Systems conceptualization and treatment of anger.
Clinicians, researchers, and patients tend to view anger as attributable to immediate circumstances and current thoughts. In contrast, systems-oriented thinking approaches anger as a contextual and dynamic phenomenon. Personal dispositional systems of anger (cognitive, physiological, and behavioral) are embedded in an interdependent network of interpersonal and environmental systems. Anger coevolves with and is in equilibrium with these systems. The more adaptive and embedded it is within a system, the greater will be its inertia or resistance to change. The automaticity of anger further challenges its regulation, as does its transfer across domains. Other troublesome systems phenomena associated with anger and aggression are escalation and threshold effects. Anger arousal, as a deviation from homeostasis, is inhibited and counteracted by various negative feedback loops that are properties of internal, interpersonal, and environmental systems. Treatment augments anger-regulatory mechanisms. Interventions aimed at anger reduction should consider the systems in which anger is embedded and the adaptive functions anger serves within those systems. These and other systems concepts are explicated and are illustrated with material from two clinical cases.


Country of birth as a risk factor for asthma among Mexican Americans.
In the United States, among Hispanics, Mexican Americans have the lowest rate of asthma. However, this population includes Mexican Americans born in the United States and in Mexico, and risk factors that might impact the prevalence of asthma differ between these groups. To determine the prevalence of and risk factors for asthma among U.S.- and Mexican-born Mexican Americans, we analyzed data from two U.S. surveys that included 4,574 persons who self-reported their ethnicity as Mexican American from the Third National Health and Nutrition Examination Survey (NHANES III) 1998-1994 and 12,980 persons who self-reported their ethnicity as Mexican American from National Health Interview Survey (NHIS) 1997-2001. U.S.-born Mexican Americans were more likely than Mexican-born Mexican Americans to report ever having asthma in both the NHANES III (7% [SE 0.5] vs. 3% [SE 0.3], p < 0.001) and NHIS surveys (8.1% [0.4] vs. 2.5% [0.2], p < 0.001). In a multivariate regression model controlling for multiple demographic variables and health care, the risk for asthma was higher among U.S.-born Mexicans in NHANES III (odds ratio 2.1, 95% confidence interval 1.4-3.3) and NHIS (odds ratio 2.7, 95% confidence interval 1.6-5.5). In conclusion, the prevalence of asthma was higher in U.S.-born than in Mexican-born Mexican Americans. This finding highlights the importance of environmental exposures in developing asthma in a migratory population.


4-Methylumbelliferyl-alpha-glycosides of partially O-acetylated N-acetylneuraminic acids as substrates of bacterial and viral sialidases.
4-O-Acetylated, 7-O-acetylated, and 9-O-acetylated 4-methylumbelliferyl-alpha-N-acetyl-neuraminic acids (Neu4,5Ac2-MU, Neu5,7Ac2-MU, Neu5,9Ac2-MU) were tested as substrates of sialidases of Vibrio cholerae and of Clostridium perfringens. Both sialidases were unable to hydrolyse Neu4,5Ac2-MU. This compound at 1 mM concentration did not inhibit significantly the cleavage of Neu5Ac-MU, the best substrate tested. The 4-O-acetylated sialic acid glycoside is hydrolysed slowly by the sialidase from fowl plague virus. The relative substrate specificity, reflected in V/Km of the Vibrio cholerae sialidase is Neu5Ac-MU much greater than Neu5,7Ac2-MU approximately Neu5,9Ac2-MU and of the clostridial enzyme it is Neu5Ac-MU greater than Neu5,9Ac2-MU greater than Neu5,7Ac2-MU. The affinities of both enzymes for the side-chain O-acetylated sialic acid derivatives are higher than for Neu5Ac-MU. The artificial, well-defined substrates, described here, provide the opportunity to quantify the influence of sialic acid O-acetylation on the hydrolysis of sialoglycoconjugates without the side effects introduced by other parts of more complex glycans.


Effects of perinatal, late foetal, and early embryonic insults on the cardiovascular phenotype in experimental animal models and humans.
Cardiovascular diseases are the main cause of mortality and morbidity in Western countries, but the underlying mechanisms are still poorly understood. Genetic polymorphisms, once thought to represent a major determinant of cardiovascular risk, individually and collectively, only explain a tiny fraction of phenotypic variation and disease risk in humans. It is now clear that non-genetic factors, i.e., factors that modify gene activity without changing the DNA sequence and that are sensitive to the environment can cause important alterations of the cardiovascular phenotype in experimental animal models and humans. Here, we will review recent studies demonstrating that distinct pathological events during the perinatal (transient perinatal hypoxemia), late foetal (preeclampsia), and early embryonic (assisted reproductive technologies) periods induce profound alterations of the cardiovascular phenotype in humans and experimental animals. Moreover, we will provide evidence that epigenetic modifications are contributing importantly to this problem and are conferring the potential for its transmission to subsequent generations.


Impact of a Province-wide Endometrial Cancer Guideline on Daily Practice.
Most women are managed by a general gynaecologist rather than being centralized in an oncogynaecology unit, resulting in different clinical management. In 2006, a hub & spoke model was introduced in the Provincial Healthcare System of Reggio Emilia, and shared guidelines were written. We aimed to verify the adherence to guidelines and the consequent improvements in quality care. All patients who underwent a hysterectomy for endometrial cancer in the Reggio Emilia Province hospitals from 2000 to 2016 were included in the study. Clinical and pathological data were carefully recorded for each patient included. This study included 132 and 277 patients in the periods before and after the implementation of the guideline, respectively. In the post-guideline period, the use of hysteroscopy, magnetic resonance, laparoscopy and adjuvant treatment significantly increased. Common shared guidelines and a clinical audit can help in improving centralization, resulting in an increased quality of care.


Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress.
Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors.


Recent advances in chronic visceral pain.
Chronic visceral pain is one of the most common causes of morbidity in the general population. Despite a gargantuan effort from academia and the pharmaceutical industry, an integrated understanding of the pathophysiological mechanisms of chronic visceral pain, particularly with respect to functional gastrointestinal disorders, remains incomplete. Advances in our understanding of the structure and function of the microanatomy of nociception has led to the identification of a number of ion channels, neurotransmitter receptors and trophic factors that may be intimately involved in chronic visceral pain. These advances have been paralleled with those in the fields of genetics, neurophysiology and functional neuroimaging. These advances have allowed the objective assessment of central processing of visceral sensation and furthermore the factors that may modulate this process in health and disease. These findings have important implications for the future direction of research. The real challenge for the future progress is to further characterize patients with chronic visceral pain in terms of their clinical phenotype, genotyping and nociceptive physiology on an individual basis towards the development of more efficacious therapeutic strategies.


[Complex results of investigating the quality of life after rectal surgery].
The recent development of rectal surgery is related to the possibility of avoiding permanent stoma formation, which is presumably believed to be the main factor that decreases quality of life. Despite the modern views of the disease, the adequacy of complex treatment and the technical improvements, low anastomoses often result in poor bowel function. The subjective perception of health is changed for these patients. There arises the question of adequacy of operative approach. The aim of our investigation was analysis of the present QoL data of patients treated in the Specialized Oncology Hospital of Veliko Tarnovo. The quality of life of 173 patients was examined with the help of EORTC questionnaires QLQ C30 and QLQ C38. The comparison is between a group with high anterior resection (N1 = 50-28.9%), a group with low sphincter-sparing operation (N2 = 59-34.3%) and primary extirpated patients (N3 = 53-30.8%). They were questioned preoperatively, in an early and late aspect, as well as before prophylactic stoma closure. The high resected patients present the best QoL values. Performing the extirpation leads to significant preoperative drop and a good adaptation afterwards. Their indexes are not much different from anterior resection group. Compared with the low technique group considerable improvement as regards the scales social functioning and global health status (P < 0.05) was observed. This group has high values of general and specific symptomology (pain, constipation, diarrhea, dyspnoea, financial difficulties, defecational problems and sexual dysfunction) generating low QoL. Their recovery is prolongated in relation with the drop of the modules before the prophylactic stoma closure. The best health perception available after treating the rectum carcinoma is for high located tumors. We recon that for patients with extirpation techniques and primary stoma formation there is no objective data of QoL decrease. In comparison, the group with low rectal resections had to undergo another operative intervention, and there were some specific complications and following poor function reducing quality of life. The requirement for very precise selection of patients must be fulfilled.


Longitudinal Patterns in Adolescent Intentions to Seek Help for Dating Violence: A Latent Transition Analysis.
As a persistent public health problem affecting thousands of adolescents every year, teen dating violence has been studied extensively. However, gaps remain in the knowledge on what adolescents think about seeking help for violence in a dating relationship and how these attitudes might change over time. This study adopts a longitudinal person-oriented approach to explore configurations of help-seeking preferences in a sample of rural adolescents (N at wave 1 = 580, Mage = 13 years, SD = 1.48; 52.7% female; 46.6% African American, 39.4% White, 14% Hispanic and other minorities), surveyed annually for four years, with each assessment approximately 12 months apart. Latent class analyses uncovered variation in adolescents' willingness to disclose dating violence, captured by six groups: (a) Multi-help-seekers (19%), (b) Reluctant help-seekers (15%), (c) Selective help-seekers (16%), (d) Parent confidants (11%), (e) Friends confidants (22%), and (f) Moderate help-seekers (17%). Follow-up analyses revealed that select sociodemographic characteristics (age, gender, and family income) were unevenly distributed among the identified groups, pointing to the need to account for individual and contextual influences in understanding heterogeneity in help-seeking attitudes. Latent transition models further showed that although individual membership in latent classes was generally stable between middle and high school, transitions between help-seeking classes were common as well. The article concludes by discussing these findings in the context of further research and programming to promote help-seeking among developing adolescents, including targeted strategies to address the needs of adolescents who think differently about disclosing dating abuse.


Cardiovascular effects of varying G-suit pressure and coverage during +1 Gz positive pressure breathing.
With the continued evolution of anti-G suits, used to counter the cardiovascular dysfunction arising from +1 Gz hypoxia protection positive pressure breathing (PPB), it was hypothesized that full-coverage anti-G-suits would offer equal protection while using lower inflation pressures than the traditional 4:1 ratio. Nine experienced subjects were exposed to 2 min of 70 mm Hg PPB while wearing either the COMBAT EDGE (CE) and Tactical Life Support System (TLSS) garments with the G-suit inflated to 4 x breathing pressure, and the Advanced Tactical Anti-G-Suit (ATAGS) at 4, 3, 2, and 1 x the breathing pressure. All subjects were measured with impedance cardiography (IC), and six were measured simultaneously with both IC and the Cardioscint nuclear probe. IC-estimated stroke volume, relative left ventricular (LV) end-diastolic volume, LV ejection fraction, and peak filling rate were depressed most in the CE and ATAGS 1 conditions (p < 0.001). Heart rate and mean arterial blood pressure changes were highest and lowest, respectively, using the CE and ATAGS 1 garments (p < 0.001). There were no differences in these variables between the TLSS and ATAGS 2-4 conditions. Thus, protection against the PPB-induced fall in LV preload and cardiovascular function may still be adequately afforded by lower G-suit inflation pressures when using full-coverage anti-G suits during PPB intended for high altitude-protection.


Study of early detection of cardiovascular risk factors in children born small (SGA) and review of literature.
Many children are born small for gestational age (SGA), due to intrauterine growth retardation (IUGR) and in recent years we have witnessed an increase in the prevalence of this problem. In our region, Aragon, 5% of children (between 550-600 per year) are born SGA, which represents a serious public health problem. Some studies have suggested that these patients have a higher risk of suffering from high blood pressure (HBP), dyslipidemia, obesity, insulin resistant diabetes and atherosclerosis in adulthood. Nevertheless other publications do not support this hypothesis, so given the lack of consensus on the potential risks of this situation, we believed it would be interesting to study, at an early stage of life, whether a sample of children born SGA would present greater cardiovascular risk factors than children born with an adequate weight for gestational age (AGA).


The ScRALF3 secreted peptide is involved in sporophyte to gametophyte signalling and affects pollen mitosis I.
Signalling events through small peptides are essential in multiple aspects of plant reproduction. The ScRALF3 Solanum chacoense Rapid Alkalinization Factor (RALF) peptide was previously shown to regulate multiple aspects of cell-cell communication between the surrounding sporophytic tissue and the female gametophyte during ovule development. We analysed the global expression pattern of ScRALF3 with GUS reporter gene under control of the ScRALF3 promoter and validated it with in situ hybridisation. To better understand the role of ScRALF3 we used three different RNA interference (RNAi) lines that reduced the expression of ScRALF3 during pollen development. Both expression methods showed the presence of ScRALF3 in different tissues, including stigma, style, vascular tissues and during stamen development. Down-regulation of ScRALF3 expression through RNAi showed drastic defects in early stages of pollen development, mainly on the first mitosis. These results suggest that the ScRALF3 secreted peptide regulates the transition from sporogenesis to gametogenesis in both male and female gametophytes.


Placebos in clinical practice and research.
The main current application of placebo is in clinical research. The term placebo effect refers to diverse non-specific, desired or non-desired effects of substances or procedures and interactions between patient and therapist. Unpredictability of the placebo effect necessitates placebo-controlled designs for most trials. Therapeutic and diagnostic use of placebo is ethically acceptable only in few well-defined cases. While "therapeutic" application of placebo almost invariably implies deception, this is not the case for its use in research. Conflicts may exist between the therapist's Hippocratic and scientific obligations. The authors provide examples in neuropsychiatry, illustrating that objective scientific data and well-considered guidelines may solve the ethical dilemma. Placebo control might even be considered an ethical obligation but some provisos should be kept in mind: (a) no adequate therapy for the disease should exist and/or (presumed) active therapy should have serious side-effects; (b) placebo treatment should not last too long; (c) placebo treatment should not inflict unacceptable risks, and (d) the experimental subject should be adequately informed and informed consent given.


Potential Dependence of Electrochemical Barriers from ab Initio Calculations.
We present a simple and computationally efficient method to determine the potential dependence of the activation energies for proton-electron transfer from a single ab initio barrier calculation. We show that the potential dependence of the activation energy is given by the partial charge transferred at the transition state. The method is evaluated against the potential dependence determined explicitly through multiple calculations at varying potential. We show that the transfer coefficient is given by the charge transferred from the initial to transition state, which has significant implications for electrochemical kinetics.


Inequities in access to VA'S aid and attendance enhanced pension benefit to help Veterans pay for long-term care.
To examine characteristics that are associated with receipt of Aid and Attendance (A&A), an enhanced pension benefit for Veterans who qualify on the basis of needing daily assistance, among Veterans who receive pensions. Secondary data analysis of 2016-2017 national VA administrative data linked with Medicare claims. Observational study examining sociodemographic, medical, and healthcare utilization characteristics associated with receipt of A&A among Veterans receiving pension. In 2017, 9.7% of Veterans with pension newly received the A&A benefit. The probability of receiving A&A among black and Hispanic pensioners was 4.6 percentage points lower than for white pensioners (95%CI = -0.051, -0.042). Married Veterans receiving pension had a 4.4-percentage point higher probability of receiving A&A (95%CI = 0.039, 0.048). Most indicators of need for assistance (eg, home health utilization, dementia, stroke) were associated with significantly higher probabilities of receiving A&A, with notable exceptions: pensioners with a diagnosis of Post-Traumatic Stress Disorder (marginal effect = -0.029 95%CI = -0.037, -0.021) or enrolled in Medicaid (marginal effect = -0.053, 95%CI = -0.057, -0.050) had lower probabilities of receiving A&A. Unadjusted and adjusted rates of receiving A&A among Veterans receiving pension varied by VA medical center. This study identified potential inequities in receipt of the A&A enhanced pension among a sample of Veterans receiving pension. Increased Veteran outreach, provider education, and VA office coordination can potentially reduce inequities in access to this benefit.


The Gut Microbiome, Seleno-Compounds, and Acute Myocardial Infarction.
Background: Gut microbiome alterations might be considered a metabolic disorder. However, the relationship between the microbiome and acute myocardial infarction (AMI) has not been properly validated. Methods: The feces of 44 subjects (AMI: 19; control: 25) were collected for fecal genomic DNA extraction. The variable region V3−V4 of the 16S rRNA gene was sequenced using the Illumina MiSeq platform. The metabolite amounts were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways. Results: The bacteria were more enriched in the AMI group both in the observed operational taxonomic units (OTUs) and faith phylogenetic diversity (PD) (p-value = 0.01 and <0.001 with 95% CI, individually). The Selenomonadales were less enriched in the AMI group at the family, genus, and species levels (all linear discriminant analysis (LDA) scores > 2). Seleno-compounds were more abundant in the AMI group at the family, genus, and species levels (all LDA scores > 2). Conclusions: This is the first study to demonstrate the association of Selenomonadales and seleno-compounds with the occurrence of AMI. Our findings provide an opportunity to identify a novel approach to prevent and treat AMI.


Cloning of the VASP (vasodilator-stimulated phosphoprotein) genes in human and mouse: structure, sequence, and chromosomal localization.
The genes encoding the vasodilator-stimulated phosphoprotein (VASP) in human and mouse were isolated, and major parts were sequenced. In both species the gene is composed of 13 exons with conserved exon-intron positions. The mouse VASP cDNA sequence was deduced from the genomic sequence. The predicted amino acid sequence is 89% identical to the human protein. The high nucleotide sequence homology extends not only over the coding regions but also into the 3'-UTRs, indicating a possible function in mRNA targeting or regulation of translation. Prominent 5' CpG islands including multiple SP1 sites indicate a housekeeping function of VASP. Using cosmid DNA as a probe for fluorescence in situ hybridization, the human VASP gene was assigned to chromosome 19q13.2-q13.3, an extended region with homology to mouse chromosome 7. A sequence overlap of the VASP 5'-region with the telomeric end of a cosmid contig physically links the VASP gene with ERCC1. VASP is located about 92 kb distal to ERCC1 and about 300 kb proximal to the myotonic dystrophy protein kinase gene.


Spontaneous massive splenic infarction in the setting of renal transplant and septic shock: a case report and review of the literature.
Massive splenic infarction (MSI) is a rare phenomenon that results from compromised blood flow to more than half of the spleen. Causes of MSI include hematological disorders, coagulopathies, infection, and embolization, and, rarely, MSI is spontaneous. The mainstay of treatment is splenectomy. We report the case of a 50-year-old man with a history of renal transplant who presented with diffuse abdominal pain and rapidly developed septic shock. A computed tomographic study (CT scan) of the abdomen demonstrated MSI. The surgical team was consulted for splenectomy but conservative management was maintained and immune function preserved. The patient's clinical condition was resolved over a three-week period. This report demonstrates successful nonoperative management of a spontaneous MSI most likely secondary to hypoperfusion and a hypercoagulable state from both septic shock and renal transplant.


Multiple ice-age refugia in Pacific cod, Gadus macrocephalus.
Pleistocene ice-ages greatly influenced the historical abundances of Pacific cod, Gadus macrocephalus, in the North Pacific and its marginal seas. We surveyed genetic variation at 11 microsatellite loci and mitochondrial (mt) DNA in samples from twelve locations from the Sea of Japan to Washington State. Both microsatellite (mean H = 0.868) and mtDNA haplotype (mean h = 0.958) diversities were large and did not show any geographical trends. Genetic differentiation between samples was significantly correlated with geographical distance between samples for both microsatellites (FST = 0.028, r(2) = 0.33) and mtDNA (FST = 0.027, r(2) = 0.18). Both marker classes showed a strong genetic discontinuity between northwestern and northeastern Pacific populations that likely represents groups previously isolated during glaciations that are now in secondary contact. Significant differences appeared between samples from the Sea of Japan and Okhotsk Sea that may reflect ice-age isolations in the northwest Pacific. In the northeast Pacific, a microsatellite and mtDNA partition was detected between coastal and Georgia Basin populations. The presence of two major coastal mtDNA lineages on either side of the Pacific Ocean basin implies at least two ice-age refugia and separate postglacial population expansions facilitated by different glacial histories. Northward expansions into the Gulf of Alaska were possible 14-15 kyr ago, but deglaciation and colonization of the Georgia Basin probably occurred somewhat later. Population expansions were evident in mtDNA mismatch distributions and in Bayesian skyline plots of the three major lineages, but the start of expansions appeared to pre-date the last glacial maximum.


Sympathetic Skin Response and Vasomotor Symptoms in Postmenopausal Osteoporotic Women.
Osteoporosis is a common disease characterized by reduction in bone mass, due to depletion of calcium and bone protein. A pivotal role of the sympathetic nervous system in bone remodeling has been considered. On the other hand, elevated central sympathetic activation in postmenopausal women is involved in the creation of vasomotor symptoms. Also, sympathetic skin response (SSR) has been performed for evaluation of the peripheral and central autonomic nervous system dysfunctions. Therefore, to determine the association of the autonomic nervous system and osteoporosis, we evaluated the correlation between the bone mineral density (BMD) with the frequency of vasomotor symptoms and also sympathetic skin responses. This is a cross-sectional study in which thirty-three postmenopausal osteoporosis women, as the case group, and 31 age-matched postmenopausal women with normal BMD, as the control group, were included in our study. To evaluate the autonomic function, we assessed the frequency of vasomotor symptoms with a questionnaire and performed SSR test for the two groups. According to the parametrical or the nonparametrical distribution of the data, Independent Samples t-test or Mann Whitney test, respectively, were used to compare group differences. The onset latencies of SSR recorded from both hands and feet were significantly prolonged in the case group compared with the control group (P<0.001). Amplitudes of SSR in the case group were significantly less than those of the control group (P<0.001). The postmenopausal osteoporotic women reported a significantly higher frequency of hot flashes and night sweats when compared with non-osteoporotic women (P<0.001). The higher frequency of vasomotor symptoms and impaired sympathetic skin responses in postmenopausal osteoporotic women suggests a role of autonomic dysfunction in osteoporosis.


LIN28B Polymorphisms Confer a Higher Postoperative Recurrence Risk in Reproductive-Age Women with Endometrial Polyps.
The RNA-binding protein LIN28B is an important factor for cell proliferation. Because LIN28B polymorphisms have been shown to be relative with the recurrence of some hyperplastic diseases, we hypothesized that genetic variants of LIN28B gene were associated with postoperative recurrence risk in reproductive-age women with endometrial polyps (EP). In a hospital-based cohort of 351 reproductive female patients underwent hysteroscopic polypectomies between May 2018 and Jan 2020, we genotyped two common polymorphisms in LIN28B gene (rs369065 C > T and rs314280 A > G) and analyzed their associations with the risk of postoperative recurrence in multiple Cox regression model. When followed up to Jun 2021, carries of rs369065 TT genotype had an increased risk of polyp recurrence (adjusting hazard ratio [HR] = 1.883, 95% confidence interval [CI] = 1.033 - 3.434) and had a shorter time to recurrence (median time 352 vs. 342 days, log-rank P < 0.01), compared to the CC/CT genotype. Further stratification analysis showed that the increased risk of rs369065 TT genotype was more evident in patients who were older than 33 years (adjusted HR = 2.597, 95%CI = 1.037 - 6.505), had a single polyp (adjusted HR = 2.545, 95%CI = 1.059 - 6.113), and had smaller polyps (<1.2 cm, adjusted HR = 2.708, 95%CI = 1.042 - 7.043). However, no significant association between rs314280 A > G polymorphism and the risk of polyp recurrence was found. Our study suggests that rs369065 TT genotype of LIN28B gene is associated with an increased postoperative recurrence risk in EP patients, especially in those with fewer and smaller polyps. These findings implicate a precise choice of clinical counseling and decision making. Larger studies in different ethnic populations are warranted.


Clamp-crushing versus stapler hepatectomy for transection of the parenchyma in elective hepatic resection (CRUNSH)--a randomized controlled trial (NCT01049607).
Hepatic resection is still associated with significant morbidity. Although the period of parenchymal transection presents a crucial step during the operation, uncertainty persists regarding the optimal technique of transection. It was the aim of the present randomized controlled trial to evaluate the efficacy and safety of hepatic resection using the technique of stapler hepatectomy compared to the simple clamp-crushing technique. The CRUNSH Trial is a prospective randomized controlled single-center trial with a two-group parallel design. Patients scheduled for elective hepatic resection without extrahepatic resection at the Department of General-, Visceral- and Transplantation Surgery, University of Heidelberg are enrolled into the trial and randomized intraoperatively to hepatic resection by the clamp-crushing technique and stapler hepatectomy, respectively. The primary endpoint is total intraoperative blood loss. A set of general and surgical variables are documented as secondary endpoints. Patients and outcome-assessors are blinded for the treatment intervention. The CRUNSH Trial is the first randomized controlled trial to evaluate efficacy and safety of stapler hepatectomy compared to the clamp-crushing technique for parenchymal transection during elective hepatic resection. ClinicalTrials.gov: NCT01049607.


Evaluation of novel HIV vaccine candidates using recombinant vesicular stomatitis virus vector produced in serum-free Vero cell cultures.
Acquired Immune Deficiency Syndrome (AIDS) in humans is a result of the destruction of the immune system caused by Human Immunodeficiency Virus (HIV) infection. This serious epidemic is still progressing world-wide. Despite advances in treatment, a safe and effective preventive HIV vaccine is desired to combat this disease, and to save millions of lives. However, such a vaccine is not available yet although extensive amounts of resources in research and development have been invested over three decades. In light of the recently approved Ebola virus disease vaccine based on a recombinant vesicular stomatitis virus (rVSV-ZEBOV), we present the results of our work on three novel VSV-vectored HIV vaccine candidates. We describe the design, rescue, production and purification method and evaluate their immunogenicity in mice prior to preclinical studies that will be performed in non-human primates. The production of each of the three candidate vaccines (rVSV-B6-NL4.3Env/SIVtm, rVSV-B6-NL4.3Env/Ebtm and rVSV-B6-A74Env(PN6)/SIVtm) was evaluated in small scale in Vero cells and it was found that production kinetics on Vero cells vary depending on the HIV gp surface protein used. Purified virus preparations complied with the WHO restrictions for the residual DNA and host cell protein contents. Finally, when administered to mice, all three rVSV-HIV vaccine candidates induced an HIV gp140-specific antibody response.


Suaeda monoica, a C(4) Plant without Typical Bundle Sheaths.
Suaeda monoica Forssk. ex J. F. Gmel was found to possess the C(4) pathway of photosynthesis. The succulent leaves of Suaeda lack a green bundle sheath formation but have a layer of chlorenchyma, containing large and centripetally arranged chloroplasts, which surrounds the water tissue. We suggest that the proximity of a chlorenchymatous cell layer to the vascular bundles is not necessary for the operation of the C(4) pathway.


CADe system integrated within the electronic health record.
The latest technological advances and information support systems for clinics and hospitals produce a wide range of possibilities in the storage and retrieval of an ever-growing amount of clinical information as well as in detection and diagnosis. In this work, an Electronic Health Record (EHR) combined with a Computer Aided Detection (CADe) system for breast cancer diagnosis has been implemented. Our objective is to provide to radiologists a comprehensive working environment that facilitates the integration, the image visualization, and the use of aided tools within the EHR. For this reason, a development methodology based on hardware and software system features in addition to system requirements must be present during the whole development process. This will lead to a complete environment for displaying, editing, and reporting results not only for the patient information but also for their medical images in standardised formats such as DICOM and DICOM-SR. As a result, we obtain a CADe system which helps in detecting breast cancer using mammograms and is completely integrated into an EHR.


A wearable system to assist walking of Parkinson s disease patients.
About 50% of the patients with advanced Parkinson's disease (PD) suffer from freezing of gait (FOG), which is a sudden and transient inability to walk. It often causes falls, interferes with daily activities and significantly impairs quality of life. Because gait deficits in PD patients are often resistant to pharmacologic treatment, effective non-pharmacologic treatments are of special interest. The goal of our study is to evaluate the concept of a wearable device that can obtain real-time gait data, processes them and provides assistance based on pre-determined specifications. We developed a real-time wearable FOG detection system that automatically provides a cueing sound when FOG is detected and which stays until the subject resumes walking. We evaluated our wearable assistive technology in a study with 10 PD patients. Over eight hours of data was recorded and a questionnaire was filled out by each patient. Two hundred and thirty-seven FOG events have been identified by professional physiotherapists in a post-hoc video analysis. The device detected the FOG events online with a sensitivity of 73.1% and a specificity of 81.6% on a 0.5 sec frame-based evaluation. With this study we show that online assistive feedback for PD patients is possible. We present and discuss the patients' and physiotherapists' perspectives on wearability and performance of the wearable assistant as well as their gait performance when using the assistant and point out the next research steps. Our results demonstrate the benefit of such a context-aware system and motivate further studies.


Cross-sectional hardness of enamel from human teeth at different posteruptive ages.
This study evaluated, by cross-sectional hardness (CSH), enamel maturation at different depths in sound human teeth at different posteruptive ages (12 per age group): unerupted (molars; control), 2-3 years (premolars), 4-10 years (premolars) and >10 years (molars). Cross-sectional Knoop hardness was measured at 10, 30, 50, 70, 90, 110, 220 and 330 mm depth from the surface. The data were subjected to two-way ANOVA followed by Bonferroni's pairwise tests (a = 0.05). The CSH significantly increased with posteruptive age, indicating that the time of exposure in the oral cavity might result in deep enamel maturation.


Validation of a manual ability questionnaire in patients with systemic sclerosis.
To adapt and validate a manual ability questionnaire, the ABILHAND, developed through the Rasch methodology in patients with systemic sclerosis (SSc). The original version of the ABILHAND, which includes 81 manual daily activities, was presented to 156 patients with SSc. They were asked to provide their perceived difficulty in performing each manual activity on a 3-level scale: impossible, difficult, or easy. Items were selected from well-established psychometric criteria. The patients were reassessed 1 month later to test the reproducibility. Concomitantly, they were clinically evaluated for their disease activity/severity, and their functional ability was tested with the Health Assessment Questionnaire (HAQ). The 26 selected items defined a unidimensional and linear measure of manual ability and showed a continuous progression in their difficulty. The item difficulty hierarchy was invariant across 12 patient-related factors and the manual ability score was reproducible over time. Finally, the manual ability was significantly poorer in SSc patients with more severe disease, and was negatively correlated with the HAQ score (rho = -0.733). The SSc-adapted ABILHAND questionnaire is a reliable, valid, reproducible, linear, and unidimensional measure to assess and followup on the manual ability of patients with SSc; therefore, it could become a useful additional tool in clinical trials to assess treatment efficacy.


Testing and estimation in flexible group sequential designs with adaptive treatment selection.
Integrating selection and confirmation phases into a single trial can expedite the development of new treatments and allows to use all accumulated data in the decision process. In this paper we review adaptive treatment selection based on combination tests and propose overall adjusted p-values and simultaneous confidence intervals. Also point estimation in adaptive trials is considered. The methodology is illustrated in a detailed example based on an actual planned study.


CaLB Catalyzed Conversion of ε-Caprolactone in Aqueous Medium. Part 1: Immobilization of CaLB to Microgels.
The enzymatic ring-opening polymerization of lactones is a method of increasing interest for the synthesis of biodegradable and biocompatible polymers. In the past it was shown that immobilization of Candida antarctica lipase B (CaLB) and the reaction medium play an important role in the polymerization ability especially of medium ring size lactones like ε-caprolactone (ε-CL). We investigated a route for the preparation of compartmentalized microgels based on poly(glycidol) in which CaLB was immobilized to increase its esterification ability. To find the ideal environment for CaLB, we investigated the acceptable water concentration and the accessibility for the monomer in model polymerizations in toluene and analyzed the obtained oligomers/polymers by NMR and SEC. We observed a sufficient accessibility for ε-CL to a toluene like hydrophobic phase imitating a hydrophobic microgel. Comparing free CaLB and Novozym® 435 we found that not the monomer concentration but rather the solubility of the enzyme, as well as the water concentration, strongly influences the equilibrium of esterification and hydrolysis. On the basis of these investigations, microgels of different polarity were prepared and successfully loaded with CaLB by physical entrapment. By comparison of immobilized and free CaLB, we demonstrated an effect of the hydrophobicity of the microenvironment of CaLB on its enzymatic activity.


Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2.
Mutations in leucine-rich repeat kinase 2 (LRRK2) that increase its kinase activity associate with familial forms of Parkinson disease (PD). As phosphorylation determines the functional state of most protein kinases, we systematically mapped LRRK2 phosphorylation sites by mass spectrometry. Our analysis revealed a high degree of constitutive phosphorylation in a narrow serine-rich region preceding the LRR-domain. Allowing de novo autophosphorylation of purified LRRK2 in an in vitro autokinase assay prior to mass spectrometric analysis, we discovered multiple sites of autophosphorylation. Solely serine and threonine residues were found phosphorylated suggesting LRRK2 as a true serine threonine kinase. Autophosphorylation mainly targets the ROC GTPase domain and its clustering around the GTP binding pocket of ROC suggests cross-regulatory activity between kinase and Roc domain. In conclusion, the phosphoprotein LRRK2 functions as an autocatalytically active serine threonine kinase. Clustering of phosphosites within two discrete domains suggest that phosphorylation may regulate its biological functions in a yet unknown fashion.


Hospital- and community-based screenings for hepatocellular carcinoma in Taiwan.
In Taiwan, hepatocellular carcinoma (HCC) has been the leading cause of cancer incidence and mortality in recent decades. The majority of patients have hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The HBV carrier rate and incidence of HCC in children have declined with the implementation of a hepatitis B vaccination program for newborns since 1984. A combination of α-fetoprotein and ultrasonography (US) has been used for surveillance in patients with chronic HBV and HCV infection in intervals of 3-6 and 6-12 months for cirrhosis and chronic liver disease, respectively. A secular survival improvement in HCC patients has been demonstrated. A reasonable screening protocol should include two stages. The first stage is identification of high-risk subjects and the second stage is US screening of high-risk subjects. Community-based HCC screening programs have been conducted for more than two decades in Taiwan. The commonly used first-stage markers are HBsAg and anti-HCV, while the platelet count should be a useful marker in HCV-endemic communities. The benefit of HCC screening was shown by a prolonged overall survival. However, this was limited to the early curable stage in elderly subjects. Prevention and control of HCC have multiple modalities. Identification of a high-risk group for active surveillance, effective antiviral treatment for chronic HBV and HCV infection, and early detection and prompt treatment of HCC should decrease the sequelae of HCC in Taiwan.


Effects of wearing and removing dentures on oropharyngeal motility during swallowing.
Wearing dentures and dysphagia are common in older individuals; however, it is still unknown how dentures affect oral and pharyngeal swallowing. The purpose of this study was to reveal the effects of wearing and removing dentures on oropharyngeal movements during pharyngeal swallowing in the feeding sequence of solid food. Participants were 25 edentulous volunteers (nine men, 16 women; mean age 76·2 years) who wore complete dentures. The test food was minced agar jelly containing barium sulphate. Subjects were instructed to feed and swallow the test food with or without dentures during observation using videofluorography. We quantitatively evaluated the range, distance and duration of oropharyngeal movements during pharyngeal swallowing. When dentures were absent, the range of mandible and hyoid movements were significantly expanded in the anterosuperior direction, and the range of laryngeal movement was significantly expanded in the anterior direction. Additionally, the posterior pharyngeal wall contraction and upper oesophageal sphincter opening significantly increased. In addition, the distances of the mandible, hyoid and laryngeal movements and the mandibular duration were significantly extended when dentures were absent. No significant differences were observed in the duration of movements of other organs between wearing and removing dentures. The hyoid bone, larynx, posterior pharyngeal wall and upper oesophageal sphincter do not change their duration of movements when dentures were removed but, rather, expand their range of movement. This might be a spatial change of oropharyngeal movement to avoid temporal changes in pharyngeal swallowing when dentures were absent in edentulous older individuals.


Immunocytochemical binding to neurons of serum from spinocerebellar degeneration patients.
Antineural antibodies have been described in sera of patients with neurodegenerative disorders. We looked for the presence of those antibodies in the sera of patients with spinocerebellar degeneration. Serum IgG from four patients with familial spinocerebellar degeneration showed strong binding to cerebral cortical neurons, Purkinje cells, and dorsal root ganglia of normal human tissue sections stained with the peroxidase antiperoxidase (PAP) method at serum dilution of 1:500. No binding to neuroglia cells or cells of the granular layer of the cerebellum was seen. Sera from four immediate, asymptomatic relatives (son or sibling) showed only moderate binding to Purkinje cells and to dorsal root ganglia, but not to cortical neurons. Sera from seven patients with neurological diseases other than spinocerebellar degeneration and from five healthy subjects showed no binding to neural elements. The findings may be of value in the diagnosis and screening of patients suspected of having spinocerebellar degeneration; however, the significance of these antineural antibodies in the pathogenesis of spinocerebellar degeneration is uncertain and awaits further studies.


18F-Labeled NaF PET-CT in Detection of Bone Metastases in Patients With Preoperative Lung Cancer.
We compared the diagnostic accuracy of F-labeled sodium fluoride (F-NaF) PET-CT with 99m-technetium methylene diphosphonate (Tc-MDP) single photon emission computed tomography (SPECT) to detect bone metastases (BMs) in patients with preoperative lung cancer. Patients with lung cancer (n = 181) were examined with F-NaF PET-CT, and another 167 patients with lung cancer were examined with Tc-MDP SPECT. F-NaF PET-CT and Tc-MDP SPECT were evaluated by 2 experienced readers. Lesions were graded on a scale of 0 (degenerative lesion) to 4 (definite BM), and equivocal lesions were determined as indifferent (grade 3). Based on patient-based analysis, there were only 4 equivocal patients in F-NaF PET-CT detection. However, in Tc-MDP SPECT detection, there were 19 equivocal patients, which indicated a significant difference in terms of occurrence ratio (χ = 9.005, P = 0.03). Sensitivity and specificity of PET-CT was significantly better than that of SPECT when equivocal reading was categorized as malignant or benign (P < 0.05). Based on lesions-based analysis, SPECT produced 26 equivocal lesions of 333 lesions, but PET-CT produced only 5 equivocal lesions of 991 lesions. PET-CT was significantly better than SPECT in the aspect of producing equivocal patients (χ = 58.141, P < 0.001). Sensitivity and specificity of PET-CT was significantly better than that of SPECT when equivocal reading was categorized as malignant or benign (P < 0.05). F-NaF PET-CT is a highly sensitive and specific modality for the detection of BM in patients with preoperative lung cancer. It is better than conventional Tc-MDP SPECT in detecting BM in patients with preoperative lung cancer.


Does the location of a vascular loop in the cerebellopontine angle explain pulsatile and non-pulsatile tinnitus?
The purpose was to investigate patients with unexplained pulsatile and non-pulsatile tinnitus by means of MR imaging of the cerebellopontine angle (CPA) and to correlate the clinical subtype of tinnitus with the location of a blood vessel (in the internal auditory canal or at the cisternal part of the VIIIth cranial nerve). Clinical presentation of tinnitus and perceptive hearing loss were correlated. In 47 patients with unexplained tinnitus, an MR examination of the CPA was performed. Virtual endoscopy reconstructions were obtained using a 3D axial thin-section high-resolution heavily T2-weighted gradient echo constructive interference in steady state (CISS) data-set. High-resolution T2-weighted CISS images showed a significantly higher number of vascular loops in the internal auditory canal in patients with arterial pulsatile tinnitus compared to patients with non-pulsatile tinnitus (P<0.00001). Virtual endoscopy images were used to investigate vascular contacts at the cisternal part of the VIIIth cranial nerve in patients with low pitch and high pitch non-pulsatile tinnitus. A significantly different distribution of the vascular contacts (P=0.0320) was found. Furthermore, a correlation between the clinical presentation of non-pulsatile tinnitus (high pitch and low pitch) and the perceptive hearing loss was found (P=0.0235). High-resolution heavily T2-weighted CISS images and virtual endoscopy of the CPA can be used to evaluate whether a vascular contact is present in the internal auditory canal or at the cisternal part of the VIIIth cranial nerve and whether the location of the vascular contact correlates with the clinical subtype of tinnitus. Our findings suggest that there is a tonotopical structure of the cisternal part of the VIIIth cranial nerve. A correlation between the clinical presentation of tinnitus and hearing loss was found.


The ubiquitin E2 enzyme UBE2QL1 mediates lysophagy.
Although damaged lysosomes with ruptured membranes can be repaired, these dangerous organelles are also selectively eliminated by autophagic degradation termed lysophagy. This process is initiated by ubiquitination of lysosomal proteins. In this issue of EMBO Reports, Koerver et al [1] identify the E2 enzyme UBE2QL1 that catalyzes ubiquitination of damaged lysosomes. Without this enzyme, the clearance of ruptured lysosomes is compromised not only upon lysosomal damage but also under normal conditions, revealing its adaptive and constitutive functions.


Long-term survival of a patient with bile duct carcinoma by endoscopic biliary drainage.
An 80-yr-old female presented with obstructive jaundice. Endoscopic retrograde cholangiopancreatography showed a carcinoma in the middle extrahepatic bile duct, and a biliary endoprosthesis was inserted. Exfoliative cytology of the bile and forceps biopsy of the tumor revealed a papillary adenocarcinoma. Surgical resection could not be done because of her cardiovascular complications, and neither chemotherapy nor radiotherapy was administered. Stents were exchanged and cleaned 21 times because of occlusion and cholangitis. Subsequent serial cholangiogram showed a slow growth of the papillary tumor, but local invasion to the adjacent organs or distant metastasis was not observed. The patient survived for 7 yr and 6 months after insertion of the biliary endoprosthesis.


(2-Amino-7-methyl-4-oxidopteridine-6-carboxyl-ato-κ(3) O (4),N (5),O (6))(ethane-1,2-diamine-κ(2) N,N')(1H-imidazole-κN (3))nickel(II) dihydrate.
In the title complex, [Ni(C8H5N5O3)(C2H8N2)(C3N2H4)]·2H2O, a tridentate 2-amino-7-methyl-4-oxidopteridine-6-carboxyl-ate (pterin) ligand, a bidentate ancillary ethane-1,2-diamine (en) ligand and a monodentate 1H-imidazole (im) ligand complete a distorted octa-hedral geometry around the Ni(II) atom. The pterin ligand forms two chelate rings. Both the en and im ligands are arranged nearly orthogonally relative to the pterin ligand [dihedral angles between the mean planes of the en and pterin ligands and of the im and pterin ligands are 84.62 (9) and 85.14 (9)°, respectively]. N-H⋯N, N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds link the complex mol-ecules and lattice water mol-ecules into a three-dimensional network.


Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management.
Sitosterolemia is an autosomal recessive disorder characterized by increased plant sterol levels, xanthomas, and accelerated atherosclerosis. Although it was originally reported in patients with normolipemic xanthomas, severe hypercholesterolemia have been reported in patients with sitosterolemia, especially in children. Sitosterolemia is caused by increased intestinal absorption and decreased biliary excretion of sterols resulting from biallelic mutations in either ABCG5 or ABCG8, which encode the sterol efflux transporter ABCG5 and ABCG8. Patients with sitosterolemia show extreme phenotypic heterogeneity, ranging from almost asymptomatic individuals to those with severe hypercholesterolemia leading to accelerated atherosclerosis and premature cardiac death. Hematologic manifestations include hemolytic anemia with stomatocytosis, macrothrombocytopenia, splenomegaly, and abnormal bleeding. The mainstay of therapy includes dietary restriction of both cholesterol and plant sterols and the sterol absorption inhibitor, ezetimibe. Foods rich in plant sterols include vegetable oils, wheat germs, nuts, seeds, avocado, shortening, margarine and chocolate. Hypercholesterolemia in patients with sitosterolemia is dramatically responsive to low cholesterol diet and bile acid sequestrants. Plant sterol assay should be performed in patients with normocholesterolemic xanthomas, hypercholesterolemia with unexpectedly good response to dietary modifications or to cholesterol absorption inhibitors, or hypercholesterolemia with poor response to statins, or those with unexplained hemolytic anemia and macrothrombocytopenia. Because prognosis can be improved by proper management, it is important to find these patients out and diagnose correctly. This review article aimed to summarize recent publications on sitosterolemia, and to suggest clinical indications for plant sterol assay.


Hydroxynonenal inactivates cathepsin B by forming Michael adducts with active site residues.
Oxidation of plasma low-density lipoprotein (oxLDL) generates the lipid peroxidation product 4-hydroxy-2 nonenal (HNE) and also reduces proteolytic degradation of oxLDL and other proteins internalized by mouse peritoneal macrophages in culture. This leads to accumulation of undegraded material in lysosomes and formation of ceroid, a component of foam cells in atherosclerotic lesions. To explore the possibility that HNE contributes directly to the inactivation of proteases, structure-function studies of the lysosomal protease cathepsin B have been pursued. We found that treatment of mouse macrophages with HNE reduces degradation of internalized maleyl bovine serine albumin and cathepsin B activity. Purified bovine cathepsin B treated briefly with 15 microM HNE lost approximately 76% of its protease activity and also developed immunoreactivity with antibodies to HNE adducts in Western blot analysis. After stabilization of the potential Michael adducts by sodium borohydride reduction, modified amino acids were localized within the bovine cathepsin B protein structure by mass spectrometric analysis of tryptic peptides. Michael adducts were identified by tandem mass spectrometry at cathepsin B active site residues Cys 29 (mature A chain) and His 150 (mature B chain). Thus, covalent interaction between HNE and critical active site residues inactivates cathepsin B. These results support the hypothesis that the accumulation of undegraded macromolecules in lysosomes after oxidative damage are caused in part by direct protease inactivation by adduct formation with lipid peroxidation products such as HNE.


Alpha7 nicotinic receptor activation inhibits ethanol-induced mitochondrial dysfunction, cytochrome c release and neurotoxicity in primary rat hippocampal neuronal cultures.
Primary hippocampal neuronal cultures exhibited a concentration- and time-dependent loss of cells when exposed to ethanol (EtOH). EtOH-induced neurotoxicity was attenuated by 2,4-dimethoxybenzilidene anabaseine (DMXB) which selectively activates alpha7 nicotinic receptors in a concentration-dependent manner. We further investigated the mechanisms of the protective effect of DMXB on EtOH- induced neurotoxicity. We found that EtOH decreased the mitochondrial membrane potential and released cytochrome c from mitochondria at neurotoxic concentrations. DMXB (3 microm) attenuated both of these actions in a manner that was in turn blocked with the nicotinic antagonist methyllyconitine (MLA) 100 nm. Neither DMXB nor MLA alone affected these parameters. These results suggest that the neuroprotection conferred by alpha7 nicotinic receptor activation may be mediated, at least in part, through preventing the decrease in the mitochondrial membrane potential and the increase in the release of cytochrome c caused by EtOH.


Macromolecular structure and aggregation states of Helicobacter pylori urease.
Urease purified from Helicobacter pylori by differential ultracentrifugation and fast pressure liquid chromatography was composed of subunits with apparent molecular weights (MrS) of 66,000 and 30,000. Electron microscopy of this purified material demonstrated that it formed disc-shaped macromolecular aggregates that were approximately 13 nm in diameter and 3 nm thick. Images of both negatively stained and shadowed preparations indicated that the discs tended to stack to form pairs and then these pairs further aggregated to form four-disc stacks. This stacking of subunits explains the heterogeneity observed previously in the molecular weight of urease preparations. In some negatively stained preparations there were also some smaller (approximately 8-nm-diameter) annular units present, which may represent individual urease units or possibly an aggregate of one of the two subunits from which urease is constructed.


Gene expression of matrix metalloproteinases 1, 3, and 9 by chondrocytes in osteoarthritic human knee articular cartilage is zone and grade specific.
Matrix metalloproteinases (MMPs) are thought to be major mediators of cartilage destruction. Osteoarthritis (OA) is characterised by cartilage degradation. This study explores gene expression of three MMPs in articular chondrocytes during the histological development of the cartilage lesion of OA. Biopsy specimens of human normal and OA cartilage, classified into four grades on the basis of histology, were probed for MMPs 1, 3, and 9 using 35S-labelled cDNA probes. The signal was measured at four different depths (zones) using an automated image analyser and compared with signal from sections probed with lambda DNA. Rheumatoid synovium was used as a positive control for MMP gene expression. Rheumatoid tissue contained mRNA for all three MMPs. Expression in chondrocytes varied with the depth of the chondrocyte in the cartilage and the histomorphological extent of the OA changes. There was no detectable mRNA signal for these three MMPs in normal cartilage. In general, in OA, MMP-1 gene expression was greatest in the superficial cartilage in established disease. By contrast mRNAs for MMP-3 and 9 were expressed deeper in the cartilage, MMP-9 early in disease and MMP-3 with a biphasic pattern in early and late stage disease, most pronounced in the latter. This was a consequence of differential expression in single cells and chondrocyte clusters in late disease. The data indicate that expression of genes for MMPs 1, 3, and 9 is differentially regulated in human articular chondrocytes and, in individual cells, is related to the depth of the chondrocyte below the cartilage surface and the nature and extent of the cartilage lesion.


Proceedings of the Third Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies.
The proceedings of the 3rd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, imaging, and computational work on DBS for the treatment of neurological and neuropsychiatric disease. Significant innovations of the past year are emphasized. The Think Tank's contributors represent a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers, and members of industry. Presentations and discussions covered a broad range of topics, including policy and advocacy considerations for the future of DBS, connectomic approaches to DBS targeting, developments in electrophysiology and related strides toward responsive DBS systems, and recent developments in sensor and device technologies.


[Detection of congenital toxoplasmosis in utero with a polymerase chain reaction on amniotic fluid].
To establish a prenatal diagnosis of congenital toxoplasmosis the PCR test was done on amniotic fluids from 47 women suspected of primary Toxoplasma infection during pregnancy. Fragments of Toxoplasma B1 gene were found in 5 examined samples. Positive tests were confirmed by mouse inoculation or by serologic testing of newborns. It was concluded that the PCR performed on amniotic fluid should be recommended for the prenatal diagnosis of congenital toxoplasmosis, however, negative results of the test can not rule out congenital infection.


Common adaptive tasks facing parents of children with chronic conditions.
Parents of chronically ill or disabled children face a number of common tasks in adapting to their child's condition. These tasks are delineated from the literature on theory, research and clinical issues and are discussed in relation to their documented importance to family adaptation, the difficulties parents have in managing the tasks and effective coping strategies parents can use to accomplish the tasks. The implications of utilizing adaptive tasks as an organizing framework for assessing and intervening with parents of children with chronic conditions are discussed.


Patients With Dementia Are Easy Victims to Predators.
Patients with dementia, especially Alzheimer's disease and particularly those in early stages, are susceptible to become victims of predators: Their agnosia (see Case 1) prevents them from detecting and accurately interpreting subtle signals that otherwise would have alerted them that they are about to fall for a scam. Furthermore, their judgment is impaired very early in the disease process, often before other symptoms manifest themselves and usually before a diagnosis is made. Patients with early stages of dementia are therefore prime targets for unscrupulous predators, and it behooves caregivers and health care professionals to ensure the integrity of these patients. In this case study, we discuss how a man with mild Alzheimer's disease was about to fall for a scam were it not for his vigilant wife. We discuss what went wrong in the patient/caregiver interaction and how the catastrophic ending could have been avoided or averted.


The imaging core lab perspective on glioblastoma imaging and response assessment in clinical trials.
Multicenter clinical trials that include medical images as a key component of response assessment often involve an imaging service provider (a core laboratory or contract research organization) to collect images and often to provide independent assessments of treatment response. The brief discussion and recommendations provided here are not intended as a rigorous academic analysis but reflect the practical experience accumulated at one such institution, which has conducted the image collection and review for numerous glioblastoma trials, in every phase of drug development, encompassing over 4000 patients scanned at over 900 sites.


Host-directed therapy in foals can enhance functional innate immunity and reduce severity of Rhodococcus equi pneumonia.
Pneumonia caused by the intracellular bacterium Rhodococcus equi is an important cause of disease and death in immunocompromised hosts, especially foals. Antibiotics are the standard of care for treating R. equi pneumonia in foals, and adjunctive therapies are needed. We tested whether nebulization with TLR agonists (PUL-042) in foals would improve innate immunity and reduce the severity and duration of pneumonia following R. equi infection. Neonatal foals (n = 48) were nebulized with either PUL-042 or vehicle, and their lung cells infected ex vivo. PUL-042 increased inflammatory cytokines in BAL fluid and alveolar macrophages after ex vivo infection with R. equi. Then, the in vivo effects of PUL-042 on clinical signs of pneumonia were examined in 22 additional foals after intrabronchial challenge with R. equi. Foals infected and nebulized with PUL-042 or vehicle alone had a shorter duration of clinical signs of pneumonia and smaller pulmonary lesions when compared to non-nebulized foals. Our results demonstrate that host-directed therapy can enhance neonatal immune responses against respiratory pathogens and reduce the duration and severity of R. equi pneumonia.


Transport of proteins into chloroplasts. Requirements for the efficient import of two lumenal oxygen-evolving complex proteins into isolated thylakoids.
The 33- and 23-kDa proteins of the photosynthetic oxygen-evolving complex are synthesized in the cytosol and targeted into the thylakoid lumen by bipartite presequences. In this report, we describe conditions for the efficient import of each of these proteins by isolated pea thylakoids. Import of the 33-kDa protein requires both light and stromal extract. The probable function of the stromal extract is to provide stromal processing peptidase to remove the first "envelope transit" signal of the presequence. Import of the 23-kDa protein is also driven by light, but stromal extract is not required for import; furthermore, efficient import is still observed if the precursor is modified to completely block cleavage by residual stromal processing peptidase activity. The intermediate form of the 23-kDa protein, which is generated by incubation of the precursor protein with stromal processing peptidase, is also efficiently imported. The results indicate that the thylakoidal protein transport system can import both the precursor and intermediate forms of the 23-kDa protein, but probably only the intermediate form of the 33-kDa protein.


Offset phase locking of noisy diode lasers aided by frequency division.
For heterodyne phase locking, frequency division of the beat note between two oscillators can improve the reliability of the phase lock and the quality of the phase synchronization. Frequency division can also reduce the size, weight, power, and cost of the instrument by excluding the microwave synthesizer from the control loop when the heterodyne offset frequency is large (5 to 10 GHz). We have experimentally tested the use of a frequency divider in an optical phase-lock loop and compared the achieved level of residual phase fluctuations between two diode lasers with that achieved without the use of a frequency divider. The two methods achieve comparable phase stability provided that sufficient loop gain is maintained after frequency division to preserve the required bandwidth. We have also numerically analyzed the noise properties and internal dynamics of phase-locked loops subjected to a high level of phase fluctuations, and our modeling confirms the expected benefits of having an in-loop frequency divider.


Medicine and science in the fight against doping in sport.
The fight against doping in sports commenced as a result of the death of a Danish cyclist during the Rome Olympic Games in 1960. The International Olympic Committee (IOC) established a Medical Commission (IOC-MC) which had the task of designing a strategy to combat the misuse of drugs in Olympic Sport. Some International Sport Federations (IF) and National Sports Federations followed suit, but progress was modest until the world's best male sprinter was found doped with anabolic steroids at the Olympic Games in Seoul in 1988. Further progress was made following the cessation of the cold war in 1989 and in 1999 public authorities around the world joined the Olympic Movement in a unique partnership by creating WADA--the 'World Anti-Doping Agency'. The troubled history of the anti-doping fight from the 1960s until today is reviewed. In particular, the development of detection methods for an ever increasing number of drugs that can be used to dope is described, as are the measures that have been taken to protect the health of the athletes, including those who may need banned substances for medical reasons.


Long-Term Outcomes of Multidisciplinary Rehabilitation for Chronic Musculoskeletal Pain.
Evidence for the effectiveness of multidisciplinary rehabilitation for chronic musculoskeletal pain (CMP) has been reported but its outcomes in the longer term and in mixed groups of chronic pain patients are largely unknown. The aim of the present study was to describe the two-year outcomes of a 15-week multidisciplinary pain rehabilitation programme in patients with mixed CMP in terms of pain, activities, participation and healthcare usage. Data were recorded routinely at admission, discharge, and at three, 12 and 24 months' follow-up for all consecutive patients with CMP referred to a rehabilitation programme over a 21-month period. The 15-week multidisciplinary rehabilitation programme consisted of cognitive behavioural therapy and exercise, as well as individual and group sessions with additional treatment modalities. Assessments included the Pain Disability Index (PDI), the Pain Catastrophizing Scale (PCS), the Multidimensional Pain Inventory (MPI) and numerical scales for pain and fatigue. Moreover, the RAND-36-Item Health Survey ('RAND-36') and questions on healthcare usage and work status were administered at admission, and at 12 and/or 24 months. Paired t-tests, Wilcoxon signed-rank tests, McNemar tests and mixed-model analyses were used to analyse changes over time. A total of 165 patients were included initially [mean age 44.1 (standard deviation 12.9) years], 143 of whom (87%) were women, with data from 125 (76%) and 120 (73%) patients being available at 12 and 24 months' follow-up, respectively. All outcomes showed statistically significant improvements between admission and discharge, and at three, 12 and 24 months' follow-up (p < 0.05). At 24 months, the median number of different healthcare providers visited in the previous year had decreased significantly compared with that at admission [from a median of 4 (range 1-13) to a median of 2 (range 0-9)], and within the group of patients working at admission (50%), the proportion of those working 25 hours or more per week had increased significantly from 16% to 48%. Improvements in pain and functioning seen directly after a 15-week multidisciplinary treatment programme for patients with CMP were maintained, health care usage decreased and the number of working hours among working patients increased at 24 months' follow-up. Future studies are needed to examine if additional interventions after discharge can enhance further the favourable results. Copyright © 2016 John Wiley & Sons, Ltd.


Infectious Myelitis.
Myelitis refers to inflammation of the spinal cord which can result in a spectrum of neurologic impairment. Infectious pathogens are an important etiologic category, and can result in myelitis through direct pathogenic effect or through immune-mediated parainfection; this review focuses on the former category. The spectrum of clinical manifestations is summarized and a diagnostic workup provided to aid clinicians in developing an approach to patients presenting with symptoms suggestive of infectious myelitis. This is followed by an overview of the important viral, bacterial, parasitic, and fungal causes of infectious myelitis. The typical presentations, diagnostic modalities, and treatment approaches are outlined for key pathogens culprit in infectious myelitis to allow clinicians to promptly recognize and diagnose specific infectious etiologies of myelitis.


Tip-enhanced THz Raman spectroscopy for local temperature determination at the nanoscale.
Local temperature of a nanoscale volume is precisely determined by tip-enhanced terahertz Raman spectroscopy in the low temperature range of several tens of degrees. Heat generated by the tip-enhanced electric field is directly transferred to single-walled carbon nanotubes by heat conduction and radiation at the nanoscale. This heating modulates the intensity ratio of anti-Stokes/Stokes Raman scattering of the radial breathing mode of the carbon nanotube based on the Boltzmann distribution at elevated temperatures. Owing to the low-energy feature of the radial breathing mode, the local temperature of the probing volume has been successfully extracted with high sensitivity. The dependence of the temperature rise underneath the tip apex on the incident power coincides with the analytical results calculated by finite element method based on the tip enhancement effect and the consequent steady-state temperature via Joule heat generation. The results show that the local temperature at the nanoscale can be controlled in the low temperature range simply by the incident laser power while exhibiting a sufficiently high tip enhancement effect as an analytical tool for thermally sensitive materials (e.g., proteins, DNA). Graphical Abstract Tip-enhanced THz Raman spectroscopy detects the low frequency Raman mode both in Stokes and anti-Stokes shifts, which precisely reflects the local temperature of the sample volume.


Methanol extract of Nymphaea lotus ameliorates carbon tetrachloride-induced chronic liver injury in rats via inhibition of oxidative stress.
Nymphaea lotus (NL) is an aquatic perennial plant used traditionally in the management of various liver diseases. In this study, the protective effect of methanol extract of NL against carbon tetrachloride (CCl4)-induced chronic hepatotoxicity in rats was investigated. Male Wistar rats were assigned into six groups of five rats each. Group I received corn oil (0.5 mL p.o.) and served as control, group II received CCl4 (1 mL/kg i.p., 1:3 in corn oil), group III received NL (200 mg/kg), and groups IV, V, and VI received CCl4+NL (50, 100, and 200 mg/kg, respectively) for 6 weeks. Twenty-four hours after the last exposure, rats were bled and killed. The activities of alanine aminotransaminase (ALT), aspartate aminotransferase (AST), and levels of total bilirubin (TB) in the serum, thiobarbituric acid reactive substances (TBARS), superoxide dismutase, catalase, glutathione peroxidase (GPx) and glutathione (GSH) in the liver, and histopathology of the liver were determined using standard procedures. NL significantly (p<0.05) lowered the levels of ALT, AST, and TB and exhibited antioxidant potentials in rats exposed to CCl4 relative to the control values. Specifically, NL at 100 and 200 mg/kg significantly (p<0.05) increased CCl4-induced decrease in hepatic GSH and GPx and also decreased the level of hepatic TBARS in CCl4-intoxicated rats. Histopathological findings revealed cellular infiltration and fibrosis in rats that received CCl4 only, which were ameliorated in rats that received NL+CCl4. The data suggest that NL exhibited hepatoprotective effects in CCl4-intoxicated rats via antioxidative mechanism.


Effects of Trypanosoma brucei infection and diminazene aceturate therapy on testicular morphology and function of Nigerian local dogs.
The effects of Trypanosoma brucei infection on testicular morphology and function and the changes associated with treatment of infected dogs with diminazene aceturate were studied using fifteen Nigerian adult male dogs. The dogs were randomly assigned into three groups A, B and C consisting of five dogs each. Groups A and B were infected with 1 × 10(6) trypanosomes and group C was the uninfected control. Following infection, parasitaemia levels were monitored daily whereas the rectal temperature, body weight, packed cell volume, scrotal circumference and serum testosterone levels were monitored weekly. At parasitaemia peak, dogs in group A were orchidectomised while dogs in group B were treated with 7.0mg/kg body weight of diminazene aceturate (DA). Dogs in groups B and C were later orchidectomised on day 73 of the experiment. The harvested testes and epididymides were weighed and the epididymal sperm reserves of all the dogs determined. Also the sperm quality (mass activity, sperm motility and sperm morphology) were determined. The testes were sectioned after processing and studied histomorphologically. Acute trypanosomosis was observed following infection. The low serum testosterone levels observed from day 14 post infection (pi) gradually improved following treatment. Testicular weight, epididymal weight and sperm quality were significantly low (p<0.05) in the infected dogs when compared to the control group but gradually improved following treatment. Histomorphological studies revealed testicular degeneration characterized by depopulation of seminiferous tubules and depletion of spermatogenic cells in dogs of group A whereas the tissue sections of the testes of dogs in group B were similar to those of the control group. It was therefore concluded that infection of dogs with T. brucei adversely affected testicular morphology and function. Treatment with diminazene aceturate reversed the reproductive abnormalities caused by the parasite.


Comparative effects of T-type and L-type Ca(2+)-antagonists against noradrenaline-induced contractions of human vas deferens.
To investigate the effects of the relatively selective T-type Ca(2+)-antagonists, mibefradil and flunarizine, and the L-type Ca(2+)-antagonist, nifedipine, on the contractions of longitudinal and circular muscles of human vas deferens, to elucidate the possible involvement of T-type voltage-gated Ca(2+) channels (VOCs) in the contractile function of the tissue. Human vas deferens specimens from elective vasectomies were cut into strips of longitudinal muscle or transversely into rings of circular muscle. These were set up for tension recording and superfused with Krebs' medium (36 degrees C). Contractions were evoked by noradrenaline or high [K(+)](o) (in the presence of the L-type Ca(2+) agonist, FPL 64176) and the effects of Ca(2+) antagonists were determined. Noradrenaline (0.1-100 micromol/L) evoked rhythmic and tonic contractions of longitudinal and circular muscles, which were potently inhibited by nifedipine (<or=0.1 micromol/L). Mibefradil (1-10 micromol/L) inhibited the contractions but was comparatively more effective in longitudinal than circular muscle. Flunarizine was ineffective except against contractions to low concentrations of noradrenaline. The drugs' potencies as antagonists of L-type VOCs were determined against contractions to high K(+) (120 mmol/L in the presence of FPL 64176, 1 micromol/L). The contractions in longitudinal and circular muscle had different times to peak and decline but were inhibited comparably by nifedipine (50% inhibitory concentration, IC(50), longitudinal and circular muscle, approximately 2 nmol/L) or by mibefradil (IC(50) longitudinal muscle, 1.1 micromol/L; circular muscle, 2.4 micromol/L) and were less sensitive to flunarizine (up to 30 micromol/L). These results indicate that noradrenaline-induced contractions of human vas deferens depend primarily on nifedipine-sensitive L-type VOCs, as opposed to mibefradil/flunarizine-sensitive T-type VOCs. The effects of mibefradil and flunarizine, at concentrations found to be effective against noradrenaline-induced contractions, involve the blockade of L-type VOCs. The modest differential effect of mibefradil in longitudinal and circular muscle is discussed in relation to factors that modulate activation and drug-sensitivity of L-type VOCs.


Stability of the circular Couette flow of a ferrofluid in an axial magnetic field: influence of polydispersity.
The gap between two concentric rotating cylinders is filled with a ferrofluid. A homogeneous magnetic field is applied parallel to the cylinder axis. The stability of the circular Couette flow is analyzed with different models that take into account the polydispersity of the ferrofluid to a varying degree. Their results are compared and their merits are discussed.


Omega-hydroxyceramides are required for corneocyte lipid envelope (CLE) formation and normal epidermal permeability barrier function.
Omega-hydroxyceramides (omega-OHCer) are the predominant lipid species of the corneocyte lipid envelope in the epidermis. Moreover, their omega-esterified-derivatives (acylCer) are major components of the stratum corneum extracellular lamellae, which regulate cutaneous permeability barrier function. Because epidermal omega-OHCer appear to be generated by a cytochrome P450-dependent process, we determined the effects of a mechanism-based inhibitor of omega-hydroxylation, aminobenzotriazole (ABT), on epidermal omega-OH Cer formation and barrier function. We first ascertained that ABT, but not hydroxybenzotriazole (OHBT), a chemical relative with no P450 inhibitory activity, inhibited the incorporation of [14C]-acetate into the omega-OH-containing Cer species in cultured human keratinocytes (68.1% +/- 6.9% inhibition versus vehicle-treated controls; p < 0.001), without altering the synthesis of other Cer and fatty acid species. In addition, ABT significantly inhibited the omega-hydroxylation of very long-chain fatty acids in cultured human keratinocytes. Topical application of ABT, but not OHBT, when applied to the skin of hairless mice following acute barrier disruption by tape-stripping, resulted in a significant delay in barrier recovery (e.g., 38.3% delay at 6 h versus vehicle-treated animals), assessed as increased transepidermal water loss. The ABT-induced barrier abnormality was associated with: (i) a significant decrease in the quantities of omega-OHCer in both the unbound and the covalently bound Cer pools; (ii) marked alterations of lamellar body structure and contents; and (iii) abnormal stratum corneum extracellular lamellar membrane structures, with no signs of cellular toxicity. Furthermore, pyridine-extraction of ABT- versus vehicle-treated skin, which removes all of the extracellular lamellae, leaving the covalently attached lipids, showed numerous foci with absent corneocyte lipid envelope in ABT- versus vehicle-treated stratum corneum. These results provide the first direct evidence for the importance of omega-OHCer for epidermal permeability function, and suggest further that acylCer and/or corneocyte lipid envelope are required elements in permeability barrier homeostasis.


Dapivirine Bioadhesive Vaginal Tablets Based on Natural Polymers for the Prevention of Sexual Transmission of HIV.
Young sub-Saharan women are a group that is vulnerable to the sexual transmission of HIV. Pre-exposure prophylaxis through vaginal microbicides could provide them an option for self-protection. Dapivirine has been demonstrated to have topical inhibitory effects in HIV, and to provide protection against the sexual transmission of this virus. This paper reports on the studies into swelling behaviour, bioadhesion and release carried out on dapivirine tablets based on chitosan, locust bean gum and pectin, to select the most suitable formulation. The modified simulated vaginal fluid led to a high solubility of dapivirine and allowed the dapivirine release profiles to be characterized in sink conditions; this aqueous medium is an alternative to organic solvents, which are not a realistic option when evaluating systems whose behaviour varies in aqueous and organic media. Of the formulations evaluated, dapivirine/pectin tablets containing 290 mg of polymer and 30 mg of dapivirine present the most moderate swelling, making them the most comfortable dosage forms. Their high bioadhesive capacity would also allow the formulation to remain in the action zone and release the drug in a sustained manner, pointing to this formulation as the most promising candidate for future evaluations of vaginal microbicides for the prevention of HIV.


Increased expression of insulin-like growth factor 2 in hepatocellular carcinoma is primarily regulated at the transcriptional level.
To investigate the control mechanisms of insulin-like growth factor 2 (IGF2) gene expression, we studied 25 hepatocellular carcinomas (HCC) to compare the levels of total IGF2 mRNA and the IGF2 peptide by using in situ hybridization and immunohistochemistry, respectively. Increased expression of IGF2 mRNA and the IGF2 peptide was observed in 13 HCC. The spatial distribution and intensity of IGF2 mRNA in these 13 HCC was almost identical to that of the IGF2 peptide, which suggests that high IGF2 expression was primarily regulated at the transcriptional level. The levels of IGF2 gene expression in the 13 HCC seemed to be inversely correlated with the degree of tumor cell differentiation. Furthermore, in situ hybridization using probes specific to transcripts expressed from the IGF2 promoters P1 and P3 revealed that transcription was predominantly from P3 rather than from P1.


Continuous glucose monitoring: an Endocrine Society Clinical Practice Guideline.
The aim was to formulate practice guidelines for determining settings where patients are most likely to benefit from the use of continuous glucose monitoring (CGM). The Endocrine Society appointed a Task Force of experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, the Diabetes Technology Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. The Task Force evaluated three potential uses of CGM: 1) real-time CGM in adult hospital settings; 2) real-time CGM in children and adolescent outpatients; and 3) real-time CGM in adult outpatients. The Task Force used the best available data to develop evidence-based recommendations about where CGM can be beneficial in maintaining target levels of glycemia and limiting the risk of hypoglycemia. Both strength of recommendations and quality of evidence were accounted for in the guidelines.


Snap decisions.
Innovative ways of making children's voices heard to shape services are being supported by the Picker Institute charity as part of its Patients Accelerating Change scheme. These include photographic projects at two NHS trusts.


Targeting classrooms' emotional climate and preschoolers' socioemotional adjustment: implementation of the Chicago School Readiness Project.
Children living in low-income families are more likely to experience less self-regulation, greater behavior problems, and lower academic achievement than higher income children. To help prevent children's later socioemotional and academic difficulties, the Chicago School Readiness Project (CSRP) team implemented a clustered, randomized controlled trial (RCT) in early childhood programs with Head Start funding. Head Start sites were randomly assigned to receive CSRP services, which were offered as part of a multicomponent, classroom-based mental health intervention. Here, we provide an overview of the CSRP model, its components, and a descriptive portrait of its implementation. In so doing, we address various aspects of the implementation of three of its components: (1) the training of teachers, (2) MHCs' coaching of teachers, and (3) teachers' behavior management of children. We conclude with a discussion of factors potentially related to the implementation of CSRP and directions for future research.


beta-carotene-induced changes in RARbeta isoform mRNA expression patterns do not influence lung adenoma multiplicity in the NNK-initiated A/J mouse model.
A number of epidemiological studies have reported associations of beta-carotene plasma levels or intake with decreased lung cancer risk. However, intervention studies in smokers reported increased lung tumor rates after high long-term beta-carotene supplementation. For insight into these conflicting results, we studied the influence of beta-carotene on tobacco smoke carcinogen-induced lung cancer development in the A/J-mouse using 4-(N-Methyl-N-nitro samino)-1-(3-pyridyl)-1-butanone (NNK) as the initiator and lung adenoma multiplicity as the functional endpoint. Gene regulation of the putative tumor suppressor RARbeta in mouse lung was analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for its relevance in predicting the endpoint of lung cancer. A/J-mice achieved plasma beta-carotene levels of up to 3 micromol/L within 4 wk and up to 6 micromol/L after 6 mo of supplementation on a diet modified to enhance beta-carotene absorption. Despite high lung beta-carotene concentrations of up to 6 micromol/kg, tumor multiplicity was not significantly affected by the beta-carotene treatment, either in carcinogen-initiated or non-initiated mice, and was unrelated to beta-carotene dose and the time point of treatment during cancer formation. Tumor multiplicity did not correlate with beta-carotene plasma levels in NNK-treated animals. All RARbeta isoforms were significantly suppressed in the lungs of NNK- and NNK plus high dose beta-carotene-treated animals. However, the number of tumors per mouse did not correlate with the RARbeta-isoform expression levels. beta-carotene alone after 3 mo of supplementation mildly but significantly increased levels of RARbeta1, beta2, and beta4. This increase persisted for 6 mo for RARbeta2 and beta4. In summary, we found no effect of beta-carotene on tumor formation in the NNK-initiated A/J-mouse lung cancer model with respect to dose or time point of treatment. beta-Carotene-induced changes in RARbeta isoform gene expression levels were not predictive for the number of lung tumors but were indicative of intact beta-carotene metabolism and persistent sensitivity to retinoic acid in the mice. Down-regulation of RARbeta in NNK-induced adenoma-bearing lungs was similar to that observed in human lung cancer and further confirms the A/J-mouse as a valuable model for lung carcinogenesis.


Evaluation of a distance consulting service based on interactive video and integrated computerized technology.
Telemedicine equipment was installed at a rural site in Drumheller and at Calgary, 85 miles (136 km) away. It allowed consultation between health-care providers at Drumheller and specialists and subspecialists at the Faculty of Medicine in Calgary. The efficacy of the system in providing more equitable access to health care for persons living in geographically remote sites was evaluated during a 12-month pilot project. Seventy-five encounters were attempted during the study. A total of 55 encounters (42 clinical and 13 non-clinical) were completed. The completed clinical encounters were distributed across a wide spectrum of medical specialties. Users of the system reported favourably on the impact of the telemedicine system on access to health services for rural patients, on diagnostic, investigative and management decisions, on patient and physician travel times, on feelings of professional isolation and educational opportunities and on overall patient health status. The study provides new knowledge and demonstrates the success of the technology in this project. As expected, other problems were raised and addressed in a preliminary manner including: the potential for health-provider education; acquisition and retention of rural physicians; ethical, legal and patient confidentiality issues; minimum acceptable technology; and network management issues.


Immunohistochemical analysis of thyroid-specific transcription factors in thyroid tumors.
Thyroid transcription factor 1 (TTF1), thyroid transcription factor 2 (TTF2) and paired box gene 8 (Pax8) are demonstrated to play a crucial role for the differentiation and organogenesis of thyroid follicular cells. Their roles in thyroid carcinogenesis are not very clear. Because dedifferentiation is a common process in thyroid carcinogenesis, thyroid-specific transcription factors seem also to be involving in thyroid carcinogenesis. The purpose of the present paper was to investigate their expression in a broad spectrum of follicular cell tumors in different degrees of differentiation, from well-differentiated benign follicular adenoma to anaplastic carcinoma. Medullary (C cell) carcinoma was also included in the investigation. Results of immunohistochemical staining showed that nuclear localization of these transcription factors was gradually decreased corresponding to the progressive dedifferentiation of thyroid tumors. Also, abnormal cytoplasmic accumulation of TTF2 and Pax8 was detected in many tumors samples, which may indicate a subtle regulation mechanism on the function of these transcription factors. In conclusion, abnormal expression of TTF1, TTF2 and Pax8 was closely related to thyroid tumorigenesis.


Antiphase synchronization in a flagellar-dominance mutant of Chlamydomonas.
Groups of beating flagella or cilia often synchronize so that neighboring filaments have identical frequencies and phases. A prime example is provided by the unicellular biflagellate Chlamydomonas reinhardtii, which typically displays synchronous in-phase beating in a low-Reynolds number version of breaststroke swimming. We report the discovery that ptx1, a flagellar-dominance mutant of C. reinhardtii, can exhibit synchronization in precise antiphase, as in the freestyle swimming stroke. High-speed imaging shows that ptx1 flagella switch stochastically between in-phase and antiphase states, and that the latter has a distinct waveform and significantly higher frequency, both of which are strikingly similar to those found during phase slips that stochastically interrupt in-phase beating of the wild-type. Possible mechanisms underlying these observations are discussed.


[Severe Head Injury in Childhood: the Importance of Early Offensive Therapy].
The case report presents the case of a five-year-old boy who fell off a scooter and sustained a blow to the left temporal region of his head. During a CT examination in the district hospital he suddenly showed a deterioration in the level of consciousness. Subsequent treatment along with transport to a specialized department were aimed at preventing secondary pathological changes and maintaining pressure-volume homeostasis of the brain. High-quality controlled ventilation with effective pharmacotherapy and gentle transport were essential. At the target specialized department, cerebral oedema in the left temporal region and aspiration in the right upper lung lobe were identified. The boy was extubated after 6 hours of controlled ventilation and discharged to an intermediate care bed two days later without any serious consequences. Key words: cerebral oedema, haemodynamic swelling, severe head injury.


Treatment of Pyonephritis Complicated by Septic Shock Using Extracorporeal Device Polymyxin B-Hemoperfusion.
Direct hemoperfusion using polymyxin B-immobilized fiber (PMX-DHP) is an established treatment method for septic shock caused by Gram-negative infections. We report one instance in which PMX-DHP therapy has been used successfully in a 33-year-old woman with septic shock from urosepsis. Although there is lack of recommendations in latest Surviving Sepsis Campaign Guidelines, evidence of PMX-DHP efficacy in this subset of patients is growing.


Effects of H1 histone variant overexpression on chromatin structure.
The importance of histone H1 heterogeneity and total H1 stoichiometry in chromatin has been enigmatic. Here we report a detailed characterization of the chromatin structure of cells overexpressing either H1(0) or H1c. Nucleosome spacing was found to change during cell cycle progression, and overexpression of either variant in exponentially growing cells results in a 15-base pair increase in nucleosome repeat length. H1 histones can also assemble on chromatin and influence nucleosome spacing in the absence of DNA replication. Overexpression of H1(0) and, to a lesser extent, H1c results in a decreased rate of digestion of chromatin by micrococcal nuclease. Using green fluorescent protein-tagged H1 variants, we show that micrococcal nuclease-resistant chromatin is specifically enriched in the H1(0) variant. Overexpression of H1(0) results in the appearance of a unique mononucleosome species of higher mobility on nucleoprotein gels. Domain switch mutagenesis revealed that either the N-terminal tail or the central globular domain of the H1(0) protein could independently give rise to this unique mononucleosome species. These results in part explain the differential effects of H1(0) and H1c in regulating chromatin structure and function.


Pharmacokinetics and efficacy of carvedilol in chronic hemodialysis patients with hypertension.
The efficacy, safety, and pharmacokinetics of carvedilol were investigated in an open trial performed on six patients with hypertension and chronic renal failure requiring hemodialysis. The plasma level of unchanged carvedilol after a single dose of 10 mg reached a peak 1-5 h after administration both on days with and without hemodialysis. The drug was gradually metabolized thereafter and had almost disappeared from the plasma after 24 h. Blood pressure was lowered by carvedilol both on days with and without hemodialysis. No carvedilol passed through the dialysis membrane. During the 4-week administration period of carvedilol at 10 mg/day, assessment of plasma samples taken just prior to early morning administration demonstrated no drug accumulation. Blood pressure was well controlled during the administration period. Tolerance to the antihypertensive effect was not observed. Heart rate was not significantly changed at any time. There were no side effects in any of the patients during the trial, and laboratory parameters remained unchanged. These results indicate that carvedilol is a safe and effective antihypertensive agent for use in patients on chronic hemodialysis.


A trait emotional intelligence perspective on schema modes.
Schema modes (or modes) are a key concept in the theory underlying schema therapy. Modes have rarely been related to established models of personality traits. The present study thus investigates the associations between trait emotional intelligence (TEI) and 14 modes, and tests a global TEI-mode factors-general psychological distress mediation model. The study draws on self-report data from 173 inpatients from a German clinic for psychosomatic medicine. Global TEI correlated positively with both healthy modes (happy child and healthy adult) and negatively with 10 maladaptive modes. When modes were regressed on the four TEI factors, six (emotionality), five (well-being), four (sociability), and four (self-control) significant partial effects on 10 modes emerged. In the parallel mediation model, the mode factors internalization and compulsivity fully mediated the global TEI-general psychological distress link. Implications of the results for the integration of modes with traits in general and with TEI in particular as well as implications of low TEI as a transdiagnostic feature of personality malfunctioning are discussed.