Dual Mini-Fragment Plate Fixation of Midshaft Clavicle Fractures Reduces Risk of Reoperation Compared With Single-Plate Fixation Techniques.
Recent studies have highlighted dual plating as a method of reducing high rates of postoperative complication after operative management of displaced midshaft clavicular fractures. However, few studies have reliably characterized reoperation rates and magnitude of risk reduction achieved when using dual versus anterior and superior single-plate techniques. There would be lower rates of reoperation among patients who underwent open reduction and internal fixation (ORIF) of displaced midshaft clavicular fractures via dual plating. Cohort study; Level of evidence, 3. This was a retrospective analysis of patients who underwent ORIF for a displaced midshaft clavicular fracture between 2010 and 2021 at a level 1 trauma center with a minimum 12-month follow-up. Patients were separated into 3 cohorts based on fixation type: (1) orthogonal dual mini-fragment plate fixation, (2) superior plate fixation, and (3) anterior plate fixation. Data on patient characteristics, fracture pattern, and reoperations were documented. All-cause reoperation rates and hazard ratio (HR) estimates of dual, superior, and anterior plating were calculated using a multivariate multilevel mixed-effects parametric survival model. Significant confounders including high-risk fracture morphology and smoking status were controlled for in the final model. A final cohort of 256 patients was identified with mean follow-up of 4.9 ± 3.8 years. In total, 101 patients underwent superior plating, 92 underwent anterior plating, and 63 underwent dual plating. Overall, 31 reoperations took place (18 in superior, 12 in anterior, 1 in dual plating) among 22 patients. Major contributors to reoperation included symptomatic hardware (n = 11), nonunion (n = 8), deep infection (n = 7), and wound dehiscence (n = 2). Superior plating revealed the highest reoperation rate of 0.031 per person-years, followed by anterior plating with 0.026 per person-years and dual plating with 0.005 per person-years. Overall, single plating (either anterior or superior placement) had a nearly 8-fold greater risk of reoperation than dual plating (HR, 7.62; 95% CI, 1.02-56.82; P = .048). Further broken down by technique, superior plating had an 8-fold greater risk of reoperation than dual plating (HR, 8.36; 95% CI, 1.10-63.86; P = .041), but anterior plating did not demonstrate a statistically significant difference compared with dual plating (HR, 6.79; 95% CI, 0.87-52.90; P = .068). Dual-plate fixation represents an excellent treatment for displaced midshaft clavicular fractures, with low rates of nonunion and reoperation. When compared with single locked superior or anterior plate fixation, dual mini-fragment plate fixation has a nearly 8-fold lower risk of reoperation.


A chronic bile duct and intravenous cannulation model in conscious rabbits for pharmacokinetic studies.
In the development of novel pharmaceutical compounds, pharmacokinetic parameters, such as the extent of biliary excretion, must be characterized. Pharmacokinetic studies in nonrodent species, typically dogs, are generally required for new drug approvals. However, in some cases, rabbits may be a more desirable model. We developed a surgical procedure for the intermittent or continuous collection of bile for long-term use. This surgery involves the removal of the gallbladder and cannulation of the proximal and distal aspects of the common bile duct using a 40 cm flexible surgical-grade cannula. The cannula loop is passed subcutaneously and exteriorized between the scapulae to divert bile flow. During use, the proximal cannula segment is attached to a collection container placed in a nylon torso jacket worn by the animal, and the distal segment of catheter is sealed with a stainless-steel adapter. An auricular catheter, secured by ligatures, is placed aseptically into the lateral ear vein and the tip is advanced to the cranial vena cava for serial blood collection. Daily infusions of a heparinized saline "lock" ensure patency. These procedures have been used in 18 rabbits for up to 1 month without clinical complications. Complete blood counts, biochemical profiles, body weights, and bile flow were monitored weekly and reflected normal enterohepatic circulation.


Teaching and learning medical ethics.
Three main questions are central to teaching and learning medical ethics. Can ethics be taught? If it can, what are some of its teachable components? And what teaching methods are appropriate? The author supports the concept of ethical competence as the basis of an ethical practice. Ethical competence is a set of insights, skills, understandings, ways of thinking which can be taught. The parallel is drawn between these kinds of competencies and the components of rigorous thinking characteristic of the training and experience of medical problem-solvers. Finally the author takes up four common criticisms of this approach.


Effects of Hyperglycemia on Vascular Smooth Muscle Ca2+ Signaling.
Diabetes is a complex disease that is characterized with hyperglycemia, dyslipidemia, and insulin resistance. These pathologies are associated with significant cardiovascular implications that affect both the macro- and microvasculature. It is therefore important to understand the effects of various pathologies associated with diabetes on the vasculature. Here we directly test the effects of hyperglycemia on vascular smooth muscle (VSM) Ca2+ signaling in an isolated in vitro system using the A7r5 rat aortic cell line as a model. We find that prolonged exposure of A7r5 cells to hyperglycemia (weeks) is associated with changes to Ca2+ signaling, including most prominently an inhibition of the passive ER Ca2+ leak and the sarcoplasmic reticulum Ca2+-ATPase (SERCA). To translate these findings to the in vivo condition, we used primary VSM cells from normal and diabetic subjects and find that only the inhibition of the ER Ca2+ leaks replicates in cells from diabetic donors. These results show that prolonged hyperglycemia in isolation alters the Ca2+ signaling machinery in VSM cells. However, these alterations are not readily translatable to the whole organism situation where alterations to the Ca2+ signaling machinery are different.


A review of the health-related quality of life literature in bipolar disorder.
This paper reviews the existing literature on health-related quality of life assessments conducted in bipolar disorder patients, and provides recommendations for the use of specific scales to measure health-related quality of life in this population. A comprehensive review of the literature revealed only a handful of studies in bipolar disorder that had incorporated quality of life assessments. While instruments from the medical outcomes study (MOS) were the most frequently used to measure health-related quality of life, a number of other instruments like the psychological general well being scale (PGWB), the streamlined longitudinal interview clinical evaluation from the longitudinal interval follow-up evaluation (SLICE/LIFE), the Euroqol, (EQ-5D), the Lehman's quality of life interview (QLI), and the quality of life in depression scale (QLDS) were also used. Only three studies out of ten reported the psychometric properties of the measures used. In the absence of a disease-targeted measure, a combination of the SF-36 and the PGWB is presently recommended as the battery of choice to assess the health-related quality of life of individuals with bipolar disorder. There is also the need to develop a disease-targeted health-related quality of life measure for bipolar disorder, which will obviate the use of a burdensome battery of generic quality of life instruments.


Recombinant proteins derived from immunodominant regions of the gag and env genes of HIV-1 and their potential for use in serologic diagnosis.
Based on the published sequences of human immunodeficiency virus (HIV-1) isolates highly conserved regions of the gag and env genes containing immunodominant epitopes were selected and expressed in E. coli. The expression vectors pKK24 and pEX41 produced viral proteins recognized by sera obtained from HIV-1 seropositive individuals. A testing system was designed to determine the practical value of bacterially synthesized proteins of HIV-1 gag and env genes for serodiagnosis of HIV-1 infection.


An Implanted Vestibular Prosthesis Improves Spatial Orientation in Animals with Severe Vestibular Damage.
Gravity is a pervasive environmental stimulus, and accurate graviception is required for optimal spatial orientation and postural stability. The primary graviceptors are the vestibular organs, which include angular velocity (semicircular canals) and linear acceleration (otolith organs) sensors. Graviception is degraded in patients with vestibular damage, resulting in spatial misperception and imbalance. Since minimal therapy is available for these patients, substantial effort has focused on developing a vestibular prosthesis or vestibular implant (VI) that reproduces information normally provided by the canals (since reproducing otolith function is very challenging technically). Prior studies demonstrated that angular eye velocity responses could be driven by canal VI-mediated angular head velocity information, but it remains unknown whether a canal VI could improve spatial perception and posture since these behaviors require accurate estimates of angular head position in space relative to gravity. Here, we tested the hypothesis that a canal VI that transduces angular head velocity and provides this information to the brain via motion-modulated electrical stimulation of canal afferent nerves could improve the perception of angular head position relative to gravity in monkeys with severe vestibular damage. Using a subjective visual vertical task, we found that normal female monkeys accurately sensed the orientation of the head relative to gravity during dynamic tilts, that this ability was degraded following bilateral vestibular damage, and improved when the canal VI was used. These results demonstrate that a canal VI can improve graviception in vestibulopathic animals, suggesting that it could reduce the disabling perceptual and postural deficits experienced by patients with severe vestibular damage.SIGNIFICANCE STATEMENT Patients with vestibular damage experience impaired vision, spatial perception, and balance, symptoms that could potentially respond to a vestibular implant (VI). Anatomic features facilitate semicircular canal (angular velocity) prosthetics but inhibit approaches with the otolith (linear acceleration) organs, and canal VIs that sense angular head velocity can generate compensatory eye velocity responses in vestibulopathic subjects. Can the brain use canal VI head velocity information to improve estimates of head orientation (e.g., head position relative to gravity), which is a prerequisite for accurate spatial perception and posture? Here we show that a canal VI can improve the perception of head orientation in vestibulopathic monkeys, results that are highly significant because they suggest that VIs mimicking canal function can improve spatial orientation and balance in vestibulopathic patients.


The Minimal Clinically Important Difference, Patient Acceptable Symptom State, and Clinical Outcomes of Anterior Cruciate Ligament Repair Versus Reconstruction: A Matched-Pair Analysis From the SANTI Study Group.
There has been increasing interest in anterior cruciate ligament (ACL) repair because of theoretical advantages over ACL reconstruction; however, the contemporary literature has failed to provide high-quality evidence to demonstrate these advantages. To compare the clinical and functional outcomes of ACL repair versus ACL reconstruction at a minimum follow-up of 2 years. Cohort study; Level of evidence, 3. Patients who underwent ACL repair were propensity matched (based on demographics, time between injury and surgery, knee laxity parameters, presence of meniscal lesions, preoperative activity level, and sport participation), in a 1:1 ratio, to those who underwent ACL reconstruction during the same period. Isokinetic testing was used to evaluate strength deficits at 6 months postoperatively. Knee laxity parameters were evaluated at 12 months. Complications, return to sport, and patient-reported outcome scores were recorded at final follow-up. In total, 75 matched pairs (150 patients) were evaluated. The repair group had significantly better mean hamstring muscle strength at 6 months compared with the reconstruction group (1.7% ± 12.2% vs -10.0% ± 12.8%, respectively; P < .0001). At a mean final follow-up of 30.0 ± 4.8 months, the repair group had a significantly better mean Forgotten Joint Score-12 (FJS-12) score compared with the reconstruction group (82.0 ± 15.1 vs 74.2 ± 21.7, respectively; P = .017). Noninferiority criteria were met for ACL repair, compared with ACL reconstruction, with respect to the subjective International Knee Documentation Committee score (86.8 ± 9.0 vs 86.7 ± 10.1, respectively; P < .0001) and side-to-side anteroposterior laxity difference (1.1 ± 1.4 vs 0.6 ± 1.0 mm, respectively; P < .0001). No significant differences were found for other functional outcomes or the pivot-shift grade. There were no significant differences in the rate of return to the preinjury level of sport (repair group: 74.7%; reconstruction group: 60.0%; P = .078). A significant difference was observed regarding the occurrence of ACL reruptures (repair group: 5.3%; reconstruction group: 0.0%; P = .045). Patients who experienced a failure of ACL repair were significantly younger than those who did not (26.8 vs 40.7 years, respectively; P = .013). There was no significant difference in rupture rates between the repair and reconstruction groups when only patients aged >21 years were considered (2.9% vs 0.0%, respectively; P = .157). The minimal clinically important difference and Patient Acceptable Symptom State (PASS) thresholds were defined for the ACL repair group. A significantly greater proportion of patients in the repair group achieved the PASS for the FJS-12 compared with their counterparts in the reconstruction group (77.3% vs 60.0%, respectively; P = .034). ACL repair was associated with some advantages over ACL reconstruction including superior hamstring muscle strength at 6 months and significantly better FJS-12 scores. However, the failure rate was significantly higher after ACL repair, and younger patients were particularly at risk.


[Hyperbaric oxygen therapy in the successful treatment of two cases of radiation-induced hemorrhagic cystitis].
Hemorrhagic cystitis resulting from radiation to pelvic visceral malignant lesions often might be incurable and there have been established no definitive treatment. We experienced 2 cases with radiation-induced severe hemorrhagic cystitis refractory to conventional therapy. The treatment with hyperbaric oxygen to control hematuria was performed and obtained successful results. Gross hematuria was disappeared and cystoscopic figure was remarkably improved. No remarkable side-effect was observed in both patient. This experience suggested that hyperbaric oxygen could be considered the primary treatment for patient with radiation-induced hemorrhagic cystitis instead of usual treatment.


Modeling the Cluster Size Distribution of Vascular Endothelial Growth Factor (VEGF) Receptors.
We previously developed a method of defining receptor clusters in the membrane based on mutual distance and applied it to a set of transmission microscopy images of vascular endothelial growth factor receptors. An optimal length parameter was identified, resulting in cluster identification and a procedure that assigned a geometric shape to each cluster. We showed that the observed particle distribution results were consistent with the random placement of receptors within the clusters and, to a lesser extent, the random placement of the clusters on the cell membrane. Here, we develop and validate a stochastic model of clustering, based on a hypothesis of preexisting domains that have a high affinity for receptors. The proximate objective is to clarify the mechanism behind cluster formation and to estimate the effect on signaling. Receptor-enriched domains may significantly impact signaling pathways that rely on ligand-induced dimerization of receptors. We define a simple statistical model, based on the preexisting domain hypothesis, to predict the probability distribution of cluster sizes. The process yielded sets of parameter values that can readily be used in dynamical calculations as the estimates of the quantitative characteristics of the clustering domains.


Construction of a proteome profile and functional analysis of the proteins involved in the initiation of mouse spermatogenesis.
Spermatogenesis is a complex process of terminal differentiation wherein mature sperm are produced. In the first wave of mouse spermatogenesis, different spermatogenic cells appear at specific time points, and their appearance is expected to be accompanied by changes in specific protein expression patterns. In this study, we used 2D-PAGE and MALDI-TOF/TOF technology to construct a comparative proteome profile for mouse testis at specific time points (days 0, 7, 14, 21, 28, and 60 postpartum). We identified 362 differential protein spots corresponding to 257 different proteins. Further cluster analysis revealed 6 expression patterns, and bioinformatics analysis revealed that each pattern was related to many specific cell processes. Among them, 28 novel proteins with unknown functions neither in somatic cells nor germ cells were identified, 8 of which were found to be uniquely or highly expressed in mouse testes via comparison with the GNF SymAtlas database. Further, we randomly selected 7 protein spots and the above 8 novel proteins to verify the expression pattern via Western blotting and RT-PCR, and 6 proteins with little information in testis were further investigated to explore their cellular localization during spermatogenesis by performing immunohistochemistry for the mouse testis tissue. Taken together, the above results reveal an important proteome profile that is functional during the first wave of mouse spermatogenesis, and they provide a strong basis for further research.


Evaluating the feasibility of the Community Score Card and subsequent contraceptive behavior in Kisumu, Kenya.
Women seeking family planning services from public-sector facilities in low- and middle-income countries sometimes face provider-imposed barriers to care. Social accountability is an approach that could address provider-imposed barriers by empowering communities to hold their service providers to account for service quality. Yet little is known about the feasibility and potential impact of such efforts in the context of contraceptive care. We piloted a social accountability intervention-the Community Score Card (CSC)-in three public healthcare facilities in western Kenya and use a mix of quantitative and qualitative methodologies to describe the feasibility and impact on family planning service provision. We implemented and evaluated the CSC in a convenience sample of three public-sector facility-community dyads in Kisumu County, Kenya. Within each dyad, communities met to identify and prioritize needs, develop corresponding indicators, and used a score card to rate the quality of family planning service provision and monitor improvement. To ensure young, unmarried people had a voice in identifying the unique challenges they face, youth working groups (YWG) led all CSC activities. The feasibility and impact of CSC activities were evaluated using mystery client visits, unannounced visits, focus group discussions with YWG members and providers, repeated assessment of score card indicators, and service delivery statistics. The involvement of community health volunteers and supportive community members - as well as the willingness of some providers to consider changes to their own behaviors-were key score card facilitators. Conversely, community bias against family planning was a barrier to wider participation in score card activities and the intractability of some provider behaviors led to only small shifts in quality improvement. Service statistics did not reveal an increase in the percent of women receiving family planning services. Successful and impactful implementation of the CSC in the Kenyan context requires intensive community and provider sensitization, and pandemic conditions may have muted the impact on contraceptive uptake in this small pilot effort. Further investigation is needed to understand whether the CSC - or other social accountability efforts - can result in improved contraceptive access.


Addressing Data Aggregation and Data Inequity in Race and Ethnicity Reporting and the Impact on Breast Cancer Disparities.
Collecting and reporting data on race and ethnicity is vital to understanding and addressing health disparities in the United States. These health disparities can include increased prevalence and severity of disease, poorer health outcomes, decreased access to healthcare, etc., in disadvantaged populations compared with advantaged groups. Without these data, researchers, administrators, public health practitioners, and policymakers are unable to identify the need for targeted interventions and assistance. When researching or reporting on race and ethnicity, typically broad racial categories are used. These include White or Caucasian, Black or African American, Asian American, Native Hawaiian or Other Pacific Islander, or American Indian and Alaska Native, as well as categories for ethnicity such as Latino or Hispanic or not Latino or Hispanic. These categories, defined by the Office of Management and Budget, are the minimum standards for collecting and reporting race and ethnicity data across federal agencies. Of note, these categories have not been updated since 1997. The lack of accurate and comprehensive data on marginalized racial and ethnic groups limits our understanding of and ability to address health disparities. This has implications for breast cancer outcomes in various populations in this country. In this paper, we examine the impact data inequity and the lack of data equity centered processes have in providing appropriate prevention and intervention efforts and resource allocations.


Tolosa-Hunt syndrome: MRI appearances.
A review of MRI findings in seven patients with Tolosa-Hunt syndrome was carried out. Seven patients presented with unilateral painful ophthalmoplegia. Magnetic resonance imaging studies were carried out to evaluate the cavernous sinuses and orbits. Coronal fast spin-echo T2-weighted images and fat-saturated T1-weighted coronal and transverse images with and without contrast enhancement were obtained for the cavernous sinuses and orbits. All patients showed focal-enhancing masses expanding the ipsilateral cavernous sinus. In one patient the mass was extending to the orbital apex and intraorbitally. All patients recovered on corticosteroid therapy and resolution of the masses was documented on follow-up MRI studies in five patients. One patient had a relapse of symptoms after discontinuing therapy. Magnetic resonance imaging studies of the cavernous sinus and orbital apex show high sensitivity for the detection and follow up of inflammatory mass lesions in Tolosa-Hunt syndrome. Magnetic resonance imaging should be the initial screening study in these patients.


EAU guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma.
On behalf of the European Association of Urology (EAU) guidelines for diagnosis, therapy and follow-up of upper urinary tract transitional cell carcinoma (UUTT) patients were established. Criteria for recommendations are based of level 2 only, as large randomised clinical trials have not been performed in this type of disease. A systematic literature research using Medline Services was conducted. References were weighted by a panel of experts. TNM classification 2002 is recommended. Recommendations are developed for diagnosis, radical and conservative treatment and for local chemo-immunotherapy. Prognostic factors are defined. Recommendations for follow-up after different types of treatment are given.


Ethics and Medical Toxicology Research.
Optimizing care in medical toxicology necessitates designing and conducting ethical research. Nevertheless, the context of medical toxicology can make clinical research ethically challenging for a variety of reasons: medical toxicology is typified by relative rare conditions; making precise and rapid diagnoses is often fraught with uncertainty; emergent and urgent clinical exigencies make consent difficult or impossible; and some exposures are stigmatized or related to illegal activities that can compromise collecting accurate data from patients. In this paper, we examine some of the ethical issues in medical toxicology research that are especially salient in effort to promote optimal research in the field. The particular issues to be addressed are as follows: (1) rare conditions and orphan agents, (2) randomization and control arms, (3) inclusion and exclusion criteria, (4) outcome measures, (5) consent, (6) confidentiality, (7) registries, (8) oversight, and (9) transparency and reporting. Thinking about these ethical issues prospectively will help researchers and clinicians appropriately navigate them.


Coronary artery calcification and chronically decreased GFR in living kidney donors.
In the presence of decreased glomerular filtration rate (GFR), the risk of morbidity and mortality caused by cardiovascular disease (CVD) is increased markedly. Increased coronary artery calcification (CAC) is proposed as a pathogenetic link between CVD and chronic kidney disease. We examined the frequency and severity of CAC in living kidney donors to test the hypothesis that decreased GFR is associated with increased CAC. We used multidetector spiral computed tomography to examine CAC in 101 living kidney donors and 99 age- and sex-matched healthy control subjects without diabetes and a history of coronary artery disease. The extent of calcification was measured by means of the Agatston score. GFR was calculated by using the abbreviated Modification of Diet in Renal Disease formula. The frequency of risk factors for coronary artery disease was compared in kidney donors and controls, and the relation between kidney donors' clinical characteristics and the presence or absence of CAC was examined. CAC frequency and mean calcification scores were similar between kidney donors (13.9%; 4.5 +/- 22.6) and controls (17.2%; 13.2 +/- 89.2). CAC was not associated with decreased GFR, and the correlation between CAC and GFR was not statistically significant. Kidney donors with calcification were more likely to be older (P = 0.003) and male (P = 0.001). Age- and sex-adjusted analysis showed an association between greater parathormone levels (odds ratio, 1.023; 95% confidence interval, 1.001 to 1.045; P = 0.037) and CAC in kidney donors. A mild decrease in GFR without the presence of diabetes does not seem to be associated with increased CAC. These findings need to be confirmed in different and larger study populations.


Harnessing speckle for a sub-femtometre resolved broadband wavemeter and laser stabilization.
The accurate determination and control of the wavelength of light is fundamental to many fields of science. Speckle patterns resulting from the interference of multiple reflections in disordered media are well-known to scramble the information content of light by complex but linear processes. However, these patterns are, in fact, exceptionally rich in information about the illuminating source. We use a fibre-coupled integrating sphere to generate wavelength-dependent speckle patterns, in combination with algorithms based on the transmission matrix method and principal component analysis, to realize a broadband and sensitive wavemeter. We demonstrate sub-femtometre wavelength resolution at a centre wavelength of 780 nm, and a broad calibrated measurement range from 488 to 1,064 nm. This compares favourably to the performance of conventional wavemeters. Using this speckle wavemeter as part of a feedback loop, we stabilize a 780 nm diode laser to achieve a linewidth better than 1 MHz.


Successful regrafting of a transplanted liver.
We report on the successful regrafting of a transplanted liver. The donor liver was first grafted into a patient suffering from cryptogenic cirrhosis; the patient died 1 day after the elective transplantation of cerebral bleeding. The well-functioning graft was harvested again and transferred to our institution. After another 12 h of cold ischemia, the liver was reperfused in an urgently registered patient with recurrence of hepatitis B in his first graft. The transplantation was successfully performed and the patient is now doing well, more than 5 months after regrafting with the reused liver.


Troponin for acute coronary syndromes: has NICE got it right?
The guidelines on the use of glycoprotein IIb/IIIa inhibitors for acute coronary syndromes issued by the National Institute for Clinical Excellence (NICE) recommend that blood troponin is used to identify patients who might benefit from therapy. There are, however, a number of circumstances in which troponin results may be misleading. Firstly, the trials which comprise the evidence base for the therapeutic effect were only based on patients with documented coronary artery disease. Secondly, troponin is elevated in patients with heart failure and concentrations fall with appropriate treatment. Thirdly, there is no internationally accepted standard for troponin, and there are therefore important differences at the 'cut-off' values between the methods of different manufacturers. Fourthly, immunoassays suffer from interfering antibodies and at least 17 case reports have been published outlining false positive tests. It is important that the shortfalls of troponin tests in the diagnosis of acute coronary syndromes are widely recognized.


Recombinant interleukin 2 and gamma-interferon act synergistically on distinct steps of in vitro terminal human B cell maturation.
The effects of recombinant interleukin 2 (IL-2) on the in vitro differentiation of human tonsillar B cells which were not preincubated with Staphylococcus aureus Cowan I or with anti-human IgM were investigated. IL-2 was shown to induce the generation of Ig-containing cells in a dose-dependent fashion from 2.5 to 2,500 U IL-2/ml. Conversely, the quantities of Ig secreted in the culture supernatant were found in the majority of experiments to peak at 25 U/ml. The possible presence, in cultures stimulated with IL-2, of cells that were capable of synthesizing Ig but that did not secrete the Ig they have produced was investigated. Among a number of factors tested, we found that gamma-interferon, which did not trigger in vitro B cell differentiation when used alone, can induce an increased secretion of Ig without noticeable change in the number of Ig-containing cells in cultures stimulated with IL-2. The possibility that gamma-interferon and IL-2 act on subsequent steps of in vitro B cell differentiation is discussed.


Initiation of inflammation and cell death during liver abscess formation by Entamoeba histolytica depends on activity of the galactose/N-acetyl-D-galactosamine lectin.
The parasite Entamoeba histolytica colonizes the human intestine causing amoebic colitis and disseminates through the vascular route to form liver abscesses. The Gal/GalNAc lectin is an adhesion protein complex which sustains tissue invasion by E. histolytica. Disruption of the Gal/GalNAc lectin function in engineered parasites (HGL-2 trophozoites) changed the pathophysiology of hamster liver abscess formation. HGL-2 trophozoites produced numerous small inflammatory foci located in the vicinity of blood vessels. The low penetration of HGL-2 trophozoites into hepatic tissue was shown to be associated with weak attraction of neutrophils and macrophages to the infiltrated areas and absence of pro-inflammatory tumour necrosis factor, in contrast to wild type or control vector infections. The low host inflammatory response in HGL-2 infections correlated with a delay in apoptosis of hepatic cells, whereas apoptosis of endothelial cells was not detected. Triggering of apoptosis in both host cell types most likely has a central role in modulating inflammation, a major landmark in hepatic amoebiasis. These data highlight the key role of the Gal/GalNAc lectin in initiation of E. histolytica hepatic infection.


Gender Differences in Machine Learning Models of Trauma and Suicidal Ideation in Veterans of the Iraq and Afghanistan Wars.
Suicide rates among recent veterans have led to interest in risk identification. Evidence of gender-and trauma-specific predictors of suicidal ideation necessitates the use of advanced computational methods capable of elucidating these important and complex associations. In this study, we used machine learning to examine gender-specific associations between predeployment and military factors, traumatic deployment experiences, and psychopathology and suicidal ideation (SI) in a national sample of veterans deployed during the Iraq and Afghanistan conflicts (n = 2,244). Classification, regression tree analyses, and random forests were used to identify associations with SI and determine their classification accuracy. Findings converged on several associations for men that included depression, posttraumatic stress disorder (PTSD), and somatic complaints. Sexual harassment during deployment emerged as a key factor that interacted with PTSD and depression and demonstrated a stronger association with SI among women. Classification accuracy for SI presence or absence was good based on the receiver operating characteristic area under the curve, men = .91, women = .92. The risk for SI was classifiable with good accuracy, with associations that varied by gender. The use of machine learning analyses allowed for the discovery of rich, nuanced results that should be replicated in other samples and may eventually be a basis for the development of gender-specific actuarial tools to assess SI risk among veterans.


[Optimization of a fluorescent qPCR detection for RNA of SARS-CoV-2].
We optimized a fluorescent quantitative polymerase chain reaction (qPCR) assay system for rapid and real time detection of SARS-CoV-2 RNA. The results show that the lowest dilution of RNA samples used for the detection of SARS-CoV-2 RNA could reach 1/10 000 (the initial value is set as 10 ng/μL). Moreover, the cycle threshold (Ct) for samples of clinically diagnosed COVID-19 was lower than 35 or 40. The sensitivity of this method was satisfactory. The results were consistent with those of the COVID-19 detection kit on the market under the same conditions, but the number of cycles required was shortened by about 2. Therefore, the optimized assay developed in this study can be used in screening and early clinical diagnosis. Our work provides a tool to facilitate rapid clinical diagnosis of COVID-19.


Accessibility Retrofit of a Shared Automated Vehicle: Challenges and Lessons Learned.
Driverless shared automated vehicles (SAVs) have the potential to substantially improve independent mobility for the growing number of older adults and people with disabilities who are unable or ineligible to drive. However, early designs and deployments of SAVs have lacked accommodations for people with disabilities. This article describes a case study where post-production modifications were performed on a commercial electric SAV in an attempt to comply with US accessibility guidelines for conventional vehicles. Findings emphasize the key human factors considerations for physical accessibility and some lessons learned in order to inform the broader conversation about the accessible design of emerging SAVs. The case study highlights the need for considering accessibility and usability early in the design of complex technological systems such as automated vehicles.


Patient-Reported Outcomes from a Pilot Plant-Based Lifestyle Medicine Program in a Safety-Net Setting.
Lifestyle medicine interventions that emphasize healthy behavior changes are growing in popularity in U.S. health systems. Safety-net healthcare settings that serve low-income and uninsured populations most at risk for lifestyle-related disease are ideal venues for lifestyle medicine interventions. Patient-reported outcomes are important indicators of the efficacy of lifestyle medicine interventions. Past research on patient-reported outcomes of lifestyle medicine interventions has occurred outside of traditional healthcare care settings. In this study, we aimed to assess patient-reported outcomes on nutrition knowledge, barriers to adopting a plant-based diet, food and beverage consumption, lifestyle behaviors, self-rated health, and quality-of-life of participants in a pilot plant-based lifestyle medicine program in an urban safety-net healthcare system. We surveyed participants at three time points (baseline, 3 months, 6 months) to measure change over time. After 6 months of participation in the program, nutrition knowledge increased by 7.2 percentage points, participants reported an average of 2.4 fewer barriers to adopting a plant-based diet, the score on a modified healthful plant-based diet index increased by 5.3 points, physical activity increased by 0.7 days per week while hours of media consumption declined by 0.7 h per day, and the percentage of participants who reported that their quality of sleep was "good" or "very good" increased by 12.2 percentage points. Our findings demonstrate that a lifestyle medicine intervention in a safety-net healthcare setting can achieve significant improvements in patient-reported outcomes. Key lessons for other lifestyle medicine interventions include using a multidisciplinary team; addressing all pillars of lifestyle medicine; and the ability for patients to improve knowledge, barriers, skills, and behaviors with adequate support.


In this Issue: Inflammation.
We live in a microbial world and are often confronted with infection and injury. Inflammation, the response that is unleashed to ward off these insults, has long been familiar to us. Indeed, the words that we still use to describe inflammation -redness and swelling with heat and pain -were coined in the first century A.D. by the Roman physician Cornelius Celsus: rubor et tumor cum calore et dolore. The word inflammation itself comes from the Latin inflammare: to set on fire. Research has taken us a long way from this first description of the overt symptoms of inflammation 2000 years ago to our current understanding of the molecular and cellular pathways that mediate the inflammatory process, regulate it, and lead to its resolution. We now know that inflammation can come in many forms and modalities depending on the context in which it is triggered, the trigger itself, and the tissues involved. Furthermore, we appreciate the contribution of inflammation to cancer and to chronic afflictions like neurodegenerative diseases and diabetes. In this year's Special Review Issue, we bring together Review articles and Essays that survey our current knowledge of inflammation and provide perspectives on the key questions and challenges ahead. We would like to thank the distinguished experts who contributed their time and effort as authors and reviewers to make this issue timely, comprehensive,and thought provoking. We hope that this collection of articles will be informative and inspiring, as we now harness the tools of modern biology in the continued effort to understand :"the old flame".


Significance of Lipolytic Enzymes in Pathogenesis and Treatment of Neglected Diseases.
Neglected diseases are infectious diseases that affect poor people of tropical countries. Drug resistance, lower availability of funds and research hinder the opportunities for the development of new drugs. The need for new drugs will persist until pathogens are eradicated. This calls for understanding the disease prognosis to initiate research for new drug targets and thus development of new drugs. As drug development is complex and expensive process, in silico drug development can aid in this regard by reducing time, effort and capital for the quest of a "better drug" for such neglected diseases. Recent knowledge about the genome and proteome has increased enthusiasm for the quest of new drug targets. One such potential target can be lipases which are involved in the lipid metabolism of pathogens. Lipases of pathogens have multitude of functions in many patho-physiological processes including virulence, transmission, life cycle development, modulation of host lipids and host immune responses. Thus the aim of this review is to describe the significance of lipases in the life cycle and pathogenesis of the pathogen and whether they can be used as drug targets. The development of research in this direction has also been brought forward. This may help in finding new drug targets for neglected disease.


A review of health care models for coronary heart disease interventions.
This article reviews models for the treatment of coronary heart disease (CHD). Whereas most of the models described were developed to assess the cost effectiveness of different treatment strategies, other models have also been used to extrapolate clinical trials, for capacity and resource planning, or to predict the future population with heart disease. In this paper we investigate the use of modelling techniques in relation to different types of health intervention, and we discuss the assumptions and limitations of these approaches. Many of the models reviewed in this paper use decision tree models for acute or short term interventions, and Markov or state transition models for chronic or long term interventions. Discrete event simulation has, however, been used for more complex whole system models, and for modelling resource-constrained interventions and operational planning. Nearly all of the studies in our review used cohort-based models rather than population based models, and therefore few models could estimate the likely total costs and benefits for a population group. Most studies used de novo purpose built models consisting of only a small number of health states. Models of the whole disease system were less common. The model descriptions were often incomplete. We recommend that the reporting of model structure, assumptions and input parameters is more explicit, to reduce the risk of biased reporting and ensure greater confidence in the model results.


Increased serotoninergic and noradrenergic activity in hepatic encephalopathy in rats with thioacetamide-induced acute liver failure.
Functional changes of various neurotransmitter systems have been implicated in the pathogenesis of hepatic encephalopathy. In this study the role of brain monoaminergic neurotransmitter systems in hepatic encephalopathy was investigated in rats with thioacetamide-induced acute liver failure. Concentrations of serotonin, dopamine, noradrenaline and of their metabolites 5-hydroxyindoleacetic acid, dihydroxyphenylalanine (following inhibition of dihydroxyphenylalanine-decarboxylase), dihydroxyphenylacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenyl-glycol, were measured in the cerebral cortex, striatum and hippocampus by high performance liquid chromatography with electrochemical detection. In hepatic encephalopathy concentrations of 5-hydroxyindoleacetic acid were increased in all three brain areas (196%, 204% and 264% of saline-treated controls, p less than 0.01), and concentrations of serotonin were increased in the frontal cortex (121%, p less than 0.01). In the frontal cortex and hippocampus of encephalopathic rats dopamine levels were increased (157% and 289%, p less than 0.05), and levels of noradrenaline (53% and 46%, p less than 0.05) were decreased associated with increased 3-methoxy-4-hydroxyphenylglycol levels (173% and 206%, p less than 0.05). The extent of these changes correlated with the stage of hepatic encephalopathy. In hepatic encephalopathy dihydroxyphenylalanine accumulation was increased in the hippocampus and unchanged in the cerebral cortex. Dopamine, noradrenaline, dihydroxyphenylacetic acid and homovanillic acid concentrations were unchanged in the striatum. The results of this study indicate that hepatic encephalopathy in thioacetamide-induced acute liver failure in rats is associated with neurochemical changes, suggesting an increased activity of the noradrenergic and serotoninergic neurotransmitter systems.


Peroneal subluxation: surgical results in 31 athletic patients.
Few studies describe the results of surgical treatment of peroneal retinaculum in athletic populations. Thirty-one athletic patients with symptomatic subluxating peroneal tendons were treated surgically by one surgeon with isolated subluxation repair, subluxation repair plus peroneus brevis tendon repair, or subluxation repair plus lateral ankle stabilization. As a group, the average time to return to activity was 3.2 +/- 0.8 months with a postoperative AOFAS score of 97.0 +/- 5.3. Patients with tendon tears were older in age (P < .01) and took longer to return to activity than the rest of the cohort (P = .02). There were a total of 4 patients with postoperative complications, although all were able to return to sports. The patients with peroneal subluxation in this study were able to return to their sport in approximately 3 months. Those with concomitant tendon tears took longer. Further study is needed to see if this is associated with longer-standing symptoms.


Has the analgesic efficacy of neurolytic celiac plexus block been demonstrated in pancreatic cancer pain?
Cancer of the pancreas is rising in incidence and will strike 27,000 Americans this year. There is no curative therapy for most patients, so palliation of symptoms should be the prime concern. Severe pain is very common, and often difficult to treat. Neurolytic celiac plexus block (NCPB) is claimed by some to be the most effective way to treat pancreatic cancer pain (PCP), yet only a minority of patients undergo this procedure. We have reviewed the literature on NCPB to determine if it has been adequately evaluated in the management of PCP. There have been 15 published series since 1964 on NCPB for PCP. A total of 480 patients with cancer of the pancreas were reported; at least a satisfactory response to NCPB was reported in 418 (87%). We found major deficiencies in these reports. None described the pre-NCPB analgesic history. Post-NCPB data were also limited. No information was given concerning post-NCPB analgesic dosages, and only 4 series stated that most patients did not require opiates. Information on whether NCPB was effective until death was lacking or incomplete in 12 series. Many claimed additional benefits of NCPB such as decreased nausea, decreased constipation, and increased appetite, but none provided any data to support these claims. We conclude that the data available on NCPB for PCP are insufficient to judge for efficacy, long-term morbidity, or cost effectiveness, and rigorous evaluation of the technique is required.


Deciduous dental pulp stem cells are involved in osteoclastogenesis during physiologic root resorption.
Multipotent mesenchymal stem cells are derived from the dental pulps of permanent teeth and exfoliated deciduous teeth, and are known to induce bone and dentin generation. However, the role of deciduous dental pulp stem cells (DDPSCs) in physiologic root resorption remains unclear. In this study, dental pulp stem cells (DPSCs) in permanent teeth (P) were retrieved and compared to DDPSCs from deciduous incisors at different root resorption stages: stable (S), middle (M), and final (F). Decalcified teeth sections showed that osteoclasts and resorption lacunae were most prevalent in the M resorption stage. DDPSC proliferation rate was also highest in the M stage. DDPSCs in the F stage produced more calcified nodules than those in the S or M stages. Alkaline phosphatase (ALP) expression was highest in the F stage, indicating that DDPSCs promote mineralization. In addition, the ratio of receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) expression was significantly higher in the M stage, indicating that DDPSCs promote resorption. Dickkopf 1 (Dkk1) expression was remarkably higher in the F and P groups, suggesting that the Wnt pathway is inhibited during the resorption process. Interestingly, despite the fact that Wnt3a down-regulated OPG in osteogenic induction medium and up-regulated RANKL in medium with 1,25-dihydroxy vitamin D3 (VD(3) ), the RANKL/OPG ratio was reduced only with VD(3) . Collectively, our data indicate that DDPSCs influence osteoclastogenesis during the physiologic root resorption process, and that the canonical Wnt pathway can change the RANKL/OPG expression ratio in DDPSCs.


The clinical and microbiological characteristics of infections in burn patients from the Formosa Fun Coast Dust Explosion.
Bloodstream infection is a leading cause of mortality among burn patients. This study aimed to evaluate the risk factors, causative pathogens, and the relationship between bloodstream infections and other infections among burn patients from the Formosa Fun Coast Dust Explosion. This retrospective study evaluated the demographic and clinical characteristics, infection types, causative pathogen(s), and isolates' antibiotic susceptibilities from patients who were hospitalized between June 27 and September 31, 2015. Fifty-eight patients were admitted during the study period (36 males, mean age: 22.6 years). The mean burned total body surface area (TBSA) was 40% for all patients. Eighteen (31%) patients with mean TBSA of 80% had 66 episodes of bloodstream infections caused by 92 isolates. Twelve (18.2%) episodes of bloodstream infections were polymicrobial. Acinetobacter baumannii (19, 20.7%), Ralstonia pickettii (17, 18.5%), and Chryseobacterium meningosepticum (13, 14.1%) were the most common pathogens causing bloodstream infections. A high concordance rate of wound cultures with blood cultures was seen in Staphylococcus aureus (3, 75%) and C. meningosepticum (8, 61.5%) infections. However, no Ralstonia isolate was found in burn wounds of patients with Ralstonia bacteremia. A high concordance rate of central venous catheter cultures with blood cultures was noted in Ralstonia mannitolilytica (5, 62.5%) and Chryseobacterium indologenes (3, 60%) infections. Approximately 21.1% of A. baumannii strains were resistant to carbapenem. All S. aureus isolates were susceptible to methicillin. Waterborne bacteria should be considered in patients of burns with possible water contact. Empirical broad-spectrum antibiotics should be considered for patients who were hospitalized for severe sepsis, or septic shock with a large burn. Antibiotic treatment should be administered based on the specific pathogens and their detection points.


Reduced anticardiolipin antibodies in first episode and chronic schizophrenia.
The objective of this study was to measure anticardiolipin antibodies (aCL) in major psychiatric diseases. In Experiment 1, 96 subjects were evaluated: 20 first episode schizophrenia patients, [SCZ1] 20 chronic schizophrenia patients in acute exacerbation [SCZ2], l9 bipolar patients, 20 schizoeffective patients and 17 healthy age matched controls. In Experiment 2, 97 subjects were studied: 20 first episode schizophrenia patients [SCZ1], 60 chronic schizophrenia patients in acute exacerbation [SCZ2] and 17 healthy matched controls. Diagnosis was performed according to DSM-IV. Serum samples were tested for aCL in parallel by enzyme-linked immunosorbent assay in the presence of bovine serum. Five positive control samples with high levels of aCL were run in parallel. Background binding to wells uncoated with cardiolipin (CL) was also measured. In Experiment 1, aCL levels were similar in the control, bipolar and schizoeffective groups. In contrast, aCL levels in the SCZ1 and SCZ2 groups were significantly lower than in controls. In Experiment 2, Significantly lower levels of aCL antibodies were found in all schizophrenic patients versus controls. Interestingly, background levels in both experiments were higher in the schizophrenic groups than in controls. Serum aCL levels are lower in schizophrenic patients, and especially in first episode cases, than in controls. One possible explanation for the lower levels of aCL in schizophrenic patients is the consumption of these antibodies in the acute phase and exacerbation of the disease. The higher background levels in schizophrenic patients may indicate a high level of antibodies to some serum component in schizophrenic patients that is still unclear and needs further elucidation.


Off-label medicine use in pediatric inpatients: a prospective observational study at a tertiary care hospital in India.
Background. In the absence of standard pediatric prescribing information, clinicians often use medicines in an off-label way. Many studies have been published across the globe reporting different rates of off-label use. There is currently no study based on Indian drug formulary. Methods. The prospective observational study included pediatric patients in ages between 0 and 12 years admitted in a tertiary care hospital. Off-label use was assessed using the National Formulary of India (NFI). Predictors of off-label use were determined by logistic regression. Results. Of the 1645 medications prescribed, 1152 (70%) were off-label based on 14 possible off-label categories. Off-label medicines were mainly due to dose difference and use in restricted age limits as indicated in NFI. Respiratory medicines (82%), anti-infectives (73%), and nervous system medicines (53%) had higher off-label use. Important predictors of off-label prescribing were pediatric patients in age of 0 to 2 years (OR 1.68, 95% CI; P < 0.001) and hospital stay of six to 10 days (OR 1.91, 95% CI; P < 0.001). Conclusion. Off-label prescribing is common among pediatric patients. There is need to generate more quality data on the safety and efficacy of off-label medicines to rationalize pediatric pharmacotherapy.


Characterization of in situ nitrogen and fiber digestion and bacterial nitrogen contamination of hay crop forages preserved at different dry matter percentages.
Alfalfa, red clover, orchardgrass and timothy were harvested in the vegetative stage, wilted and stored as hay, or ensiled in small batch silos (20 kg) at 60, 40 or 20% (direct cut) dry matter and were analyzed for compositional differences. A ruminally cannulated lactating cow, consuming 50% of her dry matter intake from hay crop silage, was used to measure in situ dry matter, N, neutral detergent fiber and acid detergent fiber disappearance. Diaminopimelic acid was used as a bacterial marker to correct for bacterial N contamination for in situ residual N. Fibrous components tended to become concentrated as percent dry matter at preservation decreased, presumably associated with leaching of water solubles during storage. For most forages, as dry matter percentage of preservation decreased, water soluble dry matter and N increased, with a concomitant increase of ruminally nondigested dry matter. Specific trends in coefficients of digestion associated with forage type or preservation dry matter percentage were not observed for dry matter, N, neutral detergent fiber or acid detergent fiber. Correction for contamination by bacterial N decreased lag time in digestion and altered rates of N digestion compared with noncorrected rates. Linear and quadratic bacterial N contamination profiles were observed with time of ruminal incubation. Rate of digestion of N was highly correlated with fibrous component concentration, and to a lesser extent to rate of neutral and acid detergent fiber digestion. Dry matter percentage at preservation had a variable effect on ruminal digestion rate of dry matter and N, which varied with forage type and had no effect on neutral detergent and acid detergent fiber digestion rates. Correction for bacterial N contamination should be considered when establishing N digestion rates for forage by the in situ technique.


Long-term outcomes after hepatic resection combined with radiofrequency ablation for initially unresectable multiple and bilobar liver malignancies.
Hepatic resection (HRE) combined with radiofrequency ablation (RFA) offers a surgical option to a group of patients with multiple and bilobar liver malignancies who are traditionally unresectable for inadequate functional hepatic reserve. The aims of the present study were to assess the perioperative outcomes, recurrence, and long-term survival rates for patients treated with HRE plus RFA in the management of primary hepatocellular carcinoma (HCC) and metastatic liver cancer (MLC). Data from all consecutive patients with primary and secondary hepatic malignancies who were treated with HRE combined with RFA between 2007 and 2013 were prospectively collected and retrospectively reviewed. A total of 112 patients, with 368 hepatic tumors underwent HRE combined with ultrasound-guided RFA, were included in the present study. There were 40 cases of HCC with 117 tumors and 72 cases of MLC with 251 metastases. Most cases of liver metastases originated from the gastrointestinal tract (44, 61.1%). Other uncommon lesions included breast cancer (5, 6.9%), pancreatic cancer (3, 4.2%), lung cancer (4, 5.6%), cholangiocarcinoma (4, 5.6%), and so on. The ablation success rates were 93.3% for HCC and 96.7% for MLC. The 1-, 2-, 3-, 4-, and 5-y overall recurrence rates were 52.5%, 59.5%, 72.3%, 75%, and 80% for the HCC group and 44.4%, 52.7%, 56.1%, 69.4%, and 77.8% for the MLC group, respectively. The 1-, 2-, 3-, 4-, and 5-y overall survival rates for the HCC patients were 67.5%, 50%, 32.5%, 22.5%, and 12.5% and for the MLC patients were 66.5%, 55.5%, 50%, 30.5%, and 19.4%, respectively. The corresponding recurrence-free survival rates for the HCC patients were 52.5%, 35%, 22.5%, 15%, and 10% and for the MLC patients were 58.3%, 41.6%, 23.6%, 16.9%, and 12.5%, respectively. HRE combined with RFA provides an effective treatment approach for patients with primary and secondary liver malignancies who are initially unsuitable for radical resection, with high local tumor control rates and promising survival data.


Developmentally regulated expression of the nerve growth factor receptor gene in the periphery and brain.
Nerve growth factor (NGF) regulates development and maintenance of function of peripheral sympathetic and sensory neurons. A potential role for the trophic factor in brain has been detected only recently. The ability of a cell to respond to NGF is due, in part, to expression of specific receptors on the cell surface. To study tissue-specific expression of the NGF receptor gene, we have used sensitive cRNA probes for detection of NGF receptor mRNA. Our studies indicate that the receptor gene is selectively and specifically expressed in sympathetic (superior cervical) and sensory (dorsal root) ganglia in the periphery, and by the septum-basal forebrain centrally, in the neonatal rat in vivo. Moreover, examination of tissues from neonatal and adult rats reveals a marked reduction in steady-state NGF receptor mRNA levels in sensory ganglia. In contrast, a 2- to 4-fold increase was observed in the basal forebrain and in the sympathetic ganglia over the same time period. Our observations suggest that NGF receptor mRNA expression is developmentally regulated in specific areas of the nervous system in a differential fashion.


Primary care physician supply, physician compensation, and Medicare fees: what is the connection?
Primary care, a cornerstone of several health reform efforts, is believed by many to be in a crisis because of inadequate supply to meet future demand. This belief has focused attention on the adequacy of primary care physician supply and ways to boost access to primary care. One suggested approach is to raise Medicare fees for primary care services. Whether higher Medicare fees would increase physician interest in primary care specialties by reducing compensation disparities between primary care and other specialties has not been established. Further, many questions remain about the assumptions underlying these policy concerns. Is there really a primary care physician crisis? Why does compensation across physician specialties vary so widely? Can Medicare physician fee changes affect access to primary care? These questions defy simple answers. This issue brief lays out the latest information on physician workforce, compensation differences across physician specialties, and Medicare's physician fee-setting process.


MR imaging assessment of myelination in the very preterm brain.
MR imaging was performed in very preterm infants by using an MR imager in the neonatal intensive care unit. The aims of this study were to assess the development of myelination in the preterm brain based on MR imaging findings and to compare the ability of T1-weighted conventional spin-echo, inversion recovery fast spin-echo, and T2-weighted fast spin-echo MR imaging to show myelination in these infants. MR imaging was performed for 26 preterm infants with a median gestational age of 28 weeks who had normal neurodevelopmental outcomes at 2 years corrected age. Myelin was evident in the gracile and cuneate nuclei and fasciculi, vestibular nuclei, cerebellar vermis, inferior and superior cerebellar peduncles, dentate nucleus, medial longitudinal fasciculus, medial geniculate bodies, subthalamic nuclei, inferior olivary nuclei, ventrolateral nuclei of the thalamus, decussation of the superior cerebellar peduncles, medial lemnisci, lateral lemnisci, and inferior colliculi at < or = 28 weeks gestational age. From this gestational age, myelination was not visualized at any new site until 36 weeks gestational age, when myelin was visualized in the corona radiata, posterior limb of the internal capsule, corticospinal tracts of the precentral and postcentral gyri, and lateral geniculate bodies. T2-weighted fast spin-echo MR imaging showed myelin in gray matter nuclei at an earlier gestational age than did T1-weighted conventional spin-echo or inversion recovery fast spin-echo MR imaging. T1-weighted conventional spin-echo MR imaging showed myelin earlier in some white matter tracts in the preterm brain. Myelination was evident in numerous gray and white matter structures in the very preterm brain. A knowledge of myelination milestones will allow delays to be detected at an early stage.


Influence of Muscle Mass and Outdoor Environmental Factors on Appetite and Satiety Feeling in Young Japanese Women.
Research on the influence of relationships among satiety, muscle mass, and outdoor environmental factors is sparse. In this work the relationships among satiety feeling, body composition, and outdoor environmental factors on eating in healthy young Japanese women are investigated. Fifty three (53) women were examined over an approximately 2-year period. All participants ate the same lunch; feelings of satiety and body composition were measured before and immediately after lunch. Satiety was assessed using a visual analog scale. Outdoor environmental factors were recorded at the time of measurement. Results showed that satiety before lunch decreased with increased muscle mass and decreased humidity (p < 0.05). The Δ satiety increased on eating with increased outdoor temperature (p < 0.05). The Δ satiety with high outdoor temperature was significantly greater than with low outdoor temperature (p = 0.005). Decreased muscle mass more influenced Δ satiety with respect to outdoor temperature than increased muscle mass (p = 0.007). The results suggest that increased muscle mass and decreased humidity increase hunger (unlike satiety) before eating. The findings also show that outdoor temperature clearly influences the magnitude of satiety on eating. Increasing muscle mass may be useful for satiety control at various outdoor temperatures in young women.


Hypoglycemic effect of insulin-loaded hydrogel-nanogel composite on streptozotocin-induced diabetic rats.
At present, how to increase insulin rapidly, availably and stably is still a conundrum in the treatment of diabetes mellitus. In vitro studies have shown that insulin can be released from hydrogel-nanogel composite according to the changes of glucose level. This study aimed to observe the glucose-lowering effects and evaluate the safety of the insulin-loaded hydrogel-nanogel composite in diabetic rats. We found that significant glycemic regulation could be observed up to 30 hours after subcutaneous injection, and the fasting blood glucose was reduced effectively. The result of an oral glucose tolerance test showed that the level of insulin expressed a stable increase from 0.5 hours to 3.5 hours, which led to a reduction of glucose with steady steps. Also, compared with Ins group, the Gel+Ins group showed slighter skin and pancreas damage, while the oxidative stress and inflammation response were similar to the normal control group. In conclusion, these results demonstrated that the glucose-lowering action of the insulin-loaded hydrogel-nanogel composite was superior to that of the regular insulin, and might thus become an insulin carrier in the future.


[Periarticular pathology of the hip].
The hip region is the seat of a rich and common periarticular pathology, with a variable involvement, depending of the location, and needs better knowledge. Anyway the clinical examination takes the major place in the diagnostic. Trochanteric bursitis and tendinitis are the more common clinical syndrome in that regional pathology. Local injections of corticosteroid are still the mean modality of the conservative treatment but are not sufficient to avoid recurrence or chronicity which may lead to tendon tears. A better knowledge of the physiopathology will lead to a better and early recovery. Apatite calcifications are not rare around the hip. Great trochanter is the first location, but the femoral insertion of the gluteus maximus and vastus lateralis on the linea aspera, the lateral side of the acetabulum and the ischial tuberosity are worth known. Iliopsoas bursitis, which has some analogy with the popliteal cyst, is often underrecognized, like ischial bursitis and tendinopathy.


Role of Hedgehog Signaling Pathway in NASH.
Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual's response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease.


pH-dependent properties of a mutant horseradish peroxidase isoenzyme C in which Arg38 has been replaced with lysine.
Arg38 in the active site of horseradish peroxidase isoenzyme C (HRP-C) has been replaced with lysine by site-directed mutagenesis. As a preclude to a detailed kinetic analysis of this variant, the present study characterizes a pH-dependent cycle of reactions for recombinant horseradish peroxidase isoenzyme C with Arg38 replaced by lysine ([R38K]HRP-C*), which involves time-dependent changes in both specific activity and the electronic absorption spectrum of the enzyme. This pH-dependent cycle resembles that previously suggested for a cytochrome-c peroxidase variant in which Asp235 was replaced with asparagine. When the pH of a solution of resting [R38K]HRP-C* at pH 6.6 (form AH) is raised to pH 8.6, a rapid alkaline transition occurs. This results in spectral changes characteristic of a shift from a predominantly pentacoordinate to a completely hexacoordinate high-spin haem iron (form A-) with a pKa of 7.5. When the pH of a solution of form A- is raised from 8.7 to 12.0, no further spectral changes are observed. The reaction is reversible, but when the high-pH form of the enzyme (A-) is allowed to stand at pH 8.6, it slowly becomes converted into a third enzyme form (form I-) at a rate which is independent of pH (k = 0.56 h-1). When the pH of a sample of form I- is lowered from 8.6 to 6.6, the original low-pH form (AH) of the enzyme is recovered. Recovery of form AH from form I- does not occur via form A-, but via at least one further intermediate, form X. Following a downward pH jump, the rate constant for the formation of form X from form I- shows a small dependence on pH, changing from 48 s-1 at pH 6.8 to 39 s-1 at pH 7.4. The rate of formation of form AH from form X is also pH dependent and biphasic in nature, with measured rate constants ranging from 11.9-2.1 h-1. The possible structures of the different forms of [R38K]HRP-C* are discussed in the light of similar data in the literature for variants of cytochrome-c peroxidase. The properties may be indicative of a greater degree of conformational flexibility within the active site of this mutant caused by the smaller bulk of the lysine side-chain and the probable disruption of a part of the haem-linked hydrogen-bonding network in the distal haem pocket. The wild-type enzyme undergoes no such pH induced changes.


alpha-1 Adrenergic receptors stimulation induces the proliferation of neural progenitor cells in vitro.
The proliferation of neural progenitor cells (NPCs) is regulated by classical neurotransmitters such as dopamine, serotonin and acetylcholine, via its own receptors. Previous studies have reported that the depletion of L-norepinephrine decreases the proliferation of NPCs in the adult rat hippocampus and it has been suggested that L-norepinephrine regulates the proliferation of NPCs. However, it remains unknown whether or not adrenergic receptors are involved in the increased proliferation of NPCs. In the present study, an MTT cell proliferation assay was carried out in order to investigate the roles played by adrenergic receptors in the proliferation of NPCs. We demonstrated that L-epinephrine enhanced the proliferation of embryonic NPCs in vitro. In addition, the alpha-1 adrenergic receptor agonist L-phenylephrine was found to enhance the proliferation of NPCs, whereas an alpha-adrenergic antagonist and selective alpha-1 antagonists significantly inhibited cell proliferation increases induced by L-epinephrine and L-phenylephrine. These results suggest that stimulation with alpha-1 adrenergic receptors induces the proliferation of embryonic NPCs.


Thyroidectomy of house sparrows (Passer domesticus) prevents photo-induced testicular growth but not the increased hypothalamic gonadotrophin-releasing hormone.
Thyroidectomy of starlings (Sturnus vulgaris) prevents the decrease in hypothalamic gonadotrophin-releasing hormone (GnRH) which normally occurs at the onset of photorefractoriness. To extend this observation to another species, changes in testicular mass, bill colour, moult, and hypothalamic GnRH content were monitored in photostimulated and nonphotostimulated intact and thyroidectomized house sparrows (Passer domesticus). Photostimulated intact birds rapidly increased testicular mass and GnRH. Later, testicular mass and GnRH decreased, and birds moulted, as they became photorefractory. Nonphotostimulated intact birds showed an increase in testicular mass and GnRH. Neither photostimulated nor nonphotostimulated thyroidectomized birds showed a marked increase in testicular mass, but both showed an increase in GnRH. Photostimulated thyroidectomized birds showed no subsequent decrease in GnRH and they did not moult. It is suggested that in this species, thyroidectomy inhibits the release of GnRH as well as preventing the downregulation of GnRH synthesis normally associated with the development of photorefractoriness.


Blood volume-monitored regulation of ultrafiltration in fluid-overloaded hemodialysis patients: study protocol for a randomized controlled trial.
Data generated with the body composition monitor (BCM, Fresenius) show, based on bioimpedance technology, that chronic fluid overload in hemodialysis patients is associated with poor survival. However, removing excess fluid by lowering dry weight can be accompanied by intradialytic and postdialytic complications. Here, we aim at testing the hypothesis that, in comparison to conventional hemodialysis, blood volume-monitored regulation of ultrafiltration and dialysate conductivity (UCR) and/or regulation of ultrafiltration and temperature (UTR) will decrease complications when ultrafiltration volumes are systematically increased in fluid-overloaded hemodialysis patients. BCM measurements yield results on fluid overload (in liters), relative to extracellular water (ECW). In this prospective, multicenter, triple-arm, parallel-group, crossover, randomized, controlled clinical trial, we use BCM measurements, routinely introduced in our three maintenance hemodialysis centers shortly prior to the start of the study, to recruit sixty hemodialysis patients with fluid overload (defined as ≥15% ECW). Patients are randomized 1:1:1 into UCR, UTR and conventional hemodialysis groups. BCM-determined, 'final' dry weight is set to normohydration weight -7% of ECW postdialysis, and reached by reducing the previous dry weight, in steps of 0.1 kg per 10 kg body weight, during 12 hemodialysis sessions (one study phase). In case of intradialytic complications, dry weight reduction is decreased, according to a prespecified algorithm. A comparison of intra- and post-dialytic complications among study groups constitutes the primary endpoint. In addition, we will assess relative weight reduction, changes in residual renal function, quality of life measures, and predialysis levels of various laboratory parameters including C-reactive protein, troponin T, and N-terminal pro-B-type natriuretic peptide, before and after the first study phase (secondary outcome parameters). Patients are not requested to revert to their initial degree of fluid overload after each study phase. Therefore, the crossover design of the present study merely serves the purpose of secondary endpoint evaluation, for example to determine patient choice of treatment modality. Previous studies on blood volume monitoring have yielded inconsistent results. Since we include only patients with BCM-determined fluid overload, we expect a benefit for all study participants, due to strict fluid management, which decreases the mortality risk of hemodialysis patients. ClinicalTrials.gov, NCT01416753.


Nuclear magnetic resonance of laser-polarized noble gases in molecules, materials, and organisms.
The sensitivity of conventional nuclear magnetic resonance (NMR) techniques is fundamentally limited by the ordinarily low spin polarization achievable in even the strongest NMR magnets. However, by transferring angular momentum from laser light to electronic and nuclear spins, optical pumping methods can increase the nuclear spin polarization of noble gases by several orders of magnitude, thereby greatly enhancing their NMR sensitivity. This review describes the principles and magnetic resonance applications of laser-polarized noble gases. The enormous sensitivity enhancement afforded by optical pumping can be exploited to permit a variety of novel NMR experiments across numerous disciplines. Many such experiments are reviewed, including the void-space imaging of organisms and materials, NMR and MRI of living tissues, probing structure and dynamics of molecules in solution and on surfaces, NMR sensitivity enhancement via polarization transfer, and low-field NMR and MRI.


Self-inflicted vocal cord paralysis in patients with vagus nerve stimulators. Report of two cases.
Vagus nerve stimulation for treatment of epilepsy is considered safe; reports of severe complications are rare. The authors report on two developmentally disabled patients who experienced vocal cord paralysis weeks after placement of a vagus nerve stimulator. In both cases, traction injury to the vagus nerve resulting in vocal cord paralysis was caused by rotation of the pulse generator at the subclavicular pocket by the patient. Traumatic vagus nerve injury caused by patients tampering with their device has never been reported and may be analogous to a similar phenomenon reported for cardiac pacemakers in the literature. As the use of vagus nerve stimulation becomes widespread it is important to consider the potential for this adverse event.


Finite-difference-based multiple-relaxation-times lattice Boltzmann model for binary mixtures.
In this paper, we propose a finite-difference-based lattice Boltzmann equation (LBE) model with multiple-relaxation times (MRT), in which the distribution functions of individual species evolve on a same regular lattice without any interpolations. Furthermore, the use of the MRT enables the model more flexible so that it can be applied to mixtures of species with different viscosities and adjustable Schmidt number. Some numerical tests are conducted to validate the model, the numerical results are found to agree well with analytical solutions/or other numerical results, and good numerical stability of the proposed LBE model is also observed.


mJustice: Preliminary Development of a Mobile App for Medical-Forensic Documentation of Sexual Violence in Low-Resource Environments and Conflict Zones.
Digital health development and use has been expansive and operationalized in a variety of settings and modalities around the world, including in low- and middle-income countries. Mobile applications have been developed for a variety of health professionals and frontline health workers including physicians, midwives, nurses, and community health workers. However, there are no published studies on the development and use of digital health related to human rights fieldwork and to our knowledge no mobile health platforms exist specifically for use by frontline health workers to forensically and clinically document sexual violence. We describe a participatory development and user design process with Congolese end-users of a novel human rights app for clinicians intended to standardize the documentation of sexual violence evidence for forensic and legal purposes, called MediCapt. The app, yet to be launched and still in the future proofing phase, has included several development phases: (1) initial needs assessment conducted in 2011, (2) prototype development and field-testing in 2014 with 8 Congolese physicians, (3) prototype refinement and field-testing in 2015 with 9 clinicians. Feedback from the first field-testing phase was incorporated into the design of the second prototype; key features that were added to MediCapt include the ability for users to take photographs and draw on a pictogram to include as part of the evidence package, as well as the ability to print a form with the completed data. Questionnaires and key-informant interviews during the second and third field-testing phases revealed overall positive attitudes about MediCapt, but multiple perceived and actual barriers to implementation were identified, from personal behaviors, such as individual clinicians' comfort with new technology, to more systemic and infrastructure factors, such as strong cultural preferences for print documentation of evidence and limited Internet connectivity. Next phases of development include consideration of patients' acceptance of this technology, how it actually fits in the clinical workflow, and testing of how to transfer the collected evidence to law enforcement and legal authorities. Ultimately, we plan on conducting a robust evaluation to assess effectiveness of the app on medical, legal, and human rights outcomes. We believe our experience of collecting data that will potentially serve as legal evidence broadens the traditional scope of digital health and crosses a wide range of fields including medical, technological, legal, and ethical, and thus propose refining and defining this unique field of exploration as mobile justice, or mJustice.


Teleportation-induced correlated quantum channels.
Quantum teleportation of an n-qubit state performed using as an entangled resource a general bipartite state of 2n qubits instead of n Bell states is equivalent to a correlated Pauli channel. This yields a new characterization of such channels in terms of many-body correlation functions of the teleporting media. It provides a relatively simple method for determining whether a correlated quantum channel is able to reliably convey quantum messages by studying the entanglement properties of the teleportation mediating system. Our model is then generalized to the continuous-variable case.


The informed consent for surgery. Update for Belgium in 2008.
Until the no-fault law in Belgium (15/05/2007) comes in action on 01/01/2009 it will be a system of fault to prove. Therefore the informed consent stays a mean or not liability progress. At this moment it stays a problem for the surgeon when he has not given any information about informed consent to the patient. If an operative intervention is unlawful. Then the signature of the patient does not remove the unlawful character of this intervention. Also the decline in standard forms with no personal contact and loss of individual adaptation cannot give a good result of information. The consequences of informed consent and how to prove the informed consent in medico legal setting are important for the surgeon's behavior. For the surgeons it will be a duty to make good informed consent brochures and forms that are adapted to the needs of the individual patients. First an oral and personal explanation between the surgeon and the patient has to be done during the first consultation. Secondly a form has to be handed over to the patient. Thirdly the patient must have the possibility to read it. Fourth the patient has to give his oral and written informed consent to the surgeon before being operated on by that same surgeon or any member of his staff. There is always a risk for sanctions in several procedures like criminal law and civil law until the no-fault system comes into action on 01/01/2009.


Delta-alpha cross-frequency coupling for different brain regions.
Neural interactions occur on different levels and scales. It is of particular importance to understand how they are distributed among different neuroanatomical and physiological relevant brain regions. We investigated neural cross-frequency couplings between different brain regions according to the Desikan-Killiany brain parcellation. The adaptive dynamic Bayesian inference method was applied to EEG measurements of healthy resting subjects in order to reconstruct the coupling functions. It was found that even after averaging over all subjects, the mean coupling function showed a characteristic waveform, confirming the direct influence of the delta-phase on the alpha-phase dynamics in certain brain regions and that the shape of the coupling function changes for different regions. While the averaged coupling function within a region was of similar form, the region-averaged coupling function was averaged out, which implies that there is a common dependence within separate regions across the subjects. It was also found that for certain regions the influence of delta on alpha oscillations is more pronounced and that oscillations that influence other are more evenly distributed across brain regions than the influenced oscillations. When presenting the information on brain lobes, it was shown that the influence of delta emanating from the brain as a whole is greatest on the alpha oscillations of the cingulate frontal lobe, and at the same time the influence of delta from the cingulate parietal brain lobe is greatest on the alpha oscillations of the whole brain.


Differential gene expression during the amoebal-plasmodial transition in Physarum.
We have prepared cDNA libraries for amoebae and plasmodia of the acellular slime mould, Physarum polycephalum. Differential screening was used to isolate cell-type-specific cDNA clones (in bacteriophage M13) and both libraries yielded approximately 5% of such sequences. The amoebal- and plasmodial-specific clones were used to assay changes in transcription during the amoebal-plasmodial transition. The results obtained substantiate the view that the switch from amoebal to plasmodial characteristics occurs over several nuclear division cycles. With one exception, the specific cDNAs came from single-gene families. Southern blotting experiments also showed that they hybridised to identical restriction fragments from amoebal and plasmodial DNAs indicating that genomic rearrangements are unlikely to be involved in the regulation of these genes.


A new integrative model of lateral epicondylalgia.
Tennis elbow or lateral epicondylalgia is a diagnosis familiar to many within the general community and presents with an uncomplicated clinical picture in most cases. However, the underlying pathophysiology presents a more complex state and its management has not been conclusively determined. Research on this topic extends across anatomical, biomechanical and clinical literature; however, integration of findings is lacking. We propose that the current understanding of the underlying pathophysiology of lateral epicondylalgia can be conceptualised as encompassing three interrelated components: (i) the local tendon pathology, (ii) changes in the pain system, and (iii) motor system impairments. This paper presents a model that integrates these components on the basis of a literature review with the express aim of assisting in the targeting of specific treatments or combinations thereof to individual patients.


How to Approach a Patient With Limited Stage Hodgkin Lymphoma Who Remains PET Positive at the End of Chemotherapy: Radiation Therapy?
The use of 18-F fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography has emerged as a crucial tool for response-adapted therapy in Hodgkin lymphoma (HL). Although more studies have focused on the predictive value of an interim or early PET obtained after 2 cycles of chemotherapy, there are indications that the end of therapy PET might even be more predictive of outcome. The optimal treatment of patients with limited stage HL who are PET-positive after chemotherapy is unknown. Here we review the prognostic significance of end of treatment PET in early stage HL, the role of consolidative radiotherapy in patients who have FDG-PET avidity at the end of chemotherapy, and discuss the place of salvage chemotherapy and autologous transplantation in these patients.


Downregulation of Circ-PITHD1 Suppressed Colorectal Cancer via Glycolysis Inhibition through miR-590-5p/HK2 Axis.
Colorectal cancer (CRC) is a frequent malignancy around the globe. Circular RNAs (circRNAs) are implicated in CRC development. Nevertheless, the regulatory mechanisms and biological functions regarding circRNAs in CRC progression are largely unclear. The present investigation employed next-generation sequencing (NGS) to study the abnormal circRNA expression in CRC tissues. The regulatory mechanism and targets were then analyzed by bioinformatics, luciferase reporter analysis, CCK8, colony formation, and Transwell migration. In vivo metastasis and tumorigenesis assays were conducted to elucidate circ-PITHD1 roles regarding CRC. The data showed that circ-PITHD1 expression increased in a CRC cell line and tissues, which indicated that circ-PITHD1 functioned in CRC progression. circ-PITHD1 downregulation inhibited CRC invasion and proliferation in the experiments. Luciferase reporter results confirmed that both miR-590-5p and hexokinase 2 (HK2) were circ-PITHD1 downstream targets. HK2 overexpression or miR-590-5p suppression reversed CRC cell proliferation and invasion after silencing of circ-PITHD1 by regulation of glycolysis. Taken together, this investigation discovered that circ-PITHD1 downregulation suppressed CRC progression by inhibiting glycolysis via the miR-590-5p/HK2 axis.


Osteoblastic bone response mimicking bone progression during treatment with pembrolizumab in advanced cutaneous melanoma.
Pembrolizumab is an immune checkpoint inhibitor approved for the treatment of patients with unresectable or metastatic melanoma. Appearance of bone metastases, either osteolytic or osteoblastic, during treatment qualifies as disease progression. We report the case of a 64-year-old White woman with a metastatic melanoma undergoing second-line treatment with pembrolizumab. At first evaluation, after 3 months of therapy, computed tomography scans showed the onset of osteosclerotic lesions and a significant reduction in all the previously identified metastases; on the contrary, a fluorine-18-fluorodeoxyglucose PET showed the normalization of fluorine-18-fluorodeoxyglucose uptake in all the baseline lesions, including bone metastases. Osteoblastic response, consisting of occurrence of new osteoblastic lesions on computed tomography imaging, as a consequence of an osteoblastic reaction of previously undetectable bone metastases, has been reported in some cancers that receive treatments such as chemotherapy, hormonal or targeted therapy. However, it had never been reported in patients with melanoma treated with immunotherapy. An apparent worsening of bone imaging on standard computed tomography scan in patients under checkpoint inhibitor should not lead to modification of treatment strategy, because misinterpretation as disease progression may lead to the premature cessation of a beneficial treatment and finally have a negative effect on patients' clinical outcome.


Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis.
Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients. Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer. A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5*1 and CYP3A4*1G (with the CYP3A5*1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared with those with lower enzymatic activity (CYP3A5*3/*3 and CYP3A4*1/*1). This is the first study to extensively determine the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients.


Th17/regulatory T cell imbalance in sepsis patients with multiple organ dysfunction syndrome: attenuated by high-volume hemofiltration.
We assessed the Th17 (T-helper cell)/Treg (Regulatory T cell) imbalance in sepsis patients with multiple organ dysfunction syndrome (MODS) and the clinical benefits of continuous high-volume hemofiltration (HVHF). 48 sepsis patients, including 22 patients with MODS (MODS group, n = 22) and 26 without (non-MODS group, n = 26), and 20 healthy volunteer controls were enrolled. The patients in MODS group were randomly divided into the continuous blood purification (CBP) group (n = 11) receiving conventional comprehensive treatment plus high-volume hemofiltration and the non-CBP group (n = 11) receiving conventional comprehensive treatment only. At day 28, all 48 patients were divided into the survival group (n = 36) and the non-survival group (n = 12). Venous blood samples, collected at 0, 6, 12 and 24 hours during hemofiltration (or equivalent times in the non-CBP group), were assessed by flow cytometry to detect the Th17 and Treg cells in peripheral blood. Serum cytokines (such as IL-6, IL-17, IL-23, IL-10 and TGF-β1) were detected by enzyme-linked immune sorbent assay (ELISA). Th17%, Treg%, Th17/Treg, IL-6, IL-17, IL-23, IL-10 and TGF-β1 were significantly higher in MODS and non-MODS group than in the health control (p<0.05), while Th17%, Treg%, Th17/Treg and measured cytokines were significantly higher in the MODS group compared to the non-MODS group (p<0.05). After HVHF treatment, Th17%, Treg%, Th17/Treg, IL-6, IL-17, and IL-10 were significantly reduced (p<0.05), while there were no significant changes in the non-CBP group (p>0.05). In addition, APACHE II and SOFA scores decreased markedly after HVHF treatment. Baseline Th17%, Treg%, Th17/Treg, IL-6, IL-17, IL-23, IL-10 and TGF-β1 were significantly higher in the non-survival group compared to the survival group. Both Th17% and Th17/Treg were positivity correlated with concentration of IL-6 and APACHE II score (p<0.01). The level of Th17/Treg imbalance in sepsis is related to the occurrence and prognosis of MODS. High-volume hemofiltration can attenuate the Th17/Treg imbalance in sepsis patients, possibly by removing inflammatory mediators.


Changing techniques in crop plant classification: molecularization at the National Institute of Agricultural Botany during the 1980s.
Modern methods of analysing biological materials, including protein and DNA sequencing, are increasingly the objects of historical study. Yet twentieth-century taxonomic techniques have been overlooked in one of their most important contexts: agricultural botany. This paper addresses this omission by harnessing unexamined archival material from the National Institute of Agricultural Botany (NIAB), a British plant science organization. During the 1980s the NIAB carried out three overlapping research programmes in crop identification and analysis: electrophoresis, near infrared spectroscopy (NIRS) and machine vision systems. For each of these three programmes, contemporary economic, statutory and scientific factors behind their uptake by the NIAB are discussed. This approach reveals significant links between taxonomic practice at the NIAB and historical questions around agricultural research, intellectual property and scientific values. Such links are of further importance given that the techniques developed by researchers at the NIAB during the 1980s remain part of crop classification guidelines issued by international bodies today.


Cost-Savings Analysis of an Individualized Exercise Oncology Program in Early-Stage Breast Cancer Survivors: A Randomized Clinical Control Trial.
In an attempt to promote the integration of exercise oncology as a standard part of clinical practice, economic evaluations are warranted. Thus, the purpose of this study was to prospectively analyze cost savings of an individualized exercise oncology program when patients were randomly assigned. For this open-label, randomized, prospective, comparative clinical trial, patients with early-stage breast cancer (stage I-II) were randomly assigned into two groups: the control group (CG, n = 120) and the exercise training group (EX, n = 123). Patients in the exercise intervention group completed 12 weeks of prescribed, individualized exercise that aligned with ACSM exercise guidelines for cancer survivors. The CG received the current standard of care, which includes a resource guide with various options available to the cancer survivor. In the EX group, all physical fitness measures significantly improved compared with baseline (P < .001), while remaining unchanged for the CG (P > .05). Patients in the CG had the highest total mean health care utilization across all measures (CG: $8,598 US dollars, compared with EX: $6,356 US dollars) for emergency visits, outpatient visits, and office-base visits that were not a part of their treatment plan. At baseline, the mean Eastern Cooperative Oncology Group (ECOG) scores did not significantly differ (P > .05); however, at follow-up, a larger proportion of the EX group had ECOG scores of 0 or 1, compared with the CG (P < .05). Finally, patient-reported outcomes were significantly higher in the exercise group, compared with the CG at the 12-week follow-up (P < .001). A supervised, individualized 12-week exercise intervention led to significant improvements in fitness parameters and ECOG scores, as well as a decrease in unplanned health care utilization among early-stage breast cancer survivors.