, excellent validity was found, with a concordance correlation coefficient of 0.99. This study showed that three-dimensional stereophotogrammetry is a reliable and valid tool for research purposes in the field of scar surface area measurements. Diagnostic, I.


RelTime Rates Collapse to a Strict Clock When Estimating the Timeline of Animal Diversification.
Establishing an accurate timescale for the history of life is crucial to understand evolutionary processes. For this purpose, relaxed molecular clock models implemented in a Bayesian MCMC framework are generally used. However, these methods are time consuming. RelTime, a non-Bayesian method implementing a fast, ad hoc, algorithm for relative dating, was developed to overcome the computational inefficiencies of Bayesian software. RelTime was recently used to investigate the timing of origin of animals, yielding results consistent with early strict clock studies from the 1980s and 1990s, estimating metazoans to have a Mesoproterozoic origin-over a billion years ago. RelTime results are unexpected and disagree with the largest majority of modern, relaxed, Bayesian molecular clock analyses, which suggest animals originated in the Tonian-Cryogenian (less that 850 million years ago). Here, we demonstrate that RelTime-inferred divergence times for the origin of animals are spurious, a consequence of the inability of RelTime to relax the clock along the internal branches of the animal phylogeny. RelTime-inferred divergence times are comparable to strict-clock estimates because they are essentially inferred under a strict clock. Our results warn us of the danger of using ad hoc algorithms making implicit assumptions about rate changes along a tree. Our study roundly rejects a Mesoproterozoic origin of animals; metazoans emerged in the Tonian-Cryogenian, and diversified in the Ediacaran, in the immediate prelude to the routine fossilization of animals in the Cambrian associated with the emergence of readily preserved skeletons.


Phenotypic and genotypic characteristics of Escherichia coli strains isolated during a longitudinal follow-up study of chronic urinary tract infections.
Worldwide, Urinary Tract Infections (UTIs) are an important health problem with many cases reported annually, women being the most affected. UTIs are relevant because they can become a recurrent condition, associated with different factors that contribute to the chronicity of the disease (cUTI). cUTI can be classified as persistent (peUTI) when the causative agent is the same each time the infection occurs or as reinfection (reUTI) when the associated microorganism is different. The purpose of this work was to characterize Escherichia coli isolates obtained in two prospective studies of patients with cUTI, to define which of them corresponded to peUTI and which to reUTI. A total of 394 isolates of E. coli were analyzed by agglutination with specific sera, antimicrobial susceptibility by diffusion disc test, and the phylogroups and presence of genes associated with virulence by PCR assays. Additionally, in some characterized strains adherence, invasiveness, and biofilm formation were analyzed by in vitro assays. The results showed that the peUTI strains belonged mainly to the classical UPEC serogroups (O25, O75, O6), were included in the B2 phylogroup, carried a great number of virulence genes, and were adherent, invasive, and biofilm-forming. Meanwhile, reUTI strains showed great diversity of serogroups, belonged mainly in the A phylogroup, and carried fewer virulence genes. Both peUTI and reUTI strains showed extensively drug-resistant (XDR) and multidrug-resistant (MDR) profiles in the antimicrobial susceptibility test. In conclusion, it appears that peUTIs are caused principally by classical UPEC strains, while reUTIs are caused by strains that appear to be a part of the common E. coli intestinal biota. Moreover, although both peUTI and reUTI strains presented different serotypes and phylogroups, their antimicrobial resistance profile (XDR and MDR) was similar, confirming the importance of regulating prophylactic treatments and seeking alternatives for the treatment and control of cUTI. Finally, it was possible to establish the features of the E. coli strains responsible for peUTI and reUTI which could be helpful to develop a fast diagnostic methodology.


TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC.
Elevated tissue inhibitor of metalloproteinase-1 (TIMP-1) is a negative prognosticator in non-small cell lung carcinoma NSCLC patients. This study sought to identify mechanisms whereby TIMP-1 impacts anticancer therapy. Using NSCLC cells and their TIMP-1 knockdown clones, we examined the chemoresistance against two chemotherapeutic agents, Gemcitabine and Cisplatin, as identified by increased apoptosis in the knockdown clones. A bead-based cytokine screening assay identified interleukin-6 (IL-6) as a key factor in chemoresistance. Exogenous human recombinant rhTIMP-1 or rhIL-6 resulted in reduced apoptosis. IL-6 expression was closely correlated with TIMP-1 kinetics and was upregulated by the addition of exogenous TIMP-1 while TIMP-1 neutralizing antibodies delayed IL-6 elevation. IL-6 production was regulated by TIMP-1, exerting its effect via activation of downstream signal transducer and activator of transcription 3 (STAT3) signaling. Both molecules and their documented transcription factors were upregulated and activated in chemoresistant NSCLC cells, confirming the roles of TIMP-1 and IL-6 in chemoresistance. To examine the role of these genes in patients, survival data from lung adenocarcinoma (LUAD) patients was curated from the cancer genome atlas (TCGA) database. Kaplan-Meier analysis found that individuals expressing low TIMP-1 and IL-6 have a higher survival rate and that the two-gene signature was more significant than the single-gene status. We define for the first time, a regulatory relationship between TIMP-1 and IL-6 in NSCLCs, suggesting that the TIMP-1/IL6 axis may be a valuable prognostic biomarker. Therapeutic interventions directed at this dual target may improve overall prognosis while negatively affecting the development of chemoresistance in NSCLC.


Prostate cancer ablation with transrectal high-intensity focused ultrasound: assessment of tissue destruction with contrast-enhanced US.
To assess contrast material-enhanced ultrasonographic (US) findings seen after high-intensity focused ultrasound (HIFU) ablation of prostate cancer and correlate the US findings with post-HIFU biopsy findings. The study was ethics committee approved. Written informed consent was obtained from all patients. Twenty-eight patients referred for HIFU prostate cancer ablation underwent contrast-enhanced prostate US before treatment, gadolinium-enhanced magnetic resonance (MR) imaging and repeat contrast-enhanced US 1-3 days after treatment, and contrast-enhanced US-guided biopsy 30-45 days after treatment. The contrast-enhanced US enhancement patterns of the biopsy sites--assigned a score of S0 for no enhancement, S1 for mild and/or patchy enhancement, or S2 for marked enhancement--were compared with corresponding biopsy findings, which were assigned a score of B0 for necrosis and/or fibrosis without viable prostate gland tissue, B1 for vascularized tissue without viable gland tissue, or B2 for viable gland tissue (benign or malignant). Then, six additional patients underwent contrast-enhanced prostate US 15-30 minutes and 1 day after HIFU ablation, and the results of these two US examinations were compared. Contrast-enhanced US performed on days 1-3 and days 30-45 after HIFU ablation depicted a large devascularized zone with peripheral enhancing areas that were localized anteriorly in all 28 patients, posteriorly in nine, laterally in five, and at the apex in 20 patients. MR findings were concordant. At biopsy, viable gland tissue was found at nine (6.2%) of 146 S0 sites, 10 (34%) of 29 S1 sites, and 44 (60%) of 73 S2 sites. The odds ratios for finding viable tissue (score B1 or B2) at S1 and S2 sites as opposed to S0 sites were 21 (95% confidence interval [CI]: 6, 71) and 73 (95% CI: 22, 243), respectively (P < .0001). Contrast-enhanced US performed 15-30 minutes and 1 day after treatment in the six additional patients had similar findings. Contrast-enhanced US is a promising tool for distinguishing between ablated (devascularized) and viable (enhancing) tissue immediately after HIFU treatment.


The Dutch language anterior cruciate ligament return to sport after injury scale (ACL-RSI) - validity and reliability.
The ACL-Return to Sport after Injury scale (ACL-RSI) measures athletes' emotions, confidence in performance, and risk appraisal in relation to return to sport after ACL reconstruction. Aim of this study was to study the validity and reliability of the Dutch version of the ACL-RSI (ACL-RSI (NL)). Total 150 patients, who were 3-16 months postoperative, completed the ACL-RSI(NL) and 5 other questionnaires regarding psychological readiness to return to sports, knee-specific physical functioning, kinesiophobia, and health-specific locus of control. Construct validity of the ACL-RSI(NL) was determined with factor analysis and by exploring 10 hypotheses regarding correlations between ACL-RSI(NL) and the other questionnaires. For test-retest reliability, 107 patients (5-16 months postoperative) completed the ACL-RSI(NL) again 2 weeks after the first administration. Cronbach's alpha, Intraclass Correlation Coefficient (ICC), SEM, and SDC, were calculated. Bland-Altman analysis was conducted to assess bias between test and retest. Nine hypotheses (90%) were confirmed, indicating good construct validity. The ACL-RSI(NL) showed good internal consistency (Cronbach's alpha 0.94) and test-retest reliability (ICC 0.93). SEM was 5.5 and SDC was 15. A significant bias of 3.2 points between test and retest was found. Therefore, the ACL-RSI(NL) can be used to investigate psychological factors relevant to returning to sport after ACL reconstruction.


Proliferative activity in the cerebellar external granular layer evaluated by bromodeoxyuridine labeling.
We have optimised an indirect immunoperoxidase technique demonstrating bromodeoxyuridine (BrdU) incorporation into dividing cells for cerebellar tissue sections of four-day-old rats injected with this marker. This permits confident identification of granule-cell precursors engaged in DNA synthesis in the external granular layer of the developing cerebellum. Preservation of BrdU immunoreactivity is attained using methanol/acetic acid fixation and different pretreatments before immunostaining, while unlabeled nuclei can be recognized clearly after Feulgen or hematoxylin counterstaining. We established conditions to ensure satisfactory BrdU uptake without affecting cell-cycle progression during the postlabeling time period. The dose of BrdU employed provides saturation S-phase labeling from at least 1 h after BrdU delivery. Various kinetic parameters and phase durations have been determined in experiments involving a single injection or cumulative labeling sequences, and the cycle time was calculated based on two models of generative behavior: steady-state and exponential growth. The working hypothesis of steady-state kinetics can be adopted successfully if the existence of neuroblasts with different proliferation rates is taken into account.


[Fatal course of pulmonary embolism after successful pulmonary endarterectomy: a rare case].
We report a case of a 43-year-old woman who suffered from recurrent pulmonary embolism leading to chronic thromboembolic pulmonary hypertension. Pulmonary endarterectomy was performed with good result. However, two years later, after a SARS-CoV2 infection and despite oral anticoagulation therapy, the patient presented with clinical symptoms of pulmonary embolism, which was confirmed by computed tomography as an extensive pulmonary embolism. Despite fibrinolysis therapy and the attempt of interventional thrombus aspiration, the patient died due to non-manageable embolism load.


Investigation of non-collinear spin states with scanning tunneling microscopy.
Most ferromagnetic and antiferromagnetic substances show a simple collinear arrangement of the local spins. Under certain circumstances, however, the spin configuration is non-collinear. Scanning tunneling microscopy with its potential atomic resolution is an ideal tool for investigating these complex spin structures. Non-collinearity can be due to topological frustration of the exchange interaction, due to relativistic spin-orbit coupling or can be found in excited states. Examples for all three cases are given, illustrating the capabilities of spin-polarized scanning tunneling microscopy.


Scanning and transmission electron microscopy of bacterial attachment to mucosal surfaces with particular reference to the human fallopian tube.
Neisseria gonorrhoeae and Chlamydia trachomatis are the common bacteria isolated from bacterial cervicitis and are the leading etiological agents for pelvic inflammatory disease. Neisseria gonorrhoeae cause infection of the mucosa of fallopian tubes in organ culture by attaching to microvilli of nonciliated cells, phagocytosis by these cells, transport across and exocytosis from the epithelial cells. In contrast the Chlamydia attach to the epithelial surface without apparent ligand binding and are taken into the cytoplasm of the epithelial cell. Exocytosis of Chlamydia is into the tubal lumen and not into the subepithelial spaces. The ciliated epithelial cells of the fallopian tube are damaged by a gonococcal toxin but chlamydia do not exhibit such activity. These observations suggest that the mechanism of attachment to and invasion of the mucosal epithelium by gonococci and chlamydia are quite different and their potential for disease production occurs by different methods.


Gliadin-mediated proliferation and innate immune activation in celiac disease are due to alterations in vesicular trafficking.
Damage to intestinal mucosa in celiac disease (CD) is mediated both by inflammation due to adaptive and innate immune responses, with IL-15 as a major mediator of the innate immune response, and by proliferation of crypt enterocytes as an early alteration of CD mucosa causing crypts hyperplasia. We have previously shown that gliadin peptide P31-43 induces proliferation of cell lines and celiac enterocytes by delaying degradation of the active epidermal growth factor receptor (EGFR) due to delayed maturation of endocytic vesicles. IL-15 is increased in the intestine of patients affected by CD and has pleiotropic activity that ultimately results in immunoregulatory cross-talk between cells belonging to the innate and adaptive branches of the immune response. Aims of this study were to investigate the role of P31-43 in the induction of cellular proliferation and innate immune activation. Cell proliferation was evaluated by bromodeoxyuridine (BrdU) incorporation both in CaCo-2 cells and in biopsies from active CD cases and controls. We used real-time PCR to evaluate IL-15 mRNA levels and FACS as well as ELISA and Western Blot (WB) analysis to measure protein levels and distribution in CaCo-2 cells. Gliadin and P31-43 induce a proliferation of both CaCo-2 cells and CD crypt enterocytes that is dependent on both EGFR and IL-15 activity. In CaCo-2 cells, P31-43 increased IL-15 levels on the cell surface by altering intracellular trafficking. The increased IL-15 protein was bound to IL15 receptor (IL-15R) alpha, did not require new protein synthesis and functioned as a growth factor. In this study, we have shown that P31-43 induces both increase of the trans-presented IL-15/IL5R alpha complex on cell surfaces by altering the trafficking of the vesicular compartments as well as proliferation of crypt enterocytes with consequent remodelling of CD mucosa due to a cooperation of IL-15 and EGFR.


Rickets in premature infants fed different formulas.
To study the role of formula as a cause of rickets, we randomly assigned 46 very-low-birth-weight (VLBW) infants (less than or equal to 1,500 gm) to one of three groups receiving either Isomil, a soy isolate formula, Similac with Iron, a common milk-based formula, or Similac 24 LBW, a hypercaloric milk-based formula designed for low-birth-weight infants during the first three to four months of life. Postnatal changes in serum calcium, phosphorus, alkaline phosphatase, and albumin were monitored during this study. Radiologic diagnosis of rickets was made in 60% of infants fed Isomil and 5% fed Similac with Iron. Significantly low levels of serum phosphorus and high levels of serum alkaline phosphatase were also seen in infants fed Isomil. The exact cause of the biochemical changes and the high incidence of rickets among infants fed Isomil is not clear. Poor solubility and possibly the decreased bioavailability of minerals in soy isolate formula may be important. We conclude that rickets occurs with high frequency among VLBW infants fed soy isolate, but not milk-based formulas. We suggest that prolonged feeding of soy isolate formulas should be avoided in VLBW infants.


Associations between human aldosterone synthase (CYP11B2) gene polymorphisms and left ventricular size, mass, and function.
Aldosterone has direct and indirect effects on the heart, and genetic variations in aldosterone synthesis could therefore influence cardiac structure and function. Such variations might be associated with polymorphisms in the gene encoding aldosterone synthase (CYP11B2), the enzyme catalyzing the last steps of aldosterone biosynthesis. A Finnish population sample of 84 persons (44 women) aged 36 to 37 years was studied by M-mode and Doppler echocardiography to assess left ventricular size, mass, and function. Subjects were genotyped through the use of the polymerase chain reaction for two diallelic polymorphisms in CYP11B2: one in the transcriptional regulatory region (promoter) and the other in the second intron. In multiple regression analyses, the CYP11B2 promoter genotype predicted statistically significant variations in left ventricular end-diastolic diameter (beta=.40, P<.0001), end-systolic diameter (beta=.33, P=.0009), and mass (beta=.17, P=.023). These effects were independent of potentially confounding factors, including sex, body size, blood pressure, physical activity, smoking, and ethanol consumption. Genotype groups also differed in a measure of left ventricular diastolic function, the heart rate-adjusted atrial filling fraction (P=.018). Increased dietary salt, which is known to predict increased left ventricular mass, had this effect only in association with certain CYP11B2 genotypes (P<.001). Genetic variations in or near the aldosterone synthase (CYP11B2) gene strongly affect left ventricular size and mass in young adults free of clinical heart disease. These polymorphisms may also influence the response of the left ventricle to increases in dietary salt.


Mechanisms of cytotoxicity in human ovarian carcinoma cells exposed to free Mce6 or HPMA copolymer-Mce6 conjugates.
It is essential to understand cellular responses on photodynamic therapy (PDT) to design delivery systems that maximize cytotoxic effects coupled with minimal induction of side effects or protective mechanisms (or both). Here, we investigated mechanisms of toxicity in human ovarian carcinoma A2780 cells treated with structurally diverse N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer (P)-mesochlorin e6 monoethylenediamine (Mce6) conjugates that possessed differential subcellular accumulation or covalent attachments of photosensitizers (or both). Apoptosis and necrosis were observed after photoactivation, with increased apoptotic responses observed in cells exposed to conjugates possessing Mce6 linkage via a lysosomally degradable tetrapeptide spacer (HPMA copolymer-Mce6 conjugates containing Mce6 bound via glycylphenylalanylleucylglycine [GFLG] linker [P-GFLG-Mce6], HPMA copolymer-Mce6 conjugates containing Mce6 bound via a GFLG spacer and containing nuclear localization sequence, PKKKRKV132K(FITC)C [NLS(fluorescein-5-isothiocyanate [FITC])] bound via a thioether linkage [P-NLS(FITC)-GFLG-Mce6]). Furthermore, the induction of necrosis was more pronounced in cells exposed to conjugates containing both a nuclear localization sequence (NLS) and Mce6 bound by a degradable linker (P-NLS(FITC)-GFLG-Mce6). Caspase-independent mechanisms of cell death were identified in cells treated with nuclear-targeted conjugates possessing Mce6 attached using a nondegradable tether (HPMA copolymer-Mce6 conjugates containing Mce6 bound via a GG spacer and containing NLS(FITC) bound via a thioether linkage [P-NLS(FITC)-GG-Mce6]), whereas low levels of apoptosis and necrosis were detected in cells exposed to photoactivated nontargeted HPMA copolymer-Mce6 conjugates containing Mce6 coupled through a nondegradable spacer (HPMA copolymer-Mce6 conjugates containing Mce6 bound via GG linker [P-GG-Mce6]). Variations in gene expression were observed in cells on PDT. Specifically, HSP70 expression was solely detected in cells treated with P-GFLG-Mce6, whereas the loss of detection of several genes were observed in cells treated with P-NLS(FITC)-GFLG-Mce6. Variations in cellular responses on PDT using different HPMA copolymer-Mce6 conjugates will prove useful in the design of optimal HPMA copolymer PDT delivery systems.


Fenestrations of intracranial arteries.
Few data are available on the frequency and location distribution of fenestrations of intracranial arteries. We used 3D rotational angiography of all intracranial arteries in a cohort of 179 patients with suspected intracranial aneurysms to assess the prevalence and location of fenestrations and the relation of fenestrations to aneurysms. Of 179 patients with subarachnoid hemorrhage admitted between March 2013 and June 2014, 140 had 3D rotational angiography of all cerebral vessels. The presence and location of aneurysms and fenestrations were assessed. In patients with both aneurysms and fenestrations, we classified the relation of the location of the aneurysm as remote from the fenestration or on the fenestration. In 140 patients, 210 aneurysms were present. In 33 of 140 patients (24%; 95% confidence interval, 17.2%-31.3%), 45 fenestrations were detected with the following locations: anterior communicating artery in 31 (69%), A1 segment of the anterior cerebral artery in 4 (9%), middle cerebral artery in 4 (9%), basilar artery in 4 (9%), vertebral artery in 1 (2%), and anterior inferior cerebellar artery in 1 (2%). Of 56 patients with anterior communicating artery aneurysms, 14 had a fenestration on the anterior communicating artery complex. The remaining 31 fenestrations had no anatomic relation to aneurysms. In 140 patients with 210 aneurysms, 14 aneurysms (7%) were located on a fenestration and 196 were not. In patients with a suspected ruptured aneurysm, fenestrations of intracranial arteries were detected in 24% (33 of 140). Most fenestrations were located on the anterior communicating artery. Of 45 fenestrations, 14 (31%) were related to an aneurysm.


Auxeticity as a Mechanobiological Tool to Create Meta-Biomaterials.
Mechanical and morphological design parameters, such as stiffness or porosity, play important roles in creating orthopedic implants and bone substitutes. However, we have only a limited understanding of how the microarchitecture of porous scaffolds contributes to bone regeneration. Meta-biomaterials are increasingly used to precisely engineer the internal geometry of porous scaffolds and independently tailor their mechanical properties (e.g., stiffness and Poisson's ratio). This is motivated by the rare or unprecedented properties of meta-biomaterials, such as negative Poisson's ratios (i.e., auxeticity). It is, however, not clear how these unusual properties can modulate the interactions of meta-biomaterials with living cells and whether they can facilitate bone tissue engineering under static and dynamic cell culture and mechanical loading conditions. Here, we review the recent studies investigating the effects of the Poisson's ratio on the performance of meta-biomaterials with an emphasis on the relevant mechanobiological aspects. We also highlight the state-of-the-art additive manufacturing techniques employed to create meta-biomaterials, particularly at the micrometer scale. Finally, we provide future perspectives, particularly for the design of the next generation of meta-biomaterials featuring dynamic properties (e.g., those made through 4D printing).


Increased fluid administration in the first three hours of sepsis resuscitation is associated with reduced mortality: a retrospective cohort study.
The surviving sepsis guidelines recommend early aggressive fluid resuscitation within 6 h of sepsis onset. Although rapid fluid administration may offer benefit, studies on the timing of resuscitation are lacking. We hypothesized that there is an association between quicker, adequate fluid resuscitation and patient outcome from sepsis onset time. This is a retrospective cohort study of consecutive adults with severe sepsis and septic shock admitted to a quaternary care medical ICU between January 2007 and December 2009. Data were collected from a previously validated electronic medical database. Multivariate regression modeling was performed, adjusting for age, admission weight, Sequential Organ Failure Assessment score, APACHE (Acute Physiology and Chronic Health Examination) III score, and total fluid administration within the first 6 h of sepsis onset time. Of 651 patients with severe sepsis and septic shock screened, 594 had detailed fluid data. In a univariate analysis, the median amount of fluid within the first 3 h for survivors at discharge was 2,085 mL (940-4,080 mL) and for nonsurvivors, 1,600 mL (600-3,010 mL; P = .007). In comparison, during the latter 3 h, the median amount was 660 mL (290-1,485 mL) vs 800 mL (360-1,680 mL; P = .09), respectively. After adjusting for confounders, the higher proportion of total fluid received within the first 3 h was associated with decreased hospital mortality (OR, 0.34; 95% CI, 0.15-0.75; P = .008). Earlier fluid resuscitation (within the first 3 h) is associated with a greater number of survivors with severe sepsis and septic shock.


Preparation of solid phantoms with defined scattering and absorption properties for optical tomography.
We have developed diffusely scattering solid phantoms with optical (scattering) properties amenable to theoretical calculations. Monodisperse quartz glass spheres were used as scatterers embedded in polyester resin. An infrared dye was added to simulate absorption by biological tissue. Solid phantoms were tested for their macroscopic homogeneity. Several phantoms were built with well-defined spatial variations in their transport scattering and absorption coefficients to be used for optical tomography. Scattering, transport scattering, and absorption coefficients of solid, homogeneous phantoms and of aqueous suspensions of monodisperse quartz glass spheres were derived from measurements of time-integrated collimated transmittance and time-resolved diffuse transmittance. For aqueous suspensions of monodisperse quartz glass spheres at known number density scattering and transport scattering coefficients calculated by Mie theory are in quantitative agreement with experimentally derived values. In addition, diffuse reflectance and diffuse transmittance of aqueous suspensions at various number densities were measured and found to be in excellent agreement with results of Monte Carlo calculations using theoretical values for the scattering coefficients and anisotropy parameters.


Association of intestinal colonization of ESBL-producing Enterobacteriaceae in poultry slaughterhouse workers with occupational exposure-A German pilot study.
Bacteria that have acquired antimicrobial resistance, in particular ESBL-producing Enterobacteriaceae, are an important healthcare concern. Therefore, transmission routes and risk factors are of interest, especially for the carriage of ESBL-producing E. coli. Since there is an enhanced risk for pig slaughterhouse employees to carry ESBL-producing Enterobacteriaceae, associated with animal contact as potential risk factor, the present study investigated the occurrence of ESBL-producing Enterobacteriaceae in poultry slaughterhouse employees. Due to the higher level of resistant Enterobacteriaceae in primary poultry production than in pig production, a higher risk of intestinal colonization of poultry slaughterhouse employees was expected. ESBL-producing Enterobacteriaceae were detected in 5.1% (5 of 99) of the fecal samples of slaughterhouse workers. The species of these isolates was confirmed as E. coli. PCR assays revealed the presence of the genes blaCTX-M-15 (n = 2) and blaSHV-12 (n = 3) in these isolates, partly in combination with the β-lactamase gene blaTEM-135. Participants were divided into two groups according to their occupational exposure and results indicated an increased probability of colonization with ESBL-producing Enterobacteriaceae for the group of 'higher exposure' (OR 3.7, exact 95% CI 0.6-23.5; p = 0.4). For intestinal colonization with ESBL-producing Enterobacteriaceae, a prevalence of 10% (3/30) was observed in the group of 'higher exposure' versus 2.9% (2/69) in the group of 'lower exposure'. Employees in working steps such as 'hanging' poultry in the process of slaughter and 'evisceration' seemed to have a higher risk for intestinal colonization with ESBL-producing Enterobacteriaceae compared to the group of 'lower exposure'. This study is the first of its kind to collect data on the occupational exposure of slaughterhouse workers to ESBL-producing Enterobacteriaceae in Europe. The results suggested that colonization with ESBL-producing Enterobacteriaceae is associated with occupational exposure in poultry slaughterhouses. However, the presence of ESBL-producing E. coli isolates in only 5.1% (5/99) of the tested employees in poultry slaughterhouses suggests a lower transmission risk than in pig slaughterhouses.


Chronotype and Improved Sleep Efficiency Independently Predict Depressive Symptom Reduction after Group Cognitive Behavioral Therapy for Insomnia.
Cognitive behavioral therapy for insomnia (CBT-I) has been shown to improve both sleep and depressive symptoms, but predictors of depression outcome following CBT-I have not been well examined. This study investigated how chronotype (i.e., morningness-eveningness trait) and changes in sleep efficiency (SE) were related to changes in depressive symptoms among recipients of CBT-I. Included were 419 adult insomnia outpatients from a sleep disorders clinic (43.20% males, age mean ± standard deviation = 48.14 ± 14.02). All participants completed the Composite Scale of Morningness and attended at least 4 sessions of a 6-session group CBT-I. SE was extracted from sleep diary; depressive symptoms were assessed using the Beck Depression Inventory (BDI) prior to (Baseline), and at the end (End) of intervention. Multilevel structural equation modeling revealed that from Baseline to End, SE increased and BDI decreased significantly. Controlling for age, sex, BDI, and SE at Baseline, stronger evening chronotype and less improvement in SE significantly and uniquely predicted less reduction in BDI from Baseline to End. Chronotype did not predict improvement in SE. In an insomnia outpatient sample, SE and depressive symptoms improved significantly after a CBT-I group intervention. All chronotypes benefited from sleep improvement, but those with greater eveningness and/or less sleep improvement experienced less reduction in depressive symptom severity. This suggests that evening preference and insomnia symptoms may have distinct relationships with mood, raising the possibility that the effect of CBT-I on depressive symptoms could be enhanced by assessing and addressing circadian factors.


Lutein exerts anti-inflammatory effects in patients with coronary artery disease.
Many coronary artery disease (CAD) patients exhibit chronic low-grade inflammation. Carotenoids are anti-oxidants with potential anti-inflammatory properties. Here, we first assessed relationships between interleukin (IL)-6 and individual carotenoids in plasma from CAD patients. Based on the results, we proceeded to assess anti-inflammatory effects of one carotenoid, lutein, in peripheral blood mononuclear cells (PBMCs) from CAD patients. Lutein + zeaxanthin (isomers with lutein being dominant), β-cryptoxanthin, lycopene, α- and β-carotene and IL-6 were measured in plasma from 134 patients with stable angina (SA) and 59 patients with acute coronary syndrome. In 42 patients, plasma measurements were also performed 3 months after coronary intervention. PBMCs from SA patients were pre-treated with lutein (1, 5 and 25 μM) for 24 h followed by 24 h incubation ± lipopolysaccharide (LPS). Cell pellets were collected for IL-6, IL-1β and TNF mRNA and intracellular lutein. Cytokine secretion was measured in cell media. Only lutein + zeaxanthin were inversely correlated with IL-6 in SA patients at baseline (r = -0.366, p < 0.001) and follow-up (r = -0.546, p < 0.001). Ex vivo, lutein was taken up by PBMCs from SA patients in a dose- and time-dependent manner. Pre-treatment with lutein dose-dependently lowered LPS-induced secretion of IL-6, IL-1β (p < 0.01) and TNF (p < 0.05), and also reduced IL-6, IL-1β and TNF mRNA expression (p < 0.05). Clinical findings highlighted the inverse association between lutein and IL-6 in CAD patients. Anti-inflammatory effects of lutein in PBMCs from CAD patients were consolidated in ex vivo experiments. Taken together, these results show that lutein has the potential to play a role in resolution of chronic inflammation in CAD patients.


[Possibilities of cognitive and functional behavior analysis and the resulting therapeutic interventions in a mentally retarded pyromaniac].
Apart from general educational and treatment practices there is practically no attempt in providing specific rehabilitation programs for the mentally retarded adult firesetter. After a brief review of cognitive-behavior modification approaches in self-control training, the authors report on a method which has proved to be effective in cognitive and behavior analysis under threatening penalty conditions in a case of mental retardation with a history of repeated firesetting. The treatment goals are derived from the functional behavioral and cognitive analysis of the problem situation, the developmental analysis including attitudes and attributions, the motivational and self-control analysis and the analysis of social conditions. Fire-setting is defined as an operant behavior under discriminative stimulus control. An individual treatment program relevant to the different therapeutic targets is established. The proceedings are described by the authors.


Demographic drivers of age-dependent sexual selection.
Sexual selection has a critical role in evolution, and it is fundamental to identify what ecological factors drive its variation. Disentangling the ecological correlates of sexual selection over the long term, however, is challenging and has rarely been done in nature. We sought to assess how demographic changes influenced the intensity, direction and form of sexual selection and whether selective pressures varied with age. We tested whether breeder sex ratio, number of competitors and age structure influenced selection differentials on horn length of wild bighorn rams (Ovis canadensis) of different age classes on Ram Mountain, Alberta. We used 21 years of data including a detailed pedigree, demographic parameters and repeated morphological measurements. Sexual selection on horn length of males of all ages was directional and positive. Selection intensity increased with the number of competitors, reflecting male-male encounter rate during the rut, but was independent of breeder sex ratio or age structure. This result can also be linked to changes in population size because the number of competitors was highly correlated to total number of sheep. This demographic effect likely arises from age-dependent mating tactics. Males aged 2-4 years are weakly competitive and experienced stronger sexual selection as they accounted for a greater proportion of all males. Selection experienced by mature males appeared independent of demography. Our study provides a rare description of the demographic determinants of sexual selection in nature.


Atypical Rathke's cleft cyst associated with ossification.
We report a case of symptomatic Rathke's cleft cyst with ossification. CT scans showed curvilinear calcification on the wall of the cyst. MR images revealed a cystic sellar lesion with a nodular solid mass extending to the floor of the third ventricle. This case shows that calcification of the suprasellar cyst does not always suggest craniopharyngioma. Rathke's cysts should be histologically differentiated from craniopharyngiomas because their treatments are different.


Use of genome-wide heterospecific single-nucleotide polymorphisms to estimate linkage disequilibrium in rhesus and cynomolgus macaques.
Rhesus and cynomolgus macaques are frequently used in biomedical research, and the availability of their reference genomes now provides for their use in genome-wide association studies. However, little is known about linkage disequilibrium (LD) in their genomes, which can affect the design and success of such studies. Here we studied LD by using 1781 conserved single-nucleotide polymorphisms (SNPs) in 183 rhesus macaques (Macaca mulatta), including 97 purebred Chinese and 86 purebred Indian animals, and 96 cynomolgus macaques (M. fascicularis fascicularis). Correlation between loci pairs decayed to 0.02 at 1146.83, 2197.92, and 3955.83 kb for Chinese rhesus, Indian rhesus, and cynomolgus macaques, respectively. Differences between the observed heterozygosity and minor allele frequency (MAF) of pairs of these 3 taxa were highly statistically significant. These 3 nonhuman primate taxa have significantly different genetic diversities (heterozygosity and MAF) and rates of LD decay. Our study confirms a much lower rate of LD decay in Indian than in Chinese rhesus macaques relative to that previously reported. In contrast, the especially low rate of LD decay in cynomolgus macaques suggests the particular usefulness of this species in genome-wide association studies. Although conserved markers, such as those used here, are required for valid LD comparisons among taxa, LD can be assessed with less bias by using species-specific markers, because conserved SNPs may be ancestral and therefore not informative for LD.


Genetic determinants of diabetes and atherosclerosis.
Common risk factors for type 2 diabetes and cardiovascular disease are suspected because of the higher than expected prevalence of cardiovascular disease in individuals with newly diagnosed type 2 diabetes and in nondiabetic individuals with impaired glucose tolerance. Some of these risk factors may be genetic in origin. The risk of diabetes and cardiovascular disease may be linked through common pathways, including insulin resistance and/or inflammation. In this review, we describe the rationale for proposing these as common mechanisms affecting both diabetes and cardiovascular risk, and we then summarize the available evidence suggesting that common genes within these pathways have pleiotropic effects influencing susceptibility to both diseases.


Impact of complementary and alternative medicine on the quality of life in inflammatory bowel disease: results from a French national survey.
Complementary and alternative medicines (CAM) are widely used by patients with inflammatory bowel disease (IBD). Few data have been published on the impact of CAM on the quality of life (QOL). The aim of the study was to describe CAM use in French patients with IBD, identify characteristics associated with CAM use, and assess the impact of CAM on the QOL. We conducted an internet survey on CAM through the French IBD patient's association website. Patients had to answer a questionnaire (LimeSurvey application) about sociodemography, IBD treatment, CAM type, socioeconomic data, and QOL using the Short IBD Questionnaire (SIBDQ). Patients noted the impact of CAM on their symptoms and on their QOL on a scale of 0-100. CAM users and nonusers were compared by univariate and multivariate analyses. A total of 936 IBD patients responded and 767 (82.4%) filled up the whole questionnaire: 503 reported CAM use and 172 had never used. The types of CAM reported were diet-based (30.7%), body-based (25.1%), homeopathic or traditional medicine (19.6%), naturopathy (15.2%), and mind-body medicine (9.1%). The gastroenterologist was aware of CAM use in only 46% of patients. CAM users were more likely to have ulcerative colitis [odds ratio (OR)=1.78, P=0.018], clinical remission (OR=1.42, P=0.06), high level of education (OR=1.51, P=0.02), poor observance (OR=1.81, P=0.017), or to have terminated conventional treatment (OR=2.03, P=0.003). CAM users tend to have higher rates of SIBDQ scores, greater than 50 (OR=1.57, P=0.06). Improvement in symptoms and QOL was reported with all CAM types except mind medicine. CAM use is widespread among IBD patients. CAM users report improvement in symptoms and QOL, but they tend to stop their conventional treatment. Better information about CAM might improve adherence to conventional treatment.


Myelination in the absence of UDP-galactose:ceramide galactosyl-transferase and fatty acid 2 -hydroxylase.
The sphingolipids galactosylceramide (GalCer) and sulfatide are major myelin components and are thought to play important roles in myelin function. The importance of GalCer and sulfatide has been validated using UDP-galactose:ceramide galactosyltransferase-deficient (Cgt-/-) mice, which are impaired in myelin maintenance. These mice, however, are still able to form compact myelin. Loss of GalCer and sulfatide in these mice is accompanied by up-regulation of 2-hydroxylated fatty acid containing (HFA)-glucosylceramide in myelin. This was interpreted as a partial compensation of the loss of HFA-GalCer, which may prevent a more severe myelin phenotype. In order to test this hypothesis, we have generated Cgt-/- mice with an additional deletion of the fatty acid 2-hydroxylase (Fa2h) gene. Fa2h-/-/Cgt-/- double-deficient mice lack sulfatide, GalCer, and in addition HFA-GlcCer and sphingomyelin. Interestingly, compared to Cgt-/- mice the amount of GlcCer in CNS myelin was strongly reduced in Fa2h-/-/Cgt-/- mice by more than 80%. This was accompanied by a significant increase in sphingomyelin, which was the predominant sphingolipid in Fa2h-/-/Cgt-/- mice. Despite these significant changes in myelin sphingolipids, compact myelin was formed in Fa2h-/-/Cgt-/- mice, and g-ratios of myelinated axons in the spinal cord of 4-week-old Fa2h-/-/Cgt-/- mice did not differ significantly from that of Cgt-/- mice, and there was no obvious phenotypic difference between Fa2h-/-/Cgt-/- and Cgt-/- mice These data show that compact myelin can be formed with non-hydroxylated sphingomyelin as the predominant sphingolipid and suggest that the presence of HFA-GlcCer and HFA-sphingomyelin in Cgt-/- mice does not functionally compensate the loss of HFA-GalCer.


Agonist action at D2(short) dopamine receptors determined in ligand binding and functional assays.
Mechanisms of agonist action at the G protein-coupled D2(short) dopamine receptor expressed in Chinese hamster ovary cells have been investigated. Agonist binding was assayed in the presence and absence of GTP (100 microM). Data in the absence of GTP were fitted best by a two-site model (apomorphine, dopamine, 10,11-dihydroxy-N-n-propylnorapomorphine hydrochloride, and quinpirole) or a one-site model [bromocriptine, dihydroergocristine, and (-)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride], whereas in the presence of GTP a one-site model was the best fit for all compounds. Agonist binding parameters were used to provide a measure of the ability of the agonist to stabilise the ternary complex of agonist/receptor/G protein. Agonist stimulation of [35S]guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding for a range of agonist concentrations was measured and the EC50 and maximal effects determined. The initial rates of [35S]GTPgammaS binding induced by maximally stimulating agonist concentrations were also recorded. Simultaneous inhibition of agonist-stimulated [35S]GTPgammaS binding and receptor occupancy by spiperone was determined. Agonist inhibition of forskolin-stimulated cyclic AMP accumulation was determined for a range of agonist concentrations and the EC50 and maximal inhibition recorded. The data on the maximal agonist responses showed that it was possible to detect a spectrum of agonist efficacy (partial and full agonism) in both functional assays. The data on the apparent potencies of agonists to elicit the functional responses showed that different extents of amplification of response were seen for different agonists in both assays. The maximal activity data have been compared with the stabilisation of the agonist/receptor/G protein ternary complex as measured in binding assays.