The comparison of the impact of ghrelin and tacrolimus on vitreous cytokine levels in an experimental uveitis model.
We aimed to compare the effects of intraperitoneal ghrelin and tacrolimus on vitreous levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) in an experimental autoimmune uveitis model. Twenty-four male rats, each weighing 300 g, were assigned into four groups, six rats in each. All the rats, except for those in group 1, were injected intravitreally with concanavalin a to induce experimental uveitis. The development of uveitis was confirmed by the histopathologic examination of two rat globes from each group. The rats in group 2 were not given any treatment after uveitis was induced. The rats in group 3 were administered 1 mg/kg/day of intraperitoneal tacrolimus on days 0, 1, 3, 5 and 7 following the induction of uveitis (on the 14th day of study). The rats in group 4 were given 10 ng/kg/day of intraperitoneal ghrelin for 7 days following the induction of uveitis. On the 21st day of the study, all rats were sacrificed, and the eyes enucleated were subjected to histopathologic examination. Vitreous levels of TNF-α, IL-1 and IL-6 were measured by the enzyme-linked immunosorbent assay method. The histopathologic evaluation carried out to confirm the development of uveitis revealed destruction in the retinae and ciliary bodies of the immunized rats. The mean vitreous levels of TNF-α, IL-1 and IL-6 were significantly higher in the sham group than in the control group (p < 0.05). The levels of these three cytokines showed a significant decrease in the tacrolimus treatment group (p < 0.05). Cytokine levels decreased in the ghrelin treatment group relative to the control group; however, the decrease was not found statistically significant (p > 0.05). Tacrolimus could be effective in uveitis treatment by neutralizing or decreasing the levels of cytokines such as TNF-α, IL-1 and IL-6 that have a critical part in the pathogenesis of uveitis. However, ghrelin failed to produce the desired effect. Further studies using different doses and different ways of administration are needed to determine the effective dose of ghrelin in uveitis.


Normal weight central obesity and hypertension in India: Cross-sectional finding from LASI, 2017-19.
The current public health guidelines for preventing and managing obesity still emphasize the importance of maintaining a normal Body Mass Index, while paying little attention to central obesity, which is common among the general population. Normal Weight Central Obesity (NWCO) is a less explored risk factor for hypertension in India. Therefore, this study aims to investigate the prevalence of NWCO and its association with hypertension in India. The cross-sectional study used data from the Longitudinal Aging Study in India (LASI), 2017-19, which included 54,016 participants (22,438 men and 31,578 women). Hypertension was evaluated following the JNC-VIII guidelines for the detection, evaluation, and treatment of hypertension. Anthropometric measurements were taken to identify NWCO. The study found that NWCO was more prevalent among women (33.9%) than men (17.8%), while men had a higher prevalence of hypertension (47.6%) than women (43.8%). In India, the state of Haryana had the highest proportion of NWCO among men (26.4%), while Kerala had the highest proportion among women (39.1%). Binary logistic regression analysis showed that NWCO was significantly associated with an increased risk of hypertension. The odds ratio (aOR) was 1.57 (95% CI 1.45-1.67, p < 0.001) in men and 1.53 (95% CI 1.43-1.63, p < 0.001) in women, compared to normal-weight study participants. The study emphasizes the importance of considering central obesity in individuals with a normal BMI when assessing cardiovascular risk, particularly for hypertension. State-specific data can help identify high-risk areas and facilitate targeted prevention and treatment strategies.


Results of targeted temperature management of patients after sudden out‑of‑hospital cardiac arrest: a comparison between intensive general and cardiac care units.
Targeted temperature management (TTM) is used to treat patients after sudden out‑of‑hospital cardiac arrest (OHCA). The aim of the study was to compare the results of TTM between intensive general and cardiac care units (ICCUs). The Polish Registry of Therapeutic Hypothermia obtained data on 377 patients with OHCA from 26 centers (257 and 120 patients treated at the ICCU and intensive care unit [ICU], respectively). Eligibility for TTM was based on the current inclusion criteria for therapy. Medical history as well as data on TTM and additional treatment were analyzed. The main outcomes included in‑hospital survival and complications as well as neurologic assessment using the Glasgow Coma Scale (GCS) and Rankin scale. Both ICU and ICCU patients were mostly male (mean age, 60 years). There were no significant differences regarding the medical history, mechanism of arrhythmia responsible for OHCA, GCS score on admission, time of cardiopulmonary resuscitation activities, and the time to target temperature (33°C). Coronary angiography and the use of dual antiplatelet therapy, intra‑aortic balloon pump, intravascular hypothermia, dopamine, and dobutamine were more common in ICCU patients, while ICU patients more often received norepinephrine. Pneumonia and acute renal failure were more frequent in the ICCU group. Death occurred in 17% and 20% of ICU and ICCU patients, respectively (P = 0.57). The Rankin class after 48 hours since discontinuation of sedation and at discharge was comparable between groups. The ICCU has become a considerable alternative to the ICU to treat OHCA patients with TTM.


Heterosocial competence of rapists and child molesters: a meta-analysis.
A meta-analysis of 119 effect sizes from 14 papers examined the heterosocial competence of sex offenders. Rapists had significantly lower heterosocial competence than non-sex-offenders, but this effect was relatively small. Rapists in prison differed from non-sex-offenders who were not in prison; however, they did not differ from non-sex-offending prisoners. When unreliable measures were excluded from the analysis, nonincarcerated students and other volunteers who reported committing rape did not differ from nonincarcerated non-sex-offenders. The difference in heterosocial competence between child molesters and non-sex-offenders was significantly larger than the difference between rapists and non-sex-offenders. Also, child molesters had significantly less heterosocial competence than rapists. Findings clarify the relationship between heterosocial competence, rape, and child sexual abuse. Implications for the research and treatment of sex offenders are discussed.


A new analytical application of nylon-induced room-temperature phosphorescence: determination of thiabendazole in water samples.
This paper discusses the first analytical determination of the widely used fungicide thiabendazole by nylon-induced phosphorimetry. Nylon was investigated as a novel solid-matrix for inducing room-temperature phosphorescence of thiabendazole, which was enhanced under the effect of external heavy-atom salts. Among the investigated salts, lead(II) acetate was the most effective in yielding a high phosphorescence signal. An additional enhancement of the phosphorescence emission was attained when the measurements were carried out under a nitrogen atmosphere. There was only a moderate increase in the presence of cyclodextrins. The room-temperature phosphorescence lifetimes of the adsorbed thiabendazole were measured under different working conditions and, in all cases, two decaying components were detected. On the basis of the obtained results, a very simple and sensitive phosphorimetric method for the determination of thiabendazole was established. The analytical figures of merit obtained under the best experimental conditions were: linear calibration range from 0.031 to 0.26 microg ml(-1) (the lowest value corresponds to the quantitation limit), relative standard deviation, 2.4% (n=5) at a level of 0.096 microg ml(-1), and limit of detection calculated according to 1995 IUPAC Recommendations equal to 0.010 microg ml(-1) (0.03 ng/spot). The potential interference from common agrochemicals was also studied. The feasibility of determining thiabendazole in real samples was successfully evaluated through the analysis of spiked river, tap and mineral water samples.


Disability, compensatory behavior, and innovation in free-ranging adult female Japanese macaques (Macaca fuscata).
Little is known about consequences of disability in nonhuman primates, yet individuals with disabilities can reveal much about behavioral flexibility, innovation, and the capabilities of a species. The Macaca fuscata population surrounding the Awajishima Monkey Center has experienced high rates of congenital limb malformation for at least 40 years, creating a unique opportunity to examine consequences of physical impairment in situ, in a relatively large sample of free-ranging adult monkeys. Here we present behavioral data on 11 disabled adult females and 12 nondisabled controls from 279 hours of randomly ordered 30-minute focal animal follows collected during May-August in 2005, 2006, and 2007. We quantified numerous statistically significant disability-related behavioral differences among females. Disabled females spent less time begging for peanuts from tourists, and employed a behavioral variant of such peanut begging; they had a lower frequency of hand use in grooming and compensated with increased direct use of the mouth or a two-arm pinch technique; and they had a higher frequency of self-scratching, and more use of feet in self-scratching. Self-scratching against substrates was almost exclusively a disability associated behavior. Two females used habitual bipedalism. These differences not withstanding, disabled females behaved similarly to controls in many respects: overall reliance on provisioned and wild foods, time spent feeding, and feeding efficiency did not differ among females, and there was no time difference in behavior performed arboreally or terrestrially. Disabled adult females were able to compensate behaviorally to perform social and life-sustaining activities, modifying existing behaviors to suit their individual physical situations and, occasionally, inventing new ways of doing things.


Examination of the Biceps Tendon.
The examination of the shoulder for conditions involving the biceps tendon continues to be challenging. Numerous examination tests for biceps and superior labrum anterior and posterior (SLAP) lesions have been scientifically evaluated. This section reports on how to perform these tests and summarizes the clinical utility of the tests. Many of the tests for the examination of the biceps and for SLAP lesions do not have high sensitivity and specificity, which limits their usefulness. Although the dynamic shear test has promise for making the diagnosis of SLAP lesions, the studies reporting its clinical utility are disparate.


Types of diet, obesity, and incident type 2 diabetes: Findings from the UK Biobank prospective cohort study.
To investigate the associations between types of diet and incident type 2 diabetes and whether adiposity mediated these associations. In total, 203 790 participants from UK Biobank (mean age 55.2 years; 55.8% women) without diabetes at baseline were included in this prospective study. Using the dietary intake data self-reported at baseline, participants were categorized as vegetarians (n = 3237), fish eaters (n = 4405), fish and poultry eaters (n = 2217), meat eaters (n = 178 004) and varied diet (n = 15 927). The association between type of diet and incident type 2 diabetes was investigated using Cox-proportional hazards models with a 2-year landmark analysis. The mediation role of adiposity was tested under a counterfactual framework. After excluding the first 2 years of follow-up, the median follow-up was 5.4 (IQR: 4.8-6.3) years, during which 5067 (2.5%) participants were diagnosed with type 2 diabetes. After adjusting for lifestyle factors, fish eaters (HR 0.52 [95% CI: 0.39-0.69]) and fish and poultry eaters (HR 0.62 [95% CI: 0.45-0.88]) had a lower risk of incident type 2 diabetes compared with meat eaters. The association for vegetarians was not significant. Varied diet had a higher risk of type 2 diabetes. Obesity partially mediated the association of fish (30.6%), fish and poultry (49.8%) and varied (55.2%) diets. Fish eaters, as well as fish and poultry eaters, were at a lower risk of incident type 2 diabetes than meat eaters, partially attributable to lower obesity risk.


The protective effect of rivaroxaban with or without aspirin on inflammation, oxidative stress, and platelet reactivity in isoproterenol-induced cardiac injury in rats.
Coronary artery diseases are principal sources of mortality and disability in global human population. Progressively, rivaroxaban is being evaluated for the prevention of atherosclerotic thrombi, particularly with anti-platelet agents. Hence, the current report aimed to investigate the cardioprotective effect of rivaroxaban on isoproterenol (ISO)-induced cardiac injury model in rats and the possible synergistic effect when combined with aspirin. Male Wistar rats were randomly assigned into five different groups. Cardiac injury was induced by subcutaneous injection of ISO (85 mg/kg) for 2 consecutive days. Rat tail bleeding time was performed prior to sacrifice. Cardiac enzymes, platelet activity, inflammatory, and oxidative stress biomarkers levels were measured using enzyme-linked immunoassay (ELISA). Pre-administration of rivaroxaban alone and on combination with aspirin prevented ISO-induced increase in cardiac thiobarbituric acid reactive substances (TBARS), interleukin 6 (IL-6), and thromboxane B2 (TXB2) levels. Moreover, a significant prolongation of bleeding time was demonstrated among aspirin, rivaroxaban, and aspirin plus rivaroxaban treated groups. On the other hand, the combination treatment of aspirin plus rivaroxaban showed no marked difference in these biomarkers and bleeding time relative to either drug administered separately. However, a prominent decrease of cardiac 6-keto prostaglandin F1α (6-Keto-PGF1α) level was displayed in the combination treatment when compared with ISO and rivaroxaban-treated groups, whereas no significant improvement was seen in cardiac glycoprotein V (GPV) levels except in aspirin-treated group. The study results demonstrated that rivaroxaban decreases cardiac oxidative stress, inflammation, and platelets reactivity. However, the addition of rivaroxaban to aspirin did not seem to show synergistic antioxidant, anti-inflammatory, or antiplatelet effect.


Preoperative imaging of the lung sentinel lymphatic basin with computed tomographic lymphography: a preliminary study.
Preoperative localization of the sentinel node basin would guide selective lymph node dissection. We tried to identify these nodal stations with indirect computed tomographic lymphography using a conventional extracellular contrast agent, iopamidol. Eleven consecutive patients scheduled to undergo anatomic resection of suspected lung cancer, without lymphadenopathy, were given a peritumoral injection of undiluted iopamidol under computed tomography guidance, and lymphatic migration was assessed by multidetector-row helical computed tomography. There were no complications such as bleeding, pneumothorax, or allergic reactions. Enhanced nodes were detected in all but 1 patient who had diffuse lymph nodal calcification. Enhanced nodes were identified at 32 ipsilateral intrathoracic nodal stations (20 hilar stations and 12 mediastinal stations). The average length of the longer axis of the enhanced nodes was 4.8 mm (range, 3 to 8 mm), and the average attenuation of the enhanced nodes was 132 (range, 46 to 261) Hounsfield units. In 9 patients with confirmed lung cancer, enhanced nodes appeared at 26 nodal stations, and all apparent enhanced nodes were identified as actual lymph nodes at appropriate position during lymphadenectomy. None of the resected lymph nodes had metastatic involvement. Indirect computed tomographic lymphography with the peritumoral injection of iopamidol effectively depicts the drainage nodes unless they are diffusely calcified. Although further study is required, this method could guide selective lymph node dissection.


Does prior sustained compression make cartilage-on-bone more vulnerable to trauma?
This study investigated how varying levels of prior creep deformation in cartilage-on-bone samples influences their mechanical response and vulnerability to structural damage following a single traumatic impact. Bovine patellae were subjected to varying intervals of prior creep loading at a constant stress of 4MPa. Immediately following removal of this stress the samples were impacted with a pendulum indenter system at a fixed energy of 2.2J. With increasing prior creep, the peak force on impact rose, the duration of impact and time to reach peak force both decreased, and both the energy dissipated during impact and the magnitude of impulse were both unchanged by the level of prior creep. With increasing prior creep, the severity of impact-induced osteochondral damage increased: articular cartilage cracks penetrated to a greater depth, extending to the calcified cartilage layer resulting in hairline fractures or articular cartilage delamination and associated secondary damage to the vascular channels in the subchondral bone. The study shows that exposure of the cartilage-on-bone system to prior creep can significantly influence its response to subsequent impact, namely force attenuation and severity of damage to the articular cartilage, calcified cartilage and vascular channel network in the subchondral bone.


Selective amplification in methotrexate-resistant mouse cells of an artificial dihydrofolate reductase transcription unit making use of cryptic splicing and polyadenylation sites.
We have constructed a recombinant ( pMOP ) which is based on the bacterial plasmid pML2 and contains bovine papilloma virus type 1 (BPV 1) sequences linked to an artificial mouse dihydrofolate reductase (DHFR) transcription unit. This unit consists of the SV40 early gene promoter, a complete DHFR coding sequence and splice and polyadenylation sites from a rabbit beta-globin gene. Intact pMOP or a fragment thereof devoid of pML2 sequences will transform mouse cells to methotrexate resistance. The lines obtained contain approximately 200 copies of the DHFR transcription unit. In no case, however, did we find evidence of extrachromosomal maintenance of BPV 1 or DHFR sequences. One line, when selected for resistance to elevated levels of methotrexate, contained amplified copies of a 'novel' DHFR transcription unit resulting from fusion of two normal units. This line contained the DHFR RNA species present in the parent line plus some additional species. The structure of these various RNA species was determined and evidence found for the use of cryptic splice and polyadenylation sites.


Integrated [18F]FDG PET/MRI demonstrates the iron-related bone-marrow physiology.
We identified predictors for bone-marrow [18F]FDG uptake and MR signals among complete blood count, C-reactive protein (CRP), and anthropometric factors, and demonstrated the bone-marrow physiology using integrated [18F]FDG-PET/MRI. 174 oncology patients without bone-marrow lesions underwent whole-body [18F]FDG-PET/MRI. The standardized uptake value (SUV), apparent diffusion coefficient (ADC), proton density fat-fraction (PDFF), and a reciprocal of T2* relaxation time (R2*) were measured in lumbar vertebrae (L3-5) and bilateral ilia. Vertebrae, pelvis, and ribs were evaluated by 3-point visual scoring on DWI. The association of the PET/MR features with the predictors was examined. Multi-regression analyses identified CRP as the strongest predictor for lumbar and iliac SUVs (standardized coefficient: β = 0.31 and β = 0.38, respectively), and for lumbar and iliac R2* (β = 0.31 and β = 0.46, respectively). In contrast, age was the strongest factor influencing lumbar and iliac ADCs (β = 0.23 and β = 0.21, respectively), and lumbar and iliac PDFFs (β = 0.53 and β = 0.54, respectively). Regarding DWI-visual scores, age was the strongest predictor for vertebrae (β = - 0.47), and the red cell distribution width (RDW) was the strongest predictor for pelvis and ribs (β = 0.33 and β = 0.47, respectively). The bone-marrow [18F]FDG uptake and R2* reflect anemia of inflammation (increased granulopoiesis and reduced iron metabolism), whereas bone-marrow DWI and PDFF reflect age and anemia-responsive erythropoiesis.


The Pharmacological Costs of Second-Line Treatments for Recurrent Ovarian Cancer.
In ovarian cancer, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrence; therefore, it might be interesting to make a balance between the cost of the drugs administered and the difference in progression-free survival (PFS) and overall survival (OS). The present evaluation was restricted to pivotal phase 3 randomized controlled trials. We calculated the pharmacological costs necessary to get the benefit in PFS and OS. The costs of drugs are at the pharmacy of our hospital and are expressed in Euros (&OV0556;). We have subsequently applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale. Our study evaluated 3 phase 3 randomized controlled trials, including 2004 patients. The most relevant increase of costs was associated with the combination chemotherapy including trabectedin, with the highest costs for month of PFS gained (15,836 &OV0556;) and for month of OS gained (7198 &OV0556;), but it substantially differs considering the data of partially platinum-sensitive populations (platinum-free interval of 6-12 months), with 3959 &OV0556; for month of OS gained. The addition of trabectedin to pegylated liposomal doxorubicin for the treatment of recurrent ovarian cancer can lead to an increase of pharmacological costs. Differently, considering OS in patients with platinum-free interval of 6 to 12 months, there is a halving of pharmacological costs with the addition of trabectedin to pegylated liposomal doxorubicin. These costs are in line with the spending suggested as sustainable (thresholds of <$61,500 per life-year gained).


Nonincisional blepharoplasty using the debulking method.
As more women work outside home, a growing number of women who want to have a natural-looking double eyelid choose the method with a short healing time and less pain. Thus blepharoplasty by the nonincisional method is performed frequently. This technique uses 7-0 nylon for simple triple ring-shaped or center doubled triple ring-shaped suture, with removal of subcutaneous fat, pretarsal muscle, and orbital septum through small incisions. This prevents the possibility that the folds will be loosened. By creation of a scar adhesion between the wider portion of the dermis and the tarsal plate after debulking of the soft tissue, the nonincisional method can be applied to a very thin eyelid without any difficulty.A retrospective review of the data for 327 patients who underwent nonincisional blepharoplasty using the debulking method from November 24, 2000 through March 9, 2003 is presented. Except for four cases, the procedures were successful. Two complications of conjunctivitis occurred, requiring removal of the buried suture, and two patients reported a mild scar.


Exome sequencing findings in children with annular pancreas.
Annular pancreas (AP) is a congenital defect of unknown cause in which the pancreas encircles the duodenum. Theories include abnormal migration and rotation of the ventral bud, persistence of ectopic pancreatic tissue, and inappropriate fusion of the ventral and dorsal buds before rotation. The few reported familial cases suggest a genetic contribution. We conducted exome sequencing in 115 affected infants from the California birth defects registry. Seven cases had a single heterozygous missense variant in IQGAP1, five of them with CADD scores >20; seven other infants had a single heterozygous missense variant in NRCAM, five of them with CADD scores >20. We also looked at genes previously associated with AP and found two rare heterozygous missense variants, one each in PDX1 and FOXF1. IQGAP1 and NRCAM are crucial in cell polarization and migration. Mutations result in decreased motility which could possibly cause the ventral bud to not migrate normally. To our knowledge, this is the first study reporting a possible association for IQGAP1 and NRCAM with AP. Our findings of rare genetic variants involved in cell migration in 15% of our population raise the possibility that AP may be related to abnormal cell migration.


Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women.
Several genes associated with sporadic Alzheimer's disease have been identified; however, approximately 50% of genetic factors remain unidentified. We investigated whether estrogen receptor 1 (ESR1) polymorphisms are associated with risk of developing cognitive impairment in older women. A total of 2625 women > or = 65 years of age completed a modified Mini-Mental Status Exam (mMMSE) at baseline and at 6-8 years of follow-up. We defined cognitive impairment as a mMMSE decline of > or = 3 points, follow-up score < or = 20, or a history of physician-diagnosed dementia. The ESR1 polymorphisms, PvuII (P or p) and XbaI (X or x), were coded so that the capital letter signifies the absence of the restriction site. Women with a p allele had a greater age, education, and baseline-score adjusted decline in mMMSE (for PP, Pp, and pp, respectively:.6 +/-.1,.8 +/-.1, and.9 +/-.1 points, p for trend =.01); women with at least one x allele also had greater score decline (XX, Xx, and xx:.7 +/-.1,.7 +/-.1, and.9 +/-.1 points, p for trend =.02). Six percent (n = 166) of the women developed cognitive impairment. Compared to those who did not develop impairment, more women who developed cognitive impairment had a p allele (62% vs. 56%, p =.03; adjusted odds ration (OR) = 1.33; 95% confidence interval [CI], 1.03-1.72) or an x allele (70% vs. 64%, p =.03; adjusted OR = 1.38; 95% CI, 1.06-1.81). There was no interaction with current estrogen use, or with serum estradiol level and ESR1 polymorphisms (p >.10). Estrogen receptor 1 polymorphisms are associated with risk of developing cognitive impairment. More research is needed to determine the mechanism whereby ESR1 polymorphisms or linked genes influence cognitive function in older women.


The effects of oral alanine administration on blood glucose, pyruvate, lactate, serum glucagon and insulin in human newborns.
Alanine (500 mg/kg body weight) was given orally to 27 healthy full term newborn infants, and the changes in blood glucose, pyruvate, lactate, alanine, glucagon and insulin were determined. Significant increments in blood glucose were found in 15 infants with blood glucose levels below 60 mg/100 ml, 4 of whom showed significant elevation of serum glucagon levels on day 1. This observation suggests that hepatic gluconeogenesis is possible immediately after birth.


Pattern Formation on Networks: from Localised Activity to Turing Patterns.
Networks of interactions between competing species are used to model many complex systems, such as in genetics, evolutionary biology or sociology and knowledge of the patterns of activity they can exhibit is important for understanding their behaviour. The emergence of patterns on complex networks with reaction-diffusion dynamics is studied here, where node dynamics interact via diffusion via the network edges. Through the application of a generalisation of dynamical systems analysis this work reveals a fundamental connection between small-scale modes of activity on networks and localised pattern formation seen throughout science, such as solitons, breathers and localised buckling. The connection between solutions with a single and small numbers of activated nodes and the fully developed system-scale patterns are investigated computationally using numerical continuation methods. These techniques are also used to help reveal a much larger portion of of the full number of solutions that exist in the system at different parameter values. The importance of network structure is also highlighted, with a key role being played by nodes with a certain so-called optimal degree, on which the interaction between the reaction kinetics and the network structure organise the behaviour of the system.


Mesoporous silica-based versatile theranostic nanoplatform constructed by layer-by-layer assembly for excellent photodynamic/chemo therapy.
Supramolecular photosensitizers (supraPSs) have emerged as effective photodynamic therapy (PDT) agents. Here, we propose the assembling capacity of supraPSs as a new strategy to construct theranostic nanoplatform with versatile functions aming at high-performance tumor therapy. By coating tirapazamine (TPZ)-loaded mesoporous silica nanoparticles (MSNs) with layer-by-layer (LbL) assembled multilayer, the versatile nanoplatform (TPZ@MCMSN-Gd3+) was obtained with the formation of supraPSs via host-guest interaction and the chelation with paramagnetic Gd3+. The TPZ@MCMSN-Gd3+ could be specifically uptaken by CD44 receptor overexpressed tumor cells and respond to hyaluronidase (HAase) to trigger the release of therapeutics. As confirmed by in vivo studies, TPZ@MCMSN-Gd3+ showed preferential accumulation in tumor site and significantly inhibited the tumor progression by the collaboration of PDT and bioreductive chemotherapy under NIR fluorescence/MR imaging guidance. Taken together, this supraPSs based strategy paves a new paradigm of the way for the construction of theranostic nanoplatform.


A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association.
RAC1 at 7p22.1 encodes a RAC family small GTPase that regulates actin cytoskeleton organization and intracellular signaling pathways. Pathogenic RAC1 variants result in developmental delay and multiple anomalies. Here, exome sequencing identified a rare de novo RAC1 variant [NM_018890.4:c.118T > C p.(Tyr40His)] in a male patient. Fetal ultrasonography indicated the patient to have multiple anomalies, including persistent left superior vena cava, total anomalous pulmonary venous return, esophageal atresia, scoliosis, and right-hand polydactyly. After birth, craniofacial dysmorphism and esophagobronchial fistula were confirmed and VACTERL association was suspected. One day after birth, the patient died of respiratory failure caused by tracheal aplasia type III. The molecular mechanisms of pathogenic RAC1 variants remain largely unclear; therefore, we biochemically examined the pathophysiological significance of RAC1-p.Tyr40His by focusing on the best characterized downstream effector of RAC1, PAK1, which activates Hedgehog signaling. RAC1-p.Tyr40His interacted minimally with PAK1, and did not enable PAK1 activation. Variants in the RAC1 Switch II region consistently activate downstream signals, whereas the p.Tyr40His variant at the RAC1-PAK1 binding site and adjacent to the Switch I region may deactivate the signals. It is important to accumulate data from individuals with different RAC1 variants to gain a full understanding of their varied clinical presentations.


Medical expert systems: design and applications in pulmonary medicine.
Expert systems are computer applications with a built-in knowledge of a special field to solve problems like a human expert on this subject. An expert system consists of an inference component for problem specification and solving, a knowledge base for storage of data, facts, rules and heuristics, an interface for knowledge acquisition, another for the interaction with the user, and a component for reasoning. Pulmonary expert systems are used for automatic interpretations of lung function data which are measured on-line and directly computed. There are also some expert systems for consultation in difficult pulmonary cases and for protection against overlooking rare diseases. Perhaps the most successful applications of pulmonary expert systems are for educational purposes and a large variety of teachware is available. Pulmonary expert systems are presently limited to small applications; often it is necessary to type in large amounts of data and to follow a deeply structured cumbersome dialog. Also, the problem of responsibility for computer decisions has to be mentioned. But pulmonary expert systems as integrated supplements of normal pulmonary measuring devices, as decision support, and as parts of pulmonary teachware will be helpful tools for the pneumological physician.


DNA methylation for cervical cancer screening: a training set in China.
Despite rapid improvements in DNA methylation tools for cervical cancer screening, few robust, exploratory studies have been performed using the combination of two host genes, EPB41L3 and JAM3, newly developed assays. A review of abnormal liquid-based cytology and/or high-risk human papillomavirus (hrHPV) data from outpatient clinics in the study center from March 2018 to March 2019 was performed. Eligible patients with definitive histological pathology results were included, and their residual cytology samples were assessed for EPB41L3 and JAM3 methylation. The diagnostic accuracies of various screening strategies for definitive pathology and for cervical intraepithelial neoplasia (CIN) 2 or more severe lesions (CIN2+) were compared. In total, 306 patients were successfully tested; 301 cases with cervical histological pathology were included in the final analysis, including 118 (39.2%) and 183 (60.8%) cases of inflammation/CIN1 and CIN2+, respectively. Regarding CIN2+ detection, methylation status and hrHPV plus methylation had similar positive predictive values (0.930 and 0.954, respectively, p = 0.395). Additionally, hrHPV, methylation, and hrHPV plus methylation had similar negative predictive values (0.612, 0.679, and 0.655, p = 0.677) that were significantly higher than that of cytology alone (0.250, p values 0.012, 0.001, and 0.001, respectively). For 49 cases with negative hrHPV results, positive methylation alone was able to differentiate CIN2+ from inflammation/CIN1. Methylation of both EPB41L3 and JAM3 is an accurate and feasible screening method for CIN2+.


Prevalence and determinants of adult consumer use and comprehension of food labels in sub-Saharan Africa: a systematic review and meta-analysis.
Food labelling is a global strategy recommended to reduce noncommunicable diseases. Few reviews, however, have focused on food label use in sub-Saharan Africa (SSA). To determine the prevalence of food label use and describe determinants of food label use and purchasing decisions of adult consumers in SSA. PubMed (Medline), Web of Science, Cochrane Central, and Google Scholar databases. Search criteria included adults (aged ≥18 years), conducted in SSA, focusing on food label use or understanding and their determinants or determinants of food-purchasing decisions, and articles published in English. Risk-of-bias assessment of included studies was done using the Joann Briggs Institute checklist for prevalence studies. Publication bias was assessed using funnel plots and Egger's test. Analysis included narrative synthesis and moderator and meta-analyses of food label use. A total of 124 articles were found, of which 21 were included in the review. Of participants in the selected studies, 58% were female. About 80% reported food label use (either used sometimes or always) (70%-88%) (I2 = 97%; n = 6223), and regular use was estimated at 36% (28%-45%) (I2 = 97%; n = 5147). Food label use was influenced by level of income, education, employment status, and household size. Food-purchasing decisions were influenced by attributes such as expiry dates, price, and taste. Major recommendations reported were tailored education campaigns and reducing barriers to food label use. Most (80%) of adults in SSA reported using food labels; however, only about one-third used them consistently. Demographic and situation factors determined patterns in food label use, whereas product attributes influenced food purchasing decisions. Complexity of these determinants requires adopting tailored, multisectoral, theory-driven programs to improve food label use. Open Science Framework (https://osf.io/kc562).


Defining Collective Priorities: Research and Learning Agendas for Family Planning Across 6 Countries.
Evidence should be the foundation for a well-designed family planning (FP) program, but existing evidence is rarely aligned with and/or synthesized to speak directly to FP programmatic needs. Based on our experience cocreating FP research and learning agendas (FP RLAs) in Côte d'Ivoire, Malawi, Mozambique, Nepal, Niger, and Uganda, we argue that FP RLAs can drive the production of coordinated research that aligns with national priorities.To cocreate FP RLAs, stakeholders across 6 countries conducted desk reviews of 349 documents and 106 key informant interviews, organized consultation meetings in each country to prioritize evidence gaps and generate research and learning questions, and, ultimately, formed 6 FP RLAs comprising 190 unique questions. We outline the process for consensus-driven development of FP RLAs and communicate the results of an analysis of the questions in each FP RLA across 4 technical areas: self-care, equity, high impact practices, and youth. Each question was categorized as a learning versus research question, the former indicating an opportunity to synthesize existing evidence and the latter to conduct new research to answer the question. Themes emerging from the data shed light on shared evidence gaps across the 6 countries. We argue that similarities and differences in the questions in each FP RLA reflect the unique implementation experience and context, as well as each country's placement on the FP S-curve. Early uses of the FP RLAs include informing the development of FP costed implementation plans and FP2030 commitments. FP RLAs have also been discussed in multiple thematic working groups. For FP stakeholders, these FP RLAs represent a consensus-based agenda that can guide the generation and synthesis of evidence to answer each country's most pressing questions, ultimately driving progress toward increasingly evidence-based programming and policy.


Reproducibility and diagnostic accuracy of three-layer speckle tracking echocardiography in a swine chronic ischemia model.
The subendocardial myocardium normally has higher systolic strain than the subepicardial myocardium and can be damaged first in face of ischemia. We investigated the reproducibility and feasibility of novel three-layer speckle tracking system and compared the diagnostic accuracy with experienced visual interpretation. An ameroid constrictor was placed around the proximal left circumflex (LCX) coronary artery in 19 pigs. Four weeks later, subtotal stenosis was confirmed in all pigs by coronary angiogram. Two dead pigs and three pigs with pathological infarction were excluded. Transthoracic left ventricle (LV) short-axis echocardiograms were recorded at rest before and 4 weeks after the operation. LV posterior wall motion was scored by two experienced doctors and analyzed by the speckle tracking system (n = 14). Strain variables gave reasonable intra/interobserver reproducibility (mean absolute percentage errors = 13/19, intraclass correlation coefficients = 0.97/0.92). All strain variables and visual wall-motion scores changed significantly during stenosis (P < 0.05). Of all variables, endocardial strains, particularly the circumferential strain demonstrated the highest area under curve (AUC), showing better diagnostic accuracy than experienced visual interpretation (sensitivity 0.93 vs. 0.79, specificity 0.93 vs. 0.73, AUC 0.95 vs. 0.77, P < 0.05). Three-layer speckle tracking is a feasible and reproducible modality. In particular, endocardial speckle tracking provides incremental value in accurately identifying regional ischemia even in the rest echocardiography.


Advanced liver fibrosis by transient elastography, fibrosis 4, and alanine aminotransferase/platelet ratio index among Asian hepatitis C with and without human immunodeficiency virus infection: role of vitamin D levels.
Vitamin D insufficiency plays an important role in liver fibrosis in hepatitis C virus (HCV)-infected patients. We assessed liver fibrosis by transient elastography and 25 hydroxy vitamin D [25(OH)D] status in HCV-infected patients, with (HIV/HCV) or without HIV co-infection (HCV) from Thailand. Fibrosis stage was defined as mild (< 7.1 kPa); moderate (7.2-9.4 kPa); severe (9.5-14 kPa), and cirrhosis (> 14 kPa). Hypovitaminosis D was defined as 25(OH)D < 30 ng/mL. Logistic regression analyses were used to assess predictors for significant fibrosis. Serum 25(OH) D levels, HCV genotypes (GT), interleukin-28B (IL28B) and HCV-RNA were assessed. A total of 331 HCV and 130 HIV/HCV patients were enrolled (70% male, 35% people who inject drugs [PWIDs]). HCV GT distribution was as follows: GT3 47%, GT1 34%, GT6 17%. IL-28B CC genotype (rs12979860) were found in 88% of HIV/HCV and 85% of HCV. In HCV, liver fibrosis was mild in 56.5%; moderate in 18.4%; severe in 12.4%; and cirrhosis in 12.7%. In HIV/HCV, these figures were 30.6%, 27.8%, 17.6%, and 24.1%, respectively. Patients with significant fibrosis were more often male, older, with HIV infection, hypovitaminosis D, and less likely to be infected with GT6. Factors associated with significant fibrosis by multivariate analysis were HIV infection (adjusted odd ratio [95% confidential interval]: 2.67, 1.20-5.93), P = 0.016, Fib-4 score > 1.45 (6.30, 2.70-14.74), P < 0.001, and hypovitaminosis D (2.48, 1.09-5.67), P = 0.031. GT 6 was less likely to have advanced liver fibrosis (0.17, 0.05-0.65), P = 0.01. HIV infection, Fib-4 score > 1.45, and hypovitaminosis D are strong and independent predictors for the presence of advanced fibrosis in our HCV-infected patients. These data highlight the urgent need of HCV treatment and vitamin D supplement in resource-limited settings.


Infectious complications resulting from use of hemostatic puncture closure devices.
Femoral access site complications have increased as the fields of invasive cardiology, radiology, and endovascular surgery have emerged. In order to address one of these complications, hemorrhage, the hemostatic puncture closure devices were developed. Retrospective review of cardiac catheterizations performed at a single institution to investigate infectious groin complications related to use of the Perclose Prostar and Techstar devices. Infectious groin complications were significantly higher in the Perclose group as compared with manual compression. Three patients had clinical and laboratory evidence of arterial infection whereas 2 had soft tissue infections. All 5 required operative intervention ranging from incision and drainage to arterial reconstruction. Hemorrhagic complications were not significantly different between the two groups. The Perclose devices provide hemostasis after femoral artery catheterization similar to manual compression. However, infectious groin complications appear to be more common with these devices.


[Embolization of the internal iliac arteries in the management of critical vaginal bleeding].
Report on the successful embolization of both arteriae iliacae internae in five woman patients with vital vaginal haemorrhages and very advanced gynaecological neoplasms.


Modifying the affective behavior of preschoolers with autism using in-vivo or video modeling and reinforcement contingencies.
The purpose of this study was to modify the affective behavior of three preschoolers with autism in home settings and in the context of play activities, and to compare the effects of video modeling to the effects of in-vivo modeling in teaching these children contextually appropriate affective responses. A multiple-baseline design across subjects, with a return to baseline condition, was used to assess the effects of treatment that consisted of reinforcement, video modeling, in-vivo modeling, and prompting. During training trials, reinforcement in the form of verbal praise and tokens was delivered contingent upon appropriate affective responding. Error correction procedures differed for each treatment condition. In the in-vivo modeling condition, the therapist used modeling and verbal prompting. In the video modeling condition, video segments of a peer modeling the correct response and verbal prompting by the therapist were used as corrective procedures. Participants received treatment in three categories of affective behavior--sympathy, appreciation, and disapproval--and were presented with a total of 140 different scenarios. The study demonstrated that both treatments--video modeling and in-vivo modeling--systematically increased appropriate affective responding in all response categories for the three participants. Additionally, treatment effects generalized across responses to untrained scenarios, the child's mother, new therapists, and time.


Identification of a Pax paired domain recognition sequence and evidence for DNA-dependent conformational changes.
Pax genes encode a family of developmentally regulated transcription factors that have been implicated in a number of human and murine congenital disorders, as well as in tumorigenesis (Gruss, P., and Walther, C. (1992) Cell 69, 719-722; Hill, R., and van Heyningen, V. (1992) Trends Genet. 8, 119-120; Chalepakis, G., Tremblay, P., and Gruss, P. (1992) J. Cell Sci. Suppl. 16, 61-67; Maulbecker, C. C., and Gruss, P. (1993) EMBO J. 12, 2361-2367; Walther, C., Guenet, J. L., Simon, D., Deutsch, U., Jostes, B., Goulding, M. D., Plachov, D., Balling, R., and Gruss, P. (1991) Genomics 11, 424-434; Barr, R. G., Galili, N., Holick, J., Biegel, J. A., Rovera, G., and Emanuel, B. S. (1993) Nature Genet. 3, 113-117). These genes are defined by the presence of an evolutionarily conserved DNA binding domain, termed the paired domain. The structure and the DNA binding characteristics of the paired domain remain largely unknown. We have utilized repetitive rounds of a polymerase chain reaction-based selection method to identify the optimal DNA binding sequences for the Pax-2 and Pax-6 paired domains. The results suggest that the paired domain family of peptides bind similar DNA sequences. Identification of this binding site has revealed an important structural clue regarding the mechanism of paired domain binding to DNA. CD and NMR structural analyses of the purified Pax-6 paired domain reveal it to be largely structureless in solution. Upon binding the recognition sequence, the complex becomes markedly less soluble and displays CD spectroscopic evidence of significant alpha-helical structure.


An ambient-temperature stable nanoparticle-based vaccine for nasal application that confers long-lasting immunogenicity to carried antigens.
Polyhedrins are viral proteins present in a large family of baculoviruses that form occlusion bodies (polyhedra). These structures protect the virus particles from the outside environment until they are ingested by susceptible insects. Occluded viruses can sustain inclement weather for long periods of time. Therefore, the polyhedra is a natural preservative that keeps the viral structure intact at ambient temperature for years. In a previous study we identified the first 110 amino acids from polyhedrin (PH(1-110)) as a good candidate to carry antigens of interest. As a proof of concept, we produced a fusion protein with PH(1-110) and the green fluorescent protein (PH(1-110)GFP). The fusion protein associates spontaneously during its synthesis resulting in the formation of nanoparticles. Nasal immunization with these nanoparticles and in the absence of any adjuvant, results in a robust immune response with the production of IgG immunoglobulins that remained elevated for months and that selectively recognize the GFP but not PH(1-110). These results indicate that PH(1-110) is poorly immunogenic but capable of enhancing the immune response to GFP.


The treatment of metastatic uveal melanoma.
Malignant melanoma can occur in various ocular structures and accounts for 70% of all primary eye malignancies. At the time of initial diagnosis of uveal melanoma, most patients have no demonstrable evidence of metastatic disease. However, within 5 years, metastases appear in 19-35% of patients. The median relapse-free interval for these patients is 2-4 years. Unlike cutaneous melanoma, uveal melanoma most commonly metastasises to the liver. In fact, the liver is the sole site or the initial site of metastasis in more than 50% of patients. This paper reviews major studies that evaluated different treatment options for metastatic uveal melanoma, including surgery, systemic chemotherapy, intra-arterial chemotherapy, chemoembolisation and chemoimmunotherapy. Surgery and systemic chemotherapy offer minimal benefits for these patients. However, the use of intra-arterial fotemustine demonstrated a 40% response rate for patients with liver metastases of uveal melanoma. Additionally, chemoimmunotherapy with a four-drug chemotherapy regimen and interferon alfa has provided response rates of approximately 20% and may contribute to prolonged survival. Ongoing multicentre trials are expected to determine the feasibility of this regimen. The activity of immunotherapy, particularly interferon, encourages its use in combination with other active therapies, such as intra-arterial fotemustine.


Factors complicating treatment sessions in spinal cord injury rehabilitation: nature, frequency, and consequences.
To describe therapist-reported factors affecting therapy sessions in spinal cord injury (SCI) inpatient rehabilitation and explore their impact on the patient's rehabilitation program. Prospective observational longitudinal cohort design. Data were obtained from systematic recordings of interventions by clinicians and from medical record abstraction. Six inpatient rehabilitation programs. Patients (N=1376) with traumatic SCI admitted for initial rehabilitation. Not applicable. Factors recorded as impacting the objective or content of treatment sessions by physical therapy, occupational therapy, speech therapy, and therapeutic recreation, patients' participation in treatment as rated using a modified Pittsburgh Rehabilitation Participation Scale (PRPS), length of stay (LOS), medical morbidity measured using the Comprehensive Severity Index, hours of therapy per week, and missed therapy minutes. Patients received 151,172 treatment sessions from 483 therapists. Pain, fatigue, and spasticity were commonly reported factors; other medical, behavioral, and logistical factors were also frequent, with 30% of sessions being affected by at least 1 factor. The number of factors was correlated with missed therapy minutes and with the PRPS score. Patients with more reported factors, overall or per average session, had a longer LOS and fewer hours of treatment per week. Medical and other factors complicating therapy are common. Those who need a longer stay because of their injury level or for other reasons have more opportunity to have sessions affected, but having many treatment sessions impacted by 1 or more factors also is likely to increase LOS. The nature of these factors and their impact on rehabilitation processes and outcomes deserve further study.


[Breaking unexpected bad news: pilot study on communication style of physicians].
The aim of this study was to explore the physician's communication pattern when breaking a bad unexpected news. 30 videotaped consultations (VRM) were collected in which the physicians met an actress as a patient. The doctors received the x-ray report in which an apical mass was detected before (condition A) or during (condition B) the consultation. The VRM were analysed through the Roter Interaction Analysis System (RIAS). Data suggested in condition B a significant decrease in "process", "counselling" and "emotional" categories. In consultation where a bad unexpected news is communicated doctors seem to be less directive in the content and more emotionally defended.


Infant apnea detection after herniorrhaphy.
To elucidate risk factors for apnea in preterm infants discharged from the hospital and in full-term healthy infants. To determine the efficacy of real-time cardiopulmonary monitoring versus computerized storage and retrieval for infants at risk. Prospective study. Operating rooms and pediatric patient care units of university medical center. 27 preterm infants and 20 full-term infants no more than 60 weeks' post-conceptional age, who were admitted for elective herniorrhaphy. Infants were monitored before and after herniorrhaphy with general anesthesia using an infant apnea impedance monitor, pulse oximetry, and nursing observation. Demographic information and medical history were correlated with postoperative apnea. The sensitivity and specificity of nursing observation and oximetry were compared with computerized apnea monitors. Five patients (11%, four preterm, one full-term) were apneic postoperatively as recorded by computerized pneumocardiography. Previous apnea history, gestational age at birth, and postconceptional age at operation positively correlated with postoperative apnea. Nursing observation failed to detect 4 of 5 patients with documented apnea (sensitivity 20%, positive predictive value 50%). Pulse oximetry failed to detect 3 of 5 patients with apnea (sensitivity 40%, positive predictive value 66%). Although it is easier to predict postoperative respiratory dysfunction in previously sick or very young infants, absolute predictability for all neonates remains elusive. Clinical monitors with both storage and retrieval capabilities and real-time monitoring increase our ability to detect significant events in children at risk for apnea after herniorrhaphy.


Profiles of Independent-Comorbidity Groups in Senior COVID-19 Patients Reveal Low Fatality Associated with Standard Care and Low-Dose Hydroxychloroquine over Antivirals.
The lack of feasible therapies and comorbidities aggravate the COVID-19 case-fatality rate (CFR). However, reports examining CFR associations with diabetes, concomitant cardiovascular diseases, chronic kidney disease, and chronic liver disease (CLD) are limited. More studies assessing hydroxychloroquine (Hcq) and antivirals are needed. To examine associations of COVID-19 CFR in comorbid patient groups each with single comorbidities and after treatment with Hcq, favipiravir, and dexamethasone (Dex), either alone or in combination versus standard care. Using statistical analysis, we descriptively determined these associations among 750 COVID-19 patient groups during the last quarter of 2021. A diabetes comorbidity (40%, n=299) showed twice the fatality (CFR 14%) of the others (CFR 7%; P=0.001). Hypertension (Htn) was the second-commonest comorbidity (29.5%, n=221), with similar CFR to diabetes (15% and 7% for Htn and non-Htn, respectively), but with higher significance (P=0.0006167). Although only 4% (n=30) heart failure (HF) was reported, the CFR (40%) was much higher than in those without it (8%). A similar rate (4%) for chronic kidney disease was reported, with CFRs of 33% and 9% among those with and without it, respectively (P=0.00048). Ischemic heart disease was 11% (n=74), followed by chronic liver disease (0.4%) and history of smoking (1%); however, these were not significant due to the sample sizes. Treatment indicated standard care and Hcq alone or in combination were superior (CFR of 4% and 0.5%, respectively) compared to favipiravir (25%) or Dex (38.5%) independently or in combination (35.4%). Furthermore, Hcq performed well (CFR 9%) when combined with Dex (9%; P=4.28-26). The dominance of diabetes and other comorbidities with significant association with CFR implied existence of a common virulence mechanism. The superiority of low-dose Hcq and standard care over antivirals warrants further studies.


Ethnic differences in creatinine kinetics in a New Zealand end-stage kidney disease cohort.
Recent data have suggested that glomerular filtration rate (GFR) is better predicted in New Zealand (NZ) Māori and Pacific People using the equations for Black people that predict higher GFR for any given serum creatinine. We hypothesized that this might be due to a higher rate of creatinine generation in NZ Māori and Pacific People. To compare creatinine kinetics between different ethnic groups in a cohort of NZ peritoneal dialysis patients. In this retrospective single-centre observational study, creatinine kinetics in 181 patients were determined from timed serum samples, peritoneal dialysate and urine collections between 1 October 2004 and 31 July 2011. Ethnicity was classified as Asian, NZ European, NZ Māori and Pacific People. A total of 799 samples from 181 patients were analysed: 194 in Asians, 127 in NZ Europeans, 268 in NZ Māori, 207 in Pacific People. Pacific People had the highest serum creatinine and lean body mass, and the highest creatinine generation rate at 1349 mg/day, compared with 1049 for Asians, 1186 for NZ Europeans and 1094 for NZ Māori (P = 0.0001). After adjustment for confounding factors, Pacific People had a greater creatinine generation by 140 mg/day compared with NZ Europeans (P = 0.047). Pacific People on peritoneal dialysis in NZ have higher serum creatinine, lean body mass and creatinine generation than other ethnic groups. This is consistent with previous observations that equations for predicting GFR in Black people may have increased accuracy in some Australasian non-White non-Asian populations.


Serial cross-sectional echocardiographic detection of multiform floating right-heart thromboemboli. A case report.
This report describes a case in which serial cross-sectional echocardiographic examinations allowed us to make the diagnosis and to follow anatomical evolution of pulmonary thromboemboli. Frequent (three times a day for seven days) echocardiographic surveillance of thromboemboli allowed us to assess the effectiveness of the therapeutic approach.


Protogynous functional hermaphroditism in the North American annual killifish, Millerichthys robustus.
Sex change (sequential hermaphroditism) has evolved repeatedly in teleost fishes when demographic conditions mediate fundamentally different sex-specific returns for individuals of particular age and size. We investigated the conditions for potential sex change in an annual killifish (Millerichthys robustus) from temporary pools in Mexico. In natural populations, we detected adults with intersex colouration and gonads. Therefore, we experimentally tested whether this apparent sex change can be generated by manipulation of ecological and social conditions, rather than being caused by environmental disturbance. We demonstrated functional protogynous (female-to-male) sex change in 60% replicates, when groups of five females interacted and had a visual and olfactory cue of a male. Only one female changed sex in any given replicate. The sex change never occurred in isolated females. Protandrous (male-to-female) hermaphroditism was not recorded. We characterized gradual changes in behaviour, colouration and gonad structure during the sex change process. The first behavioural signs of sex change were observed after 23 days. Secondary males spawned successfully after 75 days. We discuss the adaptive potential of sex change in short-lived annual fishes through the seasonal decline of males, and during colonization of new habitats. This is the first observation of functional hermaphroditism in an annual killifish.


Neuroleukin/Autocrine Motility Factor Receptor Pathway Promotes Proliferation of Articular Chondrocytes through Activation of AKT and Smad2/3.
Cartilage defect is an intractable clinical problem. Therapeutic strategies for cartilage repair are far from optimal due to poor proliferation capacity of chondrocytes. Autologous chondrocyte implantation is a cell based therapy that uses in vitro amplified healthy chondrocytes from the patient. However, chondrocyte dedifferentiation during in vitro culture limits its application. Neuroleukin (NLK) is a multifunctional protein that stimulates cell growth and migration, together with its receptor autocrine motility factor receptor (AMFR, also called gp78). We investigated expression of NLK and AMFR/gp78 during cartilage development in vivo and in cultured articular chondrocytes in vitro, and found the pair associates with chondrocyte proliferation and differentiation. While applied to isolated articular chondrocytes, NLK promotes cell proliferation and secretion of type II collagen, a marker of proliferating chondrocytes. Further work demonstrates that NLK up regulates pAKT and pSmad2/3, but down regulates pSmad1/5. In animals, NLK treatment also promotes chondrocyte proliferation while inhibits terminal differentiation, leading to expanded proliferating zone but decreased prehypertrophic and hypertrophic zones in the growth plate region. NLK is therefore a candidate factor that can be applied in the treatment of cartilage defects.


Left-handedness: its association with allergic disease.
It has been postulated that anomalous cerebral dominance is associated with disorders of the immune system and increased incidence of autoimmune diseases has been reported in left-handed individuals. In this study, 313 patients attending an allergy clinic were assessed for left- and right-handedness, using the Edinburgh Handedness Inventory. The results were compared to those in 350 age- and sex-matched control individuals. It was found that significantly more (P less than 0.02) left-handers than right-handers attended the clinic. Among atopic patients in general, patients with IgE-mediated symptoms, patients with urticaria and patients with eczema, there was a highly significant increase in left-handers (P less than 0.005). The results are discussed in terms of dominance.


A second-order nonlinear optical material with a 5-fold interpenetrating diamondoid framework based on two achiral precursors: spontaneous resolution to absolute chiral induction.
A pair of new enantiomeric Zn(ii) complexes with 5-fold interpenetrating diamondoid frameworks have been synthesized using two achiral tritopic and V-shaped ligands through spontaneous resolution, which crystallize in orthorhombic crystal systems with chiral P212121 space groups, showing a strong second harmonic generation response. In the presence of enantiopure propane-1,2-diol as a chiral inducing agent, they are driven to controllable homochiral crystallization of the desired enantiomorph, confirmed by single crystal X-ray diffraction and circular dichroism spectroscopy.


Hepatitis B "360".
There is an extremely high burden of liver disease owing to viral hepatitis B (HBV); about 2 billion people are infected and 350 million are chronic carriers of HBV worldwide. More effective medical therapy and liver transplantation are available for those with advancing disease. The interaction between the host immune system and the virus influences the rate of development of advanced liver disease or hepatocellular carcinoma (HCC); treatment that successfully reduces viral replication of HBV also reduces the incidence of development of advanced liver disease and HCC. Liver transplantation for HBV has yielded favorable outcomes since the institution of hepatitis B immune globulin and antiviral therapy. The ability to stabilize and rescue some patients with advanced liver disease owing to HBV has resulted in a changing demographic for patients with HBV undergoing liver transplantation. The main indications for transplant owing to HBV are now acute liver failure (both acute and acute reactivation on the background of chronic HBV) and HCC. Use of donor organs exposed to HBV with positive HBV core antibody is now routinely accepted for its good outcomes, and in selected cases with active HBV, HBV surface antigen-positive donors may be utilized to further expand the donor pool. Another indication for antiviral therapy for HBV is to reduce the risk of reactivation of latent virus in some patients previously exposed to HBV who are being treated with chemotherapy. Health care providers with HBV infection have an obligation to appropriately treat or monitor their disease closely to reduce the risk of transmission of disease from provider to patient. In the future, universal vaccination will reduce the overall burden of HBV liver disease, but until then appropriate utilization of available medical and surgical therapeutic options gives excellent clinical outcomes.


Polyphenols from Eriosema tuberosum.
A dichloromethane extract of the roots of Eriosema tuberosum exhibited antifungal activity against Cladosporium cucumerinum and Candida albicans using TLC bioautography. Bioassay-directed fractionation led to the isolation of four new compounds, eriosemaones A-D, together with a known compound, flemichin-D, as the active constituents. Three inactive polyphenols were also isolated after methylation, together with one new chromone, eriosematin. Structures were determined by spectroscopic analysis and from chemical evidence.


Accelerated gene transfer through a polysorbitol-based transporter mechanism.
Here we report an accelerated gene transfer through a polysorbitol-based osmotically active transporter (PSOAT) that shows several surprising results through interesting mechanisms. The nano-sized and well-complexed PSOAT/DNA particles are less toxic, stable at serum and show no aggregation after lyophilization due to their polysorbitol backbone. The transfection is remarkably accelerated both in vitro and in vivo, presumably due to a transporter mechanism of PSOAT in spite of possibility of reduction of transfection by many hydroxyl groups in the transporter. PSOAT possesses a transporter mechanism owing to its polysorbitol backbone, which enhances cellular uptake by exerting polysorbitol transporter activity, thus accelerates gene transfer to cells because transfection ability of PSOAT is drastically reduced in the presence of a cyclooxygenase (COX)-2-specific inhibitor, which we have reported as an inhibitor of the transporter to cells. Moreover, the gene expression is found to be enhanced by hyperosmotic activity and buffering capacity due to polysorbitol and polyethylenimine backbone of PSOAT, respectively. The polysorbitol in PSOAT having polyvalency showed more efficiency in accelerating gene transfer capability than monovalent sorbitol. The above interesting mechanisms display PSOAT as a remarkably potential system to deliver therapeutic (small interfering RNA) and diagnostic agents for effective treatment of cancer.


The fate of p21CDKN1A in cells surviving UV-irradiation.
p21(CDKN1A) is a critical regulator of cell cycle progression in response to DNA damage. There are conflicting conclusions as to whether p21(CDKN1A) levels increase or decrease after ultraviolet (UV)-irradiation and recently it was even reported to disappear entirely following 2.5-30 Jm(-2) of UV-irradiation in the presence of growth medium. The latter would suggest an alternative mechanism for cell cycle arrest after UV-irradiation, since p21(CDKN1A) induction has been considered to be the major mediator of p53-mediated cell cycle arrest after DNA damage. Using physiological UV doses based on cell-killing, we previously observed and here verify that low doses (1.2-6 Jm(-2)) induce p21(CDKN1A) immediately after UV-irradiation, though higher doses cause a latency during which p21(CDKN1A) levels remain fairly constant before increasing. As expected, p53 induction preceded p21(CDKN1A) induction at all doses. Thus, p21(CDKN1A) levels after low doses of UV-irradiation may be controlled in a p53-dependent manner without severe reduction. We propose that physiological relevant UV doses should be determined for each target cell type prior to studying UV-induced responses and that p21(CDKN1A) is indeed critical for cell cycle arrest in cells that survive UV-irradiation.


Effect of industrial pollution on seafood content and dietary intake of total and methylmercury.
The total mercury and methylmercury content of seafood was studied in an area of the Adriatic Sea polluted with inorganic mercury from a local industrial plant. The industrial pollution has affected both the total and the methylmercury content of seafood, but only the difference in the total mercury level was statistically significant when compared with a control area with no local industry. Studies of seafood consumption patterns indicate that, when the subjects examined from both areas were matched by their seafood consumption, both total mercury and methylmercury intake was higher in the industrially polluted area. The percentage of subjects ingesting total mercury above the WHO Provisional Weekly Tolerance Intake (PWTI) of 300 micrograms was also higher in the industrially polluted area. However, the percentage of subjects whose methylmercury intake was above the PWTI of 200 micrograms was higher in the control area, primarily due to the increased number of subjects consuming fish more than 5 times a week.


Evaluation of smoking-induced effects on sympathetic, hemodynamic and metabolic variables with respect to plasma nicotine and COHb levels.
The effect of smoking cigarettes containing 1.5 mg and 0.08 mg nicotine per cigarette and of sham-smoking was studied in six healthy habitual smokers. Levels of carboxyhemoglobin (COHb) and plasma nicotine were measured simultaneously with hemodynamic variables, such as heart rate and blood pressure, and with the metabolic parameters, plasma DBH, cortisol, blood glucose, lactate and free fatty acids. All variables, with the exception of COHb are dose related to plasma nicotine levels. Blood pressure, heart rate and lactate show simultaneous peaks together with maximal nicotine levels, while DBH and cortisol, blood glucose and free fatty acids show a delayed reaction compared to nicotine concentrations. No effects of COHb, even with levels up to 5.6 +/- 0.5% have been observed on the variables investigated. These results demonstrate, that it is nicotine which induces considerable hemodynamic and metabolic alterations after smoking.


Physiotherapists' perceptions on using a multidimensional clinical reasoning form during psychologically informed training for low back pain.
Building clinical reasoning skills is important to effectively implement psychologically informed practice. We developed a multidimensional clinical reasoning form (CRF) to be used by physiotherapists in a psychologically informed practice training programme for low back pain. In this paper we describe the development of the CRF, how the CRF was used in the training, and present an evaluation of physiotherapists' perceptions of the CRF. Qualitative semi-structured interviews were conducted with ten physiotherapists purposively sampled in primary care. Data were gathered through pre, and post training focus group interviews and a secondary analysis of individual physiotherapist interviews conducted after the training. Thematic analysis was used to analyse the data and capture the emergent themes. Two main themes emerged before the training: (1) the CRF 'needs formal training' and (2) 'lacked instruction'. Three main themes emerged after the training (1) it provided 'a helpful framework for multidimensional clinical reasoning' (2) the CRF, and accompanying operational definitions, helped physiotherapists 'elicit information, with 'question prompts' helpful in facilitating patient disclosure (3) 'Utility' - although the CRF was not formally used by the physiotherapists it provided a conceptual reasoning framework to work from with more challenging patients. The CRF was not designed to be used in isolation by clinicians without training. However, when used as a training adjunct it appears to be valued by physiotherapists to help develop their critical thinking and better characterise patients' presentations in order to personalise care from a bio-psychosocial perspective.


Limited Evidence Suggests Metformin Might Be Beneficial to Reduce Head and Neck Cancer Risk and Increase Overall Survival, While Any Benefit With Antiinflammatory Drugs Is Inconsistent.
Protective effects of metformin, statins, and antiinflammatory drugs on head and neck cancer: A systematic review. Saka Herrán C, Jané-Salas E, Devesa AE, López-López J. Oral Oncol 2018;85:68-81. None. Systematic review with meta-analysis.


[Changes in the function of external respiration and circulation in patients with acute pneumonia at the outpatient clinic stage of rehabilitation].
External respiration, circulation and gas exchange trends were investigated in acute pneumonia convalescents followed up on an outpatient basis. It was found that 72% of patients admitted to hospital for acute pneumonia, upon discharge demonstrated residual clinicoroentgenological effects. Cardiorespiratory distress, more pronounced in concomitant chronic bronchitis was recorded in 82% of acute pneumonia convalescents. Long-term tachycardia, hyperventilation, disturbed bronchial permeability, low aerobic productivity registered at outpatient stage of rehabilitation after acute pneumonia indicated ineffectiveness of the aftercare being a sign of a poor prognosis. Variations in cardiorespiratory basic parameters revealed suggest additional criteria of the assessment of the completeness of the recovery after acute pneumonia and promote more individualized approach to the patients' aftercare.


Body mass index in spinal cord injury -- a retrospective study.
Retrospective chart review. To identify the prevalence of overweight and severely overweight (obese) in veterans with spinal cord injury. Veterans Administration Hospital in Wisconsin. A retrospective chart review of all the patients registered in the current database with the Spinal Cord Injury Unit in the Veterans Administration Hospital was undertaken Data collected for each patient included age, sex, height, date of assessment of the height, weight, date of assessment of the weight, duration of spinal cord injury and the type of spinal cord injury -- paraplegia versus quadriplegia. The body mass index (BMI) was subsequently calculated for each patient and the prevalence of overweight and obesity were determined. There were a total of 408 patients registered in the database with the Spinal Injury Unit. The median age was 56 years, and the mean age 55.8 years. Of all patients with spinal cord injury, 52.2% patients had paraplegia and 47.7% had quadriplegia. The mean duration of injury was 19 years. Of the total number of patients, 46.0% were ASIA A, 11.0% were ASIA B, 12.7% were ASIA C and 29.1% were ASIA D. In all, 27.9% patients had a normal BMI and 3.6% patients were undernourished (BMI less than 18.5 kg/m(2)). The prevalence of overweight was 65.8% and 29.9% patients were obese. Overweight and obesity are problems of a significant magnitude in veterans with spinal cord injury.


Hyperpolarized nanodiamond with long spin-relaxation times.
The use of hyperpolarized agents in magnetic resonance, such as (13)C-labelled compounds, enables powerful new imaging and detection modalities that stem from a 10,000-fold boost in signal. A major challenge for the future of the hyperpolarization technique is the inherently short spin-relaxation times, typically <60 s for (13)C liquid-state compounds, which limit the time that the signal remains boosted. Here we demonstrate that 1.1% natural abundance (13)C spins in synthetic nanodiamond can be hyperpolarized at cryogenic and room temperature without the use of free radicals, and, owing to their solid-state environment, exhibit relaxation times exceeding 1 h. Combined with the already established applications of nanodiamonds in the life sciences as inexpensive fluorescent markers and non-cytotoxic substrates for gene and drug delivery, these results extend the theranostic capabilities of nanoscale diamonds into the domain of hyperpolarized magnetic resonance.


Microbial Growth on Plate Beef During Extended Storage After Washing and Sanitizing.
Plate beef was washed and/or sanitized with cold water, hot water, steam, sodium hypochlorite, or acetic acid before being stored for up to 28 days at 3.3 C and 90% relative humidity. Microbial counts initially and at regular intervals thereafter disclosed that, compared with untreated controls, time to reach counts of 108 bacteria per cm2 were (a) 1 day less with steam- or water-treated samples, (b) 2 to 3 days more with hypochlorite-treated samples, (c) 5 days more with hot-water-treated samples, and (d) 16 to 17 days more with acetic acid-treated samples. Re-sanitization with acetic acid extended time to reach equivalent counts by 7 additional days.


The 2021 IXA Keith Reemtsma Lecture: Moving xenotransplantation to the clinic.
Keith Reemtsma was a pioneer in xenotransplantation, the Honorary Founding President of the International Xenotransplantation Association (in 1998), and a wonderful personality. It is a privilege to be invited to give this lecture in his memory. If he were alive today, he would be delighted to see the progress that has been made in pig organ transplantation into nonhuman primate recipients. This progress has largely resulted from two major advances: (i) the increasing availability of pigs with multiple genetic manipulations aimed at protecting the cells of the organ from the primate immune response and (ii) the introduction of novel immunosuppressive agents that block the CD40/CD154 costimulation pathway. There is strong evidence from numerous in vitro studies that the transplantation of a triple-knockout pig organ, particularly if expressing several human protective proteins, into a patient is likely to be significantly more successful than if that same organ is transplanted into a nonhuman primate recipient. With this fact in mind, and in view of the advances currently being made, the time has surely come when we need to consider moving from the laboratory to the clinic. However, there are still questions we need to definitively resolve: (i) What exact genetic modifications do we need in the organ-source pig? (ii) What exact immunosuppressive regimen will we choose? (iii) How will we monitor the immune response and diagnose and treat rejection? and (iv) How do we plan to prevent or treat potential infectious complications? Furthermore, when these matters have been resolved, which patients will be offered a pig organ in the first trial? We have suggested that patients who are very unlikely to survive until a suitable deceased human donor kidney becomes available are those who should be considered for the initial trials. Assessing public attitudes to xenotransplantation is also important before embarking on a clinical trial. I suggest that progress is much more likely to be made from a small clinical trial than if we persist in carrying out experiments in an animal model that no longer mimics the clinical situation.


Efficacy and safety of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: A systematic review and meta-analysis.
Olanzapine is an anti-psychotic drug that has been used for preventing and treating Chemotherapy-Induced Nausea and Vomiting (CINV). This study aimed to systematically review and meta-analyze the efficacy and safety of olanzapine for prophylaxis and treatment of CINV. We conducted a systematic literature search of MEDLINE, EMBASE, SCOPUS, and the Cochrane Central Register of Controlled Trials-CENTRAL up to July 15, 2016. All observational and intervention studies were included, but only the intervention studies were pooled for meta-analysis. The efficacy outcome was the proportion of patients achieving complete response (CR) - no emesis and no rescue therapy, in the acute, delayed, and overall phases. The safety outcomes were the adverse events associated with olanzapine according to Common Terminology Criteria for Adverse Events (CTCAE). Sixteen studies were eligible: 15 clinical trials and 1 observational study. Nine of the interventional studies were pooled for meta-analysis. The CR of olanzapine was superior to other anti-emetic regimens, in both the delayed and overall phases (RR=1.27, 95% CI 1.07-1.49, RR=1.32, 95% CI 1.08-1.62, respectively). However, olanzapine was not better than standard CINV prophylaxis of the nausea and emesis outcome in the acute phase. Drowsiness and constipation were the most reported adverse events. No grade 3 or 4 adverse events were reported. Olanzapine is effective and safe at reducing during the delayed and overall phase of the CINV prevention. Other regimens might be added, in cases of CINV during the acute phase of CINV.


Emergency preparedness and public health systems lessons for developing countries.
Low- and middle-income countries, where emerging diseases often make their debut, are also likely to bear the harshest consequences of a potential influenza pandemic. Yet public health systems in developing countries are underfunded, understaffed, and in many cases struggling to deal with the existing burden of disease. As a result, developed countries are beginning to expand assistance for emergency preparedness to the developing world. Given developing countries' weak infrastructure and many competing public health priorities, it is not clear how to best direct these resources. Evidence from the U.S. and other developed countries suggests that some investments in bioterror and pandemic emergency preparedness, although initially implemented as vertical programs, have the potential to strengthen the general public health infrastructure. This experience may hold some lessons for how global funds for emergency preparedness could be invested in developing countries to support struggling public health systems in responding to current health priorities as well as potential future public health threats.


Mutation at the CK2 phosphorylation site on Cdc28 affects kinase activity and cell size in Saccharomyces cerevisiae.
We have recently reported that protein kinase CK2 phosphorylates both in vivo and in vitro residue serine-46 of the cell cycle regulating protein Cdc28 of budding yeast Saccharomyces cerevisiae, confirming a previous observation that the same site is phosphorylated in Cdc2/Cdk1, the human homolog of Cdc28. In addition, S. cerevisiae in which serine-46 of Cdc28 has been mutated to alanine show a decrease of 33% in both cell volume and protein content, providing the genetic evidence that CK2 is involved in the regulation of budding yeast cell division cycle, and suggesting that this regulation may be brought about in G1 phase of the mammalian cell cycle. Here, we extended this observation reporting that the mutation of serine-46 of Cdc28 to glutamic acid doubles, at least in vitro, the H1-kinase activity of the Cdc28/cyclin A complex. Since this mutation has only little effects on the cell size of the cells, we hypothesize multiple roles of yeast CK2 in regulating the G1 transition in budding yeast.


Thermoelasticity of ice explains widespread damage in dripstone caves during glacial periods.
Damage to speleothems is a common phenomenon in mid-latitude caves, and multiple causes have been proposed. Here we report on one of such type of damage, namely stalagmites that are broken and partially sheared near their base but are still in upright position. Such stalagmites occur in the Obir Caves (Austria) associated with cryogenic cave carbonates, demonstrating the former presence of cave ice. 230Th dating suggests damage to the speleothems during the Last Glacial Maximum. Numerical modelling combined with laboratory measurements demonstrates that internal deformation within a cave ice body cannot fracture stalagmites, even on a steep slope. Instead, temperature changes lead to thermoelastic stresses within an ice body that reach values equaling to and exceeding the tensile strength of even large stalagmites. Differences in thermal expansion coefficients cause a sharp vertical jump in stress between the stalagmite and the surrounding ice body, and the ice lifts the stalagmite as it expands with increasing temperature. This study refutes the previously accepted model that flow of ice breaks stalagmites, and suggests a link between glacial climate variability and corresponding cooling and warming cycles in the subsurface that weaken and eventually fracture stalagmites due to the opposing thermoelastic properties of calcite and ice.


Prevalence and associated factors of renal dysfunction and proteinuria in cyanotic congenital heart disease.
Cyanotic nephropathy (CN), seen in 30-50% of patients with congenital cyanotic heart disease (CCHD), affects both tubular and glomerular function, resulting in proteinuria and azotemia. Microalbuminuria is an early marker for glomerular damage and an independent predictor of progressive renal disease. A cross-sectional study was conducted. A total of 116 patients aged 1 month to 15 years with CCHD at Chiang Mai University Hospital between 2015 and 2016 were assessed and 94 patients were enrolled. To determine the prevalence and associated factors of significant albuminuria in CCHD patients, baseline characteristics, oxygen saturation, surgery, hemoglobin (Hb), hematocrit (Hct), spot urine albumin, urine protein, and creatinine were obtained. Binary logistic-regression modeling was used to identify associated factors. Prevalence of CN in children with CCHD was 58.51% and 92.55% according to albuminuria and proteinuria staging respectively. Prevalence of significant proteinuria, significant albuminuria, and decreased GFR was 88.30%, 41.49% and 31.91% respectively. Participants with significant albuminuria had fewer previous surgeries (p = 0.05), a longer waiting time for surgery (p = 0.02), enalapril usage (p = 0.04), pulmonary hypertension (p = 0.03), higher Hct z-score (p = 0.03) and lower platelet count (p = 0.001) compared with those without significant albuminuria. Using multivariate logistic regression analysis, waiting duration for surgery (p = 0.04), Hct >40% (p = 0.02), and platelet count <290,000/mm3 (p = 0.04) were predictive of microalbuminuria. Cyanotic nephropathy can be detected in the first decade of life with the presentation of microalbuminuria. High Hct level and low platelet count were identified as a predictor of microalbuminuria, whereas early cardiac surgery decreased the risk of developing significant albuminuria.


Preoperative chronic kidney disease predicts poor oncological outcomes after radical cystectomy in patients with muscle-invasive bladder cancer.
To evaluate the impact of preoperative chronic kidney disease (CKD) on oncologic outcomes in muscle-invasive bladder cancer patients who underwent radical cystectomy. A total of 581 patients who underwent radical cystectomy at four medical centers between January 1995 and February 2017 were examined retrospectively. We investigated oncologic outcomes, including progression-free, cancer-specific, and overall survival (PFS, CSS, and OS, respectively) stratified by preoperative CKD status (pre-CKD vs. non-CKD). We performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) to evaluate the impact of preoperative CKD on prognosis and developed the prognostic factor-based risk stratification nomogram. Of the 581 patients, 215 (37%) were diagnosed with CKD before radical cystectomy. Before the background adjustment, PFS, CSS, and OS after radical cystectomy were significantly lower in the pre-CKD group compared to the non-CKD group. Background-adjusted IPTW analysis showed that preoperative CKD was significantly associated with poor PFS, CSS, and OS after radical cystectomy. The nomogram for predicting 5-year PFS and OS probability showed significant correlation with actual PFS and OS (c-index = 0.73 and 0.77, respectively). Muscle-invasive bladder cancer patients with preoperative CKD had a significantly lower survival probability than those without CKD.


Efficacy of exercise therapy during radiotherapy to prevent reduction in mouth opening in patients with head and neck cancer: A randomized controlled trial.
The aim of this study was to compare the efficacy of 2 protocols of exercise therapy to avoid reduction in mouth opening (MO) in patients undergoing radiotherapy for head and neck cancer. This was a randomized, controlled, double-blind, 3-arm, parallel-group, prevention clinical trial. Ninety patients were randomized into 3 groups to perform exercises during radiotherapy treatment: intervention group 1 (G1); intervention group 2 (G2); and control group (CG). Maximum MO was measured before (T0), immediately after (T1), and at 12 months (T2) after completion of radiotherapy treatment. Generalized estimating equations model complemented by the least significant difference test was applied to group comparisons. There was no significant difference in MO measure between the groups at the 3 assessment time points (P = .264). The difference in MO measure from baseline to 12 months after having completed radiotherapy was -1 mm in CG (95% confidence interval [CI] -4.0 to 2.0); 1.3 mm in G1 (95% CI -1.7 to 4.3); and 0.5 mm in G2 (95% CI -3.4 to 4.4). It was not possible to conclude that the exercise protocols performed in this study are more effective than the usual guidance to prevent reduction in MO in patients undergoing radiotherapy for head and neck cancer.


Bier's spots reconsidered: a tale of two spots, with speculation on a humerus vein.
It is a widely accepted opinion that some of the spots produced on the forearm and hand by external compression of the brachial artery are the visible evidence of an intraosseous shunt in the humerus. These spots were first evaluated systematically by Bier in 1898. Additional studies were conducted by Rehberg and Carrier in 1922 and by Wolf in 1924, the latter's conclusions providing the currently accepted view. We examined these spots with laser Doppler velocimetry and found no differences in cutaneous perfusion among spots of different coloration. Further, there was no difference between any of the spots produced by occluding the brachial artery and values obtained from the forearm of postmortem subjects. It appears that the differences in coloration are not due to an intraosseous vascular shunt at the level of the mid humerus but, instead, are due to a capacitance phenomenon with venodilation in the dark areas and venoconstriction in the pale areas.


Improved hepatoprotective activity of Beta vulgaris L. leaf extract loaded self-nanoemulsifying drug delivery system (SNEDDS): in vitro and in vivo evaluation.
Beta vulgaris L. (beetroot) is a vegetable plant rich in phytochemical compounds such as phenolic acids, carotenoids and flavonoids. The objective of the current study is the development and optimization of self-nanoemulsifying drug delivery systems (SNEDDSs) to enhance the hepatoprotective activity of beet leaf (BL) extract. Total flavonoids content was estimated in the BL extract and its solubility was evaluated in various vehicles to select proper component combinations. Pseudo-ternary phase diagrams were constructed employing olive, linseed, castor and sesame oils (oil phase), Tween® 20 (Tw20) and Tween® 80 (Tw80) (surfactants (SAs)) as well as dimethyl sulfoxide (DMSO) and propylene glycol (PG) (co-surfactants (Co-SAs)). Optimization of formulations from the phase diagrams took place through testing their thermodynamic stability, dispersibility and robustness to dilution. Four optimized BL-SNEDDS formulations, comprising linseed oil or olive oil, Tw80 and DMSO at two SA/Co-SA ratios (2:1 or 3:1) were chosen. They exhibited high cloud point and percentage transmittance values with spherical morphology of mean droplet sizes ranging from 14.67 to 16.06 nm and monodisperse distribution with negatively charged zeta potential < -9.51 mV. The in vitro release profiles of the optimized formulations in pH 1.2 and 6.8 were nearly similar, with a non-Fickian release mechanism. In vivo evaluation of BL-SNEDDSs hepatoprotective activity in a thioacetamide-induced hepatotoxicity rat model depicted promoted liver functions, inflammatory markers and histopathological findings, most prominently in the group treated by F7. The results indicate that SNEDDS, as a nanocarrier system, has potential to improve the hepatoprotective activity of the BL extract.


The signal peptide of pro-opiomelancortin: validation of a specific radioimmunoassay.
The N-terminus portion of the POMC leader sequence (signal peptide) was synthesized, and an antiserum was raised against it. A radioimmunoassay was developed which is effective at a dilution of 1:500,000, and sensitive at less than 1 fmole/tube. Since leader sequences often exhibit structural homologies, and since synthetic peptides are not readily available, we resorted to an unusual procedure to establish specificity. This involved extraction of pituitary RNA, cell-free translation to produce the pre-prohormones, and purification by B-END and signal antibody affinity columns. The eluates were then tested by SDS gel electrophoresis and by multiple immunoprecipitations. All results showed that the signal antibody captured a single molecular species, approximately 30,000 in MW, which was also captured by the B-END column, and was immunoprecipitable by B-END and ACTH antisera. It therefore appears that this antibody selectively measures the POMC leader sequence and should be valuable in measuring the newly synthesized pre-prohormone.


Distribution of phthalate metabolites, benzophenone-type ultraviolet filters, parabens, triclosan and triclocarban in paired human hair, nail and urine samples.
In this study, the distribution of nineteen ingredients of personal care product (PCPs), including seven metabolites of phthalates (mPAEs), five benzophenone-type ultraviolet filters (BPs), and seven antimicrobial agents (AAs), were investigated in paired human hair, nail and urine samples. The median concentrations of ΣmPAEs, ΣBPs and ΣAAs were 135, 2.76 and 179 ng/g in hair, 37.3, 2.95 and 297 ng/g in nails, and 345, 4.03 and 50.1 ng/mL in urine, respectively. Mono-methyl phthalate (49%), 2,4-dihydroxybenzophenone (45%) and triclosan (71%) were the most abundant mPAE, BP and AA in hair samples, respectively, and had similar abundance in nail samples. In contrast, mono-n-butyl phthalate (45%), 4-hydroxy benzophenone (29%) and methyl paraben (54%) were the predominant mPAE, BP and AA in urine samples, respectively. Significant differences in the concentrations of some target compounds were observed between male and female but inconsistent across different matrices. Moreover, most compounds with significant correlations had quite different correlation coefficients in each matrix. No significant correlations were found between hair, nail and urine samples for most of the target analytes. These results suggest these analytes have matrix-specific distribution, and it is necessary to use multiple matrices to comprehensively assess the risk of ingredients of PCPs to human health.


The Cardiopulmonary Complications of Sickle Cell Disease.
Sickle cell disease (SCD) is a genetic hemoglobinopathy associated with extensive morbidity and early mortality. While there have been recent improvements in available disease-modifying therapies for SCD, cardiopulmonary complications remain a major risk factor for death in this population. We provide an overview of current knowledge regarding several of the major acute and chronic cardiopulmonary complications in SCD, including: acute chest syndrome, airway disease, lung function abnormalities, nocturnal hypoxemia and sleep disordered breathing, pulmonary vascular disease, and sickle cell cardiomyopathy.


The role of hydration effects in 5-fluorouridine binding to SOD1: insight from a new 3D-RISM-KH based protocol for including structural water in docking simulations.
Misfolded Cu/Zn superoxide dismutase enzyme (SOD1) shows prion-like propagation in neuronal cells leading to neurotoxic aggregates that are implicated in amyotrophic lateral sclerosis (ALS). Tryptophan-32 (W32) in SOD1 is part of a potential site for templated conversion of wild type SOD1. This W32 binding site is located on a convex, solvent exposed surface of the SOD1 suggesting that hydration effects can play an important role in ligand recognition and binding. A recent X-ray crystal structure has revealed that 5-Fluorouridine (5-FUrd) binds at the W32 binding site and can act as a pharmacophore scaffold for the development of anti-ALS drugs. In this study, a new protocol is developed to account for structural (non-displaceable) water molecules in docking simulations and successfully applied to predict the correct docked conformation binding modes of 5-FUrd at the W32 binding site. The docked configuration is within 0.58 Å (RMSD) of the observed configuration. The docking protocol involved calculating a hydration structure around SOD1 using molecular theory of solvation (3D-RISM-KH, 3D-Reference Interaction Site Model-Kovalenko-Hirata) whereby, non-displaceable water molecules are identified for docking simulations. This protocol was also used to analyze the hydrated structure of the W32 binding site and to explain the role of solvation in ligand recognition and binding to SOD1. Structural water molecules mediate hydrogen bonds between 5-FUrd and the receptor, and create an environment favoring optimal placement of 5-FUrd in the W32 binding site.