Effects of pharmaceutical care interventions on humanistic outcomes in hypertensive people living with HIV: results of a randomized controlled trial.
To evaluate the effects of pharmaceutical care (PC) interventions on humanistic outcomes in HIV-positive patients with hypertension. This prospective, open-label, parallel randomized controlled trial was conducted in the HIV clinic of the University of Uyo Teaching Hospital, Akwa Ibom State, Nigeria, from August 2018 to October 2019. Eligible patients were randomized sequentially and equally into two study arms: the control arm (CA), where participants received the traditional care and the intervention arm (IA), where participants received PC by the research pharmacist. The patient's HIV knowledge questionnaire, the Hypertension Knowledge-Level Scale, the Medical Outcome Study-HIV Health Survey and the Patient Satisfaction with Pharmaceutical Service questionnaire were used to assess participants' HIV-related knowledge, hypertension-related knowledge, health-related quality of life (HRQoL) and satisfaction with PC, respectively. These were self-completed at baseline, 6 months and 12 months. Data were analysed using SPSS (IBM version 25.0). Out of the 206 participants randomized, 182 completed the 12-month follow-up. After 12 months, there was a significant improvement in HIV-related knowledge (∆ = 11.28%, t(180) = 4.41, P < 0.001) and hypertension-related knowledge (∆ = 5.94%, t(180) = 3.25, P = 0.001) in the IA over and above those observed in the CA. Similarly, PC interventions led to significant improvements in HRQoL (∆ = 6.5%, t(180) = 5.50, P < 0.001) and satisfaction with PC in the IA (∆ = 18.12%, t(180) = 11.85, P < 0.001) at the end of the study. PC significantly improved humanistic outcomes in HIV-positive patients with hypertension after a 12-month intervention.


Molds, Mycotoxins, the Brain, the Gut and Misconceptions.
Molds are present in homes and other indoor places that are water damaged and they produce mycotoxins. One mold species can produce several different mycotoxins and one mycotoxin can come from several different molds. Even small amounts of mold growth in an air conditioner or in ducts will result in the occupants being chronically exposed, constantly breathing mold spores and mycotoxins, causing illness.


Effects of high vs low glycemic index of dietary carbohydrate on cardiovascular disease risk factors and insulin sensitivity: the OmniCarb randomized clinical trial.
Foods that have similar carbohydrate content can differ in the amount they raise blood glucose. The effects of this property, called the glycemic index, on risk factors for cardiovascular disease and diabetes are not well understood. To determine the effect of glycemic index and amount of total dietary carbohydrate on risk factors for cardiovascular disease and diabetes. Randomized crossover-controlled feeding trial conducted in research units in academic medical centers, in which 163 overweight adults (systolic blood pressure, 120-159 mm Hg) were given 4 complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks, and completed at least 2 study diets. The first participant was enrolled April 1, 2008; the last participant finished December 22, 2010. For any pair of the 4 diets, there were 135 to 150 participants contributing at least 1 primary outcome measure. (1) A high-glycemic index (65% on the glucose scale), high-carbohydrate diet (58% energy); (2) a low-glycemic index (40%), high-carbohydrate diet; (3) a high-glycemic index, low-carbohydrate diet (40% energy); and (4) a low-glycemic index, low-carbohydrate diet. Each diet was based on a healthful DASH-type diet. The 5 primary outcomes were insulin sensitivity, determined from the areas under the curves of glucose and insulin levels during an oral glucose tolerance test; levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides; and systolic blood pressure. At high dietary carbohydrate content, the low- compared with high-glycemic index level decreased insulin sensitivity from 8.9 to 7.1 units (-20%, P = .002); increased LDL cholesterol from 139 to 147 mg/dL (6%, P ≤ .001); and did not affect levels of HDL cholesterol, triglycerides, or blood pressure. At low carbohydrate content, the low- compared with high-glycemic index level did not affect the outcomes except for decreasing triglycerides from 91 to 86 mg/dL (-5%, P = .02). In the primary diet contrast, the low-glycemic index, low-carbohydrate diet, compared with the high-glycemic index, high-carbohydrate diet, did not affect insulin sensitivity, systolic blood pressure, LDL cholesterol, or HDL cholesterol but did lower triglycerides from 111 to 86 mg/dL (-23%, P ≤ .001). In this 5-week controlled feeding study, diets with low glycemic index of dietary carbohydrate, compared with high glycemic index of dietary carbohydrate, did not result in improvements in insulin sensitivity, lipid levels, or systolic blood pressure. In the context of an overall DASH-type diet, using glycemic index to select specific foods may not improve cardiovascular risk factors or insulin resistance. clinicaltrials.gov Identifier: NCT00608049.


Revising the history of Cold War research ethics.
President Clinton's charge to the Advisory Committee on Human Radiation Experiments included the identification of ethical and legal standards for evaluating government-sponsored radiation experiments conducted during the Cold War. In this paper, we review the traditional account of the history of American research ethics, and then highlight and explain the significance of a number of the Committee's historical findings as they relate to this account. These findings include both the national defense establishment's struggles with legal and insurance issues concerning human experiments, and the medical profession's perspective on human experimentation in the years following the Nuremberg Medical Trials. We conclude that the Committee's work both enriches the traditional view of the history of research ethics and opens important new areas for study.


Quality of anthropometric data in India's National Family Health Survey: Disentangling interviewer and area effect using a cross-classified multilevel model.
India has adopted a target-based approach to reduce the scourge of child malnourishment. Because the monitoring and evaluation required by this approach relies primarily on large-scale data, a data quality assessment is essential. As field teams are the primary mode of data collection in large-scale surveys, this study attempts to understand their contribution to variations in child anthropometric measures. This research can help disentangle the confounding effects of regions/districts and field teams on the quality of child anthropometric data. The anthropometric z-scores of 2,25,002 children below five years were obtained from the fourth round of India's National Family and Health Survey (NFHS-4), 2015-16. Unadjusted and adjusted standard deviations (SD) of the anthropometric measures were estimated to assess the variations in measurements. In addition, a cross-classified multilevel model (CCMM) approach was adopted to estimate the contribution of geographical regions/districts and teams to variations in anthropometric measures. The unadjusted SDs of the measures of stunting, wasting, and underweight were 1.7, 1.4, and 1.2, respectively. The SD of stunting was above the World Health Organisation threshold (0.8-1.2), as well as the Demographic and Health Survey mark. After adjusting for team-level characteristics, the SDs of all three measures reduced marginally, indicating that team-level workload had a marginal but significant role in explaining the variations in anthropometric z-scores. The CCMM showed that the maximum contribution to variations in anthropometric z-scores came from community-level (Primary Sampling Unit (PSU)) characteristics. Team-level characteristics had a higher contribution to variations in anthropometric z-scores than district-level attributes. Variations in measurement were higher for child height than weight. The present study decomposes the effects of district- and team-level factors and highlights the nuances of introducing teams as a level of analysis in multilevel modelling. Population size, density, and terrain variations between PSUs should be considered when allocating field teams in large-scale surveys.


Characteristics of mandibular injuries caused by bullets and improvised explosive devices: a comparative study.
The purpose of this study was to investigate the difference in mandibular trauma caused by two mechanisms for the delivery of missile injuries: firearms and improvised explosive devices (IEDs). The data investigated included sex, age, mechanism of injury, and other clinical and radiographic manifestations. Seventy consecutive patients, predominantly male, with a mean age of 28.6±14 years (range 2-60 years) were enrolled: 38 patients (54.3%) sustained mandibular fractures caused by bullet injuries and 32 patients (45.7%) had mandibular fractures caused by IED explosion injuries. The study revealed that the differences in most of the investigated variables were not statistically significant; the only significant differences were the incidence of trauma to other body regions and the presence of retained foreign bodies. The effect on the mandible of IED explosion resembles that of bullets. Bullet injuries are associated with a relatively higher number of mandibular sites involved and more bilateral fractures, in addition to more extensive bone loss. IEDs, on the other hand, cause more multisystem injuries and result in more retained foreign bodies.


Evolution of robot-assisted orthotopic ileal neobladder formation: a step-by-step update to the University of Southern California (USC) technique.
To describe our, step-by-step, technique for robotic intracorporeal neobladder formation. The main surgical steps to forming the intracorporeal orthotopic ileal neobladder are: isolation of 65 cm of small bowel; small bowel anastomosis; bowel detubularisation; suture of the posterior wall of the neobladder; neobladder-urethral anastomosis and cross folding of the pouch; and uretero-enteral anastomosis. Improvements have been made to these steps to enhance time efficiency without compromising neobladder configuration. Our technical improvements have resulted in an improvement in operative time from 450 to 360 min. We describe an updated step-by-step technique of robot-assisted intracorporeal orthotopic ileal neobladder formation.


Roles of N-linked glycosylation and glycan-binding proteins in placentation: trophoblast infiltration, immunomodulation, angiogenesis, and pathophysiology.
Protein N-linked glycosylation is a structurally diverse post-translational modification that stores biological information in a larger order of magnitude than other post-translational modifications such as phosphorylation, ubiquitination and acetylation. This gives N-glycosylated proteins a diverse range of properties and allows glyco-codes (glycan-related information) to be deciphered by glycan-binding proteins (GBPs). The intervillous space of the placenta is richly populated with membrane-bound and secreted glycoproteins. Evidence exists to suggest that altering the structural nature of their N-glycans can impact several trophoblast functions, which include those related to interactions with decidual cells. This review summarizes trophoblast-related activities influenced by N-glycan-GBP recognition, exploring how different subtypes of trophoblasts actively adapt to characteristics of the decidualized endometrium through cell-specific expression of N-glycosylated proteins, and how these cells receive decidua-derived signals via N-glycan-GBP interactions. We highlight work on how changes in N-glycosylation relates to the success of trophoblast infiltration, interactions of immunomodulators, and uterine angiogenesis. We also discuss studies that suggest aberrant N-glycosylation of trophoblasts may contribute to the pathogenesis of pregnancy complications (e.g. pre-eclampsia, early spontaneous miscarriages and hydatidiform mole). We propose that a more in-depth understanding of how N-glycosylation shapes trophoblast phenotype during early pregnancy has the potential to improve our approach to predicting, diagnosing and alleviating poor maternal/fetal outcomes associated with placental dysfunction.


A 72-kilodalton fyn-related polypeptide (p72fyn-R) binds to the antigen-receptor/CD3 (TcR/CD3) complex.
Protein-tyrosine kinases play crucial roles in the activation and transformation of T lymphocytes. In this study, we have identified a variant of the fyn kinase at 70-72 kDa (termed p72fyn-R) that can preferentially associate with the TcR/CD3 complex in certain T cells. Phosphoamine acid analysis revealed that the CD3-associated p72fyn-R is labeled on both tyrosine and serine/threonine residues. TcR/CD3-associated p72fyn-R could be specifically reprecipitated using anti-fyn antisera to both the N and C terminus of p59fyn. In addition, two-dimensional phosphotryptic peptide map patterns of TcR/CD3-associated p72fyn and anti-fyn-precipitable p72 were identical. By contrast, a comparison of p72fyn-R and p62fyn showed similarities and differences. p72fyn-R possesses a peptide corresponding to the autophosphorylation site that migrates in the same position as found for p59/62fyn. However, p72fyn-R possessed at least four novel phosphorylated sites labeled on serine and threonine residues that are absent in the p62fyn pattern. Phosphatase digestion experiments indicated that p72fyn-R is more resistant to dephosphorylation than p59/62fyn. Two-dimensional phosphotryptic analysis indicated that the novel serine/threonine phosphorylation sites were responsible for the resistance to phosphatase digestion. Although the exact nature of the relationship between p72fyn-R and p59/62fyn remains undetermined, these data indicate that TcR/CD3 may utilize novel variants of src-related kinases in the generation of signals which regulate T-cell growth.


Assessing ego strength: spinning straw into gold.
The reexamination of ego function from the perspective of ego strength rather than ego deficit. To promote the assessment of ego strength as a valuable skill for nurse psychotherapists, and to underscore the importance of ego strength as a relevant construct for both assessment and psychotherapy outcome measurement. The literature of modern psychoanalysis and ego psychology, Bellak's research on ego function, Parse's nursing theory, and the nursing literature on ego assessment. Identifying and assessing ego strength helps nurse psychotherapists locate clients on a developmental continuum, suggests a place to join with the client at the inception of therapy, and provides data to develop therapeutic goals.


Changes in surfactant protein gene expression in a neonatal rabbit model of hyperoxia-induced fibrosis.
Lung injuries, including bronchopulmonary dysplasia, alter the surfactant system. We developed a newborn rabbit model of acute, followed by chronic, hyperoxic injury to study surfactant protein (SP) gene expression. Initial litters were exposed to >95% O2 until 50% died (LD50; 7-11 days old). Subsequent litters were exposed to >95% O2 for 8 days, followed by 60% O2 until 22-36 days. Controls were exposed to room air. LD50 animals displayed acute pulmonary inflammation, edema, protein leak, and surfactant dysfunction. These changes resolved, and fibrosis developed by 22 days. Whole lung SP-A mRNA expression (measured by membrane hybridization) was twice control levels at 4 days of >95% O2, with specific elevations in terminal bronchioles and type II cells at 4 days and the LD50 by in situ hybridization. Whole lung SP-B and SP-C mRNA were unchanged from control throughout exposure. However, in situ hybridization showed elevations in SP-B and SP-C mRNA in type II cells in inflamed areas at the LD50. SP mRNA alterations resolved by 22-36 days. The surfactant system recovers from acute hyperoxic injury, despite continued 60% O2 exposure.


Viral warts, herpes simplex and herpes zoster in patients with secondary immune deficiencies and neoplasms.
The incidence of viral warts, recurrent herpes simplex and herpes zoster has been assessed in a group of patients with possible secondary immune deficiency states and compared to a control group. Patients with cell-mediated immune deficiency appear to be more prone to warts and zoster infection as compared to patients with humoral immune deficiency. Recurrent herpes simplex infection was not increased in either group.


[Isolation of low-molecular-mass antibacterial mixtures from human seminal plasma].
To isolate low-molecular-mass antibacterial mixtures from healthy human seminal plasma. Semen was obtained by masturbation after at least three days of abstinence from healthy donors. Semen samples were allowed to liquefy at room temperature and then centrifuged at 10,000 r/min for 10 min to separate spermatozoa from seminal plasma. High sensitive antimicrobial activity was measured with radial diffusion assay. Antibacterial activity toward E. coli (ATCC25922) was monitored for each purification steps. The mixture of seminal plasma samples was applied to a SP-Sepharose column. Fractions which showed strong bactericidal activities, were combined and lyophilized. The lyophilized components were dissolved with Milli-Q water and applied to AKTA Superdex 75 column. Peak II of the Superdex 75 column, which showed antibacterial activity and represented the low-molecular-weight cationic fractions of the seminal plasma, was collected and lyophilized. Finally, peak II of the Superdex 75 column was applied to reverse phase HPLC C18 column. Fractions which showed strong antibacterial activity, were lyophilized and store at -20 degrees C. The molecular weight of the low-molecule-mass antibacterial mixtures was determined by Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. The low-molecular-mass mixtures with obviously higher antibacterial activity, which were termed HSLAMs(Human semen low-molecular-mass antibacterial mixtures), were isolated from the healthy human seminal plasma. Based on the mass spectrometry results, some molecules of RP-HPLC peaks were confirmed to be the semenogelin I derived peptides. The low-molecule-mass antibacterial mixtures may play an important role in males innate immunity. Semenogelin I derived peptides may be one of the sources of the low-molecule-mass antimicrobial mixtures in human seminal plasma.


Experimental heterotopic bone transplant.
We studied the reaction in rats to implants of heterotopic bone in the paravertebral region, using three types of material: bone preserved in alcohol, homologous bone preserved in alcohol associated with autogenous cancellous bone obtained from the iliac crest of the same animal, and isolated autogenous cancellous bone. Thirty rats were operated on, ten in each group. Some were sacrificed after 6, 14 and 21 days. The excised grafts were histologically studied. Animals in the third group showed new bone formation even in the first days, those in the second group presented less intense bone formation and those in the first group showed only traces of new bone tissue in the third week.


Reasonable hope: construct, clinical applications, and supports.
Hope may be the most laden shorthand term of all time. Everyone wants it; few know how to articulate what it is. Although family therapists frequently work to restore hope with hopeless families, they have contributed little to the abundant literature on hope. I present a new conceptualization of hope-reasonable hope-that reflects how family therapists think and practice. By subscribing to reasonable hope, clinicians enhance their ability to offer accompaniment and bear witness to clients. I describe clinical practices that, informed by reasonable hope, also facilitate its cocreation. Finally, I suggest supports for clinicians who practice reasonable hope.


ABO blood types associated with the risk of venous thromboembolism in Han Chinese people: A hospital-based study of 200,000 patients.
ABO blood types are putatively associated with the risk of venous thromboembolism (VTE), but it is not proved in Chinese people. A large population of Han Chinese patients discharged from Peking Union Medical College Hospital between January 2010 and June 2016 were retrospectively analyzed in a case-control study. A total of 1412 VTE patients were identified from 200,660 discharged Han Chinese patients, including 600 patients with deep vein thrombosis (DVT), 441 patients with pulmonary embolism, and 371 patients with both DVT and pulmonary embolism. The prevalence of non-O blood type was weakly but statistically higher in VTE patients compared with 199,248 non-VTE patients, with an odds ratio (OR) of 1.362 (95% confidence interval [CI], 1.205-1.540). Subgroup analysis showed that the OR for non-O blood type was still increased. It was greater in pre-hospital VTE (OR = 1.464) than that in hospital-acquired VTE (OR = 1.224), and greater in unprovoked VTE (OR = 1.859) than that in provoked VTE (OR = 1.227). The OR for non-O blood type decreased with age in subgroup analysis. These results suggest a weak but statistically significant correlation between non-O blood type and risk of VTE in Han Chinese people.


Parasitic infection of man on Kar Kar Island, New Guinea.
The prevalence of protozoan and helminth parasites of the intestinal tract in a Papua New Guinea island with a population of 16,800 was assessed by surveys of a series of randomly selected villages. There were significant differences in the severity of infection with these parasites between the two linguistic groups inhabiting the eastern and western halves of the island. Blood examinations for malaria and microfilariae also differed. It is thought that these differences reflect obscure microenvironmental factors in what would appear to be an epidemiologically homogeneous population.


Thermally activated delayed fluorescence in fullerenes.
This report reviews the thermally activated delayed fluorescence (TADF) displayed by fullerenes. From the analysis of the steady-state data, time-resolved data, or by a combination of both, it is possible to determine several important photophysical parameters of fullerenes. Herein we also cover the development of temperature and oxygen sensors based on the TADF effect exhibited by fullerene C(70). Despite the work already carried out, knowledge of the photophysics of fullerenes and derivatives is still incomplete, and much remains to be done in this area and in the improvement of sensor systems based on fullerenes.


SCN5A mutation G615E results in NaV1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity.
SCN5A is expressed in cardiomyocytes and gastrointestinal (GI) smooth muscle cells (SMCs) as the voltage-gated mechanosensitive sodium channel NaV1.5. The influx of Na+ through NaV1.5 produces a fast depolarization in membrane potential, indispensable for electrical excitability in cardiomyocytes and important for electrical slow waves in GI smooth muscle. As such, abnormal NaV1.5 voltage gating or mechanosensitivity may result in channelopathies. SCN5A mutation G615E - found separately in cases of acquired long-QT syndrome, sudden cardiac death, and irritable bowel syndrome - has a relatively minor effect on NaV1.5 voltage gating. The aim of this study was to test whether G615E impacts mechanosensitivity. Mechanosensitivity of wild-type (WT) or G615E-NaV1.5 in HEK-293 cells was examined by shear stress on voltage- or current-clamped whole cells or pressure on macroscopic patches. Unlike WT, voltage-clamped G615E-NaV1.5 showed a loss in shear- and pressure-sensitivity of peak current yet a normal leftward shift in the voltage-dependence of activation. In current-clamp, shear stress led to a significant increase in firing spike frequency with a decrease in firing threshold for WT but not G615E-NaV1.5. Our results show that the G615E mutation leads to functionally abnormal NaV1.5 channels, which cause disruptions in mechanosensitivity and mechano-electrical feedback and suggest a potential contribution to smooth muscle pathophysiology.


Unique properties of NADP-thioredoxin reductase C in legumes.
NADP-thioredoxin reductases (NTRs) reduce thioredoxins (Trxs), using NADPH as a reductant, together constituting complete redox systems (NTS). Beside NTRA and NTRB targeted to both cytosol and mitochondria of plant cells, there is in chloroplasts an unusual NTR (NTRC) harbouring a Trx domain in a C-terminal extension, as recently reported in Oryza sativa. Although NTRC may constitute a complete NTS, it was described as a bifunctional enzyme. Because the gene is only present in photosynthetic organisms and the protein in green tissues, NTRC was thought to have a role restricted to photosynthetic cells. To determine whether NTRC from dicot plants is a bifunctional enzyme or a complete NTS, as well as to identify its putative target, NTRC from Medicago truncatula was cloned and NTRA was cloned for comparison. Here evidence is presented that MtNTRC (i) acts as an NTS and reduces dithiobisnitrobenzoate (DTNB) with a turnover (0.62 s(-1)) similar to that measured with MtNTRA in the presence of a Trxh (0.81 s(-1)); (ii) is able to use both NADPH (k(M)=2.4 microM) and NADH (k(M)=11 microM) as cofactors; (iii) efficiently reduces BAS1, a plastidial peroxiredoxin; and (iv) is expressed in both leaves and stems but unexpectedly is even more abundant in cotyledons from dry and germinating seeds. Because BAS1 is also present in both green tissues and seeds, NTRC/BAS1 may be involved in the scavenging of peroxides produced in green tissues during the day or the night and in seeds during germination. These results suggest different roles for NTRC in monocot and dicot plants.


Serum potassium concentration as a predictor of resuscitation outcome in hypothermic cardiac arrest.
The purpose of this study was to determine whether serum potassium concentration (SK) can predict resuscitation outcome in a canine model of severe hypothermic cardiac arrest. Fifteen adult mongrel anesthetized dogs were immersed to the neck in a 4 degrees C water bath and ventilated with room air, with ventilation halved at 45 min and stopped at 90 min. After cardiac arrest, 14 of the dogs were kept in the water bath for periods of 2-7 h, and another was held in arrest for 13 h. Following 10 min of closed chest cardiopulmonary resuscitation (CPR) (simulating a short transport time to a hospital), animals were placed on cardiopulmonary bypass and rapidly rewarmed. With appearance of ventricular fibrillation, animals were defibrillated up to three times. Standard advanced cardiac life support was initiated at a core temperature (Tc) of 30 degrees C. Eight of the 15 dogs had return of spontaneous circulation (ROSC), at Tc ranging from 30.4 to 36.5 degrees C. The eight dogs with ROSC did not differ from the seven without ROSC in time to arrest (128 +/- 48 versus 128 +/- 23 min) (mean +/- SD) or Tc at arrest (18.1 +/- 2.2 versus 17.9 +/- 3.1 degrees C), but had higher Tc at the end of the arrest period (9.7 +/- 3.0 versus 5.2 +/- 2.0 degrees C), reflecting a shorter arrest period in the dogs with ROSC (225 +/- 95 versus 420 +/- 193 min). SK (mEq liter(-1)) did not differ between dogs with and without ROSC at baseline (3.5 +/- 0.4 versus 3.7 +/- 0.4) or at arrest (3.4 +/- 0.7 versus 4.3 +/- 2.2), but there was a trend toward higher SK at the end of arrest in the group without ROSC (4.6 +/- 1.5 versus 9.4 +/- 6.3; range 3.2-7.8 versus 3.5-21.4; p = .053). SK was similar after 10 min of CPR in the groups with and without ROSC (6.6 +/- 2.9 versus 9.0 +/- 2.4; range 2.5-11.1 versus 4.5-11.0; p = .107). SK after 10 min of CPR was higher in some animals with ROSC (9.6 and 11.1) than in others which did not have ROSC (4.5 and 7.9). We conclude that very high SK following prolonged hypothermic cardiac arrest may be suggestive of an inability to resuscitate. However, SK after both prolonged hypothermic cardiac arrest and a brief period of CPR is not a good predictor of resuscitation using cardiopulmonary bypass rewarming in an animal model.


Novel "protecting group-dependent" alkylation-RCM strategy to medium-sized oxacycles: first total synthesis of --isoprelaurefucin.
[reaction: see text] A novel "protecting group-dependent" alkylation strategy was developed for complementary diastereoselective syntheses of alpha,alpha'-syn- and alpha,alpha'-anti-bis-alkenes 2 and 3, which represent ring-closing metathesis (RCM) substrates for medium-sized oxacycles. This principle has been applied to a stereoselective and concise total synthesis of (-)-isoprelaurefucin (4) in 14 steps in 12% overall yield from known epoxide 8.


Direct Noncovalent Activation of α,β-Unsaturated Aldehydes for the Stereodivergent Synthesis of Substituted Cyclohexenes.
HOMO-raising noncovalent activation of α-aryl α,β-unsaturated aldehydes using a bifunctional Brønsted base catalyst is achieved. The catalytically generated dienolate intermediate undergoes all-carbon [4+2] cyclizations with nitroolefins, leading to chiral cyclohexenes with four contiguous stereocenters in high yields and with excellent enantioseletivity. Furthermore, the diastereodivergent synthesis of the products is realized by introducing a second steric control to the bifunctional catalyst; 4 isomers out of 16 possible stereoisomers of the products were selectively produced by simple use of two catalysts and their (pseudo)enantiomers. The results presented here provide new insights into the remote activation of the carbonyl functionality as well as the stereodivergent synthesis of complex chiral molecules with multiple stereocenters.


Changes in the quality of jaboticaba fruit (Myriciaria jaboticaba (Vell) Berg. cv. Sabará) stored under different oxygen concentrations.
Jaboticaba (Myriciaria jaboticaba (Vell) Berg.) is a highly perishable Brazilian berry with a shelf life of only 2 days under ambient conditions. Low temperatures and controlled atmosphere (CA) have been used to extend the shelf life of perishable fruit. Thus the aim of this study was to determine the effect of CA with varying concentrations of oxygen (1, 5, 10, 15 and 21 kPa) during cold storage (12.5 °C) of 'Sabará' jaboticaba fruit. Atmospheres with lower oxygen concentrations (1 and 5 kPa O(2) ) significantly reduced jaboticaba respiration rate. Fruit stored under these conditions had higher L values, and titratable acidity (TA), and lower ratios of soluble solids content (SSC)/TA. However, at the lowest concentration of oxygen (1 kPa O(2) ), firmness decreased markedly compared to fruits stored at higher O(2) levels (P < 0.05). After only 2 days of storage at ambient temperature jaboticaba received a score of 1.6 (dislike strongly - 1) compared to fruit stored under CA, which scored 7.4 (like moderately - 7). After 9 days of storage, fruit from all treatments remained above the limit of acceptability (score 5) and were rated as 6.2. With respect to appearance, statistical differences between treatments were not observed. The total anthocyanin content was not affected by oxygen concentration but decreased 40.4% during CA storage. 'Sabará' jaboticaba fruit can be satisfactorily stored under atmospheres containing 5-21 kPa O(2) at 12.5 °C for up to 6 days.


Coronary anatomy, anatomic variations and anomalies: a retrospective coronary angiography study.
The incidence of coronary artery anomalies (CAAs) varies from 0.2% to 8.4%. Knowledge of such anatomical variations is important as coronary procedures are regularly performed these days. We aimed to find the coronary dominance pattern, intermediate artery (IMA) frequency and CAA incidence in our clinic, and compare them to those in the literature. The medical reports of 5,548 patients who had undergone coronary angiography (CAG) between 2005 and 2009 were retrospectively investigated. Dominance pattern and presence of IMA and CAA were recorded. CAAs were described using two different classifications: Angelini and Khatami's classification, and a new modified classification that was derived from Angelini and Khatami's classification. Some procedural details and clinical features of the patients with CAA were also investigated. Coronary dominance pattern was: 81.6% right coronary artery, 12.2% circumflex artery and 6.2% co-dominant. IMA was present in 613 (11.0%) patients. The incidences of overall anomaly were 2.7% and 1.4%, according to the different classifications. Absent left main coronary artery, which was the most common anomaly in the present study, was found in 51 (0.9%) patients. Incidences of myocardial bridge, coronary arteriovenous fistulae and aneurysms were 1.1%, 0.2% and 0.3%, respectively. CAAs are generally asymptomatic, isolated lesions. Some may lead to anginal symptoms, myocardial infarction or sudden death. We found that CAA was associated with increased radiation and contrast exposure in patients who underwent CAG. This risk could be reduced if appropriate catheters were designed and training programmes on ostial cannulation were developed.


A microgenetic study of insightful problem solving.
An eight-session microgenetic study of acquisition of an insightful problem-solving strategy was conducted. A total of 35 second graders who did not use this insightful strategy initially were assigned to two groups that differed in the frequency of problems likely to facilitate discovery and generalization of the strategy. Children in the facilitative problems group discovered the insightful strategy earlier, used it more often subsequently, and transferred it more often to novel problems than did those in the nonfacilitative problems group. Children generally discovered the insightful strategy on the most facilitative items and extended it progressively to items on which its advantages were smaller but still substantial. The results indicate that experience outside the experimental situation, as well as experience inside the experimental situation, influences use of new strategies.


A Comparative Study of Three Imaging Modalities for Size Selection of a Watchman Left Atrial Appendage Closure Device.
To compare the results of computed tomography angiography (CTA), transesophageal echocardiography (TEE), and digital subtraction angiography (DSA) measurements and analyze their accuracy, correlation, and consistency in patients who have successfully undergone left atrial appendage closure (LAAC). A total of 157 non-valvular atrial fibrillation (AF) patients who underwent LAAC with Watchman devices were included in the study. The maximum diameter and depth of LAA were recorded using CTA, TEE, and DSA. Correlations and agreements were compared. The LAAC procedure was performed successfully in all patients using the Watchman device. There was no significant difference between DSA and TEE measurements of the diameter of the LAA ostium. LAA ostium diameter obtained by CTA, however, was greater than that from DSA and TEE. Correlations were good between LAA ostium diameter measured by TEE, CTA, and DSA and Watchman device size. DSA measurements and actual device size showed the widest limits of agreement, followed by TEE; CTA measurements showed the narrowest limits of agreement. For LAA depth measurements, mean CTA measurements were higher than those of TEE and DSA. There was no significant difference in depth measurements among the three imaging modalities. CTA, TEE, and DSA measurements exhibited good correlations with Watchman device size. The ostium diameter and depth of the LAA measured by CTA were greater than those measured by TEE and DSA. The relevance and concordance of CTA measurements were the strongest.


The effect of anti-alpha-fetoprotein-adriamycin conjugate on a human hepatoma.
Conjugates between chemotherapeutic agents and antibodies, linked by a dextran bridge, were previously shown to be effective in suppression of hepatoma growth in vitro and in vivo. However, scaling up of production of such conjugates may lead to a high degree of variation in molar ratios of drug to antibody in different batches. In this study, an alternative link between drug and antibody was evaluated. A conjugate between adriamycin and murine IgGI monoclonal antibodies to human alpha-fetoprotein was prepared using a polyglutamic-acid bridge. The simple and reproducible method of linking adriamycin to a specific site on the antibody enabled the binding of the drug to alpha-fetoprotein with a high yield (63% to 68%); the molar ratio of drug/antibody was in the range of 110:1 to 120:1. The conjugate retained its capacity to bind to purified alpha-fetoprotein. Incorporation of [3H]-thymidine or [3H]-leucine into hepatoma cells, which express alpha-fetoprotein, was inhibited by the conjugate, compared with unconjugated antibody. Furthermore, 90% of this pharmacological activity was preserved, compared with free adriamycin. In vitro, the inhibitory activity of the polyglutamic acid conjugate was higher than that of a conjugate in which dextran was used as the linker between drug and antibody. In vivo, both conjugates were equally effective in suppression of hepatoma growth transplanted subcutaneously in athymic mice. However, this effect lasted only during the treatment period of 2 to 3 wk. Six days after discontinuation of therapy, reacceleration of tumor growth was observed regardless of the conjugate used.(ABSTRACT TRUNCATED AT 250 WORDS)


[The conditioned reflex behavior of dogs to the intracaudate administration of corticoliberin].
Situational conditioned reflexes in dogs were studied before and after intracaudate bilateral microinjections of corticoliberin (CRF). Intracaudate microinjections led to an enhancement of locomotor activity, the restoration of earlier extinct exploratory behaviour, impairment of differentiation inhibition, changes of emotional reactions. Behavioural changes were accompanied by shifts of cortisol, vasopressin, norepinephrine and adrenalin levels in blood of experimental animals. The maximal impairment of conditioned behaviour was observed 30 min after CRF microinjections and coincided with maximal activation of pituitary-adrenocortical system. On the basis of the data obtained we conclude that CRF-sensitive systems of the neostriatum participate in the mechanisms, underlying behavioural, vegetative and hormonal changes.


Prognostic value of gross motor function measure to evaluate the severity of cerebral palsy.
Early adequate evaluation of motor development and prognosis of degree of long-term motor disability is very important not only for parents, but also for correct management of goal oriented rehabilitation treatment and for planning of preventive measures. To estimate the value of Gross Motor Function Measure in evaluation of severity of cerebral palsy, for prognostic counseling with parents and for planning of clinical management. Total of 397 children aged 1 to 12 years at study onset with cerebral palsy were observed for up to 3,5 years during the period from 2002 to 2005. Children were assessed by GMFM-88 (Gross Motor Function Measure), by GMFCS (Gross Motor Function Classification System). Over the course of the study 397 children had a total of 6875 GMFM assessments, or an average of 17,3 observations per child. The study revealed significant differences between developmental limit of each level of gross motor function. Children with lower motor development potential reach their limit more quickly, than children with higher potentials. Children with cerebral palsy reach about 90% of their gross motor function by around age 5 years or younger, depending on their GMFCS level. After this age intervention programs have to address increasing independent activity and to promote participation of children with disabilities.


Tunable stiffness of graphene oxide/polyacrylamide composite scaffolds regulates cytoskeleton assembly.
The stiffness of the extracellular matrix (ECM) not only provides mechanical resistance to support the cellular shape, but also plays significant roles in many cell functions. However, it's difficult to utilize traditional substrate materials to investigate cell behaviors under physical microenvironments due to their unphysiological stiffness or intrinsic secondary effects. Herein, a stiffness-tunable graphene oxide/polyacrylamide composite scaffold was fabricated to investigate the effect of substrate stiffness on cytoskeleton assembly and specific gene expression during cell growth. In the composite structure, the polyacrylamide (PAAm) hydrogel plays an exceptional role in controlling the substrate stiffness; in contrast, graphene oxide (GO) sheets not only provide permissive surfaces for cell adhesion and growth, but also effectively eliminate the secondary effects of the PAAm hydrogel. It's found that substrate stiffness could affect cell morphology and cytoskeleton assembly via specific genetic pathways. Therefore, the composite structure can be considered an attractive candidate as a scaffold and provides potential to elucidate the disease association of ECMs.


Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors alpha and beta.
Lipid-loaded macrophage "foam cells" accumulate in the subendothelial space during the development of fatty streaks and atherosclerotic lesions. To better understand the consequences of such lipid loading, murine peritoneal macrophages were isolated and incubated with ligands for two nuclear receptors, liver X receptor (LXR) and retinoic acid receptor (RXR). Analysis of the expressed mRNAs using microarray technology led to the identification of four highly induced genes that encode apolipoproteins E, C-I, C-IV, and C-II. Northern blot analysis confirmed that the mRNA levels of these four genes were induced 2-14-fold in response to natural or synthetic ligands for LXR and/or RXR. The induction of all four mRNAs was greatly attenuated in peritoneal macrophages derived from LXRalpha/beta null mice. The two LXR response elements located within the multienhancers ME.1 and ME.2 were shown to be essential for the induction of apoC-II promoter-reporter genes by ligands for LXR and/or RXR. Finally, immunohistochemical studies demonstrate that apoC-II protein co-localizes with macrophages within murine arterial lesions. Taken together, these studies demonstrate that activated LXR induces the expression of the apoE/C-I/C-IV/C-II gene cluster in both human and murine macrophages. These results suggest an alternative mechanism by which lipids are removed from macrophage foam cells.


A Rare Case of Benign Xanthogranuloma Located on the Uterine Cervix - a Case Report.
We report the case of a 44-year-old woman who presented with vaginal bleeding. Vaginal examination and colposcopy showed a tumor on the anterior lip of the cervix. Trans-vaginal sonography revealed a thickened endometrium with accentuated vascularization. Samples from the tumor and endometrium were collected by byopsic curettage. Histopathologic examination showed atypical hyperplasia of the endometrium and benign xanthogranuloma of the cervix. Therefore, surgical intervention was performed.


Coexistence of Cervical Disc Herniation and Shoulder Soft Tissue Pathologies and the Effect of Sleeping Positions and Orthopedic Pillows.
Background/aim This study investigates the degree of coexistence of cervical disc herniation and shoulder soft tissue pathology, as well as the effect of sleeping positions and orthopedic pillow use. Materials and methods This present study was conducted on 72 patients with shoulder/arm pain operated on for cervical disc herniation. Two groups were examined according to the presence of shoulder soft tissue pathology, four common sleeping positions, and the use of an orthopedic pillow. Preoperative and postoperative shoulder/arm visual analog scale (VAS) scores were compared. Results The preoperative VAS values were 7.35, while the postoperative VAS values were 3.32. Twenty-one patients (29.2%) had a disc at the C3-4 level, a rate equal to that for the C5-6 level. Twenty-four patients (33.3%) had a disc at the C4-5 level. Thirty-two cases (44.4%) slept in a side-lying position on the same side as their disc herniation. Among those with a herniated disc at the C3-4 level, 8 (53.3%) preferred sleeping side-lying on the opposite side of the disc. In contrast, those with a herniated disc at the C4-5 level more frequently (40.6%) slept side-lying on the same side as the disc. Mean VAS scores were significantly higher in cases with shoulder soft tissue pathology and were significantly lower in the group that used orthopedic pillows (p<0.001). Conclusion Shoulder soft tissue pathologies should be considered in postoperative shoulder pain. The use of orthopedic pillows is effective in preoperative and postoperative pain. Sleeping positions do not affect the shoulder/arm pain before and after the operation, but they affect the level of cervical disc herniations.


[Improvement of physical performance and aerobic capacity mediated by a novel 4--week ambulatory cardiac rehabilitation program].
During a 4-week ambulatory cardiac rehabilitation program, 262 patients with coronary artery disease (CAD), 235 men and 27 women, 53.6 +/- 10.2 years, performed 30.5 +/- 2.9 exercise units. Before and after the rehabilitation program exercise, capacity was assessed by bicycle ergometry. There was a significant (p < 0.001) increase in the maximum exercise capacity at the end of the program (105.3 +/- 32.3 vs. 121.9 +/- 37.3 W). Physical work capacity on the 2.0 mmol lactate level improved (p < 0.001) from 72.2 +/- 23.5 to 86.4 +/- 25.8 W, on the 2.5 mmol/l level (p < 0.001) from 83.5 +/- 23.2 to 97.4 +/- 26.4 W, and on the 3.0 mmol/l level (p < 0.001) from 93.1 +/- 23.0 to 106.6 +/- 26.1 W. Despite enhanced performance, heart rate remained unaltered on the 2.0, 2.5, and 3.0 mmol/l lactate level. Furthermore, ergometric performance on predefined heart rate levels was significantly (p < 0.001) increased: 85/min: from 56.0 +/- 24.1 to 65.8 +/- 24.5 W, 90/min: from 62.0 +/- 27.3 to 71.2 +/- 26 W; 95/min: from 67.2 +/- 26.4 to 77.5 +/- 27.6 W; 100/min: from 71.1 +/- 29.6 to 80.6 +/- 28.1 W; 105/min: from 69.8 +/- 26.2 to 81.9 +/- 28.2 W and 110/min: from 73.6 +/- 28.9 to 90.4 +/- 29.4 W. The results demonstrate that physical performance in patients with CAD was improved by our novel ambulatory cardiac rehabilitation program. This improvement included an increase in maximum as well as endurance work capacity; furthermore, this increase was accompanied by a decrease in resting and exercise heart rates. The results demonstrate an absolute increase of physical performance, more importantly an increase of physical performance at defined lactate levels in the presence of unchanged heart rates mediated by the rehabilitation program. Thus, this increase was independent of motivational factors in the patients and/or the investigators during the re-exercise test. On the contrary, our data demonstrate that it is based on an improvement of aerobic endurance capacity associated with a therapeutically beneficial significant decrease of heart rate for a defined workload. The effects were independent of pharmacological influences (e.g., beta-receptor antagonists). These findings are of clinical importance with respect to reduction of myocardial oxygen consumption in patients with CAD.


Managing vascular impairment following orthopaedic injury.
Orthopaedic trauma is associated with vascular impairment in approximately 1% of cases, complicating management of the injury, particularly to the shoulder, elbow, pelvis and knee. Doctors treating trauma would be expected to detect and manage several such patients a year.


Safety and feasibility of radiofrequency ablation for treatment of Bosniak IV renal cysts.
To describe our initial experience with radiofrequency ablation (RFA) of Bosniak IV renal cysts. From 2010 to 2014, 154 renal tumor cases were treated with percutaneous thermal ablation, of which 10 cases (6.4%) from nine patients were complex renal cysts and were treated with radiofrequency ablation. All complex cysts were classified as Bosniak IV (four women and five men; mean age: 63.6 yrs, range: 33-83 years). One patient had a single kidney. Lesion size ranged from 1.5 to 4.1cm (mean: 2.5cm) and biopsy was performed on four cysts immediately before the procedure, all of which were malignant (two clear cell and two papillary carcinoma). Mean volume reduction of complex cysts was 25% (range: 10-40%). No patients required retreatment with RFA and no immediate or late complications were observed. The follow-up of Bosniak IV cysts had a median of 27 months (interquartile range [IQR], 23 to 38) and no recurrence or significant loss of renal function were observed. Mid-term follow-up of the cases in our database suggests that image-guided percutaneous RFA can treat Bosniak IV cysts with very low complication rates and satisfactorily maintain renal function.


Demonstration of C-type viruses in N-methyl-N-nitroso urea (MNU)-induced leukemia of mice by reverse transcriptase activity and XC assay.
A significantly higher MuLV expression was demonstrated in cells of MNU-induced leukemia of mice compared to corresponding cells of untreated control animals by reverse transcriptase activity and XC cell assay. These positive findings were verified by determination of indirect immunofluorescence test to look for intracytoplasmic MuLV p30. The problem is discussed whether these viruses play a role in chemical leukemogenesis.


A qualitative exploration of how lifetime stressor exposure influences sport performers' health, well-being, and performance.
Recent research has shown that lifetime stressor exposure can negatively impact sport performers. However, this work has predominantly relied on quantitative methods, which has provided limited information regarding how stressors occurring over the life course affect health, well-being, and performance. This study aimed to explore how relatively high levels of lifetime (non-sport and sport-specific) stressor exposure influenced sport performers' health, well-being, and performance. To identify participants who had experienced high lifetime (non-sport and sport-specific) stressors, we used criterion-based purposeful sampling from a prior study. Subsequently, semi-structured interviews, complemented by timelining, were conducted with 22 sport performers (17 female; Mage = 25.89, SD = 10.20). We used reflexive thematic analysis to develop three overarching themes that illustrate how high lifetime (non-sport and sport-specific) stressor exposure influences sport performers' health, well-being, and performance. These were: psychological (e.g., maladaptive coping strategies), social (e.g., difficulties in building relationships), and behavioral (e.g., risky behaviors) factors. These findings can help practitioners identify sport performers at risk of developing stress-related health, well-being, and performance problems, and may aid the development of effective interventions.


A Novel Measure of "Good" Mentoring: Testing Its Reliability and Validity in Four Academic Health Centers.
Despite the well-recognized benefits of mentoring in academic medicine, there is a lack of clarity regarding what constitutes effective mentoring. We developed a tool to assess mentoring activities experienced by faculty and evaluated evidence for its validity. The National Initiative on Gender, Culture, and Leadership in Medicine-"C-Change"-previously developed the C-Change Faculty Survey to assess the culture of academic medicine. After intensive review, we added six items representing six components of mentoring to the survey-receiving help with career and personal goals, learning skills, sponsorship, and resources. We tested the items in four academic health centers during 2013 to 2014. We estimated reliability of the new items and tested the correlation of the new items with a mentoring composite variable representing faculty mentoring experiences as positive, neutral, or inadequate and with other C-Change dimensions of culture. Among the 1520 responding faculty (response rate 61-63%), there was a positive association between each of the six mentoring activities and satisfaction with both the amount and quality of mentoring received. There was no difference by sex. Cronbach α coefficients ranged from 0.89 to 0.95 across subgroups of faculty (by sex, race, and principal roles). The mentoring responses were associated most closely with dimensions of Institutional Support (r = 0.58, P < .001), Institutional Change Efforts for Faculty Support (r = 0.52, P < .001), Values Alignment (r = 0.58, P < .001), Self-efficacy (r = 0.43; P < .001), and Relationships/Inclusion/Trust (r = 0.41; P < .001). Data demonstrated that the Mentoring scale is a valid instrument to assess mentoring. Survey results could facilitate mentoring program development and evaluation.


Comparison of Exenatide and Metformin Monotherapy in Overweight/Obese Patients with Newly Diagnosed Type 2 Diabetes.
The present study assessed the therapeutic effect of exenatide and metformin as the initial therapy on overweight/obese patients with newly diagnosed type 2 diabetes (T2D). The prospective, nonrandomized, interventional study enrolled a total of 230 overweight or obese patients with newly diagnosed T2D who were administrated exenatide or metformin hydrochloride for 12 weeks. 224/230 patients, including 106 in the exenatide group and 118 in the metformin group, completed the 12-week treatment. Both exenatide and metformin significantly decreased the HbA1c levels in overweight/obese patients with newly diagnosed T2D (all P < 0.05). The reduction in HbA1c and the proportion of patients with HbA1c < 7.0% (53 mmol/mol) were higher in the exenatide group than in the metformin group (all P < 0.05). The exenatide treatment caused a greater decline in the body weight and BMI as compared to the metformin treatment (all P < 0.01). The exenatide treatment (β = 0.41, P < 0.01) and baseline HbA1c level (β = -0.84, P < 0.01) were independent influencing factors for the decrease in HbA1c level. For an initial therapy in overweight/obese patients with newly diagnosed T2D, exenatide causes a better glycemic control than metformin. This trial is registered with NCT03297879.


Existential loneliness in a palliative home care setting.
The diagnosis of an incurable disease implies an existential crisis. This study focused on the emotions, perceptions, and experiences of existential isolation in palliative patients with cancer and their families. A total of 40 respondents (20 patients and 20 family members) were interviewed in depth. All were Swedes who defined themselves as nonreligious. The patients were enrolled in an advanced hospital-based home care team. The interviews were taped, transcribed, and analyzed with a qualitative, hermeneutic method. The data revealed experiences of existential loneliness with the impending death as a primary source. Experiences of being alone in "a world of one's own" were common. The changes in everyday life and the increasingly restricted social interaction because of the illness meant that the patient partly lost the protection against isolation that the spirit of community normally provides. Other situations that had a triggered the existential isolation were, for example, when a patient in need of support was left alone, when he or she was treated disrespectfully or in a way that made him or her feel invisible, or when people avoided contact because of uneasiness or fear. Changes in one's own body and mood gave rise to feelings of loneliness and unfamiliarity toward oneself. When a staff member touched the patient's body in a nonempathic way, this could induce feelings of being treated like an animal.


[The fixed charge of protoplasm in barnacle muscle fiber; effect of the length of the sarcomeres].
The thermodynamically effective charge density (phi X) of myoplasm was measured on barnacle muscle fibers. A small section of a muscle cell formed a liquid junction between two electrolyte solutions and the electrical potential between the solutions permitted to evaluate phi X. If the sarcomere length was kept constant (Ls = 12.5 micron), phi X increased from 0.068 to 0.090 equiv./L when the water content was reduced from 75 to 65 g/100 g wet weight. This increment of X resulted from an increase of X when the concentration of macromolecules is raised in the sample of cytoplasm. But it also indicates that the counterions of the fixed charges concur less to the activity of the counterions when X is increased by lowering the water content. If the water content is maintained constant, phi X increased from 0.068 to 0.084 equiv./L for sarcomere lengths equal to 9.6 and 11.5 micron but phi X remained constant for Ls greater than 12 micron. Thus, when the length of the sarcomere is greater than 12 micron the contribution of the counterions of the fixed charges to the activity of the counterion is larger than for Ls = 9.6 micron.


Pharmacokinetics of Antibiotics in Sub-Saharan African Patient Populations: A Systematic Review.
In sub-Saharan Africa (SSA), severe febrile illness accounts for a large majority of medical admissions. SSA patients may also suffer from cachexia and organ dysfunction resulting from tuberculosis, hepatitis B, and hypertension. It is hard to tell how these conditions influence the pharmacokinetics (PK) of antibiotics in this population. The aim of this systematic review was to summarize antibiotic PK data of SSA adult patient populations to clarify whether inappropriate drug concentrations that may also lead to antimicrobial resistance are likely to occur. An electronic search was conducted in Ovid MEDLINE, Embase, and the African Index Medicus collecting studies from 1946 to May 2016. Reviewers independently selected studies reporting outcome data on volume of distribution (V), clearance, and half-life. Relevant information was abstracted and quality assessed. Twelve studies were selected, addressing 6 antibiotic classes. There were 6 studies on fluoroquinolones and 1 on β-lactam antibiotics. Nine out of 12 originated from South Africa and 6 of those dealt with intensive care unit (ICU) populations. The quality of most studies was low. Studies on amikacin, teicoplanin, and ertapenem (n = 4) displayed a pattern of a large V with low drug concentrations. Fluoroquinolone PK changes were less prominent and more diverse whereas the probability of pharmacodynamic target attainment was low for the treatment of tuberculosis in South Africa. Interindividual variability of V was high for 10/12 studies. Antibiotic PK data of SSA adult patient populations are scarce, but disease-induced inappropriate drug concentrations do occur. Data from non-ICU, severely ill patients, and β-lactam data are particularly lacking, whereas β-lactam antibiotics are commonly used, and typically vulnerable to disease-induced PK changes. Studies investigating the PK and pharmacodynamics of β-lactam antibiotics in severely ill, adult SSA patient populations are needed to improve local antibiotic dosing strategies.


Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine.
Aberrant DNA methylation plays a key role in human carcinogenesis. 5-aza-2'-deoxycytidine inhibits DNA methylation and induces the expression of genes putatively silenced by promoter methylation in vitro. There are few studies of the biological and clinical significance of 5-aza-2'-deoxycytidine in human hepatocellular carcinoma. This study explored the mechanism of 5-aza-2'-deoxycytidine targeting transcriptional repressor complexes affecting global gene expression in hepatocellular carcinoma cell line. High density oligonucleotide gene expression microarrays were used to examine the effects of 5-aza-2'-deoxycytidine treatments on human hepatocellular carcinoma cell line SMMC-7721. The 5' ends of the genes upregulated or downregulated in this manner were compared with BLAST database to determine whether they might have promoter CpG islands. Flow cytometry was used to detect stages of the cell cycle and apoptosis of SMMC-7721 after being treated with 5-aza-2'-deoxycytidine. Data obtained 3 days after 4 days of treatment with 5-aza-2'-deoxycytidine showed that more genes were induced in tumorigenic cells including genes that function in cell proliferation, differentiation, regulation of transcription, and cytokine signalling. Approximately 30% of induced genes did not have CpG islands within their 5' regions, suggesting that some genes activated by 5-aza-2'-deoxycytidine may not result from the direct inhibition of promoter methylation. This phenomenon may contribute to a number of upregulated genes involving regulation of transcription in the treated cell. Results showed that 100 micromol/L 5-aza-2'-deoxycytidine blocked cell cycle at S/G2-M phase increasing rate of apoptosis. Notably, we found differential expression of molecular action in the methylation although DNA methyltransferases did not show significant difference in the treated cell line. 5-aza-2'-deoxycytidine could restore some silenced genes expression independently of DNA methylation inhibition and expression of DNA methyltransferases.


TAL1 cooperates with PI3K/AKT pathway activation in T-cell acute lymphoblastic leukemia.
TAL1 is ectopically expressed in about 30% of T-cell acute lymphoblastic leukemia (T-ALL) due to chromosomal rearrangements leading to the STIL-TAL1 fusion genes or due to non-coding mutations leading to a de novo enhancer driving TAL1 expression. Analysis of sequence data from T-ALL cases demonstrates a significant association between TAL1 expression and activating mutations of the PI3K-AKT pathway. We investigated the oncogenic function of TAL1 and the possible cooperation with PI3K-AKT pathway activation using isogenic pro-T-cell cultures ex vivo and in vivo leukemia models. We found that TAL1 on its own suppressed T-cell growth, in part by affecting apoptosis genes, while the combination with AKT pathway activation reduced apoptosis and was strongly driving cell proliferation ex vivo and leukemia development in vivo. As a consequence, we found that TAL1+AKTE17K transformed cells are more sensitive to PI3K-AKT pathway inhibition compared to AKTE17K transformed cells, related to the negative effect of TAL1 in the absence of activated PI3K-AKT signaling. We also found that both TAL1 and PI3K-AKT signaling increased the DNA-repair signature in T cells resulting in synergy between PARP and PI3K-AKT pathway inhibition. In conclusion, we have developed a novel mouse model for TAL1+AKTE17K driven T-ALL development and have identified a vulnerability of these leukemia cells to PI3K-AKT and PARP inhibitors.


High-resolution retinal swept source optical coherence tomography with an ultra-wideband Fourier-domain mode-locked laser at MHz A-scan rates.
We present a new 1060 nm Fourier domain mode locked laser (FDML laser) with a record 143 nm sweep bandwidth at 2∙ 417 kHz = 834 kHz and 120 nm at 1.67 MHz, respectively. We show that not only the bandwidth alone, but also the shape of the spectrum is critical for the resulting axial resolution, because of the specific wavelength-dependent absorption of the vitreous. The theoretical limit of our setup lies at 5.9 µm axial resolution. In vivo MHz-OCT imaging of human retina is performed and the image quality is compared to the previous results acquired with 70 nm sweep range, as well as to existing spectral domain OCT data with 2.1 µm axial resolution from literature. We identify benefits of the higher resolution, for example the improved visualization of small blood vessels in the retina besides several others.


Anticipating Emerging Mosquito-borne Flaviviruses in the USA: What Comes after Zika?
New mosquito-borne diseases have emerged on multiple occasions over the last several decades, raising fears that there are yet more poorly understood viruses that may emerge in the USA. Here, we provide a data-driven 'watch list' of viruses in the Flaviviridae family with high potential to emerge in the USA, identified using statistical techniques, to enable the public health community to better target surveillance. We suggest that public health authorities further incorporate predictive modeling techniques into disease-prevention strategies.


Fabrication of nanoscale metallic spirals using phospholipid microtubule organizational templates.
We describe the fabrication of metallic Cu spiral/helical nanostructures prepared via selective electroless metallization of a phospholipid microtubule template. The metallization template is created through selective, sequential adsorption of the oppositely charged polyelectrolytes, sodium poly(styrenesulfonate) (PSS) and poly(ethyleneimine) (PEI), onto nanoscale seams naturally occurring on the microtubule surface. A negatively charged Pd(II) nanoparticle catalyst is bound to the terminal cationic PEI layer of the multilayer film and initiates selective template metallization to form the helical Cu nanostructures. Details of the process are presented, and a mechanism and factors affecting the control of the feature critical dimensions are discussed.


Stenotic lesions in vascular access: treatment with transluminal angioplasty using high-pressure balloons.
In our institute, one hundred sixty-four balloon dilatations of stenotic lesions in vascular access have been performed since November 1991. All of these procedures were done with high-pressure balloon catheters. In addition to seventy-four cases treated with only percutaneous transluminal angioplasty, there were thirty-four cases which were treated by thrombectomy and/or surgical revision with subsequent intraoperative balloon angioplasty. These angioplastic procedures were initially successful in 142 (87%) of 164 stenoses. The patency rate after 3 months was 68%; after 6 months, 42%; and after 1 year, 25%. There were no serious adverse reactions in our series. This procedure can be safely done with minimal traumatization and, although long-term patency rates are low, repeated dilatations can be performed with ease, when restenosis occurs, to keep a fistula functioning for a long time in appropriate patients.


Suspected COVID-19-Induced Myopericarditis.
Background: The incidence of myocarditis in patients with coronavirus disease 2019 (COVID-19) remains unknown; however, increasing evidence links COVID-19 to cardiovascular complications such as arrhythmias, heart failure, cardiogenic shock, fulminant myocarditis, and cardiac death. We present a case of suspected COVID-19-induced myopericarditis and discuss the diagnostic implications, pathophysiology, and management. Case Report: A 72-year-old female was admitted to the hospital with acute on chronic respiratory failure in the setting of COVID-19. The next day, she developed pressure-like retrosternal chest pain. Laboratory findings revealed elevated cardiac enzymes and inflammatory markers consistent with myocardial injury. Electrocardiogram revealed diffuse ST segment elevations without reciprocal changes, concerning for myopericarditis. Transthoracic echocardiography showed new findings of severely reduced left ventricular (LV) systolic function, with an estimated ejection fraction (EF) of 20%. Her hospital course was further complicated by cardiogenic shock that required treatment in the intensive care unit with vasopressors and inotropes. During the next few days, she had almost full recovery of her LV function, with EF improving to 50%. However, her clinical status deteriorated, likely the result of a bowel obstruction. She was transitioned to comfort care at the request of her family, and she died shortly after. Conclusion: This case highlights diagnostic and therapeutic challenges that physicians may encounter when managing acute cardiac injury in the setting of COVID-19. The multiple mechanisms of COVID-19-related myocardial injury may influence the approach to diagnosis and treatment.


Impact of the presence of HLA 1-locus mismatch and the use of low-dose antithymocyte globulin in unrelated bone marrow transplantation.
HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. We retrospectively analyzed 3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD (n=2089) and 1MMUD with antithymocyte globulin (ATG) (1MM-ATG(+); n=109) with those of 1MMUD without ATG (1MM-ATG(-); n=1115). The median total dose of ATG (thymoglobulin) was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MM-ATG(+) group. The rates of grade III-IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM-ATG(-) group (hazard ratio (HR) 0.77, P=0.016; HR 0.74; P<0.001; and HR 0.87, P=0.020, respectively). Likewise, the rates of grade III-IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(-) group (HR 0.42, P=0.035; HR 0.35, P<0.001; and HR 0.71, P=0.042, respectively). The outcome of allo-HCT from 1MM-ATG(-) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse.


Cytoplasmic trafficking, endosomal escape, and perinuclear accumulation of adeno-associated virus type 2 particles are facilitated by microtubule network.
Understanding adeno-associated virus (AAV) trafficking is critical to advance our knowledge of AAV biology and exploit novel aspects of vector development. Similar to the case for most DNA viruses, after receptor binding and entry, AAV traverses the cytoplasm and deposits the viral genome in the cell nucleus. In this study, we examined the role of the microtubule (MT) network in productive AAV infection. Using pharmacological reagents (e.g., nocodazole), live-cell imaging, and flow cytometry analysis, we demonstrated that AAV type 2 (AAV2) transduction was reduced by at least 2-fold in the absence of the MT network. Cell surface attachment and viral internalization were not dependent on an intact MT network. In treated cells at 2 h postinfection, quantitative three-dimensional (3D) microscopy determined a reproducible difference in number of intracellular particles associated with the nuclear membrane or the nucleus compared to that for controls (6 to 7% versus 26 to 30%, respectively). Confocal microscopy analysis demonstrated a direct association of virions with MTs, further supporting a critical role in AAV infection. To investigate the underling mechanisms, we employed single-particle tracking (SPT) to monitor the viral movement in real time. Surprisingly, unlike other DNA viruses (e.g., adenovirus [Ad] and herpes simplex virus [HSV]) that display bidirectional motion on MTs, AAV2 displays only unidirectional movement on MTs toward the nuclei, with peak instantaneous velocities at 1.5 to 3.5 μm/s. This rapid and unidirectional motion on MTs lasts for about 5 to 10 s and results in AAV particles migrating more than 10 μm in the cytoplasm reaching the nucleus very efficiently. Furthermore, electron microscopy analysis determined that, unlike Ad and HSV, AAV2 particles were transported on MTs within membranous compartments, and surprisingly, the acidification of AAV2-containing endosomes was delayed by the disruption of MTs. These findings together suggest an as-yet-undescribed model in which after internalization, AAV2 exploits MTs for rapid cytoplasmic trafficking in endosomal compartments unidirectionally toward the perinuclear region, where most acidification events for viral escape take place.


Effect of enamel morphology on nanoscale adhesion forces of streptococcal bacteria : An AFM study.
We explore the influence of enamel surface morphology on nanoscale bacterial adhesion forces. Three dimensional morphology characteristics of enamel slices, which were treated with phosphoric acid (for 0 s, 5 s, 10 s, 20 s, and 30 s), were acquired. Adhesion forces of three initial colonizers (Streptococcus oralis, Streptococcus sanguinis, and Streptococcus mitis) and two cariogenic bacterial strains (Streptococcus mutans and Streptococcus sobrinus) with etched enamel surfaces were determined. Comparison of the forces was made by using bacterial probe method under atomic force microscope (AFM) in adhesion buffer. The results showed that enamel morphology was significantly altered by etching treatment. The roughness, peak-to-valley height, and valley-to-valley width of the depth profile, surface area, and volume increased linearly with acid exposure time, and reached the maximum at 30s, respectively. The adhesion forces of different strains increased accordingly with etching time. Adhesion forces of S. oralis, S. mitis, S. mutans, and S. sobrinus reached the maximum values of 0.81 nN, 0.84 nN, 0.73 nN, and 0.64 nN with enamel treated for 20s, respectively, whereas that of S. sanguinis at 10s (1.28nN), and dropped on coarser enamel surfaces. In conclusion, enamel micro-scale morphology may significantly alter the direct adhesion forces of bacteria. And there may be a threshold roughness for bacterial adhesion on enamel surface.


Typing of human polyomavirus JC virus on the basis of restriction fragment length polymorphisms.
JC virus DNA clones from the urine of nonimmunosuppressed Japanese individuals regularly contain an archetypal regulatory sequence which may have generated various regulatory sequences of JC virus isolates from patients with progressive multifocal leukoencephalopathy (PML). In this study, we established 15 new clones from the urine of Dutch, German, and Taiwanese healthy volunteers and patients. Most of these clones contained regulatory sequences essentially identical to the archetypal regulatory sequence. These clones, along with two representative urine-derived clones in Japan and five clones from the brains of PML patients (four established in the United States and one established in Japan), were analyzed with a number of restriction enzymes. We found nine restriction fragment length polymorphisms by which all clones were classified into either of the two types, A and B. Type A contained only clones from the West, while type B contained some from the West and all from eastern Asia. Each type contained both urine-derived and PML-derived clones. Furthermore, there was a close relationship between some urine-derived clones and some PML-derived clones in restriction site mapping analysis. These findings support the adaptation hypothesis which has been postulated to explain the genesis of PML-type JC viruses.


p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain.
ATF4 plays a crucial role in the cellular response to stress and multiple stress responses pathways converge to the translational up-regulation of ATF4. ATF4 is a substrate of the SCF(betaTrCP) ubiquitin ligase that binds to betaTrCP through phosphorylation on a DSGXXXS motif. We show here that ATF4 stability is also modulated by the histone acetyltransferase p300, which induces ATF4 stabilization by inhibiting its ubiquitination. Despite p300 acetylates ATF4, we found that p300-mediated ATF4 stabilization is independent of p300 catalytic activity, using either the inactive form of p300 or the acetylation mutant ATF4-K311R. ATF4 deleted of its p300 binding domain is no more stabilized by p300 nor recruited into nuclear speckles. In consequence of ATF4 stabilization, both p300 and the catalytically inactive enzyme increase ATF4 transcriptional activity.


"Gasket-seal" watertight closure in minimal-access endoscopic cranial base surgery.
Transnasal endoscopic cranial base surgery is a novel minimal-access method for reaching the midline cranial base. Postoperative cerebrospinal fluid leak remains a persistent challenge. A new method for watertight closure of the anterior cranial base is presented. To achieve watertight closure of the anterior cranial base, autologous fascia lata was used to create a "gasket seal" around a bone buttress, followed by application of a tissue sealant such as DuraSeal (Confluent Surgical, Inc., Waltham, MA). The gasket-seal closure was used to seal the anterior cranial base in a series of 10 patients with intradural surgery for suprasellar craniopharyngiomas (n = 5), planum meningiomas (n = 3), clival chordoma (n = 1), and recurrent iatrogenic cerebrospinal fluid leak (n = 1). Lumbar drains were placed intraoperatively in five patients and remained in place for 3 days postoperatively. After a mean follow-up period of 12 months, there were no cerebrospinal fluid leaks. The gasket-seal closure is an effective method for achieving watertight closure of the anterior cranial base after endoscopic intradural surgery.


Two-dimensional electronic spectroscopy reveals ultrafast energy diffusion in chlorosomes.
Chlorosomes are light-harvesting antennae that enable exceptionally efficient light energy capture and excitation transfer. They are found in certain photosynthetic bacteria, some of which live in extremely low-light environments. In this work, chlorosomes from the green sulfur bacterium Chlorobaculum tepidum were studied by coherent electronic two-dimensional (2D) spectroscopy. Previously uncharacterized ultrafast energy transfer dynamics were followed, appearing as evolution of the 2D spectral line-shape during the first 200 fs after excitation. Observed initial energy flow through the chlorosome is well explained by effective exciton diffusion on a sub-100 fs time scale, which assures efficiency and robustness of the process. The ultrafast incoherent diffusion-like behavior of the excitons points to a disordered energy landscape in the chlorosome, which leads to a rapid loss of excitonic coherences between its structural subunits. This disorder prevents observation of excitonic coherences in the experimental data and implies that the chlorosome as a whole does not function as a coherent light-harvester.


Higher Levels of Galectin-1 and Galectin-3 in Young Subjects with Autism Spectrum Disorder Compared to Unaffected Siblings and Healthy Controls.
: Despite being highly genetic, the etiology of autism spectrum disorder (ASD), has not yet been clarified. Recent research has focused on the role of neuroinflammation and immune system dysfunction in the pathophysiology of neurodevelopmental disorders including ASD. Galectin-1 and galactin-3 are considered among the biomarkers of neuroinflammation and there has been recent reports on the potential role of galectins in the etiology of neurodevelopmental disorders. However, there has been no study examining the relationship between ASD and galectin levels. : Current study aimed to investigate galectin-1 and galectin-3 serum levels in young subjects with ASD comparing with their unaffected siblings and healthy controls. : We found significantly higher levels of galectin-1 in case group compared to both unaffected siblings and healthy controls, and higher levels of galectin-3 in case group compared to healthy controls. However, there was no significant association between galectin-1 and galectin-3 levels with the severity of ASD. : Findings of our study may support neuroinflammation hypothesis in the etiology of ASD and the potential role of galectin-1 and galectin-3 as biomarkers.


Blood, urine and faecal metabolite profiles in the study of adult renal disease.
Chronic kidney disease (CKD) is a major public health burden and to date traditional biomarkers of renal function (such as serum creatinine and cystatin C) are unable to identify at-risk individuals before the disease process is well under way. To help preventive strategies and maximize the potential for effective interventions, it is important to characterise the molecular changes that take place in the development of renal damage. Metabolomics is a promising tool to identify markers of renal disease since the kidneys are involved in the handling of major biochemical classes of metabolites. These metabolite levels capture a snap-shot of the metabolic profile of the individual, allowing for the potential identification of early biomarkers, and the monitoring of real-time kidney function. In this review, we describe the current status of the identification of blood/urine/faecal metabolic biomarkers in different entities of kidney diseases including: acute kidney injury, chronic kidney disease, renal transplant, diabetic nephropathy and other disorders.


Modulation of clinical expression of plaque-induced gingivitis: effects of personality traits, social support and stress.
Studies have shown an association between an acute stressful event and gingivitis. However, the possible effects of personality traits associated with stress resistance/susceptibility and current level of stress on the clinical expression of plaque-induced inflammation remain to be examined. The aim of this study was to characterize the subject-based clinical behaviour of the gingiva during experimental gingivitis in relation to personality profile, psychological stress and coping behaviour. Ninety-six systemically and periodontally healthy subjects (mean age: 23.6+/-1.7 years), 46 males and 50 females, non-smokers, participated in a randomized, split-mouth, localized experimental gingivitis trial. Prior to the trial, subjects were asked to complete self-administered questionnaires evaluating personality traits (Hardiness scale and Courtauld Emotional Control Scale), subjective stress (Visual Analogue Scale-Total Distress), social support (Multidimensional Scale of Perceived Social Support, MSPSS) and life events (Life Experiences Survey (LES)). The influence of psychosocial factors was investigated in the overall population as well as in two sub-populations with different inflammatory response to plaque accumulation. No significant relationships were found between gingival inflammation variables and psychological measures. No significant differences were detected between subjects with different susceptibilties to plaque-associated gingivitis for any considered psychological variable. A significant association between plaque variables and LES (negative) or MSPSS (positive) was found; however, the variance explained by the model was low. Differences in the current level of stress and psychosocial variables indicative of stress susceptibility do not account for variability in plaque accumulation and gingival inflammation during experimental gingivitis in young adults.


Prevalence and significance of arrhythmias in long-term survivors of cardiac transplantation.
The prevalence and significance of arrhythmias after cardiac transplantation were evaluated in the absence of acute rejection in 13 long-term survivors (greater than 3 months). ECGs were obtained daily for the first 70 days 8- and 24-hour ambulatory electrocardiographic monitoring was performed 3 months after the transplantation and every 6 months thereafter. Junctional rhythm occurred during the early transplant period (less than 70 days) in nine of 13 patients. Complex premature ventricular depolarizations (Lown grade III or higher) were present in the late transplant period (greater than 70 days) in all five patients in whom severe coronary artery disease was found in the donor heart at postmortem, compared with two of the eight remaining patients (six survivors and two patients who died but did not have coronary artery disease at postmortem) (p less than 0.05). The high prevalence of junctional rhythm in the early transplant period appeared to be due to sympathetic denervation and reversible surgical damage to and ischemia of the sinus node region of the donor heart. Routine ambulatory electrocardiographic monitoring detected complex premature ventricular depolarizations, which were a sensitive marker for the subsequent mortality related to accelerated atherosclerosis of chronic rejection in the donor heart.


Enzymes and Pathways of Kavain Bioactivation and Biotransformation.
Kavain is an active and major component in Piper methysticum Forst. (kava), which is a widely used dietary supplement for the treatment of anxiety, insomnia, and stress. However, kava-containing products can cause liver toxicity, and its underlying mechanisms are understudied. Cytochrome P450s (CYPs)-mediated bioactivation and biotransformation are highly associated with drug toxicity. In the current study, we profiled the metabolic pathways of kavain in mouse liver, urine, and feces. Overall, 28 kavain metabolites were identified including 17 new ones. The metabolic pathways of kavain include glutathione (GSH) conjugation, oxidation, dehydrogenation, O-demethylation, sulfation, and glucuronidation. The identification of kavain-GSH adducts suggests the formation of reactive metabolites of kavain in the liver. We further illustrated that CYP2C19, a highly polymorphic and inducible enzyme, was the major enzyme contributing to kavain biotransformation and bioactivation. Our data can be used to guide the safe use of kava products by preventing potential herb-drug interactions and hepatotoxicity.


Functional Outcome after Reimplantation in Patients Treated with and without an Antibiotic-Loaded Cement Spacers for Hip Prosthetic Joint Infections.
A staged revision with placement of a temporary antibiotic-loaded cement spacer after removal of the implant is the "gold standard" for treatment of chronic prosthetic joint infection (PJI). It enables local delivery of antibiotics, maintenance of limb-length and mobility, easier reimplantation. However, bacterial colonization of spacers and mechanical complications can also occur. The aim of this study is to evaluate functional results and infection control in two-stage treatment of total hip arthroplasty (THA) PJI with and without a spacer. A retrospective review of 64 consecutive patients was conducted: 34 underwent two-stage revision using a cement spacer (group A), 30 underwent two-stage revision without a spacer (group B). At the final follow-up, functional evaluation of patients with a THA in site, without PJI recurrence, was performed using the Harris hip score (HHS). Measurement of limb-length and off-set discrepancies was performed using anteroposterior pelvic X-rays. Most patients in group B were older with more comorbidities preoperatively. Thirty-three patients (97.1%) in group A underwent THA reimplantation versus 22 patients (73.3%) in group B (P<0.001). No significant differences in limb-length and off-set were observed. The results of functional evaluation performed during the final follow-up (mean, 41 months) showed better function in patients in group A (mean HHS, 76.3 vs. 55.9; P<0.001). The use of antibiotic-loaded cement spacer seems superior in terms of functional outcomes and reimplantation rate. Resection arthroplasty might be reserved as a first-stage procedure in patients who are unfit, who might benefit from a definitive procedure.


Accurately localizing the thyroid tissue in mature cystic teratoma of ovary by single-photon emission computerized tomography/computerized tomography.
A 30-year-old woman with hyperthyroidism was admitted to hospital. Although increased thyroid function was found, the gland was normal in ultrasonography (USG). Additionally, thyroid iodine uptake and Tc-99m pertechnetate scintigraphy was normal. Abdomen USG detected a cystic pelvic mass in left ovary. A whole-body scan was performed 48 hours after oral ingestion of 29.6 MBq (0.8 mCi) I-131 (iodine-131) revealed a round structure located to the left lower abdomen. Iodine uptake was detected in this cyst which was compatible with functional thyroid tissue demonstrated by SPECT/CT. The patient was underwent surgical operation and histopathology confirmed mature cystic teratoma. Accurate localization and depiction of thyroid tissue in ovary mass was provided with SPECT/CT.


Stroke-induced damage on the blood-brain barrier.
The blood-brain barrier (BBB) is a functional phenotype exhibited by the neurovascular unit (NVU). It is maintained and regulated by the interaction between cellular and non-cellular matrix components of the NVU. The BBB plays a vital role in maintaining the dynamic stability of the intracerebral microenvironment as a barrier layer at the critical interface between the blood and neural tissues. The large contact area (approximately 20 m2/1.3 kg brain) and short diffusion distance between neurons and capillaries allow endothelial cells to dominate the regulatory role. The NVU is a structural component of the BBB. Individual cells and components of the NVU work together to maintain BBB stability. One of the hallmarks of acute ischemic stroke is the disruption of the BBB, including impaired function of the tight junction and other molecules, as well as increased BBB permeability, leading to brain edema and a range of clinical symptoms. This review summarizes the cellular composition of the BBB and describes the protein composition of the barrier functional junction complex and the mechanisms regulating acute ischemic stroke-induced BBB disruption.


Effect of rapamycin on the cyclosporin A-resistant CD28-mediated costimulatory pathway.
The consequences of T-cell activation depend exclusively on costimulation during antigen-T-cell receptor interaction. Interaction between the T-cell coreceptor CD28 and its ligand B7 during antigen-antigen receptor engagement results in full activation of T cells, the outcomes of which are proliferation and effector functions. The ability of CD28 to costimulate the production of interleukin-2 (IL-2) explains the importance of this costimulation. The signaling event mediated by CD28 engagement has been proposed to have 2 components: one is sensitive to the immunosuppressive drug cyclosporin A (CsA), and the other one is CsA-resistant. In this report, we demonstrate that the CsA-resistant pathway is sensitive to the immunosuppressive drug rapamycin. Treatment with rapamycin blocked IL-2 production after activation of human peripheral blood T cells with phorbol ester (PMA) and anti-CD28 (CsA-resistant pathway), whereas this drug did not have any effect on PMA plus ionomycin stimulation (CsA-sensitive pathway). The inhibitory effect of rapamycin was on messenger RNA stability and translation, rather than on IL-2 transcription or protein turnover.


Regulation of the dissolved phosphate concentration of a mountainous stream, Kitakyushu, southwestern Japan.
The phosphate concentration in mountainous stream water can be a measure of the forest condition, because its concentration will be low when the biomass in the forest is increasing and vice versa when the forest is declining. To investigate the seasonal change in the dissolved phosphate concentration of the mountainous stream water of the Yamakami River, Kitakyushu, from June 2009 to August 2010, and the regulation mechanism of the phosphate concentration, solid-phase spectrophotometry, which can be applicable to natural water without any pretreatment procedures, was employed for the determination of phosphate at μg P L(-1) levels in natural water. The phosphate concentrations in the mountainous stream waters at 6 sites ranged from 2.2 to 13 μg P L(-1), and those from the catchment area of the steady state forest were 5.3 ± 1.6 (±1 SD) μg P L(-1). Changes in the concentration were fairly small even during a storm runoff. The average phosphate concentration of rain was 2.8 ± 0.7 μg P L(-1), about half of the concentration in the stream water. The rate of runoff in forest areas is generally considered to be about 50% of the total precipitation. For a forest under a climax condition, the phosphate concentration is estimated to be regulated by the fallout and evapotranspiration (α = 0.05). At one of the sites, an upstream tributary, where a fairly big landslide occurred before July in 2009, the phosphate concentration was the highest, suggesting that the biomass may still be decreasing. For all of the six sites examined, a characteristic seasonal change in phosphate concentration was observed, reflecting the local budget between the biological decomposition of plant matter and the consumption by the biomass. The increase in the phosphate concentration during late spring and early summer may result from the extensive decomposition of plant litter mainly supplied in autumn and of plant matter relating to spring blooming such as fallen flowers, pollen and immature fruits. The proposed method using the phosphate concentration in surface stream waters without the period of the seasonal change mentioned above is expected to be very helpful in diagnosing the condition of forests.


Neuron Regeneration and Proliferation Effects of Danshen and Tanshinone IIA.
This study evaluates the proliferative effects of danshen and its monomer extract, tanshinone IIA, on Schwann cell proliferation. A piece of silicone rubber was guided across a 15-mm gap in the sciatic nerve of a rat. This nerve gap was then filled with different concentrations of danshen (0-100 mg/mL). The results showed that danshen increased the expressions of uPA, cyclin D1, E and ERK, JNK, and P38 MAP kinases via the FGF-2 signaling pathway in a dose-dependent manner. RSC96, Schwann cells were also administered with danshen (0, 20, 40, 60, 80, and 100 μg/mL) and tanshinone IIA (0, 2, 4, 6, 8, and 10 μg/mL). In lower concentrations, danshen and tanshinone IIA exhibited an apparent effect on Schwann cells. Similar effects were also demonstrated in the FGF-2-uPA regulating cascade and cell cycle proliferative protein results. Schwann cell migration was elevated as well. We used MAPK-signaling chemical inhibitors and identified the proliferative effects of danshen and tanshinone IIA as MAPK-signaling dependent. The results from the in vitro systems indicate that danshen and tanshinone IIA can be used to induce Schwann cell proliferation, and in vivo results potentially suggest that danshen and tanshinone IIA might enhance neuron regeneration.


Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors.
Immune checkpoint inhibitors (ICIs) induce impressive antitumor responses but may lead to acute kidney injury (AKI) associated with ICI therapy (AKI-ICI). Biomarkers distinguishing AKI-ICI from AKI because of other causes (AKI-other) are currently lacking. Because ICIs block immunoregulatory pathways, we hypothesized that biomarkers related to immune cell dysregulation, including tumor necrosis factor alpha (TNF-α) and other markers of B and T cell activation in the systemic circulation and kidney tissue, may aid with the diagnosis of AKI-ICI. This is a prospective study consisting of 24 participants who presented with AKI during ICI therapy, adjudicated to either have AKI-ICI (n = 14) or AKI-other (n = 10). We compared markers of kidney inflammation and injury (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1) as well as plasma and urine levels of T cell-associated cytokines (TNF-α, interferon-γ, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-9, and IL-10) between groups. We also compared T-cell responses in the systemic circulation and in kidney tissue across groups, using mass cytometry systems. We observed increase in several specific immune cells, including CD4 memory, T helper cells, and dendritic cells in the kidney tissue, as well as in the urine cytokines IL-2, IL-10, and TNF-α, in patients who developed AKI-ICI compared to patients with AKI-other (P < 0.05 for all). The discriminatory ability of TNF-α on AKI cause was strong (area under the curve = 0.814, 95% confidence interval: 0.623-1.00. The CD4+ T cells with memory phenotype formed the dominant subset. These results suggest that specific T-cell responses and their respective cytokines may be indicative of AKI associated with ICI therapy and may help to differentiate AKI-ICI from AKI-other. Urine TNF-α is a promising biomarker for AKI-ICI, which is most often caused by acute interstitial nephritis (AIN), and TNF-α pathway may serve as a potential target for therapeutic intervention.


Redox sensitive lipid-camptothecin conjugate encapsulated solid lipid nanoparticles for oral delivery.
Camptothecin (CPT) is an important topoisomerase I enzyme (Topo I) targeting anti-cancer drug, but its oral administration is limited by poor bioavailability and severe side effects. In this study, a redox sensitive CPT prodrug loaded solid lipid nanoparticles (SLN) system for oral delivery was developed. First of all, CPT-palmitic acid conjugate via a cleavable disulfide bond linker (CPT-SS-PA) was synthesized and encapsulated into SLN. The drug release of SLN was evaluated in neutral environment, simulated gastrointestinal fluid and reductive solution. The results indicated that CPT-SS-PA SLN maintained chemical structural stability in simulated physiological environment but exhibited quick reduction-response release of CPT in the presence of dithiothreitol. Furthermore, in vitro cytotoxicity of CPT-SS-PA SLN was tested against cancer cell lines, and the cellular uptake behavior for oral delivery was checked by confocal laser scanning microscopy (CLSM) using Caco-2 cells model. From the data, CPT-SS-PA SLN revealed high anti-cancer activity and enhanced Caco-2 cell absorption. Finally, the oral bioavailability and intestinal safety of CPT-SS-PA SLN were preliminary evaluated by in vivo pharmacokinetic and histopathological study, respectively. This study demonstrated that CPT-SS-PA SLN could be developed as an effective CPT oral delivery system due to its enhanced oral bioavailability and reduced intestinal side effect.