Apolipoprotein D overexpression alters hepatic prostaglandin and omega fatty acid metabolism during the development of a non-inflammatory hepatic steatosis.
Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. Overexpression of ApoD in mouse neural tissue induces the development of a non-inflammatory hepatic steatosis in 12-month-old transgenic animals. Previous data indicates that accumulation of arachidonic acid, ApoD's preferential ligand, and overactivation of PPARγ are likely the driving forces in the development of the pathology. However, the lack of inflammation under those conditions is surprising. Hence, we further investigated the apparent repression of inflammation during hepatic steatosis development in aging transgenic animals. The earliest modulation of lipid metabolism and inflammation occurred at 6 months with a transient overexpression of L-PGDS and concomitant overproduction of 15d-PGJ2, a PPARγ agonist. Hepatic lipid accumulation was detectable as soon as 9 months. Inflammatory polarization balance varied in time, with a robust anti-inflammatory profile at 6 months coinciding with 15d-PGJ2 overproduction. Omega-3 and omega-6 fatty acids were preferentially stored in the liver of 12-month-old transgenic mice and resulted in a higher omega-3/omega-6 ratio compared to wild type mice of the same age. Thus, inflammation seems to be controlled by several mechanisms in the liver of transgenic mice: first by an increase in 15d-PGJ2 production and later by a beneficial omega-3/omega-6 ratio. PPARγ seems to play important roles in these processes. The accumulation of several omega fatty acids species in the transgenic mouse liver suggests that ApoD might bind to a broader range of fatty acids than previously thought.


Systemic immune-inflammation index (SII) and the risk of all-cause, cardiovascular, and cardio-cerebrovascular mortality in the general population.
An elevated systemic immune-inflammation index (SII) is associated with higher mortality in patients with coronary artery disease and other diseases. However, the potential of SII for predicting mortality in the general population has been underexplored. Therefore, this study aimed to analyze the relationship between the SII and all-cause, cardiovascular disease, and cardiocerebrovascular disease mortality in the general population. This study involved 26,855 participants (≥ 18 years) from the National Health and Nutrition Examination Survey 1999-2014 who were grouped according to the SII tertiles. Survival differences between the groups were analyzed using log-rank tests and Kaplan-Meier plots. Furthermore, multivariate Cox regression and restricted cubic spline analyses were used to examine the relationship between the SII and all-cause, cardiovascular, and cardio-cerebrovascular mortality. Overall, 1947 (7.425%) participants died following an average follow-up of 87.99 ± 54.04 months. Among these, 325 (1.210%) deaths were related to cardiovascular diseases and 392 (1.459%) to cardio-cerebrovascular mortality. Kaplan-Meier analysis revealed statistically significant differences in all-cause, cardiovascular, and cerebrovascular mortality between the SII tertiles (log-rank test: all P < 0.001). Multi-adjusted models showed that participants in the highest tertile of SII had a higher risk of death from all-cause (hazard ratio [HR] = 1.48, 95% confidence interval [CI] 1.48-1.48) and cardiovascular mortality (HR = 1.60, 95% CI 1.60-1.61) compared with those in the lowest tertile. In addition, the restricted cubic spline curve indicated a nonlinear association between SII and all-cause mortality (P < 0.001), with threshold value of SII at 18.284. There was a 15% decrease in the risk of all-cause mortality for each twofold change in SII on the left flank (HR = 0.85, 95% CI 0.69-1.05) and a 42% increase (HR = 1.42, 95% CI 1.23-1.64) on the right flank of the inflection point. In addition, the risk of cardiovascular mortality increased nonlinearly by 39% per twofold change in SII (HR = 1.39, 95% CI 1.07-1.81). There was also a nonlinear increase in the risk of cardio-cerebrovascular mortality per twofold change in SII (HR = 1.29, 95% CI 1.00-1.66). In the general population, the SII was significantly associated with all-cause, cardiovascular, and cardio-cerebrovascular mortality, regardless of the established risk factors.


Complications of splenic artery aneurysm other than intraperitoneal rupture.
Thirty-eight patients with aneurysms of the splenic artery were identified in the records of 11 years, but only one aneurysm was ruptured. Portal hypertension was found in nine patients (24%); in two of these the reaction surrounding the aneurysm prevented the construction of a patent splenorenal shunt or caused compartmented portal hypertension. One aneurysm encountered during the survey period and another encountered just after its conclusion ruptured into the stomach. There was a twofold overrepresentation of multiparous women. Intraperitoneal rupture is rare, except in pregnancy. If elective therapy is considered, angiography should be performed. Exclusion or resection of the aneurysm is advocated only for patients with symptomatic or ruptured aneurysms or (very rare) large aneurysms and for women of childbearing age. The spleen should be preserved, when possible. In high-risk patients occlusion of the aneurysm via an intra-arterial catheter should be considered. If the splenic artery aneurysm causes compartmented portal hypertension, splenectomy is indicated; if portal hypertension is general, the form of portasystemic decompression chosen should avoid the region of the aneurysm.


Early administration of heme arginate for acute porphyric attacks.
We investigated the efficacy of early administration of heme arginate in acute porphyric attacks. The series consisted of 51 consecutive acute attacks in 22 patients with acute intermittent porphyria and in two patients with variegate porphyria referred to a hospital in France or in Finland. Four attacks were associated with pareses, and 47 attacks were not. Heme in a dose of 250 mg or 3 mg/kg was started within 24 hours after admission in 37 (72.5%) of the attacks and within 4 days in 49 (96%) of the attacks. During all except five attacks, four daily infusions were given. The mean (+/- SD) duration of abdominal or nonabdominal pain was 2.5 +/- 0.97 days, and opiates were stopped an average of 2.8 +/- 0.72 days after the first heme infusion was started. All patients responded. In 46 (90%) of the attacks, the total hospitalization time was 7 days or less. The mean urinary excretion of porphobilinogen decreased to 16.2% +/- 7.7% and that of 5-aminolevulinic acid to 11.6% +/- 5.6% of pretreatment values. The only side effect was moderate thrombophlebitis in one patient. Favorable responses in every attack suggest specific effects of heme. In patients with acute attacks, heme therapy should be started immediately on admission.


Brain-specific polypeptide 1B236 exists in multiple molecular forms.
The COOH-terminal amino acid sequence of the rat brain-specific polypeptide 1B236 was previously deduced from molecular cloning and nucleotide sequence determination of its mRNA and the 1B236 protein shown to exist in the rat brain. The amino acid sequence of 1B236 contained at least three peptide sequences demarcated by pairs of basic amino acids--a structure similar to known neuropeptide and hormone precursors--which suggested that the protein might be processed in vivo to generate peptides. We have developed radioimmunoassays specific for 1B236 with antibodies against three synthetic peptides corresponding to putative cleavage products of this protein and have used these assays to define the molecular forms of 1B236 in rat brain extracts. The most abundant form is of high molecular weight (ca. 100,000) and requires detergent for solubilization; hence, it is probably membrane-bound. However, a small fraction of the high molecular weight material is soluble in the absence of detergent. In addition, several low molecular weight species are detectable in brain extracts prepared under conditions preventing proteolysis. These molecules correspond in size to two of the possible products of proteolytic processing predicted from the amino acid sequence of 1B236. The multiplicity of 1B236 forms, together with other data, suggests that this protein undergoes extensive post-translational modification, including proteolytic processing to generate peptides that may be physiologically relevant.


Retention behaviors of different attachment systems: precious versus nonprecious, precision versus semi-precision.
The aims of this study were to investigate the retention force changes of different attachment systems after 10,000 insertion-separation cycles and the difference in retention force between precious and non-precious materials of the same attachment system. Four types of attachments (Ball, Rod, M3 stud, and AP-Piccolino), produced using both precious and non-precious metal alloys, were tested (n=6). Data were analyzed using analysis of variance (ANOVA), Tukey's multiple comparison test, and t-test at a significance level of p≤0.05. Retention forces of all attachment types were significantly decreased after 10,000 insertion-separation cycles (p≤0.05). Rod and M3 attachment systems showed an initial increase in retention force, then an eventual decrease. At the end of the test, precious types of M3 and AP-Piccolino attachments had significantly higher retention force values than their non-precious ones (p≤0.05). Friction between non-precious attachment parts resulted in a higher retention loss than precious metal alloys.


Introducing WikiPathways as a Data-Source to Support Adverse Outcome Pathways for Regulatory Risk Assessment of Chemicals and Nanomaterials.
A paradigm shift is taking place in risk assessment to replace animal models, reduce the number of economic resources, and refine the methodologies to test the growing number of chemicals and nanomaterials. Therefore, approaches such as transcriptomics, proteomics, and metabolomics have become valuable tools in toxicological research, and are finding their way into regulatory toxicity. One promising framework to bridge the gap between the molecular-level measurements and risk assessment is the concept of adverse outcome pathways (AOPs). These pathways comprise mechanistic knowledge and connect biological events from a molecular level toward an adverse effect outcome after exposure to a chemical. However, the implementation of omics-based approaches in the AOPs and their acceptance by the risk assessment community is still a challenge. Because the existing modules in the main repository for AOPs, the AOP Knowledge Base (AOP-KB), do not currently allow the integration of omics technologies, additional tools are required for omics-based data analysis and visualization. Here we show how WikiPathways can serve as a supportive tool to make omics data interoperable with the AOP-Wiki, part of the AOP-KB. Manual matching of key events (KEs) indicated that 67% could be linked with molecular pathways. Automatic connection through linkage of identifiers between the databases showed that only 30% of AOP-Wiki chemicals were found on WikiPathways. More loose linkage through gene names in KE and Key Event Relationships descriptions gave an overlap of 70 and 71%, respectively. This shows many opportunities to create more direct connections, for example with extended ontology annotations, improving its interoperability. This interoperability allows the needed integration of omics data linked to the molecular pathways with AOPs. A new AOP Portal on WikiPathways is presented to allow the community of AOP developers to collaborate and populate the molecular pathways that underlie the KEs of AOP-Wiki. We conclude that the integration of WikiPathways and AOP-Wiki will improve risk assessment because omics data will be linked directly to KEs and therefore allow the comprehensive understanding and description of AOPs. To make this assessment reproducible and valid, major changes are needed in both WikiPathways and AOP-Wiki.


Gp78 deficiency in hepatocytes alleviates hepatic ischemia-reperfusion injury via suppressing ACSL4-mediated ferroptosis.
Ferroptosis, which is driven by iron-dependent lipid peroxidation, plays an essential role in liver ischemia-reperfusion injury (IRI) during liver transplantation (LT). Gp78, an E3 ligase, has been implicated in lipid metabolism and inflammation. However, its role in liver IRI and ferroptosis remains unknown. Here, hepatocyte-specific gp78 knockout (HKO) or overexpressed (OE) mice were generated to examine the effect of gp78 on liver IRI, and a multi-omics approach (transcriptomics, proteomics, and metabolomics) was performed to explore the potential mechanism. Gp78 expression decreased after reperfusion in LT patients and mice with IRI, and gp78 expression was positively correlated with liver damage. Gp78 absence from hepatocytes alleviated liver damage in mice with IRI, ameliorating inflammation. However, mice with hepatic gp78 overexpression showed the opposite phenotype. Mechanistically, gp78 overexpression disturbed lipid homeostasis, remodeling polyunsaturated fatty acid (PUFA) metabolism, causing oxidized lipids accumulation and ferroptosis, partly by promoting ACSL4 expression. Chemical inhibition of ferroptosis or ACSL4 abrogated the effects of gp78 on ferroptosis and liver IRI. Our findings reveal a role of gp78 in liver IRI pathogenesis and uncover a mechanism by which gp78 promotes hepatocyte ferroptosis by ACSL4, suggesting the gp78-ACSL4 axis as a feasible target for the treatment of IRI-associated liver damage.


Nano-vehicles give new lease of life to existing antimicrobials.
Antibiotic resistance has become one of the greatest challenges for modern medicine, and new approaches for the treatment of bacterial infections are urgently needed to avoid widespread vulnerability again to infections that have so far been easily treatable with existing drugs. Among the many approaches investigated to overcome this challenge is the use of engineered nanostructures for the precise and targeted delivery of existing antimicrobial agents in a fashion that will potentiate their effect. This idea leans on lessons learned from pioneering research in cancer, where the targeted delivery of anti-cancer drugs to mammalian cells has been a topic for some time. In particular, new research has demonstrated that nanomaterials can be functionalised with active antimicrobials and, in some cases, with targeting molecules that potentiate the efficiency of the antimicrobials. In this mini-review, we summarise results that demonstrate the potential for nanoparticles, dendrimers and DNA nanostructures for use in antimicrobial delivery. We consider material aspects of the delivery vehicles and ways in which they can be functionalised with antibiotics and antimicrobial peptides, and we review evidence for their efficacy to kill bacteria both in vitro and in vivo. We also discuss the advantages and limitations of these materials and highlight the benefits of DNA nanostructures specifically for their versatile potential in the present context.


MR evaluation of response to targeted treatment in cancer cells.
The development of molecular technologies, together with progressive sophistication of molecular imaging methods, has allowed the further elucidation of the multiple mutations and dysregulatory effects of pathways leading to oncogenesis. Acting against these pathways by specifically targeted agents represents a major challenge for current research efforts in oncology. As conventional anatomically based pharmacological endpoints may be inadequate to monitor the tumor response to these targeted treatments, the identification and use of more appropriate, noninvasive pharmacodynamic biomarkers appear to be crucial to optimize the design, dosage and schedule of these novel therapeutic approaches. An aberrant choline phospholipid metabolism and enhanced flux of glucose derivatives through glycolysis, which sustain the redirection of mitochondrial ATP to glucose phosphorylation, are two major hallmarks of cancer cells. This review focuses on the changes detected in these pathways by MRS in response to targeted treatments. The progress and limitations of our present understanding of the mechanisms underlying MRS-detected phosphocholine accumulation in cancer cells are discussed in the light of gene and protein expression and the activation of different enzymes involved in phosphatidylcholine biosynthesis and catabolism. Examples of alterations induced in the MRS choline profile of cells exposed to different agents or to tumor environmental factors are presented. Current studies aimed at the identification in cancer cells of MRS-detected pharmacodynamic markers of therapies targeted against specific conditional or constitutive cell receptor stimulation are then reviewed. Finally, the perspectives of present efforts addressed to identify enzymes of the phosphatidylcholine cycle as possible novel targets for anticancer therapy are summarized.


ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects.
Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive. We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls. We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts. Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.


Diclofenac Administration after Physical Training Blunts Adaptations of Peripheral Systems and Leads to Losses in Exercise Performance: In Vivo and In Silico Analyses.
Recovery in athletes is hampered by soreness and fatigue. Consequently, nonsteroidal anti-inflammatory drugs are used as an effective strategy to maintain high performance. However, impact of these drugs on adaptations induced by training remains unknown. This study assessed the effects of diclofenac administration (10 mg/kg/day) on rats subjected to an exhaustive test, after six weeks of swimming training. Over the course of 10 days, three repeated swimming bouts were performed, and diclofenac or saline were administered once a day. Trained animals exhibited higher muscle citrate synthase and lower plasma creatinine kinase activities as compared to sedentary animals, wherein diclofenac had no impact. Training increased time to exhaustion, however, diclofenac blunted this effect. It also impaired the increase in plasma and liver interleukin-6 levels. The trained group exhibited augmented catalase, glutathione peroxidase, and glutathione reductase activities, and a higher ratio of reduced-to-oxidized glutathione in the liver. However, diclofenac treatment blunted all these effects. Systems biology analysis revealed a close relationship between diclofenac and liver catalase. These results confirmed that regular exercise induces inflammation and oxidative stress, which are crucial for tissue adaptations. Altogether, diclofenac treatment might be helpful in preventing pain and inflammation, but its use severely affects performance and tissue adaptation.


[Intercostal muscle motor unit activity during shivering].
The activity of single motor units of the intercostal muscles has been studied during reactions of thermoregulation in cats. It has been shown that during shivering both respiratory and tonic units are functioning with a frequency of discharges of 5--12/sec. A marked increased in the quantity of active tonic motor units was revealed in shivering. During warming of the animal and cessation of shivering first the tonic units and then the respiratory ones ceased to discharge. The thermoregulatory function of the intercostal muscles seems to be achieved essentially by tonic motoneurons activated by cold stimulation.


High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation.
The major transformation activity of the high-risk human papillomaviruses (HPV) is associated with the E7 oncoprotein. The interaction of HPV E7 with retinoblastoma family proteins is important for several E7 activities; however, this interaction does not fully account for the high-risk E7-specific cellular immortalization and transformation activities. We have determined that the cellular non-receptor protein tyrosine phosphatase PTPN14 interacts with HPV E7 from many genus alpha and beta HPV types. We find that high-risk genus alpha HPV E7, but not low-risk genus alpha or beta HPV E7, is necessary and sufficient to reduce the steady-state level of PTPN14 in cells. High-risk E7 proteins target PTPN14 for proteasome-mediated degradation, which requires the ubiquitin ligase UBR4, and PTPN14 is degraded by the proteasome in HPV-positive cervical cancer cell lines. Residues in the C terminus of E7 interact with the C-terminal phosphatase domain of PTPN14, and interference with the E7-PTPN14 interaction restores PTPN14 levels in cells. Finally, PTPN14 degradation correlates with the retinoblastoma-independent transforming activity of high-risk HPV E7. High-risk human papillomaviruses (HPV) are the cause of cervical cancer, some other anogenital cancers, and a growing fraction of oropharyngeal carcinomas. The high-risk HPV E6 and E7 oncoproteins enable these viruses to cause cancer, and the mechanistic basis of their carcinogenic activity has been the subject of intense study. The high-risk E7 oncoprotein is especially important in the immortalization and transformation of human cells, which makes it a central component of HPV-associated cancer development. E7 oncoproteins interact with retinoblastoma family proteins, but for several decades, it has been recognized that high-risk HPV E7 oncoproteins have additional cancer-associated activities. We have determined that high-risk E7 proteins target the proteolysis of the cellular protein tyrosine phosphatase PTPN14 and find that this activity is correlated with the retinoblastoma-independent transforming activity of E7.


Nonbacterial thrombotic endocarditis in a male homosexual with Kaposi's sarcoma.
Nonbacterial thrombotic endocarditis (NBTE), or marantic endocarditis, was found at autopsy in a young male homosexual with Kaposi's sarcoma. Vegetations were seen in the mitral and aortic valves. Embolic phenomena and cytomegalovirus infection were noted in the brain, spleen, liver, lung, gastrointestinal tract, and bone marrow. To our knowledge, this is the first reported case of NBTE in a young immunosuppressed homosexual man with Kaposi's sarcoma.


Introduction Christmas-themed scientific articles are becoming increasingly popular and may represent a shortcut to scientific demise due to their demand for time better spent on "serious" research. We aimed to investigate whether authorship on Christmas-themed medical articles could damage the scientific careers of authors. We hypothesized that Christmas-authorships had a negative impact on core bibliometric outcomes such as publication rates. Methods We extracted demographic and bibliometric data on first- and last authors of medical papers written for the Christmas edition of Journal of The Danish Medical Association through the years 2010-2012. These cases were compared with controls representing authors of original "serious" research papers written in the same years. We performed a negative binomial regression with the number of publications ten years after the index date (defined as the publication year of Christmas/"serious" article) as the outcome and adjusted models for sex and age. Results We found that first authors of Christmas-themed papers had a publication rate ratio (PRR) of 3.8 (95% confidence interval (CI): 1.4-12.4) in unadjusted analysis and last authors had a PRR of 0.6 (95% CI: 0.2-1.6). The associations weakened and were statistically insignificant in adjusted analyses. Conclusion Our results indicate that first authors publish more in the years following the publication of a Christmas article, although the association may be entirely driven by sex and age. Causality remains uncertain and further studies (such as RCTs) which randomize authors to produce Christmas-themed (preferably in a Santa's workshop setting) or serious articles are needed. Funding. None. Trial registration. None.


Structure, topology and chemical order in Ge-As-Te glasses: a high-energy x-ray diffraction study.
High-energy x-ray diffraction is employed to study the atomic structure of bulk Ge(x)As(2x)Te(100-3x) glasses with compositions in the range 25 ≤ 3x ≤ 70. The coordination environments of Te atoms suggest significant violation of chemical order in these glasses. Analyses of the nearest-neighbor coordination environments and the parameters for the first sharp diffraction peak indicate that these telluride glasses are structurally and chemically more disordered as compared with their sulfide or selenide analogs. The compositional evolution of the structural parameters is shown to be consistent with the corresponding variation in molar volume and glass transition temperature.


Pulmonary veno-occlusive disease.
Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that mainly affects children and young adults. Its cause is unknown, although viral infections and drugs have been implicated. Patients with PVOD present with symptoms of right-sided heart failure. Radiologic examination shows prominent pulmonary arteries with Kerley B lines, pleural effusion, and mediastinal adenopathy. The definite diagnosis is made by histologic examination. Eccentric intimal fibrosis and recanalized thrombi in pulmonary veins and venules, arterialized veins, alveolar edema, and medial hypertrophy of arteries are seen on lung biopsy. No effective treatment is available; lung transplantation has been tried. The prognosis associated with PVOD is poor.


Recreational use of nitrous oxide causes seizure, pneumothorax, pneumomediastinum, and pneumopericardium: nitrous oxide and its harm, a case report.
Nitrous oxide, commonly known as 'laughing gas', has become a popular recreational drug. Whippets, small canisters containing gas in pressurized form, can be easily obtained from a food store. However, inhaling nitrous oxide from these canisters, which contain a 100% concentration, can lead to hypoxia, resulting in seizures or even death. Inhalation of nitrous oxide rarely causes pneumothorax, pneumomediastinum, and pneumopericardium. This case study highlights the potential dangers of recreational abuse of nitrous oxide.


Cell-to-cell interaction in the immune response. X. T-cell-dependent suppression in tolerant mice.
Specific immunological tolerance was induced in CBA mice by a single injection of deaggregated fowl immunoglobulin G (FgammaG). The unresponsive state was stable on adoptive transfer and irreversible by pretreatment of tolerant cells with trypsin. Tolerant spleen cells could suppress the response of normal syngeneic recipients. They also suppressed the adoptive primary response of spleen cells to FgammaG in irradiated hosts. The inhibitory effect was on the indirect (7S) plaque-forming cell (PFC) response. Incubation of the tolerant cell population with anti-theta serum and complement reversed the suppressor effect. Furthermore, the addition of purified T cells from normal donors restored the capacity of the anti-theta serum-treated tolerant cells to transfer an adoptive response to FgammaG. The existence of FgammaG-reactive B cells was supported by the demonstration of normal numbers of antigen-binding cells in the spleen and thoracic duct lymph from tolerant animals. Moreover, the formation of caps by these cells implied that they could bind antigen normally. These experiments provided direct evidence for the existence of suppressor T cells in the tolerant population. Further evidence was derived from examination of the effect of antigen "suicide". Tolerant spleen cells were treated with radioactive FgammaG under conditions known to abrogate T-cell helper function. When these cells were transferred together with normal spleen cells into irradiated hosts, suppression of the primary adoptive response to FgammaG was no longer observed. Inhibition of an adoptive secondary response to FgammaG was obtained by transferring tolerant spleen cells with primed B cells provided high doses of tolerant cells were used. By contrast low doses exerted a helper rather than a suppressor effect in this system.


Case-control exercise challenge study on the pathogenesis of high serum gamma-glutamyl transferase activity in racehorses.
High serum γ-glutamyl-transferase (GGT) activity syndrome in racehorses has been associated with maladaption to exercise. Investigation of affected horses before and immediately after standard exercise may provide critical insight into the syndrome's pathophysiology. To investigate blood biomarker changes in actively competing racehorses with high GGT activity associated with an exercise challenge. Case-control study. High GGT case (age: 2-3 years) and normal GGT control (age: 2-7 years) pairs (3 Thoroughbred, 4 Standardbred pairs) at least 3 months into their training/racing season were included. Horses with a recent history of high GGT activity (≥50 IU/L) without additional biochemical evidence of liver disease were identified by veterinarians. Horses were tested again in the week prior to a planned exercise challenge to confirm persistent increases in GGT activity. Controls from the same stable with similar training/racing intensity and serum GGT activity ≤36 IU/L were matched with each case. Blood samples were obtained immediately before, 15 and 120 min after exercise. Pre-exercise serum samples were analysed for baseline select serum chemistries, selenium and vitamin E concentrations. Cortisol concentration and markers of oxidative status were measured in serum or plasma for all time points. Individual serum bile acid and coenzyme Q10 concentrations, plasma lipid mediator (fatty acids, oxylipids, isoprostanes) concentrations and targeted metabolomics analyses were performed using liquid chromatography-mass spectrometry. Serum viral PCR for equine hepaci- and parvovirus was performed in each animal. Cases had higher baseline concentrations of total glutathione, taurocholic acid, cortisol and cholesterol concentrations and higher or lower concentrations of specific oxylipid and isoprostane mediators, but there were no case-dependent changes after exercise. Small sample size. Results indicated that glutathione metabolism was altered in high GGT horses. Enhanced glutathione recycling and mild cholestasis are possible explanations for the observed differences.


Feasibility of repeat transradial access for neuroendovascular procedures.
Transradial artery access (TRA) for cerebrovascular angiography is increasing due to decreased access site complications and overwhelming patient preference. While interventional cardiologists have reported up to 10 successive TRA procedures via the same radial access site, this is the first study examining successive use of the same artery for repeat procedures in neurointerventional procedures.1 METHODS: We reviewed our prospective institutional database for all patients who underwent a transradial neurointerventional procedure between 2015 and 2019. Index procedures were defined as procedures performed via TRA after which there was a second TRA procedure attempted. Reasons for conversion to a transfemoral approach (TFA) for subsequent procedures were identified. 104 patients underwent 237 procedures (230 TRA, 7 TFA). 97 patients underwent ≥2 TRA procedures, 20 patients >3, four patients >4, three patients >5, and two patients >6 TRA procedures. The success rate was 94.7% (126/133) with 52% (66/126) of successive procedures performed via the same radial access site (snuffbox vs antebrachial) while the alternate radial artery segment was used for access in 48% (60/126) of subsequent procedures. There were seven (5.3%) cases requiring crossover to TFA, six cases for radial artery occlusion (RAO) and one for radial artery narrowing. Successive TRA is both technically feasible and safe for neuroendovascular procedures in up to six procedures. The low failure rate (5.3%) was primarily due to RAO. Thus, even without clinical consequences, strategies to minimize RAO should be optimized for patients to continue to benefit from TRA in future procedures.


The University of California at Los Angeles Alzheimer's and Dementia Care program for comprehensive, coordinated, patient-centered care: preliminary data.
Dementia is a chronic disease that requires medical and social services to provide high-quality care and prevent complications. As a result of time constraints in practice, lack of systems-based approaches, and poor integration of community-based organizations (CBOs), the quality of care for dementia is poorer than that for other diseases that affect older persons. The University of California at Los Angeles (UCLA) Alzheimer's and Dementia Care (UCLA ADC) program partners with CBOs to provide comprehensive, coordinated, patient-centered care for individuals with Alzheimer's disease and other dementias. The goals of the program are to maximize function, independence, and dignity; minimize caregiver strain and burnout; and reduce unnecessary costs. The UCLA ADC program consists of five core components: recruitment and a dementia registry, structured needs assessments of individuals in the registry and their caregivers, creation and implementation of individualized dementia care plans based on needs assessments and input from the primary care physicians, monitoring and revising care plans as needed, and around-the-clock access for assistance and advice. The program uses a comanagement model with a nurse practitioner Dementia Care Manager working with primary care physicians and CBOs. Based on the first 150 individuals served, the most common recommendations in the initial care plans were referrals to support groups (73%) and Alzheimer's Association Safe Return (73%), caregiver training (45%), and medication adjustment (41%). The program will be evaluated on its ability to achieve the triple aim of better care for individuals, better health for populations, and lower costs.


Pituitary adenomas.
Pituitary adenomas produce a complex collection of disorders. Some are incidental findings. Some distort local anatomical structures which can lead to disorders of vision or hormone production. Some produce excesses of hormones which can be either life threatening or clinically distressing. The management requires the expertise of a variety of experts who plan together. No single treatment is universally successful in controlling these conditions. Medical, biochemical, surgical and radiosurgical management can all have parts to play. Coordinate co-operation between specialists will provide patients with the best available treatment.


Single-stage surgical procedure for patients with primary esophageal and lung cancers.
Background The purpose of this study was to evaluate the safety and feasibility of simultaneous surgery for patients with primary esophageal and lung cancers. Methods Patients with primary esophageal and lung cancers who underwent simultaneous surgical procedures between January 2016 and January 2022 were retrospectively analyzed. The data of patients who underwent esophagectomy and lobectomy (group EL) were compared with those of patients who underwent esophagectomy and sublobar resection (group ES). Results A total of 21 patients were included with an average age of 64.62±5.24 years. Group EL contained 8 patients and group ES contained 13 patients. All procedures were completed uneventfully with a mean operative time of 251.19 ±66.93 min. Pulmonary complications occurred in 6(28.57%) patients. Other complications included anastomotic leakage in 1 patient, pleural effusion requiring drainage in 8 patients, atrial fibrillation in 2 patients, and incision infection in 1 patient. All patients were followed up for 30.23±21.82 months. During the follow-up period, 9 patients had a recurrence of cancer and died of tumor progression, and one patient died of a tracheothoracogastric fistula. Complications and mortality in group EL did not increase when compared to those in group ES. Conclusion It is safe and feasible to perform a single-stage surgical procedure for patients with primary esophageal and lung cancers. Simultaneous esophagectomy and lobectomy did not increase postoperative complications or mortality compared with esophagectomy and sublobar resection.


Choline-Based Multi-Ingredient Supplementation Can Improve Explosive Strength during a Fatiguing Task.
Various choline-based multi-ingredient supplementations (CMS) have been suggested in the current market, but the research is limited. The purpose of this study was to investigate the acute effect of a CMS on physical performance. Fourteen male college football players (20.4 ± 1.0 years) participated in a randomized double-blind crossover experiment separated by 7 days. Subjects were given a CMS or a placebo 60 min before physical performance testing measures, including maximum vertical jumps, maximum voluntary isometric contractions (MVIC), maximal voluntary concentric contractions (MVCC), and fatiguing contractions. Four MVICs and seven sets of two MVCCs at various loads (1 N·m to 60% MVIC torque) were performed with the knee extensor muscles while seated on a dynamometer before and after the fatiguing tasks. During the fatiguing tasks, 120 MVCCs (4 sets × 30 reps) were performed with a load equivalent to 20% MVIC. Twitch interpolation technique was used to assess muscle contractile properties and voluntary activation. No significant differences were seen at baseline between sessions for all testing measures including vertical jump height, strength, power, muscle contractile properties and voluntary activation. Rate of torque development and impulse was higher in supplemental session compared to control session throughout the fatiguing contractions (p = 0.018, p < 0.001, respectively). Acute CMS can improve explosive strength by delaying the onset of fatigue.


Follow-up of children born of bromocriptine-treated mothers.
A survey carried out in France at the beginning of 1984 concerning development of children born of mothers treated with bromocriptine (BC) during part or all of the pregnancy showed the absence of any adverse effects of BC in 64 children born from 53 mothers. In 60 cases, BC was prescribed (2.5-7.5 mg/day) for hyperprolactinemia; 23 mothers were treated with BC for 4 weeks or less, and 23 others for 30 weeks or more. After a follow-up of between 6 months and 9 years, all children are normal. Psychological development in the 23 children born to mothers treated with BC during more than 30 weeks of pregnancy actually appears more precocious, with excellent scholastic performance in the oldest.


[An update on catheter-associated urinary tract infection. Inter-Society recommendations].
Representatives of the Argentine Society of Infectious Diseases (SADI) and the Argentine Society of Intensive Therapy (SATI) issued the present recommendations on diagnosis, treatment, and prevention of catheter associated urinary tract infection (CA-UTI). Articles published during 2006-2016 were analyzed in the light of experts' opinion and local data. This document aims to offer basic strategies to optimize the diagnosis based on clinical and microbiological criteria, provide guidance in empirical and targeted antibiotic schemes, and promote effective measures to reduce the risk of CA-UTI. The joint work of both societies highlights the experts' concern about the mismanagement of CA-UTI, which is associated to the indiscriminate use of antimicrobials, and the importance of improving daily practices of CA-UTI management. Through these recommendations, local guidelines are established to optimize the diagnosis, treatment and prevention of CAUTI in order to reduce morbimortality, days of hospitalization, costs and antibiotic resistance due to the misuse of antimicrobials.


Dipole-bound anions of beta-alanine: canonical and zwitterionic conformers.
The remarkable stabilities of the dipole-bound anions of the canonical and zwitterionic conformers of beta-alanine are predicted at the high level of theories, in which the former is the global minimum and the latter, the anti zwitterionic anion, is the local minimum. In contrast to the dipole-bound anions of glycine, the gauche zwitterionic anion of beta-alanine is an unstable conformer. The vertical electron detachment energies for the canonical and anti zwitterionic anions are 58 and 1145 meV, respectively. The photodetachment electron spectrum of the canonical anion is theoretically simulated on the basis of the Franck-Condon factor calculations.


Sleep apnea is associated with cardiovascular risk factors among kidney transplant patients.
We assessed the prevalence of obstructive sleep apnea (OSA) and its clinical correlates in a large sample of patients who received a kidney transplant (Tx). We also compared the prevalence of the disorder between dialysis patients who were on the waiting list for a Tx (WL) and Tx patients. This was a cross-sectional study of 100 Tx and 50 WL patients who underwent one-night polysomnography (SLeep disorders Evaluation in Patients after kidney Transplantation [SLEPT] Study). Sociodemographic information and data about medication, comorbidity, and laboratory parameters were collected. The prevalence of mild (apnea-hypopnea index [AHI] > or =5/h and <15/h), moderate (AHI > or =15/h and <30/h), and severe OSA (AHI > or =30/h) was 18, 11, and 14% in the Tx group and 28, 16, and 10% in the WL group, respectively. The AHI was significantly correlated with age (rho = 0.34), body mass index (rho = 0.45), neck circumference (rho = 0.4), abdominal circumference (rho = 0.51), and hemoglobin (rho = 0.24) in the Tx group. The proportion of Tx patients who were treated with three or more antihypertensive drugs was significantly higher in the OSA group (56 versus 31%; P = 0.022). Despite taking significantly more antihypertensive drugs, the average systolic BP was still higher in patients with versus without OSA (147 +/- 21 versus 139 +/- 18 mmHg; P = 0.059). The prevalence of OSA is similar in Tx and WL patients and it may contribute to presence of hypertension in patients who receive a Tx.


Cardiac Physiology for Radiologists: Review of Relevant Physiology for Interpretation of Cardiac MR Imaging and CT.
Cardiac computed tomography (CT) and magnetic resonance (MR) imaging provide clinicians with important insights into cardiac physiology and pathology. However, not all radiologists understand the language and concepts of cardiac physiology that are used daily by cardiologists. This review article covers basic cardiac physiology as it relates to cardiac CT and MR imaging. Topics include a review of the cardiac cycle and left ventricular pressure-volume loops as they relate to different pathologic states, evaluation of cardiac function, and calculation of key parameters such as left ventricular volumes and the ejection fraction. The hemodynamics of cardiac shunts are covered, with an emphasis on factors important to cardiologists, including the ratio of pulmonary flow to systemic flow. Additionally, valvular physiologic function is reexamined, with a focus on understanding pressure gradients within the heart and also the changes associated with valvular pathologic conditions, including measurement of regurgitant fractions in patients with valvular insufficiency. Understanding these basic concepts will help radiologists tailor the reporting of cardiac studies to clinically relevant information.


An unusual case of unicystic intramural ameloblastoma and review of the literature.
Ameloblastoma is the most common tumor of odontogenic origin. There are various types of this tumor and confusion still exists among the clinicians about the correct classification. Multicystic ameloblastoma is the most frequent subtype while unicystic ameloblastoma can be considered as a variant of the solid or multycistic. This subtype is considered as a less aggressive tumor with a variable recurrence rate. However, its frequency is often underestimated. The aim of this article is reviewing the recent literature about unicystic ameloblastoma using our unusual clinical case as a starting point to illustrate this discussion. A 30-year-old man who had been complaining of slight pain in the premolar and molar area of the left side of mandible had a check up at our department. X-rays revealed a unilocular radiotrasparency with radiopaque margins. The first histological diagnosis was an odontogenic cyst. Successive histological evaluations revealed that ameloblastic epithelial islands were present in lassus connective tissue. We think that our case report provides new insights into the approach to the ameloblastoma diagnosis. We agree with authors who have pointed out that a single small biopsy may often be inadequate for the correct diagnosis of amelobastoma. Moreover, in the light of our experience, it should be kept in mind that ameloblastomas may have sometimes unusual presentations and this fact should induce surgeons and pathologists to consider carefully each lesion.


[Significance of fundus evaluation in the staging of hypertensive disease compared to electrocardiography and renal circulation].
In order to determine the relevance of ophthalmoscopic findings in cases of hypertension as compared to electrocardiographic abnormalities and disorders of the renal function, the authors examined 728 patients admitted to the German diagnostic Clinic (Wiesbaden) with hypertension over a period of 2 years. In all cases blood pressure was measured twice, and ophthalmoscopy, electrocardiography, a chest X-ray, and a laboratory checkup were performed. The effective renal plasma flow was measured in 100 cases using the 131 iodine-Hippuran clearance method. The results revealed that ophthalmoscopy is the most reliable method for classifying early and more advanced stages of hypertension, as compared to ECG and measurement of the effective renal plasma flow.


Continuum modeling of deformation and aggregation of red blood cells.
In order to gain better understanding for rheology of an isolated red blood cell (RBC) and a group of multiple RBCs, new continuum models for describing mechanical properties of cellular structures of an RBC and inter-cellular interactions among multiple RBCs are developed. The viscous property of an RBC membrane, which characterizes dynamic behaviors of an RBC under stress loading and unloading processes, is determined using a generalized Maxwell model. The present model is capable of predicting stress relaxation and stress-strain hysteresis, of which prediction is not possible using the commonly used Kelvin-Voigt model. Nonlinear elasticity of an RBC is determined using the Yeoh hyperelastic material model in a framework of continuum mechanics using finite-element approximation. A novel method to model inter-cellular interactions among multiple adjacent RBCs is also developed. Unlike the previous modeling approaches for aggregation of RBCs, where interaction energy for aggregation is curve-fitted using a Morse-type potential function, the interaction energy is analytically determined. The present aggregation model, therefore, allows us to predict various effects of physical parameters such as the osmotic pressure, the thickness of a glycocalyx layer, the penetration depth, and the permittivity, on the depletion and electrostatic energy among RBCs. Simulations for elongation and recovery deformation of an RBC and for aggregation of multiple RBCs are conducted to evaluate the efficacy of the present continuum modeling methods.


A nonsense mutation of bone morphogenetic protein-15 (BMP15) causes both infertility and increased litter size in pigs.
Atypical external genitalia are often a sign of reproductive organ pathologies and infertility with both environmental or genetic causes, including karyotypic abnormalities. Genome-wide association studies (GWAS) provide a means for identifying chromosomal regions harboring deleterious DNA-variants causing such phenotypes. We performed a GWAS to unravel the causes of incidental cases of atypically small vulvae in German Landrace gilts. A case-control GWAS involving Illumina porcine SNP60 BeadChip-called genotypes of 17 gilts with atypically small vulvae and 1818 control animals (fertile German Landrace sows) identified a significantly associated region on the X-chromosome (P = 8.81 × 10- 43). Inspection of whole-genome sequencing data in the critical area allowed us to pinpoint a likely causal variant in the form of a nonsense mutation of bone morphogenetic protein-15 (BMP15; Sscrofa11.1_X:g.44618787C>T, BMP15:p.R212X). The mutant allele occurs at a frequency of 6.2% in the German Landrace breeding population. Homozygous gilts exhibit underdeveloped, most likely not functional ovaries and are not fertile. Male carriers do not seem to manifest defects. Heterozygous sows produce 0.41±0.02 (P=4.5 × 10-83) piglets more than wildtype animals. However, the mutant allele's positive effect on litter size accompanies a negative impact on lean meat growth. Our results provide an example for the power of GWAS in identifying the genetic causes of a fuzzy phenotype and add to the list of natural deleterious BMP15 mutations that affect fertility in a dosage-dependent manner, the first time in a poly-ovulatory species. We advise eradicating the mutant allele from the German Landrace breeding population since the adverse effects on the lean meat growth outweigh the larger litter size in heterozygous sows.


Effects of human growth hormone administration on growth rate and growth-stimulating activity of serum, measured by lymphocyte bioassay in hypopituitary children.
The acute effect of human growth hormone (hGH) upon the serum bioassayable growth-stimulating activity was compared to the long-term effects of hGH on growth rate in two groups of hypopituitary patients aged 2-18 years. 12 patients had complete GH deficiency with GH peak below 3.5 ng/ml at two stimulation tests. 15 others, having both GH peaks below 8 ng/ml and at least one above 3.5 ng/ml, were considered as having partial GH deficiency. The growth-stimulating activity of serum was measured by its effect at concentrations 0.03 to 1.25% upon thymidine incorporation into lectin-activated normal human lymphocytes, named thymidine activity (TA). In patients with complete GH deficiency, the pre-treatment TA was positively correlated with the peak response of GH to stimulation tests. The increase of TA after 3-4 days of hGH treatment was positively correlated with the pretreatment TA level, and negatively correlated with the peak GH level. The effect of a 6-12 months therapeutic course of hGH upon the growth rate was positively correlated with the acute increase of TA. No such correlations were found in patients with partial GH deficiency. Many works have discussed the relationship of acute somatomedin responses and long-term clinical results of treatment with hGH in GH-deficient children. The present data, using a highly sensitive bioassay of serum stimulating activity, suggest that the degree of GH deficiency is an important factor to be considered. The response of GH-dependent serum growth factors to acute treatment with hGH could have more predictive value in cases with total lack of growth hormone than in cases of partial deficiency.


Decoding Cinnabarinic Acid-Specific Stanniocalcin 2 Induction by Aryl Hydrocarbon Receptor.
Aryl hydrocarbon receptor (AhR) is a ligand-mediated transcription factor known for regulating response to xenobiotics, including prototypical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the activation of CYP1A1 expression. Upon ligand-binding, AhR translocates to the nucleus, interacts with the AhR nuclear translocator, and binds to xenobiotic response elements (XREs; GCGTG) present in the promoter region of AhR-regulated genes. Recently, we identified a novel tryptophan catabolite, cinnabarinic acid (CA), as an endogenous AhR agonist capable of activating expression of AhR target gene stanniocalcin 2 (stc2). The CA-driven stc2 induction bestowed cytoprotection against hepatotoxicity in an AhR-dependent manner. Interestingly, only CA but not TCDD was able to induce stc2 expression in liver, and CA was unable to upregulate the TCDD responsive cyp1a1 gene. In this report, we identified CA-specific histone H4 lysine 5 acetylation and H3 lysine 79 methylation at the AhR-bound stc2 promoter. Moreover, histone H4 lysine 5 acetylation writer, activating transcription factor 2 (Atf2), and H3 lysine 79 methylation writer, disruptor of telomeric silencing 1-like histone lysine methyltransferase (Dot1l), were interacting with the AhR complex at the stc2 promoter exclusively in response to CA treatment concurrent with the histone epigenetic marks. Suppressing Atf2 and Dot1l expression using RNA interference confirmed their role in stc2 expression. CRISPR/Cas9-assisted replacement of cyp1a1 promoter-encompassing XREs with stc2 promoter XREs resulted in CA-dependent induction of cyp1a1, underlining a fundamental role of quaternary structure of XRE sequence in agonist-specific gene regulation. In conclusion, CA-driven recruitment of specific chromatin regulators to the AhR complex and resulting histone epigenetic modifications may serve as a molecular basis for agonist-specific stc2 regulation by AhR. SIGNIFICANCE STATEMENT: Results reported here provide a mechanistic explanation for the agonist-specific differential gene regulation by identifying interaction of aryl hydrogen receptor with specific chromatin regulators concomitant with unique histone epigenetic marks. This study also demonstrated that the agonist-specific target-gene expression can be transferred with the gene-specific promoter xenobiotic response element-sequence in the context of chromatin architecture.


Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins.
The TPR proteins FKBP52, FKBP51, Cyp40, and PP5 are found in steroid receptor (SR) complexes, but their receptor-specific preferences and roles remain unresolved. We have undertaken a systematic approach to this problem by examining the contribution of all four TPRs to the localization properties of glucocorticoid (GR) and progesterone (PR) receptors. The GR of L929 cells was found in the cytoplasm in a complex containing PP5 and FKBP51, while the GR of WCL2 cells was nuclear and contained PP5 and FKBP52. Cyp40 did not interact with the GR in either cell line. To test whether FKBP interaction determined localization, we overexpressed Flag-tagged FKBP51 in WCL2 cells and Flag-FKBP52 in L929 cells. In WCL2 cells, the GR exhibited a shift to greater cytoplasmic localization that correlated with recruitment of Flag-FKBP51. In contrast, Flag-FKBP52 was not recruited to the GR of L929 cells, and no change in localization was observed, suggesting that both cell-type-specific mechanisms and TPR abundance contribute to the SR-TPR interaction. As a further test, GR-GFP and PR-GFP constructs were expressed in COS cells. The GR-GFP construct localized to the cytoplasm, while the PR-GFP construct was predominantly nuclear. Similar to L929 cells, the GR in COS interacted with PP5 and FKBP51, while PR interacted with FKBP52. Analysis of GR-PR chimeric constructs revealed that the ligand-binding domain of each receptor determines both TPR specificity and localization. Lastly, we analyzed GR and PR localization in cells completely lacking TPR. PR in FKBP52 KO cells showed a complete shift to the cytoplasm, while GR in FKBP51 KO and PP5 KO cells showed a moderate shift to the nucleus, indicating that both TPRs contribute to GR localization. Our results demonstrate that SRs have distinct preferences for TPR proteins, a property that resides in the LBD and which can now explain long-standing differences in receptor subcellular localization.


[Cimetidine treatment of primary hyperparathyroidism].
Since Sherwood's report in 1979, contradictory findings have been published with regards to the treatment of primary hyperparathyroidism with cimetidine. We studied 16 patients with primary hyperparathyroidism treated with 1,200 mg of Cimetidine and followed-up clinically and biochemically. A decrease in serum calcium and urinary CAMP was observed after the fourth week of cimetidine therapy with no significant change in parathormone levels. In none of the cases did Cimetidine seem to provide a treatment of hyperparathyroidism, a condition which remains curable with surgery.


Comparative Effects of Co-Ingesting Whey Protein and Glucose Alone and Combined on Blood Glucose, Plasma Insulin and Glucagon Concentrations in Younger and Older Men.
The ingestion of dietary protein with, or before, carbohydrate may be a useful strategy to reduce postprandial hyperglycemia, but its effect in older people, who have an increased predisposition for type 2 diabetes, has not been clarified. Blood glucose, plasma insulin and glucagon concentrations were measured for 180 min following a drink containing either glucose (120 kcal), whey-protein (120 kcal), whey-protein plus glucose (240 kcal) or control (~2 kcal) in healthy younger (n = 10, 29 ± 2 years; 26.1 ± 0.4 kg/m2) and older men (n = 10, 78 ± 2 years; 27.3 ± 1.4 kg/m2). Mixed model analysis was used. In both age groups the co-ingestion of protein with glucose (i) markedly reduced the increase in blood glucose concentrations following glucose ingestion alone (p < 0.001) and (ii) had a synergistic effect on the increase in insulin concentrations (p = 0.002). Peak insulin concentrations after protein were unaffected by ageing, whereas insulin levels after glucose were lower in older than younger men (p < 0.05) and peak insulin concentrations were higher after glucose than protein in younger (p < 0.001) but not older men. Glucagon concentrations were unaffected by age. We conclude that the ability of whey-protein to reduce carbohydrate-induced postprandial hyperglycemia is retained in older men and that protein supplementation may be a useful strategy in the prevention and management of type 2 diabetes in older people.


Automated pressure map segmentation for quantifying phalangeal kinetics during cylindrical gripping.
Inverse dynamics models used to investigate musculoskeletal disorders associated with handle gripping require accurate phalangeal kinetics. Cylindrical handles wrapped with pressure film grids have been used in studies of gripping kinetics. We present a method fusing six degree-of-freedom hand kinematics and a kinematic calibration of a cylinder-wrapped pressure film. Phalanges are modeled as conic frusta and projected onto the pressure grid, automatically segmenting the pressure map into regions of interest (ROIs). To demonstrate the method, segmented pressure maps are presented from two subjects with substantially different hand length and body mass, gripping cylinders 50 and 70 mm in diameter. For each ROI, surface-normal force vectors were summed to create a reaction force vector and center of pressure location. Phalangeal force magnitudes for a data sample were similar to that reported in previous studies. To evaluate our method, a surrogate was designed for each handle such that when modeled as a phalanx it would generate a ROI around the cells under its supports; the classification F-score was above 0.95 for both handles. Both the human subject results and the surrogate evaluation suggest that the approach can be used to automatically segment the pressure map for quantifying phalangeal kinetics of the fingers during cylindrical gripping.


Smad-interacting protein-1 and microRNA 200 family define a nitric oxide-dependent molecular circuitry involved in embryonic stem cell mesendoderm differentiation.
Smad-interacting protein-1 (Sip1/ZEB2) is a transcriptional repressor of the telomerase reverse transcriptase catalytic subunit (Tert) and has recently been identified as a key regulator of embryonic cell fate with a phenotypic effect similar, in our opinion, to that reported for nitric oxide (NO). Remarkably, SIP1/ZEB2 is a known target of the microRNA 200 (miR-200) family. In this light, we postulated that Sip1/ZEB2 and the miR-200 family could play a role during the NO-dependent differentiation of mES. The results of the present study show that Sip1/ZEB2 expression is downregulated during the NO-dependent expression of mesendoderm and early cardiovascular precursor markers, including Flk1 and CXCR4 in mES. Coincidently, members of the miR-200 family, namely miR-429, -200a, -200b, and -200c, were transcriptionally induced in parallel to mouse Tert. This regulation occurred at the level of chromatin. Remarkably, miR-429/miR-200a overexpression or Sip1/ZEB2 knockdown by short hairpin RNA interference elicited a gene expression pattern similar to that of NO regardless of the presence of leukemia inhibitory factor. These results are the first demonstrating that the miR-200 family and Sip1/ZEB2 transcription factor are regulated by NO, indicating an unprecedented molecular circuitry important for telomerase regulation and early differentiation of mES.


Clinical photography in severe idiopathic scoliosis candidate for surgery: is it a useful tool to differentiate among Lenke patterns?
Clinical photography has proven to be reliable for posture assessment in adolescents and young adults with idiopathic scoliosis. This paper attempts to elucidate whether clinical photography is capable of distinguishing the distinctive characteristics in trunk deformity of the different Lenke patterns in patients with severe scoliosis candidate for surgery. One hundred and seventy-three patients (82% women), average age of 20.8 years and average largest curve magnitude of 58.7° were included. PA standing full-spine X-rays and digital photographs from the back of the trunk were measured. It is used to measure magnitude of the proximal thoracic (PTC), main thoracic (MTC) and thoracolumbar/lumbar (TL/LC) curves, T1 tilt and the clavicle-rib intersection angle. It is used to measure shoulder height angle, axilla height angle, waist height angle (WHA), right and left waist angles and trunk areas. One-way ANOVA to test mean differences among Lenke types for radiological and photographic measurements was performed. ROC curve analysis was conducted to find out cutoff values in photographic measurements to differentiate among curve patterns. Most radiological and photographic measurements differ among curve patterns. On ROC curve analysis, solid cutoff values were found for WHA (AUC = 0.8), left waist angle (AUC = 0.81), right waist angle (AUC = 0.81) and the difference between left and right waist angles (AUC = 0.86) to differentiate between types 1 and 2 and the other three types (3, 5 and 6). Clinical photography is a valid method for assessing trunk asymmetry in severe idiopathic scoliosis. Specifically, for waist area measurements, robust cutoff values can be determined to discriminate among different curve patterns according to Lenke classification. These slides can be retrieved under Electronic Supplementary Material.


Spatial structure and Lamarckian adaptation explain extreme genetic diversity at CRISPR locus.
Even within similar bacterial strains, it has been found that the clustered, regularly interspaced short palindromic repeat (CRISPR) shows a large variability of spacers. Modeling bacterial strains with different levels of immunity to infection by a single virulent phage, we find that coexistence in a well-mixed environment is possible only when these levels are distinctly different. When bacterial strains are similar, one subpopulation collapses. In the case of bacteria with various levels of CRISPR immunity to a range of phages, small differences in spacer composition will accordingly be suppressed under well-mixed conditions. Using a numerical model of populations spreading in space, we predict that it is the Lamarckian nature of CRISPR evolution that combines with spatial correlations to sustain the experimentally observed distribution of spacer diversity.


Factors determining the frequency of the killer trait within populations of the Paramecium aurelia complex.
The factors maintaining the cytoplasmically inherited killer trait in populations of Paramecium tetraurelia and Paramecium biaurelia were examined using, in part, computer simulation. Frequency of the K and k alleles, infection and loss of the endosymbionts, recombination during conjugation and autogamy, cytoplasmic exchange and natural selection were incorporated in a model. Infection during cytoplasmic exchange at conjugation and natural selection were factors that would increase the proportion of killers in a population. Conversely, k alleles reduced the proportion of killers in a population, acting through conjugation and autogamy. Field studies indicate that the odd mating type is prevalent in P. tetraurelia isolated from nature. Conjugation and therefore transmission by cytoplasmic transfer would be rare. Competition studies indicate a strong selective disadvantage for sensitives at concentrations found in nature. Natural selection must therefore be the factor maintaining the killer trait in P. tetraurelia.


Measuring client experiences in maternity care under change: development of a questionnaire based on the WHO Responsiveness model.
Maternity care is an integrated care process, which consists of different services, involves different professionals and covers different time windows. To measure performance of maternity care based on clients' experiences, we developed and validated a questionnaire. We used the 8-domain WHO Responsiveness model, and previous materials to develop a self-report questionnaire. A dual study design was used for development and validation. Content validity of the ReproQ-version-0 was determined through structured interviews with 11 pregnant women (≥28 weeks), 10 women who recently had given birth (≤12 weeks), and 19 maternity care professionals. Structured interviews established the domain relevance to the women; all items were separately commented on. All Responsiveness domains were judged relevant, with Dignity and Communication ranking highest. Main missing topic was the assigned expertise of the health professional. After first adaptation, construct validity of the ReproQ-version-1 was determined through a web-based survey. Respondents were approached by maternity care organizations with different levels of integration of services of midwives and obstetricians. We sent questionnaires to 605 third trimester pregnant women (response 65%), and 810 women 6 weeks after delivery (response 55%). Construct validity was based on: response patterns; exploratory factor analysis; association of the overall score with a Visual Analogue Scale (VAS), known group comparisons. Median overall ReproQ score was 3.70 (range 1-4) showing good responsiveness. The exploratory factor analysis supported the assumed domain structure and suggested several adaptations. Correlation of the VAS rating and overall ReproQ score (antepartum, postpartum) supported validity (r = 0.56; 0.59, p<0.001 Spearman's correlation coefficient). Pre-stated group comparisons confirmed the expected difference following a good vs. adverse birth outcome. Fully integrated organizations performed slightly better (median = 3.78) than less integrated organizations (median = 3.63; p<0.001). Participation rate of women with a low educational level and/or a non-western origin was low. The ReproQ appears suitable for assessing quality of maternity care from the clients' perspective. Recruitment of disadvantaged groups requires additional non-digital approaches.


Extreme ultraviolet performance of a multilayer coated high density toroidal grating.
The performance of a multilayer coated diffraction grating has been evaluated at EUV wavelengths both in terms of absolute efficiency and spectral resolution. The application of a ten-layer Ir/Si multilayer coating to a 3600-lines/mm blazed toroidal replica grating produced a factor of 9 enhancement in peak efficiency near the design wavelength approximately 30 nm in first order, without degrading its excellent quasistigmatic spectral resolution. The measured EUV efficiency peaked at 3.3% and was improved over the full spectral range between 25 and 35 nm compared with the premultilayer replica which had a standard gold coating. In addition, the grating's spectral resolution of >5000 was maintained.


Surgical Treatment on Subungual Osteochondromas in Paediatric Feet: A Case Series Study.
Subungual osteochondroma (SO) is an infrequent and non-malignant bone tumour of the distal phalanx, especially prominent in paediatric populations. The aim of this research was to describe a case series of paediatric feet with SO which received surgical treatments. The secondary purpose was to compare these descriptive data by sex distribution. Twenty-three paediatric feet with SO confirmed by clinical or radiological features received surgical treatment. Socio-demographic (age, sex, height, weight and BMI) and clinical features (side, location, tumour or pain presence, and nail lift before surgery, as well as recurrence and adverse effects at one month after intervention) were reported. Regarding clinical features before intervention, the most frequent locations of SO were the first toe (86.8%) and the right lower limb (56.5%). In addition, the presence of the tumour, pain and nail lift showed a prevalence of 91.3%, 69.5% and 47% of the study sample, respectively. Considering clinical features at one month after intervention, the most frequent adverse effect was the pain presence (69.5%). In addition, one case (4.4%) presented ulceration. Only one patient (4.4%) suffered from recurrence with a new tumour. There were not statistically significant differences by sex distribution (p > 0.05). This novel study showed that surgery treatment for SO in paediatric populations presented a very low recurrence degree with minor adverse effects and without differences by sex distribution. Thus, further randomized clinical trials should be carried out in order to determine the effectiveness of this intervention in this special population.


Reprogramming Human Adult Fibroblasts into GABAergic Interneurons.
Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric acid (GABA) expressing interneurons can be generated from different cell sources, such as glia cells or fetal fibroblasts. Nevertheless, the generation of neurons from adult human fibroblasts, an easily accessible cell source to obtain patient-derived neurons, has proved to be challenging due to the intrinsic blockade of neuronal commitment. In this paper, we used an optimized protocol for adult skin fibroblast reprogramming based on RE1 Silencing Transcription Factor (REST) inhibition together with a combination of GABAergic fate determinants to convert human adult skin fibroblasts into GABAergic neurons. Our results show a successful conversion in 25 days with upregulation of neuronal gene and protein expression levels. Moreover, we identified specific gene combinations that converted fibroblasts into neurons of a GABAergic interneuronal fate. Despite the well-known difficulty in converting adult fibroblasts into functional neurons in vitro, we could detect functional maturation in the induced neurons. GABAergic interneurons have relevance for cognitive impairments and brain disorders, such as Alzheimer's and Parkinson's diseases, epilepsy, schizophrenia and autism spectrum disorders.


[Preventive care and treatment of hearing problems in persons exposed to radiation].
Neurosensory hypoacusis (NSHA) was treated in 193 patients exposed to radiation consequently to the Chernobyl accident. The article describes changes observed in the examinees on audiograms, ECG, rheoencephalograms (REG) and acoustic evoked potentials. Treatment of patients with radiation-induced NSHA was aimed at normalization of tonicity of the cerebral vessels, venous outflow, pulse blood filling, arterial pressure, bioelectric activity of the brain, cardiac activity with account to hearing defects in different portions of the acoustic system. The treatment has improved parameters of tonal and speech audiometry, cortical acoustic evoked potentials, REG and EEG in 63.4% of the patients. The rest of the patients achieved stabilization of the process, arrest of progressive hearing loss. Also, positive effects were seen on the general condition of the patients, their working ability. The patients experienced relief of the headache, stuffy ears, noise in the ears, etc.


3D laparoscopic revision thyroidectomy through an anterior chest approach: a case report.
The detection rate of differentiated thyroid cancers, especially the papillary subtype, is rapidly increasing, and these malignancies have an excellent prognosis. Surgery remains the cornerstone of treatment, and numerous innovations in surgical techniques have been made in the past decade. Laparoscopic thyroidectomy is being gradually recognized as a safe and effective surgical procedure with good cosmetic results. Revision thyroidectomy is routinely performed via the open approach and rarely via laparoscopy. Three-dimensional laparoscopy offers advantages over two-dimensional laparoscopy in terms of visualization of the operative field and surgical manipulation and has been used at multiple surgical sites, but is rarely used in thyroid surgery. We present the first case of three-dimensional laparoscopic revision thyroidectomy, which was successfully performed through an anterior chest approach in a young, unmarried woman who was pathologically confirmed to have papillary thyroid cancer after an initial laparoscopic partial thyroidectomy performed 10 days prior to the revision surgery.


The effect of Hydrocortisone on the kinetics of normal human lymphocytes.
Lymphocyte kinetic studies employing 51-chromium-labeled autologous lymphocytes were performed in nine normal volunteers in order to determine the effects of hydrocortisone administration on the recirculating versus the nonrecirculating intravascular lymphocyte pools. Following infusion of labeled cells, the recirculating portion of the labeled cells rapidly equilibrated with the total intravascular lymphocyte pool and the vastly larger total-body recirculating lymphocyte pool, so that by 1 hr following infusion 21.8% plus or minus 3.2% of the labeled lymphocytes were left in the circulation. Four hundred milligrams of intravenous hydrocortisone administered 24 hr after infusion of labeled cells caused a profound but transient lymphocytopenia which was maximal at 4 hr with return of lymphocyte counts to normal by 24 hr after injection. Concomitant with the lymphocytopenia there was a dramatic increase in lymphocyte specific activity (cpm per 10-6 lymphocytes), while the total lymphocyte-associated radioactivity remaining in the circulation was unchanged, indicating that corticosteroid administration depleted the unlabeled recirculating cells. As the lymphocyte counts returned to normal following hydrocortisone, the specific activity also returned to normal. These studies indicated that hydrocortisone administration caused a transient lymphocytopenia by a preferential depletion of the recirculating portion of the intravascular lymphocyte pool


Fluorescence anisotropy of diphenylhexatriene and its cationic Trimethylamino derivative in liquid dipalmitoylphosphatidylcholine liposomes: opposing responses to isoflurane.
The mechanism of action of volatile general anesthetics has not yet been resolved. In order to identify the effects of isoflurane on the membrane, we measured the steady-state anisotropy of two fluorescent probes that reside at different depths. Incorporation of anesthetic was confirmed by shifting of the main phase transition temperature. In liquid crystalline dipalmitoylphosphatidylcholine liposomes, isoflurane (7-25 mM in the bath) increases trimethylammonium-diphenylhexatriene fluorescence anisotropy by ~0.02 units and decreases diphenylhexatriene anisotropy by the same amount. The anisotropy data suggest that isoflurane decreases non-axial dye mobility in the headgroup region, while increasing it in the tail region. We propose that these results reflect changes in the lateral pressure profile of the membrane.


The TRANSPARENT TESTA12 gene of Arabidopsis encodes a multidrug secondary transporter-like protein required for flavonoid sequestration in vacuoles of the seed coat endothelium.
Phenolic compounds that are present in the testa interfere with the physiology of seed dormancy and germination. We isolated a recessive Arabidopsis mutant with pale brown seeds, transparent testa12 (tt12), from a reduced seed dormancy screen. Microscopic analysis of tt12 developing and mature testas revealed a strong reduction of proanthocyanidin deposition in vacuoles of endothelial cells. Double mutants with tt12 and other testa pigmentation mutants were constructed, and their phenotypes confirmed that tt12 was affected at the level of the flavonoid biosynthetic pathway. The TT12 gene was cloned and found to encode a protein with similarity to prokaryotic and eukaryotic secondary transporters with 12 transmembrane segments, belonging to the MATE (multidrug and toxic compound extrusion) family. TT12 is expressed specifically in ovules and developing seeds. In situ hybridization localized its transcript in the endothelium layer, as expected from the effect of the tt12 mutation on testa flavonoid pigmentation. The phenotype of the mutant and the nature of the gene suggest that TT12 may control the vacuolar sequestration of flavonoids in the seed coat endothelium.


Altered interaction between plasminogen activator inhibitor type 1 activity and sympathetic nerve activity with aging.
It has been reported that sympathetic nerve activity (SNA) is associated with fibrinolysis, but the interaction between SNA and the fibrinolytic system with aging has not been elucidated in humans. The purpose of this study was to examine the effect of age-related SNA on the activity of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) using muscle SNA (MSNA). This study included 16 young subjects (mean age 26.1 years) and 10 aged subjects (mean age 56.9 years). Lower body negative pressure (LBNP) was performed at -40 mmHg for 30 min. LBNP significantly increased both tPA and PAI-1 activity (from 5.2+/-0.5 to 7.3+/-1.2 IU/ml and from 2.85+/-0.68 to 4.06+/-0.73 U/ml, p<0.01, respectively) in the aged group. In the young group, tPA activity tended to increase, whereas PAI-1 activity was unchanged. There was a correlation between MSNA and PAI-1 activity in the aged group (r=0.47, p<0.01). SNA in an aging subject leads to an increase in the activity of PAI-1, which indicates that an altered interaction between SNA and PAI-1 activity contributes to increased cardiovascular events in the elderly population.


Correlates of Nonimprovement to Pharmacotherapy for Chronic, Antidepressant-Resistant, Military Service-Related Posttraumatic Stress Disorder: Insights From the Veterans Affairs Cooperative Study No. 504.
Posttraumatic stress disorder (PTSD) is a chronic and often difficult-to-treat condition that is prevalent among military veterans. First-line pharmacotherapy for this population typically involves antidepressants; however, veterans who do not improve are sometimes prescribed antipsychotics such as risperidone. A 2011 randomized controlled trial of adjunctive risperidone versus placebo for veterans with chronic, antidepressant-resistant, military service-related PTSD revealed no difference between groups. Hence, there is a need to examine predictors of nonimprovement for chronic, treatment-resistant PTSD. We examined correlates of nonimprovement and delayed improvement (ie, ≥12 weeks) using data from 267 veterans with chronic, antidepressant-resistant PTSD who were prescribed adjunctive risperidone or a placebo. Veterans received 1 to 4 mg adjunctive risperidone (n = 133; mean dose, 2.74 mg) or a placebo daily (n = 134) in addition to their original treatment regimen over the 24-week trial. Greater severity of PTSD symptoms at baseline, specifically reexperiencing (ie, nightmares) and emotional numbing (ie, sense of foreshortened future), was independently associated with nonimprovement. Of the 194 veterans (72.7%) who did improve, 95 (49.0%) showed delayed improvement, taking 12 weeks or longer to demonstrate a 10-point reduction in Clinician-Administered PTSD Scale scores. Emotional difficulties affecting role functioning, as assessed using the Veterans RAND 36-item Health Survey, independently predicted nonimprovement. While results are indicative of nonspecific pharmacotherapeutic effects, they suggest that specific PTSD symptom clusters and impairment are associated with variable improvement in veterans with antidepressant-resistant PTSD. They underscore the importance of developing more effective and targeted pharmacotherapies for specific symptom clusters in this population.


Comparative toxicity of the cardiovascular toxin allylamine to porcine aortic smooth muscle and endothelial cells.
This study supports a recent hypothesis that the cardiovascular toxin, allylamine, is toxic to smooth muscle cells of large elastic arteries (aorta). Cultures of the porcine aortic smooth muscle, endothelial, and fibroblastic cells were exposed to varying concentrations of allylamine ranging from 5 microM to 340 microM. Monitored cytotoxic and cytolytic activities demonstrated that final concentrations of 60 microM allylamine decreased cell population viability of smooth muscle cells as much as 50%. Viability decreased approximately linearly with increasing concentrations of allylamine including spontaneous lysing of smooth muscle cells at 90 microM. Endothelial cells were more resistant to lower concentrations of allylamine requiring 90 microM to decrease cell population viability by 50%. In contrast, fibroblastic cells were very resistant to lower concentrations of allylamine. The specific lytic response of these cells in culture, measured by release of [3H]thymidine, gave findings parallel to the viability studies, i.e. at 100 microM allylamine smooth muscle cells demonstrated 75% specific lysis while endothelial cells showed 29%. Growth studies of cells surviving an 8-h exposure to allylamine indicate that surviving endothelial cells have better growth characteristics than surviving smooth muscle cells; both cell lines are also apparently injured at concentrations of allylamine much lower than the CT50. These studies show that of the cellular components of the vascular wall, smooth muscle cells appear to be the most sensitive to the toxic effects of allylamine.


A predictive model of the dynamics of body weight and food intake in rats submitted to caloric restrictions.
Dynamics of body weight and food intake can be studied by temporally perturbing food availability. This perturbation can be obtained by modifying the amount of available food over time while keeping the overall food quantity constant. To describe food intake dynamics, we developed a mathematical model that describes body weight, fat mass, fat-free mass, energy expenditure and food intake dynamics in rats. In addition, the model considers regulation of food intake by leptin, ghrelin and glucose. We tested our model on rats experiencing temporally variable food availability. Our model is able to predict body weight and food intake variations by taking into account energy expenditure dynamics based on a memory of the previous food intake. This model allowed us to estimate this memory lag to approximately 8 days. It also explains how important variations in food availability during periods longer than these 8 days can induce body weight gains.


Abnormal relationship between medial temporal lobe and subcortical dopamine function in people with an ultra high risk for psychosis.
Neuroimaging studies in humans have implicated both dysfunction of the medial temporal lobe (MTL) and the dopamine system in psychosis, but the relationship between them is unclear. We addressed this issue by measuring MTL activation and striatal dopaminergic function in individuals with an At Risk Mental State (ARMS) for psychosis, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), respectively. Thirty-four subjects (20 ARMS and 14 Controls), matched for age, gender, digit span performance, and premorbid IQ, were scanned using fMRI, while performing a verbal encoding and recognition task, and using 18F-DOPA PET. All participants were naïve to antipsychotic medication. ARMS subjects showed reduced MTL activation when encoding words and made more false alarm responses for Novel words than controls. The relationship between striatal dopamine function and MTL activation during both verbal encoding and verbal recognition was significantly different in ARMS subjects compared with controls. An altered relationship between MTL function and dopamine storage/synthesis capacity exists in the ARMS and may be related to psychosis vulnerability.


Assessing work ability--a cross-sectional study of interrater agreement between disability claimants, treating physicians, and medical experts.
It is unclear to what extent assessments of work ability differ between disability claimants, their treating physicians, and multidisciplinary medical expert teams. We compared assessments of work ability for consecutive disability claimants referred to a multidisciplinary assessment center in Switzerland over a 4-year period. Assessments were made for the last job (LJ) prior to claiming a disability benefit and an alternative job (AJ) thought to suit the claimant's physical and mental abilities. Mean differences (MD) in percentage work ability between assessments from claimants, physicians, and experts were then estimated in a linear regression model. The 3562 claims made during the study period were mostly due to musculoskeletal and depressive disorders. Assessments differed little between claimants and physicians [LJ MD 1.3% (95% confidence interval [95% CI] 0.5-2.2%); AJ MD 11% (95% CI 10-12%)]. Experts on average assessed a claimant's work ability higher than either the claimant or physician, particularly in the AJ [MD between expert and claimant 57% (95% CI 56-58%) and between expert and physician 46% (95% CI 45-48%)]. Assessments of work ability differed substantially between experts in multidisciplinary medical teams and both claimants and their treating physicians. A careful evaluation of the disability assessment process is needed in an effort to reduce disagreement between expert teams and treating physicians and so improve acceptance of the process.


A prospective study of the use of alternative therapies by men with localized prostate cancer.
Although the use of alternative therapies is highly prevalent amongst men with prostate cancer, research about the predictors of such use is limited. The current study aimed to describe prospectively the use of alternative therapies by men diagnosed with localized prostate cancer and identify predictors of alternative therapy use. In all, 111 men newly diagnosed with localized prostate cancer (93% response) were recruited to the study prior to treatment. Men's use of alternative therapies and psychological variables including: psychological distress, orientation to health care, decisional conflict, and health locus of control, were assessed at three time points-(1) before treatment; (2) 2 months after completion of treatment; and (3) 12 months after completion of treatment. Demographic information was also obtained. The percentage of men using alternative therapies was 25, 17 and 14% before treatment, 2 and 12 months after treatment, respectively. In general, the most commonly used therapies were dietary changes, vitamins and herbal and nutrient remedies. Alternative therapy use was not related to final treatment choices. Before treatment, men who used alternative therapies were more uncertain about prostate cancer compared to men who were not using these therapies. Men who were using alternative therapies 12 months after treatment were less psychologically distressed that men who were not using these therapies. Health locus of control and orientation to health care were not found to be related to men's use of alternative therapies. In conclusion, men's use of alternative therapies after localized prostate cancer varied across time in terms of the incidence of use, the types of therapies used, and the psychological correlates of therapy use. Informational support that targets uncertainty about prostate cancer may assist men at diagnosis who are considering alternative therapy use. The potential for alternative therapies to have a supportive function in patient care requires further investigation.


Assessment of Agaricus Bisporus S-II Extract as a Bio-Controlling Agent against Human Pathogenic Bacterial Species.
Agaricus bisporus mushrooms are well known for their nutritional and medicinal values. A. bisporus is a source of protein (about 40% on a dry basis), ergosterol, several minerals, carbohydrate, and fat. The present study was conducted to investigate the effect of A. bisporus S-II extracts on human pathogenic bacteria in-vitro condition. Totally, three human pathogenic bacterial strains (MTCC culture type) were procured from the Institute of Microbial Technology, India. Out of these three bacterial strains, one was Gram-negative (namely P. aeruginosa MTCC741), and the other two were Gram-positive (B. cereus MTCC9786 and S. aureus MTCC740). Microdilution assay was applied for the evaluation of the minimum inhibitory concentration (MIC). The highest antimicrobial activity was observed in methanol extract (26.5%) against S. aureus MTCC740, compared to ethanol extract (17%). Similar results were obtained for P. aeruginosa MTCC741 (21.8%) and B. cereus MTCC9786 (15%) in methanol extract. Least microbial growth inhibition observed for B. cereus MTCC9786 (13.82%) followed by P. aeruginosa MTCC741 (14%), compared to control in ethanol extract. The highest antimicrobial activity up to 17% with ethanolic extracts recorded against S. aureus MTCC740. The MIC results in microtitre plates showed the growth inhibition of P. aeruginosa MTCC741 and S. aureus MTCC740 at extract concentrations of 15 mg/ml and 20 mg/ml, respectively. However, no MIC detected for B. cereus MTCC9786 below 20 mg/ml extract concentration. Regarding minimum bactericidal concentration, the bactericidal value for P. aeruginosa MTCC741 and S. aureus MTCC740 was obtained at 10 mg/ml concentration. The present study indicated that the extracts of the A. bisporus S-II mushrooms had promising antimicrobial activities against the tested organisms.


PRELIMINARY EVALUATION OF NOVEL BODILY ATTENTION TASK TO ASSESS THE ROLE OF THE BRAIN IN CHEMOTHERAPY-INDUCED PERIPHERAL NEUROTOXICITY (CIPN).
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, sometimes dose-limiting side effect of neurotoxic chemotherapy. Treatment is limited because its pathophysiology is poorly understood. Compared to research on peripheral mechanisms, the role of the brain in CIPN is understudied and it may be important to develop better treatments. We propose a novel task that assesses brain activation associated with attention to bodily sensations (interoception), without the use of painful stimulation, to understand how CIPN symptoms may be processed in the brain. The goals of this preliminary study were to assess, 1) feasibility of the task, 2) sensitivity to changes in brain activity, and 3) suitability for assessing relationships between brain activation and CIPN severity. Eleven participants with varying types of cancer completed a brain fMRI scan and rated CIPN severity (CIPN-20) before and/or 12 weeks after starting neurotoxic chemotherapy. The Bodily Attention Task is a 7.5-min long fMRI task involving attentional focus on the left fingertips, the heart, or a flashing word "target" for visual attention (reference condition). Feasibility was confirmed, as 73% of all data collected were usable and participants reported feeling or focus during 75% of the trials. Regarding brain activity, finger attention increased activation in somatosensory regions (primary sensory cortex, insula) and sensory integration regions (precuneus, dorsolateral prefrontal cortex). Exploratory analyses suggested that brain activation may be associated with CIPN severity. A larger sample size and accounting of confounding factors is needed to test for replication and to identify brain and interoceptive biomarkers to help improve the prediction, prevention, and treatment of CIPN.


Multiple dimensions of embodiment in medical practices.
In this paper I explore the various meanings of embodiment from a patient's perspective. Resorting to phenomenology of health and medicine, I take the idea of 'lived experience' as starting point. On the basis of an analysis of phenomenology's call for bracketing the natural attitude and its reduction to the transcendental, I will explain, however, that in medical phenomenological literature 'lived experience' is commonly one-sidedly interpreted. In my paper, I clarify in what way the idea of 'lived experience' should be revisited and, subsequently, what this reconsideration means for phenomenological research on embodiment in health and medicine. The insight that the body is a condition of possibility for world-disclosing yet, at the same time, itself conditioned by this world forces us to not only zoom in on the body's subject-side, but also on its object-side. I argue that in order to render account for this double body ontology, phenomenology should include empirical sociological analyses as well. I thus argue in favor of the idea of a socio-phenomenology. Drawing on material from my own research project on embodied self-experiences after breast surgery, I show how this approach can be fruitful in interpreting the impact of disfigurements on a person's embodied agency, or a person's 'I can'.


An arterial and venous graft holder for coronary artery bypass grafting.
An innovative arterial and venous graft holder has been developed for use during proximal and distal anastomosis in coronary artery bypass grafting. The device consists of a flexible arm and a handle. The handle in turn is composed of three parts: (1) a T-shaped body, (2) an atraumatic clip for holding the graft, and (3) a coronary probe attached by an adjustable fixation screw to the body. The handle can be used to easily hold the graft either by an assistant or attached to a flexible arm. The flexible arm can be used while attached to a standard sternal retractor or a railway sternal retractor. It facilitates opening the heel of the graft and stitching the most difficult angle of the anastomosis. This new instrument provides excellent exposure and a more comfortable anastomosis.


Complement receptor enhancement and chemotaxis of human neutrophils and eosinophils by leukotrienes and other lipoxygenase products.
The lipoxygenase products of arachidonic acid, 5-HPETE, 5-HETE, LTB4, LTC4 and LTD4, were examined for their capacity to enhance the expression of complement (C3b) receptors and to evoke chemotaxis of human neutrophils and eosinophils. With the exception of LTD4 all gave enhancement of C3b receptors. LTB4 and LTC4 enhanced over the concentration range 10(-7) to 10(-11) moles/l, and 5-HETE and 5-HPETE from 5 X 10(-6) to 5 X 10(-10) moles/l. The rank order of activity, as assessed by the magnitude of enhancement, was LTB4 (concentration for maximal effect = 10(-7) moles/l) greater than 5-HETE (5 X 10(-7)) greater than 5-HPETE (5 X 10(-6)) greater than LTC4 (10(-9)). High dose inhibition was observed with LTC4 and 5-HETE. Chemotaxis experiments performed in parallel over the same concentration ranges indicated that neither neutrophils nor eosinophils migrated towards LTC4 or LTD4. However, LTB4 evoked chemotaxis with a linear dose response from 10(-9) to 10(-7) moles/l and 5-HPETE and 5-HETE from 5 X 10(-8) to 5 X 10(-6) moles/l. At 10(-7) moles/l LTB4 was approximately 6 and 8 X more potent in chemotaxis than 5-HPETE and 5-HETE respectively. In general, complement receptor enhancement and chemotaxis of eosinophils were similar to that observed with neutrophils and did not vary with the patient source.