Effects of video digitization in pubic arch interference assessment for prostate brachytherapy.
Recently, it has been shown that prior to surgery a transrectal ultrasound (TRUS) study of the prostate and pubic arch can effectively determine pubic arch interference (PAI), a major stumbling block for the prostate brachytherapy (radioactive seed implantation) procedure. This PAI determination is currently being done with digital images taken directly from an ultrasound (US) machine. However, 70-75% of US machines used in prostate brachytherapy do not have a method to save or transfer digital image data for external use. To allow PAI assessment regardless of US platform and to keep costs to a minimum, we need to digitize the images from the US video output when there is no direct digital transfer capability. D/A and A/D conversions can introduce quantization error and other noises in these digitized images. The purpose of this work is to assess the image degradation caused by digitization and quantitatively evaluate whether after digitization it is still possible to accurately assess PAI. We used a PAI assessment algorithm (developed in previous research by our group) to predict the location of the pubic arch on both digital images and those captured after digitization. These predicted arch locations were compared to the "true" position of the pubic arch as established during surgery. Despite apparent image degradation due to the D/A and A/D conversions, we found no statistically significant difference between the accuracy of the predicted arch locations from the digitized images and those from the digital images. By demonstrating equally accurate determination of pubic arch locations using digital and digitized images, we conclude that TRUS-based PAI assessment can be easily and inexpensively performed in clinics where it is needed.


Investigation of cytotoxic, apoptosis-inducing, genotoxic and protective effects of the flavonoid rutin in HTC hepatic cells.
Rutin is a flavonoid with antioxidant, vasodilatory, anti-inflammatory and immune-stimulating activities. To study the toxicity of rutin and its protective effect, this work investigated the cytotoxic, apoptosis-inducing, genotoxic and protective effects of rutin in HTC cells. In the MTT assay, the highest concentration tested (810 μM) showed cytotoxicity after 72 h of treatment, where cell viability and cell proliferation was diminished. None of the concentrations of rutin tested induced apoptosis after 24h treatment. The highest concentration of rutin after 24h treatment induced DNA damage, shown in the comet assay, but did have a genotoxic effect in the micronucleus test. Rutin was tested against the pro-carcinogenic agent benzo(a)pyrene, at concentrations of 90, 270 and 810 μM, and was found to reduce induced DNA damage significantly. This protective effect of rutin against a pro-carcinogen, suggests an important biological activity for this compound, which can contribute to human health through the diet.


Involvement of PU.1 in mast cell/basophil-specific function of the human IL1RL1/ST2 promoter.
The human IL1RL1/ST2 gene encodes IL33 receptor. Recently, IL33 has been recognized as a key molecule for the development of Th2 response. Although mast cells and basophils are major targets of IL33 and play important roles in IL33-mediated Th2-type immune responses, the expression mechanism of ST2 in mast cells and basophils is largely unknown. In the present study, we analyzed regulation mechanism of the human ST2 promoter in the human mast cell line LAD2 and basophilic cell line KU812. Promoter activity was determined by reporter assay with plasmids carrying the wild-type ST2 promoter obtained from human genomic DNA and its mutant. The transcription factor binding to the identified cis-element was identified by an electrophoretic mobility shift assay (EMSA). The effect of candidate transcription factor on ST2 expression was confirmed by analyzing ST2 mRNA level in siRNA-introduced cells. Reporter assay demonstrated that a cis-element of typical Ets-family binding sequence was critical for promoter activity in LAD2 and KU812. An Ets-family transcription factor PU.1 bound to this element in an EMSA. When PU.1 expression was suppressed by siRNA, ST2 mRNA level was significantly reduced in KU812. These observations indicated that PU.1 positively regulates the ST2 promoter as a transcription factor that directly transactivates the ST2 promoter via Ets-family-related cis-element in mast cells and basophils.


Cost-Effectiveness Analysis of Screening for Pancreatic Cancer Among High-Risk Populations.
We evaluated the potential cost-effectiveness of combined magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) screening for pancreatic ductal adenocarcinoma (PDAC) among populations at high risk for the disease. We used a microsimulation model of the natural history of PDAC to estimate the lifetime health benefits, costs, and cost-effectiveness of PDAC screening among populations with specific genetic risk factors for PDAC, including BRCA1 and BRCA2, PALB2, ATM, Lynch syndrome, TP53, CDKN2A, and STK11. For each high-risk population, we simulated 29 screening strategies, defined by starting age and frequency. Screening included MRI with follow-up EUS in a subset of patients. Costs of tests were based on Medicare reimbursement for MRI, EUS, fine-needle aspiration biopsy, and pancreatectomy. Cancer-related cost by stage of disease and phase of treatment was based on the literature. For each high-risk population, we performed an incremental cost-effectiveness analysis, assuming a willingness-to-pay (WTP) threshold of $100,000 US dollars (USD) per quality-adjusted life year (QALY) gained. For men with relative risk (RR) 12.33 (CDKN2A) and RR 28 (STK11), annual screening was cost-effective, starting at age 55 and 40 years, respectively. For women, screening was only cost-effective for those with RR 28 (STK11), with annual screening starting at age 45 years. Combined MRI/EUS screening may be a cost-effective approach for the highest-risk populations (among mutations considered, those with RR >12). However, for those with moderate risk (RR, 5-12), screening would only be cost-effective at higher WTP thresholds (eg, $200K USD/QALY) or with once-only screening.


Current Occurrence of the Atlantic Sturgeon Acipenser oxyrinchus in Northern Spain: A New Prospect for Sturgeon Conservation in Western Europe.
Acipenser oxyrinchus is considered extirpated in Europe, but numerous breeding populations still exist on the Atlantic coast of North America. An adult female A. oxyrinchus, 2500 mm total length and 120 kg wet weight, was accidentally fished on 24 November 2010 near the coast of Gijón, Asturias, Spain. The fish was identified by its morphological pattern as well as by mitochondrial and nuclear DNA analyses. Because the sturgeon was found far away from any known breeding area, it was considered a stray or vagrant specimen. It certainly has a natural origin, but its eventual birthplace could not be determined. Because its current occurrence was unknown in southwestern Europe until now, the species is not cataloged or protected in this area. Therefore, the residual European stocks of A. oxyrinchus ought to be listed as Critically Endangered (CR) according to the IUCN categories. Likewise, it is imperative for southwestern European countries with an historic or recent occurrence of A. oxyrinchus to protect the species through domestic and international legislation. The present sympatric occurrence of A. sturio and A. oxyrinchus raises new challenges about key questions, such as the species selection for restoration program in European countries. Accurate monitoring is mandatory to obtain appropriate information for an assessment of the current occurrence of A. oxyrinchus in southwestern Europe.


Electrical membrane events in response to alpha-adrenoceptor stimulation.
Strips of rabbit main pulmonary artery (RMPA) were used to study the effects of several agonists on tension development and membrane potential of the vascular smooth muscle cells. The following alpha-adrenoceptor agonists were employed: methoxamine and St 587 (alpha 1-selective), B-HT920 (alpha 2-selective) and clonidine, which stimulates preferentially alpha 2-adrenoceptors. By the use of the selective antagonists prazosin and yohimbine it was not possible to differentiate convincingly between alpha 1- and alpha 2-adrenoceptors in the RMPA. Methoxamine and B-HT920 produced depolarization of similar magnitude of the membrane of the vascular smooth muscle cells. In spite of these results, which point to a uniform alpha-adrenoceptor in the RMPA, contractions to alpha 1- and alpha 2-agonists differed in some important aspects. Contractions in response to alpha 2-agonists were highly susceptible to the inhibitory effects of calcium withdrawal and calcium antagonists whereas contractions to alpha 1-agonists were much less so. Reduction of the membrane potential of the vascular cells by K+ at 12 mmol/l had no effect on the concentration-contraction curve of methoxamine but shifted that of B-HT920 to the left. Conversely hyperpolarization of the membrane of the vascular smooth muscle cells by strychnine totally suppressed contraction to B-HT920 and caused only a rightward shift of the concentration-contraction curve of methoxamine and St 587. Interaction of alpha 1- and alpha 2-agonists with an apparently uniform alpha-adrenoceptor induces in the RMPA contraction which seems to be triggered by different membrane processes.


Enabling multi-enzyme biocatalysis using coaxial-electrospun hollow nanofibers: redesign of artificial cells.
Highly efficient immobilization of multi-enzyme systems involving cofactor regeneration represents one of the greatest challenges in bioprocessing. Particulate artificial cells with enzymes and cofactors encapsulated within microcapsules have long been the major type of multi-enzyme biocatalysts. In the present work, a novel hollow nanofiber-based artificial cell that performs multi-step reactions involving efficient coenzyme regeneration was fabricated in situ by a facile co-axial electrospinning process. To that end, a mixture of glycerol and water containing the dissolved multi-enzyme system for the bile acid assay, which included 3α-hydroxysteroid dehydrogenase (3α-HSD), diaphorase (DP) and NADH was fed as the core phase solution, and a N,N-dimethylacetylamide solution of 30 wt% polyurethane was fed as the shell phase solution during the co-axial electrospinning. The relationship between the structures of the hollow nanofibers and the activity and stability of the encapsulated enzymes was studied. At core and shell phase electrospinning solution flow rates of 0.07 and 0.5 mL h-1, activity recoveries as high as 76% and 82% were obtained for the encapsulated 3α-HSD and DP. The hollow nanofiber-based artificial cells were successfully used for the bile acid assay, yielding good linearity for bile acid concentrations ranging from 0-200 μM. Compared with the solution-based multi-enzyme system, the hollow nanofiber-based multi-enzyme system presented a lumped activity recovery of 75%. In addition, the hollow nanofiber provided the multi-enzyme system confined inside the nano-domain of the hollow fibers with a unique stabilizing mechanism, such that more than a 170-fold increase in half-life at 25 °C was obtained for the encapsulated 3α-HSD and DP. This study is expected to greatly promote and broaden the application of multi-enzyme systems in industry, biosensor, biomedical, and many other related research fields.


Mitochondria-targeting photoacoustic therapy using single-walled carbon nanotubes.
In vitro photoacoustic therapy using modified single-walled carbon nanotubes (SWNTs) as "bomb" agents is a newly reported approach for cancer. Herein, a mitochondria-targeting photoacoustic modality using unmodified SWNTs and its in vitro and in vivo antitumor effect are reported. Unmodified SWNTs can be taken up into cancer cells due to a higher mitochondrial transmembrane potential in cancerous cells than normal cells. Under the irradiation of a 1064 nm pulse laser, 79.4% of cancer cells with intracellular SWNTs die within 20 s, while 82.3% of normal cells without SWNTs remain alive. This modality kills cancer cells mainly by triggering cell apoptosis that initiates from mitochondrial damage, through the depolarization of mitochondria and the subsequent release of cytochrome c after photoacoustic therapy. It is very effective in suppressing tumor growth by selectively destroying tumor tissue without causing epidermis injury. Taken together, these discoveries provide a new method using mitochondria-localized SWNTs as photoacoustic transducers for cancer treatment.


Consistent characterization of the electronic ground state of iron(II) phthalocyanine from valence and core-shell electron spectroscopy.
We studied the iron(II) phthalocyanine molecule in the gas-phase. It is a complex transition organometallic compound, for which, the characterization of its electronic ground state is still debated more than 50 years after the first published study. Here, we show that to determine its electronic ground state, one needs a large corpus of data sets and a consistent theoretical methodology to simulate them. By simulating valence and core-shell electron spectra, we determined that the ground state is a 3Eg and that the ligand-to-metal charge transfer has a large influence on the spectra.


Severe forward flexion of the trunk in Parkinson's disease: focal myopathy of the paraspinal muscles mimicking camptocormia.
Pronounced forward flexion of the trunk, often termed camptocormia, is a typical symptom of patients with Parkinson's disease. In 4 parkinsonian patients with camptocormia, paraspinal muscles were studied by electromyography (EMG) and axial computerized tomography (CT) or magnetic resonance imaging (MRI) scans and muscle biopsy. EMG of the lumbar and thoracic paravertebral muscles showed abundant fibrillations, positive sharp waves, and bizarre high-frequency discharges. Spinal CT and MRI scans revealed variable degrees of atrophy and fatty replacement of the thoracolumbar paraspinal muscles on both sides. No other signs of neuromuscular disease were found. Biopsy of the paraspinal muscles revealed end-stage myopathy with autophagic vacuoles, chronic inflammatory myopathy, unspecific myopathic changes, or mitochondrial myopathy. In parkinsonian patients with pronounced forward flexion of the trunk, myopathy confined to the erector spinae muscles must be considered.


Intestinal subocclusion due to colonic lipoma: a case report.
Colonic lipomas are rare benign tumors infrequently met in clinical practice. Most of them are asymptomatic making frequent their fortuitous discovery. The therapeutic approach to the fortuitous discovery of a lipoma is even less clear. The treatment depends essentially on the clinical picture, on the size of the lipoma and on its location. We report the case of a 31-year old woman, which sub-occlusive accidents events revealed a lipoma of the descending colon. The diagnosis was suspected on colonoscopy and segmental colectomy was performed. The diagnosis was confirmed by histological examination. We review the literature and discuss the clinical features, diagnosis and treatment of this uncommon disease.


Peroxiredoxin isoforms are associated with cardiovascular risk factors in type 2 diabetes mellitus.
The production of oxygen free radicals in type 2 diabetes mellitus contributes to the development of complications, especially the cardiovascular-related ones. Peroxiredoxins (PRDXs) are antioxidant enzymes that combat oxidative stress. The aim of this study was to investigate the associations between the levels of PRDX isoforms (1, 2, 4, and 6) and cardiovascular risk factors in type 2 diabetes mellitus. Fifty-three patients with type 2 diabetes mellitus (28F/25M) and 25 healthy control subjects (7F/18M) were enrolled. We measured the plasma levels of each PRDX isoform and analyzed their correlations with cardiovascular risk factors. The plasma PRDX1, -2, -4, and -6 levels were higher in the diabetic patients than in the healthy control subjects. PRDX2 and -6 levels were negatively correlated with diastolic blood pressure, fasting blood sugar, and hemoglobin A1c. In contrast, PRDX1 levels were positively correlated with low-density lipoprotein and C-reactive protein levels. PRDX4 levels were negatively correlated with triglycerides. In conclusion, PRDX1, -2, -4, and -6 showed differential correlations with a variety of traditional cardiovascular risk factors. These results should encourage further research into the crosstalk between PRDX isoforms and cardiovascular risk factors.


[Analysis of the polyploidization kinetics of the parenchymal cells in the rat liver].
Methodological approaches to kinetics of cell polyploidization in the rat liver parenchyma are discussed. Different ways of hepatocyte polyploidization in the course of postnatal liver growth have been assessed. The intensities of hepatocyte transitions from one ploidy class to another were determined. On the basis of literary experimental data the following is summarized: With the increase in the animal age, there is a decrease in hepatocyte transition from one ploidy class to and ther; in young animals the intensity of formation of tetraploid hepatocytes through the stage of binuclear cells (2c----2c X 2----4c) is 0.39-0.55 within two weeks, the intensity of direct transitions (2c----4c) being 0.00-0.19 within the same time. The intensity of entering to DNA synthesis is reduced with the increase in hepatocyte ploidy levels; in this case the coefficient of the reducing of mitotic activity is calculated as 0.10-0.22, and 0.01-0.05 for 4c- and 8c-hepatocytes, resp. The factors stimulating proliferation in the liver increase the intensity of the direct cell transition (2c----4c) by several times which can exceed the intensity of transition through the binuclear cell stage.


Nmp4/CIZ suppresses the response of bone to anabolic parathyroid hormone by regulating both osteoblasts and osteoclasts.
How parathyroid hormone (PTH) increases bone mass is unclear, but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth, we treated 10-week-old Nmp4-knockout (KO) and wild-type (WT) mice with intermittent human PTH(1-34) at 30 μg/kg daily or vehicle, 7 days/week, for 2, 3, or 7 weeks. Null mice treated with hormone (7 weeks) gained more vertebral and tibial cancellous bone than WT animals, paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 weeks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone, these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 weeks into treatment. Unexpectedly, the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptide, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4-KO bone marrow cultures produced more osteoclasts, which exhibited elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts was elevated in Nmp4-KO mice at 2 weeks, but not 3 weeks, of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity and number of both osteoblasts and osteoclasts.


Mineralization of DNA into nanoparticles of hydroxyapatite.
Encapsulation of DNA into hydroxyapatite (HAp) has been investigated using a rational approach that involves computer simulation and experimental techniques. The temporal evolution of the radial distribution functions derived from atomistic molecular dynamics simulations of Ca(2+), PO4(3-) and OH(-)-containing aqueous solutions in the presence and absence of B-DNA has been used to conclude that the backbone of the double helix acts as a template for HAp growth. More specifically, results reveal the formation of calcium phosphate clusters at the first stages of the simulations, which subsequently re-organize to nucleate HAp. This effect is produced in the absence and, especially, presence, of DNA indicating that the biomolecules do not inhibit but even promote mineral growth. Furthermore, computer simulations suggest that the diffusion of the OH(-) anions through the inorganic solution is the limiting step for the nucleation of the biomineral. Nanocapsules and crystalline nanorods of HAp containing DNA molecules inside have been prepared by mixing solutions containing Ca(2+) and PO4(3-) ions with fish sperm DNA at high pH. The dimensions and morphology of such nanostructures have been examined by transmission electron microscopy, while the characterization of the biomineral has been focused on the identification of DNA inside HAp using infrared, X-ray photoelectron and UV-vis spectroscopies, as well as gel electrophoresis. The biominerals reported in this work are important for biomedical applications requiring the protection of DNA from aggressive environmental conditions.


Hormone receptor levels and aspiration cytology in cancer of the breast.
The cytopathologic findings of 196 cases of cancer of the breast were correlated with the hormonal receptor levels. The strict cytologic criteria that allow a positive diagnosis to be used as bases for definitive treatment include adequate cellularity, lack of cohesion, and nuclear abnormalities, including increased nuclear size. On this basis, 58% of the carcinomas of the breast, including 62% of the 157 infiltrating duct carcinomas but none of 12 infiltrating lobular carcinomas, could be diagnosed by aspiration smears alone. Seventy-four per cent of the carcinomas were estrogen-receptor-positive. No correlation could be demonstrated between the cytologic pattern and diagnosis and the level of estrogen, progesterone, or androgen receptors, alone or in any combination.


Isolation and determination of deoxynivalenol by reversed-phase high-pressure liquid chromatography.
Deoxynivalenol (DON) is a mycotoxin produced by food contamination. It is a pharmacologically active compound that acts on the serotonin receptor, leading to several neuroendocrine and hematological disorders. In this article we describe a simple, accurate, and sensitive method for the quantification of DON. DON was quantified using a Phenomenex(®) ODS analytical C18 column (150 mm × 46 mm, 5 μm) with a mobile phase composed of mixture of water-acetonitrile-methanol (5:4:1, v/v/v) at a flow rate of 1.5 ml/min and at 254 nm in an ultraviolet (UV) detector The method has been validated with isolated samples of DON and provides a tool for the control of substandard and counterfeit commercial food products.


How different priming stimulations affect the corticospinal excitability induced by noninvasive brain stimulation techniques: a systematic review and meta-analysis.
Noninvasive brain stimulation (NIBS) techniques could induce changes in corticospinal excitability (CSE) and neuroplasticity. These changes could be affected by different factors, including having a session of stimulation called the 'priming' protocol before the main stimulation session called the 'test' protocol. Literature indicates that a priming protocol could affect the activity of postsynaptic neurons, form a neuronal history, and then modify the expected effects of the test protocol on CSE indicated by the amplitude of transcranial magnetic stimulation-induced motor-evoked potentials. This prior history affects a threshold to activate the necessary mechanism stabilizing the neuronal activity within a useful dynamic range. For studying the effects of this history and related metaplasticity mechanisms in the human primary motor cortex (M1), priming-test protocols are successfully employed. Thirty-two studies were included in this review to investigate how different priming protocols could affect the induced effects of a test protocol on CSE in healthy individuals. The results showed that if the history of synaptic activity were high or low enough to displace the threshold, the expected effects of the test protocol would be the reverse. This effect reversal is regulated by homeostatic mechanisms. On the contrary, the effects of the test protocol would not be the reverse, and at most we experience a prolongation of the lasting effects if the aforementioned history is not enough to displace the threshold. This effect prolongation is mediated by nonhomeostatic mechanisms. Therefore, based on the characteristics of priming-test protocols and the interval between them, the expected results of priming-test protocols would be different. Moreover, these findings could shed light on the different mechanisms of metaplasticity involved in NIBS. It helps us understand how we can improve the expected outcomes of these techniques in clinical approaches.


A comparison of somatic relaxation and EEG activity in classical progressive relaxation and transcendental meditation.
Oxygen consumption, electroencephalogram (EEG), and four other measures of somatic relaxation were monitored in groups of long-term practitioners of classical Jacobson's progressive relaxation (PR) and Transcendental Meditation (TM) and also in a group of novice PR trainees. All subjects (1) practiced relaxation or meditation (treatment), (2) sat with eyes closed (EC control), and (3) read from a travel book during two identical sessions on different days. EEG findings indicated that all three groups remained primarily awake during treatment and EC control and that several subjects in each group displayed rare theta (5-7 Hz) waveforms. All three groups demonstrated similar decrements in somatic activity during treatment and EC control which were generally of small magnitude (e. g., 2-5% in oxygen consumption). These results supported the "relaxation response" model for state changes in somatic relaxation for techniques practiced under low levels of stress but not the claim that the relaxation response produced a hypometabolic state. Despite similar state effects, the long-term PR group manifested lower levels of somatic activity across all conditions compared to both novice PR and long-term TM groups. We concluded that PR causes a generalized trait of somatic relaxation which is manifested in a variety of settings and situations. Two likely explanations for this trait were discussed: (1) PR practitioners are taught to generalize relaxation to daily activities, and/or (2) according to a "multiprocess model," PR is a "somatic technique," which should produce greater somatic relaxation than does TM, a "cognitive technique." Further research is required to elucidate these possibilities.


[Neostigmine treatment of acute pseudo-obstruction of colon (Ogilvie syndrome)].
In a 77-year-old male patient with Parkinson's disease and with acute pseudo-obstruction of the colon (Ogilvie's syndrome) conservative therapy was ineffective. Neostigmine was recently shown to be effective and safe for the treatment of Ogilvie's syndrome. Intravenous neostigmine treatment caused a prompt clinical and radiological response in the patient. Early recognition of the condition and prompt neostigmine treatment if conservative measures fail is important to reduce the risk of bowel perforation.


Indications and results of surgery in patients with Crohn's disease with onset under 10 years of age: a series of 18 patients.
In order to examine the presentation and course of Crohn's disease (CD) with an onset of CD before the age of 10 and to assess indications and effects of surgery, a retrospective study was performed in 18 children. One hundred and twenty-two children with CD have been followed over the last 22 years in our institution. Thirty of them had the first onset of disease before 10 years of age. Eighteen out of these 30 underwent intestinal resection (IR). The mean age at the onset of CD was 6.4 years and the average duration of follow-up was 11.1 years. Most common symptoms were abdominal pain (72 %), diarrhoea (72 %), and growth retardation (50 %). Colon and ileum were the most frequently involved areas. Most of the children (94.5 %) received extensive medical and or nutritional treatment before surgery. We performed 26 IRs and 14 other operations in 18 patients. Indications for IR were chronic intestinal obstruction (13 cases) and chronic intestinal disability (13 cases). Improvements in the general clinical state were obtained in 17 cases out of 18. IR is beneficial for chronically ill children with ineffective medical therapy. A disease-free interval after surgery may provide an important time for improved growth and pubertal development and a return to nearly normal life for a long time.


Nanoemulsions containing Garcinia mangostana L. pericarp extract for topical applications: Development, characterization, and in vitro percutaneous penetration assay.
A highly stable oil-in-water nanoemulsion for topical applications, containing mangostins extracted from the pericarp of mangosteen (Garcinia mangostana L.), is a promising strategy to protect mangostins as well as to improve penetration of these important antioxidants through the skins. Nanoemulsions consisted of virgin coconut oil as the oil phase, Tween-80 and Span-80 as surfactants, and xanthan gum as the thickening agent, were prepared using the high-energy and low-energy emulsification methods. The nanoemulsions that were stable up to 28 days had oil droplet diameter of 220 nm to 353 nm and zeta potential of -46.9 mV to -63.7 mV. The accelerated stability test showed that the most stable nanoemulsions were those prepared using the low-energy emulsification method with an estimated shelf life of eleven months, composed of 11% oil phase, 17% surfactant, and 72% aqueous phase. The in vitro percutaneous penetration test for the nanoemulsion with added xanthan gum provided high cumulative skin penetration of mangostins of up to 114 μg/cm2. The results of this study indicate that virgin coconut oil-based nanoemulsions containing mangostins, prepared using the low-energy emulsification method, stabilized by xanthan gum and mixed at 40°C can prospectively be used for topical applications.


Assessing Effectiveness of a Nonhuman Animal Welfare Education Program for Primary School Children.
Nonhuman animal welfare education aims to promote positive relationships between children and animals and thus improve animal welfare, yet few scientific evaluations of these programs exist. This study aimed to evaluate the effectiveness of an education program developed by the Scottish Society for the Prevention of Cruelty to Animals (SPCA) that included 4 interventions focusing on pets (companion animals), wild animals, farm animals, and general animal rescues. Knowledge, attachment to pets, and attitudes and beliefs about animal minds were assessed at pretest, posttest, and delayed posttest using a questionnaire administered to 1,217 Scottish children aged 7 to 13 years old. Results showed a significant positive impact of the program on knowledge about animals and the Scottish SPCA for all interventions. The pet and farming interventions significantly impacted children's beliefs about animal minds. There were trends toward improvements in a range of other measures. This study highlights the importance of teaching animal welfare education to children for early prevention of animal cruelty, discusses the need to base this education on theory and research to find effective change, and demonstrates how evidence-based practice can inform future education programs.


[Risks and benefits of paracetamol in children with fever].
Worldwide, paracetamol is the most commonly used antipyretic for children and the drug of first choice for reducing fever named in the majority of practice guidelines. However, whether or not it is necessary or desirable to treat fever is questionable. The provision of accurate information on the causes and treatment of fever can decrease the help-seeking behaviour of parents. Paracetamol is both effective and advisable when there is a combination of fever and pain. Fever on its own does not require treatment and doctors should therefore show caution about advising paracetamol for children who have just this symptom. The effect of paracetamol on the general well-being of children with fever on its own has not been unequivocally proven. Treatment with paracetamol for the prevention of febrile convulsions has been proven ineffective. There are indications that inhibiting fever through paracetamol can adversely affect the immune response. The use of paracetamol can produce mild side effects and hepatotoxicity.


Layered learning. Improved learning through phased education.
If you do have the time and money to put on a "train everyone all at once in every new skill they need" educational program, then by all means, "Go for it!" However, for the rest of us, this traditional approach to education just may make initial implementation of our restructuring designs impractical. For us, Layered Learning comes to the rescue. That's the up-side of Layered Learning. Sooner. Faster. Timelier. Safer. Healthier. Cheaper. A better approach to restructuring education. The challenge of Layered Learning is that it raises restructuring education from just another "to do" on a project plan to a strategic weapon to be carefully structured and put in place. By definition, we will have to make some tough decisions in terms of defining layers and interim designs. Still, more and more hospitals around the country are discovering that Layered Learning can be a powerful ally in their restructuring initiatives. You just can't turn your back on it.


An Artificial Neural Network Stratifies the Risks of Reintervention and Mortality after Endovascular Aneurysm Repair; a Retrospective Observational study.
Lifelong surveillance after endovascular repair (EVAR) of abdominal aortic aneurysms (AAA) is considered mandatory to detect potentially life-threatening endograft complications. A minority of patients require reintervention but cannot be predictively identified by existing methods. This study aimed to improve the prediction of endograft complications and mortality, through the application of machine-learning techniques. Patients undergoing EVAR at 2 centres were studied from 2004-2010. Pre-operative aneurysm morphology was quantified and endograft complications were recorded up to 5 years following surgery. An artificial neural networks (ANN) approach was used to predict whether patients would be at low- or high-risk of endograft complications (aortic/limb) or mortality. Centre 1 data were used for training and centre 2 data for validation. ANN performance was assessed by Kaplan-Meier analysis to compare the incidence of aortic complications, limb complications, and mortality; in patients predicted to be low-risk, versus those predicted to be high-risk. 761 patients aged 75 +/- 7 years underwent EVAR. Mean follow-up was 36+/- 20 months. An ANN was created from morphological features including angulation/length/areas/diameters/volume/tortuosity of the aneurysm neck/sac/iliac segments. ANN models predicted endograft complications and mortality with excellent discrimination between a low-risk and high-risk group. In external validation, the 5-year rates of freedom from aortic complications, limb complications and mortality were 95.9% vs 67.9%; 99.3% vs 92.0%; and 87.9% vs 79.3% respectively (p<0.001). This study presents ANN models that stratify the 5-year risk of endograft complications or mortality using routinely available pre-operative data.


Principles of Spatial Transcriptomics Analysis: A Practical Walk-Through in Kidney Tissue.
Spatial transcriptomic technologies capture genome-wide readouts across biological tissue space. Moreover, recent advances in this technology, including Slide-seqV2, have achieved spatial transcriptomic data collection at a near-single cell resolution. To-date, a repertoire of computational tools has been developed to discern cell type classes given the transcriptomic profiles of tissue coordinates. Upon applying these tools, we can explore the spatial patterns of distinct cell types and characterize how genes are spatially expressed within different cell type contexts. The kidney is one organ whose function relies upon spatially defined structures consisting of distinct cellular makeup. Thus, the application of Slide-seqV2 to kidney tissue has enabled us to elucidate spatially characteristic cellular and genetic profiles at a scale that remains largely unexplored. Here, we review spatial transcriptomic technologies, as well as computational approaches for cell type mapping and spatial cell type and transcriptomic characterizations. We take kidney tissue as an example to demonstrate how the technologies are applied, while considering the nuances of this architecturally complex tissue.


Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters.
The biosimilar concept is now well established. Clinical data accumulated pre- and post-approval have supported biosimilar uptake, in turn stimulating competition in the biologics market and increasing patient access to biologics. Following technological advances, other innovative biologics, such as "biobetters" or "value-added medicines," are now reaching the market. These innovative biologics differ from the reference product by offering additional clinical or non-clinical benefits. We discuss these innovative biologics with reference to CT-P13, initially available as an intravenous (IV) biosimilar of reference infliximab. A subcutaneous (SC) formulation, CT-P13 SC, has now been developed. Relative to CT-P13 IV, CT-P13 SC offers clinical benefits in terms of pharmacokinetics, with comparable efficacy, safety, and immunogenicity, as well as increased convenience for patients and reduced demands on healthcare system resources. As was once the case for biosimilars, nomenclature and regulatory pathways for innovative biologics require clarification to support their uptake and ultimately benefit patients.


Impact of case volume on hospital performance assessment.
Process performance measures are increasingly used to assess and reward hospital quality. The impact of small hospital case volumes on such measures is not clear. Using data from the Hospital Quality Alliance, we examined hospital performance for 8 publicly reported process measures for acute myocardial infarction (AMI) from 3761 US hospitals during the reporting period of January to December 2005. For each performance measure, we examined the association between hospital case volume, process performance, and designation as a "top hospital" (performance at or above the 90% percentile score). Sample sizes available for process performance assessment varied considerably, ranging from a median of 3 patients per hospital for timely administration of thrombolytics therapy to 62 patients for aspirin given on arrival at the hospital. In aggregate, hospitals with larger AMI case volumes had better process performance; for example, use of beta-blockers at arrival rose from 72% of patients at hospitals with less than 10 AMI cases to 80% of patients at hospitals with more than 100 cases (P < .001 for volume trend). In contrast, owing to an artifact of wide sampling variation in sites with small denominators, classification of a center as a top hospital actually declined rapidly with increasing case volume using current analytic methods (P < .001). This unexpected association persisted after excluding very low volume centers (<25 cases) and when using Achievable Benchmarks of Care. Using hierarchical models removed the paradoxical association but may have introduced a bias in the opposite direction. Large-volume hospitals had better aggregate performance but were less likely to be identified as top hospitals. Methods that account for small and unequal denominators are needed when assessing hospital process measure performance.


Interactions among pro-inflammatory cytokines, IGF system and thyroid function in pre-pubertal obese subjects.
Obesity is a state of chronic inflammation. Data on IGF system are often discrepant, and their relationships with mediators of inflammation are unknown. Furthermore, changes in thyroid function have been reported. We aimed at investigating the changes in these systems, and verify any relationships among cytokines, IGF system, thyroid function and insulin-insensitivity. Fifty obese pre-pubertal children, and 55 normal-weight subjects comparable for age and sex were enrolled. Serum IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, IL-6 and TNF-alpha were assayed. In obese children insulin, TSH and FT4 were measured also, and the HOMA-IR index was calculated. Increased IGF-II, IL-6 and TNF-alpha, and decreased IGFBP-1 and IGFBP-2 concentrations were found in obese compared to normal-weight children. The IGF-I/IGFBP-3 molar ratio was also reduced in the obese subjects. In the obese children with high HOMA-IR index, IGFBP-1 and -2 serum concentrations were significantly decreased compared with those with normal insulin sensitivity, and in the obese subjects with increased TSH, IGFBP-2 concentrations were lower, and IGFBP-3 levels were higher compared to their counterparts with normal TSH levels. Among the significant correlations, BMISDS was correlated with IGF-II, and TSH. IGF-II concentrations showed a positive relationship with IL-6. TSH was correlated with IGFBP-2 also. The data showed interactions among IL-6, IGF system, insulin sensitivity, and thyroid function with changes being related to the degree of obesity. Chronic inflammation in obese children was confirmed. Some of the changes in the IGF system could be a consequence of insulin resistance and could account also for later complications in obese subjects.


Explosive heavy-resistance training in old and very old adults: changes in rapid muscle force, strength and power.
Age-related decline in muscle power predicts falls, motor impairments and disability. Recent guidelines suggested that training programs should be tailored to maximize muscle power. This study investigated the effects of 12 weeks of explosive-type heavy-resistance training (75-80% of 1 repetition maximum) in old (60-65 years, TG60) and very old (80-89 years, TG80) community-dwelling women. Training was performed with maximal intentional acceleration of the training load during the concentric movement phase. Maximal isometric voluntary muscle strength (MVC), rapid force capacity, assessed as rate of force development (RFD), and impulse, maximal muscle power during a countermovement jump (CMJ) and during unilateral leg extension task (LEP) were evaluated. RFD, impulse and MVC increased by 51%, 42% and 28% in TG80, and by 21%, 18% and 18% in TG60, respectively. CMJ jump height increased by 18% and 10% in TG80 and TG60, respectively, while jump peak power increased in TG60 (5%). Finally, LEP increased 28% in TG80 and 12% in TG60. These findings demonstrate that explosive-type heavy-resistance training seems to be safe and well tolerated in healthy women even in the eighth decade of life and elicits adaptive neuromuscular changes in selected physiological variables that are commonly associated with the risk of falls and disability in aged individuals.


Recommendations to Improve Quality of Probiotic Systematic Reviews With Meta-Analyses.
Systematic reviews and meta-analyses often report conflicting results when assessing evidence for probiotic efficacy, partially because of the lack of understanding of the unique features of probiotic trials. As a consequence, clinical decisions on the use of probiotics have been confusing. To provide recommendations to improve the quality and consistency of systematic reviews with meta-analyses on probiotics, so evidence-based clinical decisions can be made with more clarity. For this consensus statement, an updated literature review was conducted (January 1, 2020, to June 30, 2022) to supplement a previously published 2018 literature search to identify areas where probiotic systematic reviews with meta-analyses might be improved. An expert panel of 21 scientists and physicians with experience on writing and reviewing probiotic reviews and meta-analyses was convened and used a modified Delphi method to develop recommendations for future probiotic reviews. A total of 206 systematic reviews with meta-analysis components on probiotics were screened and representative examples discussed to determine areas for improvement. The expert panel initially identified 36 items that were inconsistently reported or were considered important to consider in probiotic meta-analyses. Of these, a consensus was reached for 9 recommendations to improve the quality of future probiotic meta-analyses. In this study, the expert panel reached a consensus on 9 recommendations that should promote improved reporting of probiotic systematic reviews with meta-analyses and, thereby, assist in clinical decisions regarding the use of probiotics.


Barriers and enablers to patient recruitment for randomised controlled trials on treatment of chronic wounds: A systematic review.
Randomised controlled trials represent the gold standard in intervention efficacy evaluation. However, suboptimal recruitment affects completion and the power of a therapeutic trial in detecting treatment differences. We conducted a systematic review to examine the barriers and enablers to patient recruitment for randomised controlled trials on chronic wound treatment. Review registration was under PROSPERO 2017:CRD42017062438. We conducted a systematic search of Ovid MEDLINE, EBSCOhost CINAHL, Ovid Cochrane Library, Ovid EMBASE, and Ovid PsycINFO databases in June 2017 for chronic wound treatment randomised controlled trials. Twenty-seven randomised controlled trials or qualitative studies met the inclusion criteria. Among the 24 randomised controlled trials, 21 were assessed as low quality in relation to recruitment, and 3 were assessed as high quality. All 27 studies reported barriers to recruitment in chronic wound randomised controlled trials. The reported barriers to recruitment were: study-related, patient-related, clinician-related, health system-related, and/or operational-related. No study reported recruitment enablers. To enhance randomised controlled trial recruitment, we propose the need for improved integration of research and clinical practice. To alleviate the problems arising from inadequate reporting of randomised controlled trials, the Consolidated Standards of Reporting Trials Statement could include an additional item on recruitment barriers. This approach will allow for increased awareness of the potential barriers to recruitment for Randomised controlled trials (RCTs) in both wound management and other health care research.


When and How To Use Endoscopic Tattooing in the Colon: An International Delphi Agreement.
There is a lack of clinical studies to establish indications and methodology for tattooing, therefore technique and practice of tattooing is very variable. We aimed to establish a consensus on the indications and appropriate techniques for colonic tattoo through a modified Delphi process. The baseline questionnaire was classified into 3 areas: where tattooing should not be used (1 domain, 6 questions), where tattooing should be used (4 domains, 20 questions), and how to perform tattooing (1 domain 20 questions). A total of 29 experts participated in the 3 rounds of the Delphi process. A total of 15 statements were approved. The statements that achieved the highest agreement were as follows: tattooing should always be used after endoscopic resection of a lesion with suspicion of submucosal invasion (agreement score, 4.59; degree of consensus, 97%). For a colorectal lesion that is left in situ but considered suitable for endoscopic resection, tattooing may be used if the lesion is considered difficult to detect at a subsequent endoscopy (agreement score, 4.62; degree of consensus, 100%). A tattoo should never be injected directly into or underneath a lesion that might be removed endoscopically at a later point in time (agreement score, 4.79; degree of consensus, 97%). Details of the tattoo injection should be stated clearly in the endoscopy report (agreement score, 4.76; degree of consensus, 100%). This expert consensus has developed different statements about where tattooing should not be used, when it should be used, and how that should be done.


Birthweight and gestational age by ethnic group, England and Wales 2005: introducing new data on births.
Low birthweight babies and babies born preterm are at increased risk of morbidity and mortality in the first year of life, as well as in the longer-term. Since information on ethnic group is not recorded at birth registration in England and Wales, it has not been possible to produce routine statistics on birthweight or gestational age by ethnic group. A new system, introduced in 2002, for allocating NHS numbers at birth (NN4B) provided the opportunity to obtain ethnic group information. The NN4B record includes information on the ethnic group of the baby classified according to the 2001 Census categories. This paper presents the first analyses of ethnic differences in birthweight and gestational age at birth for England and Wales as a whole. Utilising NN4B records linked with birth registration records for all births occurring in England and Wales in 2005, birthweight and gestational age distributions, including the percentages low birthweight and preterm, are compared between ethnic groups. The paper also examines how parental socio-demographic circumstances vary by ethnic group.


Recent advances in clinical practice: management of inflammatory bowel disease during the COVID-19 pandemic.
The COVID-19 pandemic has raised considerable concerns that patients with inflammatory bowel disease (IBD), particularly those treated with immunosuppressive therapies, may have an increased risk of SARS-CoV-2 acquisition, develop worse outcomes following COVID-19, and have suboptimal vaccine response compared with the general population. In this review, we summarise data on the risk of COVID-19 and associated outcomes, and latest guidance on SARS-CoV-2 vaccines in patients with IBD. Emerging evidence suggests that commonly used medications for IBD, such as corticosteroids but not biologicals, were associated with adverse outcomes to COVID-19. There has been no increased risk of de novo, or delayed, IBD diagnoses, however, an overall decrease in endoscopy procedures has led to a rise in the number of missed endoscopic-detected cancers during the pandemic. The impact of IBD medication on vaccine response has been a research priority recently. Data suggest that patients with IBD treated with antitumour necrosis factor (TNF) medications had attenuated humoral responses to SARS-CoV-2 vaccines, and more rapid antibody decay, compared with non-anti-TNF-treated patients. Reassuringly, rates of breakthrough infections and hospitalisations in all patients who received vaccines, irrespective of IBD treatment, remained low. International guidelines recommend that all patients with IBD treated with immunosuppressive therapies should receive, at any point during their treatment cycle, three primary doses of SARS-CoV-2 vaccines with a further booster dose as soon as possible. Future research should focus on our understanding of the rate of antibody decay in biological-treated patients, which patients require additional doses of SARS-CoV-2 vaccine, the long-term risks of COVID-19 on IBD disease course and activity, and the potential risk of long COVID-19 in patients with IBD.


Health equity and COVID-19: global perspectives.
The COVID-19 is disproportionally affecting the poor, minorities and a broad range of vulnerable populations, due to its inequitable spread in areas of dense population and limited mitigation capacity due to high prevalence of chronic conditions or poor access to high quality public health and medical care. Moreover, the collateral effects of the pandemic due to the global economic downturn, and social isolation and movement restriction measures, are unequally affecting those in the lowest power strata of societies. To address the challenges to health equity and describe some of the approaches taken by governments and local organizations, we have compiled 13 country case studies from various regions around the world: China, Brazil, Thailand, Sub Saharan Africa, Nicaragua, Armenia, India, Guatemala, United States of America (USA), Israel, Australia, Colombia, and Belgium. This compilation is by no-means representative or all inclusive, and we encourage researchers to continue advancing global knowledge on COVID-19 health equity related issues, through rigorous research and generation of a strong evidence base of new empirical studies in this field.


Antigenicity of rat collagen. Demonstration of antibody to rat collagen in the renal glomeruli of rats by fluorescence microscopy.
Rabbit serum or globulin, containing antibody to rat collagen, injected intravenously or intracardially into normal or adjuvant-prepared rats becomes fixed in the basement membranes of renal glomeruli and, to a slight extent, of the tubules. When examined by ultraviolet light, this antibody can be identified in tissue sections by the yellow-green fluorescence occurring where the rabbit globulin, associated with the fixed collagen antibody, has reacted with fluorescein-conjugated anti-rabbit globulin from ducks. The reaction of the antibody to rat collagen with its antigen in the kidney is a primary factor in the production of the renal glomerular injury which occurs in rats prepared with adjuvant. Adjacent control sections failed to fluoresce when pretreated with unlabeled anti-rabbit globulin or when treated with heterologous conjugated anti-duck globulin from rabbits. The antibody to rat collagen remains in the kidney as long as 92 days and has been detected as early as 45 minutes after injection. When normal rabbit serum, rabbit anti-fish collagen serum, or rabbit anti-rat collagen serum absorbed with rat collagen was substituted for the rabbit anti-rat collagen serum, fixed antibody could not be demonstrated by fluorescence; but absorption of the anti-rat collagen serum with fish collagen did not affect the antibody fixation. This series of immunologic tests indicates that the anti-collagen serum reacts with its homologous antigen, presumably collagen, in the basement membranes of renal glomeruli and tubules, and that specific antibody can be used to identify collagen in other tissues of the animal body.


Superblindsight, Inverse Anton, and tweaking A-consciousness further.
It is argued that Block's thought experiment on superblindsight and "the Inverse Anton's syndrome" are not cases of A-consciousness without P-consciousness. "Weak dispositional states" should be excluded from the set of A-conscious states, and a subject's being reflectively conscious of a P-conscious state is suggested as a better candidate for A-consciousness. It is further pointed out that dreams, according to Block's own criterion but contrary to what he claims, are A-unconscious and it is argued that Block should not accept the idea that high-information representational content is an empirically sufficient condition of phenomenality in human beings.


Homozygous HLA-G*0105N healthy individuals indicate that membrane-anchored HLA-G1 molecule is not necessary for survival.
HLA-G is expected to play an important role during fetal development. Recently, a healthy individual homozygous for the HLA-G*0105N allele has been described, suggesting that HLA-G expression was not essential for fetal survival. We now report studies of one family with five healthy siblings homozygous for HLA-G*0105N, who had been normally delivered; three of these siblings were females who also had normal deliveries. In addition, HLA-G*0105N cDNA has been fully sequenced, and normal G1 membrane anchored protein cannot be translated since after the codon 130 cytosine deletion (exon 3) a reading frameshift is observed leading to the existence of premature stop codon at position 189 (beginning of exon 4). Other protein isoforms (G2, G3 and G6), all containing the leader peptide and the alpha1 domain, are possible and their messenger mRNAs were found; any of these may undertake the necessary HLA-G functions. Our data show that the membrane anchored HLA-G molecule is not necessary in either mother or fetus for a normal pregnancy and survival. Also, individuals homozygous for HLA-G*0105N are healthy and with no indications of immunodeficiency or autoimmunity.


Carbimazole-associated hypersensitivity vasculitis in a cat.
Feline hyperthyroidism can be treated medically, surgically or with radioactive iodine. Carbimazole inhibits both triiodothyronine and thyroxine synthesis in the thyroid gland and reported side effects include mild eosinophilia, leucopenia and lymphocytosis, thrombocytopenia, elevated liver enzyme activities, gastrointestinal signs and skin abnormalities. This case report describes a cat with carbimazole-associated apparent hypersensitivity vasculitis causing digital and tail necrosis, with multiple renal infarcts. Withdrawal of carbimazole resulted in stable disease.


Differential expression of inflammatory and fibrogenic genes and their regulation by NF-kappaB inhibition in a mouse model of chronic colitis.
Fibrosis is a major complication of chronic inflammation, as seen in Crohn's disease and ulcerative colitis, two forms of inflammatory bowel diseases. To elucidate inflammatory signals that regulate fibrosis, we investigated gene expression changes underlying chronic inflammation and fibrosis in trinitrobenzene sulfonic acid-induced murine colitis. Six weekly 2,4,6-trinitrobenzene sulfonic acid enemas were given to establish colitis and temporal gene expression patterns were obtained at 6-, 8-, 10-, and 12-wk time points. The 6-wk point, TNBS-w6, was the active, chronic inflammatory stage of the model marked by macrophage, neutrophil, and CD3(+) and CD4(+) T cell infiltrates in the colon, consistent with the idea that this model is T cell immune response driven. Proinflammatory genes Cxcl1, Ccl2, Il1b, Lcn2, Pla2g2a, Saa3, S100a9, Nos2, Reg2, and Reg3g, and profibrogenic extracellular matrix genes Col1a1, Col1a2, Col3a1, and Lum (lumican), encoding a collagen-associated proteoglycan, were up-regulated at the active/chronic inflammatory stages. Rectal administration of the NF-kappaB p65 antisense oligonucleotide reduced but did not abrogate inflammation and fibrosis completely. The antisense oligonucleotide treatment reduced total NF-kappaB by 60% and down-regulated most proinflammatory genes. However, Ccl2, a proinflammatory chemokine known to promote fibrosis, was not down-regulated. Among extracellular matrix gene expressions Lum was suppressed while Col1a1 and Col3a1 were not. Thus, effective treatment of fibrosis in inflammatory bowel disease may require early and complete blockade of NF-kappaB with particular attention to specific proinflammatory and profibrogenic genes that remain active at low levels of NF-kappaB.


What is a multiple treatments meta-analysis?
Standard meta-analyses are an effective tool in evidence-based medicine, but one of their main drawbacks is that they can compare only two alternative treatments at a time. Moreover, if no trials exist which directly compare two interventions, it is not possible to estimate their relative efficacy. Multiple treatments meta-analyses use a meta-analytical technique that allows the incorporation of evidence from both direct and indirect comparisons from a network of trials of different interventions to estimate summary treatment effects as comprehensively and precisely as possible.


How Has COVID-19-Related Income Loss and Household Stress Affected Adolescent Mental Health in Kenya?
Adolescent mental health has been under-researched, particularly in Africa. COVID-19-related household economic stress and school closures will likely have adverse effects. We investigate the relationship among adolescent mental health, adult income loss, and household dynamics during the pandemic in Kenya. A cross-sectional mobile phone-based survey was conducted with one adult and adolescent (age 10-19 years) pair from a sample of households identified through previous cohort studies in three urban Kenyan counties (Nairobi, Kilifi, Kisumu). Survey questions covered education, physical and mental health, and COVID-19-related impacts on job loss, food insecurity, and healthcare seeking. Logistic regression models were fit to explore relationships among adult income loss, household dynamics, food insecurity, and adult and adolescent depressive symptoms (defined as PHQ-2 score ≤2). A total of 2,224 adult-adolescent pairs (Nairobi, n = 814; Kilifi, n = 914; Kisumu, n = 496) completed the survey. Over a third (36%) of adolescents reported depressive symptoms, highest among older (15-19 years) boys. Adult loss of income was associated with skipping meals, depressive symptoms, household tensions/violence, and forgoing healthcare. Adolescents had 2.5 higher odds of depressive symptoms if COVID-19 was causing them to skip meals (odds ratio 2.5, 95% confidence interval 2.0-3.1), if their adult head of household reported depressive symptoms (odds ratio 2.6, 95% confidence interval 2.1-3.2). Income loss during the pandemic adversely affects food insecurity, household dynamics, healthcare-seeking behavior, and worsening adolescent depressive symptoms. With schools reopening, adolescent mental health should be formally addressed, potentially through cash transfers, school or community-based psychosocial programming.


A novel experimental setup for simultaneous adsorption and induced deformation measurements in microporous materials.
A new experimental setup is presented allowing the simultaneous measurement of adsorption isotherms and adsorption-induced deformations. It is composed of a manometric technique coupled with a digital image correlation setup for full-field displacement measurements. The manometric part is validated by comparing adsorption isotherms with those obtained by a gravimetric method. The principles and methods of both adsorption isotherm and induced deformation measurements are presented in detail. As a first application of this new apparatus, the coupling between adsorption and induced deformation is characterised for a microporous media (activated carbon) saturated by pure CO2 (318.15 K, [0-60] bars) and pure CH4 (303.15 K, [0-130] bars). For this very homogeneous porous material, the induced deformation is characteristic of a pure volumetric swelling but the full-field setup may allow the characterisation of the localised pattern of deformation for heterogenous or cracked microporous media.


Advantageous use of tBu2P-N=P(iBuNCH2CH2)3N in the Hiyama coupling of aryl bromides and chlorides.
An efficient catalytic route to biaryls by employing (generally) only 0.25 mol % of Pd(OAc)(2) and 0.5 mol % of 1 in the Hiyama coupling reaction is reported. High yields for electron-rich, -neutral, and -deficient aryl chlorides are obtained. A variety of phenylsiloxanes undergo coupling with aryl bromides and chlorides with low Pd(OAc)(2)/1 loadings.


Chlorine stabilizer T-128 enhances efficacy of chlorine against cross-contamination by E. coli O157:H7 and Salmonella in fresh-cut lettuce processing.
During fresh-cut produce processing, organic materials released from cut tissues can rapidly react with free chlorine in the wash solution, leading to the potential survival of foodborne bacterial pathogens, and cross-contamination when the free chlorine is depleted. A reported chlorine stabilizer, T-128, has been developed to address this problem. In this study, we evaluated the ability of T-128 to stabilize free chlorine in wash solutions in the presence of high organic loads generated by the addition of lettuce extract or soil. Under conditions used in this study, T-128 significantly (P<0.001) decreased the rate of free chlorine depletion at the presence of soil. T-128 also slightly decreased the rate of free chlorine depletion caused by the addition of lettuce extract in wash solution. Application of T-128 significantly reduced the survival of bacterial pathogens in wash solutions with high organic loads and significantly reduced the potential of cross-contamination, when contaminated and uncontaminated produce were washed together. However, T-128 did not enhance the efficacy of chlorinated wash solutions for microbial reduction on contaminated iceberg lettuce. Evaluation of several produce quality parameters, including overall visual appearance, package headspace O2 and CO2 composition, and lettuce electrolyte leakage, during 15 d of storage indicated that iceberg lettuce quality and shelf life were not negatively impacted by washing fresh-cut lettuce in chlorine solutions containing 0.1% T-128. Reported chlorine stabilizer is shown to enhance chlorine efficacy against potential bacterial cross-contamination in the presence of high organic loads without compromising product quality and shelf life.


Structures of transcription pre-initiation complex with TFIIH and Mediator.
For the initiation of transcription, RNA polymerase II (Pol II) assembles with general transcription factors on promoter DNA to form the pre-initiation complex (PIC). Here we report cryo-electron microscopy structures of the Saccharomyces cerevisiae PIC and PIC-core Mediator complex at nominal resolutions of 4.7 Å and 5.8 Å, respectively. The structures reveal transcription factor IIH (TFIIH), and suggest how the core and kinase TFIIH modules function in the opening of promoter DNA and the phosphorylation of Pol II, respectively. The TFIIH core subunit Ssl2 (a homologue of human XPB) is positioned on downstream DNA by the 'E-bridge' helix in TFIIE, consistent with TFIIE-stimulated DNA opening. The TFIIH kinase module subunit Tfb3 (MAT1 in human) anchors the kinase Kin28 (CDK7), which is mobile in the PIC but preferentially located between the Mediator hook and shoulder in the PIC-core Mediator complex. Open spaces between the Mediator head and middle modules may allow access of the kinase to its substrate, the C-terminal domain of Pol II.


Lid splitting and posterior lamella cryosurgery for congenital and acquired distichiasis.
Congenital distichiasis is a rare condition with an accessory row of lashes at the Meibomian gland orifices. We suggest "acquired distichiasis" as an appropriate term for the accessory row of lashes in or near the Meibomian gland orifices, occurring as a result of such conditions as Stevens-Johnson syndrome, ocular pemphigoid, or chemical and physical injuries. We report a new treatment technique in which the eyelid is divided along the gray line then followed by cryotherapy to the posterior lid lamella. This removes the distichiatic lashes without damaging the normal lashes in the anterior lid lamella and avoids depigmentation. Histologic examination demonstrates the aberrant lashes result from a metaplasia of tissues in or around the Meibomian glands. Thirteen eyelids with acquired distichiasis and four eyelids with congenital distichiasis have been followed up for eight to 48 months. All have been greatly improved.


Longitudinal relationships between cognitive functioning and depressive symptoms among Hispanic older adults.
This study examines the relationship between cognitive functioning and depressive symptoms across 3 years in a prospective study of 273 community-dwelling, Hispanic older adults in Miami. The analyses extend the literature by testing for a bidirectional or reciprocal relationship between depressive symptoms and cognitive functioning over time and by examining the relationship between these variables among Hispanics, an understudied population at risk of developing depressive symptoms and cognitive impairments. Structural equation modeling with a cross-lagged panel design showed that depressive symptoms were unrelated to subsequent cognitive functioning. However, cognitive functioning was related to subsequent depressive symptoms at every time point, such that poorer cognitive functioning was related to higher depressive symptoms. Findings suggest that cognitive declines may predict depressive symptoms in community-dwelling Hispanic older adults.


Development and Initial Validation of the Menstrual Sensitivity Index.
The present study sought to develop and perform the initial validation of a scale assessing sensitivity to menstrual pain and symptoms. Data were taken from a larger parent study in which participants were recruited from a nationwide sample of individuals via the UniVox platform (www.univoxcommunity.com). In that study, participants were stratified by age and self-reported menstrual pain. Participants in the parent study completed two online surveys, one at baseline and one at a 3-month follow up. Participants who provided complete responses to the potential scale items, as well as a variety of validated questionnaires, were included in the present analyses. Final item selection was determined by factor analyses, and measures of validity and reliability were examined. Factor analyses support an 8-item scale assessing menstrual sensitivity. This scale, the Menstrual Sensitivity Index, demonstrates excellent internal consistency, good item-total correlations, and good total score test-retest reliability. Convergent validity emerged for menstrual- and pain-specific measures, and divergent validity emerged for anxiety sensitivity, anxiety, depression, non-menstrual bodily pain, and premenstrual symptoms. Menstrual sensitivity is a unique construct that reflects women's attunement to and fear of menstrual symptoms, and the Menstrual Sensitivity Index is a valid and reliable measure of this construct. This scale may be useful in advancing research and clinical work targeting menstrual pain.


Inhibition by glucocorticosteroid hormones of interferon and prostaglandin E induction by poly(rI). Poly(rC).
We have examined the relationship between induction of interferon (IFN) and prostaglandin E (PGE) production by poly(rI).poly(rC) in cultured human foreskin fibroblasts (FS11). Hydrocortisone and dexamethasone (2 . 5 x 10(-7) M), which are known inhibitors of PGE synthesis, significantly decreased the induction of both IFN and PGE in IFN-pretreated (primed) cells. Desoxycorticosterone, progesterone and estradiol were devoid of this activity. Hydrocortisone also blocked the induction of IFN by double-stranded RNA (dsRNA), cycloheximide and actinomycin D in FS11 cells. Arachidonic acid overcame the inhibitory effect of hydrocortisone on PGE production, but failed to restore IFN production in the presence of the steroid. Moreover, the prostaglandin synthetase inhibitors, indomethacin, aspirin and flufenamic acid, did not change IFN production by dsRNA in primed FS11 cells, although prostaglandin synthesis was abolished. Although the induction of IFN and PGE by poly(rI).poly(rC) might be consequences of the same initial event in the cell, the accumulation of PGE does not seem to have a regulatory effect on the synthesis of IFN in this system.


Scalable Biosynthetic Production of Knotted Peptides Enables ADME and Thermodynamic Folding Studies.
Knotted peptides present a wealth of structurally diverse, biologically active molecules, with the inhibitor cystine knot/knottin class among the most ecologically common ones. Many of these natural products interact with extracellular targets such as voltage-gated ion channels with exquisite selectivity and potency, making them intriguing therapeutic modalities. Such compounds are often produced in low concentrations by intractable organisms, making structural and biological characterization challenging, which is frequently overcome by various expression strategies. Here, we sought to test a biosynthetic route for the expression and study of knotted peptides. We screened expression constructs for a biosynthesized knotted peptide to determine the most influential parameters for successful disulfide folding and used NMR spectroscopic fingerprinting to validate topological structures. We performed pharmacokinetic characterization, which indicated that the interlocking disulfide structure minimizes liabilities of linear peptide sequences, and propose a mechanism by which knotted peptides are cleared. We then developed an assay to monitor solution folding in real time, providing a strategy for studying the folding process during maturation, which provided direct evidence for the importance of backbone organization as the driving force for topology formation.


DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?
Bone turnover markers (BTMs) are useful in clinical practice as they are inexpensive, and they have proven useful for treatment monitoring and identification of poor adherence. BTMs cannot be used in individual patients for identifying accelerated bone loss or an increase in fracture risk or in deciding on the optimal therapy. They are useful for monitoring both anti-resorptive and anabolic treatment. Response can be defined as a result that exceeds an absolute target, or by a change greater than the least significant change; if such a response is not present, then poor compliance or secondary osteoporosis are likely causes. A baseline BTM measurement is not always made; in that case, a value of BTM on anti-resorptive treatment that is low or low normal or above the reference interval for anabolic therapy may be taken to indicate a satisfactory response. We provide an approach to using these bone turnover markers in clinical practice by describing algorithms for anti-resorptive and anabolic therapy and describing the changes we observe in the clinical practice setting.


p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver.
p18(INK4c) belongs to the family of cyclin-dependent kinase inhibitory proteins that target the cyclin-dependent kinases and inhibit their catalytic activity. The role of p18(INK4c) for cell cycle progression in vivo is characterized poorly. Therefore, we studied the expression and physiologic relevance of p18 in quiescent and proliferating hepatocytes during liver regeneration. For our analysis we used single- (p18[INK4c], p27[KIP1], p21[CIP1/WAF1]), and double-mutant (p18/p21, p18/p27) mice. p18 expression was found in quiescent hepatocytes and a slight up-regulation was evident after partial hepatectomy (PH). p18 knockout animals showed normal cell cycle progression after PH. However, when p18/p21 and p18/p27 double-mutant mice were used, differences in cell cycle progression were evident compared with wild-type (wt) and single knockout animals. In p18/p21 knockout animals, the G1 phase was shortened as evidenced by an earlier onset of cyclin D and proliferating cell nuclear antigen (PCNA) expression and cyclin-dependent kinase (CDK) activation after PH. In contrast, in p18/p27 knockout animals, the G1 phase was unchanged, but the amount of proliferating hepatocytes (5-bromo-2'-deoxyuridine [BrdU] and PCNA positive) 48 hours after PH was elevated. In conclusion, our results suggest that p18 is involved in cell cycle progression after PH. Additionally we provide evidence that timing and strength of DNA synthesis in hepatocytes after PH is regulated tightly through the collaboration of different cell cycle inhibitors.


Inhalation exposure of animals.
Relative advantages and disadvantages and important design criteria for various exposure methods are presented. Five types of exposures are discussed: whole-body chambers, head-only exposures, nose or mouth-only methods, lung-only exposures, and partial-lung exposures. Design considerations covered include: air cleaning and conditioning; construction materials; losses of exposure materials; evenness of exposure; sampling biases; animal observation and care; noise and vibration control, safe exhausts, chamber loading, reliability, pressure fluctuations; neck seals, masks, animal restraint methods; and animal comfort. Ethical considerations in use of animals in inhalation experiments are also discussed.


Machine-learning-assisted performance improvements for multi-resonance thermally activated delayed fluorescence molecules.
With favorable colour purity, multi-resonance thermally activated delayed fluorescence (MR-TADF) molecules exhibit enormous potential in high-definition displays. Due to the relatively small chemical space of MR-TADF molecules, it is challenging to improve molecular performance through domain-specific expertise alone. To address this problem, we focused on optimizing the classic molecule, DABNA-1, using machine learning (ML). Molecular morphing operations were initially employed to generate the adjacent chemical space of DABNA-1. Subsequently, a machine learning model was trained with a limited database and used to predict the properties throughout the generated chemical space. It was confirmed that the top 100 molecules suggested by machine learning present excellent electronic structures, characterized by small reorganization energy and singlet-triplet energy gaps. Our results indicate that the improvement in electronic structures can be elucidated through the view of the molecular orbital (MO). The results also reveal that the top 5 molecules present weaker vibronic peaks of the emission spectrum, demonstrating higher colour purity when compared to DABNA-1. Notably, the M2 molecule presents a high RISC rate, indicating its promising future as a high-efficiency MR-TADF molecule. Our machine-learning-assisted approach facilitates the rapid optimization of classical molecules, addressing a crucial requirement within the organic optoelectronic materials community.


"We need our own food, to grow our own veggies…" Remote Aboriginal food gardens in the Top End of Australia's Northern Territory.
Remote Aboriginal community gardens (gardens) frequently operate below their full potential. A set of gardening sustainability principles may improve their planning, operation and long-term sustainability. This paper aims to document the principles of sustainability of non-profit remote Aboriginal community gardens in the Top End of the Northern Territory. Throughout 2011, gardens in the Top End of the Northern Territory were visited. Interviews and observational data were used to explore the principles of garden sustainability with participants. Subsequent iterative thematic analysis informed development of a set of gardening sustainability principles. Principles of sustainability included effective garden planning; community autonomy, consultation and engagement; growing community vetted crops; employing long-term, effective, culturally sensitive managers; long-term, transparent funding organisations and cycles; garden integration into existing food supply chains; culturally appropriate employment arrangements; and physical aspects of successful gardening. This work uniquely consults gardeners, managers and Aboriginal and non-Aboriginal people of both genders in the largest reported study of its type, resulting in new and expanded findings, particularly including new social factors for gardening success. Expanding the understanding of what makes gardens work to include the important social factors identified here may have merit.


Contribution to carrier detection and genetic counselling in X linked retinoschisis.
X linked retinoschisis (RS) is a vitreoretinal disease resulting from microcystic degeneration of the macula associated with peripheral lesions. The disease gene has already been assigned to the distal short arm of the X chromosome (Xp22.2) by linkage studies. In order to contribute both to a better localisation of the RS locus and to genetic counselling in RS families, we have carried out a clinical and genetic analysis in seven pedigrees. We show, first, that in contrast with previous reports, heterozygote carriers frequently express the disease, and display peripheral retinal alterations similar to those found in affected males. Second, while distal markers DXS16, DXS207, and DXS43 are closely linked to the disease locus, a high level of recombination events was found with centromeric markers, namely DXS274, DXS41, and DXS164. These findings must be taken into account for both carrier detection and prenatal diagnosis in X linked RS.


Expression of store-operated Ca2+ entry and transient receptor potential canonical and vanilloid-related proteins in rat distal pulmonary venous smooth muscle.
Chronic hypoxia causes remodeling and alters contractile responses in both pulmonary arteries and pulmonary veins. Although pulmonary arteries have been studied extensively in these disorders, the mechanisms by which pulmonary veins respond to hypoxia and whether these responses contribute to chronic hypoxic pulmonary hypertension remain poorly understood. In pulmonary arterial smooth muscle, we have previously demonstrated that influx of Ca(2+) through store-operated calcium channels (SOCC) thought to be composed of transient receptor potential (TRP) proteins is likely to play an important role in development of chronic hypoxic pulmonary hypertension. To determine whether this mechanism could also be operative in pulmonary venous smooth muscle, we measured intracellular Ca(2+) concentration ([Ca(2+)](i)) by fura-2 fluorescence microscopy in primary cultures of pulmonary venous smooth muscle cells (PVSMC) isolated from rat distal pulmonary veins. In cells perfused with Ca(2+)-free media containing cyclopiazonic acid (10 μM) and nifedipine (5 μM) to deplete sarcoplasmic reticulum Ca(2+) stores and block voltage-dependent Ca(2+) channels, restoration of extracellular Ca(2+) (2.5 mM) caused marked increases in [Ca(2+)](i), whereas MnCl(2) (200 μM) quenched fura-2 fluorescence, indicating store-operated Ca(2+) entry (SOCE). SKF-96365 and NiCl(2), antagonists of SOCC, blocked SOCE at concentrations that did not alter Ca(2+) responses to 60 mM KCl. Of the seven known canonical TRP (TRPC1-7) and six vanilloid-related TRP channels (TRPV1-6), real-time PCR revealed mRNA expression of TRPC1 > TRPC6 > TRPC4 > TRPC2 ≈ TRPC5 > TRPC3, TRPV2 > TRPV4 > TRPV1 in distal PVSMC, and TRPC1 > TRPC6 > TRPC3 > TRPC4 ≈ TRPC5, TRPV2 ≈ TRPV4 > TRPV1 in rat distal pulmonary vein (PV) smooth muscle. Western blotting confirmed protein expression of TRPC1, TRPC6, TRPV2, and TRPV4 in both PVSMC and PV. Our results suggest that SOCE through Ca(2+) channels composed of TRP proteins may contribute to Ca(2+) signaling in rat distal PV smooth muscle.


Can codon usage bias explain intron phase distributions and exon symmetry?
More introns exist between codons (phase 0) than between the first and the second bases (phase 1) or between the second and the third base (phase 2) within the codon. Many explanations have been suggested for this excess of phase 0. It has, for example, been argued to reflect an ancient utility for introns in separating exons that code for separate protein modules. There may, however, be a simple, alternative explanation. Introns typically require, for correct splicing, particular nucleotides immediately 5' in exons (typically a G) and immediately 3' in the following exon (also often a G). Introns therefore tend to be found between particular nucleotide pairs (e.g., G|G pairs) in the coding sequence. If, owing to bias in usage of different codons, these pairs are especially common at phase 0, then intron phase biases may have a trivial explanation. Here we take codon usage frequencies for a variety of eukaryotes and use these to generate random sequences. We then ask about the phase of putative intron insertion sites. Importantly, in all simulated data sets intron phase distribution is biased in favor of phase 0. In many cases the bias is of the magnitude observed in real data and can be attributed to codon usage bias. It is also known that exons may carry either the same phase (symmetric) or different phases (asymmetric) at the opposite ends. We simulated a distribution of different types of exons using frequencies of introns observed in real genes assuming random combination of intron phases at the opposite sides of exons. Surprisingly the simulated pattern was quite similar to that observed. In the simulants we typically observe a prevalence of symmetric exons carrying phase 0 at both ends, which is common for eukaryotic genes. However, at least in some species, the extent of the bias in favor of symmetric (0,0) exons is not as great in simulants as in real genes. These results emphasize the need to construct a biologically relevant null model of successful intron insertion.


G x E: a NIAAA workshop on gene-environment interactions.
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) sponsored a May 2002 workshop on gene-environment interaction (G x E) research to identify potential roadblocks to further research and to propose solutions to those roadblocks, to optimize investigative opportunities and multidisciplinary or multi-institution collaborations, and to explore ways that NIAAA can facilitate G x E studies. Sessions included panels on animal models; phenotypes; genetic findings in humans; study designs and analytical methods; and assessment of environmental risk. Key among the identified challenges to progress in G x E research were issues of study design and sampling strategies; logistic and methodological costs and constraints; availability and understanding of data analysis techniques; potential stigmatization of study populations; and organizational/bureaucratic structures that are inadequate to address the unique needs of large-scale, multicenter, longitudinal projects. Participants proposed a series of recommendations to address these issues. Session coordinators included: Gayle Boyd, Kendall Bryant, Page Chiapella, Vivian Faden, David Goldman, and Antonio Noronha. Session participants included: Laura Almasy, Henri Begleiter, Raul Caetano, Bruce Dudek, Mary Dufour, Cindy Ehlers, Mary-Anne Enoch, Joel Gelernter, David Goldman, Bridget Grant, Lorraine Gunzerath, Deborah Hasin, Andrew Heath, Victor Hesselbrock, J. Dee Higley, Shirley Hill, Kerry Jang, Raynard S. Kington, Rick Kittles, George Koob, Kenneth Leonard, Ting-Kai Li, Jeffrey Long, William McBride, Matthew McGue, Kathleen Merikangas, Tamara Phillips, Bernice Porjesz, Carol Prescott, Theodore Reich, John Rice, Richard Rose, Charmaine Royal, Arnold Sameroff, Marc Schuckit, Kenneth Sher, Renee Sieving, Robert Taylor, Michael Windle, and Robert Zucker.


[Effect of testenate in the treatment of epilepsy in men].
The paper is concerned with the mechanisms of the effect of hormones on convulsive preparedness of the brain. A study was made of the effect of the androgenous hormonal drug testenat on the clinical course of epilepsy. Testenat was found to be an effective drug decreasing the rate of epileptic seizures, transforming generalized convulsive attacks to partial, reducing the gravity and duration of the ++post-paroxysmal period. The mechanisms by which testenat affects the bioelectric activity of the brain at the cellular level are under discussion.


Radioimmunotherapy using vascular targeted 213Bi: the role of tumor necrosis factor alpha in the development of pulmonary fibrosis.
A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to cyclohexyl diethylenetriaminepentaacetic acid, successfully delivers chelated 213Bi, an alpha-particle emitter, (213Bi-201B) rapidly to lung vascular endothelium. When injected at doses of 1 MBq/mouse, 213Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors, and others had extended life spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4-6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3-4 months later, these mice developed pulmonary fibrosis and died. The mechanisms leading to the fibrotic response in other pulmonary irradiation models strongly implicate tumor necrosis factor alpha (TNF-alpha), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events that culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (rhuTNFR:Fc) as inhibitors of TNF-alpha, were unsuccessful. Additionally, mice genetically deficient for TNF-alpha production developed pulmonary fibrosis following 213Bi-201B treatment. Interestingly, non-tumor-bearing BALB/c mice receiving rhuTNFR:Fc or mice genetically deficient in TNF-alpha production and treated with 213Bi-201B, had significantly reduced life spans compared to mice receiving no treatment or 213Bi-201B alone. We speculate that in normal mice, although TNF-alpha may induce an inflammatory response following alpha-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.


A First Report of Secondary Hemophagocytic Lymphohistiocytosis Associated With Papillary Thyroid Carcinoma.
Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal immune-deficiency disorder that develops in response to diseases that produce strong immunologic activation, such as infection and malignancy. Although secondary HLH is reported to occur in association with various malignancies, there is no report of its association with thyroid cancer. We evaluated a 19-year-old man who presented with HLH. During investigation for an underlying cause of his HLH computed tomographic scan of the neck discovered thyroid nodules that were confirmed with biopsy to be papillary thyroid carcinoma. He was treated with surgery followed by radioactive iodine therapy and remains without any recurrence of malignancy or his secondary HLH. This report documents the first observation of HLH associated with thyroid cancer, and illustrates the need to include imaging of the neck while evaluating patients with secondary HLH for an underlying malignancy.


A sequential sampling scheme for detecting infestation levels of tracheal mites (Heterostigmata: Tarsonemidae) in honey bee (Hymenoptera: Apidae) colonies.
The introduction of parasitic honey bee mites, the tracheal mite, Acarapis woodi (Rennie) in 1984 and the Varroa mite, Varroa jacobsoni, in 1987, has dramatically increased the winter mortality of honey bee, Apis mellifera L., colonies in many areas of the United States. Some beekeepers have minimized their losses by routinely treating their colonies with menthol, currently the only Environmental Protection Agency-approved and available chemical for tracheal mite control. Menthol is also expensive and can interfere with honey harvesting. Because of inadequate sampling techniques and a lack of information concerning treatment, this routine treatment strategy has increased the possibility that tracheal mites will develop resistance to menthol. It is important to establish economic thresholds and treat colonies with menthol only when treatment is warranted rather than treating all colonies regardless of infestation level. The use of sequential sampling may reduce the amount of time and effort expended in examining individual colonies and determining if treatment is necessary. Sequential sampling also allows statistically based estimates of the percentage of bees in standard Langstroth hives infested with mites while controlling for the possibility of incorrectly assessing the amount of infestation. On the average, sequential sampling plans require fewer observations (bees) to reach a decision for specified probabilities of type I and type II errors than are required for fixed sampling plans, especially when the proportion of infested bees is either very low or very high. We developed a sequential sampling decision plan to allow the user to choose specific economic injury levels and the probability of making type I and type II errors which can result inconsiderable savings in time, labor and expense.


Occult head injuries in infants evaluated for physical abuse.
Abusive head injuries in infants may be occult but clinically or forensically important. Data conflict regarding yield of neuroimaging in detecting occult head injuries in infants evaluated for physical abuse, with prior studies identifying yields of 4.3-37.3 %. (1) To quantify yield of computed tomography or magnetic resonance imaging in identification of occult head injuries in infants with concerns for physical abuse and (2) to evaluate risk factors for occult head injuries. We conducted a retrospective, stratified, random systematic sample of 529 infants <12 months evaluated for physical abuse at 4 urban children's hospitals in the United States from 2008-2012. Infants with signs or symptoms suggesting head injury or skull fracture on plain radiography (N = 359), and infants without neuroimaging (N = 1) were excluded. Sampling weights were applied to calculate proportions of infants with occult head injuries. We evaluated for associations between hypothesized risk factors (age <6 months, rib or extremity fracture, facial bruising) and occult head injury using chi-square tests. Of 169 neurologically normal infants evaluated for abuse, occult head injury was identified in 6.5 % (95 % CI: 2.6, 15.8). Infants <6 months were at higher risk (9.7 %; 95 % CI: 3.6, 23.3) than infants 6-12 months (1.0 %; 95 % CI: 1.3, 20.2). Rib fracture, extremity fracture and facial bruising were not associated with occult head injury. Occult head injuries were less frequent than previously reported in some studies, but were identified in 1 in 10 infants <6 months. Clinicians should have a low threshold to obtain neuroimaging in young infants with concern for abuse.


Introduction-Case by Case: Private and Public Representations of Patients in the Grenfell Mission in Newfoundland and Labrador in the Early 20th Century.
This article provides context for three studies about early 20th-century medical cases in the geographically distributed humanitarian aid organization founded by Wilfred Grenfell in pre-Confederation Newfoundland and Labrador. It situates these studies within historiographical and theoretical approaches to case histories and their publication by medical practitioners, the background for research on the clinical records of the Grenfell organization's main hospital, and the history behind specific case information for coastal patients. While the cases examined cohere through their organizational origin, the authors of these three studies reveal sometimes unexpected representations of the patient in text and illustration. In these ways, both this introductory article and the following three studies emphasize the enduring appeal of narrative approaches to case writing while also pointing to the evolving ethics of publishing medical reports for general readers and scholars. Together they invite renewed attention to the representation of medical cases in publications that increasingly are available globally in internet collections.


Primary hepatic neuroendocrine tumor: Five cases with different preoperative diagnoses.
Neuroendocrine tumors, also known as carcinoid tumors, behave like benign tumors; however, they show the characteristics of carcinoma. While more than 80% of the neuroendocrine tumors found in the liver are metastatic, primary hepatic neuroendocrine tumors are very rare. Five patients with hepatic mass who admitted to our clinic between August 2003 and July 2007 were treated surgically. Ultrasonography, computerized tomography and magnetic resonance imaging were performed in all patients. Endoscopy and colonoscopy were conducted to exclude malignancy of other sites. Hepatectomy was carried out in all patients. Diagnosis was confirmed with immunohistochemical examination. The five patients treated surgically were diagnosed as primary hepatic neuroendocrine tumor histopathologically. Abdominal pain was the most common complaint of all patients. Hepatectomy was conducted in all patients due to tumors originating from the liver lobes. Only one patient (Case 2) underwent transarterial chemoembolization before hepatectomy to reduce tumor bleeding. Owing to tumor recurrence on the left lobe of the liver in Case 2, transarterial chemoembolization was performed four years after hepatectomy. R0 resection was achieved in two patients (Cases 1 and 3). In conclusion, primary hepatic neuroendocrine tumors are very rare and asymptomatic tumors. Thus, high-sensitive laboratory and imaging examinations are required. At present, hepatectomy remains the main treatment for primary hepatic neuroendocrine tumor.