Internal Versus External Fixation of Charcot Midfoot Deformity Realignment.
Internal and external fixation techniques have been described for realignment and arthrodesis of Charcot midfoot deformity. There currently is no consensus on the optimal method of surgical reconstruction. This systematic review compared the clinical results of surgical realignment with internal and external fixation, specifically in regard to return to functional ambulation, ulcer occurrence, nonunion, extremity amputation, unplanned further surgery, deep infection, wound healing problems, peri- or intraoperative fractures, and total cases with any complication. A search of multiple databases for all relevant articles published from January 1, 1990, to March 22, 2014, was performed. A logistic regression model evaluated each of the outcomes and its association with the type of fixation method. The odds of returning to functional ambulation were 25% higher for internal fixation (odds ratio [OR], 1.259). Internal fixation had a 42% reduced rate of ulcer occurrence (OR, 0.578). External fixation was 8 times more likely to develop radiographic nonunion than internal fixation (OR, 8.2). Internal fixation resulted in a 1.5-fold increase in extremity amputation (OR, 1.488), a 2-fold increase in deep infection (OR, 2.068), a 3.4-fold increase in wound healing complications (OR, 3.405), and a 1.5-fold increase in the total number of cases experiencing any complication (OR, 1.525). This was associated with a 20% increase in the need for unplanned further surgery with internal fixation (OR, 1.221). Although internal fixation may decrease the risk of nonunion and increase return to functional ambulation, it had a higher rate of overall complications than external fixation for realignment and arthrodesis of Charcot midfoot deformity. [Orthopedics. 2016; 39(4):e595-e601.].


Can We Detect Chronic Pancreatitis With Low Serum Pancreatic Enzyme Levels?
The aims of this study were to evaluate whether serum pancreatic enzyme levels could be used to aid screening for chronic pancreatitis (CP). 170 healthy volunteers were screened and prospectively enrolled in the control group. 150 patients who were diagnosed with calcific CP were enrolled in the patient group by retrospective review. Serum amylase and lipase levels were compared between the 2 groups. The mean values ± SD of the control group were compared with those of the patient group for serum amylase level (48.1 ± 13.2 vs 34.8 ± 17.2 U/L, P < 0.001) and serum lipase level (26.4 ± 11.3 vs 16.3 ± 11.2 U/L, P < 0.001). On the receiver operating characteristic curve analysis for amylase level, area under the curve was 0.740 (95% confidence interval), and sensitivity and specificity were 38.7% and 94.1%, respectively, with a cutoff value of 27.5 U/L. On the receiver operating characteristic curve analysis for lipase level, area under the curve was 0.748 (95% confidence interval), and sensitivity and specificity were 33.3% and 95.9%, respectively, with a cutoff value of 10.5 U/L. Our results suggest that low serum pancreatic enzyme levels can be used to aid in detection of CP.


Changes in vitelline and utero-placental hemodynamics: implications for cardiovascular development.
Analyses of cardiovascular development have shown an important interplay between heart function, blood flow, and morphogenesis of heart structure during the formation of a four-chambered heart. It is known that changes in vitelline and placental blood flow seemingly contribute substantially to early cardiac hemodynamics. This suggests that in order to understand mammalian cardiac structure-hemodynamic functional relationships, blood flow from the extra-embryonic circulation needs to be taken into account and its possible impact on cardiogenesis defined. Previously published Doppler ultrasound analyses and data of utero-placental blood flow from human studies and those using the mouse model are compared to changes observed with environmental exposures that lead to cardiovascular anomalies. Use of current concepts and models related to mechanotransduction of blood flow and fluid forces may help in the future to better define the characteristics of normal and abnormal utero-placental blood flow and the changes in the biophysical parameters that may contribute to congenital heart defects. Evidence from multiple studies is discussed to provide a framework for future modeling of the impact of experimental changes in blood flow on the mouse heart during normal and abnormal cardiogenesis.


[Cerebral cysticercosis. Diagnostic value of x-ray computed tomography. Apropos of 117 cases].
117 cases of cerebral cysticercosis in La Réunion are reported. Different CT features are related and situated with the evolutive state of the parasite. CT scan provided accurate diagnostic information except in some intraventricular or subarachnoid location where NMR study seems already to be superior.


[Mental disorder as a risk factor of suicide; a clinical study of failed suicides].
This is a clinical study of failed suicides, in order to contribute to the explanation of completed suicides. 423 suicidal patients were admitted to the emergency critical care unit of a metropolitan municipal hospital during 6 years. The catchment area of the unit is the east four wards of Tokyo. Almost all patients who attempted suicide and four who later on completed suicide were interviewed by consultating psychiatrists. The total number of cases thus investigated was 265. Medical and psychiatric charts were retrospectively evaluated for the study. According to the lethality of respective suicidal methods, the 265 cases were divided to the ABSOLUTELY DANGEROUS GROUP (133 patients) and the RELATIVELY DANGEROUS GROUP (132 patients). The former, except for the few patients who later on died, could be considered as "failed suicides"; 75% of these patients were mentally disordered (psychoses, depressive disorders or psychoactive substance use disorders), whereas in the latter group the respective figure was 48%. The rates of each disorder were different in the age classes: younger (below 30), middle aged (30-49), and older (50 and over). In the younger group, psychoses (F2 cord of ICD-10 draft) were the main cause (52%). By contrast, endogenous major depression was the main cause in the older group (48%). The rate of psychoactive substance use disorders was highest (22%) in the middle aged among the three classes. There were 1562 officially recorded completed suicides in the catchment area during the same 6 years. From the distribution of diagnoses in each of the three age classes of the ABSOLUTELY DANGEROUS GROUP and the distribution of age classes in 1562 completed suicides, the rates of mental disorders amongst the completed suicides were estimated as roughly 26% psychoses, 46% depressive disorders and 18% substance use disorders. The total figure was 90% and quite similar to the results of previous studies by psychological autopsies in the western countries. For an attempt to decrease the rates of suicide, the most important point seems to be the prevention of suicides by the mentally disordered. Depression is most prevalent among elderly suicidal patients. In contrast to previous studies, the author found psychoses most often in younger patients. Psychotic symptoms of schizophrenic and of alcoholic suicidal patients were analysed in detail. None of them nor any other patient could be considered as a "rational suicide" case.


Factors Affecting Carotid Artery Stenosis in the Elderly Living at High Altitudes.
Factors affecting carotid artery stenosis have been generally investigated. However, considering the protective effect of altitude, studies on elderly individuals at high altitudes are few. Our aim is to investigate the systematic adaptive changes caused by high-altitude exposure through the causes of carotid artery stenosis. Carotid Doppler ultrasound was performed on 250 patients over the age of 50 years. The patients' age, gender, height, weight, smoking history, place of residence, and presence of comorbidities were questioned. Those with diabetes, hypertension, hyperlipidemia, and coronary disease were excluded from the study. Those who did not reside at high altitudes were excluded from the study. One hundred and thirty-five patients were included in the study. Carotid artery Doppler findings and biochemical parameters were recorded. Factors affecting stenosis in the carotid arteries were compared. In our study, the factors affecting carotid stenosis were determined to be age, gender, presence of plaque, plaque type, and mean carotid intima-media thickness (CIMT). The mean CIMT of the patients was calculated as 0.71±0.14 mm. The mean CIMT measurement level was significantly higher in patients with plaque in the carotid artery (p<0.05). According to receiver operating characteristic curves, CIMT values higher than 0.72 mm increase plaque and stenosis formation in the common carotid artery (CCA) and internal carotid artery (ICA) in elderly people living at high altitudes (p<0.05, area under the curve [AUC]: 0.71-0.83). The most important factors affecting carotid stenosis in individuals living at high altitudes are age, gender, CIMT, plaque, and plaque type. When soft plaques were detected, the risk of stenosis was found to be higher than in calcific plaques. Additionally, the number of factors affecting stenosis was greater on the left (ICA). This suggests that the left carotid system is more vulnerable. It can be said that in elderly individuals living at high altitudes, a CIMT higher than 0.72 mm is a cutoff value in the presence of plaque and stenosis in the carotid arteries.


Cardiac calcium release channel (ryanodine receptor) in control and cardiomyopathic human hearts: mRNA and protein contents are differentially regulated.
Abnormal intracellular calcium handling in cardiomyopathic human hearts has been associated with an impaired function of the sarcoplasmic reticulum, but previous reports on the gene expression of the ryanodine receptors (Ry2) are contradictory. We measured the mRNA levels, the protein levels and the number of high affinity [3H]ryanodine binding sites in the left ventricle of non-failing (n = 9) and failing human hearts [idiopathic dilated (IDCM n = 16), ischemic (ICM n = 7) or mixed (MCM n = 8) cardiomyopathies]. Ry2 mRNA levels were significantly reduced in IDCM (-30%) and unchanged in MCM and ICM and Ry2 protein levels were similar. In contrast, we observed a two-fold increase in the number of high affinity Ry2 (B(max) = 0.43 +/- 0.11 v 0.22 +/- 0.13 pmol/mg protein, respectively; P<0.01) and an unchanged K(d). Furthermore, levels of myosin heavy chain mRNA and protein per g of tissue were similar in failing and non-failing hearts, suggesting that the observed differences in Ry2 are not caused by the increase in fibrosis in failing heart. Therefore, the dissociation between the two-fold increase in the number of high affinity ryanodine receptors observed in all failing hearts and the slightly decreased mRNA level or unchanged protein level suggests that the ryanodine binding properties are affected in failing myocardium and that such modifications rather than a change in gene expression alter the channel activity and could contribute to abnormalities in intracellular Ca2+ handling.


[Analysis of chemical components of Huanbei Zhike Prescription based on UPLC-Q-TOF-MS/MS technology].
To characterize the chemical constituents of Huanbei Zhike Prescription by ultra-high performance liquid chromatography-time of flight mass spectrometry( UPLC-Q-TOF-MS/MS). A Thermo Syncronls C18 column( 2. 1 mm×100 mm,1. 7 μm) was used with methanol( A)-0. 1% formic acid solution( B) as the mobile phase for gradient elution. The injection volume was 2 μL; the column temperature was 40 ℃; the flow rate was 0. 3 m L·min-1; and electrospray ionization( ESI) source was used to collect data in positive and negative ion modes. The ion scanning range was m/z 50-1 200,with capillary voltage of 3 000 V,ion source temperature of100 ℃,atomization gas flow rate of 50 L·h-1,desolvent gas flow rate of 800 L·h-1,desolvent temperature of 400 ℃,cone hole voltage of 40 V,with argon as the collision gas and the collision energy was 20-35 V. The excimer ion peak information was analyzed by Waters UNIFI data processing software. The molecular formula with error within 1×10-5 was compared with the data in database to identify the compounds. The secondary fragment ion information of the target compound was selected,and then compared with the retention time and fragmentation patterns provided by the database and the existing literature to further confirm the compositions and structures of the compounds. A total of 68 main compounds in Huanbei Zhike Prescription were identified,including 38 flavonoids,10 organic acids,6 terpenoids and 10 nitrogen-containing compounds,of which 12 compounds were verified by the control substances. This method is rapid and accurate,which provides a new strategy for the qualitative analysis of the chemical constituents of Huanbei Zhike Prescription,and lays a foundation for the further study and quality control of the compound pharmacodynamic substance.


Validation of a rat seminiferous tubule culture model as a suitable system for studying toxicant impact on meiosis effect of hexavalent chromium.
There is evidence that exposure to environmental factors is at least partly responsible for changes in semen quality observed over the past decades. The detection of reproductive toxicants under Registration, Evaluation and Authorisation of Chemicals (REACH) will impact animal use for regulatory safety testing. We first validated a model of culture of rat seminiferous tubules for toxicological studies on spermatogenesis. Then, using this model of culture, we assessed the deleterious effects of 1, 10, and 100 microg/l hexavalent chromium [Cr(VI)] on meiotic cells. The prophase I of meiosis was studied in vivo and ex vivo. Bromo-2'-deoxyuridine (BrdU) was used to describe the kinetics of germ cell differentiation. SCP3 labeling allowed to establish the distribution of the stages of the meiotic prophase I and to perform a qualitative study of the pachytene stage in the absence or presence of Cr(VI). The development of the meiotic step of pubertal rats was similar in vivo and ex vivo. The number of total cells appeared not affected by the presence of Cr(VI) irrespective of its concentration. However, the numbers of late spermatocytes and of round spermatids were decreased by Cr(VI) even at the lower concentration. The percentage of synaptonemal complex abnormalities increased slightly with the time of culture and dramatically with Cr(VI) concentrations. This model of culture appears suitable for toxicological studies. This study shows that Cr(VI) is toxic for meiotic cells even at low concentrations, and its toxicity increases in a dose-dependent manner.


Spatial Patterns of Potentially Hazardous Metals in Soils of Lin'an City, Southeastern China.
Urban soils are strongly related to human health. In this study, Lin'an city was chosen as a typical small-scale city with which to study the spatial variation of potentially hazardous metals (PHMs) in urban soils and their potential ecological risks using multivariate analysis, geostatistics and GIS techniques. A total of 62 soil samples were collected from the study area. The results showed that the average concentrations of total soil Mn, Cu, Zn, Pb, Cr, Cd were 439.42, 42.23, 196.80, 62.55, 63.65, 0.22 mg·kg-1, respectively. Compared with the background values and the environmental quality standards, these PHMs were accumulated in urban soils to some extent. The single potential ecological risk indices of PHMs indicated that Pb and Cd had relatively high ecological risks. The pH and most of the PHMs had significant correlations (p < 0.05). The principle components analysis (PCA) showed that Pb, Zn and Cu had similar pollution sources related to the vehicles' exhaust emission; Mn and Cr were mainly from the parent materials; while Cd was from the emission of industrial manufactories. The spatial structures and distributions of PHMs and their corresponding available fractions had strong/moderate spatial autocorrelation, which were influenced by human activities.


Genetic predictor of working memory and prefrontal function in women with HIV.
The Val158Met (rs4680) single-nucleotide polymorphism (SNP) of the catechol-O-methyltransferase gene (COMT) influences executive function and prefrontal function through its effect on dopamine (DA) metabolism. Both HIV and the Val allele of the Val158Met SNP are associated with compromised executive function and inefficient prefrontal function. The present study used behavioral and neuroimaging techniques to determine independent and interactive associations between HIV serostatus and COMT genotype on working memory and prefrontal function in women. For the behavioral study, 54 HIV-infected and 33 HIV-uninfected women completed the 0-, 1-, and 2-back conditions of the verbal N-back, a working memory test. For the imaging study, 36 women (23 HIV-infected, 13 HIV-uninfected) underwent functional magnetic resonance imaging (fMRI) assessments while completing the N-back task. HIV-infected women demonstrated significantly worse N-back performance compared with HIV-uninfected women (p < 0.05). A significant serostatus by genotype interaction (p < 0.01) revealed that, among Val/Val, but not Met allele carriers, HIV-infected women performed significantly worse than HIV-uninfected controls across N-back conditions (p < 0.01). Analogous to behavioral findings, a serostatus by genotype interaction revealed that HIV-infected Val/Val carriers showed significantly greater prefrontal activation compared with HIV-uninfected Val/Val carriers (p < 0.01). Conversely, HIV-uninfected Met allele carriers demonstrated significantly greater prefrontal activation compared with HIV-infected Met allele carriers. Findings suggest that the combination of HIV infection and the Val/Val COMT genotype leads to working memory deficits and altered prefrontal function in HIV-infected individuals.


Specialized myrmecophily at the ecological dawn of modern ants.
Myrmecophiles--species that depend on ant societies--include some of the most morphologically and behaviorally specialized animals known. Remarkable adaptive characters enable these creatures to bypass fortress-like security, integrate into colony life, and exploit abundant resources and protection inside ant nests. Such innovations must result from intimate coevolution with hosts, but a scarcity of definitive fossil myrmecophiles obscures when and how this lifestyle arose. Here, we report the earliest known morphologically specialized and apparently obligate myrmecophile, in Early Eocene (∼ 52 million years old) Cambay amber from India. Protoclaviger trichodens gen. et sp. nov. is a stem-group member of Clavigeritae, a speciose supertribe of pselaphine rove beetles (Coleoptera: Staphylinidae) heavily modified for myrmecophily via reduced mouthparts for trophallaxis with worker ants, brush-like trichomes that exude appeasement compounds, and fusions of many body and antennal segments. Protoclaviger captures a transitional stage in the evolutionary development of this novel body plan, most evident in its still-distinct abdominal tergites. The Cambay paleobiota marks one of the first occurrences in the fossil record of a significant presence of modern ants. Protoclaviger reveals that sophisticated social parasites were nest intruders throughout, and probably before, the ascent of ants to ecological dominance, with ancient groups such as Clavigeritae primed to radiate as their hosts became increasingly ubiquitous.


Prevalence trends in the characteristics of patients with allergic asthma in Beijing, 1994 to 2014.
This study aimed to determine the clinical profiles and prevalence trends during 1994 to 2014 among patients with allergic asthma (AA), which is a clinical phenotype of asthma.We retrospectively analyzed the characteristics of 319 patients who were diagnosed with AA between March 1, 1994 and February 28, 2014 at 3 Beijing centers.The patients included 155 males and 164 females, and the mean age was 50.86 ± 15.27 years (range 13-86 years). The proportions of asthma attacks in summer and autumn were 60.7% (1994-1999), 61.8% (1999-2004), 56.4% (2004-2009), and 33.1% (2009-2014). The most frequently used medication at home was theophylline (27.9%), which was followed by inhaled corticosteroids (20.38%), inhaled corticosteroids/long-acting beta-2-agonists (10.66%), and leukotriene receptor antagonists (9.4%). The elderly group had the highest rates of summer and autumn attacks, multiple hospitalizations, reduced pulmonary function, smoking history, and positive allergen tests. The middle-aged group had the lowest rates of summer and autumn attacks, and multiple hospitalizations. The youngest group had the lowest rates of reduced pulmonary function, smoking history, and positive allergen tests. The top 5 allergens were dust (9.1%), mites (8.8%), seafood (8.2%), pollen (6.3%), and animal fur (6%). Women were significantly more likely to have a positive allergen test (93 women vs 68 men).The present study revealed the characteristics of Chinese patients with AA, and allergen-specific differences in sex and age during 1994 to 2014. The use of therapeutic drugs at home remains insufficient.


Effect of four intermediate layer treatments on microleakage of Class II composite restorations.
This in vitro study examines the marginal sealing ability of four different intermediate materials applied before placement of a condensable composite. Class II preparations were made with gingival margins placed 1.0 mm apical to the cementoenamel junction of 60 extracted teeth, randomly assigned to five groups of 12. Following restoration, teeth were thermocycled, soaked in 0.5% basic fuchsin, and sectioned longitudinally. The resin-modified glass ionomer cement demonstrated significantly less microleakage than the use of a dentin bonding agent alone or in combination with flowable composite, flowable compomer, or autoploymerizing composite (p < 0.05, Dunn's test). This study supports the use of the glass ionomer open sandwich technique in deep Class II direct composite restorations.


Multiple myeloma presenting with multiple thoracic manifestations.
Multiple myeloma is a malignant proliferation of plasma cells that affects mainly bone marrow but may also involve other organs as well. We report thoracic involvement in the form of left-sided pleural effusion, osseous lesions, bronchial infiltration, and mediastinal lymphadenopathy in a 61-year-old woman, non-smoker presented with chest pain, dyspnoea, cough and deterioration in general health over the preceding seven months. Immunoelectrophoresis and immunofixation showed raised kappa-light chain immunoglobulin G (IgG) in serum and pleural fluid. Bronchial and pleural biopsies documented myelomatous infiltration and bone marrow aspirate revealed extensive plasma cell infiltration. At eight months, following the fourth cycle of melphalan, endoxan and prednisone based chemotherapy, the patient died.


[Treatment of sudden hearing loss].
A total of 27 patients affected by sudden idiopathic deafness (SID) and 3 with sudden idiopathic anacousia (SIA) were treated within 10 days of onset of the disorder. The treatment consisted of intramuscular or per os administration of corticosteriods for 10 days and the simultaneous administration of carbogene for 5 days. At the 5th day of corticosonic treatment, if audiometry did not reveal complete recovery, the treatment was associated for 7 days with Destrane 500 ml. The cases included neurosensorial deafness of 30 dB or more over at least 3 adjacent frequencies and arising over a 12 hour period. Soft cord deafness was not included in the study. The following variables were analyzed: 1) patient age; 2) extent of the hearing loss: average tone threshold for the frequencies of 500 -1000-2000 Hz equal to or better than 70 dB HL (group A); tone threshold ranging between 71 and 89 dB HL (group B), tone threshold ranging from 90 to 110 dB HL (group C), anacousia (group D); 3) audiometric curve; 4) presence or lack of vertigo. After treatment 25 subjects (83%) indicated a recovery ranging from good to complete. It is significant that among this 83% there were 12 subjects, 9 with profound deafness and 3 with anacousia. The therapeutic association adopted made it possible to achieve two-fold activity: anti-edemagene and hemorheological. The most highly implicated etiology for SID was viral causing not only neural but also endothelial damage and leading to acute microcirculatory insufficiency.


Fracture behavior of Lennard-Jones glasses.
The fracture behavior of binary Lennard-Jones (LJ) glasses is studied by extensive molecular dynamics simulations. These LJ glasses represent a nonbond limit of polymer network glasses. We determine that the low strain behavior of the LJ and polymer glasses is similar. Two different LJ glasses are fractured under tensile strain without any preexisting crack. Void formation and resulting growth as strain increases is the mechanism through which the system fails. Void formation initiates at the yield strain of varepsilon (y) approximately 0.09, which is approximately the same strain at which the yielding behavior is first observed in cross-linked network models of polymer adhesives. The yield stress increased only by small amounts with increased strain rate and with increased system size (from N=30 000 atoms to 120 000 atoms). Within the ranges tested, the stress-strain behavior of these systems is independent of the temperature drop during quench and the initial molecular configuration.


Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury.
Traumatic brain injury (TBI) with its associated morbidity is a major area of unmet medical need that lacks effective therapies. TBI initiates a neuroinflammatory cascade characterized by activation of astrocytes and microglia, and increased production of immune mediators including proinflammatory cytokines and chemokines. This inflammatory response contributes both to the acute pathologic processes following TBI including cerebral edema, in addition to longer-term neuronal damage and cognitive impairment. However, activated glia also play a neuroprotective and reparative role in recovery from injury. Thus, potential therapeutic strategies targeting the neuroinflammatory cascade must use careful dosing considerations, such as amount of drug and timing of administration post injury, in order not to interfere with the reparative contribution of activated glia. We tested the hypothesis that attenuation of the acute increase in proinflammatory cytokines and chemokines following TBI would decrease neurologic injury and improve functional neurologic outcome. We used the small molecule experimental therapeutic, Minozac (Mzc), to suppress TBI-induced up-regulation of glial activation and proinflammatory cytokines back towards basal levels. Mzc was administered in a clinically relevant time window post-injury in a murine closed-skull, cortical impact model of TBI. Mzc effects on the acute increase in brain cytokine and chemokine levels were measured as well as the effect on neuronal injury and neurobehavioral function. Administration of Mzc (5 mg/kg) at 3 h and 9 h post-TBI attenuates the acute increase in proinflammatory cytokine and chemokine levels, reduces astrocyte activation, and the longer term neurologic injury, and neurobehavioral deficits measured by Y maze performance over a 28-day recovery period. Mzc-treated animals also have no significant increase in brain water content (edema), a major cause of the neurologic morbidity associated with TBI. These results support the hypothesis that proinflammatory cytokines contribute to a glial activation cycle that produces neuronal dysfunction or injury following TBI. The improvement in long-term functional neurologic outcome following suppression of cytokine upregulation in a clinically relevant therapeutic window indicates that selective targeting of neuroinflammation may lead to novel therapies for the major neurologic morbidities resulting from head injury, and indicates the potential of Mzc as a future therapeutic for TBI.


Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Health Care System.
We investigated the real-world effectiveness of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) in treatment of different subgroups of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4. We performed a retrospective analysis of data from 17,487 patients with HCV infection (13,974 with HCV genotype 1; 2131 with genotype 2; 1237 with genotype 3; and 135 with genotype 4) who began treatment with sofosbuvir (n = 2986), ledipasvir/sofosbuvir (n = 11,327), or PrOD (n = 3174), with or without ribavirin, from January 1, 2014 through June 20, 2015 in the Veterans Affairs health care system. Data through April 15, 2016 were analyzed to assess completion of treatments and sustained virologic response 12 weeks after treatment (SVR12). Mean age of patients was 61 ± 7 years, 97% were male, 52% were non-Hispanic white, 29% were non-Hispanic black, 32% had a diagnosis of cirrhosis (9.9% with decompensated cirrhosis), 36% had a Fibrosis-4 index score >3.25 (indicator of cirrhosis), and 29% had received prior antiviral treatment. An SVR12 was achieved by 92.8% (95% confidence interval [CI], 92.3%-93.2%) of subjects with HCV genotype 1 infection (no significant difference between ledipasvir/sofosbuvir and PrOD regimens), 86.2% (95% CI, 84.6%-87.7%) of those with genotype 2 infection (treated with sofosbuvir and ribavirin), 74.8% (95% CI, 72.2%-77.3%) of those with genotype 3 infection (77.9% in patients given ledipasvir/sofosbuvir plus ribavirin, 87.0% in patients given sofosbuvir and pegylated-interferon plus ribavirin, and 70.6% of patients given sofosbuvir plus ribavirin), and 89.6% (95% CI 82.8%-93.9%) of those with genotype 4 infection. Among patients with cirrhosis, 90.6% of patients with HCV genotype 1, 77.3% with HCV genotype 2, 65.7% with HCV genotype 3, and 83.9% with HCV genotype 4 achieved an SVR12. Among previously treated patients, 92.6% with genotype 1; 80.2% with genotype 2; 69.2% with genotype 3; and 93.5% with genotype 4 achieved SVR12. Among treatment-naive patients, 92.8% with genotype 1; 88.0% with genotype 2; 77.5% with genotype 3; and 88.3% with genotype 4 achieved SVR12. Eight-week regimens of ledipasvir/sofosbuvir produced an SVR12 in 94.3% of eligible patients with HCV genotype 1 infection; this regimen was underused. High proportions of patients with HCV infections genotypes 1-4 (ranging from 75% to 93%) in the Veterans Affairs national health care system achieved SVR12, approaching the results reported in clinical trials, especially in patients with genotype 1 infection. An 8-week regimen of ledipasvir/sofosbuvir is effective for eligible patients with HCV genotype 1 infection and could reduce costs. There is substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections.


Use of Medicare Benefit Scheme mental health services in young people who experienced self-harm and/or suicidal behaviours: Data from the Young Minds Matter survey.
To examine healthcare utilisation patterns in a sample of young people with self-reported experiences of self-harm and/or suicidal behaviours. A national survey examining mental health in a nationally representative sample of young Australians aged 12-17 years, linked to routinely collected healthcare and dispensing data. For respondents that self-reported experience of self-harm, suicidal ideation, suicidal plan and/or suicide attempt, we assessed attendance at a Medicare Benefits Scheme (MBS) subsidised MH service or non-MH general practitioner (GP) attendance at three time periods: 1) ever, 2) in the 12 months prior to completing the survey and 3) after completing the survey until 31 Dec 2015. We also assessed correlates associated with attendance and non-attendance at a MH service. The study included 311 young people. MH services were attended in the 12 months before the survey by 38.3% with attempted suicide, 28.7% with a suicidal plan, 28.9% with suicidal ideation and 29.4% with self-harm. MH treatment administered by a GP was the most common MH service (25%); followed treatment by psychologist (15%) and psychiatrist (5%). Attendance at a MH service was observed highest alongside more severe self-reported depression. Potential underutilisation of MBS MH services by young people with self-harm and/or suicidal behaviours.


Validity of the MCAT in predicting performance in the first two years of medical school.
In this paper, the authors present the first systematic summary of predictive validity research on the new Medical College Admission Test (MCAT) since its introduction in 1977. Data are drawn primarily from the MCAT Interpretive Studies Program, a cooperative effort between the Association of American Medical Colleges and 30 of its member schools to conduct research that will both facilitate local use of the test scores and contribute to a national perspective on their value in medical school admissions. The results show that MCAT scores by themselves have significant predictive validity with respect to first- and second-year medical school course grades and National Board of Medical Examiners Part I examination scores and that they complement the predictive validity of undergraduate college grades. The MCAT Science Knowledge areas of assessment, particularly Biology and Chemistry, and the Science Problems subtest tend to have higher correlations than the Skills Analysis subtests with initial performance in medical school; however, the Skills Analysis: Reading subtest may retain its predictive value best over time. Correlation values are discussed in terms of methodological factors which constrain their size. They are also compared with those found for other professional and graduate school admission tests. Further directions for MCAT validity research are described.


Bone turnover markers in children living with HIV remaining on ritonavir-boosted lopinavir or switching to efavirenz.
We previously found lower bone mass but similar bone turnover in pre-pubertal children living with HIV (CLWH) on a ritonavir-boosted lopinavir (LPV/r)-based vs. efavirenz-based antiretroviral therapy regimen 2 years after switch. Here, we evaluate if bone turnover differed between the groups close to the time of switch. Samples from 108 children remaining on LPV/r and 104 children switched to efavirenz were available for analysis 8 weeks post-randomization. Bone turnover markers, including C-telopeptide of type 1 collagen (CTx), procollagen type-I N-terminal propeptide (P1NP), and osteocalcin were measured. Markers of immune activation were also measured, including IL-6, TNF-alpha, soluble CD14 and high-sensitivity C-reactive protein (CRP). Eight weeks post-randomization, we did not detect differences in CTx (1.42 vs. 1.44 ng/mL, p = 0.85) or P1NP concentrations (622 vs. 513 ng/mL, p = 0.68) between treatment groups. At 8 weeks, the treatment groups also had similar levels of IL-6, TNF-alpha, soluble CD14 and high-sensitivity CRP. Osteocalcin (ng/mL) was higher in the LPV/r than efavirenz group both at 8 weeks (88.6 vs. 67.3, p = 0.001) and 2 years (67.6 vs. 49.8, p = 0.001). Overall, we failed to detect difference in bone turnover by P1NP and CTx in virologically-suppressed CLWH on different regimens at a time point close to the switch. We did observe higher levels of total osteocalcin in children remaining on LPV/r compared to children switched to efavirenz. Future studies should focus on uncovering the mechanism and determining whether perturbation in undercarboxylated osteocalcin could explain some of the bone side effects noted with protease inhibitors.


Communication between physicians and Spanish-speaking Latin American women with pelvic floor disorders: a cycle of misunderstanding?
This study aimed to assess the effect of the initial visit with a specialist on disease understanding among Spanish-speaking women with pelvic floor disorders. Spanish-speaking women with referrals suggestive of urinary incontinence (UI) and/or pelvic organ prolapse (POP) were recruited from public urogynecology clinics. Patients participated in a health literacy assessment and interview before and after their physician encounter. All interviews were analyzed using Grounded Theory qualitative methods. Twenty-seven women with POP (n = 6), UI (n = 11), and POP/UI (n = 10) were enrolled in this study. The mean age was 55.5 years, and most women had marginal levels of health literacy. From our qualitative analysis, 3 concepts emerged. First, was that patients had poor understanding of their diagnosis before and after the encounter regardless of how extensive the physician's explanation or level of Spanish-proficiency. Second, patients were overwhelmed with the amount of information given to them. Lastly, patients ultimately put their trust in the physician, relying on them for treatment recommendations. Our findings emphasize the difficulty Spanish-speaking women with low health literacy have in understanding information regarding pelvic floor disorders. In this specific population, the physician has a major role in influencing patients' treatment decisions and helping them overcome fears they may have about their condition.


Differential radio-adaptive responses in BALB/c and C57BL/6 mice: pivotal role of calcium and nitric oxide signalling.
Purpose: Our earlier studies demonstrated that transient radio-adaptive responses (RAR) in BALB/c mice were due to MAPK hyperactivation. The objective of this study was to determine the time duration of this low dose induced MAPK activation in BALB/c mice and to find out if similar adaptive responses are observed in C57BL/6 mice. Materials and methods: Mice were irradiated with 0.1 Gy priming dose (PD), 2 Gy challenge dose (CD) with an interval of 4 h (P + CD) and radiation induced immunosuppression in splenic lymphocytes was monitored as the endpoint for RAR. Results: Time kinetics following 0.1 Gy demonstrated persistence of MAPK hyperactivation till 48 h. Similar experiments in C57BL/6 mice indicated absence of RAR at 24 h following CD, in spite of MAPK activation which was also confirmed by time kinetics. Therefore, upstream activators of MAPK, viz., reactive oxygen and nitrogen species (ROS, RNS) and calcium levels were estimated. There was increased intracellular calcium (Ca2+) and nitric oxide (NO) in BALB/c and an increase in intracellular ROS in C57BL/6 mice 24 h after PD. Inhibition of NO and calcium chelation abrogated RAR in BALB/c mice. In vitro treatment of spleen cells with combination of NO donor and Ca2+ ionophore mimicked the effect of PD and induced adaptive response after 2 Gy not only in BALB/c but also in C57BL/6 mice confirming their crucial role in RAR. Conclusions: These results suggest that low dose induced differential induction of Ca2+ and NO signaling along with MAPK was responsible for contrasting RAR with respect to immune system of BALB/c and C57BL/6 mice. Abbreviations [3H]-TdR: 3H-methyl-thymidine; BAPTA: 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; CD: Challenge Dose; CFSE: Carboxy Fluorescein Succinamidyl Ester; on A: Concanavalin A; DAF-FM: 4-amino-5-methylamino-2',7'-difluorescein; DCF-DA: 2',7'-dichlorofluorescein diacetate; DSB: Double Strand Break; ELISA: Enzyme Linked ImmunoSorbent Assay; ERK: Extracellular signal-Regulated protein Kinase; FBS: Fetal Bovine Serum; HIF-1A: Hypoxia-Inducible Factor 1-alpha; LDR: Low Dose Radiation; MAPK: Mitogen Activated Protein Kinase; MAPKK/MKK: MAPK Kinase; MAPKKK: MAPK Kinase Kinase; NO: Nitric Oxide; NOS: Nitric Oxide Synthase; P + CD: Priming + Challenge dose; PBS: Phosphate Buffered Saline; PBST: Phosphate Buffered Saline-Tween 20; PD: Priming Dose; PI3K: Phosphatidyl Inositol 3-Kinase; PKC: Protein Kinase C; RAR: Radio Adaptive Response; RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen Species; RPMI-1640: Roswell Park Memorial Institute-1640 medium; SAPK/JNK: Stress-Activated Protein Kinase/ c-Jun NH2-terminal Kinase; SEM: Standard Error of Mean; SNAP: S-nitro amino penicillamine; TP53: Tumor Protein 53; γ-H2AX: Gamma- H2A histone family member X; Th1: Type 1 helper T cell responses; Th2: Type 2 helper T cell responses.


Sunlight-induced covalent marriage of two triply interlocked Pd6 cages and their facile thermal separation.
A template-free triply interlocked Pd6 cage (2) was synthesized by two-component self-assembly of cis-blocked 90° acceptor cis-(tmen)Pd(NO3)2 (M) and 1,3,5-tris((E)-2-(pyridin-3-yl)vinyl)benzene (L). Assembly 2 was characterized by (1)H NMR and ESI-MS, and the structure was confirmed by X-ray crystallography, which revealed a parallel conformation of the olefin double bonds belonging to the adjacent cages in the solid state at a distance of 3.656 Å, thereby indicating the feasibility of [2+2] photochemical reaction. Two adjacent interlocked cages were covalently married together by intermolecular [2+2] cycloaddition in a single crystal-to-single crystal fashion upon exposure to sunlight/UV irradiation. Most surprisingly, the covalently married pair was easily separated thermally in aqueous medium under mild reaction conditions.


Outcomes after the surgery for acquired nonaccommodative esotropia.
To analyze the surgical outcomes for patients diagnosed with acquired nonaccommodative esotropia (ANAET). In this retrospective study, the medical records of 35 patients who had undergone the surgery for ANAET with a postoperative follow-up period of 6 months or more were reviewed. The main outcome measures were postoperative esodeviation angle, final success rate, and factors affecting surgical outcome. Surgical success was considered to be an alignment within 8 prism diopters (PD) at distance and near. The preoperative mean esodeviation angles were 37.3 ± 13.7 PD at distance and 38.6 ± 16.6 PD at near. The postoperative mean esodeviation angles at distance were as follows: 4.2 PD at day 1, 4.0 PD at month 1, 3.9 PD at month 3, 4.9 PD at month 6, 4.7 PD at year 1, and 4.8 PD at final follow-up. There was no statistically significant difference in angle of esodeviation between the initial postoperative period (day 1 to month 6) and the final follow-up day (p > 0.05). The surgical success rate at final follow-up was 65.7% (23/35). Among the 12 patients for whom the surgery failed, 9 (24.3%) showed esotropia and 3 (8.1%) exotropia of more than 8 PD. Six patients (16.2%) underwent reoperation (4 for esotropia and 2 for exotropia). There was no factor influencing surgical outcome (p > 0.05). The surgical outcome in patients with ANAET was relatively favorable: the final success rate was 65.7% and the reoperation rate was 17.1%.


A single brain-derived neurotrophic factor infusion into the dorsomedial prefrontal cortex attenuates cocaine self-administration-induced phosphorylation of synapsin in the nucleus accumbens during early withdrawal.
Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration-induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal.


[Primary health care teams management models according to the supplier and the effects on its dynamics in Catalonia].
The catalan primary care (PC) management model is differentiated from the rest of regional autonomies because it has a greater diversity of providers The objective was to explore and compare management models according to the primary care provider in Catalonia based on the professionals' vision. An online survey was carried out on February 1st 2017 to March 17th 2017 and structured in 6 sections that explored filiation, organization, accessibility, resolution, leadership and commitment. The analysis compares the answers grouped by entity providing Primary Health Care (PHC) services in Catalonia: Institut Català de la Salut (ICS), Public Consortium (CP), Public Consortium that also manages Hospital (CPH), Associative Base Entities (EBA) and Private Entities. The continuous variables were analyzed with the ANOVA test, and the categorical ones with chi-square or Fisher's exact test. T1474 responses were obtained, female gender was 78,1%, mean age was 48 years. 90% were doctors or nurses, 87% working in non-rural environments and 71% in ICS. The professionals of EBA declared greater ease (79.1%) and recognition (76.1%) for the development of professional skills, delay under 72h in scheduled appointments (83.9%) and increased self-management of agenda (87.5%). 54.2% of Public Consortium professionals (CP) and 55.4% of EBApresented high access to diagnostic tests and advanced nurse management of demand, 54.2% and 51.8%, respectively. It was highlighted a greater commitment, in entities with greater possibility of agenda self-management, a plan for training professional activities, objectives recognition, feedback on the activity results and EBA. The management models of PHC providers determine different characteristics. The most favourable answers to autonomous management, resolution, accessibility and commitment stand out in the EBA and CP professionals group who answered the survey.


Breakpoint characterization: a new approach for segregation analysis of paracentric inversion in human sperm.
Paracentric inversions (PAI) are structural chromosomal rearrangements generally considered to be harmless. Nevertheless, cases of viable recombinants have been reported, indicating the interest of studying the meiotic behaviour of these chromosomal abnormalities. To date, the few studies reported have been performed using either the human-hamster fertilization system or fluorescence in situ hybridization with centromeric or telomeric DNA probes. In order to improve the assessment of meiotic segregation in PAI, we present a new strategy based on the use of bacterial artificial chromosome (BAC) probes which allow a precise localization of chromosome breakpoints and the identification of all meiotic products in human sperm. Sperm samples from carriers of an inv(5) and an inv(14) were used to test this new high-resolution procedure.


Metaproteome analysis to determine the metabolically active part of a thermophilic microbial community producing biogas from agricultural biomass.
Complex consortia of microorganisms are responsible for biogas production. A lot of information about the taxonomic structure and enzymatic potential of such communities has been collected by a variety of gene-based approaches, yet little is known about which of all the assumable metabolic pathways are active throughout the process of biogas formation. To tackle this problem, we established a protocol for the metaproteomic analysis of samples taken from biogas reactors fed with agricultural biomass. In contrast to previous studies where an anaerobic digester was fed with synthetic wastewater, the complex matrix in this study required the extraction of proteins with liquid phenol and the application of paper bridge loading for 2-dimensional gel electrophoresis. Proteins were subjected to nanoHPLC (high-performance liquid chromatography) coupled to tandem mass spectrometry for characterization. Several housekeeping proteins as well as methanogenesis-related enzymes were identified by a MASCOT search and de novo sequencing, which proved the feasibility of our approach. The establishment of such an approach is the basis for further metaproteomic studies of biogas-producing communities. In particular, the apparent status of metabolic activities within the communities can be monitored. The knowledge collected from such experiments could lead to further improvements of biogas production.


Mulliken method of bilateral cleft lip repair: anthropometric evaluation.
Simultaneous surgical correction of bilateral cleft lip and nasal deformity is becoming more common. This is a major change from the conventional strategy of secondary nasal correction. Thirty patients with bilateral cleft lip and nasal deformity were repaired using the Mulliken method between July of 1997 and December of 2002. This series was composed of 10 infants with bilateral complete cleft lip, 12 with bilateral incomplete cleft lip, and eight with bilateral asymmetric cleft lip, defined as complete on one side and incomplete on the other. A preoperative orthopedic appliance was employed in five infants who had severe collapse of the lateral maxillary segments. Mean age at the time of repair was 3.8 months. Postoperative results were evaluated anthropometrically. The mean follow-up period was 3.8 years (range, 1.2 to 5.5 years). Nasal tip protrusion was low; interalar dimension was wide; columellar length was slightly short; upper cutaneous labial height was short; and vermilion-mucosal height was near normal. All anthropometric values approached controls by 5 years. Our modified Mulliken method is effective in correction of all forms of bilateral cleft lip and nasal deformity. Further evaluation is needed for possible differences in outcome based on race and age at the time of operation.


Computer-assisted analysis of the impact of respiratory quotient on blood CO2 tension and pH changes.
A computer model for the accurate quantification of blood gas exchange components was used to assess the impact of respiratory quotient (RQ) on venoarterial CO2 tension and pH differences over a large group of patient measurements. The combined use of measured and computer-generated data has shown that, for any given increase in blood CO2 concentration (i.e., when the arterial blood becomes venous), the associated increase in CO2 tension and decrease in pH are inversely related to the RQ, and that this relationship is mediated by the Haldane effect. These results are useful for a through understanding of blood gas and metabolic interactions in normal and abnormal states, and for improving the interpretation of changes in venoarterial CO2 tension gradient in clinical monitoring.


Activity of the multidrug transporter results in alkalinization of the cytosol: measurement of cytosolic pH by microinjection of a pH-sensitive dye.
Multidrug-resistant cells contain a plasma membrane efflux pump, the multidrug transporter, which actively expels certain hydrophobic drugs from the cytosol to the cell exterior. These drugs are usually positively charged at physiological pH. Because one might predict that this efflux of positively charged molecules might deplete the cytosol of protons, raising the cytosolic pH, we examined the cytosolic pH of multidrug-resistant cells directly using a pH-sensitive dye coupled to a membrane-impermeable molecule. The dye (SNARF), covalently coupled to 10,000 MW dextran, was mechanically microinjected into the cytosol of cultured multidrug-resistant mouse NIH3T3 cells which express the human multidrug transporter. The fluorescence emission of the dye in living cells was measured using epifluorescence microscopy at different wavelengths to provide a measure of the pH of the cytosolic environment. Multidrug-resistant cells had a higher cytosolic pH than drug-sensitive normal parental cells. As the pH of the culture medium was increased, normal cells maintained their cytosolic pH below 7.0, whereas the cytosolic pH of multidrug resistant cells rose. The difference in cytosolic pH between the two cell types was more than 0.2 pH units at an external culture medium pH of 8.2. Treatment with agents that inhibit multidrug transporter-mediated efflux, such as verapamil and vinblastine, essentially eliminated the elevation of cytosolic pH, presumably because they are good substrates for the pump which overwhelm its capacity to pump other materials. These results suggest that the multidrug transporter is indirectly a proton pump, and that cells may contain an endogenous substrate or substrates for this transporter in the absence of added drugs.


Multiple fuzzy neural network system for outcome prediction and classification of 220 lymphoma patients on the basis of molecular profiling.
A fuzzy neural network (FNN) using gene expression profile data can select combinations of genes from thousands of genes, and is applicable to predict outcome for cancer patients after chemotherapy. However, wide clinical heterogeneity reduces the accuracy of prediction. To overcome this problem, we have proposed an FNN system based on majoritarian decision using multiple noninferior models. We used transcriptional profiling data, which were obtained from "Lymphochip" DNA microarrays (http://llmpp.nih.gov/DLBCL), reported by Rosenwald (N Engl J Med 2002; 346: 1937-47). When the data were analyzed by our FNN system, accuracy (73.4%) of outcome prediction using only 1 FNN model with 4 genes was higher than that (68.5%) of the Cox model using 17 genes. Higher accuracy (91%) was obtained when an FNN system with 9 noninferior models, consisting of 35 independent genes, was used. The genes selected by the system included genes that are informative in the prognosis of Diffuse large B-cell lymphoma (DLBCL), such as genes showing an expression pattern similar to that of CD10 and BCL-6 or similar to that of IRF-4 and BCL-4. We classified 220 DLBCL patients into 5 groups using the prediction results of 9 FNN models. These groups may correspond to DLBCL subtypes. In group A containing half of the 220 patients, patients with poor outcome were found to satisfy 2 rules, i.e., high expression of MAX dimerization with high expression of unknown A (LC_26146), or high expression of MAX dimerization with low expression of unknown B (LC_33144). The present paper is the first to describe the multiple noninferior FNN modeling system. This system is a powerful tool for predicting outcome and classifying patients, and is applicable to other heterogeneous diseases.


Joint Learning of Representations of Medical Concepts and Words from EHR Data.
There has been an increasing interest in learning low-dimensional vector representations of medical concepts from electronic health records (EHRs). While EHRs contain structured data such as diagnostic codes and laboratory tests, they also contain unstructured clinical notes, which provide more nuanced details on a patient's health status. In this work, we propose a method that jointly learns medical concept and word representations. In particular, we focus on capturing the relationship between medical codes and words by using a novel learning scheme for word2vec model. Our method exploits relationships between different parts of EHRs in the same visit and embeds both codes and words in the same continuous vector space. In the end, we are able to derive clusters which reflect distinct disease and treatment patterns. In our experiments, we qualitatively show how our methods of grouping words for given diagnostic codes compares with a topic modeling approach. We also test how well our representations can be used to predict disease patterns of the next visit. The results show that our approach outperforms several common methods.


Factors Influencing Delay in Diagnosis of Head and Neck Cancer in Rwanda.
Head and neck cancer is a significant contributor to global otolaryngologic disease burden, with a disproportionate impact on low- and middle-income countries. This study investigates the factors contributing to delays in head and neck cancer diagnosis at the University Teaching Hospital of Kigali (CHUK). Cross-sectional study of all patients with a pathologic diagnosis of head and neck cancer presenting to CHUK between January 2021 and June 2022. Sociodemographic data, tumor characteristics, and reasons for delay were collected. Univariate and multivariable analyses were undertaken to evaluate risk factors for delays. Eighty-one patients met criteria for inclusion. Median duration from patient first reported symptoms to initial medical consultation was 52 weeks, from initial medical consultation to referral to CHUK was 4 weeks, and from referral to final pathologic diagnosis was 6 weeks. The most common reason for delay to referral to CHUK was financial (37.04%). Patients who visited traditional healers had higher odds of delay between symptom onset and medical consultation (OR 3.51, CI 1.05-11.70). Delays in final diagnosis after referral were most commonly due to OR availability for biopsy (37.04%) and time for pathology results after biopsy (35.80%). OR availability had a significant impact on duration to final diagnosis (OR 59.48, CI 7.17-493.67). Stage 4 disease had the shortest time to final diagnosis (OR 0.05, CI 0.01-0.45). Understanding the reasons for delayed diagnosis of head and neck cancer may help guide improvements in care, with the goal of reducing global head and neck burden of disease. 3; prospective non-random follow-up study Laryngoscope, 2023.


Microscopic and histological examination of the mouse hindpaw digit and flexor tendon arrangement with 3D reconstruction.
Mice are currently the species of choice for the in vivo study of injury, but few detailed anatomical descriptions have been made of rodent digits, limiting their use for the investigation of intrasynovial tendon healing. In this study a detailed microscopic and histological investigation was performed using C57/BL6 and Tie2 LacZ reporter gene transgenic mice. Serial-sectioned mouse hindpaw digits were characterized using haematoxylin and eosin, Masson's trichrome (collagen), Alcian blue (fibrocartilage), Miller's stain (elastin) and TRITC-phalloidin (cellular cytoskeleton) staining. Digital vasculature was demonstrated using FITC-labelled dextran perfusion studies supplemented with LacZ expression in Tie2 LacZ transgenic mice digits. Imaging of the digit used a combination of brightfield and confocal microscopy with three-dimensional reconstruction. Our findings demonstrated that the mouse hindpaw possesses deep and superficial flexor tendons within a synovial sheath comparable with that found in other mammalian species. The intrasynovial tendons were avascular and had regions of fibrocartilaginous specialization relating to areas of compression. Corresponding vascular networks were demonstrated around the sheath using Tie2 LacZ mice and FITC-perfused hindpaws. Furthermore, there is an area of digit where both deep and superficial tendons reside between two pulleys, similar to zone 2 in the human hand where it would be possible to study intrasynovial tendon injury and adhesion formation. In conclusion, although the dimensions of the mouse digit pose technical challenges for surgical intervention, we have identified a model for the study of flexor tendon injury that will permit future genetic manipulation studies.


A Case of Congenital Glucose Galactose Malabsorption with a New Mutation in the SLC5A1 Gene.
Congenital glucose-galactose malabsorption (CGGM) is an autosomal recessive disorder originating from an abnormal transporter mechanism in the intestines. It was sourced from a mutation in the SLC5A1 gene, which encodes a sodium-dependent glucose transporter. Here we report a 2-day-old girl with CGGM who presented with severe hypernatremic dehydration due to diarrhea beginning in the first hours of life. Mutation analysis revealed a novel homozygous mutation NM_000343.3 c.127G > A (p.Gly43Arg) in the SLC5A1 gene. Since CGGM can cause fatal diarrhea in the early neonatal period, timely diagnosis of the disease seems to be essential.


Anti-VEGF treatment of diabetic macular edema in clinical practice: effectiveness and patterns of use (ECHO Study Report 1).
To evaluate the efficacy, safety, and injection frequency of vascular endothelial growth factor (VEGF) inhibitors as used in clinical practice for the treatment of diabetic macular edema. Multicenter (10 sites), retrospective chart review in patients (n=156) who received ≥3 anti-VEGF injections. Data collected for ≥6 months after the first injection included Snellen best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by time-domain or spectral-domain optical coherence tomography (TD-OCT or SD-OCT). Mean number of anti-VEGF injections (627 bevacizumab, 594 ranibizumab, 1 aflibercept) was 5.8 (year 1), 5.0 (year 2), and 3.4 (year 3). Percentage of patients with BCVA of 20/40 or better and CRT ≤250 μm on TD-OCT or ≤300 μm on SD-OCT at the same visit (primary endpoint) ranged from 16.4% to 38.9% after the first 10 injections; 51.9%-62.3% achieved ≥20/40 BCVA and 26.2%-48.0% met CRT criteria. Therapy was well tolerated with 19 treatment-related adverse events (all ocular) reported. Anti-VEGF injections were administered less frequently and were less effective than those in the ranibizumab registration trials. After each of the first 9 injections, <25% of patients achieved both BCVA of 20/40 or better and a dry macula. A substantial proportion of patients are suboptimal responders to anti-VEGF therapy; these patients may be candidates for other therapies, including intravitreal corticosteroid and laser therapy.


Alcohol use and a safe environment.
Three areas are discussed which illustrate the potential for drinking to increase the threat to personal safety, i.e. family harm and disruption, violence and crime, and traffic safety. Such threats to safety are especially important in that they extend well beyond the individual drinker into the lives of family members, friends, work colleagues, and even strangers who can become injured or killed in a drinking and driving accident. Thus, alcohol policy is a concern for all citizens whose personal safety can be at risk. From this perspective, alcohol-involved problems are public health and safety issues. Controlled evaluations of a number of strategies provide evidence of potential effectiveness to reduce problems related to safety.


[Leflunomide in systemic lupus erythematosus].
Leflunomide is an antirheumatic drug. One of its main features is its ability to inhibit de novo pyrimidine ribonucleotide biosynthesis. It has been reported as an effective drug in the treatment of patients with Rheumatoid Arthritis. Recently pilot studies have demonstrated the benefit of leflunomide in systemic lupus erythematosus patients. Herein we describe the successful treatment of two lupus patients with leflunomide and review the current literature.


Detection and relative quantification of proteins by surface enhanced Raman using isotopic labels.
Accurate quantification of protein content and composition has been achieved using isotope-edited surface enhanced resonance Raman spectroscopy. Synthesis of isotopomeric Rhodamine dye-linked bioconjugation reagents enabled direct labeling of surface lysines on a variety of proteins. When separated in polyacrylamide gels and stained with silver nanoparticles. The spectral signatures reflect the expected statistical distribution of isotopomeric labels on the labeled proteins in the gel matrix format without interference from protein features.


Polymicrogyria in chromosome 22q11 deletion syndrome.
Central nervous system (CNS) dysfunction is a cardinal feature in 22q11 deletion. The underlying CNS abnormalities remain, however, unknown. We report unilateral hemispheric polymicrogyria in a child with 22q11 deletion presenting with hemiplegia and cognitive and behavioural disorders. This observation widens the spectrum of brain malformations associated with this genetic defect. It further suggests a relationship between the 22q11 deletion and disorders of cerebral gyration. It would therefore be interesting to look for neuronal migration disorders in patients with 22q11 deletion presenting neurological signs, and on the other hand to screen for 22q11 deletion in patients with isolated neuronal migration disorders.


Social representations of gender and their influence in Supported Employment: employment specialists' experiences in Sweden.
Gender differences have been found in the outcomes of vocational rehabilitation (VR) and in Supported Employment (SE), therefore, the purpose of this study was to explore employment specialists' (ES) social representations of gender in relation to work and VR and how these social representations influence the ES's work in the VR process according to SE. The qualitative method of focus group discussions was employed. Ten focus groups were held with 39 ESs from four categories of SE organizations in Sweden. Topic analysis was applied to the transcribed material from the focus groups. Five themes with different social representations about gender and disability in relation to VR and working life formed in the analysis: (1) differences in personal and health factors among VR-participants, (2) gender norms in society influencing VR, (3) energy-intensive environmental issues influencing VR, (4) gender-specific interactions in VR, and (5) gendered paths in the welfare system. Social representations of higher strains on women with disabilities compared to men with disabilities both in private and working life, which reflect the lived experiences of the ESs, is a possible explanation for gender differences in VR and working life for persons with disabilities.IMPLICATIONS FOR REHABILITATIONGender differences in the outcomes of vocational rehabilitation (VR) interventions have been noticed worldwide. In this study, pervasive social representations about gender and disability in relation to VR were found, but also unconsciousness about gender among VR professionals. Therefore, awareness of gender is necessary in VR.Individualized and person-centered approaches to VR like Supported Employment, although considered best practice, might hide structures like gender, which could lead to reproducing discriminating processes and therefore not achieving gender equality in VR. Therefore, knowledge of discrimination is important in VR.Gender-sensitivity in vocational rehabilitation models with a person-centered and individualized approach is needed and there might also be a need to systematically tailor vocational rehabilitation models to reach gender equality in the outcomes of the interventions. Therefore, gender equality indicators are needed for VR models, to evaluate model effectiveness from a gender perspective.


Use of ketamine sedation for the management of displaced paediatric forearm fractures.
To determine if ketamine sedation is a safe and cost effective way of treating displaced paediatric radial and ulna fractures in the emergency department. Following an agreed interdepartmental protocol, fractures of the radius and ulna (moderately to severely displaced) in children between the age of 2 and 16 years old, presenting within a specified 4 mo period, were manipulated in our paediatric emergency department. Verbal and written consent was obtained prior to procedural sedation to ensure parents were informed and satisfied to have ketamine. A single attempt at manipulation was performed. Pre and post manipulation radiographs were requested and assessed to ensure adequacy of reduction. Parental satisfaction surveys were collected after the procedure to assess the perceived quality of treatment. After closed reduction and cast immobilisation, patients were then followed-up in the paediatric outpatient fracture clinic and functional outcomes measured prospectively. A cost analysis compared to more formal manipulation under a general anaesthetic was also undertaken. During the 4 mo period of study, 10 closed, moderate to severely displaced fractures were identified and treated in the paediatric emergency department using our ketamine sedation protocol. These included fractures of the growth plate (3), fractures of both radius and ulna (6) and a single isolated proximal radius fracture. The mean time from administration of ketamine until completion of the moulded plaster was 20 min. The mean time interval from sedation to full recovery was 74 min. We had no cases of unacceptable fracture reduction and no patients required any further manipulation, either in fracture clinic or under a more formal general anaesthetic. There were no serious adverse events in relation to the use of ketamine. Parents, patients and clinicians reported extremely favourable outcomes using this technique. Furthermore, compared to using a manipulation under general anaesthesia, each case performed under ketamine sedation was associated with a saving of £1470, the overall study saving being £14700. Ketamine procedural sedation in the paediatric population is a safe and cost effective method for the treatment of displaced fractures of the radius and ulna, with high parent satisfaction rates.


[Mycobacteriosis of ornamental birds--frequency, pathologo-anatomic, histologic and microbiologic data].
Mycobacteriosis was diagnosed in 146 (3.8%) of 3801 necropsied pet birds between 1986 und 1991. Gross changes in 62 pet birds with histologically and culturally confirmed mycobacteriosis were predominantly enlargement of liver and spleen and thickening of intestinal walls. Three histological patterns could be observed: granulomas, sheet-like proliferations of mycobacteria-laden epithelioid cells and single scattered macrophages filled with acid-fast bacteria. Mycobacteria grew in 27 (43.6%) of 62 cultures, but the species could only be identified in 13 (21.0%) cases (5 x M. avium-Complex, 3 x M. genavense, 2 x M. fortuitum, 1 x M. gordonae, 1 x M. nonchromogenicum and 1 x M. tuberculosis). The significance of mycobacteriosis in pet birds as a zoonosis remains to be determined.


Trismus in the paediatric population.
Trismus is a rare presentation affecting neonates, children, and adults. In newborns there are serious implications, with potential to affect feeding, cause airway problems, and make intubation difficult. Causes of trismus seen in the paediatric patient are discussed in this review article; they are divided into intra- and extra-articular types. The extra-articular group consists of congenital and acquired disorders. The acquired group includes infective causes such as tetanus, iatrogenic causes related to drugs, cancer or dental treatment, and trauma causing articulation difficulty or triggering a rare type of bone growth in myositis ossificans. Changes in the mouth resulting from oral submucous fibrosis can undergo malignant transformation. This review aims to raise awareness of potential causes of trismus in paediatric populations, helping clinicians identify the underlying pathology so appropriate strategies for treatment be applied, with the ultimate aim of improving long-term outlook and quality of life for affected children.


Malfunction and failure of robotic systems during general surgical procedures.
There has been recent interest in using robots for general surgical procedures. This shift in technique raises the issue of patient safety with automated instrumentation. Although the safety of robotics has been established for urologic procedures, there are scant data on its use in general surgical procedures. The aim of this study is to analyze the incidence of robotic malfunction and its consequences for general surgical procedures. All robotic general surgical procedures performed at a tertiary center between 2008 and 2011 were reviewed from institutional review board (IRB)-approved prospective databases. A total of 223 cases were done robotically, including 102 endocrine, 83 hepatopancreaticobiliary, 17 upper gastrointestinal, and 21 lower gastrointestinal colorectal procedures. There were 10 cases of robotic malfunction (4.5%). These failures were related to robotic instruments (n = 4), optical system (n = 3), robotic arms (n = 2), and robotic console (n = 1). None of these failures led to adverse patient consequences or conversion to open. Six (2.7%) cases were converted to open due to bleeding (n = 3), difficult dissection plane (n = 1), invasion of tumor to surrounding structures (n = 1), and intolerance of pneumoperitoneum due to CO(2) retention (n = 1). There was no mortality, and morbidity was 1% (n = 2). To our knowledge, this is the largest North American report to date on robotic general surgical procedures. Our results show that robotic malfunction occurs in a minority of cases, with no adverse consequences. We believe that awareness of these failures and knowing how to troubleshoot are important to maintain the efficiency of these procedures.


Dimensional accuracy of a binder jet model produced from computerized tomography data for dental implants.
A full-scale model produced by multislice helical computerized tomography (CT) was made by using the binder jet method and applied for presurgical diagnosis, surgical simulation, and the production of surgical templates for dental implant treatment. In this study, accuracy of the full-scale model with plaster powder was assessed by shifting the binary threshold values. A step phantom was made from bone-equivalent material. When it was placed in water, the CT imaging was performed with a multislice helical CT unit. Three-dimensional (3-D) images were reconstructed by 3-D visualization software. Using 4 different threshold values, full-scale models were produced by a binder jet method with plaster powder. All sides of the full-scale models were directly measured, and their values were compared with that of the step phantom. The mean difference was approximately 0.1 mm in the axial plane when the setting was 0.75 for the threshold. In total, the mean difference was approximately 0.2 mm when the setting was 0.50 for the threshold. It is suggested this full-scale model could be applied for presurgical diagnosis, surgical simulation, and the production of surgical templates in dental implant treatment.


A prospective study of collapsing focal segmental glomerulosclerosis.
Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by rapid progression to end-stage renal disease (ESRD). We evaluated the clinicopathological spectrum of cFSGS and compared its clinical behavior to steroid and tacrolimus (TAC)-resistant noncollapsing focal segmental glomerulosclerosis (FSGS). All patients (>14 years) diagnosed with cFSGS were enrolled in the study. Staining for differentiated podocyte markers such as WT 1, PAX and KI67 were performed in all patients. The outcome and histological features of cFSGS was compared with a prospectively followed cohort of steroid and TAC-resistant noncollapsing FSGS. The study included 22 cFSGS patients and 19 cases of steroid and TAC-resistant FSGS. Complete remission, partial remission, steroid resistance, progression to ESRD and death were observed in 13.6%, 4.5%, 27.3%, 36.4% and 18.2% patients, respectively. Patients with cFSGS had higher serum creatinine and more advanced tubulointerstitial changes compared to resistant FSGS. Twenty-six percent of therapy resistant noncollapsing FSGS progressed to ESRD after two years of stopping TAC. However, there was no difference in progression to ESRD between cFSGS and therapy-resistant noncollapsing FSGS at the end of two years. Glomerular collapse in the setting of FSGS is poorly responsive to treatment and has a high rate of progression to ESRD. The long-term prognosis of cFSGS and steroid and TAC-resistant FSGS are similar.


Mechano-bioengineering of the knee meniscus.
The meniscus is a fibrocartilaginous structure of the knee joint that serves a crucial role in joint health and biomechanics. Degeneration or removal of the meniscus is known to lead to a chronic and debilitating disease known as knee osteoarthritis, whose prevalence is expected to increase in the next few decades. Meniscus bioengineering has been developed as a potential alternative to current treatment methods, wherein meniscus-like tissues are engineered using cells, materials, and biomechanical stimuli. The application of mechanical stimulation in meniscus bioengineering has presented varied results but, for the most part, it has been shown to enhance meniscus-like tissue formation. In this review, we summarized literature over the last 10 years of various mechanical stimuli applied in bioengineering meniscus tissues. The role of individual loading types is examined, and the effects on engineered meniscus are evaluated on both molecular and tissue levels. In addition, simulated microgravity is highlighted as a new area of interest in meniscus engineering, and its potential use as a disease-driving platform is discussed. Taken together, with the increased understanding of the effects of mechanical stimulation on bioengineered meniscus tissues, the most suitable loading regime could be developed for meniscus tissue engineering and osteoarthritis modeling.


Polymorphisms in major cytokine genes: a study among human immunodeficiency Virus-1 serodiscordant couples in Mumbai, India.
Polymorphism in cytokine genes may affect its production, which play an important role in modulation of human immunodeficiency virus (HIV) infection. Evaluation of these polymorphisms might help to understand why some individuals remain uninfected in spite of several exposures to HIV infection, such as the negative spouses of discordant couples. The aim of this study was to evaluate the association of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and their receptors with HIV infection in serodiscordant couples, attending the Integrated Counselling and Testing Centre of a Municipality Hospital. At the end of at least 2 years of follow up, 42 couples were confirmed as being serodiscordant. Genotyping was carried out in blood samples of these couples using the polymerase chain reaction-sequence-specific amplification method. Significantly high frequency of interleukin-1 receptor antagonist IL-1RA mspa 11100 CC (P=0.04), tumor necrosis factor-alpha TNF-α -238 AG (P=0.01) and IL-4 -33 TT (P=0.01) was observed in HIV seropositives (HSP) while frequency of TNF-α -238 GG (P=0.02) was significantly high among the exposed uninfected (EU). However, application of Bonferroni correction identified only two SNPs i.e., TNF-α -238 AG and IL-4 -33 TT to be significantly associated with the acquisition of HIV. In remaining cytokine genes, no significant association was observed. Our study highlighted possible association of certain specific polymorphisms with HIV transmission, whereas presence or absence of certain other polymorphism in EU individuals might be offering protection from HIV infection. These variations at the genetic level might help to explore new insights into treatment and HIV prevention strategies.


Post-traumatic valgus deformity of the knee in proximal tibial metaphyseal fractures in children.
Fractures of the proximal metaphysis of the tibia in children, not involving the growth cartilage and even if there is no significant displacement between the fragments, may give rise to post-traumatic valgus deformity of the knee. This deformity generally tends to be self-correcting if less than 15 degrees but if it is beyond this it does not have the same tendency to spontaneous correction. In such circumstances the normal alignment should be re-established by osteotomy and epiphysiodesis.


Removing the neglect from neglected tropical diseases: the Rwandan experience 2008-2010.
While there has been increasing recognition of the importance of neglected tropical diseases (NTDs), national scale action and funding remain limited. In 2007, a 3-year, $1 million per year programme was launched in Rwanda to address NTDs. While more than $100 million had flowed into Rwanda's health sector annually, not $1 was allocated for NTDs. This article describes the development of a national NTD strategy in Rwanda and outlines lessons learned, with particular regard to integrated approaches to NTD prevention. A baseline survey revealed that more than 65% of children had intestinal worms with high levels of concurrent multiple parasite infection. Within a year, mass treatment administration was provided for the first time. A repeat survey found that prevalence of soil-transmitted helminths and Schistosoma mansoni infection had been reduced significantly, including a reduction in prevalence of S. mansoni of 82% and of 72% in hookworm. Infection intensity and signs of early clinical morbidity also decreased significantly. Despite ongoing global neglect, the Rwandan NTD response presents a promising and unheralded success in science-based national public health action at scale. Looking forward, greater integration of the NTD response with water and sanitation activities are needed to consolidate impact and sustainably reduce the disease burden.


Postoperative hydrocephalus in patients undergoing decompressive hemicraniectomy for ischemic or hemorrhagic stroke.
We have frequently observed the development of postoperative communicating hydrocephalus in patients undergoing decompressive hemicraniectomy. This condition may persist in some patients after cranioplasty and require permanent cerebrospinal fluid (CSF) diversion. To confirm an independent correlation between hemicraniectomy and the development of communicating hydrocephalus, and to detail the frequency and potential clinical factors contributing to this complication, we evaluated our series of patients undergoing hemicraniectomy for life-threatening increases in intracranial pressure secondary to ischemic or hemorrhagic stroke. A retrospective analysis was performed with a cohort of consecutive patients who underwent emergent hemicraniectomy for medically refractory elevations in intracranial pressure. Patients with known independent risk factors for the development of communicating hydrocephalus were excluded. Clinical and imaging data were reviewed to determine the incidence and type of hydrocephalus after hemicraniectomy, the persistence of hydrocephalus after cranioplasty, and the need for permanent CSF diversion. Eighty-eight percent of the eligible patients undergoing hemicraniectomy in our cohort developed postoperative communicating hydrocephalus. Half of these patients harbored persistent hydrocephalus after cranioplasty and required placement of a ventriculoperitoneal shunt. We noted a strong correlation between prolonged time to replacement of the bone flap and persistence of hydrocephalus. Communicating hydrocephalus is an almost universal finding in patients after hemicraniectomy. Delayed time to cranioplasty is linked with the development of persistent hydrocephalus, necessitating permanent CSF diversion in some patients. We propose that early cranioplasty, when possible, may restore normal intracranial pressure dynamics and prevent the need for permanent CSF diversion in patients after hemicraniectomy.


MicroRNA‑146a‑5p enhances cisplatin‑induced apoptosis in ovarian cancer cells by targeting multiple anti‑apoptotic genes.
MicroRNAs play a crucial role in gene expression regulation in various types of cancers. Previous studies show the expression level of miR‑146a‑5p is downregulated in epithelial ovarian cancer. Further investigations suggest this downregulation is responsible for apoptosis resistance in ovarian cancer cells. However, the mechanism of how miR‑146a‑5p promotes apoptosis remains unclear. In this study, the role of miR‑146a‑5p in cisplatin‑induced apoptosis of ovarian cancer cells was assessed by DAPI staining, MTT assays, and monitoring expression of XIAP, BCL2L2, BIRC2 and BIRC5 through a dual‑luciferase assay. Our results show that miR‑146a‑5p can regulate three important anti‑apoptotic genes including XIAP, BCL2L2 and BIRC5 via their 3'UTRs. Not only can overexpression of miR‑146a‑5p downregulate the expression of XIAP in SKOV3 cells, but it also lowers the IC50 values of cisplatin in OVCAR3 and SKOV3 cells and enhances the susceptibility of OVCAR3, SKOV3 and primary ovarian cancer cells to cisplatin‑induced apoptosis. The effect of XIAP rescuing cisplatin‑induced apoptosis accelerated by miR‑146a‑5p further supports our conclusion. Our results suggest that the regulation of three anti‑apoptotic genes by miR‑146‑5p enhances the therapeutic effects of cisplatin.


Modulation by beta-adrenoceptors and angiotensin II receptors of splanchnic nerve evoked catecholamine release from the adrenal medulla.
In the present study, we have evaluated the effect of both facilitatory beta 2-adrenoceptor and angiotensin II receptor on the release of adrenal catecholamines induced by electrical stimulation of the splanchnic nerve in anaesthetized and vagotomized dog. In these experiments, individual or combined treatments with the beta 2-adrenoceptor antagonist ICI 118551 (0.3 mg/kg i.v.), the converting enzyme inhibitor captopril (2 mg/kg i.v.), or the angiotensin II receptor antagonist saralasin (2 micrograms.kg-1.min-1 i.v.) were found to significantly decrease the release of adrenal catecholamines during splanchnic nerve stimulation (5-V pulses of 2 ms duration for 3 min at 1 Hz) whatever the order of administration of the drugs. On the other hand, the infusion of angiotensin II (20 ng.kg-1.min-1) was shown to potentiate the release of adrenal catecholamines in response to electrical stimulation, and this effect was totally blocked by treatment with saralasin (4 micrograms.kg-1.min-1 i.v.). This facilitating angiotensin mechanism differed from beta-adrenoceptor facilitating mechanism, since following beta-blockade with ICI 118551, angiotensin II infusion still significantly potentiated the release of catecholamines during splanchnic nerve stimulation. These observations thus suggest that both facilitating beta 2-adrenoceptors and angiotensin II receptors can independently modulate the release of adrenal catecholamines.


Role of [68Ga]Ga-PSMA-11 PET radiomics to predict post-surgical ISUP grade in primary prostate cancer.
The aim of this study is to investigate the role of [68Ga]Ga-PSMA-11 PET radiomics for the prediction of post-surgical International Society of Urological Pathology (PSISUP) grade in primary prostate cancer (PCa). This retrospective study included 47 PCa patients who underwent [68Ga]Ga-PSMA-11 PET at IRCCS San Raffaele Scientific Institute before radical prostatectomy. The whole prostate was manually contoured on PET images and 103 image biomarker standardization initiative (IBSI)-compliant radiomic features (RFs) were extracted. Features were then selected using the minimum redundancy maximum relevance algorithm and a combination of the 4 most relevant RFs was used to train 12 radiomics machine learning models for the prediction of PSISUP grade: ISUP ≥ 4 vs ISUP < 4. Machine learning models were validated by means of fivefold repeated cross-validation, and two control models were generated to assess that our findings were not surrogates of spurious associations. Balanced accuracy (bACC) was collected for all generated models and compared with Kruskal-Wallis and Mann-Whitney tests. Sensitivity, specificity, and positive and negative predictive values were also reported to provide a complete overview of models' performance. The predictions of the best performing model were compared against ISUP grade at biopsy. ISUP grade at biopsy was upgraded in 9/47 patients after prostatectomy, resulting in a bACC = 85.9%, SN = 71.9%, SP = 100%, PPV = 100%, and NPV = 62.5%, while the best-performing radiomic model yielded a bACC = 87.6%, SN = 88.6%, SP = 86.7%, PPV = 94%, and NPV = 82.5%. All radiomic models trained with at least 2 RFs (GLSZM-Zone Entropy and Shape-Least Axis Length) outperformed the control models. Conversely, no significant differences were found for radiomic models trained with 2 or more RFs (Mann-Whitney p > 0.05). These findings support the role of [68Ga]Ga-PSMA-11 PET radiomics for the accurate and non-invasive prediction of PSISUP grade.


Fermi-surface truncation from thermal nematic fluctuations.
We analyze how thermal fluctuations near a finite temperature nematic phase transition affect the spectral function A(k,ω) for single-electron excitations in a two-dimensional metal. Perturbation theory yields a splitting of the quasiparticle peak with a d-wave form factor, reminiscent of a pseudogap. We present a resummation of contributions to all orders in the Gaussian fluctuation regime. Instead of a splitting, the resulting spectral function exhibits a pronounced broadening of the quasiparticle peak, which varies strongly around the Fermi surface and vanishes upon approaching the Brillouin-zone diagonal. The Fermi surface obtained from a Brillouin-zone plot of A(k,0) seems truncated to Fermi arcs.


Predictors of residual pulmonary vascular obstruction after anticoagulation monotherapy in patients with intermediate-risk pulmonary embolism.
Patients with intermediate-risk pulmonary embolism (PE) can be treated with anticoagulation monotherapy. However, clinicians are concerned as to whether anticoagulation monotherapy is sufficient to reduce mortality in patients with a large embolic burden, and to resolve vascular obstruction. We investigated whether anticoagulation monotherapy was appropriate in patients with intermediate risk PE in terms of the occurrence of residual pulmonary vascular obstruction (RPVO), and the factors that independently predict the occurrence of RPVO. This was a multicenter retrospective observational study of patients at intermediate risk of PE who were admitted to three hospitals between January 2012 and December 2017. Of total 91 patients, the median age was 72 years and 37 (40.7%) were male. Twenty-five patients (27.5%) were diagnosed with RPVO during follow-up. Multivariate logistic regression revealed chronic lung disease [odds ratio (OR), 4.14; 95% confidence interval (CI), 1.243-13.797; P=0.021] and the ratio of the diameters of the main pulmonary artery and ascending aorta ratio (P/A ratio) >1.0 documented on a chest computed tomography (CT) at presentation (OR, 3.46; 95% CI, 1.113-10.770; P=0.032) were significant independent predictors of RPVO occurrence. The incidence of RPVO in patients without these two factors was only 9.7%, but in those with the two factors it was 60% (P=0.004). Anticoagulation monotherapy did not seem to be a sufficient treatment to reduce RPVO, but the outcome was similar to that of patients treated with other therapies. Therefore, considering the risk-benefit ratio, we do not need to change the initial treatment as systemic thrombolytic therapy or catheter-based therapy in patient with intermediate risk PE. Underlying chronic lung disease and a P/A ratio >1 on the initial chest CT predicted the occurrence of RPVO. Therefore, we should carefully assess persistent of dyspnea and exercise limitations using various methods in patients with these risk factors, to detect the occurrence of chronic thromboembolic pulmonary disease (CTEPD) earlier.


Recognition of viral RNA stem-loops by the tandem double-stranded RNA binding domains of PKR.
In humans, the double-stranded RNA (dsRNA)-activated protein kinase (PKR) is expressed in late stages of the innate immune response to viral infection by the interferon pathway. PKR consists of tandem dsRNA binding motifs (dsRBMs) connected via a flexible linker to a Ser/Thr kinase domain. Upon interaction with viral dsRNA, PKR is converted into a catalytically active enzyme capable of phosphorylating a number of target proteins that often results in host cell translational repression. A number of high-resolution structural studies involving individual dsRBMs from proteins other than PKR have highlighted the key features required for interaction with perfectly duplexed RNA substrates. However, viral dsRNA molecules are highly structured and often contain deviations from perfect A-form RNA helices. By use of small-angle X-ray scattering (SAXS), we present solution conformations of the tandem dsRBMs of PKR in complex with two imperfectly base-paired viral dsRNA stem-loops; HIV-1 TAR and adenovirus VA(I)-AS. Both individual components and complexes were purified by size exclusion chromatography and characterized by dynamic light scattering at multiple concentrations to ensure monodispersity. SAXS ab initio solution conformations of the individual components and RNA-protein complexes were determined and highlight the potential of PKR to interact with both stem and loop regions of the RNA. Excellent agreement between experimental and model-based hydrodynamic parameter determination heightens our confidence in the obtained models. Taken together, these data support and provide a framework for the existing biochemical data regarding the tolerance of imperfectly base-paired viral dsRNA by PKR.


Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts.
Electrophilic fatty acid nitroalkene derivatives, products of unsaturated fatty acid nitration, exert long-term cardiovascular protection in experimental models of metabolic and cardiovascular diseases. The goal of this study is to examine the effects of nitro-fatty acids in the regulation of upstream signalling events in nuclear factor-κB (NF-κB) activation and determine whether low-dose acute administration of nitro-fatty acids reduces vascular inflammation in vivo. Using NF-κB-luciferase transgenic mice, it was determined that pre-emptive treatment with nitro-oleic acid (OA-NO2), but not oleic acid (OA) inhibits lipopolysaccharide (LPS)-induced NF-κB activation both in vivo and in isolated macrophages. Acute intravenous administration of OA-NO2 was equally effective to inhibit leukocyte recruitment to the vascular endothelium assessed by intravital microscopy and significantly reduces aortic expression of adhesion molecules. An acute treatment with OA-NO2 in vivo yielding nanomolar concentrations in plasma, is sufficient to inhibit LPS-induced Toll-like receptor 4 (TLR4)-induced cell surface expression in leukocytes and NF-κB activation. In vitro experiments reveal that OA-NO2 suppresses LPS-induced TLR4 signalling, inhibitor of κB (IκBα) phosphorylation and ubiquitination, phosphorylation of the IκB kinase (IKK), impairing the recruitment of the TLR4 and TNF receptor associated factor 6 (TRAF6) to the lipid rafts compartments. These studies demonstrate that acute administration of nitro-fatty acids is effective to reduce vascular inflammation in vivo. These findings reveal a direct role of nitro-fatty acids in the disruption of the TLR4 signalling complex in lipid rafts, upstream events of the NF-κB pathway, leading to resolution of pro-inflammatory activation of NF-κB in the vasculature.


Reduced Diet-induced Thermogenesis in Apolipoprotein A-IV Deficient Mice.
In the presence of dietary lipids, both apolipoprotein A-IV (ApoA-IV) production and brown adipose tissue (BAT) thermogenesis are increased. The effect of dietary lipid-induced AproA-IV on BAT thermogenesis and energy expenditure remains unknown. In the present study, we hypothesized that ApoA-IV knockout (ApoA-IV-KO) mice exhibited decreased BAT thermogenesis to affect energy homeostasis. To test this hypothesis, BAT thermogenesis in wildtype (WT) and ApoA-IV-KO mice fed either a standard low-fat chow diet or a high-fat diet (HFD) was investigated. When fed a chow diet, energy expenditure and food intake were comparable between WT and ApoA-IV-KO mice. After 1 week of HFD consumption, ApoA-IV-KO mice had comparable energy intake but produced lower energy expenditure relative to their WT controls in the dark phase. After an acute feeding of dietary lipids or 1-week HFD feeding, ApoA-IV-KO mice produced lower levels of uncoupling protein 1 (UCP1) and exhibited reduced expression of thermogenic genes in the BAT compared with WT controls. In response to cold exposure, however, ApoA-IV-KO mice had comparable energy expenditure and BAT temperature relative to WT mice. Thus, ApoA-IV-KO mice exhibited reduced diet-induced BAT thermogenesis and energy expenditure.


Killing, letting die and moral perception.
There are a number of arguments that purport to show, in general terms, that there is no difference between killing and letting die. These are used to justify active euthanasia on the basis of the reasons given for allowing patients to die. I argue that the general and abstract arguments fail to take account of the complex and particular situations which are found in the care of those with terminal illness. When in such situations, there are perceptions and intuitions available that do not easily find propositional form but lead most of those whose practice is in the care of the dying to resist active euthanasia. I make a plea for their intuitions to be heeded above the sterile voice of abstract premises and arguments by examining the completeness of the outline form of the pro-euthanasia argument. In doing so, I make use of Nussbaum's discussion of moral perception and general claims to be found in the literature of moral particularism.