Radiofrequency ablation of the nerve to the corrugator muscle for elimination of glabellar furrowing.
Glabellar furrows are caused by hyperdynamic activity of the corrugator supercilii muscles. A minimally invasive, percutaneous technique for eliminating glabellar furrows is described. An insulated, bipolar needle is inserted vertically through the eyebrow skin to entrap the corrugator nerve plexus. To confirm proper positioning, a stimulating current is delivered to the needle during observation of corrugator supercilii muscle response. Radiofrequency energy is then delivered to the needle, thereby ablating the intervening nerve tissue. This technique is in the early stage of optimization and is being evaluated in an ongoing Stanford University Human Subjects protocol, Stanford, Calif. The preliminary results are reported herein.


[The benefits of using patient-reported outcomes in cancer treatment: an overview].
The patient's perspective evaluated by patient-reported outcomes (PROs) gains more and more importance, since treatment efficacy is no longer solely linked to clinical outcomes like cure and overall survival. Ailments like pain, fatigue and social isolation can only be assessed by patients' direct expression without any interpretation made by medical staff. PROs facilitate the disclosure of quality of life issues and patients feel a stronger support due to improved communication. PROs offer many further advantages like saving of time, cost and staff, targeted intervention and sensitizing of clinicians. Also, internationally validated questionnaires are available and the development of electronic PROs eases data-collection, calculation and storage. PROs collected within clinical routine are versatile concerning their applicability: They can be used for scientific analyses, quality assurance, and health technology assessment.


Worth the paper they are printed on? Findings from an independent evaluation of the understandability of patient information leaflets for antiseizure medications.
The Patient Information Leaflet (PIL) is an authoritative document that all people with epilepsy in the EU receive when prescribed antiseizure medication (ASM). We undertook the first independent, comprehensive assessment to determine how understandable they are. Regulators state that when patients are asked comprehension questions about them, ≥80% should answer correctly. Also, recommended is that PILs have a maximum reading requirement of US grade 8. Study 1: We obtained 140 current ASM PILs written in English. "Readability" was assessed using four tests, with and without adjustment for influence of familiar, polysyllabic words. A total of 179 online materials on epilepsy were also assessed. Study 2: Two PILs from Study 1 were randomly selected (Pregabalin Focus; Inovelon) and shown to 35 people from the UK epilepsy population. Their comprehension was assessed. Study 3: To understand whether the student population provides an accessible alternative population for future examination of ASM PILs, Study 3 was completed, using the same methods as Study 2, except that participants were 262 UK university students. Study 1: No PIL had a reading level of grade 8. Median was grade 11. Adjusting for context, the PILs were still at grade 10.5. PILs for branded ASMs were most readable. PILs were no more readable than (unregulated) online materials. Study 2: Users struggled to comprehend the PILs' key messages. The eight questions asked about pregabalin were typically answered correctly by 54%. For Inovelon, it was 62%. Study 3: Most student participants comprehended the PILs' key messages. The questions about Inovelon were answered correctly by 90%; for pregabalin it was 86%. This is the first independent and comprehensive examination of ASM PILs. It found that PILs being used fail to meet recommendations and regulatory requirements and risk not being understandable to a substantial proportion of users. In finding that people from the epilepsy population differ markedly in comprehension of PILs compared to students, this study highlights the importance of completing user testing with the target population.


The Effect of (-)-Epigallocatechin-3-Gallate on the Amyloid-β Secondary Structure.
Amyloid-β (Aβ) is a macromolecular structure of great interest because its misfolding and aggregation, along with changes in the secondary structure, have been correlated with its toxicity in various neurodegenerative diseases. Small drug-like molecules can modulate the amyloid secondary structure and therefore have raised significant interest in applications to active and passive therapies targeting amyloids. In this study, we investigate the interactions of epigallocatechin-3-gallate (EGCG), found in green tea, with Aβ polypeptides, using a combination of in vitro immuno-infrared sensor measurements, docking, molecular dynamics simulations, and ab initio calculations. We find that the interactions of EGCG are dominated by only a few residues in the fibrils, including hydrophobic π-π interactions with aromatic rings of side chains and hydrophilic interactions with the backbone of Aβ, as confirmed by extended (1-μs-long) molecular dynamics simulations. Immuno-infrared sensor data are consistent with degradation of Aβ fibril induced by EGCG and inhibition of Aβ fibril and oligomer formation, as manifested by the recovery of the amide-I band of monomeric Aβ, which is red-shifted by 26 cm-1 when compared to the amide-I band of the fibrillar form. The shift is rationalized by computations of the infrared spectra of Aβ42 model structures, suggesting that the conformational change involves interchain hydrogen bonds in the amyloid fibrils that are broken upon binding of EGCG.


Cross-Cultural Mentorship in Military Family Medicine: Defining the Problem.
Mentorship is critical to physician recruitment, career development, and retention. Many underrepresented in medicine (URiM) physicians experience minority taxes that can undermine their professional objectives. Use of cross-cultural mentoring skills to navigate differences between non-URiM and URiM physicians can make mentorship relationships with URiM physicians more effective. This survey examined military family physician demographics and mentorship practices. Design and Setting: Cross-sectional study using voluntary, anonymous data from the 2021 Uniformed Services Academy of Family Physicians (USAFP) Annual Meeting Omnibus Survey. USAFP Members attending 2021 Virtual Annual Meeting. None. Descriptive statistics and χ2 tests. The response rate to the omnibus survey was 52.9%, n=258. More than half of respondents did not have a URiM mentee and had not collaborated with a URiM colleague on a scholarly activity within the last 3 years. Only 54.7% of respondents could recognize and address minority taxes. URiM physicians were more likely to have a URiM mentee (65.4% vs 44.4%, P=.042) and to recognize and address minority taxes (84.6% vs 51.3%, P=.001). They also were more confident (84.6% vs 60.3%, P=.015) and more skilled in discussing racism (80.8% vs 58.2%, P=.026). Structured programs are needed to improve knowledge and skills to support cross-cultural mentorship. Additional studies are needed to further evaluate and identify implementation strategies.


The effects of acute morphine treatment on the incorporation of [3H]L-lysine by normal and regenerating facial nucleus neurons.
Although opiates significantly alter RNA and protein synthesis in a variety of neuronal cell types, their effect on the biosynthetic activity of regenerating neurons has not been investigated. In the present study, the effect of morphine on the incorporation of [3H]L-lysine into proteins of facial nucleus neurons was examined by light microscopic radioautography. Silver grains present within various compartments of normal and regenerating (3-, 7-, 14- and 21 days post-axotomy) neurons from saline-treated Wistar rats were compared with the amount present in similar cells from animals receiving 40 mg/kg morphine sulfate i.v. At 14- and 21-days post-axotomy, regenerating neurons were larger and the grain count in the emulsion over these cells was greater than that observed in normal (unoperated) neurons. In normal facial neurons, the accumulation of lysine into the nucleus and nucleolus was significantly lower 60 min after morphine administration. However, morphine's inhibition of lysine incorporation was even more pronounced in regenerating neurons. In these cells, nuclear lysine uptake was depressed at 3 and 7 days, while maximum inhibition of cytoplasmic incorporation occurred at 14-days post-axotomy. Morphine administration decreased nucleolar lysine incorporation at all survival intervals.


Hour 25: Neuro ICU.
This short story focuses on two patients in a neuro intensive care unit. (PsycINFO Database Record


Lutzomyia longipalpis (Diptera: Psychodidae: Phlebotominae) in the region of Saquarema: potential area of visceral leishmaniasis transmission in the state of Rio de Janeiro, Brazil.
Lutzomyia longipalpis is the main vector of Leishmania infantum chagasi in the Americas. Phlebotomine captures were conducted during 2008 and 2009 in a rural area endemic for cutaneous leishmaniasis located in the municipality of Saquarema, Rio de Janeiro. Among other species captured, we observed the presence of Lutzomyia longipalpis. This is the first report of the occurrence of Lutzomyia longipalpis in this region, demonstrating the potential risk of visceral leishmaniasis transmission in the coastal area of the State of Rio de Janeiro. Therefore, active vigilance by all municipalities in the area is necessary.


Sensitive ferrocene reagents for derivatization of thiol compounds in high-performance liquid chromatography with dual-electrode coulometric detection.
Three N-substituted maleimides possessing ferrocene as an electrophore were prepared and evaluated for pre-column derivatization of thiol compounds in high-performance liquid chromatography with dual-electrode coulometric detection. The utility of these reagents was investigated by employing N-acetyl-L-cysteine as a model compound. Among the three, N-(ferrocenyl) maleimide was the most favourable reagent with respect to reactivity, stability and electrochemical properties. The dual-electrode coulometric detection of the adduct showed high selectivity and sensitivity with a detection limit of 0.06 pmol. The proposed method is applicable to the determination of glutathione in biological specimens.


On the possibility of detecting fissile nuclear materials using coincident gamma rays.
Almost every radiation monitor installed at the customs and border control points designed for detection of nuclear fissile materials uses gas neutron counters tracing decay neutrons. They have a low background level, but at the same time small efficiency. This work describes the nuclear fissile materials detection methodology based on the instantaneous gamma-radiation accompanying the decay. The tests results of designed and produced radiation monitors based on this principle to control pedestrian and vehicles are presented.


Dynamic metabolic flux analysis--tools for probing transient states of metabolic networks.
Computational approaches for analyzing dynamic states of metabolic networks provide a practical framework for design, control, and optimization of biotechnological processes. In recent years, two promising modeling approaches have emerged for characterizing transients in cellular metabolism, dynamic metabolic flux analysis (DMFA), and dynamic flux balance analysis (DFBA). Both approaches combine metabolic network analysis based on pseudo steady-state (PSS) assumption for intracellular metabolism with dynamic models for extracellular environment. One strategy to capture dynamics is by combining network analysis with a kinetic model. Predictive models are thus established that can be used to optimize bioprocessing conditions and identify useful genetic manipulations. Alternatively, by combining network analysis with methods for analyzing extracellular time-series data, transients in intracellular metabolic fluxes can be determined and applied for process monitoring and control.


Acute mitral valve endocarditis complicated by right atrial fistula in beta-thalassemia major.
Infection is considered to be among the major complications encountered in beta-thalassemia major, with an incidence that may reach 13%. The majority of cases are caused by repeated blood transfusion potentiated by the associated immune defects among these patients. The present case represents a severe form of infection affecting the mitral valve, causing acute heart failure and a fistulous communication between the left ventricle and right atrium.


Results of the United Kingdoms first pilot study for nonmedical endoscopy practitioners.
Spencer and Ready published the first description of nonmedically qualified endoscopists in 1977 [Dis Colon Rectum 1977; 20: 94]. Since then there has been an explosion of interest in this concept. Duthie et al. [Gut 1998; 43: 711] first described Nurse Endoscopy (NE) in the UK in 1998. In recent years, endoscopy services in England have been subject to review as a consequence of perceived inadequacies in service provision and delivery. Increasing pressure on endoscopic services led the Modernisation Agency to commission a pilot study evaluating nontraditional individuals to practice flexible sigmoidoscopy (FS). A science graduate, basic grade nurse and nonclinical member of staff were successfully trained. As a result, a second pilot scheme was introduced, whereby nine nonmedically qualified individuals received education and training in FS. A curriculum was designed, developed and implemented to create an endoscopic practitioner (EP) who was both safe and competent to undertake FS. The student backgrounds included administration, health-care assistants, phlebotomist, junior doctor assistant and clinical physiologist. In the context of academic achievement, prescribed learning outcomes were achieved at a rate of 93% (101 from 108) of success in first attempt at assessment. In terms of practical achievement, each student demonstrated competency in FS. The curriculum designed provides a suitable framework to develop individuals with the necessary knowledge, skills and attitudes required for safe, competent practice within FS. This indicates that the curriculum provides a broad range of learning, teaching and assessment strategies befitting to a range of individuals.


Short-term administration of a new free radical scavenger, edaravone, is more effective than its long-term administration for the treatment of neonatal hypoxic-ischemic encephalopathy.
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a new free radical scavenger that is used for the treatment of adult acute cerebral infarction in Japan. We examined the effect of edaravone on the optimal duration of treatment, the long-term effect on the brain, and the effect on learning and memory disability in a rat model of neonatal hypoxic-ischemic encephalopathy. Seven-day-old Wistar rats were subjected to left common carotid artery ligation then 2 hours of hypoxic-ischemic insult or sham operation. Edaravone was administered intraperitoneally (9 mg/kg) after hypoxic-ischemic insult every 24 hours for 2, 5, or 10 consecutive days. The neuroprotective effect of edaravone was evaluated by behavioral test and histological analysis. Two-day treatment with edaravone significantly gave protection to the learning and memory capability, as well as morphological recovery compared with control rats. Five-day treatment showed morphological improvement but no behavioral improvement. In contrast, 10-day treatment did not show either morphological or behavior improvement. These findings indicate that edaravone is a promising candidate as a treatment of choice for neonatal hypoxic-ischemic encephalopathy, when its use is limited to the acute phase after hypoxia-ischemia.


Copper allergy and copper IUD.
Epicutaneous tests with copper, nickel and cobalt were performed in 37 patients using copper IUD who had shown side-effects to the IUD. None of them was allergic to copper; four were allergic to nickel and one to cobalt. Metal allergy was not considered to be the cause of the side-effects in any of the patients.


Dysregulation of Aldh1a2 underlies motor neuron degeneration in spinal muscular atrophy.
Lower motor neuron degeneration is the pathological hallmark of spinal muscular atrophy (SMA), a hereditary motor neuron disease caused by loss of the SMN1 gene and the resulting deficiency of ubiquitously expressed SMN protein. The molecular mechanisms underlying motor neuron degeneration, however, remain elusive. To clarify the cell-autonomous defect in developmental processes, we here performed transcriptome analyses of isolated embryonic motor neurons of SMA model mice to explore mechanisms of dysregulation of cell-type-specific gene expression. Of 12 identified genes that were differentially expressed between the SMA and control motor neurons, we focused on Aldh1a2, an essential gene for lower motor neuron development. In primary spinal motor neuron cultures, knockdown of Aldh1a2 led to the formation of axonal spheroids and neurodegeneration, reminiscent of the histopathological changes observed in human and animal cellular models. Conversely, Aldh1a2 rescued these pathological features in spinal motor neurons derived from SMA mouse embryos. Our findings suggest that developmental defects due to Aldh1a2 dysregulation enhances lower motor neuron vulnerability in SMA.


Computed tomography of a traumatic, diaphragmatic, Richter's hernia: findings mimicking an abscess.
We present a case of a Richter's hernia through a traumatic, diaphragmatic defect presenting with the appearance of an abscess on computed tomography. We underscore the importance of this hernia variant, the need for its recognition, and stress caution in percutaneous aspiration of a lesion where a hernia might exist.


Clinical relevance of silent atrial fibrillation: prevalence, prognosis, quality of life, and management.
Although first described about 100yr ago, atrial fibrillation (AF) is now recognized as the most common of all arrhythmias. It has a substantial morbidity and presents a considerable health care burden. Improved diagnosis and an ageing population with an increased likelihood of underlying cardiac disease results in AF in more than 1% of population. AF is associated with an approximately two-fold increase in mortality, largely due to stroke which occurs at an annual rate of 5-7%. Another risk to survival is heart failure, which is aggravated by poor control of the ventricular rate during AF. Usually AF is associated with a variety of symptoms: palpitations, dyspnea, chest discomfort, fatigue, dizziness, and syncope. Paroxysmal AF is likely to be symptomatic and frequently presents with specific symptoms, while permanent AF is usually associated with less specific symptoms. However, in at least one third of patients, no obvious symptoms or noticeable degradation of quality of life are observed. This asymptomatic, or silent, AF is diagnosed incidentally during routine physical examinations, pre-operative assessments or population surveys. Recently, a very large incidence of generally short paroxysms of AF has been seen in patients with implantable pacemakers or defibrillators and these arrhythmias are often silent. Pharmacological suppression of arrhythmia may be associated with a conversion from a symptomatic to an asymptomatic form of AF. Holter monitoring and transtelephonic monitoring studies have demonstrated that asymptomatic episodes of AF exceed symptomatic paroxysms by twelve-fold or more. Although symptoms may not stem directly from AF, the risk of complications is probably the same for symptomatic and asymptomatic patients. AF is found incidentally in about 25% of admissions for a stroke. Studies in patients with little or no awareness of their arrhythmia condition indicate that unrecognized and untreated AF may cause congestive heart failure. In patients with coronary bypass, AF may not only represent risk for immediate postoperative morbidity and increase hospital resource utilization, but being unrecognized, may produce a significant impact on long-term survival and quality of life. Although silent AF merits consideration for anticoagulation and rate control therapy according to standard criteria, whether antiarrhythmic therapy is relevant in this condition remains unclear.


Prenatal diagnosis of amniotic sheets by magnetic resonance imaging.
We report prenatal diagnosis of an amniotic sheet by magnetic resonance imaging (MRI) at 28 weeks' gestation. The amniotic sheet divided the uterine cavity into 2 compartments, with the fetus and placenta located in the upper portion of the amniotic cavity. Although prenatal diagnosis of amniotic sheets can be performed with ultrasonography, the wider field of view and excellent tissue contrast provided by MRI may allow better spatial visualization of the amniotic sheet and, therefore, improve the diagnostic accuracy.


Telomere maintenance and DNA replication: how closely are these two connected?
The maintenance of the DNA at chromosome ends, the telomeres, depends on conventional semiconservative replication and on the action of telomerase, a specialized reverse transcriptase. Current research strongly suggests a regulatory interplay between this conventional semiconservative replication and telomerase, thus ensuring that no sequences are lost at the very ends of the telomeres during replication. Here, we describe recent findings on the interactions between the conventional replication machinery and telomere replication, and we discuss how DNA-integrity checkpoints might impinge on both the processing of the telomeric DNA ends and the establishment of the DNA end structure required for end protection and genome stability.


Phosphorylation and assembly of nicotinic acetylcholine receptor subunits in cultured chick muscle cells.
The assembly of the nicotinic acetylcholine receptor (AChR), an oligomeric cell surface protein, was studied in cultured muscle cells. To measure this process, the incorporation of metabolically labeled alpha-subunit into oligomeric AChR was monitored in pulse-chase experiments, either by the shift of this subunit from the unassembled (5 S) to the assembled (9 S) position in sucrose density gradients, or by its coprecipitation with antisera specific for the delta-subunit. We have found that AChR assembly is initiated 15-30 min after subunit biosynthesis and is completed within the next 60 min. The alpha-subunit is not overproduced, as all detectable pulse-labeled alpha-subunit can be chased into the oligomeric complex, suggesting that AChR assembly in this system is an efficient process. The rate of AChR assembly is decreased by metabolic inhibitors and by monensin, an ionophore that impairs the Golgi apparatus. We have observed that the gamma- and delta-subunits of AChR are phosphorylated in vivo. The delta-subunit is more highly phosphorylated in the unassembled than in the assembled state, indicating that its phosphorylation precedes assembly and that its dephosphorylation is concomitant with AChR assembly. These findings suggest that subunit assembly occurs in the Golgi apparatus and that phosphorylation/dephosphorylation mechanisms play a role in the control of AChR subunit assembly.


Renal dysfunction in recurrent urinary tract infections in childhood.
One hundred children aged 1.5-19.5 years, with recurrent urinary tract infections, at least one of which was febrile (pyelonephritis, PN), were investigated by means of inulin and para-aminohippurate (PAH) clearance tests for the evaluation of glomerular filtration rate (GFR), effective renal plasma flow, and concentrating and diluting capacities. Renal function data were collated with the clinical history and radiological findings. GFR and PAH clearance were found to be reduced compared with controls. Patients whose first PN was diagnosed before the age of 3--particularly those with a history of three or more PN infections--showed the lowest values for GFR and PAH clearance. Furthermore, parenchymally reduced kidneys were found most frequently in this group of patients. Concentrating capacity was decreased in some patients, but a low concentrating capacity did not reveal patients with reduced GFRs. Diluting capacity evaluated as minimal urine osmolality was normal, but was reduced when evaluated as free water clearance in some patients with reduced values for GFR.


Treatment of Subclinical Hyperthyroidism in the Elderly: Comparison of Radioiodine and Long-Term Methimazole Treatment.
Background: This study aimed to compare the effectiveness and safety of radioiodine (RAI) and long-term methimazole (MMI) in the treatment of subclinical hyperthyroidism (SH) in the elderly. Methods: From 306 patients, aged ≥65 years, with SH, 83 patients with thyrotropin <0.1 mU/L entered the study. In this randomized parallel-group trial, 41 and 42 patients were randomized to either RAI or long-term MMI treatment, respectively. Results: In the RAI and MMI groups, 3 and 4 patients were excluded due to side effects, choosing other modes of treatment, and not returning for follow-up; 35 and 36 patients completed 60 months of follow-up, respectively. In the RAI group, 23 (66%) became hypothyroid, and 12 (34%) remained euthyroid 60 months after a fixed dose of 15 mCi RAI. In the MMI group, the starting dose was 10 mg daily and decreased to 4.9 ± 1.0, 4.3 ± 1.0, 4.4 ± 1.4, 4.3 ± 1.8, and 3.7 ± 1.3 mg after 1, 2, 3, 4, and 5 years of continuous MMI treatment, employing titration method. By the end of study, 34 (94%) patients were euthyroid and 2 patients with diffuse goiter developed spontaneous hypothyroidism with MMI treatment. Minor adverse events occurred in both groups in the first four months of treatment. No death or serious side effects were observed during 60 months of follow-up. Conclusions: Both RAI and long-term low-dose MMI therapies are effective and safe for treatment of SH in the elderly.


Iron Content of Commercially Available Infant and Toddler Foods in the United States, 2015.
To describe the iron content of commercially available infant and toddler foods. Nutrition Facts label data were used from a 2015 database of 1037 commercial infant and toddler food and drink products. Products were grouped into food categories on the basis of name, ingredients, target age, and reference amounts customarily consumed (RACC). Mean and median iron content per 100 g and per RACC were calculated. The proportion of products considered good and excellent sources of iron were determined on the basis of percent daily value (% DV) thresholds. Among products marketed for infants (aged 4-12 months), infant cereals had the highest mean (6.19 mg iron per RACC; 41.25 iron mg per 100 g) iron content. Among products marketed for toddlers (aged 12-36 months), vegetable-based mixtures or meals contained the highest mean iron in mg per RACC (mean: 2.97 mg) and dry, grain-based desserts had the highest mean iron in mg per 100 g (mean: 6.45 mg). Juice and drink products had the lowest mean iron contents in both infant and toddler products. Most commercially available infant cereals are considered to be an excellent source of iron, likely from fortification, but wide variability was observed in iron content by food category. Products that are considered good or excellent sources of iron (≥10% DV) can help consumers identify products with higher iron content, such as infant cereals or toddler vegetable-based mixtures/meals.


Surgical treatment of tricuspid atresia.
Despite increasing experience with the surgical treatment of tricuspid atresia, controversy exists regarding the early and late results of the various surgical options. Between January 1, 1967, and September 1, 1982, 92 patients underwent 147 operations for tricuspid atresia. Eighty-five patients underwent 1 or more palliative operations (108 procedures), with 8 hospital deaths (9%; confidence limits [CL], 6 to 14%). Thirty-eight patients underwent 44 classic (Blalock-Taussig or Gore-Tex) shunts, with 3 early (7%; CL, 3 to 13%) and 3 late deaths. Actuarial survival at 5 years was 78%, but only 56% were alive and free from having to undergo further operation at 5 years. Thirty-seven patients underwent a Fontan procedure, with 5 hospital deaths (14%; CL, 8 to 22%). Of these 37 patients, 34 (92%) had a nonvalved connection between the right atrium and the right ventricular infundibulum or the pulmonary artery. Incremental risk factors for hospital mortality after the Fontan procedure in patients with tricuspid atresia as well as other cardiac anomalies include young age (p = 0.0003), diagnosis other than tricuspid atresia (p = 0.03), and complex associated procedures (p = 0.02). During the year 1983, hospital mortality was 7% (1 out of 14; CL, 1 to 22%) for the Fontan procedure without complex additional procedures. Actuarial survival after a Fontan procedure was 71% at 5 years, with 3 patients requiring late reoperation. Of the survivors, 96% are in New York Heart Association Functional Class I or II. The Fontan procedure without a valve offers good intermediate survival, good functional results, and few reoperations. In patients with diminished pulmonary blood flow, a classic shunt also provides good palliation and good intermediate survival, but there is a necessity for additional operations in many patients within 5 years.


Potentiation of in vivo neuroprotection by BclX(L) and GDNF co-expression depends on post-lesion time in deafferentiated CNS neurons.
To elucidate effective and long-lasting neuroprotective strategies, we analysed a combination of mitochondrial protection and neurotrophic support in two well-defined animal models of neurodegeneration, traumatic lesion of optic nerve and complete 6-hydroxydopamine (6-OHDA) lesion of nigrostriatal pathway. Neuroprotection by BclX(L), Glial cell line-derived neurotrophic factor (GDNF) or BclX(L) plus GDNF co-expression were studied at 2 weeks and at 6-8 weeks after lesions. In both lesion paradigms, the efficacy of this combination approach significantly differed depending on post-lesion time. We show that BclX(L) expression is more important for neuronal survival in the early phase after lesions, whereas GDNF-mediated neuroprotection becomes more prominent in the advanced state of neurodegeneration. BclX(L) expression was not sufficient to finally inhibit degeneration of deafferentiated central nervous system neurons. Long-lasting GDNF-mediated neuroprotection depended on BclX(L) co-expression in the traumatic lesion paradigm, but was independent of BclX(L) in the 6-OHDA lesion model. The results demonstrate that neuroprotection studies in animal models of neurodegenerative diseases should generally be performed over extended periods of time in order to reveal the actual potency of a therapeutic approach.


Prognostic variables in malignant epithelial tumors of the parotid.
A retrospective analysis was performed on 209 patients with carcinoma of the parotid who were treated with curative intent using surgery and post-operative irradiation. The five and ten-year actuarial survival were 71% and 65%. Failure at the primary site occurred in 24%, at nodal sites in 14%, and distantly in 23%. Multivariate analysis of prognostic variables identified age greater than 60 years, involved nodes, post-surgical residual disease, and poor differentiation to be bad prognostic variables.


Using cortico-cerebellar structural patterns to classify early- and late-trained musicians.
A body of current evidence suggests that there is a sensitive period for musical training: people who begin training before the age of seven show better performance on tests of musical skill, and also show differences in brain structure-especially in motor cortical and cerebellar regions-compared with those who start later. We used support vector machine models-a subtype of supervised machine learning-to investigate distributed patterns of structural differences between early-trained (ET) and late-trained (LT) musicians and to better understand the age boundaries of the sensitive period for early musicianship. After selecting regions of interest from the cerebellum and cortical sensorimotor regions, we applied recursive feature elimination with cross-validation to produce a model which optimally and accurately classified ET and LT musicians. This model identified a combination of 17 regions, including 9 cerebellar and 8 sensorimotor regions, and maintained a high accuracy and sensitivity (true positives, i.e., ET musicians) without sacrificing specificity (true negatives, i.e., LT musicians). Critically, this model-which defined ET musicians as those who began their training before the age of 7-outperformed all other models in which age of start was earlier or later (between ages 5-10). Our model's ability to accurately classify ET and LT musicians provides additional evidence that musical training before age 7 affects cortico-cerebellar structure in adulthood, and is consistent with the hypothesis that connected brain regions interact during development to reciprocally influence brain and behavioral maturation.


The effect of the mirid bug Capsodes infuscatus on fruit production of the geophyte Asphodelus ramosus in a desert habitat.
The effect of feeding of the mirid bug Capsodes infuscatus on fruit production of the geophyte Asphodelus ramosus was studied in a desert area in Israel. Plant and bug densities and percent loss of fruit production were measured in a relatively dry lower colluvial slope, an intermediate upper colluvial slope, and a relatively mesic wadi. Overall damage levels were very high, with 100% loss of fruit production in many plants. Within each habitat, the number of nymphs per plant clone was positively correlated with the number of ramets per clone and percent damage was positively correlated with number of nymphs per clone. However, percent damage was not correlated with number of plants per clone in any habitat. Although damage did significantly increase with plant density in the slope habitats, mean damage to fruit production per clone was lowest (50%) in the wadi where Asphodelus density was highest. As new ramets are tightly interwoven with their mother plants, occupation of new microsites depends on establishment of new clones from seeds. Therefore, the strong and density-dependent reduction in fruit production inflicted by Capsodes on the Asphodelus population on the slope has the potential to regulate the plant density in this habitat.


Effectiveness of Medical Rehabilitation on Return-to-Work Depends on the Interplay of Occupation Characteristics and Disease.
Introduction Work disability causes high costs for economy, organizations, and employees. However, medical rehabilitation does not always enable employees to return to their old jobs. In the present study, we investigated how disease classification and work characteristics interact in predicting the success of medical rehabilitation in terms of one's ability to return to a former job. Methods To this end, we matched 2009 patient data from the German Statutory Pension Insurance agency with job characteristics data from the Occupational Information Network (O*NET) 17.0 database. We used a multilevel approach and a sample of N = 72,029, nested in 194 occupational groups. Results We found that workers are less likely to reenter a former job if mental illnesses coincide with emotionally demanding labor and if musculoskeletal diseases coincide with extreme environmental conditions. We did not find different effects between occupational groups for other types of diseases (circulatory system, neoplasms, injuries, others). Conclusion Thus, the contextual overlap of disease and occupational characteristics notably lowers the chances of a successful return-to-work. These findings should be taken into account by physicians when attempting to set realistic goals for rehabilitation in collaboration with the patient and the funding agency.


Customer decision-making analysis based on big social data using machine learning: a case study of hotels in Mecca.
Big social data and user-generated content have emerged as important sources of timely and rich knowledge to detect customers' behavioral patterns. Revealing customer satisfaction through the use of user-generated content has been a significant issue in business, especially in the tourism and hospitality context. There have been many studies on customer satisfaction that take quantitative survey approaches. However, revealing customer satisfaction using big social data in the form of eWOM (electronic word of mouth) can be an effective way to better understand customers' demands. In this study, we aim to develop a hybrid methodology based on supervised learning, text mining, and segmentation machine learning approaches to analyze big social data on travelers' decision-making regarding hotels in Mecca, Saudi Arabia. To do so, we use support vector regression with sequential minimal optimization (SMO), latent Dirichlet allocation (LDA), and k-means approaches to develop the hybrid method. We collect data from travelers' online reviews of Mecca hotels on TripAdvisor. The data are segmented, and travelers' satisfaction is revealed for each segment based on their online reviews of hotels. The results show that the method is effective for big social data analysis and traveler segmentation in Mecca hotels. The results are discussed, and several recommendations and strategies for hotel managers are provided to enhance their service quality and improve customer satisfaction.


Functional analysis of intergenic regulatory regions of genes encoding surface adhesins in Staphylococcus aureus isolates from periprosthetic joint infections.
Staphylococcus aureus is a leading cause of prosthetic joint infections (PJI). Surface adhesins play an important role in the primary attachment to plasma proteins that coat the surface of prosthetic devices after implantation. Previous efforts to identify a genetic component of the bacterium that confers an enhanced capacity to cause PJI have focused on gene content, kmers, or single-nucleotide polymorphisms (SNPs) in coding sequences. Here, using a collection of S. aureus strains isolated from PJI and wounds, we investigated whether genetic variations in the regulatory region of genes encoding surface adhesins lead to differences in their expression levels and modulate the capacity of S. aureus to colonize implanted prosthetic devices. The data revealed that S. aureus isolates from the same clonal complex (CC) contain a specific pattern of SNPs in the regulatory region of genes encoding surface adhesins. As a consequence, each clonal lineage shows a specific profile of surface proteins expression. Co-infection experiments with representative isolates of the most prevalent CCs demonstrated that some lineages have a higher capacity to colonize implanted catheters in a murine infection model, which correlated with a greater ability to form a biofilm on coated surfaces with plasma proteins. Together, results indicate that differences in the expression level of surface adhesins may modulate the propensity of S. aureus strains to cause PJI. Given the high conservation of surface proteins among staphylococci, our work lays the framework for investigating how diversification at intergenic regulatory regions affects the capacity of S. aureus to colonize the surface of medical implants.


Know thy Sef: a novel class of feedback antagonists of receptor tyrosine kinase signaling.
The strength and duration of intracellular signals must be precisely regulated, since inappropriate signaling can cause disease. Negative feedback mechanisms provide an effective means of controlling growth factor-mediated signaling, either by restricting the incoming signal or by inducing counter-regulatory mechanisms affecting signal propagation. Sef proteins represent a new class of feedback antagonists capable of regulating receptor tyrosine kinase signaling. The involvement of Sef in development, as well as in other biological processes, was demonstrated by biochemical and genetic approaches.


Purification and characterization of a low-Km 3':5'-cyclic adenosine phosphodiesterase from post-meiotic male mouse germ cells.
We describe the purification and the study of the kinetic and hydrodynamic properties of a 'low Km' cAMP phosphodiesterase specifically expressed in haploid male germ cells of the mouse. The enzyme has been purified approx. 13,000-fold with respect to the activity in total cell homogenate. The purified enzyme hydrolyzed specifically cAMP with a Km of 3.3 microM and with a Vmax of 10.5 mumol of cAMP hydrolyzed/min per mg of protein. The hydrolytic activity was neither stimulated nor inhibited by cGMP, whereas it was inhibited by RO 20-1724 and Rolipram. The enzyme showed a Stokes radius of 3.8 nm and a sedimentation coefficient of 3.1 S, corresponding to a native molecular mass of 50 kDa and a frictional ratio of 1.53. Sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis of sucrose gradient fractions of the purified enzyme showed a major band of 43 kDa copeaking with enzyme activity.


A new approach to the neurolytic block of the coeliac plexus: the transaortic technique.
The present study critically examines the coeliac plexus block techniques hitherto adopted, pointing out the complications involved and stressing the seriousness of the neurological complications due to spread of the neurolytic agent to the sympathetic chain and the lumbar plexus. Contrast enhanced CT scans demonstrate the difficulties involved in confining the neurolytic agent to the anterior, peri-aortic and precrural regions. The authors report their recent experience with coeliac plexus block by means of a single transaortic needle in 28 patients. In 12 of the patients, the CT scan revealed a spread was anterior to the medial crura of the diaphragm, sometimes extending laterally towards the costovertebral gutter along the ventral surface of the diaphragm.


[SNP array and cytogenetic analysis of a patient with unexplained mental retardation].
To analyze a patient with unexplained mental retardation by using three primer PCR (TP-PCR) and single nucleotide polymorphisms array (SNP-array), and to correlate the genotype with phenotype. Peripheral blood sample was taken from the patient for the extraction of DNA. TP-PCR was used to determine the copy number of CGG repeats in the 5'UTR of the FMR1 gene. SNP array was used for high resolution analysis of the patient's genome. TP-PCR has shown no abnormal amplification of CGG in the 5'UTR of FMR1 gene. Hence, Fragile X syndrome was excluded as the cause for mental retardation. SNP array analysis has identified a 0.93 Mb duplication at 7q36.1-q36.2 and a 2.2 Mb deletion at 12p13.1-p13.2 in the patient. The microduplication and microdeletion discovered in the patient probably underlies the intelligence disability. The high-resolution SNP array can provide accurate information for the identification of pathogenesis, and is the preferred method for the diagnosis of unexplained mental retardation.


Blood clearance of three radioactively labelled platinum complexes: cis-dichlorodiammine platinum II, cis, trans-dichlorodihydroxy-bis-(isopropylamine) platinum IV, and cis-dichloro-bis-cyclopropylamine platinum II, in patients with malignant disease.
The blood clearances of three platinum compounds, cis-dichlorodiammine platinum II (DDP), cis, trans-dichloro-dihydroxy-bis-(isopropylamine) platinum IV (CHIP), and cis-dichloro-bis-cyclopropylamine platinum II (CP), were determined in nine patients with malignant disease. The complexes were prepared using radioactive platinum (191Pt and 193Pt). A 10-mu Ci dose of each complex, containing the equivalent of 1-2 mg elemental platinum, was injected IV into groups of three patients. Serial blood and urine samples were collected over 72 h. No obvious difference was found between the three complexes for blood clearance, median t1/2a being 16.8 (range 11.2-23.5) min and median t1/2 beta 89 (range 63.7-127) h. The urinary excretion was greatest for CHIP, 60% of injected dose as against 42.6% for CP and 38.8% for DDP. Differences in renal excretion of DDP analogues could indicate potentially less nephrotoxic agents. The use of radioactive Pt will allow in vivo dynamic imaging of the distribution of platinum compounds in areas of interest.


The role of postoperative alkylating agent therapy in early-stage epithelial ovarian cancer.
Forty-six patients with early (Stage I and II) ovarian cancer referred as free of residual disease after primary surgery, selected for high-risk features, were treated with adjuvant single-agent alkylating therapy comprising either intravenous cyclophosphamide (1 g/m2) in 36 patients, or oral melphalan (0.2 mg/kg daily for 5 days) in eight. Cyclophosphamide was repeated every 3 weeks for 10 cycles and melphalan every 6 weeks for 12 cycles. With a median follow-up of 36+ months, 18 patients have relapsed. The actuarial 5-year relapse-free survival was 48% and the overall 5-year survival was 54%; median survival was 84 months. Pretreatment FIGO stage was the single most important predictor of relapse-free and overall survival duration. For patients with Stage IA and IB tumours the 5-year actuarial relapse-free survival was 89%; for patients with stage IC and II (all substages), the 5-year relapse-free survival was 24% (P = 0.001). For this latter group adjuvant single alkylating agent therapy was not adequate and alternative therapeutic regimens are required. The problem of suboptimal primary surgical staging is also addressed.


Reversibly tunable lower critical solution temperature utilizing host-guest complexation of pillar[5]arene with triethylene oxide substituents.
A thermoresponsive macromolecule consisting of 10 outer triethylene oxide groups and a pillar[5]arene core was prepared. The macromolecule showed lower critical solution temperature behavior. Moreover, its clouding point can be reversibly tuned based on the addition of guest and host compounds; the clouding point increased upon addition of a guest didecylviologen salt and decreased when the competitive host cucurbit[7]uril was added.


Are cost-effective technologies feasible to measure gait in older adults? A systematic review of evidence-based literature.
Unrestricted by time and place, innovative technologies seem to provide cost-effective solutions for gait assessment in older adults. The objective of this study is to provide an overview of gait assessment for older adults by investigating critical gait characteristics of older adults, discussing advantages and disadvantages of the current gait assessment technologies, as well as device applicability. The Preferred Reporting Item for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed during the review. Inclusion criteria were: (1) Sample consisting of adults older than 60 years; (2) qualitative, quantitative, or mixed-method researches using one or more specific gait assessment technologies; and (3) publication in English between 2000 and 2018. In total, twenty-one studies were included. Gait speed, stride length, frequency, acceleration root mean square, step-to-step consistency, autocorrelation, harmonic ratio were reported in the existing literatures to be associated with falls. The enrolled studies address the use of pedometer, wearable accelerometer-based devices, Kinect, Nintendo Wii Balance Board as cost-effective gait assessment technologies. Gait parameters and assessment approaches for older adults are diverse. Cost-effective technologies such as a wearable accelerometer-based device, Kinect, and the Nintendo Wii Balance Board provide potential alternatives for gait assessment with acceptable validity and reliability compared with sophisticated devices. The popularity and development of cost-effective devices have made large-scale data collection for gait assessment possible in the daily environment. Further study could involve older adults and their family members/caregivers in use of these technologies to design elderly-friendly products.


The influence of orlistat on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers.
To assess the influence of orlistat on the pharmacokinetics and pharmacodynamics (the blood glucose-lowering effect) of glyburide, an open-label, placebo-controlled, randomized, two-way crossover study was done in 12 healthy male volunteers. Each subject received single 5-mg oral doses of glyburide (Micronase; The Upjohn Company, Kalamazoo, MI) on the fifth day of treatment with placebo (treatment A) and 80-mg orlistat (treatment B) three times a day for 4 1/3 days; the two treatments were separated by a five-day washout period. Serial blood samples were collected before and at appropriate intervals after each glyburide dose to determine plasma concentrations and blood glucose levels. Values of Cmax and AUC of glyburide showed an equality of the two treatments by the analysis of variance. There was an apparent correlation between blood glucose level and the logarithm of plasma glyburide concentration; this relationship appeared to not be altered when glyburide was administered with orlistat. In conclusion, orlistat administered at doses of 80-mg three times daily does not significantly alter the pharmacokinetics and blood glucose-lowering effect of a single 5-mg oral dose of glyburide in healthy volunteers.


A narrative review of schemas and schema therapy outcomes in the eating disorders.
Whilst cognitive-behavioural therapy has demonstrated efficacy in the treatment of eating disorders, therapy outcomes and current conceptualizations still remain inadequate. In light of these shortcomings there has been growing interest in the utility of schema therapy applied to eating pathology. The present article first provides a narrative review of empirical literature exploring schemas and schema processes in eating disorders. Secondly, it critically evaluates outcome studies assessing schema therapy applied to eating disorders. Current evidence lends support to schema-focused conceptualizations of eating pathology and confirms that eating disorders are characterised by pronounced maladaptive schemas. Treatment outcomes also indicate that schema therapy, the schema-mode approach, and associated techniques are promising interventions for complex eating disorders. Implications for clinical practice and future directions for research are discussed.


Fructose-1,6-bisphosphatase from Corynebacterium glutamicum: expression and deletion of the fbp gene and biochemical characterization of the enzyme.
The class II fructose-1,6-bisphosphatase gene of Corynebacterium glutamicum, fbp, was cloned and expressed with a N-terminal His-tag in Escherichia coli. Purified, His-tagged fructose-1,6-bisphosphatase from C. glutamicum was shown to be tetrameric, with a molecular mass of about 140 kDa for the homotetramer. The enzyme displayed Michaelis-Menten kinetics for the substrate fructose 1,6-bisphosphate with a K(m) value of about 14 micro M and a V(max) of about 5.4 micro mol min(-1) mg(-1) and k(cat )of about 3.2 s(-1). Fructose-1,6-bisphosphatase activity was dependent on the divalent cations Mg(2+) or Mn(2+) and was inhibited by the monovalent cation Li(+) with an inhibition constant of 140 micro M. Fructose 6-phosphate, glycerol 3-phosphate, ribulose 1,5-bisphosphate and myo-inositol-monophosphate were not significant substrates of fructose-1,6-bisphosphatase from C. glutamicum. The enzymatic activity was inhibited by AMP and phosphoenolpyruvate and to a lesser extent by phosphate, fructose 6-phosphate, fructose 2,6-bisphosphate, and UDP. Fructose-1,6-bisphosphatase activities and protein levels varied little with respect to the carbon source. Deletion of the chromosomal fbp gene led to the absence of any detectable fructose-1,6-bisphosphatase activity in crude extracts of C. glutamicum WTDelta fbp and to an inability of this strain to grow on the carbon sources acetate, citrate, glutamate, and lactate. Thus, fbp is essential for growth on gluconeogenic carbon sources and likely codes for the only fructose-1,6-bisphosphatase in C. glutamicum.


Blind Source Separation for Compositional Time Series.
Many geological phenomena are regularly measured over time to follow developments and changes. For many of these phenomena, the absolute values are not of interest, but rather the relative information, which means that the data are compositional time series. Thus, the serial nature and the compositional geometry should be considered when analyzing the data. Multivariate time series are already challenging, especially if they are higher dimensional, and latent variable models are a popular way to deal with this kind of data. Blind source separation techniques are well-established latent factor models for time series, with many variants covering quite different time series models. Here, several such methods and their assumptions are reviewed, and it is shown how they can be applied to high-dimensional compositional time series. Also, a novel blind source separation method is suggested which is quite flexible regarding the assumptions of the latent time series. The methodology is illustrated using simulations and in an application to light absorbance data from water samples taken from a small stream in Lower Austria.


Radiographic assessment of renal trauma: a 10-year prospective study of patient selection.
To develop criteria to determine which patients require radiographic assessment after blunt renal trauma, we studied prospectively 1,146 consecutive patients with either blunt (1,007) or penetrating (139) renal trauma between 1977 and 1987. Based on our preliminary results from 1977 to 1983, in which none of the 221 patients with blunt trauma and microscopic hematuria without shock had significant renal injuries, we designed a prospective study to determine if such patients could be managed safely without radiographic staging. During the last 10 years significant renal injuries were found in 44 patients (4.4 per cent) with blunt trauma and gross hematuria or microscopic hematuria associated with shock, and in 88 patients (63 per cent) with penetrating trauma. No significant injuries occurred in the 812 patients with blunt trauma and microscopic hematuria without shock, 404 of whom had complete radiographic assessment and 408 of whom did not. There were no delayed operations or significant sequelae related to the renal injury in these patients. We conclude that complete radiographic staging is mandatory in patients with penetrating trauma to the flank or abdomen and in patients with blunt trauma associated with either gross hematuria or microscopic hematuria and shock. However, patients with blunt trauma, microscopic hematuria and no shock who do not have associated major intra-abdominal injuries can be managed safely without excretory urography.


Likely Age-Related Hearing Loss (Presbycusis) in a Stranded Indo-Pacific Humpback Dolphin (Sousa chinensis).
The hearing of a stranded Indo-Pacific humpback dolphin (Sousa chinensis) in Zhuhai, China, was measured. The age of this animal was estimated to be ~40 years. The animal's hearing was measured using a noninvasive auditory evoked potential (AEP) method. The results showed that the high-frequency hearing cutoff frequency of the studied dolphin was ~30-40 kHz lower than that of a conspecific younger individual ~13 year old. The lower high-frequency hearing range in the older dolphin was explained as a likely result of age-related hearing loss (presbycusis).


Active sensation: insights from the rodent vibrissa sensorimotor system.
Rats sweep their vibrissae through space to locate objects in their immediate environment. In essence, their view of the proximal world is generated through pliable hairs that tap and palpate objects. The texture and shape of those objects must be discerned for the rat to assess the value of the object. Furthermore, the location of those objects must be specified with reference to the position of the rat's head for the rat to plan its movements. Recent in vivo and in vitro electrophysiological measurements provide insight into the algorithms and mechanisms that underlie these behavioral-based computations.


The toxic dinoflagellate Karenia brevis encodes novel type I-like polyketide synthases containing discrete catalytic domains.
Karenia brevis is the Florida red tide dinoflagellate responsible for detrimental effects on human and environmental health through the production of brevetoxins. Brevetoxins are thought to be synthesized by a polyketide synthase (PKS) complex, but the gene cluster for this PKS has yet to be identified. Here, eight PKS transcripts were identified in K. brevis by high throughput cDNA library screening. Full length sequences were obtained through 3' and 5' RACE, which demonstrated the presence of polyadenylation, 3'-UTRs, and an identical dinoflagellate-specific spliced leader sequence at the 5' end of PKS transcripts. Six transcripts encoded for individual ketosynthase (KS) domains, one ketoreductase (KR), and one transcript encoded both acyl carrier protein (ACP) and KS domains. Transcript lengths ranged from 1875 to 3397 nucleotides, based on sequence analysis, and were confirmed by northern blotting. Baysian phylogenetic analysis of the K. brevis KS domains placed them well within the protist type I PKS clade. Thus although most similar to type I modular PKSs, the presence of individual catalytic domains on separate transcripts suggests a protein structure more similar to type II PKSs, in which each catalytic domain resides on an individual protein. These results identify an unprecedented PKS structure in a toxic dinoflagellate.


A preliminary characterization of human cementum collagen.
Human teeth were used to obtain cementum. Collagen could not be significantly solubilized from the cementum by salt and acetic acid extraction or by pepsin digestion. CNBr digestion (86%) of cementum and subsequent carboxymethyl cellulose chromatography suggests that human cementum consists of type I collagen only as identified by amino acid and hexose analyses.


Computational studies of the early intermediates of the bacteriorhodopsin photocycle.
Starting from a refined model of bacteriorhodopsin's ground state, alternative models of the K and L intermediates with retinal in either 13-cis or 13-14-dicis configuration have been generated by molecular dynamics simulations. All models have been submitted to electrostatic calculations in order to determine the pK1/2 values of particular residues of interest in the active site. Our pK1/2 calculations for the refined ground state can reestablish our former results, this time without adjusting the intrinsic pK of the Schiff base. For the K intermediate the electrostatic calculations show no significant change in the pK1/2 values compared to the ground state for most of the titrating groups in the active site. For the L intermediate where retinal possesses a 13-cis configuration, we found that electrostatic factors decrease the pK1/2 value of the Schiff base by 4-5 pK-units compared to the ground state. The calculations suggest that changes of the electrostatic environment via a pure 13-cis model are sufficient to produce a pK reduction of the Schiff base that will promote subsequent proton transfer steps.


Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidized low density lipoprotein hypothesis.
The oxidation hypothesis proposes that low density lipoprotein must be oxidatively modified to trigger the pathological events of atherosclerosis. In this article, we evaluate recent studies addressing the pathways that promote low density lipoprotein oxidation in vivo and the impact of antioxidants on atherogenesis in animals, paying particular attention to the clinical implications of these studies for the oxidation hypothesis.


Four indicators of socioeconomic position: relative ranking across causes of death.
A study was undertaken to examine the relative ability of occupational class, education, household income, and housing conditions to discriminate all cause and cause-specific mortality-risk in Oslo, and to see if this relative ability is consistent across the 12 most common causes of death. Census records of inhabitants in Oslo 1990 aged 45 to 64 were linked to death records 1990-98 (n?=?88,159). All inhabitants were included except those who lacked census data on the independent variables. The relative index of inequality (RII) for each indicator was calculated. Education, occupation, and housing conditions had similar RIIs for all-cause mortality in both sexes. Household income had low RIIs, particularly in men. For the 12 most common causes of death some heterogeneity in the relative ranking between the four indicators was observed, with causes of death known to be related to early-life social circumstances (stomach cancer, cardiovascular disease, chronic obstructive pulmonary disease) being particularly strongly related to education, and causes of death which were likely to be determined by adult social circumstances (violence, sudden unexpected death) being particularly strongly related to occupation and housing conditions. Education, occupational class, and housing conditions all seemed to discriminate all-cause mortality to a similar degree. However, the cause-specific analysis revealed a heterogeneous pattern.


Appropriate Use and Clinical Impact of Echocardiographic "Evaluation of Murmur" in Pediatric Patients.
To determine the appropriateness and yield of transthoracic echocardiograms (TTE) for murmur evaluation based on the pediatric Appropriate Use Criteria (AUC) and study the influence of patient age and physician experience on TTE appropriateness, yield, and ordering frequency. Retrospective review of medical records of patients referred to our practice for murmur evaluation from April to September 2014. Data collected included indication for TTE, patient age, physician experience since fellowship, TTE findings and exit diagnosis. Appropriateness was assigned based on the AUC document. Pediatric cardiology clinics affiliated with a large pediatric cardiology practice. One thousand seven hundred one consecutive patients (≤ 18 years) referred to our practice for murmur evaluation. Not applicable OUTCOME MEASURES: The primary outcome was appropriateness of TTE orders. The secondary outcomes were the yield of abnormal TTE findings and the influence of patient age and physician experience on appropriateness, yield, and frequency of ordering TTEs. Of the 1701 patients referred for a murmur, 526 (30.9%) had a TTE [441/526 (83.8%) Appropriate; 85/526 (16.2%) Rarely Appropriate]. Abnormal findings were present in 130/441 rated Appropriate and none rated Rarely Appropriate. Infants <3 months had the highest rate of TTEs rated Appropriate and the highest yield of abnormal findings. Physicians with >20 years of experience not only had the lowest TTE ordering rate but also the lowest appropriateness rate with no difference in the yield of abnormal findings. Most TTEs ordered for murmur were for indications rated Appropriate. Abnormal findings were present in one-fourth and only those rated Appropriate. Patient age and physician experience can significantly influence TTE utilization. This information is helpful in designing quality initiatives to optimize TTE utilization for murmur evaluation.


Postresection Outcomes of Combined Hepatocellular Carcinoma-Cholangiocarcinoma, Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.
Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is rare. This study investigated the clinicopathological features of cHCC-CC and compared the postresection survival outcomes of cHCC-CC, hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (IHC). Between January 2000 and September 2012, 53 patients with cHCC-CC underwent tumor resection, accounting for 1.1 % of surgeries for primary liver malignancies. Control groups included patients with HCC (n = 1452) and IHC (n = 149) who underwent R0 resection of stage I/II tumors ≤5 cm. Mean tumor diameter of cHCC-CC group was 5.5 ± 2.9 cm, and single tumor was identified in 50. Pathological classification included combined (n = 41), mixed (n = 11), and double (n = 1) tumors. The 1-, 3-, 5-, and 10-year tumor recurrence rates were 60.8, 71.8, 80.7, and 80.7 %, respectively. The 1-, 3-, 5-, and 10-year overall survival rates were 73.3, 35.6, 30.5, and 11.1 %, respectively. Tumor recurrence and patient survival did not differ significantly according to AJCC tumor staging and histological type (all p ≥ 0.2). Tumor recurrence rates did not differ significantly between the cHCC-CC, HCC, and IHC groups (p = 0.43), whereas differences in survival rates were significant (p = 0.000), with a median survival after tumor recurrence of 8, 51, and 6 months, respectively (p = 0.000). Patients with cHCC-CC showed similar recurrence rates to those of control patients with HCC and IHC, whereas their survival outcomes were worse than those of control HCC patients because of poor responses to recurrence treatment. Further evaluation of differences in tumor characteristics and tumor biology is necessary to accurately predict the prognosis of patients with cHCC-CC.


Submitochondrial distribution of basic drugs in the isolated perfused lung.
To clarify the mechanism by which basic drugs accumulate in the lung mitochondria, the binding selectivity of drugs to different submitochondrial components of the perfused rat lung was examined. The accumulation of basic drugs was the highest in the mitochondrial outer membrane fraction. The drug accumulation in this fraction increased with lipid solubility and was dose-dependent. It appears then that selective binding sites for basic drugs are present in the mitochondrial outer membrane.


Anatomical Features of Neural Foramen at T12â€"L1 Level for Endoscopic Transforaminal Approach of Paramedian and Foraminal Disc Herniations: An Anatomical Study on Fresh Human Cadavers.
To explore the anatomic features of the neural foramen in particularly at the T12-L1 level in order to assess reveal the safety and efficiency of the endoscopic transforaminal approach for paramedian and foraminal disc herniations at this level. The study included 15 fresh human cadavers. The soft tissues were removed at the T12-L1 level and bony tissues, were exposed including the transverse processes. The bilateral facets and pars interarticulares at this level were resected revealing the foraminal anatomy and exiting roots. The anatomical structures constituting the triangular safe working zone (TSWZ) were explored. The nerve root length, nerve root width, nerve root angle, TSWZ height, and base of TSWZ base, nerve root width, nerve root angle and disc height were recorded. The root length is the hypotenuse of the TSWZ between the axilla of the exiting root and the lateral margin of the pedicle, and the mean root length was 14.94 ± 2.45 mm. The dural height is the interval between the axilla of the exiting nerve root axilla and the superior end plate of the caudal vertebra, and the mean of the dural height was 10.95 ± 1.74 mm. The base of TSWZ is the distance between the lateral margin of the dural sac and the medial margin of the exiting root, and the mean measurement for the base measurement was 11.83 ± 2.26 mm. According to the results data from our cadaveric study, we believe that Kambin's triangular working zone is a safe area to consider for the endoscopic transforaminal approach at the T12-L1 level, especially for paramedian and foraminal disc herniations.


Liver collagen turnover in hamsters during infection by the human liver fluke, Opisthorchis viverrini.
Hamsters infected with Opisthorchis viverrini, a liver fluke of man, showed an increased deposition of collagen in their livers. However, increased collagen breakdown as well as its synthesis were observed in the infected livers. Thus, stimulated synthesis might be the main factor responsible for the net increase in collagen content. Synthesis and degradation increased to a greater extent in short-term infection than in long-term infection whereas the hepatic collagen content was equally elevated in both cases. The results, therefore, suggested a difference in collagen metabolism of short-term and long-term infected livers.


The association of race, sociodemographic, and behavioral characteristics with response to highly active antiretroviral therapy in women.
To determine the association of race with clinical and laboratory outcomes after initiation of highly active antiretroviral therapy (HAART) in HIV-1-infected women in the United States. Prospective cohort study. A total of 961 HIV-1-infected women participating in the Women's Interagency HIV Study initiating HAART between July 1, 1995 and September 30, 2003. Over a median of 5.1 years of follow-up, in univariate Cox regression analyses, white women were more likely than African American women to attain a virologic response (relative hazard [RH]=1.34, P=0.005), less likely to experience viral rebound (RH=0.76, P=0.051), and less likely to die (RH=0.63, P=0.040). There were no significant differences, however, among racial groups in outcomes after adjustment for pre-HAART CD4, HIV-1 RNA, history of AIDS-defining illness, age, antiretroviral therapy use, baseline HIV-1 exposure category, and post-HAART behavioral and clinical variables associated with poorer response (discontinuation of HAART, lower income, smoking, current drug use, and depression). Continuous HAART use and lack of depression differed by race and were the strongest predictors of favorable outcomes. No significant differences by race were found in virologic, immunologic, or clinical outcomes after adjustment for continued HAART use and depression. These findings suggest that strategies to enhance HAART continuation, including assessing pharmacogenetic influences that may result in greater toxicity and discontinuation rates, and treating depression can improve individual and population-based effects of treatment and potentially mitigate racial disparities in AIDS-related outcomes.


Mesenchymal stem cell marker Stro-1 is a 75 kd endothelial antigen.
Stro-1 is the best-known mesenchymal stem cell (MSC) marker. However, previous studies have observed its expression in the endothelium. In the present study we performed immunofluorescence (IF) staining for Stro-1, using endothelial marker vWF as reference. In the liver, both proteins were expressed in the endothelium of the central veins and hepatic sinusoids. In the lung, both were expressed in the endothelium of pulmonary blood vessels, but while vWF was absent in the alveolar capillaries, Stro-1 was present. In the kidney, both were expressed in the endothelium of renal arterial branches, but while vWF was strongly expressed in the glomeruli, Stro-1 only scantly. IF staining in cultured endothelial cells also showed extensive overlaps between Stro-1 and vWF. Western blot analysis with Stro-1 antibody detected a single protein band of 75 kd in endothelial cells but not smooth muscle cells, fibroblasts, or B cells. Cancer cell lines PC3, DU145, MCF7, and K562 were also positive. Adipose-derived stem cells (ADSCs) expressed higher levels of Stro-1 when cultured beyond the first passage or when induced to differentiate into endothelial cells. These data, together with previous studies, indicate that Stro-1 is intrinsically an endothelial antigen, and its expression in MSC is probably an induced event.


Interactive community-based theatre to address social barriers to accessing reproductive health services in patriarchal societies: the case of Jordan.
Interactive community-based theatre is used to engage with audience members and allow for free exchange of ideas relevant to context. It aims to bring about a new understanding of an issue while challenging people's attitudes and perceptions. Its application within the field of sexual and reproductive health has been limited, particularly in low and middle-income contexts. This paper presents the rationale for a research-arts partnership in Jordan and describes the process and some lessons learned from the development and country-wide performances of a research-informed interactive play. The play, Mish 'Ayb (Not a Shame) was designed to address social barriers to accessing sexual and reproductive services in a patriarchal society. The sensitive portrayal by Jordanian actors of real-life scenarios pertaining to specific health issues encouraged identification of the audience with the actors, thereby building trust. This process helped to uncover cultural norms that facilitate and impede people's access to health services and information. Qualitative research designs that incorporate interactive theatre present a strong potential avenue to explore sensitive topics related to sexuality, particularly in patriarchal contexts.


Bilateral panuveitis in HIV-1-infected patients with CD8 lymphocytosis.
To report the presence of HIV-1-infected patients with bilateral panuveitis, CD8 lymphocytosis, and an absence of parotid involvement. Case series of four HIV-1-infected patients naive to antiretroviral treatment. Four patients with symptomatic panuveitis are presented. Ocular, systemic, and investigation findings are reported. Recognised causes of panuveitis were excluded. All patients showed a clinical response to steroids and antiretroviral therapy. Symptomatic panuveitis may occur in HIV-1-infected individuals with CD8 lymphocytosis in the absence of a recognised cause. These patients have clinical features that resemble diffuse infiltrative lymphocytosis syndrome and may represent a subgroup of this syndrome.


Emerging strategies: PARP inhibitors in combination with immune checkpoint blockade in BRCA1 and BRCA2 mutation-associated and triple-negative breast cancer.
Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor monotherapy in germline BRCA1 and BRCA2 mutation-associated metastatic breast cancer is a well-tolerated and an effective therapeutic strategy, however, the durability of response can be limited. Checkpoint inhibitors targeting the PD-1/PD-L1 axis as monotherapy in metastatic triple-negative breast cancer (mTNBC) have a limited role due to low response rates, but are capable of long, durable responses. Combination PARP inhibition with checkpoint blockade is an emerging area of investigation with potential synergy to produce robust responses with durability. Mechanistically, PARP inhibition activates the stimulator of interferon gene (STING) pathway to promote dendritic cell and T lymphocyte recruitment, increases tumor neoantigens, and upregulates PD-L1 expression to increase the immunogenicity of the tumor and thereby potentially enhance responses to immunotherapy. Several clinical trials have reported early results on PARP inhibitor and PD-1/PD-L1 checkpoint inhibitor combinations. All studies have shown safety and tolerability of this combination regimen. In advanced breast cancer associated with a germline BRCA1 or BRCA2 mutation, response rates have been high and similar to what is observed with PARP inhibitor monotherapy. Additional follow-up is needed to see if combination with a checkpoint inhibitor can lead to a clinically meaningful extension of durability of response in patients with germline mutations in BRCA1 and BRCA2. In unselected mTNBC in the 1st-3rd line setting, response rates of combined PARP inhibitor and PD-1/PD-L1 inhibitors have ranged from 18-21%, with higher rates of response among those with alterations in homologous recombination DNA repair pathway genes. Multiple ongoing studies will report additional data on combinations of PARP inhibitors and checkpoint blockade in the future and this combination strategy remains an active area of investigation.


Effect of long-term exposure, biogenic substrate presence, and electron acceptor conditions on the biodegradation of multiple substituted benzoates and phenolates.
Biodegradation rates of benzoate and related aromatic compounds, 3-nitrobenzoate, 4-chlorobenzoate, 4-chlorophenol, and 2,4-dichlorophenol by unexposed (unacclimated) and long-term exposed (acclimated) biomass were quantified using a modified fed-batch technique. The acclimated biomass was taken after approximately 1-year of operation from three lab-scale sequencing batch reactors (SBR). These reactors were operated under various cycling electron acceptor conditions with a continuous feed of a synthetic wastewater containing biogenic and nonbiogenic chemicals including benzoate, 3-nitrobenzoate, and 4-chlorophenol, but not 4-chlorobenzoate or 2,4-dichlorophenol. The unexposed biomass was taken from a full-scale wastewater treatment plant, which constituted one of the original sources of inoculum for the lab-scale SBRs. The acclimated biomass manifested high removal rates of benzoate and related aromatic compounds with additional removal of structurally similar chemicals (4-chlorobenzoate and 2,4-dichlorophenol). The unacclimated biomass showed no removal of 3-nitrobenzoate, 4-chlorobenzoate or 2,4-dichlorophenol. Addition of biogenic substrates reduced the degradation of most aromatic compounds tested, but it enhanced 2,4-dichlorophenol removal. Biodegradation rates of each aromatic compound with the biomass from the anoxic/aerobic SBR were further determined under anaerobic (absence of aeration and NO3-), anoxic (no aeration, but with surplus NO3-), standard oxygen (DO > 0.2 mg/L), and elevated oxygen (DO > 25 mg/L) conditions. The removal rate of both benzoate and 3-nitrobenzoate decreased under anaerobic condition but not under the anoxic condition; 4-chlorophenol biodegradation, on the other hand, was reduced significantly under both anoxic and anaerobic conditions. The removal rates of aromatic compounds, particularly those of 3-nitrobenzoate and 2,4-dichlorophenol, increased significantly under elevated dissolved oxygen conditions. Our results demonstrated that when the biochemical conditions shifted from oxygen-respiration to nitrate respiration, to anaerobiosis, the biodegradation rates of test aromatic compounds decreased or ceased.


COVID-19: No Distinction for Children's Spiritual Growth.
COVID-19 cannot rob us of our ability to perform our ministry for children. As adults and ministers, we can show our support for the spiritual growth of children. COVID-19 has not deprived us of our creativity in praise, telling of God's love, prayers, and support for all the children and parents. COVID-19 has not defeated our spiritual life.


Reverse-docking study of the TADDOL-catalyzed asymmetric hetero-Diels-Alder reaction.
The reverse-docking of a TADDOL catalyst to rigid transition-state (TS) representations of an asymmetric hetero-Diels-Alder reaction is described. The resulting docking poses represent a simplified geometric model of the TS for the catalyzed reaction. The conformational space of the catalyst in proximity to the catalyst-free TS models is sampled stochastically and the energetically favored poses are subjected to a clustering procedure to highlight structural attributes compatible with organocatalysis. Each pose is scored and ranked based on its molecular-mechanics docking energy. The reverse-docking procedure reveals a clear energetic trend in favor of the experimentally preferred product enantiomers. Analysis of the best poses suggests a geometric model that is consistent with principles of molecular recognition, catalysis, and experimental data.


Vitamin D deficiency and dyslipidemia in early pregnancy.
Vitamin D deficiency is a common nutritional issue and dietary supplementation in the general population, including pregnant women, is generally advised. Appropriately high levels of vitamin D are expected to play a role in containing the glycemic and atherogenic profiles observed in pregnancy. However, the relation between vitamin D status and the lipid metabolic profile in Saudi women, who are known to suffer from chronic vitamin D deficiency and high incidence of obesity and type II DM, during the course of pregnancy is not known. In this study, we analyzed the relation between serum vitamin D level and various serum metabolic markers among Saudi women (n = 515) in their first trimester of pregnancy (11.2 ± 3.4 weeks). Coefficients of Pearson correlation and Spearman rank correlation were calculated for Gaussian and non-Gaussian variables, respectively. Serum vitamin D status was defined as (in nmol/L): deficient (<25), insufficient (25-50); sufficient (50-75) and desirable (>75). Results indicated that vitamin D status was sufficient in only 3.5% of the study participants and insufficient and deficient in 26.2% and 68.0% of participants, respectively. Serum vitamin D values in the overall study population correlated positively with serum levels of total cholesterol (R = 0.172; p < 0.01), triglycerides (R = 0.184; p < 0.01) and corrected calcium (R = 0.141; p < 0.05). In the subgroup of vitamin D deficient subjects (n = 350), log serum vitamin D values correlated with serum triglycerides (R = 0.23; p = 0.002) and cholesterol (R = 0.26; p = 0.001). The positive correlations between serum vitamin D and the atherogenic factors such as total cholesterol and triglycerides indicate a pro-atherogenic metabolic status in vitamin D deficient expectant mothers. This may represent an adaptation to the high metabolic demands of pregnancy.


Lessons learned: Outcomes and methodology of a coping skills intervention trial comparing individual and group formats for patients with cancer.
Nucare, a short-term psychoeducational coping skills training intervention was evaluated in a randomized controlled clinical trial (RCT) of 225 newly diagnosed breast and colon cancer patients. Measures of psychosocial distress, well being and optimism were evaluated every four months during a one-year period. Patients were randomized to one of four arms: Nucare presented in an individual basis; Nucare presented in a group format; a non-directive supportive group; and a no-intervention control. The interventions were provided in five sessions of ninety minutes each. Patients with breast cancer who received Nucare presented in an individual format showed more significant improvements in well-being over time compared to those in the control and group arms. We were unable to develop functioning groups within the RCT. Partial explanations for the latter finding include the structural limitations of the RCT: the groups were small, difficult to schedule and patients indicated that they would have preferred to choose whether or not to participate in a group. The positive changes in women with breast cancer who received Nucare persisted at 12 months.


aPKC phosphorylates JAM-A at Ser285 to promote cell contact maturation and tight junction formation.
The PAR-3-atypical protein kinase C (aPKC)-PAR-6 complex has been implicated in the development of apicobasal polarity and the formation of tight junctions (TJs) in vertebrate epithelial cells. It is recruited by junctional adhesion molecule A (JAM-A) to primordial junctions where aPKC is activated by Rho family small guanosine triphosphatases. In this paper, we show that aPKC can interact directly with JAM-A in a PAR-3-independent manner. Upon recruitment to primordial junctions, aPKC phosphorylates JAM-A at S285 to promote the maturation of immature cell-cell contacts. In fully polarized cells, S285-phosphorylated JAM-A is localized exclusively at the TJs, and S285 phosphorylation of JAM-A is required for the development of a functional epithelial barrier. Protein phosphatase 2A dephosphorylates JAM-A at S285, suggesting that it antagonizes the activity of aPKC. Expression of nonphosphorylatable JAM-A/S285A interferes with single lumen specification during cyst development in three-dimensional culture. Our data suggest that aPKC phosphorylates JAM-A at S285 to regulate cell-cell contact maturation, TJ formation, and single lumen specification.


Folic acid mediated attenuation of loss of heterozygosity of DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas.
Loss of heterozygosity (LOH) and/or inactivation of tumor suppressor genes are implicated in the initiation and progression of many malignancies, including colorectal cancer. Although accumulating evidence suggests a chemopreventive role for folate in colorectal cancer, regulatory mechanisms are poorly understood. The primary objective of the current investigation was to determine whether folic acid would prevent LOH of the three tumor suppressor genes, deleted in colorectal cancer (DCC), adenomatous polyposis coli (APC) and p53 in macroscopically normal appearing rectal mucosa of patients with adenomatous polyps. In addition, the effect of folic acid on rectal mucosal proliferation was determined. Twenty patients were randomized in a double-blind study to receive either folic acid 5mg once daily or identical placebo tablets for 1 year. Genomic DNA and total protein were extracted from the rectal mucosa at baseline and after 1 year of treatment and analyzed for LOH and protein levels of APC, DCC and p53 genes. In addition, paraffin-embedded mucosal specimens were analyzed for proliferating cell nuclear antigen (PCNA) immunoreactivity, as a measure of cellular proliferative activity. Folate supplementation prevented LOH of DCC gene in five out of five (100%) patients who demonstrated baseline heterozygosity, whereas two out of four (50%) placebo-treated patients with baseline heterozygosity demonstrated allelic loss. Mucosal protein levels of DCC were also reduced in 7 of 10 (70%) placebo-treated patients compared to only 2 of 10 (20%) of patients treated with folate. Levels increased, however, in eight and three patients in the folic acid and placebo groups, respectively (P<0.02). Folic acid caused no change in allelic status of either APC or p53 gene. Folate supplementation caused a small, but not statistically significant, 16% reduction in mucosal proliferation, whereas placebo treatment resulted in a 88% (P<0.05) increase in this parameter, when compared with the corresponding baseline values. Our results indicate that folic acid prevents an increase in proliferation and arrests LOH of DCC gene and also stabilizes its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Taken together, our data suggest that one of the ways folate may exert its chemopreventive effect is by stabilizing certain tumor suppressor gene(s) and preventing further increases in proliferation.


Using association mapping and local interval haplotype association analysis to improve the cotton drought stress response.
Drought stress has a serious impact on the growth and development of cotton. To explore the relevant molecular mechanism of the drought stress response in cotton, gene mapping based on the QTL interval mapped by simplified genome BSA-seq of the drought-resistance-related RIL population was performed. A QTL region spanning 2.02 Mb on chromosome D07 was selected, and 201 resource materials were genotyped using 9 KASP markers in the interval. After local interval haplotype association analysis, the overlap of the 110 kb peak region confirmed the reliability of this region, and at the same time, the role of GhGF14-30, the only gene in the overlapping region, was modeled in the response of cotton to drought stress. qRTPCR analysis of the materials and population parents proved that this gene plays a role in the drought stress response in cotton. Virus-induced gene silencing proved the importance of this gene in drought-sensitive materials, and drought-resistance-related marker genes also proved that the GhGF14-30 gene may play an important role in the ABA and SOS signaling pathways. This study provides a basis for mining drought stress response functional genes in cotton and lays the foundation for the molecular mechanism of the GhGF14-30 gene in response to drought stress in cotton.


Epidemiological survey of biomarkers of hepatitis virus in patients with extrahepatic cholangiocarcinomas.
Hepatitis virus B and C (HBV and HCV) are suggested to be risk factors for intrahepatic cholangiocarcinoma (ICC), but whether they are risk factors for extrahepatic cholangiocarcinoma (ECC) is disputed. To test the biomarkers in patients with ECC and further elucidate the relationship of HBV or HCV infection with ECC risk, we conducted a retrospective survey on hepatitis virus markers in patients with ECC. A hospital-based case-control study was conducted to review prior infection with hepatitis virus and the seroprevalence of hepatitis virus markers in the patients with ECC or with benign biliary disease (BBD). HBV X antigen (HBxAg) was detected in the tissues by immunohistochemical staining. A total of 305 patients with ECC and 480 with BBD were enrolled in this study. Compared with BBD patients, ECC patients had a higher prevalence of prior infection with HBV (6.2 vs 2.3%) and chronic HBV infection (9 vs 1.9%). The overall seropositive rate for HBV markers in the two groups was 22.6 versus 6% (P < 0.01) and for HBxAg detection it was 75 versus 26% (P < 0.001). The seroprevalence of anti-HCV was 4.3% in the EEC patients and 5.6% in BBD patients with no significant difference between them. The high prevalence of HBV biomarkers in ECC strongly supports the notion that HBV infection may be a risk factor for ECC. The high frequency of HBxAg expression suggests its important role in the pathogenesis of bile duct neoplasm.


[Concentration of lysozyme during mineralization in callous tissue of healing fractures (author's transl)].
Investigations have suggested that lysozyme (E.C. 220.127.116.11) is involved in bone mineralization. High concentrations of lysozyme is found in the growth plate near cartilage bone junction, where it is located at the collagen fibrils and in the ground substance. Quantitative studies of lysozyme levels were made in ossifying tissue of healing fractures, to confirm the existence of this relationship on bone repair. Callous tissue, serum samples and normal bone was collected from 42 rats at 15 intervalls during a 50 day healing period. Agar gel diffusion test was used for quantitation of lysozyme. Electrophoresis of tissue extract and standard henn egg white lysozyme served as control. Lysozyme levels in callous tissue increased significantly (4--5-fold) from 4.--21. day p. trauma and subsequently decreased. The concentration in serum samples did not change significantly. Changes in Ca concentration and histological studies during tests confirm a direct relationship between bone mineralization and lysozyme level changes.


Systemic Therapy for Advanced Hepatocellular Carcinoma: An Update of a Rapidly Evolving Field.
Hepatocellular carcinoma (HCC) incidence and mortality have shown an unfavorable upward trend over the last two decades, especially in developed countries. More than one-sixth of the patients have advanced HCC at presentation. Systemic therapy remains the treatment of choice for these patients. Current options include tyrosine kinase inhibitors (TKIs) and immunotherapy. This review aims to summarize current knowledge on the rapidly evolving field of systemic therapy with several newly approved medications over the last year. Sorafenib remains one of the first-line treatment choices for patients with hepatitis C etiology, intermediate to advanced HCC stage, and Child-Pugh class A. Lenvatinib is the other first-line drug that might have better efficacy in non-hepatitis C etiologies and advanced HCC without portal vein thrombosis. Patients intolerant to first-line therapy might benefit from immunotherapy with nivolumab or pembrolizumab. In those who fail first-line therapy, the choice should be based on the side effects related to previous treatment, performance status, and underlying liver dysfunction. Ongoing studies are investigating immunotherapy alone or immunotherapy in combination with TKIs as first-line therapy. Several second-line options for combination systemic therapy and systemic plus local-regional treatment are under investigation. Future studies should focus on identifying reliable biomarkers to predict response to therapy and to better stratify patients at high risk for progression. Multidisciplinary approach is pivotal for successful outcomes in patients with advanced HCC.


Sociodemographic and prescribing characteristics that impact long-term retention in buprenorphine treatment for opioid use disorder among a statewide population.
Partial opioid agonist medications for opioid use disorder reduce mortality and morbidity, however long-term retention in treatment is challenging. The objective of this study was to identify patient and prescription characteristics associated with long-term buprenorphine treatment retention. We used data from the Rhode Island prescription drug monitoring program to identify residents who initiated buprenorphine treatment and determine if they were retained in long-term buprenorphine treatment 12-months after treatment initiation. Multivariable logistic regression models were used to identify sociodemographic and prescription characteristics associated with long-term buprenorphine retention. During the study period 4898 unique Rhode Island residents initiated buprenorphine treatment, of whom 37.8 % were retained in treatment at 12-months. Demographic factors associated with a higher odds of long-term buprenorphine retention included older age, female sex, Medicaid insurance (vs private), and living closer to the pharmacy where the prescription was filled. Individuals who were prescribed the tablet formulation (aOR: 0.82 [95 % CI 0.72, 0.93]) or received a non-buprenorphine opioid during the follow-up window (aOR: 0.37 [95 % CI 0.31, 0.44]) had lower odds of long-term treatment at 12-months. Individuals who received at least one day of overlapping benzodiazepine and buprenorphine prescriptions (aOR: 2.00 [95 % CI 1.70, 2.34]) and those given a longer days supply (aOR: 1.26 [95 % CI 1.01, 1.56]) had higher odds of long-term treatment at 12-months. Findings were similar for treatment retention at 6-months in sensitivity analyses. These findings highlight several modifiable prescribing practices associated with long-term buprenorphine retention, suggesting that clinicians and public health practitioners can help remove barriers to long-term retention.


Prevalence and treatment of cancer pain in Italian oncological wards centres: a cross-sectional survey.
The aim of this national cross-sectional survey was to draw information on pain prevalence and intensity from a large sample of patients who were admitted to oncologic centres for different reasons and to evaluate the pain treatment and possible influencing factors. A total of 2,655 patients completed the study. Nine hundred and one patients (34%) reported pain. Higher pain levels were observed in inpatients, in the presence of bone metastases, and with low levels of Eastern Cooperative Oncology Group status. The number of patients receiving strong opioids increased with the highest levels of pain. However, a significant part of patients with moderate-severe pain were not receiving appropriate medication, patients being predominantly administered non-opioid drugs. General practitioners' attitudes did not negatively influence the opioid prescription. The results of this survey indicate a need for continuing educational and informative program in pain management for oncologists and more generally for any physician dealing with cancer patients.


Mouse hepatocyte synthesis and induction of the acute phase reactant: serum amyloid P-component.
A methodology for obtaining reproducible in vitro induction of the synthesis of the acute phase reactant serum amyloid P-component (SAP) by purified mouse hepatocytes was established. Optimal hepatocyte culture conditions for the induction and synthesis of SAP required certain hormones, a substratum for cell attachment, and activated macrophages. Leibowitz L15 medium had to be supplemented with dexamethasone, indomethacin, insulin, glucose, and fetal bovine serum. Purified mouse IL 1 could substitute for activated macrophages in the induction of SAP. Hepatocytes were allowed to adhere to a collagen matrix to enhance both cell viability and SAP synthesis induced by IL 1. Elicited macrophages cultured with hepatocytes were capable of augmenting SAP synthesis in the presence of IL 1.


Independent predictive value of the overall number of metastatic N1 and N2 stations in lung cancer.
The number of metastatic N2 stations is a known prognostic factor in patients with non-small-cell lung cancer (NSCLC). However, involvement of N1 stations as well as that of N2 stations seems to be important in the prognosis of these patients. We therefore attempt to clarify the significance of the total number of metastatic stations in pathologic N1 and N2 NSCLCs. Patients with either pathologic N1 (n = 51) or N2 (n = 96) NSCLC who had undergone major pulmonary resection with complete mediastinal dissection were included in this retrospective study. All positive nodes were characterized by location according to the TNM classification system. The hilar station was included with the N2 stations. The total number of metastatic stations in patients with N2 disease ranged from 1 to 8 (average 2.5), whereas that in patients with N1 disease ranged from 1 to 3 (average 1.2). The incidence of multiple-station metastasis (> or = 3 metastatic stations) among N2 patients (35%) was significantly higher than that among N1 patients (2%) (p < 0.001). Multivariate analysis of survival showed pathologic N1 status (relative risk = 0.443, p = 0.013) and < or = 2 metastatic stations (relative risk = 0.515, p = 0.020) to be significant and independent prognostic factors. Age, sex, cell type, resected lobe, and pathological T status were statistically insignificant determinates of survival. The total number of metastatic stations (< or = 2 vs > or = 3) is an independent prognostic indicator in patients with completely resected pathologic N1 or N2 NSCLC. The number of metastatic stations will be useful as a stratification factor in prospective clinical trials of these patients.