Friendship as a framework for resolving dilemmas in clinical ethics.
Healthcare professionals often need to make clinical decisions that carry profound ethical implications. As such, they require a tool that will make decision-making intuitive. While the discussion about the principles that should guide clinical ethics has been going on for over two thousand years, it does not seem that making such decisions is becoming any more straight forward. With an abundance of competing ethical systems and frameworks for their application in real life, the clinician is still often not sure how to proceed in the face of ethical dilemmas, either due to a lack of background ethical knowledge or experience in applying it. This paper will discuss whether considering what one would expect one's friend to do if one was the patient, or what would one think they would do for a friend if they were the patient, can be a helpful, more intuitive, tool for clinical decision-making that can produce outcomes that are congruent with major ethical systems.


Use of end-to-side arterial and venous anastomosis techniques for renal transplantation in two dogs.
A sexually intact male Old English Sheepdog and a sexually intact female Bull Terrier were evaluated for renal dysplasia and chronic renal failure, respectively. Both dogs were anemic and had high serum concentrations of urea nitrogen and creatinine. Electrolyte abnormalities (calcium and phosphorus) were also evident. The decision was made to pursue renal transplantation, and donor dogs were identified. End-to-side anastomosis of the renal artery and vein of each donor's left kidney to the recipient's ipsilateral external iliac artery and vein, respectively, was performed. The left caudal abdominal musculature was scarified by making an incision, and nephropexy to that musculature was performed with a simple interrupted pattern of polypropylene sutures. No intraoperative or postoperative complications associated with the vascular anastomoses were encountered. Azotemia, anemia, and electrolyte imbalances resolved after transplantation. The end-to-side anastomosis technique described here, which is a preferred method in human medicine, was successful, providing an alternative to other renal transplantation techniques in dogs. Additional studies are needed to determine whether any vascular anastomosis technique is preferable for use in dogs requiring renal transplantation.


Developmental Eye Movement Test: reliability and symptomatology.
The Developmental Eye Movement Test (DEM) is a widely used visual skill test, especially in the context of a vision therapy evaluation. It is intended to diagnose oculomotor dysfunction (OMD) and can also identify deficient rapid automatized naming. As such, its reliability and associated symptomatology are important. The DEM test-retest reliability was investigated within two populations: a group of 53 office patients who were participating in vision therapy evaluation in a private optometry practice, and a smaller group of 13 subjects at their school. One to four weeks separated the test and retest for both groups. We also studied the relationship between results on a questionnaire of symptoms associated with OMD and DEM test performance in these two populations. The first administration of the DEM significantly correlated with the second for all four of its scores for both groups. The office group had higher intra-class correlation coefficients than the school group. There was good agreement between test and re-test in terms of pass-fail classification for the office group. Symptomatic subjects performed poorer than asymptomatic subjects on the DEM. Failing the DEM Ratio, the score used to diagnose OMD, identified 90% of the subjects who were symptomatic. The DEM has good intra-subject test-retest reliability for all four of its scores when it is administered in an office setting to patients participating in a vision therapy evaluation. It also has good consistency in classifying patients as pass or fail. Performance on the DEM relates to certain symptoms that are associated with OMD.


Initial experience with megavoltage (MV) CT guidance for daily prostate alignments.
The on-board megavoltage (MV) computed tomography (CT) capabilities of a TomoTherapy Hi*ART unit were used to obtain daily MVCT images of prostate cancer patients. For patient alignment the daily MVCT image needs to be registered with the planning CT image to calculate couch shifts. Three manual techniques of registering the MVCT images with the planning kilovoltage (kV) CT images were evaluated. The techniques are based on visual alignment of (1) fiducial prostate markers, (2) CT anatomy, and (3) kVCT contours. One hundred and twelve alignments from 3 patients were available for analysis. The radiation therapists visually registered the MVCT images with the planning kVCT images based on fiducial markers for actual patient alignment. Retrospectively, the therapists registered each image set using anatomy and contour-based techniques. In addition to the therapists, a physician retrospectively registered each image set based on each of the three techniques. For each MVCT to kVCT image pair a reference alignment was computed from the center-of-mass (COM) of the three fiducial markers. All registration results were compared with these reference alignments. The physician's image registrations were compared with the radiation therapists' registrations to assess the user variability of the different techniques. The marker-based registration results agree best with the reference alignments, while the contour-based registrations show the least degree of agreement. Using anatomy and contour-based registrations, the radiation therapist's alignments differed by > or = 3 mm from the reference alignments in 24%, 33%, and 3% and 55%, 48%, and 21% of all registrations in the anterior-posterior, superior-inferior, and lateral directions, respectively. The respective values for the marker-based alignments were 3%, 6%, and 3%. The physician's registrations showed the same general trend. The marker-based registrations showed the least amount of inter-user variability while the contour-based ones showed the most. The use of fiducial markers for MVCT image guidance is advantageous to reduce the inter-user variability of the image registration. If fiducial markers are not used, anatomy-based registrations outperform contour-based registrations in terms of (1) agreement with a reference alignment and (2) inter-user variability.


The effects of age, dietary restriction, exercise and maternity on the abundance and volume of adipocytes in twelve adipose depots of adult guinea-pigs.
1. The mean adipocyte volume and cellularity of adipose tissue in twelve anatomically defined depots were measured in 190 virgin and reproductive guinea-pigs aged 6 months to 2 years, maintained on five different regimens of diet and exercise. 2. The total adipocyte complement was constant up to the age of about 10 months and increased by 65-70% during the 2nd year of life. At constant percentage body-weight as fat, age-related accumulation of adipocytes was accompanied by reduction in average adipocyte volume. A period of high percentage body-weight as fat was not a necessary antecedent to age-related accumulation of adipocytes, and the effect was not observed in specimens that exercised regularly. 3. In guinea-pigs over 13 months old, changes in adipose tissue cellularity made a major contribution to total fatness. The mean volume of samples of adipocytes was a satisfactory indicator of fatness only in younger specimens in which adipose tissue cellularity was not changing. 4. The lean body mass and the total adipocyte complement were lower in guinea-pigs on the sedentary, restricted-diet regimen, whether the regimen began at the age of 19 weeks or 31 weeks, but the depots studied were not equally affected. Both moderate and strenuous exercise on an ad lib. diet caused a reduction in the percentage body-weight as fat in males but not in females. The total adipocyte complement and lean body mass were unchanged, although the males became almost as thin following exercise as those on the restricted-diet regimen. 5. Among guinea-pigs under 400 d old, there were no significant differences between males and virgin females in the site-specific volume of adipocytes relative to the size of those in other depots of the same specimen; there was only one significant difference in this index between the older and the younger specimens. The diet and exercise regimens modified the site-specific adipocyte volume relative to those in other depots; adipocytes under the trapezius muscle of the neck (UMN), at the interscapular depot (HUMP) and those in the depots anterior to the forelimb became relatively smaller following exercise, while those in the popliteal fat mass were relatively larger. Adipocytes in the UMN and HUMP also became more numerous relative to those in the other depots following both moderate and strenuous exercise. Those in the groin site, the intra-abdominal depots and the intermuscular depots became relatively smaller following dietary restriction without exercise.(ABSTRACT TRUNCATED AT 400 WORDS)


Design and synthesis of a selective EP4-receptor agonist. Part 1: discovery of 3,7-dithiaPGE1 derivatives and identification of their omega chains.
Improvement of EP4-receptor selectivity and the agonist activity by introduction of heteroatoms into the alpha chain of PGE1 was investigated. Among the compounds tested, 3,7-dithiaPGE1 4a exhibited good EP4-receptor selectivity and agonist activity. Further modification of the omega chain of 3,7-dithiaPGE1 was performed to improve EP4-receptor selectivity and agonist activity. Of the compounds produced, 16-phenyl-omega-tetranor-3,7-dithiaPGE1 4p possessing moderate EP4-receptor selectivity and agonist activity, was identified as a new chemical lead for further optimization by modification of the aromatic moiety.


Inflammatory pseudotumor of the retroperitoneum removed via a retroperitoneoscopic approach.
Inflammatory pseudotumors were mostly encountered in the lung. Retroperitoneal inflammatory pseudotumors are relatively rare. Although laparoscopic surgery with a modified flank position is widely performed for retroperitoneal tumors, we placed the patient in the supine position to maintain the normal anatomical view of the retroperitoneal space. We report a case of retroperitoneal inflammatory pseudotumor extracted via retroperitoneoscopic surgery in the supine position. A 53-year-old man presented with back pain and frequent urination. Ultrasonographic examination revealed a solid tumor above the urinary bladder. This tumor was diagnosed as a primary retroperitoneal tumor by computed tomography, magnetic resonance imaging, and angiography. The retroperitoneoscopic procedure was adopted to remove this tumor. Histopathologic examination revealed an inflammatory pseudotumor. There was no evidence of recurrence 5 years after surgery. The diagnosis of the inflammatory pseudotumor is rarely made before histologic examination. Only pathologic examination allows the correct diagnosis. Consequently, most patients undergo surgical treatment. A recurrence rate of 25% has been reported for inflammatory pseudotumors. Thus, radical resection is needed. The retroperitoneal laparoscopic approach with the patient in the supine position is useful for surgically treating these primary retroperitoneal tumors located below the level of the renal vessels.


Studies on the effects of protease substrate analogues on some of the actions of insulin.
Added TAME (N alpha-p-tosyl-1-anginine methyl ester) or BAME (benzoyl-anginine methyl ester) inhibited insulin induced activation of glucose oxidation and fat cell PDH activation without affecting spermine action on PDH activation and glucose oxidation in fat cells. BAME inhibited insulin-induced generation of both PDH stimulator and PDH inhibitor from liver particulate fraction. In contrast, insulin-induced internalization of insulin receptors and negative cooperativity of insulin receptors were not affected by protease substrate inhibitors. These results suggest that certain actions of insulin (glucose oxidation, generation of PDH regulators) are mediated by proteolytic events, while insulin-induced down regulation and negative cooperativity of insulin receptors are not mediated by activation of endogenous proteases.


Comparative pharmacological response of an in vitro whole bladder preparation (rabbit) with response of isolated smooth muscle strips.
Although much of our knowledge of the pharmacological response of the urinary bladder comes from in vitro muscle strip studies, it is not clear if these studies can be directly correlated with bladder function. We have compared the pharmacological response of an in vitro whole bladder model with the response of the standard muscle strip technique. The whole bladder model has the advantage of being able to measure both the isometric contractile response to drugs as well as a functional response in which the bladder can empty in the presence of a constant resistance. The results of these studies may be summarized as follows: 1) bethanechol was equipotent in contracting the muscle strips and in the closed whole bladder model; 2) at low and intermediate bladder volumes, the bladder fully emptied at concentrations of bethanechol significantly below the concentration required for maximal contraction; 3) isoproterenol, a potent beta-adrenergic agonist, stimulated a strong relaxation in muscle strips, whereas the whole bladder responded very poorly to isoproterenol; 4) in muscle strips isoproterenol strongly antagonized bethanechol contraction, whereas, in the whole bladder system, isoproterenol did not significantly antagonize bethanechol contraction; 5) methoxamine and adenosine triphosphate produced a moderate, equipotent contraction in both models.


Assessment and treatment of asylum seekers after a suicide attempt: a comparative study of people registered at mental health services in a Swedish location.
Even though asylum seekers are considered vulnerable to mental ill-health, knowledge of their suicidal behaviour is limited. The aim of this study was to improve our understanding of factors that influence the clinical assessment of asylum seekers who have attempted suicide compared to the assessment of non-asylum seekers. The study focused on 88 asylum seekers registered for suicide attempts in mental health services 2005-2009, who were matched for age and gender and compared with 88 suicide attempters with Swedish personal identity numbers. The medical records were analysed with a quantitative protocol, focusing on social risk and protective factors, health history, current clinical picture as well as the assessment procedure, diagnostics, patterns of treatment and follow-up in this clinical group. Data was analysed using the chi-square test, Fisher's exact probability test, and the Mann-Whitney U test. As in earlier studies, asylum seekers were more traumatized, had different social risk factors and received different diagnoses than the controls. Asylum seekers were referred to less specialized follow-up after treatment, in spite of their health history and of previous and current clinical pictures indicating a similar or--in the case of the female asylum seekers--more serious mental health condition. Female asylum seekers also received more intense and prolonged in-patient treatment than female controls. Asylum seekers appeared to have social networks more often than the control group. However, there was less documentation of the social context, previous suicidal behaviour, and on suicide in the family and close environment of the asylum-seeking men. Information on suicidal intent was lacking in a majority of both groups. The time relation of the suicide attempt and the asylum process suggested the importance of the asylum decision, as well as the possible role of earlier mental health problems and premigration stress, for the suicidal behaviour. The groups had different sets of risk factors and clinical pictures. There was a lack of early and thorough exploration of suicide intent for both groups, and of contextual and subjective factors for the asylum seekers. Differences in follow-up indicate unequal access to care.


[New directions in radiotherapy. The use of fast electrons].
The post-surgical radiotherapy of breast cancer and its problems are discussed and an account is given of recent trends in this field. The use of fast electrons is regarded as an optimal form of management for the chest wall, and the ipsilateral subscapular and internal mammary lymph gland chains.


[The highest permissible levels of resection of the esophagus in cancer during surgery with intrathoracic or cervical esophagogastric anastomoses].
The levels of esophageal resection for squamous carcinoma were determined in 84 patients by measuring the distance from the incisors to the ring of the esophagogastric anastomosis during esophagoscopy. The radicalism of the operations was evaluated from the difference in the distance between the incisors and the upper border of the tumor and the distance between the incisors and the anastomosis. The mean levels of the highest possible resections of the esophagus were at a distance of 33.5 +/- 2.8, 23.6 +/- 2.0, and 20.4 +/- 2.0 cm from the incisors, respectively, in Garlock's operation, Lewis' operation, and Dobromyslov-Torek's operation with esophagoplasty using an antiperistaltic gastric pedicle. It is suggested that the choice of the method of surgical treatment should be based on comparison of the determined levels of the highest possible resection of the esophagus with the endoscopic assessment of the level of the upper border of the tumor in the esophagus.


Effective co-delivery of doxorubicin and curcumin using a glycyrrhetinic acid-modified chitosan-cystamine-poly(ε-caprolactone) copolymer micelle for combination cancer chemotherapy.
A glycyrrhetinic acid-modified chitosan-cystamine-poly(ε-caprolactone) copolymer (PCL-SS-CTS-GA) micelle was developed for the co-delivery of doxorubicin (DOX) and curcumin (CCM) to hepatoma cells. Glycyrrhetinic acid (GA) was used as a targeting unit to ensure specific delivery. Co-encapsulation of DOX and CCM was facilitated by the incorporation of poly(ε-caprolactone) (PCL) groups. The highest drug loading content was 19.8% and 8.9% (w/w) for DOX and CCM, respectively. The PCL-SS-CTS-GA micelle presented a spherical or ellipsoidal geometry with a mean diameter of approximately 110nm. The surface charge of the micelle changed from negative to positive, when the pH value of the solution decreased from 7.4 to 6.8. Meanwhile, it also exhibited a character of redox-responsive drug release and GA/pH-mediated endocytosis in vitro. In simulated body fluid with 10mM glutathione, the release rate in 12h was 80.6% and 67.2% for DOX and CCM, respectively. The cell uptake of micelles was significantly higher at pH 6.8 than pH 7.4. The combined administration of DOX and CCM was facilitated by PCL-SS-CTS-GA micelle. Results showed that there was strong synergic effect between the two drugs. The PCL-SS-CTS-GA micelle might turn into a promising and effective carrier for improved combination chemotherapy.


Human bone marrow mesenchymal stem cell-derived extracellular vesicles inhibit shoulder stiffness via let-7a/Tgfbr1 axis.
Shoulder stiffness (SS) is a common shoulder disease characterized by increasing pain and limited range of motion. SS is considered to be an inflammatory and fibrotic disorder pathologically. However, there is no consensus on the most effective conservative treatment for fibrosis. Given that human Bone Marrow Mesenchymal Stem Cell-derived extracellular vesicles (BMSC-EVs) displayed promising therapeutic effects for various tissues, we investigated the therapeutic effect of BMSC-EVs on fibrosis in a mice immobilization model and two cell models. By conducting a series of experiments, we found that BMSC-EVs can significantly inhibit the fibrogenic process both in vitro and in vivo. In detail, BMSC-EVs suppressed the aberrant proliferation, high collagen production capacity, and activation of fibrotic pathways in TGF-β-stimulated fibroblasts in vitro. Besides, in vivo, BMSC-EVs reduced cell infiltration, reduced fibrotic tissue in the shoulder capsule, and improved shoulder mobility. In addition, via exosomal small RNA sequencing and qPCR analysis, let-7a-5p was verified to be the highest expressed miRNA with predicted antifibrotic capability in BMSC-EVs. The antifibrotic capacity of BMSC-EVs was significantly impaired after the knockdown of let-7a-5p. Moreover, we discovered that the mRNA of TGFBR1 (the membrane receptor of transforming growth factor β) was the target of let-7a-5p. Together, these findings elucidated the antifibrotic role of BMSC-EVs in shoulder capsular fibrosis. This study clarifies a new approach using stem cell-derived EVs therapy as an alternative to cell therapy, which may clinically benefit patients with SS in the future.


Transferrin binding protein-B from Neisseria meningitidis C as a novel carrier protein in glycoconjugate preparation: an in silico approach.
The linking of polysaccharide in glycoconjugate vaccine with carrier protein is an imperative step to develop a strong memory response. The excessive use of similar carrier protein known to result in bystander immunity warrants an urgent need for new carrier protein. The preparation of the glycoconjugate vaccine using cyanylation chemistry is to link the active cyanate ester site of polysaccharide with the carrier protein. In the present study, transferrin binding protein-B (Tbp-B) has been explored as a new carrier protein to develop in silico pneumococcal polysaccharide serotype-5 (PnPs-5) conjugate vaccine. The homology model of Tbp-B was constructed using the Prime module and stereochemically validated using ProSA, PDBsum and ProQ. The selected model revealed a Z-score of -5.6 within the X-ray region in ProSA analysis, LGscore: 9.776, and MaxSub: 0.8 in protein quality predictor suggesting its preferred use. Loop modeling and active site analysis followed by in silico PnPs-5 activation with cyanalyting agent CDAP was docked with Tbp-B using Glide module. The complex stability of cyanate esters with Tbp-B, analyzed by molecular dynamics (MD) simulation, revealed an average RMSD of 2.49 Å for its binding to the receptor. The RMSF values of cyanate ester-1, -2, and -3 were observed to be 1.06, 1.39 and 0.79 Å, respectively. The higher RMSF of 1.39 Å of cyanate ester-2 was further found unstable which corroborates its non-binding to the protein and also incurring conformational changes to a carrier protein. Molecular simulations revealed that cyanate ester-1 and cyanate ester-3 formed stable conjugates with carrier protein Tbp-B. Communicated by Ramaswamy H. Sarma.


Systemic benefit of radiation therapy via abscopal effect.
Evidence of a systemic response related to localized radiation therapy (RT) in cancer management is rare. However, enhancing the immune response via immunotherapy followed by localized RT has shown evidence of tumor shrinkage to non-irradiated metastatic disease thereby inducing an "abscopal effect." Combined induction of the cGAS-STING pathway and activation of IFN-gamma signaling cascade related to RT within an activated immune environment promotes neoantigen presentation and expansion of cytotoxic effector cells enabling enhancement of systemic immune response. A proposed mechanism, case examples, and clinical trial evidence of "abscopal effect" benefit are reviewed. Results support strategic therapeutic testing to enhance "abscopal effect."


Serum uric acid shows a J-shaped trend with coronary mortality in non-insulin-dependent diabetic elderly people. The CArdiovascular STudy in the ELderly (CASTEL).
The relationship between serum uric acid (SUA) and risk of coronary heart disease (CHD) mortality remains controversial, particularly in diabetic subjects. The aim of the present study is to evaluate whether SUA independently predicts CHD mortality in non-insulin-dependent elderly people from the general population and to investigate the interactions between SUA and other risk factors. Five hundred and eighty-one subjects aged >/=65 years with non-insulin-dependent diabetes mellitus were prospectively studied in the frame of the CArdiovascular STudy in the ELderly (CASTEL). Historical and clinical data, blood tests and 12-year fatal events were recorded. SUA as a continuous item was divided into tertiles and, for each tertile, adjusted relative risk (RR) with 95% confidence intervals (CI) was derived from multivariate Cox analysis. CHD mortality was predicted by SUA in a J-shaped manner. Mortality rate was 7.9% (RR 1.28, CI 1.05-1.72), 6.0% (reference tertile) and 12.1% (RR 1.76, CI 1.18-2.27) in the increasing tertiles of SUA, respectively, without any difference between genders. In diabetic elderly subjects, SUA independently predicts the risk of CHD mortality in a J-shaped manner.


Volitional control of beta activities in Parkinson's disease patients.
Patients diagnosed with Parkinson's disease (PD) have difficulty initiating and executing movements due to an acquired imbalance of the basal ganglia thalamocortical circuit secondary to loss of dopaminergic input into the striatum. The unbalanced circuit is hyper-synchronized, presenting as larger and longer bursts of beta-band (13-30 Hz) oscillations in the subthalamic nucleus (STN). As a first step toward a novel PD therapy that aims to improve symptoms through beta desynchronization, we sought to determine if individuals with PD could acquire volitional control of STN beta power in a neurofeedback task. We found a significant difference in STN beta power between task conditions, and relevant brain signal features could be detected and decoded in real time. This demonstration of volitional control of STN beta motivates development of a neurofeedback therapy to modulate PD symptom severity.


Distinguishing between legitimate and illegitimate roles for values in transdisciplinary research.
In this paper, we argue that the new demarcation problem does not need to be framed as the problem of defining a set of necessary and jointly sufficient criteria for distinguishing between acceptable and unacceptable roles that non-epistemic values can play in science. We introduce an alternative way of framing the problem and defend an open-ended list of criteria that can be used in demarcation. Applying such criteria requires context-specific work that clarifies which principles should be used, and possibly leads to the identification of new principles - which then can be added to the open-ended list. We illustrate our approach by examining a context where distinguishing between acceptable and unacceptable value influences in science is both needed and tricky: transdisciplinary research.


Rural Hospital Disparities in Goals of Care Documentation.
Goals of care conversations for seriously ill hospitalized patients are associated with high-quality patient-centered care. We aimed to assess the prevalence of documented goals of care conversations for rural hospitalized patients compared to nonrural hospitalized patients. We retrospectively assessed goals of care documentation using a template note for adult patients with predicted 90-day mortality greater than 30% admitted to eight rural and nine nonrural community hospitals between July 2021 and April 2023. We compared predictors and prevalence of goals of care documentation among rural and nonrural hospitals. Of the 31,098 patients admitted during the study period, 21% were admitted to a rural hospital. Rural patients were more likely than nonrural patients to be >65 years old (89% vs. 86%, P = <.0001), more likely to live in a neighborhood classified in the highest quintile of socioeconomic disadvantage (40% vs. 16%, P = <.0001), and less likely to receive a palliative care consult (8% vs. 18%, P = <.0001). Goals of care documentation occurred less often for patients admitted to rural vs. nonrural community hospitals (2% vs. 7%, P < .0001). In the base multivariable logistic regression model adjusting for patient characteristics, the odds of goals care documentation were lower in rural vs. nonrural community hospitals (aOR 0.4, P = .0232). In a second multivariable logistic regression model including both patient characteristics and severity of illness, the odds of goals of care documentation in rural community hospitals were no longer statistically different than nonrural community hospitals (aOR 0.5, P = .1080). Patients who received a palliative care consult had a lower prevalence of goals of care documentation in rural vs. nonrural hospitals (16% vs. 37%, P = <.0001). In this study of 17 rural and nonrural community hospitals, we found low overall prevalence of goals of care documentation with particularly infrequent documentation occurring within rural hospitals. Future study is needed to assess barriers to goals of care documentation contributing to low prevalence of goals of care conversations in rural hospital settings.


Changes in serum iron levels following very high-dose cisplatin.
A four-fold (P less than 0.001) mean increase in iron levels was found in 18 patients (a total of 36 courses of therapy) with ovarian cancer at the end of a 5-day course of cisplatin (40 mg/m2 per day every 4-5 weeks). The kinetics of these modifications began very early (24-48 h after initiation of therapy): they reached their maximum on the 4th-5th day, coinciding with the last drug administration, and basal levels were recovered after the 10th day. A subsequent eight-fold average increase (P less than 0.001) in ferritin serum levels, beginning 2 days after the iron changes, was observed, but showed a slower regression (after the 15th day). Reticulocyte counts were lowered (P less than 0.001) with the same time-course of the iron increases, but returned to pretreatment levels within 2 weeks. Total bilirubin and serum glutamate-pyruvate transaminase showed significantly delayed increases compared with iron. The results are in keeping with a reduced iron utilization by the erythroid precursors, but other mechanisms cannot be excluded. There is no statistical correlation between the early iron increases and the subsequent hemoglobin nadir values.


Author Correction: Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form.
A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19873-9.


Rational design of photoactivatable metal complexes to target and modulate amyloid-β peptides.
The accumulation of amyloid-β (Aβ) aggregates is found in the brains of Alzheimer's disease patients. Thus, numerous efforts have been made to develop chemical reagents capable of targeting Aβ peptides and controlling their aggregation. In particular, tunable coordination and photophysical properties of transition metal complexes, with variable oxidation and spin states on the metal centers, can be utilized to probe Aβ aggregates and alter their aggregation profiles. In this review, we illustrate some rational strategies for designing photoactivatable metal complexes as chemical sensors for Aβ peptides or modulators against their aggregation pathways, with some examples.


The Association Between Illicit Drug Use and the Duration of Renal Replacement Therapy in Patients With Acute Kidney Injury From Severe Rhabdomyolysis.
Background and Aims: Acute kidney injury is a known complication of severe rhabdomyolysis. In patients who present to hospital with rhabdomyolysis, illicit drug use is associated with a higher risk of acute kidney injury needing renal replacement therapy (RRT), independent of the peak serum creatine kinase level. The aim of this study was to assess if RRT duration and renal outcomes were also worse in illicit drug use-associated rhabdomyolysis. Methods: We conducted a cohort study of adult patients who presented to Monash Health (Jan 2011-June 2020) with rhabdomyolysis and required RRT. Patients with isolated myocardial injury and cardiac arrest were excluded. We used survival analysis to examine the time to RRT independence, utilizing the Fine-Gray competing risks regression and death as the competing event. A subdistribution hazard ratio (SHR) < 1.0 represents a relatively greater duration of RRT and a worse outcome. Results: We included 101 patients with a mean age of 58 years, of which 17% were cases associated with illicit drug use. The median peak creatine kinase level was 5,473 U/L (interquartile range, 1,795-17,051 U/L). Most patients (79%) initiated RRT within 72 h of admission, at a median serum creatinine of 537 μmol/L (interquartile range, 332-749 μmol/L). In the competing risks analysis, the estimated SHR was 1.48 (95% CI: 0.78-2.84, P = 0.23) for illicit drug use, 0.87 (95% CI: 0.76-0.99, P = 0.041) for the log-transformed peak creatine kinase, and 0.41 (95% CI: 0.25-0.67, P < 0.001) for sepsis. A 50% cumulative incidence of RRT independence occurred at 11 days (95% CI: 8-16 days). Only 5% of patients remained on RRT at 3 months. Conclusion: In rhabdomyolysis-associated acute kidney injury, it is unlikely that patients with illicit drug use-associated rhabdomyolysis require a longer duration of RRT compared to patients with rhabdomyolysis from other causes.


Characterization of a cryptic plasmid from Lactobacillus plantarum.
The complete nucleotide sequence of pLB4, a cryptic plasmid isolated from Lactobacillus plantarum NCDO1088 has been determined. Three open reading frames, which encode proteins of 42, 25 and 6 kDa, have been identified. In vitro transcription/translation of pLB4-derived DNA restriction fragments confirm the existence of all three polypeptides, which show homology to replication proteins and site-specific recombinases from other Gram+ plasmids. Three major regions of dyad symmetry with delta G of -28.8, -15.0 and -17.0 kcal were observed. One of these regions contains a sequence which shows perfect homology to the nick site of the Gram+ replicons, pE194, pLS1 and pADB201. In addition, a 21-bp sequence located upstream from the site-specific recombinase shows 80% homology to the recombination sites of pE194 and pT181.


Phenotype modulation in non-adherent and adherent sublines of Walker carcinosarcoma cells: the role of cell-substratum contacts and microtubules in controlling cell shape, locomotion and cytoskeletal structure.
We characterised two sublines of Walker carcinosarcoma cells generated by epigenetic changes. Subline 1 cells were mostly polarised and made no or only non-adhesive cell-substratum contacts. Subline 2 cells were spread, adhesive and mainly non-polar. Subline 1 cells migrate in a non-adhesive mode which is very efficient but operates only in a 3D environment, whereas subline 2 cells migrate in an adhesive mode, which is less efficient but works on 2D and 3D substrata. Nocodazole had little or no effect on shape, polarity and locomotion of subline 1 cells. In glass-adherent subline 2 cells, 10(-6)M nocodazole increased the proportion of polarised cells migrating in an adhesive mode and decreased adhesion to the substratum, whereas 10(-5)M nocodazole further reduced the contacts and the cells reverted to a non-adhesive mode of locomotion. When non-polar subline 2 cells were detached mechanically or by nocodazole, they became polarised and morphologically indistinguishable from non-adherent subline 1 cells. On more adhesive plastic substrata, subline 2 cells produced heterogeneous responses to nocodazole including loss of polarity. The phenotypes of Walker carcinosarcoma sublines have similarities with a broad range of cell types ranging from leucocytes to fibroblast-like cells, suggesting that these phenotypic differences can be controlled by the adhesive and contractile state rather than the cell type. Adhesion modulates contractility (isometric or isotonic contraction) and vice versa and this determines morphology (shape, F-actin, myosin and alpha-actinin), locomotion and responses to microtubule-disassembly. The model may be applied to analyse the mechanisms controlling the phenotype of cells in general.


High SNR rapid T1 -weighted MPRAGE using spiral imaging with long readouts and improved deblurring.
The goal of this work is to present the implementation of 3D spiral high-resolution MPRAGE and to demonstrate that SNR and scan efficiency increase with the increment of readout time. Simplified signal equations for MPRAGE indicate that the T1 contrast can be kept approximately the same by a simple relationship between the flip angle and the TR. Furthermore, if T1 contrast remains the same, image SNR depends on the square root of the product of the total scan time and the readout time. MPRAGE spiral sequences were implemented with distributed spirals and spiral staircase on 3 Tesla scanners. Brain images of three volunteers were acquired with different readout times. Spiral images were processed with a joint water-fat separation and deblurring algorithm and compared to Cartesian images. Pure noise data sets were also acquired for SNR evaluation. Consistent T1 weighting can be achieved with various spiral readout lengths, and between spiral MPRAGE imaging and the traditional Cartesian MPRAGE imaging. Noise performance analysis demonstrates higher SNR efficiency of spiral MPRAGE imaging with matched T1 contrast compared to the Cartesian reference imaging. Fast, high SNR MPRAGE imaging is feasible with long readout spiral trajectories.


Drug-induced sleep endoscopy findings in surgically-naïve obese vs non-obese children.
To determine if drug-induced sleep endoscopy (DISE) findings are different in obese versus non-obese pediatric patients with obstructive sleep apnea (OSA) or sleep-disordered breathing (SDB). Prospective, observational cohort study from June 2017 to June 2018 at a tertiary academic pediatric medical center that included surgically-naïve children ages 2-12 with diagnoses of OSA or sleep-disordered breathing. Subjects with a known diagnosis of craniofacial syndromes, genetic disorders, prior adenoidectomy or tonsillectomy, or chronic tonsillitis as the indication for surgery were excluded. Two groups were assessed for patterns of obstruction based on DISE videos at each anatomic airway level using a previously published DISE scoring system. The groups included obese subjects (BMI ≥ 95th percentile) and non-obese controls (BMI <85th percentile). Each video was graded by two blinded, fellowship-trained Pediatric Otolaryngologists. Fifty-one patients were included, 26 non-obese and 25 obese. Based on anatomic airway level, there was no statistically significant difference in airway obstruction at the velum (p = 0.134), adenoid (p = 0.592), lateral pharyngeal walls (p = 0.867), tongue base (p = 0.977), or supraglottis (p = 0.428) between obese and non-obese children. Our prospective study did not associate severity of obstruction with obesity status based on anatomic airway levels. Further studies are needed to elucidate the etiology of the high rate of persistent obstructive sleep apnea in obese children.


Physiological, biochemical and transcriptional responses of cyanobacteria to environmentally relevant concentrations of a typical antibiotic-roxithromycin.
The frequent occurrence of antibiotics in source waters may affect the formation of harmful algal blooms (HABs) dominated by the cyanobacterium Microcystis aeruginosa. However, it remains poorly understood whether dissolved algal organic matters (AOM) can be altered by the introduction of antibiotics in source waters. To resolve these discrepancies, this study investigated the physiological, biochemical, and transcriptional responses of a toxigenic strain of M. aeruginosa to the commonly-detected antibiotic roxithromycin (ROX) at environmentally relevant concentrations ranging from 30 to 8000 ng L-1. The growth and microcystin (MC) production of M. aeruginosa was significantly stimulated by 300 and 1000 ng L-1 ROX, whereas inhibited by 5000 and 8000 ng L-1 ROX. This may be owing to the regulation of genes related to photosynthesis and MCs. Although the membrane of cyanobacterial cells remained intact, the release of MCs was increased significantly with the growing ROX dosages, which may cause additional challenges in drinking water treatment. The amounts of AOM were enhanced by 300 and 1000 ng L-1 ROX, while decreased by 5000 and 8000 ng L-1 ROX. It may be attributed to the changes of cyanobacterial cell growth and the gene expression related to carbon fixation, carbohydrate metabolism and nitrogen metabolism. To further understand the regulation of related genes in M. aeruginosa exposed to ROX, trend analysis of differentially expressed genes was performed. The results indicated that the regulation of metabolism-related genes (e.g., lipopolysaccharide biosynthesis) may be also responsible for the changes of cyanobacterial cell densities. Generally, low levels of ROX (300 and 1000 ng L-1) could stimulated the cyanobacterial growth, MC synthesis and AOM production, which may promote the formation of HABs and reduce the source water quality. Although higher levels of ROX (5000 and 8000 ng L-1) inhibited the formation of HABs, the threat of increasing extracellular MCs should be considered.


Effect of probiotics on serum bile acids in patients with ulcerative colitis.
Evaluation of bile acids (BA) is useful for assessing the changes of intestinal flora in patients with ulcerative colitis (UC). During enterohepatic circulation, the intestinal micro flora cause 7 alpha-dehydroxylation of cholic acid (CA) and chenodeoxycholic acid (CDCA), yielding deoxycholic acid(DCA) and lithocholic acid, respectively. The aim of the present study was to investigate the effects of probiotics in patients with UC by examining changes of the serum BA profile. Twenty-seven patients were divided into the following 2 groups based on endoscopic findings: Fifteen patients with distal UC (dUC group) and 12 patients with pancolitis (pUC group). After treatment with mesalazine or salazosulfapyridine (5-ASA), all patients achieved remission. Then they were given 5-ASA plus the probiotic Clostridium butyricum Miyairi (3.0 g/day) for 4 weeks. After 4 weeks of probiotic treatment, %CDCA was significantly higher and %DCA was significantly lower in the pUC group than in the HV group. In contrast, the dUC group showed no significant differences of %CDCA or %DCA from the HV group after 4 weeks. Probiotic therapy restored intestinal flora involved in 7 alpha-dehydroxylation in the dUC group, but not in the pUC group.


Part 2. Distinguishing physical characteristics and management of brachial plexus injuries.
Brachial plexus injuries (BPI) are usually readily apparent at or shortly after birth. Failure of caregivers to recognize and appropriately treat BPI may contribute to the risk of life-long neuromuscular dysfunction for the infant and represents a serious medical-legal liability for the delivery provider. This article is the second in a series on BPI and provides a standard classification and a systematic guide to physical examination of the infant with suspected BPI. Conditions that mimic BPI are discussed along with diagnostic studies used to confirm this disorder. The natural history and predictors of outcome are presented along with a sample treatment protocol. Pictures and video clips are provided to enhance the reader's understanding of the consequences of this injury and the potential for improvement with surgical treatment. Useful Internet resources for parents, focused discharge planning, and guidelines for appropriate monitoring and follow-up are provided. Advantages of early referral and management by a multidisciplinary team at a brachial plexus specialty center are discussed.


Urinary Sodium-to-Potassium Ratio and Incident Chronic Kidney Disease: Results From the Korean Genome and Epidemiology Study.
To evaluate the association of sodium-potassium intake balance on kidney function. Data from the Korean Genome and Epidemiology Study were used. The participants were enrolled between June 1, 2001, and January 31, 2003, and were followed-up until December 31, 2016. The 24-hour excretion levels of sodium and potassium were calculated using the Kawasaki formula with spot urinary potassium and sodium measurements. Participants were categorized into tertiles according to the estimated 24-hour urinary sodium-to-potassium (Na/K) ratio. The primary outcome was incident chronic kidney disease (CKD), defined as an estimated glomerular filtration rate of <60 mL/min per 1.73 m2 in two or more consecutive measurements during the follow-up period. This study included 4088 participants with normal kidney function. The mean age was 52.4±8.9 years, and 1747 (42.7%) were men. The median estimated 24-hour urinary sodium excretion level, potassium excretion level, and Na/K ratio (inter quartile range) were 4.9 (4.1-5.8) g/d, 2.1 (1.8-2.5) g/d, and 2.3 (1.9-2.7) g/d, respectively. During 37,950 person-years of follow-up (median, 11.5 years), 532 participants developed CKD, and the corresponding incidence rate was 14.0 (95% CI, 12.9-15.3) per 1000 person-years. Multivariable Cox hazard analysis revealed that the risk of incident CKD was significantly lower in the lowest tertile than in the highest tertile (HR, 0.78; 95% CI, 0.63-0.97). However, no significant association was found with incident CKD risk when urinary excretion levels of sodium or potassium were evaluated individually. A low urinary Na/K ratio may relate with lower CKD development risk in adults with preserved kidney function.


Inhibition effect of dietary inulin and oligofructose on the growth of transplantable mouse tumor.
The influence of 15% inulin or oligofructose incorporated in to the basal diet on the growth of transplantable mouse tumor (TLT) was investigated. This dietary treatment was performed starting at day 7 before tumor transplantation and continued until the end of observation. The results were evaluated by the mortality rates in the ascitic form of tumor, or by twice weekly solid tumor measurements, with vernier caliper. Mortality rates in ascitic tumors and mean solid tumor surface in these experimental groups was compared with those of animals from control groups fed basal diet without supplementary beta (2-1) fructans. The growth of both forms of transplantable mouse tumors was significantly inhibited by the supplementation of the diet with inulin or oligofructose. Such a nontoxic dietary treatment appears to be easily used ad without any risk for patients, and is applicable as an adjuvant factor to classical protocols of human cancer therapy.


Iron-binding characteristics of neuromelanin of the human substantia nigra.
The vulnerability of the dopaminergic neurons of the substantia nigra (SN) in Parkinson's disease has been related to the presence of the pigment neuromelanin (NM) in these neurons. It is hypothesised that NM may act as an endogenous storage molecule for iron, an interaction suggested to influence free radical production. The current study quantified and characterised the interaction between NM and iron. Iron-binding studies demonstrated that both NM and synthetically-produced dopamine melanin contain equivalent numbers of high and low-affinity binding sites for iron but that the affinity of NM for iron is higher than that of synthetic melanin. Quantification of the total iron content in iron-loaded NM and synthetic melanin demonstrated that the iron-binding capacity of NM is 10-fold greater than that of the model melanin. This data was in agreement with the larger iron cluster size demonstrated by Mössbauer spectroscopy in the native pigment compared with the synthetic melanin. These findings are consistent with the hypothesis that NM may act as an endogenous iron-binding molecule in dopaminergic neurons of the SN in the human brain. The interaction between NM and iron has implications for disorders such as Parkinson's disease where an increase in iron in the SN is associated with increased indices of oxidative stress.


Assimilation of liquid hydrocarbon by microorganisms. II. Growth kinetics.
The growth kinetics of a microorganism with high affinity for liquid hydrocarbon which has a low solubility in water was investigated for Candida intermedia IFO 0761 in our previous work. The microorganism contained a hydrocarbon pool in and/or on the cell. The transfer of water-soluble substrates to the cell was not the rate-limiting step in the growth of C. intermedia accompanied by clump formation with liquid hydrocarbon. The operating conditions necessary for the oxygen supply for the growth were adequate for the growth of C. intermedia on n-tetradecane. The saturation kinetics was valid for the specific growth rate of C. intermedia and specific concentration of hydrocarbon per unit cell mass; the specific growth rate was expressed by the following equation: (formula: see text).


Heterogeneous FASnI3 Absorber with Enhanced Electric Field for High-Performance Lead-Free Perovskite Solar Cells.
Lead-free tin perovskite solar cells (PSCs) have undergone rapid development in recent years and are regarded as a promising eco-friendly photovoltaic technology. However, a strategy to suppress charge recombination via a built-in electric field inside a tin perovskite crystal is still lacking. In the present study, a formamidinium tin iodide (FASnI3) perovskite absorber with a vertical Sn2+ gradient was fabricated using a Lewis base-assisted recrystallization method to enhance the built-in electric field and minimize the bulk recombination loss inside the tin perovskites. Depth-dependent X-ray photoelectron spectroscopy revealed that the Fermi level upshifts with an increase in Sn2+ content from the bottom to the top in this heterogeneous FASnI3 film, which generates an additional electric field to prevent the trapping of photo-induced electrons and holes. Consequently, the Sn2+-gradient FASnI3 absorber exhibits a promising efficiency of 13.82% for inverted tin PSCs with an open-circuit voltage increase of 130 mV, and the optimized cell maintains over 13% efficiency after continuous operation under 1-sun illumination for 1,000 h.


Proportion-altering factor (PAF) stimulates nerve cell formation in Hydractinia echinata.
The low-molecular weight proportion altering factor (PAF) from colonial hydroids has general animalizing effects on morphogenesis in hydroid development. On the cellular level, the factor stimulates the formation of nerve cells in several developmental stages of Hydractinia echinata. Treatment during metamorphosis yielded a fivefold increase in the number of nerve cells with FMRF-amide-like immunoreactivity. In non-metamorphosing planula larvae, PAF triggered the differentiation of nerve cells that normally develop only upon initiation of metamorphosis and that occur in the polyp stage. After post-metamorphic treatment of young primary polyps, nerve cell numbers increased to 2.5 times the normal value.


Systematic review identifies deficiencies in reporting of diagnostic test accuracy among clinical decision support systems.
This systematic review assesses the reporting quality and risk of bias in studies evaluating the diagnostic test accuracy (DTA) of clinical decision support systems (CDSS). The Cochrane Library, PubMed/MEDLINE, Scopus, and Web of Science were searched for studies, published between January 1, 2016 and May 31, 2021, evaluating the DTA of CDSS for human patients. Articles using a patient's self-diagnosis, assessing disease severity, focusing on treatment/follow-up, or comparing pre-post CDSS implementation periods were excluded. All eligible studies were assessed for reporting quality using STARD 2015 and for risk of bias using QUADAS-2. Item ratings were presented using heat maps. This study was reported as per PRISMA-DTA. In total, 158 of 2,820 screened articles were included in the analysis. The studies were heterogeneous in terms of study characteristics, reporting quality, risk of biases, and applicability concerns with few highly rated studies. Mostly the overall quality was deficient for items addressing the domains 'methodology,' 'results,' and 'other information'. Our analysis revealed shortcomings in critical domains of reporting quality and risk of bias, indicating the need for additional guidance and training in an interdisciplinary scientific field with mixed biostatistical expertise.


Adaptations of the reed frog Hyperolius viridiflavus (Amphibia, Anura, Hyperoliidae) to its arid environment : IV. Ecological significance of water economy with comments on thermoregulation and energy allocation.
After breeding African savanna dwelling reed-frogs of the "superspecies" Hyperolius viridiflavus face a severe dry season. The frogs withstand the adverse abiotic conditions in exposed positions, clinging to dry vegetation. Only juveniles (300-700 mg) are able to adjust water economy and metabolism to a prolonged dry season. Wet season frogs attain low levels of evaporative water loss (EWL) within 6-8 days after incipient water shortage. This time course is mainly determined by the animal's ability to lower metabolism and activity level to the minimum demands of a dry season. Barriers against diffusion of water which most probably are built up by the stratum corneum and/or the overlying film of dried mucus seem not to be essentially modified during adjustment to dry season conditions. Changeover to dry season physiology is greatly accelerated through preconditioning frogs to water shortage. AdultHyperoliusare unable to reduce activity and metabolism as fast and effectively as juveniles. Most probably these are the main reasons for their very restricted survival capability under dry season conditions; the generally poor energy reserves after the breeding period may further shorten their survival time. At the critical thermal maximum (CTM) Hyperolius uses skin gland secretions for evaporative cooling. Acclimation effects and regulation of evaporative cooling within some 1/10° C help to employ limited water reserves very economically. Dry adapted, dehydrated frogs take up water, whenever available, via specialized skin areas. Rate of uptake is high and is mainly determined by the actual stage of dehydration. The onset of the water-balance-response is also affected by preconditioning. Survival time of small (<500 mg) estivating Hyperolius is limited by their water reserves.Due to their unfavourable surface to volume ratio they loserelatively more water by evaporation than larger conspecifics. Therefore, smaller specimens should allocate energy preferably to growth, until reducing EWL so far to survive the average periods between the rare precipitations. In larger frogs (>500 mg) the amount of stored energy determines maximal survival time. When a critical size is reached in postmetamorphic growth, a change in energy allocation from body growth to energy storage would improve prospects of survival and should therefore be expected. Species specific differences in regard to EWL and CTM indicate a strong correlation between physiological properties and ecological demands.


Silencing lncRNA PVT1 inhibits activation of astrocytes and increases BDNF expression in hippocampus tissues of rats with epilepsy by downregulating the Wnt signaling pathway.
The aim of this study is to investigate the effects of long-chain noncoding RNA plasmacytoma variant translocation 1 (PVT1) on the activation of astrocytes and the expression of brain-derived neurotrophic factor (BDNF) in hippocampus tissues of epileptic rats. The epilepsy rat model was induced by intraperitoneal injection of lithium chloride-pilocarpine. Successfully modeled rats were grouped, and their spatial learning and memory, neuronal loss, number of TdT-mediated dUTP nick labeling (TUNEL)-positive cells, and the expression of cleaved-caspase-3, pro-caspase-3, Bax, Bcl-2, GFAP, BDNF, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, axin, and cyclin D1 in hippocampus tissues were evaluated. Increased expression of PVT1 was found in hippocampus tissues of epileptic rats. Silencing of PVT1 improved spatial learning and memory, decreased neuronal loss, decreased the number of TUNEL-positive cell, decreased the expression of cleaved-caspase-3 and Bax while increased pro-caspase-3 and Bcl-2 expression, decreased the expression of GFAP, increased the expression of BDNF, decreased the expression of TNF-α, IL-1β, and IL-6, and decreased the expression of axin and cyclin D1 in hippocampus tissues in epileptic rats. Our study provides evidence that the inhibition of PVT1 may decrease the loss of neurons, inhibit the activation of astrocytes, and increase the expression of BDNF in hippocampus by downregulating the Wnt signaling pathway.


ARRONAX, a high-energy and high-intensity cyclotron for nuclear medicine.
This study was aimed at establishing a list of radionuclides of interest for nuclear medicine that can be produced in a high-intensity and high-energy cyclotron. We have considered both therapeutic and positron emission tomography radionuclides that can be produced using a high-energy and a high-intensity cyclotron such as ARRONAX, which will be operating in Nantes (France) by the end of 2008. Novel radionuclides or radionuclides of current limited availability have been selected according to the following criteria: emission of positrons, low-energy beta or alpha particles, stable or short half-life daughters, half-life between 3 h and 10 days or generator-produced, favourable dosimetry, production from stable isotopes with reasonable cross sections. Three radionuclides appear well suited to targeted radionuclide therapy using beta ((67)Cu, (47)Sc) or alpha ((211)At) particles. Positron emitters allowing dosimetry studies prior to radionuclide therapy ((64)Cu, (124)I, (44)Sc), or that can be generator-produced ((82)Rb, (68)Ga) or providing the opportunity of a new imaging modality ((44)Sc) are considered to have a great interest at short term whereas (86)Y, (52)Fe, (55)Co, (76)Br or (89)Zr are considered to have a potential interest at middle term. Several radionuclides not currently used in routine nuclear medicine or not available in sufficient amount for clinical research have been selected for future production. High-energy, high-intensity cyclotrons are necessary to produce some of the selected radionuclides and make possible future clinical developments in nuclear medicine. Associated with appropriate carriers, these radionuclides will respond to a maximum of unmet clinical needs.


Subthalamic deep brain stimulation identifies frontal networks supporting initiation, inhibition and strategy use in Parkinson's disease.
Initiation and inhibition are executive functions whose disruption in Parkinson's disease impacts substantially on everyday activities. Management of Parkinson's disease with subthalamic deep brain stimulation (DBS) modifies initiation and inhibition, with prior work suggesting that these effects may be mediated via the connectivity of the subthalamic nucleus (STN) with the frontal cortex. Here, we employed high-resolution structural neuroimaging to investigate the variability in initiation, inhibition and strategy use in a cohort of twenty-five (ten females, mean age 62.5, mean Hoehn and Yahr stage 2.5) participants undertaking subthalamic DBS for Parkinson's disease. Neuropsychological assessment of initiation and inhibition was performed preoperatively and at six months postoperatively. We first reconstructed the preoperative connectivity of the STN with a frontal network of anterior and superior medial cortical regions. We then modelled the postoperative site of subthalamic stimulation and reconstructed the connectivity of the stimulation field within this same network. We found that, at both pre- and postoperative intervals, inter-individual variability in inhibition and initiation were strongly associated with structural network connectivity. Measures of subcortical atrophy and local stimulation effects did not play a significant role. Preoperatively, we replicated prior work, including a role for the right inferior frontal gyrus in inhibition and strategy use, as well as the left inferior frontal gyrus in tasks requiring selection under conditions of maintained inhibition. Postoperatively, greater connectivity of the stimulation field with right anterior cortical regions was associated with greater rule violations and suppression errors, supporting prior work implicating right-hemispheric STN stimulation in disinhibition. Our findings suggest that, in Parkinson's disease, connectivity of the frontal cortex with the STN is an important mediator of individual variability in initiation and inhibition,. Personalised information on brain network architecture could guide individualised brain circuit manipulation to minimise neuropsychological disruption after STN-DBS.


A method to distinguish between gaseous and solid cerebral emboli in patients with prosthetic heart valves.
The difficulty of distinguishing solid from air emboli using transcranial Doppler has limited its use in situations where both types of emboli can occur, such as in mechanical heart valve patients. To make transcranial Doppler clinically useful, a method must be found to distinguish benign air bubbles from the more damaging solid particulates. Since inhalation of 100% oxygen reduces the amount of air bubbles in mechanical heart valve patients, the ultrasonic features of the remaining emboli would be characteristic of solid particulates. We determined the accuracy of the signal relative intensity measured with transcranial Doppler to distinguish between gaseous and non-gaseous emboli in mechanical heart valve patients examined during room air and 100% oxygen. Embolic signals detected in patients with bioprosthetic valves examined during 100% oxygen comprised the source of solid particulates. Embolic signals were detected during room air (n=141) and 100% oxygen (n=45) from 17 mechanical valve patients at two Doppler examinations (4h and 4 days after surgery). Solid embolic signals (n=31) from seven patients with bioprosthetic valves were identified with 100% oxygen within the first 4h after surgery. Frequency plots and receiver operating characteristic curves assessed signal intensity differences between mechanical and bioprosthetic valve groups during 100% oxygen and the efficacy of the relative intensity for differentiating gaseous from solid emboli. Administration of 100% oxygen during transcranial Doppler examination in mechanical heart valve patients decreased the count of embolic signals compared with room air (p=0.006). The embolic signals of mechanical heart valve patients breathing 100% oxygen showed lower relative intensities compared with those during room air. The distribution of the signal relative intensity between mechanical and bioprosthetic valve groups during 100% oxygen was similar. A 16dB cut-off threshold achieved the best accuracy for differentiating non-gaseous from gaseous emboli (sensitivity: 60%; specificity: 82%; area: 0.721; p<0.0001). The use of a signal intensity cut-off offers adequate discrimination of the embolic composition in mechanical heart valve patients. Future studies evaluating prophylactic treatments of thrombosis in these patients should assess the predictive value of this intensity threshold and their potential association with outcome indicators and procoagulant markers.


Capillary permeability in ALS, determined through transcapillary escape rate of 125I-albumin.
Since various macromolecules have experimentally been demonstrated to be taken up by the motor end-plates and subsequently transported through retrograde axoplasmic flow, noxious substances may gain entrance to the lower motorneurons through the same route. Consequently, the function of the capillary barrier in skeletal muscle is of interest in diseases of the lower motorneurons. The transcapillary escape of 125I-albumin was determined in six ALS patients. The values fell within the range earlier reported for normals.


Pulmonary oedema in the course of severe maternal outcome in South Africa: A cohort study combined with clinical audit.
To describe the incidence and outcomes of pulmonary oedema in women with severe maternal outcome during childbirth and identify possible modifiable factors through audit. All women with severe maternal outcome (maternal deaths or near misses) who were referred to Tygerberg referral hospital from health facilities in Metro East district, South Africa, during 2014-2015 were included. Women with severe maternal outcome and pulmonary oedema during pregnancy or childbirth were evaluated using three types of critical incident audit: criterion-based case review by one consultant gynaecologist, monodisciplinary critical incident audit by a team of gynaecologists, multidisciplinary audit with expert review from anaesthesiologists and cardiologists. Of 32,161 pregnant women who gave birth in the study period, 399 (1.2%) women had severe maternal outcome and 72/399 (18.1%) had pulmonary oedema with a case fatality rate of 5.6% (4/72). Critical incident audit demonstrated that pre-eclampsia/HELLP-syndrome and chronic hypertension were the main conditions underlying pulmonary oedema (44/72, 61.1%). Administration of volumes of intravenous fluids in already sick women, undiagnosed underlying cardiac illness, administration of magnesium sulphate as part of pre-eclampsia management and oxytocin for augmentation of labour were identified as possible contributors to the pathophysiology of pulmonary oedema. Women-related factors (improved antenatal care attendance) and health care-related factors (earlier diagnosis and management) would potentially have improved maternal outcome. Although pulmonary oedema in pregnancy is rare, among women with severe maternal outcome a considerable proportion had pulmonary oedema (18.1%). Audit identified options for prevention of pulmonary oedema and improved outcome. These included early detection and management of preeclampsia with close monitoring of fluid intake and cardiac evaluation in case of suspected pulmonary oedema. Therefore, a multidisciplinary clinical approach is recommended.


Long-Term Prognostic Impact of Contrast-Enhanced Ultrasound and Power Doppler in Renal Transplantation.
Contrast-enhanced ultrasound (CEUS) and power Doppler ultrasound (US) are established tools in the study of acute renal allograft (RA) dysfunction. The aim of this study was to investigate their long-term prognostic impact. A total of 39 kidney recipients underwent CEUS and US at 5 and 15 days and at 1, 3, 6, and 12 months after grafting, with yearly clinical, laboratory, and US follow-up for a total of 4 years. CEUS analysis according to the gamma variate model was performed on cortical and medullary regions. Patients were divided into 2 subsets: death or graft failure vs patients with functioning grafts; higher vs lower than 50% glomerular filtration rate (GFR) reduction from the first month to the fourth year after grafting. Receiver-operator characteristic (ROC) analysis for death/graft failure and 50% GFR reduction events was performed for variables with significant differences between groups (t test) or with significant correlation to GFR (Pearson correlation). ROC analysis confirms the reliability of clinical and radiologic variables for the evaluation of long-term graft survival or of GFR reduction, with high sensitivity (for resistive index) or specificity (for GFR, medullary peak, and regional blood flow). Combining CEUS and US allows the evaluation of long-term RA function in terms of GFR reduction and graft survival. Resisitive-indexes show a good sensitivity, relating to kidney disfunction, while CEUS parameters show a good specificity, identifiying well-perfused grafts.


Airway inflammation and symptoms in children following liver and heart transplantation.
To describe the upper airway endoscopic findings of children with upper airway symptoms after liver transplantation (LT) or heart transplantation (HT). Review of children undergoing airway endoscopy after LT or HT from 2011 to 2015 at a tertiary care pediatric hospital. Airway findings, biopsy results, immunosuppression, and Epstein-Barr virus (EBV) levels were recorded. Twenty-three of 158 LT (111) and HT (47) recipients underwent endoscopy. Median time from LT to endoscopy was 9 months (range 4-25) and 31 months (range 1-108) for HT. Thirteen of 23 patients presented with upper airway symptoms, and 10/23 presented with respiratory failure or for surveillance. Thirteen patients with upper airway symptoms had abnormal findings (7 LT; 6 HT), most commonly arytenoid edema (13 patients). There were five EBV-positive biopsies (four with post-transplant lymphoproliferative disorder), and six EBV-negative biopsies with lymphocytic inflammation. One biopsy demonstrated fungal infection. Immunosuppression was decreased in seven patients, and three received steroids. There were no episodes of allograft rejection. No patients had airway symptoms at last follow-up. In pediatric solid organ transplant recipients, symptoms of airway obstruction are not uncommon and should be evaluated with endoscopy. Endoscopy without symptoms is low-yield. Treatment with decreased immunosuppression improved airway symptoms.


Comparison of dynamic digital pupillometry and static measurements of pupil size in determining scotopic pupil size before refractive surgery.
To compare 2 digital infrared pupillometers. Anterior Segment Service, Moorfields Eye Hospital, London, England. Eighty-eight eyes of 44 healthy subjects were recruited into the study. The scotopic pupil size was measured with 2 instruments, a digital pupillometer (Procyon) and a Hartman-Shack wavefront aberrometer (Visx WaveScan). Agreement between the instruments was assessed. There were 21 men and 23 women with a mean age 38.1 years +/- 9.2 (SD) (range 23 to 62 years). The mean scotopic pupil diameter was significantly larger with the WaveScan (6.61 +/- 0.92 mm) than with the Procyon pupillometer (6.40 +/- 0.90 mm), P<.001. There was good agreement in measurement of scotopic pupil size between the two instruments. The larger pupil diameter found with the Visx WaveScan than with the Procyon digital pupillometer probably represents the different illumination level used by each instrument, the effects of accommodation, and target fogging.


The effect of grasses on the quality of transmitted radiation and its influence on the growth of white clover Trifolium repens.
Plants of white clover Trifolium repens were grown under the canopies of three grass species, Lolium perenne, Agrostis tenuis and Holcus lanatus, and under simulated canopies of black polythene and controls were exposed to unfiltered natural radiation. The canopies were adjusted so that they transmitted equal intensities of Photosynthetically Active Radiation (P.A.R.). The ratio of red to far red radiation (ζ) was unchanged under the black polythene canopies but was reduced under canopies of Lolium and Agrostis and even more so under Holcus. The effect of canopy filtered radiation on the growth of clover was greatly to reduced internode length, mean number of nodes, the number of branched nodes and the number of rooted nodes and greatly to increase petiole length. The effect of canopies of Holcus was greater than that of the other grass species both in its effect on ζ and on the responses of the clover plant to its shade.


Internal double-J stent was associated with a lower incidence of ureteroileal anastomosis stricture than external ureteral catheter for patients undergoing radical cystectomy and orthotopic neobladder: A systematic review and meta-analysis.
Proper techniques used in procedures might play an important role in reducing ureteroileal anastomosis stricture (UIAS) for patients undergoing orthotopic neobladder. The present study was to evaluate the efficacy of internal double-J stent versus external ureteral catheter on UIAS for patients undergoing radical cystectomy and orthotopic neobladder. A comprehensive search of the literature referring to the topic was performed on 10th January 2019 in PubMed, EMBASE and Google Scholar, by using key words as radical cystectomy, orthotopic neobladder, stricture, stenosis. The Cochrane Collaboration's RevMan 5.3 software was employed for data analysis. The incidence of UIAS was evaluated as primary outcome. Five studies were included eventually. The incidence of UIAS was lower in the group of internal double-J stent than that in the group of external ureteral catheter (odds ratio [OR], 0.49; 95% CI, 0.25-0.97; p = 0.04) with a low heterogeneity (I2 = 0%). Besides, internal double-J stent group had a trend of a shorter length of stay than external ureteral catheter group. Based on the present meta-analysis, internal double-J stent placement was associated with a lower incidence of UIAS than external ureteral catheter for patients undergoing orthotopic neobladder. In addition, a trend of a shorter hospital stay was also detected, thus, internal double-J stent placement may be favored in the view of the enhanced recovery after surgery (ERAS).


Burden of migraine among Japanese patients: a cross-sectional National Health and Wellness Survey.
Limited studies have measured the burden of migraine in Japan. This study aimed at estimating the disease burden of migraine in Japan and identifying factors associated with the burden using the 2017 National Health and Wellness Survey. Migraine patients were defined by ICHD-3 like criteria with ≥4 monthly headache days (MHDs), and non-migraine respondents were selected using 1:4 propensity score matching. Multivariate analyses were conducted to compare Health-related Quality of Life (HRQoL), work productivity and activity impairment (WPAI), healthcare resource utilization (HRU) and costs between the two groups, and to identify factors associated with these outcomes in migraine patients. In 30,001 respondents, 378 migraine patients were identified. Compared to matched controls (N = 1512), migraine patients had lower physical (45.17 vs. 49.89), mental (42.28 vs. 47.71) and role/social (37.91 vs. 44.19) component summary scores (p < 0.001). Migraine patients had higher absenteeism (6.4% vs. 2.2%), presenteeism (40.2% vs. 22.5%), total work productivity impairment (44.3% vs. 24.5%), total activity impairment (45.0% vs. 23.9%), indirect costs (1,492,520 JPY vs. 808,320 JPY) and more visits to healthcare providers in the past 6 months (7.23 vs. 3.96) (p < 0.001). More MHDs was associated with worse HRQoL, and higher HRU and indirect costs. Japanese migraine patients experience an incremental burden. This demonstrates the unmet needs among Japanese migraine patients.


Impact of Estradiol Variability and Progesterone on Mood in Perimenopausal Women With Depressive Symptoms.
Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated. To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology. Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models. Academic medical center. Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3). Depressive symptoms (MADRS score). During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (β = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; β = -2.62 [95% CI, -4.52 to -0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events. Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.


International adoption: what is fact, what is fiction, and what is the future?
Despite the popularity of international adoption in North America and Western Europe as a means to build a family, the knowledge of health care professionals is often limited regarding the historical context of this phenomenon as well as the motivations and process experienced by adoptive parents. Although international adoption is viewed as an acceptable if not admirable method of forming kinships in accepting countries, opinions in the international community are mixed. Whether international adoptions increase or are drastically curtailed depends on addressing the misgivings that many countries have about placing their children abroad. Concerns center in two broad areas: sensitivity toward preservation of family and culture and whether the process has sufficient integrity to act in the best interests of children and birth parents.


Identity by descent and association analysis of dichotomous traits based on large pedigrees.
The goals of our analysis were to map functional loci, which contribute to the case-control status of a trait of interest, using large pedigrees. We used logistic regression fitted with the generalized estimation equation to test associations between a dichotomous phenotype and all genotyped common and rare single-nucleotide polymorphisms. In addition to the association study, we also developed and applied a simple and fast identical-by-descent-based test to identify loci that were shared among affected individuals more often than expected by chance. Among the top significant loci, we assessed the statistical power and the false discovery rate of both methods. We also demonstrated that family-based studies, compared with the standard population-based association studies, have great values and advantages for the discovery of multiple rare causal variants.


Heart Transplantation in Children and Adults With Congenital Heart Disease: 3 Decades of Evolution.
Heart transplantation is the treatment of choice for children and adults with congenital heart disease. We report the heart transplant single-center experience. The number of transplantations has increased over the last 3 decades. The Kaplan-Meier survival curves in the first, second, and third decades at 5 and 10 years were 69% and 59%, 62% and 52%, and 66% and 60%, respectively.


[Gender identity disorder in children and adolescents].
There has been an explosion of public interest and concern about children and adolescents who show an interest in changing their gender. And it is an emerging problem for pediatricians, which brings many inquiries about what to do? Both the diagnosis and treatment of gender identity disorder are controversial. But there are a new early treatment using puberty blocking hormones.


Halohydroxybenzonitriles as a new group of halogenated aromatic DBPs in drinking water: Are they of comparable risk to halonitrophenols?
Halogenated aromatic disinfection byproducts (DBPs) exhibited similar total organic halogen levels in chlorinated drinking water samples as compared with aliphatic ones, and they predominantly accounted for the overall toxicity of the samples. Among the reported halogenated aromatic DBPs, halonitrophenols (HNPs) have received particular attention in recent years due to the relatively high risk in drinking water. In this study, a new group of halogenated aromatic DBPs were detected and then proposed to be halohydroxybenzonitriles (HHBNs) by employing the ultra-performance liquid chromatography/tandem mass spectrometers. Thereafter, the specific HHBN species in drinking water were theoretically speculated and then thoroughly identified with standard compounds. Their occurrence in drinking water was investigated, their cytotoxicity was evaluated, and their stability in the presence of chlorine was assessed. Seven newly identified HHBNs, including 3,5-dichloro-4-hydroxybenzonitrile, 3,5-dichloro-2-hydroxybenzonitrile, 5-bromo-3-chloro-4-hydroxybenzonitrile, 5-bromo-3-chloro-2-hydroxybenzonitrile, 3,5-dibromo-4-hydroxybenzonitrile, 3,5-dibromo-2-hydroxybenzonitrile, and 3,5-diiodo-4-hydroxybenzonitrile, showed 100% detection frequency in the collected drinking water samples with concentrations up to 36 ng/L. HHBNs exhibited significantly higher cytotoxicity in Chinese hamster ovary cells than regulated DBPs (e.g., trihalomethanes and haloacetic acids), which might be contributed by their cellular uptake efficiency and nucleophilicity. The seven HHBNs were proved to undergo transformation during chlorination following pseudo-first-order decay with half-lives in the range of 9-63 h. More importantly, in comparison to HNPs, which showed relatively high toxicity and strong stability among the halogenated aromatic DBPs, HHBNs presented comparable concentration-cytotoxicity contribution (50%) and slightly weaker stability (43%), suggesting that HHBNs should be a new group of DBPs of concern in drinking water.


Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons.
Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors associate with distinct sets of mRNAs and RNA-binding proteins. Cue stimulation of growing Xenopus retinal ganglion cell axons induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by co-exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and suggest a generalizable model for cue-selective control of the local proteome.


Range of the influence of the carbohydrate moiety on the conformation of the poly(amino acid) backbone in glycosylated mucins.
The influence of glycosylation on the conformational properties of porcine submaxillary gland mucin has been investigated using rotational isomeric state theory. The specific objective was to determine the conditions under which the polypeptide has the relatively large mean square unperturbed radius of gyration mean value of s2(0), demanded by the measurements of Shogren et al., while retaining the overall architecture of a random coil. The mean square dimensions were monitored as the dimensionless characteristic ratio defined as C = mean value of s2(0)/npl2p, and the overall architecture was monitored by another dimensionless ratio mean value of r2(0)/mean value of s2(0), where mean value of r2(0) denotes the mean square unperturbed end-to-end distance. The computed values of C cannot reproduce the measured values if the conformational influence of glycosylation is restricted to each Ser or Thr, or if this influence extends only as far as their nearest neighbors. Values of C compatible with experiment can be obtained if the influence extends to next nearest neighbors. The behavior of the computed values of mean value of r2(0)/mean value of s2(0) permits an assignment of 7 +/- 1 as the likely upper limit to the number of consecutive amino acid residues that experience alterations in phi and psi if the sequence contains a glycosylated Ser or Thr.


An ethnobotanical study on wild plants used by Tibetan people in Gyirong Valley, Tibet, China.
Gyirong Valley known as the "Back Garden of the Himalayas" is located in the core area of the Everest National Nature Reserve. It is also one of the important ports from ancient Tibet to Kathmandu, Nepal, since ancient times. Over the years, the Tibetans of Gyirong had accumulated sufficient traditional knowledge about local plant resources. However, there is almost no comprehensive report available on ethnobotanical knowledge about the local people. The purposes of this study were to (1) conduct a comprehensive study of wild plants used by Tibetan people in Gyirong Valley and record the traditional knowledge associated with wild useful plants, (2) explore the influence of Tibetan traditional culture and economic development on the use of wild plants by local people, and (3) explore the characteristics of traditional knowledge about wild plants of Tibetans in Gyirong. Ethnobotanical data were documented through free listings, key informant interviews and semi-structured interviews during fieldwork. The culture importance index and the informant consensus factor index were used as quantitative indices. In total, 120 informants (61 women and 59 men) and 3333 use reports and 111 wild plant species belonging to 39 families and 81 genera were included. These use reports were then classified into 27 categories belonging to three major categories. The use category that contained the most plant species was edible plants (62), followed by medicinal plants (32) and economic plants (22), and other uses (71). Plants with high CI included Allium prattii, Neopicrorhiza scrophulariiflora, Gymnadenia orchidis, Rhododendron anthopogon and Fritillaria cirrhosa. Thirty-six species of plants in the catalog of Gyirong and Yadong were the same, but only 17 species were the same in Gyirong and Burang. There were only 11 overlapping species between all the three regions. Tibetans of Gyirong have rich and unique knowledge about plant use, and wild edible and medicinal plants play an important role in the nutrition and health protection of local people. However, traditional knowledge is slowly being lost and is being hit by modern tourism. In the future, more attention needs to be paid to the important role of traditional knowledge in biodiversity conservation.


Sleep staging automaton based on the theory of evidence.
This paper addresses sleep staging as a medical decision problem. It develops a model for automated sleep staging by combining signal information, human heuristic knowledge in the form of rules, and a mathematical framework. The EEG/EOG/EMG events relevant for sleep staging are detected in real time by an existing front-end system and are summarized per minute. These token data are translated, normalized, and constitute the input alphabet to a finite state machine (automaton). The processed token events are used as partial belief in a set of anthropomimetic rules, which encode human knowledge about the occurrence of a particular sleep stage. The Dempster-Shafer theory of evidence weighs the partial beliefs and attributes the minutes sleep stage to the machine state transition that displays the highest final belief. Results are briefly presented.


Treatment of hypopharyngeal carcinoma with primary chemoradiotherapy: functional morbidity.
This review aims at unravelling the medical literature which has reported on the treatment of 'larynx preserving' chemoradiotherapy strategies and separating the treatment sites, larynx and hypopharynx, from each other and reporting on the adverse effects and functional outcomes of patients with hypopharyngeal cancer. The literature reports on the treatment of advanced laryngeal and hypopharyngeal cancer with chemoradiotherapy together as a 'common cancer site'. Although the chemotherapeutic drugs affect the tumour and the normal tissues similarly in both the larynx and hypopharynx, their effects on the patient groups are different, mainly affecting swallow, airway protection mechanisms and voice/speech to a greater or lesser extent. Pretreatment symptoms and function should be documented subjectively and objectively prior to commencing nonsurgical treatment. Hypopharyngeal cancer should be reported separately, and preferably stratified into the three subsites, according to the T stage of disease rather than TNM stage. Equipment for such testing and the process for such documentation are available in most clinical areas, worldwide. Future analysis relies on the conscientious monitoring of adverse effects of all treatment modalities and an assessment of function as well as quality of life impact on the patient. Thus, the specialty can make informed decisions on the most appropriate and most suitable mode of treatment for individual patients based upon their tumour, their preoperative organ function, their likely future organ function and the likelihood of cure.


Opposing regulation of cell proliferation by retinoic acid and the serotonin2B receptor in the mouse frontonasal mass.
Development of the frontonasal mass (FNM), branchial arches, heart, and limbs depends on neural crest-mediated epithelial-mesenchymal (E-M) interactions. Teratogenesis by retinoic acid (RA) or blockade of serotonergic (5-HT) signaling by the pan-5-HT(2) receptor antagonist, ritanserin, perturbs development of these embryonic structures. In both cases, resulting phenotypes include forebrain and olfactory placode anomalies, malformations of the face, eye and lens, as well as posterior neural tube and cardiac defects. Similar sites of malformations, together with the presence of RA response elements in the 5-HT(2B) receptor promoter, have led to the suggestion that a negative regulatory relationship may exist between RA and 5-HT(2)-mediated 5-HT signaling at sites of E-M interaction (Choi et al. 1997); however, another possibility is that RA and 5-HT act independently as opposing signals to regulate development of common embryonic targets. Together with recent evidence for opposite effects on chondrogenic differentiation in hindlimb micromass cultures (Bhasin et al. 2003a), results of the present study raise the possibility that these pathways may act as opposing signals for common targets in the mouse embryo. The RA receptors, co-factors and metabolic enzymes, and 5-HT(2B) receptors were found to be are coordinately expressed at sites of E-M interaction, including the FNM, in the embryonic day (E)10.5 mouse. Cell proliferation experiments using [(3)H]thymidine incorporation demonstrated that RA or activation of 5-HT(2B) receptors caused opposite effects in FNM explants, namely stimulation or inhibition of cell proliferation, respectively, 5-HT(2B) receptor activation did not appreciably alter patterning in FNM explants. While RA has been shown to regulate lateral patterning in the FNM (LaMantia et al. 2000), 5-HT(2B) receptor activation did not alter patterning in FNM explants. Quantification of 5-HT(2B) receptor transcripts by real-time PCR provided no evidence of negative regulation of 5-HT(2B) receptor expression by RA in FNM explants, although preliminary studies using in situ hybridization had suggested that this was a possibility in both explants and RA teratogenized embryos. Future studies using quantitative PCR may still show this to be the case in teratogenized embryos. Together with the finding of coordinate expression of 5-HT(2B )receptors and RA signaling molecules, results of the present study suggest that RA, and 5-HT mediated by 5-HT(2B )receptors, may act as opposing signals to regulate cell proliferation during craniofacial development in the mouse embryo.


Validation study of case-identifying algorithms for severe hypoglycemia using hospital administrative data in Japan.
The purpose of this study was to evaluate the performance of algorithms for identifying cases of severe hypoglycemia in Japanese hospital administrative data. This was a multicenter, retrospective, observational study conducted at 3 acute-care hospitals in Japan. The study population included patients aged ≥18 years with diabetes who had an outpatient visit or hospital admission for possible hypoglycemia. Possible cases of severe hypoglycemia were identified using health insurance claims data and Diagnosis Procedure Combination data. Sixty-one algorithms using combinations of diagnostic codes and prescription of high concentration (≥20% mass/volume) injectable glucose were used to define severe hypoglycemia. Independent manual chart reviews by 2 physicians at each hospital were used as the reference standard. Algorithm validity was evaluated using standard performance metrics. In total, 336 possible cases of severe hypoglycemia were identified, and 260 were consecutively sampled for validation. The best performing algorithms included 6 algorithms that had sensitivity ≥0.75, and 6 algorithms that had positive predictive values ≥0.75 with sensitivity ≥0.30. The best-performing algorithm with sensitivity ≥0.75 included any diagnoses for possible hypoglycemia or prescription of high-concentration glucose but excluded suspected diagnoses (sensitivity: 0.986 [95% confidence interval 0.959-1.013]; positive predictive value: 0.345 [0.280-0.410]). Restricting the algorithm definition to those with both a diagnosis of possible hypoglycemia and a prescription of high-concentration glucose improved the performance of the algorithm to correctly classify cases as severe hypoglycemia but lowered sensitivity (sensitivity: 0.375 [0.263-0.487]; positive predictive value: 0.771 [0.632-0.911]). The case-identifying algorithms in this study showed moderate positive predictive value and sensitivity for identification of severe hypoglycemia in Japanese healthcare data and can be employed by future pharmacoepidemiological studies using Japanese hospital administrative databases.


Development of a Photoinduced Chemiluminescent Method for the Determination of the Herbicide Quinmerac in Water.
A new, simple, and sensitive method, based on photoinduced chemiluminescence, was developed for the determination of quinmerac. The photoproduct, obtained after ultraviolet irradiation in basic medium, was mixed with sodium sulfite (sensitizer), and Ce(IV) (oxidant) in acid medium. A wide linear dynamic range (2-600 ng mL(-1)) and a limit of detection of 0.6 ng mL(-1) were obtained without any pretreatment (0.08 ng mL(-1) after solid-phase extraction). The determination was performed using a flow-injection manifold, which allowed a high throughput (144 h(-1)). The interday reproducibility was 5.6% (n = 5), and the intraday repeatability was 3.9 and 2.9% for 20 and 200 ng mL(-1) of quinmerac, respectively (n = 21). Finally, the method was applied to surface water and groundwater, with recoveries ranging from 78.1 to 94.5%.


Molecular characterization of Streptococcus pneumoniae invasive serotype 19A isolates from adults in two Spanish regions (1994-2009).
From 1994 to 2009, the incidence of invasive serotype 19A pneumococci isolated from adults in Barcelona and San Sebastian almost doubled every 4 years. Genotyping of the 167 invasive isolates studied showed serotype 19A to be highly heterogeneous, with 35 different sequence types (STs) and a different clonal structure in each region and time period. Multiresistance, defined as non-susceptibility to three or more antimicrobials, was found in 86 (51.5%) isolates. The most frequent ST was the multidrug-resistant ST276 (n = 28), which is a single-locus variant of the Denmark(14)-ST230 global clone. The ST276 clone, only present in San Sebastian before 2001, was successfully disseminated from 2002 in both cities and was the main contributor to the overall increase of serotype 19A infections.


Cell cycle-associated change in the expression of the proliferation-sensitive and heat-shock protein hs x 70 (IEF14): increased synthesis during mitosis.
The major heat-inducible protein of transformed human amnion cells (AMA) has been identified as the proliferation-sensitive polypeptide IEF14 (Mr 66 kDa; HeLa protein catalogue). From its mobility in two-dimensional gels (Mr and pI) as well as from the fact that this protein is immunoprecipitated by mAb C92 F3-5 (W. J. Welch, and J. P. Suhan, (1986) J. Cell Biol. 103, 2035-2052), we concluded that this polypeptide is either closely related or identical to the 72 kDa inducible stress human protein hs X 70 (H. R. B. Pelham (1986) Cell 46, 959-961). It is further shown that in AMA cells the rate of synthesis of this protein increases preferentially during mitosis. These results provide further evidence suggesting that the levels of hs X 70 can be modulated by mechanisms independent of heat shock.


Regional cerebral blood flow in parkinsonism. Measurement before and after levodopa.
Data from recent studies in experimental animals suggest that central dopaminergic mechanisms may be involved in regulation of the regional cerebral blood flow (rCBF) in the mammalian brain. In order to evaluate possible effects of dopaminergic stimulation on human cerebral circulation, rCBF was measured by the 133Xenon inhalation technique in 26 patients with Parkinson's disease before and after the chronic oral administration of levodopa combined with a peripheral Dopa-decarboxylase inhibitor. Treatment with levodopa did not induce significant alterations in the mean brain, mean hemispheric or regional flow values in these patients. These findings suggest that the dopaminergic system does not play an important role in modulation of the rCBF in man.