[Dietary intervention and follow-up study in 1-to-2-year-old children on macrobiotic diets].
As a follow-up of a population-based descriptive study on the nutritional status and growth of infants on macrobiotic diets (n = 53), an intervention study was carried out in 27 selected infants with clear nutritional deficiencies. This intervention program consisted of information on the nutrient content of macrobiotic foods, a regular newsletter, personal advice if needed, and reference to teachers in macrobiotics for further advice. Adaptation of the diet within the scope of current macrobiotic guidelines did not lead to an improvement in nutritional intake, growth and blood values. As a consequence of these findings, the macrobiotic community in the Netherlands and abroad has become more aware of the need for adaptation of the macrobiotic diet. It is recommended to include a source of dietary fat (minimum 20-25 g/day), fatty fish (minimum 100-150 g/wk) and dairy products (minimum 150-250 g/day).


Primary spindle cell lesions of the thyroid gland; an overview.
Spindle cell lesions of the thyroid gland (T-SCL) are not encountered routinely in clinical practice or in the context of thyroid pathology. They commonly are classified as primary or secondary to metastatic disease. Primary T-SCL can be derivedfromfollicular, C-cell (parafollicular), or mesenchymal components and may be the result of reactive or neoplastic processes, including post-fine-needle aspiration spindle cell nodules, Riedel thyroiditis, solitary fibrous tumor, leiomyoma, peripheral nerve sheath tumor, hyalinizing trabecular tumor, spindle epithelial tumor with thymus-like differentiation, follicular dendritic cell tumor, medullary carcinoma, papillary carcinoma, anaplastic carcinoma, sarcoma, squamous cell carcinoma, and carcinoma showing thymus-like differentiation. Because T-SCL may represent the expression of benign and highly malignant neoplasms, distinction among these processes is crucial because it dictates therapy and defines prognosis. The present article reviews the clinical, imaging, pathologic, and immunohistochemical characteristics of primary T-SCL.


The use of flash visual evoked potentials in the early diagnosis of suspected optic nerve lesions due to craniofacial trauma.
Craniofacial trauma encroaching on the orbital apex and optic canal can result in direct or indirect optic nerve lesions, leading to visual impairment or blindness. Early diagnosis of a visual loss and immediate therapy are generally considered crucial for a successful restoration of vision in indirect trauma. However, in comatose or sedated patients the assessment of optic nerve function by testing pupillary reactivity may be severely compromised or impossible because of tensely swollen eyelids, conjunctival oedema, concussion of the ciliary muscle or pharmacological effects. In the event that clinical ophthalmic examination, computer tomography or nuclear magnetic resonance scanning fail to clarify the state of the optic nerve, visual evoked potentials (VEPs) to flash stimulation appear to provide reliable information on function within the visual pathway. On this basis, treatment with corticosteroids and/or surgical decompression can be rapidly initiated. Our results in a preliminary patient series confirm the value of acutely monitored VEPs as an objective test of optic nerve function in cases of suspected optic nerve injury immediately after admission to the emergency care unit. The imaging techniques usually applied may be complemented by VEPs to show the functional significance of structural abnormalities found in the vicinity of the optic nerve.


Migraine and low-tension glaucoma. A case-control study.
The authors administered a standardized headache questionnaire to 54 patients with low-tension glaucoma, 182 patients with primary open-angle glaucoma, 126 patients with ocular hypertension, and 493 normal subjects. Patients with low-tension glaucoma had headaches with or without features of migraine (unilateral headache, nausea or vomiting, or visual prodromata) more frequently than did any of the other groups. The higher prevalence of headache in low-tension glaucoma patients, who were usually elderly, was especially striking when their age was considered, since headaches are less common in elderly normal subjects than in young normal subjects. Headaches were present in 86% of elderly low-tension glaucoma patients (70 yr of age or older) but in only 64% of elderly normal subjects (P = 0.04) and only 59% of elderly ocular hypertensive patients (P = 0.02). Because migraine is an ischemic disorder, its possible association with low-tension glaucoma has etiologic and therapeutic implications.


Use of electronic medical records in development and validation of risk prediction models of hospital readmission: systematic review.
To provide focused evaluation of predictive modeling of electronic medical record (EMR) data to predict 30 day hospital readmission. Systematic review. Ovid Medline, Ovid Embase, CINAHL, Web of Science, and Scopus from January 2015 to January 2019. All studies of predictive models for 28 day or 30 day hospital readmission that used EMR data. Characteristics of included studies, methods of prediction, predictive features, and performance of predictive models. Of 4442 citations reviewed, 41 studies met the inclusion criteria. Seventeen models predicted risk of readmission for all patients and 24 developed predictions for patient specific populations, with 13 of those being developed for patients with heart conditions. Except for two studies from the UK and Israel, all were from the US. The total sample size for each model ranged between 349 and 1 195 640. Twenty five models used a split sample validation technique. Seventeen of 41 studies reported C statistics of 0.75 or greater. Fifteen models used calibration techniques to further refine the model. Using EMR data enabled final predictive models to use a wide variety of clinical measures such as laboratory results and vital signs; however, use of socioeconomic features or functional status was rare. Using natural language processing, three models were able to extract relevant psychosocial features, which substantially improved their predictions. Twenty six studies used logistic or Cox regression models, and the rest used machine learning methods. No statistically significant difference (difference 0.03, 95% confidence interval -0.0 to 0.07) was found between average C statistics of models developed using regression methods (0.71, 0.68 to 0.73) and machine learning (0.74, 0.71 to 0.77). On average, prediction models using EMR data have better predictive performance than those using administrative data. However, this improvement remains modest. Most of the studies examined lacked inclusion of socioeconomic features, failed to calibrate the models, neglected to conduct rigorous diagnostic testing, and did not discuss clinical impact.


Interval laparoscopy as predictor of response to chemotherapy in ovarian carcinoma.
Fifty-one patients with FIGO stage III and IV ovarian adenocarcinoma underwent six-month interval laparoscopy for assessment of chemotherapy response. Thirty-nine of these patients were followed by a second-look procedure at 12 months or to disease progression if it occurred earlier. A positive interval laparoscopy was predictive of disease in 91% of patients, whereas a negative interval laparoscopy showed absence of disease at second look in only 70.5% of patients. A positive laparoscopic biopsy at six months showed presence of disease at second look procedure in 100% (11 of 11) of patients. It is concluded that either an intensive initial chemotherapy or change in therapy such as intraperitoneal chemotherapy after positive interval laparoscopy is indicated in future studies.


Effects of TGFbeta1 on dental pulp cells in cultured human tooth slices.
Transforming growth factor-beta1 (TGF beta1) is a potent modulator of tissue repair in various tissues. To analyze its role during human dental repair, we used thick-sliced teeth cultured as described previously (Magloire et al., 1996). The supply of TGF beta1 to the pulp tissue was accomplished by means of a small tube glued onto the dentin. We show that this device allowed the growth factor to diffuse locally through dentinal tubules and to bind to the cells present in the coronal pulp opposite the TGF beta1-delivery tube. The tube was filled with 20 ng/mL TGF beta1, and slices were cultured for 4 days. Results show a preferential accumulation of cells in the odontoblastic and subodontoblastic layers in the vicinity of the tube. Cell proliferation increased in the subodontoblastic layer and in the underlying pulp, and BrdU-positive cells were abundant around the blood vessels. TGF beta1 induced type I collagen production by the odontoblastic/subodontoblastic/pulp cells in the stimulated zone, as demonstrated by in situ hybridization. These results suggest that TGF beta1 could be directly involved in the regulation of cell proliferation, migration, and extracellular matrix production in the human dental pulp and eventually in the repair process occurring after tooth injury.


From diagnosis to therapy in lung cancer: management of CT detected pulmonary nodules, a summary of the 2015 Chinese-German Lung Cancer Expert Panel.
The first Chinese-German Lung Cancer Expert Panel was held in November 2015 one day after the 7th Chinese-German Lung Cancer Forum, Shanghai. The intention of the meeting was to discuss strategies for the diagnosis and treatment of lung cancer within the context of lung cancer screening. Improved risk classification criteria and novel imaging approaches for screening populations are highly required as more than half of lung cancer cases are false positive during the initial screening round if the National Lung Screening Trial (NLST) demographic criteria [≥30 pack years (PY) of cigarettes, age ≥55 years] are applied. Moreover, if the NLST criteria are applied to the Chinese population a high number of lung cancer patients are not diagnosed due to non-smoking related risk factors in China. The primary goal in the evaluation of pulmonary nodules (PN) is to determine whether they are malignant or benign. Volumetric based screening concepts such as investigated in the Dutch-Belgian randomized lung cancer screening trial (NELSON) seem to achieve higher specificity. Chest CT is the best imaging technique to identify the origin and location of the nodule since 20% of suspected PN found on chest X-ray turn out to be non-pulmonary lesions. Moreover, novel state-of-the-art CT systems can reduce the radiation dose for lung cancer screening acquisitions down to a level of 0.1 mSv with improved image quality to novel reconstruction techniques and thus reduce concerns related to chest CT as the primary screening technology. The aim of the first part of this manuscript was to summarize the current status of novel diagnostic techniques used for lung cancer screening and minimally invasive treatment techniques for progressive PNs that were discussed during the first Chinese-German Lung Cancer. This part should serve as an educational part for the readership of the techniques that were discussed during the Expert Panel. The second part summarizes the consensus recommendations that were interdisciplinary discussed by the Expert Panel.


Topological data analysis of zebrafish patterns.
Self-organized pattern behavior is ubiquitous throughout nature, from fish schooling to collective cell dynamics during organism development. Qualitatively these patterns display impressive consistency, yet variability inevitably exists within pattern-forming systems on both microscopic and macroscopic scales. Quantifying variability and measuring pattern features can inform the underlying agent interactions and allow for predictive analyses. Nevertheless, current methods for analyzing patterns that arise from collective behavior capture only macroscopic features or rely on either manual inspection or smoothing algorithms that lose the underlying agent-based nature of the data. Here we introduce methods based on topological data analysis and interpretable machine learning for quantifying both agent-level features and global pattern attributes on a large scale. Because the zebrafish is a model organism for skin pattern formation, we focus specifically on analyzing its skin patterns as a means of illustrating our approach. Using a recent agent-based model, we simulate thousands of wild-type and mutant zebrafish patterns and apply our methodology to better understand pattern variability in zebrafish. Our methodology is able to quantify the differential impact of stochasticity in cell interactions on wild-type and mutant patterns, and we use our methods to predict stripe and spot statistics as a function of varying cellular communication. Our work provides an approach to automatically quantifying biological patterns and analyzing agent-based dynamics so that we can now answer critical questions in pattern formation at a much larger scale.


Survival of GacS/GacA mutants of the biological control bacterium Pseudomonas aureofaciens 30-84 in the wheat rhizosphere.
GacS/GacA comprises a two-component regulatory system that controls the expression of secondary metabolites required for the control of plant diseases in many pseudomonads. High mutation frequencies of gacS and gacA have been observed in liquid culture. We examined whether gacS/gacA mutants could competitively displace the wild-type populations on roots and thus pose a threat to the efficacy of biological control. The survival of a gac mutant alone and in competition with the wild type on roots was examined in the biological control strain Pseudomonas aureofaciens 30-84. In this bacterium, GacS/GacA controls the expression of phenazine antibiotics that are inhibitory to plant pathogenic fungi and enhance the competitive survival of the bacterium. Wheat seedlings were inoculated with strain 30-84, and bacteria were recovered from roots after 21 days in sterile or nonsterile soil to check for the presence of gacS or gacA mutants. Although no mutants were detected in the inoculum, gacS/gacA mutants were recovered from 29 out of 31 roots and comprised up to 36% of the total bacterial populations. Southern hybridization analysis of the recovered gacA mutants did not indicate a conserved mutational mechanism. Replacement series analysis on roots utilizing strain 30-84 and a gacA mutant (30-84.gacA) or a gacS mutant (30-84.A2) demonstrated that although the mutant population partially displaced the wild type in sterile soil, it did not do so in natural soil. In fact, in natural soil final rhizosphere populations of wild-type strain 30-84 starting from mixtures were at least 1.5 times larger than would be predicted from their inoculation ratio and generally were greater than or equal to the population of wild type alone despite lower inoculation rates. These results indicate that although gacS/gacA mutants survive in natural rhizosphere populations, they do not displace wild-type populations. Better survival of wild-type populations in mixtures with mutants suggests that mutants arising de novo or introduced within the inoculum may be beneficial for the survival of wild-type populations in the rhizosphere.


Nursing home residents attending the emergency department: clinical characteristics and outcomes.
Nursing home (NH) residents represent the frailest group of older people, and providing gerontologically attuned care that addresses these frailties is often a challenge within the emergency department (ED). This study sought to prospectively profile acutely unwell NH residents in order to clarify some of the challenges of providing emergency care to this group. Over an 18-week period, we prospectively reviewed all NH residents presenting to the ED of an urban university teaching hospital. Relevant data were retrieved by direct physician review (as part of a comprehensive geriatric assessment in the ED), collateral history from NH staff and primary carers, and review of electronic records. There were 155 ED visits by 116 NH residents. Their mean age was 80.3 (±9.6) years. High pre-morbid levels of dependency were reflected by a mean Barthel Index of 34.1 (±20) and almost two-thirds had a pre-existing diagnosis of dementia. One-third of visits were during 'normal' working hours. Patients were reviewed by their regular NH doctor pre-transfer for 36% of visits. Using accepted international criteria, over half of the visits were deemed 'potentially preventable'. Unwell NH residents have complex medical needs. The decision to refer these patients to the ED is often made by 'out of hours' general practitioners and their initial care in the ED is directed by physicians with limited experience in geriatric medicine. Most referrals to the ED are potentially preventable but this would require enhancements to the package of care available in NHs.


Lymphocytic interstitial pneumonitis (LIP) in Sjögren's syndrome: a case report and a review of the literature.
Sjõgren's disease is one of the most common rheumatological diseases and can present with a variety of extra-glandular manifestations. Lymphocytic Interstitial Pneumonitis (LIP) is the most common lung pathology in these patients. It is important to know and recognize this condition because it is potentially treatable. It is also frequently misdiagnosed and treated as infectious pneumonia multiple times before the correct diagnosis is made. It is a benign lymphoproliferative disorder characterized histologically by interstitial infiltration with polyclonal lymphocytes and plasma cells. High-resolution CT scan of the lungs shows extensive areas of ground-glass attenuation and interlobular septal thickening with scattered thin-walled cysts. An open-lung biopsy is the best method of diagnosing this condition, as less invasive techniques do not provide an adequate tissue specimen. LIP occurs in a wide variety of settings such as autoimmune disease, HIV disease, and as an adverse reaction to some medications; it is, therefore, considered to be a nonspecific response to many stimuli. The treatment usually consists of corticosteroids and other immunosuppressants, though there have been no controlled trials to date. Establishment of a registry may help better evaluate and treat this disease. We present the case of a patient who was diagnosed with LIP secondary to Sjögren's syndrome and also review the literature available.


Improved slice selection for R2* mapping during cryoablation with eddy current compensation.
To improve the slice profile and image quality of R2* mapping in the iceball during cryoablation with ultrashort echo time (UTE) imaging by compensating for eddy currents induced by the selective gradient when half-pulse radiofrequency (RF) excitation is employed to achieve UTEs. A method to measure both B0 and linear eddy currents simultaneously is first presented. This is done with a least-square fitting process on calibration data collected on a phantom. Eddy currents during excitation are compensated by redesigning the RF pulse and the selective gradient accordingly, while that resultant from the readout gradient are compensated for during image reconstruction. In vivo data were obtained continuously during the cryoablation experiments to calculate the R2* values in the iceball and to correlate them with the freezing process. Image quality degradation due to eddy currents is significantly reduced with the proposed approaches. R2* maps of iceball throughout the cryoablation experiments were achieved with improved quality. The proposed approaches are effective for compensating eddy currents during half-pulse RF excitation as well as readout. TEs as short as 100 microsec were obtained, allowing R2* maps to be obtained from frozen tissues with improved quality.


The scanning laser ophthalmoscope.
The imaging of the fundus of the eye poses two major technical challenges. First, it is necessary for both the illuminating and reflected beams to pass through the same aperture, the iris. In some commonly used instruments this leads to the use of levels of illumination close to the maximum tolerable by a patient. Second, in order to visualize the different structures present in the various layers of the fundus it is necessary to perform tomographic imaging. The scanning laser ophthalmoscope provides an answer to these particular problems. By scanning the fundus with a narrow laser beam most of the area of the iris is then available for the reflected light and so the intensity of the illuminating beam can be kept low, making it more acceptable for patients. The use of confocal imaging allows 3D images to be produced. In this short review the performance of the instrument will be discussed and its application to a number of clinical problems in ophthalmology considered. Finally there will be a brief description of other instrumentation currently under development.


Randomized double-blind cross-over study of iohexol and Amipaque in cerebral angiography.
Iohexol was compared with Amipaque (metrizamide) in a double-blind study in one pair of injections in each of 20 patients referred for routine cerebral angiography. Catheter position, patient position, injection pressure, contrast medium volume, and concentration (300 mg l/ml) were the same in the two injections, with iohexol and Amipaque being used alternately. Except for these two injections iohexol was used throughout. The parameters studied included diagnostic information obtained (quality of the examination), circulation time, and comparison of patient reactions to the pair of injections (e.g., electrocardiogram, heart rate, and subjective reactions). The patients' reactions to the noncomparative part of the examination were evaluated also, and the patients were observed for possible adverse reactions after the examination. No difference could be detected between the two contrast media in this series. No serious adverse reactions occurred.


ON THE "RAWNESS" OF SUBSOILS.
1. Suboils of arid regions are certainly no less "raw" than those of semi-arid regions, and probably only slightly less so than those of humid regions. 2. If, as seems as yet unproved, inoculated legume seeds fail to develop on humid subsoil material, such failure can not justifiably be attributed as is done by Alway, McDole and Rost, to a lack of available phosphoric acid and potash. 3. A lack of available nitrogen probably is sufficient to account for rawness of subsoils. 4. The poor aeration of subsoils which indirectly results in their rawness, may be accounted for more simply than by Hilgard's explanation of the washing down of fine particles into the subsoil, which prevents proper aeration.


Topography of photochemical initiation in molecular materials.
We propose a fluctuation model of the photochemical initiation of an explosive chain reaction in energetic materials. In accordance with the developed model, density fluctuations of photo-excited molecules serve as reaction nucleation sites due to the stochastic character of interactions between photons and energetic molecules. A further development of the reaction is determined by a competition of two processes. The first process is growth in size of the isolated reaction cell, leading to a micro-explosion and release of the material from the cell towards the sample surface. The second process is the overlap of reaction cells due to an increase in their size, leading to the formation of a continuous reaction zone and culminating in a macro-explosion, i.e., explosion of the entire area, covering a large part of the volume of the sample. Within the proposed analytical model, we derived expressions of the explosion probability and the duration of the induction period as a function of the initiation energy (exposure). An experimental verification of the model was performed by exploring the initiation of pentaerythritol tetranitrate (PETN) with the first harmonic of YAG: Nd laser excitation (1,064 nm, 10 ns), which has confirmed the adequacy of the model. This validation allowed us to make a few quantitative assessments and predictions. For example, there must be a few dozen optically excited molecules produced by the initial fluctuations for the explosive decomposition reaction to occur and the life-time of an isolated cell before the micro-explosion must be of the order of microseconds.


Environmental pathology. Mast cell and eosinophil infiltration in intestinal mucosa of Lewis rats treated with L-tryptophan implicated in human eosinophilia myalgia syndrome.
A recently developed animal model for the L-tryptophan-associated eosinophilia myalgia syndrome was used to examine the small intestine and colon, because there is clinical involvement at these sites in patients. Increased perivascular inflammatory infiltrates rich in degranulating mast cells, eosinophils, and monocytes were seen in the lamina propria of experimental animals when compared with controls. L-Tryptophan-associated disease also shares many clinical features with idiopathic scleroderma/eosinophilic fasciitis, in which there is gastrointestinal involvement as well. These features are similar to those found in the recently described animal model. The apparent morphologic and clinical similarities between these entities suggest that the animal model is suitable for further studying the pathogenesis of the gastrointestinal involvement in all these diseases.


Mixed bacterial meningitis: a complication of ventriculo- and lumboperitoneal shunts.
Infectious complications of ventriculo- and lumboperitoneal shunts in two patients are presented. Cerebrospinal fluid infection due to aerobic and anaerobic enteric flora was characteristic of each case. Both infections occurred several months after shunt surgery and were associated with colonic perforation by the distal limb of the peritoneal catheter. These cases emphasize this unusual hazard of peritoneal shunts and demonstrate methods for diagnosis and effective therapy.


Extracellular traps formation following cervical spinal cord injury.
Spinal cord injuries involve a primary injury that can lead to permanent loss of function and a secondary injury associated with pathologic and inflammatory processes. Extracellular traps are extracellular structures expressed by immune cells that are primarily composed of chromatin, granular enzymes and histones. Extracellular traps are known to induce tissue damage when overexpressed and could be associated in the occurrence of secondary damage. In the present study, we used flow cytometry to demonstrate that at 1 day following a C2 spinal cord lateral hemisection in male Swiss mice, resident microglia form vital microglia extracellular traps, and infiltrating neutrophils form vital neutrophil extracellular traps. We also used immunolabelling to show that microglia near the lesion area are most likely to form these microglia extracellular traps. As expected, infiltrating neutrophils are located at the site of injury, though only some of them engage in post-injury extracellular trap formation. We also observed the formation of microglia and neutrophil extracellular traps in our sham animal models of durotomy, but formation was less frequent than following the C2 hemisection. Our results demonstrate for the first time that microglia form extracellular traps in the spinal cord following injury and durotomy. It remains however to determine the exact mechanisms and kinetics of neutrophil and microglia extracellular traps formation following spinal cord injury. This information would allow to better mitigate this inflammatory process that may contribute to secondary injury and to effectively target extracellular traps to improve functional outcomes following spinal cord injury.


Homologous recombination in planta is stimulated in the absence of Rad50.
Chromosomal double-strand DNA breaks must be repaired; in the absence of repair the resulting acentromeric (and telomereless) fragments may be lost and/or the broken DNA ends may recombine causing general chromosomal instability. The Rad50/Mre11/Xrs2 protein complex acts at DNA ends and is implicated in both homologous and non-homologous recombination. We have isolated a rad50 mutant of the plant Arabidopsis thaliana and show here that it has a somatic hyper-recombination phenotype in planta. This finding supports the hypothesis of a competition between homologous and illegitimate recombination in higher eukaryotes. To our knowledge, this is the first direct in vivo support for the role of this complex in chromosomal recombination in a multicellular organism and the first description of a mutation of a known gene leading to hyper-recombination in plants.


X-ray emission from comets.
The discovery of x-ray emission from comet Hyakutake was surprising given that comets are known to be cold. Observations by x-ray satellites such as the Röntgen Satellite (ROSAT) indicate that x-rays are produced by almost all comets. Theoretical and observational work has demonstrated that charge-exchange collisions of highly charged solar wind ions with cometary neutral species can explain this emission. X-ray observations of comets and other solar system objects may be used to determine the structure and dynamics of the solar wind.


Assembling oppositely charged lock and key responsive colloids: A mesoscale analog of adaptive chemistry.
We have seen a considerable effort in colloid sciences to copy Nature's successful strategies to fabricate complex functional structures through self-assembly. This includes attempts to design colloidal building blocks and their intermolecular interactions, such as creating the colloidal analogs of directional molecular interactions, molecular recognition, host-guest systems, and specific binding. We show that we can use oppositely charged thermoresponsive particles with complementary shapes, such as spherical and bowl-shaped particles, to implement an externally controllable lock-and-key self-assembly mechanism. The use of tunable electrostatic interactions combined with the temperature-dependent size and shape and van der Waals interactions of these building blocks provides an exquisite control over the selectivity and specificity of the interactions and self-assembly process. The dynamic nature of the mechanism allows for reversibly cycling through various structures that range from weakly structured dense liquids to well-defined molecule-shaped clusters with different configurations through variations in temperature and ionic strength. We link this complex and dynamic self-assembly behavior to the relevant molecular interactions, such as screened Coulomb and van der Waals forces and the geometrical complementarity of the two building blocks, and discuss our findings in the context of the concepts of adaptive chemistry recently introduced to molecular systems.


Associated injuries in traumatic sternal fractures: a review of the National Trauma Data Bank.
Sternal fractures occur infrequently with blunt force trauma. The demographics and epidemiology of associated injuries have not been well characterized from a national trauma database. The National Trauma Data Bank was queried for patients with closed sternal fractures. The demographics were analyzed by age, gender, mechanism and indicators of anatomic and physiologic injuries. Types of commonly associated injuries were also determined. A total of 23,985 records were analyzed. Males accounted for 68.3 per cent and whites 70.9 per cent. Motor vehicle crash was the leading mechanism. More than 56 per cent had severe injuries based on Injury Severity Score (greater than 15) and 17 per cent with Glasgow Coma Score 8 or less. Crude mortality was 7.9 per cent. The majority (57.8%) and approximately one-third (33.7%) of the patients had rib fractures and lung contusions, respectively, 22.0 per cent with closed pneumothorax, 21.6 per cent had a closed thoracic vertebra fracture, 16.9 per cent with lumbar spine fracture, 3.9 per cent with concussion, and blunt cardiac injury in 3.6 per cent. Sternal fractures are usually associated with severe blunt trauma. Lung contusion remains the leading associated injury followed by vertebral spine fractures. Cardiac injuries are less frequent and vascular injuries less so. Mechanism of injury and presence of sternal fractures should alert providers to these potential associated injuries.


Rotavirus Infection in the Auckland Region After the Implementation of Universal Infant Rotavirus Vaccination: Impact on Hospitalizations and Laboratory Implications.
In July 2014, New Zealand introduced universal infant vaccination with RotaTeq (Merk & Co.) administered as 3 doses at 6 weeks, 3 and 5 months of age. We sought to assess the impact of rotavirus vaccination on gastroenteritis (GE) hospitalizations in the greater Auckland region and analyze changes in rotavirus testing in the period around vaccine introduction. Hospitalizations, laboratory testing rates and methods were compared between the pre-vaccine period (2009-2013), post-vaccine period (January 2015 to December 2015) and year of vaccine introduction (2014). There was a 68% decline in rotavirus hospitalizations of children <5 years of age after vaccine introduction (from 258/100,000 to 83/100,000) and a 17% decline in all-cause gastroenteritis admissions (from 1815/100,000 to 1293/100,000). Reductions were also seen in pediatric groups too old to have received vaccine. Despite these changes, rotavirus testing rates in our region remained static in the year after vaccine introduction compared with the 2 prior years, and after vaccine introduction, we observed a high rate of false positives 19/58 (33%) in patients with reactive rotavirus tests. Rotavirus vaccine has had a significant early impact on gastroenteritis hospitalizations for children in the Auckland region. However, continued rotavirus testing at pre-vaccine rates risks generating false positive results. Laboratories and clinicians should consider reviewing their testing algorithms before vaccine introduction.


Dysmaturation of Somatostatin Interneurons Following Umbilical Cord Occlusion in Preterm Fetal Sheep.
Cerebral white matter injury is the most common neuropathology observed in preterm infants. However, there is increasing evidence that gray matter development also contributes to neurodevelopmental abnormalities. Fetal cerebral ischemia can lead to both neuronal and non-neuronal structural-functional abnormalities, but less is known about the specific effects on interneurons. In this study we used a well-established animal model of fetal asphyxia in preterm fetal sheep to study neuropathological outcome. We used comprehensive stereological methods to investigate the total number of oligodendrocytes, neurons and somatostatin (STT) positive interneurons as well as 3D morphological analysis of STT cells 14 days following umbilical cord occlusion (UCO) in fetal sheep. Induction of asphyxia was performed by 25 min of complete UCO in five preterm fetal sheep (98-100 days gestational age). Seven, non-occluded twins served as controls. Quantification of the number of neurons (NeuN), STT interneurons and oligodendrocytes (Olig2, CNPase) was performed on fetal brain regions by applying optical fractionator method. A 3D morphological analysis of STT interneurons was performed using IMARIS software. The number of Olig2, NeuN, and STT positive cells were reduced in IGWM, caudate and putamen in UCO animals compared to controls. There were also fewer STT interneurons in the ventral part of the hippocampus, the subiculum and the entorhinal cortex in UCO group, while other parts of cortex were virtually unaffected (p > 0.05). Morphologically, STT positive interneurons showed a markedly immature structure, with shorter dendritic length and fewer dendritic branches in cortex, caudate, putamen, and subiculum in the UCO group compared with control group (p < 0.05). The significant reduction in the total number of neurons and oligodendrocytes in several brain regions confirm previous studies showing susceptibility of both neuronal and non-neuronal cells following fetal asphyxia. However, in the cerebral cortex significant dysmaturation of STT positive neurons occurred in the absence of cell loss. This suggests an abnormal maturation pattern of GABAergic interneurons in the cerebral cortex, which might contribute to neurodevelopmental impairment in preterm infants and could implicate a novel target for neuroprotective therapies.


[Epidemiological aspects of otosclerosis (1). Its frequency in comparison with other ear pathologies, incidence and prevalence].
A planned study was made with the group of patients seen for first time at Otologic External Consulting Department of ENT Service of the universitary Hospital Complex of Santiago de Compostela. The total amount 1,050 patients, 83 of them suffering otosclerosis. Most frequently diagnosed was sensorineural deafness (29.1%), in second place were chronic middle otitis (27.8%) and as last one was otosclerosis (8.7%). Clinic otosclerosis amounted for 19.20 cases of each 100,000 inhabitants yearly and stapedectomies performed 7.78. Prevalence was evaluated at 7.13 by 1,000 (10.86 women and 3.14 men). Higher value compared with other series published previously are linked to differences on sanitary development as well as health concept and the type of community where people lived through.


Epstein-Barr virus specific marker molecules for early diagnosis of infectious mononucleosis.
The molecular specificity of the antibody response against Epstein-Barr Virus (EBV) is studied in patients with acute primary EBV-infection, i.e. infectious mononucleosis syndrome. Using the immunoblot technique both IgM and IgG antibody responses are studied in sera obtained serially until week 20 after onset of symptoms. Healthy seropositive blood donors are used as control. Antigens are prepared from virus producer cell lines B95-8, P3HR1 and HH514-c16 (a superinducible derivative of P3HR1), induced for the expression of early antigens (EA) or viral capsid antigens (VCA) and from the EBV-negative cell lines BJAB and RAMOS. The 'WC'-serum, described by Edson et al. (J. Immunol. 130, 1983) is used to characterize EA- and VCA-specific polypeptides and to define their subcellular location. The immunoblot studies reveal an enormous diversity in EBV-specific polypeptides recognised by different individual patients, both for IgM and IgG. In addition, these patterns were markedly different from those found with control blood donor sera. The latter predominantly recognised bands at 72 kDa (EBNA) and 41 and 18 kDa respectively (both VCA components). Despite the great individual variation observed, EA-specific polypeptides at 138 kDa and at 45-52 kDa were recognised by both IgM and IgG antibodies in first serum samples of all patients tested.


[SGLT2 inhibitorsfor treatment of chronic kidney disease without diabetes or heart failure].
This review summarises the current knowledge of electroconvulsive therapy (ECT) which is still the most potent and fast-acting antidepressant intervention. The modern procedure is safe when general precautions are taken. Cognitive side effects are transient in most patients, and concerns about side effects should not prevent relevant use. Due to the prognostic benefits of rapid remission, ECT should, in relevant patients, be considered early in the treatment course. Patients should be offered maintenance pharmacotherapy, and, in high-risk cases, tapering of the acute ECT course or maintenance ECT, in order to reduce the risk of relapse.


Novel multifunctional plant growth-promoting bacteria in co-compost of palm oil industry waste.
Previously, a unique co-compost produced by composting empty fruit bunch with anaerobic sludge from palm oil mill effluent, which contributed to establishing a zero-emission industry in Malaysia. Little was known about the bacterial functions during the composting process and fertilization capacity of this co-compost. We isolated 100 strains from the co-compost on 7 types of enumeration media and screened 25 strains using in vitro tests for 12 traits, grouping them according to three functions: plant growth promoting (fixation of nitrogen; solubilization of phosphorus, potassium, and silicate; production of 3-indoleacetic acid, ammonia, and siderophore), biocontrolling (production of chitinase and anti-Ganoderma activity), and composting (degradation of lignin, xylan, and cellulose). Using 16S rRNA gene sequence analysis, 25 strains with strong or multi-functional traits were found belong to the genera Bacillus, Paenibacillus, Citrobacter, Enterobacter, and Kosakonia. Furthermore, several strains of Citrobacter sedlakii exhibited a plant growth-stimulation in vivo komatsuna plant cultivation test. In addition, we isolated several multifunctional strains; Bacillus tequilensis CE4 (biocontrolling and composting), Enterobacter cloacae subsp. dissolvens B3 (plant growth promoting and biocontrolling), and C. sedlakii CESi7 (plant growth promoting and composting). Some bacteria in the co-compost play significant roles during the composting process and plant cultivation after fertilization, and some multifunctional strains have potential for use in accelerating the biodegradation of lignocellulosic biomass, protecting against Ganoderma boninense infection, and increasing the yield of palm oil.


Transferring public-health nursing research to health-system planning: assessing the relevance and accessibility of systematic reviews.
A descriptive study was designed to gain an understanding of the research needs, perceptions of barriers to research utilization, and attitudes towards systematic reviews of decision-makers in public health at the level of systems planning. Public-health consultants and managers in Ontario were surveyed about barriers to research utilization and awareness of and attitudes towards systematic reviews as a method of/vehicle for research transfer. Access to 5 completed reviews was provided in summary, abstract, and full form, and on diskette, hard copy, and Internet. A follow-up survey at 3 months assessed use, relevance, application, and further dissemination of the reviews. A total of 242 people in positions of public-health policy and decision-making participated. Respondents reported a great, largely unmet, need for research evidence. They viewed systematic reviews as likely to overcome the barriers to research use related to critical appraisal, time, timeliness, availability, cost and credibility, but not the barriers related to policy climate, authority, or implementation resources. Three months after requesting a review, 93% said they would follow it up; 91% remembered receiving it, and 71% of these had read it while 23% stated it played a part in program planning or decision-making.


SMIM1, carrier of the Vel blood group, is a tail-anchored transmembrane protein and readily forms homodimers in a cell-free system.
Antibodies to the Vel blood group antigen can cause adverse hemolytic reactions unless Vel-negative blood units are transfused. Since the genetic background of Vel-negativity was discovered in 2013, DNA-based typing of the 17-bp deletion causing the phenotype has facilitated identification of Vel-negative blood donors. SMIM1, the gene underlying Vel, encodes a 78-amino acid erythroid transmembrane protein of unknown function. The transmembrane orientation of SMIM1 has been debated since experimental data supported both the N- and C-termini being extracellular. Likewise, computational predictions of its orientation were divided and potential alternatives such as monotopic or dual-topology have been discussed but not investigated. We used a cell-free system to explore the topology of SMIM1 when synthesized in the endoplasmic reticulum (ER). SMIM1 was tagged with an opsin-derived N-glycosylation reporter at either the N- or C-terminus and synthesized in vitro using rabbit reticulocyte lysate supplemented with canine pancreatic microsomes as a source of ER membrane. SMIM1 topology was then determined by assessing the N-glycosylation of its N- or C-terminal tags. Complementary experiments were carried out by expressing the same SMIM1 variants in HEK293T/17 cells and establishing their membrane orientation by immunoblotting and flow cytometry. Our data consistently indicate that SMIM1 has its short C-terminus located extracellularly and that it most likely belongs to the tail-anchored class of membrane proteins with the bulk of the polypeptide located in the cytoplasm. Having established its membrane orientation in an independent model system, future work can now focus on functional aspects of SMIM1 as a potential regulator of erythropoiesis.


The quality of antenatal care in rural Tanzania: what is behind the number of visits?
Antenatal care (ANC) provides an important opportunity for pregnant women with a wide range of interventions and is considered as an important basic component of reproductive health care. In 2008, severe maternal morbidity audit was established at Saint Francis Designated District Hospital (SFDDH), in Kilombero district in Tanzania, to ascertain substandard care and implement interventions. In addition, a cross-sectional descriptive study was carried out in 11 health facilities within the district to assess the quality of ANC and underlying factors in a broader view. Of 363 severe maternal morbidities audited, only 263 (72%) ANC cards were identified. Additionally, 121 cards (with 299 ANC visits) from 11 facilities were also reviewed. Hemoglobin and urine albumin were assessed in 22% - 37% and blood pressure in 69% - 87% of all visits. Fifty two (20%) severe maternal morbidities were attributed to substandard ANC, of these 39 had severe anemia and eclampsia combined. Substandard ANC was mainly attributed to shortage of staff, equipment and consumables. There was no significant relationship between assessment of essential parameters at first ANC visit and total number of visits made (Spearman correlation coefficient, r = 0.09; p = 0.13). Several interventions were implemented and others were proposed to those in control of the health system. This article reflects a worrisome state of substandard ANC in rural Tanzania resulting from inadequate human workforce and material resources for maternal health, and its adverse impacts on maternal wellbeing. These results suggest urgent response from those in control of the health system to invest more resources to avert the situation in order to enhance maternal health in this country.


Synchronous left subclavian and axillary artery aneurysms associated with melorheostosis.
Melorheostosis is a benign, rare congenital disorder of hyperostosis of one or more bones. A case of melorheostosis associated with synchronous left subclavian and axillary artery aneurysms necessitated resection of the aneurysms and replacement with a Gore-Tex interposition graft (W. L. Gore & Associates, Inc., Elkton, Md.) and a reversed saphenous vein graft, respectively. Numerous soft-tissue and vascular anomalies have been noted in patients with melorheostosis, although arterial aneurysms have not been reported previously.


A review on antifungal activity of mushroom (basidiomycetes) extracts and isolated compounds.
The present review reports the antifungal activity of mushroom extracts and isolated compounds including high (e.g. peptides and proteins) and low (e.g. sesquiterpenes and other terpenes, steroids, organic acids, acylcyclopentenediones and quinolines) molecular weight compounds. Most of the studies available on literature focused on screening of antifungal activity of mushroom extracts, rather than of isolated compounds. Data indicate that mushroom extracts are mainly tested against different Candida species, while mushroom compounds are mostly tested upon other fungi. Therefore, the potential of these compounds might be more useful in food industry than in clinics. Oudemansiella canarii and Agaricus bisporus methanolic extracts proved to be the most active mushroom extracts against Candida spp. Grifolin, isolated from Albatrellus dispansus, seemed to be the most active compound against phytopathogenic fungi. Further studies should be performed in order to better understand the mechanism of action of this and other antifungal compounds as well as safety issues.


Excision of a Protein-Derived Amine for p-Aminobenzoate Assembly by the Self-Sacrificial Heterobimetallic Protein CADD.
Chlamydia protein associating with death domains (CADD), the founding member of a recently discovered class of nonheme dimetal enzymes termed hemeoxygenase-like dimetaloxidases (HDOs), plays an indispensable role in pathogen survival. CADD orchestrates the biosynthesis of p-aminobenzoic acid (pABA) for integration into folate via the self-sacrificial excision of a protein-derived tyrosine (Tyr27) and several additional processing steps, the nature and timing of which have yet to be fully clarified. Nuclear magnetic resonance (NMR) and proteomics approaches reveal the source and probable timing of amine installation by a neighboring lysine (Lys152). Turnover studies using limiting O2 have identified a para-aminobenzaldehyde (pABCHO) metabolic intermediate that is formed on the path to pABA formation. The use of pABCHO and other probe substrates shows that the heterobimetallic Fe/Mn form of the enzyme is capable of oxygen insertion to generate the pABA-carboxylate.


[10-methacryloyloxydecyl dihydrogen phosphate in resin-to-zirconia bonding durability: a systematic review and meta-analysis].
Objective: To systematically assess the durability of the 10-methacryloyloxydecyl dihydrogen phosphate (10-MDP) pretreated resin-to-zirconia bonding and conducted a meta-analysis to provide clinical guidance on zirconia bonding strategies. Methods: A comprehensive search was conducted on PubMed, Scopus, Web of Science, CNKI, and Wanfang database to identify relevant studies on the resin-to-zirconia bonding after surface pretreatment with 10-MDP. Strict inclusion and exclusion criteria were applied to select appropriate literature and extract essential information and data. The included studies were categorized based on aging methods (water storage, thermocycling, or both), 10-MDP application methods (within primer, adhesive, resin cement, or both), and additional surface treatments (alumina sandblasting, tribochemical silica coating, acid etching, laser etching, and plasma treatment) and were analyzed by Review Manager 5.4. The evaluation indicator was the bonding strength of zirconia after surface pretreatment with 10-MDP. Results: A total of 72 studies were included in the systematic review, with 68 studies eligible for the meta-analysis. The bonding strength of zirconia decreased significantly after aging (P<0.000 01; MD: 5.58; 95%CI: 5.11-6.05). No significant differences in bonding strength of zirconia were observed after aging when employing various application methods of 10-MDP (all P>0.05). The bonding strength of zirconia was significantly enhanced after aging when 10-MDP was applied in conjunction with additional surface treatments, as compared to the application of 10-MDP alone (P<0.000 01; MD: 10.17; 95%CI: 8.20-12.14). Conclusions: The bonding strength of zirconia pretreated with 10-MDP exhibited a reduction after undergoing water storage or thermocycling. The application of 10-MDP with additional surface treatments enhanced the bonding strength of zirconia after aging, while the application methods of 10-MDP did not exert an influence.


[Medical, psychological and social study in 350 patients in a precarious situation, undertaken by a permanently maintained health care facility in 2002].
Precariousness and its consequences have not been re-evaluated in France since the introduction of the Law to fight exclusion, which instituted Universal Medical Cover (CMU) and permanently maintained health care facilities (PASS) in 1998. Throughout the year 2002, a descriptive medical, psychological and social prospective study was carried out amongst PASS patients seen in 2002 at Avignon Hospital. Three hundred and fifty out of 359 patients have been analysed. Most of them were adults (93%), young (mean age 38), male (56%), foreigners from non-EU countries (73%), with an illegal status (69%). They were without any declared income (77%), but with accommodation (67%), living as married (or such) or single in equal proportion. They were often without social security cover (48%). Their dominant pathologies were infections (42% of the patients). The most frequently diagnosed conditions were obesity (14%), pregnancy (8%), lower back pain (7%), high blood pressure (7%), chronic hepatitis C virus infection (6%), fungal infections (6%) and traumas (6%). Dental (43%) and psychiatric (27%) disorders were very frequent. The analysis of sub-groups has shown that some disorders are more frequent in French and European patients: chronic hepatitis C virus infection (14% vs. 4%), traumas (14% vs. 4%), psychopathy (11% vs. 0%), alcohol abuse (32% vs. 5%), smoking (80% vs. 25%), cannabis (20% vs. 2%) or opioids (16% vs. 0%) use. Access to health care has been difficult in 2002 in Avignon mostly for illegal immigrants for whom the only valid response should be of a political nature. Both French and European communities who still do not benefit from CMU improvements probably mean local interventions and combined operations because of the homelessness and the addictions of these people.


Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide.
The objective of this Phase I dose escalation study was to explore the safety and tolerability of eltrombopag, an oral, nonpeptide, thrombopoietin receptor agonist, in patients with advanced soft tissue sarcoma (STS) and thrombocytopenia due to treatment with doxorubicin and ifosfamide (AI) combination chemotherapy. Patients aged 18 or older with histologically confirmed, locally advanced or metastatic STS were treated with 1 cycle of AI followed by AI with eltrombopag starting at Cycle 2, using 2 different dosing schedules. The study design included an eltrombopag dose escalation phase starting at 75 mg daily to determine the optimal biological dose (OBD). Eighteen patients were enrolled and 15 received at least 1 dose of chemotherapy; 3 patients withdrew prior to receiving eltrombopag. Seven, 4, and 1 patients received 75 mg, 100 mg, and 150 mg eltrombopag daily, respectively. No dose-limiting toxicities were reported. Due to slow recruitment, the study was closed prior to identifying an OBD. The most common hematologic adverse events (AEs) were thrombocytopenia (80%), neutropenia (73%), and anemia (67%). The most common nonhematologic AEs were fatigue (53%), alanine aminotransferase increased, constipation, and nausea (47% each). Eleven of 12 patients who received eltrombopag completed at least 2 chemotherapy cycles; all had increased platelet counts on Day 1 of Cycle 2 (cycle with eltrombopag) compared to Day 1 of Cycle 1 (cycle without eltrombopag). Although data are limited, safety data were consistent with the known toxicities of AI combination chemotherapy or the side effect profile of eltrombopag seen in other studies. Available data suggest a potential pre- and post-chemotherapy dosing scheme for eltrombopag when administered with AI chemotherapy, and support further investigation of eltrombopag treatment in patients with chemotherapy-induced thrombocytopenia.


Relationships Between Weight Change and Physical and Psychological Distress in Early-Stage Breast Cancer Survivors.
Weight gain and unfavorable changes in body composition are common in a growing population of breast cancer survivors, but the etiology of these changes is poorly understood. The aim of this study was to investigate relationships between weight change and symptoms of physical and psychological distress in the first 12 months of completing treatment in women who had completed treatment for breast cancer. Physical distress and psychological distress were assessed using the Rotterdam Symptom Checklist, the Distress Thermometer, and the Fatigue Symptom Inventory. Weight change in 28 women since the completion of treatment (mean, 6.4 ± 4.4 months) ranged from -6.0 kg to +5.2 kg (mean, -0.4 ± 3.2), with 6 women gaining and 7 women losing an average of 3.5 ± 1.0 and 5.1 ± 0.8 kg, respectively. Rotterdam mean scores for physical (17.5 ± 9.0) and psychological distress (27.1 ± 16.9) were similar to previous findings for patients with early-stage breast cancer in active treatment and appear to be markedly higher than distress levels previously reported in cancer-free adults. Distress levels, based on the Distress Thermometer, were moderate to severe in 35% of women. Fatigue was common and associated with interference in daily living for some women. Fatigue duration was negatively correlated with weight change (P = -0.46, P < .05). Symptoms of physical and psychological distress persist for some women in the first year after completing treatment and may associate with weight change. These findings underscore a need for ongoing assessment and supportive care across the breast cancer trajectory and may guide dietary counseling aimed at promoting healthy body weight and overall health in early survivorship.


The influence of intensive physical exercise on bone acquisition in adolescent elite female and male artistic gymnasts.
Physical exercise enhances bone acquisition during adolescence. The aim of the study was to evaluate the influence of intensive physical exercise on bone acquisition in adolescent elite artistic gymnasts. The study included 262 athletes (93 males and 169 females, aged 13-23 yr) participating in the 24th European Championship held in Greece. Bone age compared with chronological age was delayed by 2 yr for females (n = 120) and 1 yr for males (n = 68). For both sexes, the growth chart of bone mineral density (BMD) followed a normal pattern when estimated according to bone age rather than chronological age. For females, BMD was positively correlated with bone age, chronological age, height, body weight, body mass index, body fat, lean body mass, and with age of onset of training, and negatively with duration of exercise and intensity of training (P values range from <0.05 to <0.0001). Multiple regression analysis revealed that age of onset of training was the major parameter attenuating the effect of exercise on BMD (P < 0.001). The latter was related to the stage of puberty (P < 0.05). For males, BMD was correlated positively with bone age, height, body weight, and lean body mass (P values range from <0.01 to 0.0001). Multiple regression analysis revealed that the more powerful factor influencing BMD was weight (P < 0.01). In conclusion, bone acquisition in adolescents under intensive physical training follows the normal pattern only when estimated according to bone age. The age of onset, the duration, and the intensity of exercise attenuate the bone acquisition, at least in female artistic gymnasts.


Characteristics, management, and healthcare resources of patients with advanced non-small-cell lung cancer surviving 5 years after nivolumab treatment initiation: A national database analysis.
Data on long-term survivors with advanced non-small-cell lung cancer (NSCLC) treated with nivolumab are available from randomized trials. Characteristics, management, and healthcare resources of those patients need to be confirmed with real-world data. The UNIVOC retrospective observational study included all patients with advanced NSCLC recorded in the French national hospital database starting nivolumab in 2015 and followed them until December 2020. The Kaplan-Meier method estimated the overall survival (OS). A machine learning approach identified patients with similar treatment sequences. Within the 3,050 patients who had nivolumab initiation,5-year OS rate was 14.6 % (95 %CI 13.3 %-16.2 %). In total, data covering at least 5 years of follow-up were retrieved for 231 surviving patients. Survivors were younger, often female and had fewer comorbidities than non-survivors. Three clusters of patients with different nivolumab treatment durations were identified: 1/ Continuous nivolumab treatment; 2/ Long period of nivolumab treatment followed by chemotherapy or no treatment; 3/ Short period of nivolumab treatment then chemotherapy or no treatment. At 5 years, 61.0 % of survivors were no longer receiving systemic therapy, 26.4 % were treated with nivolumab, 8.7 % chemotherapy, and 3.9 % other immunotherapies. Among 5-y survivor patients, the average number of hospitalisations per patient decreased from 23.4 to 12.8 between the 1st and the 5th year. In the 5th year, 46 % of patients had no more hospitalization for lung cancer. This large nationwide study confirms the long-term benefit of nivolumab treatment for advanced NSCLC patients in the real-world setting, with a 5-year survival rate similar to that reported in clinical trials.


Diabetes self-management profile short form: a preliminary report.
Effective family management of type 1 diabetes in childhood is critical to maintaining optimal glycemic control. The purpose of this study was to provide preliminary evidence for a reduced form of the Diabetes Self-Management Profile (DSMP) using Rasch modeling techniques. The study was a secondary analysis of DSMP data drawn from a previous study on patterns of self-management from 239 preadolescents with type 1 diabetes. Rasch modeling strategies were used to identify the most informative items and then a reduced score composite was correlated with hemoglobin A1c (A1c) and blood glucose monitoring (BGM) frequency. A short form of the DSMP was obtained using seven items that comprised all five subscales of the DSMP. The DSMP Short-Form (DSMP-SF) composite score correlated significantly with child's HbA1c and BGM frequency. The DSMP-SF may be considered a valid and effective screening interview alternative to the longer, original, DSMP, particularly when attempting to identify high-risk patients.


A simple, cheap, effective and safe procedure for general anesthesia.
A simplified, safe and flexible technique of anesthesia, based on a limited number of relatively cheap drugs, and allowing ventilation with air, was applied to 60 patients undergoing operations of at least 60 minutes' duration. The required depth of hypnosis was produced by intravenous diazepam or gamma-OH, whilst droperidol and fentanyl provided a satisfactory degree of sedation and analgesia. Pancuronium bromide was used for muscle relaxation. Spontaneous respiration was resumed immediately after postoperative use of nalorphine and neostigmine. The anesthetic course was smooth and predictable, with cardiovascular stability and an uneventful postoperative recovery. Emphasis is laid on the suitability of this procedure on the Battle Field or in Developing Countries, and on its safety (no toxic volatile liquids). (Acta anaesth. belg., 1976, 27, 25-34).


Wavelet-based analysis of surface mechanomyographic signals from subjects with differences in myosin heavy chain isoform content.
The purpose of this study was to use a wavelet analysis designed specifically for surface mechanomyographic (MMG) signals to determine if the % myosin heavy chain (MHC) isoform content affected the shape of the MMG frequency spectrum during isometric muscle actions. Five resistance-trained (mean +/- SD age = 23.2 +/-3.7 yrs), five aerobically-trained (mean +/- SD age = 32.6 +/- 5.2 yrs), and five sedentary (mean +/- SD age = 23.4 +/- 4.1 yrs) men performed isometric muscle actions of the dominant leg extensors at 20%, 40%, 60%, 80%, and 100% of the maximum voluntary contraction (MVC). Surface MMG signals were detected from the vastus lateralis during each muscle action and processed with the MMG wavelet analysis. In addition, muscle biopsies were taken from the vastus lateralis and analyzed for % MHC isoform content. The results showed that there were distinct differences among the three groups of subjects for % MHC isoform content. These differences were not manifested, however, in the isometric force-related changes in the total intensity of the MMG signal in each wavelet band. It is possible that factors such as the thicknesses of the subcutaneous adipose tissue and/or iliotibial band reduced the potential influence of differences in % MHC isoform content on the MMG signal.


The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling.
Several somatic ribosome defects have recently been discovered in cancer, yet their oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent R98S mutation in ribosomal protein L10 (RPL10 R98S) found in T-cell acute lymphoblastic leukemia (T-ALL). The JAK-STAT signaling pathway is a critical controller of cellular proliferation and survival. A proteome screen revealed overexpression of several Jak-Stat signaling proteins in engineered RPL10 R98S mouse lymphoid cells, which we confirmed in hematopoietic cells from transgenic Rpl10 R98S mice and T-ALL xenograft samples. RPL10 R98S expressing cells displayed JAK-STAT pathway hyper-activation upon cytokine stimulation, as well as increased sensitivity to clinically used JAK-STAT inhibitors like pimozide. A mutually exclusive mutation pattern between RPL10 R98S and JAK-STAT mutations in T-ALL patients further suggests that RPL10 R98S functionally mimics JAK-STAT activation. Mechanistically, besides transcriptional changes, RPL10 R98S caused reduction of apparent programmed ribosomal frameshifting at several ribosomal frameshift signals in mouse and human Jak-Stat genes, as well as decreased Jak1 degradation. Of further medical interest, RPL10 R98S cells showed reduced proteasome activity and enhanced sensitivity to clinical proteasome inhibitors. Collectively, we describe modulation of the JAK-STAT cascade as a novel cancer-promoting activity of a ribosomal mutation, and expand the relevance of this cascade in leukemia.


Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity.
Botulinum neurotoxins (BoNT) are among the most poisonous substances known, and of the 7 serotypes (A-G) identified thus far at least 4 can cause death in humans. The goal of this work was identification of inhibitors that specifically target the light chain catalytic site of the highly pathogenic but lesser-studied E serotype (BoNT/E). Large-scale computational screening, employing the program DOCK, was used to perform atomic-level docking of 1.4 million small molecules to prioritize those making favorable interactions with the BoNT/E site. In particular, 'footprint similarity' (FPS) scoring was used to identify compounds that could potentially mimic features on the known substrate tetrapeptide RIME. Among 92 compounds purchased and experimentally tested, compound C562-1101 emerged as the most promising hit with an apparent IC50 value three-fold more potent than that of the first reported BoNT/E small molecule inhibitor NSC-77053. Additional analysis showed the predicted binding pose of C562-1101 was geometrically and energetically stable over an ensemble of structures generated by molecular dynamic simulations and that many of the intended interactions seen with RIME were maintained. Several analogs were also computationally designed and predicted to have further molecular mimicry thereby demonstrating the potential utility of footprint-based scoring protocols to help guide hit refinement.


Characterization of integrated hepatitis B viral DNA cloned from a human hepatoma and the hepatoma-derived cell line PLC/PRF/5.
Recombinant phage clones carrying integrated hepatitis B virus (HBV) DNA sequences have been isolated from two phage libraries made from human DNA of a hepatoma and a hepatoma-derived cell line. One clone from each library has been characterized both by restriction mapping and by electron microscopy. In one clone there is at least one complete and uninterrupted HBV genome, and in the other the HBV sequences are composed of two major subgenomic fragments inverted with respect to each other. The host-virus junctions are localized within the positions 1,700-2,600 base pairs on the physical map of the free viral genome. The pre-S/S (surface antigen gene) region is conserved between the two clones. The two clones do not have common cellular sequences nor do they contain cellular homologues to six retroviral oncogenes. For one clone, the hepatitis B surface antigen gene was found to be functional when introduced into mouse thymidine kinase-negative cells by transfection.


Connective tissue content of fibrolamellar carcinoma and other human liver tumors.
The connective tissue content of four different human liver tumors (Fibrolamellar carcinoma, FLC; hepatocellular carcinoma, HCC; focal nodular hyerplasia, FNH and hepatocellular adenoma, HCA) was investigated by computer aided morphometry. A significantly higher connective tissue content was found in FNH and FLC as compared to HCA and HCC. The distribution of the connective tissue was homogeneous in the cases of FNH, HCA and HCC, while a highly unhomogeneous distribution was observed in FLC cases.


Long-Term Functional Outcome after Internal Delorme's Procedure for Obstructed Defecation Syndrome, and the Role of Postoperative Rehabilitation.
To evaluate long-term functional outcomes of Internal Delorme's Procedure (IDP) in patients refractory to conservative treatment for Obstructed Defecation Syndrome (ODS), and to compare those who received postoperative rehabilitation with those who did not. All patients with ODS refractory to nonoperative therapy were identified across three regional pelvic floor referral hospitals, and IDP was performed. Postoperatively selected patients received biofeedback therapy. Functional outcomes were established using the Cleveland Clinic Constipation (CCC) score and obstructed defecation score (OD score) preoperatively at 12 months and at the last available follow-up. Patient satisfaction was assessed with a visual analogue score. From October 2006 to September 2013, IDP was performed in 170 patients: 77 received postoperative biofeedback and 93 did not. Mean follow-up was 6.3 years (range 1-8 years). CCC and OD scores improved significantly in both groups after 12 months and at the last follow-up (p > 0.05). When comparing two groups while there was no significant difference between CCC and OD scores at 12 months, score was significantly better in the group that received rehabilitation at the last follow-up (p = 0.001). Patient satisfaction was higher in the rehabilitation group (67%) compared with those without rehabilitation (55%). Clinical recurrence was recorded in nine patients who did not have postoperative rehabilitation. It has been demonstrated that IDP is associated with good long-term functional outcomes. Patients receiving rehabilitation had a better long-term follow-up, a higher overall satisfaction, and lower recurrence rate when compared with the patients who did not receive postoperative rehabilitation.


Isokinetic Strength Responses to Season-long Training and Competition in Turkish Elite Soccer Players.
There are not enough studies that describe the isokinetic strength of professional soccer players at high angular velocities. The purpose of this study was to evaluate the seasonal changes in isokinetic strength of Turkish professional soccer players (n=14) over the course of a 24-week soccer season. The isokinetic strength of players who underwent usual soccer training and weekly competition throughout the soccer season was assessed by means of the Biodex System 3 dynamometer with the knee attachment. The peak torque of knee extensor and flexor muscles were measured at angular velocities of 60°/s, 300°/s and 500°/s. Players were tested at the beginning and end of the competitive season. While the first- and second-test measurements did not show significant changes at 60°/s and 300°/s angular velocities, at the end of the training period, players' knee strength changed significantly at 500°/s angular velocities. In addition, the H/Q ratio improved significantly for the dominant as well as non-dominant leg at 500°/s. Significant bilateral strength improvements for knee flexors were also observed at 500°/s. The findings of this study suggest that usual daily soccer training (technical, tactical, power, strength, endurance, flexibility, etc.) and weekly competition might produce changes in knee strength at high angular velocities.


The influence of distance to school on the associations between active commuting and physical activity.
The purpose of this cross-sectional study was to examine the associations between active commuting behavior, levels of physical activity and distance to school in 9-10 year old children. Participants were children (n = 1824) who took part in the SPEEDY study (Sport, Physical activity and Eating behavior: Environmental Determinants in Young people). For both boys and girls, significant positive associations were observed between walking to school and physical activity and moderate-to-vigorous physical activity during weekday journey times (8-9 am and 3-4 pm), and the size of association also became stronger with increasing distance from school. Promotion of active commuting to school might be an important way to increase levels of physical activity in school children.


Field evaluation of the Determine rapid human immunodeficiency virus diagnostic test in Honduras and the Dominican Republic.
Rapid detection of human immunodeficiency virus (HIV) infection can result in improved patient care and/or faster implementation of public health preventive measures. A new rapid test, Determine (Abbott, Abbott Park, Ill.), detects HIV type 1 (HIV-1) and HIV-2 antibodies within 15 min by using 50 microl of serum or plasma. No specialized equipment or ancillary supplies are required, and results are read visually. A positive result is noted by the appearance of a red line. An operational control (red line) indicates proper test performance. We evaluated the Determine rapid HIV detection test with a group of well-characterized serum samples (CD4 counts and viral loads were known) and serum samples from HIV-positive individuals at field sites in Honduras and the Dominican Republic. In the field evaluations, the results obtained by the Determine assay were compared to those obtained by local in-country HIV screening procedures. We evaluated serum from 100 HIV-positive patients and 66 HIV-negative patients. All samples gave the expected results. In a companion study, 42 HIV-positive samples from a Miami, Fla., serum bank were tested by the Determine assay. The samples had been characterized in terms of CD4 counts and viral loads. Fifteen patients had CD4 counts <200 cells/mm(3), while 27 patients had CD4 counts >200 cells/mm(3). Viral loads ranged from 630 to 873,746 log(10) copies/ml. All samples from the Miami serum bank were positive by the Determine test. Combined results from the multicenter studies indicated that the correct results were obtained by the Determine assay for 100% (142 of 142) of the HIV-positive serum samples and 100% (66 of 66) of the HIV-negative serum samples. The Determine test was simple to perform and the results were easy to interpret. The Determine test provides a valuable new method for the rapid identification of HIV-positive individuals, especially in developing countries with limited laboratory infrastructures.


Miniaturized cavity ring-down detection in a liquid flow cell.
A novel method for applying cavity ring-down spectroscopy in the liquid phase, compatible with LC analyses, is presented. The core of the setup is a home-built cavity ring-down flow cell (cell volume 12 microL) that is constructed using a silicon rubber spacer, which is clamped leak-tight between two high-reflectivity mirrors. The mirrors are in direct contact with the liquid flow, which provides for a small path length and short ring-down times. Inside the cavity there are no windows, reflection losses, or Brewster angles to be considered. Due to the small size of the presented cavity geometry, the setup can be implemented in conventional-size LC apparatuses. With a flow injection setup, a detection limit of 2.5 nM was obtained for Crystal Violet in ethanol, and the linear dynamic range of the system is at least 2 orders of magnitude. The method has the potential to become a powerful alternative for commercial LC UV/visible absorbance detectors.


Zinc suppresses the iron-accumulation phenotype of Saccharomyces cerevisiae lacking the yeast frataxin homologue (Yfh1).
Analysis of Saccharomyces cerevisiae cell transcriptome revealed that iron deprivation/supplementation affects genes other than those of the iron regulon (controlled by Aft proteins). Several genes regulated by zinc (induced by zinc deprivation) were induced by iron. Cells lacking the yeast frataxin homologue Yfh1 accumulate large amounts of iron in their mitochondria. We have shown that the zinc metabolism of these cells is also impaired: zinc uptake and zinc accumulation were both much lower in Delta yfh1 cells than in wild-type cells. Excess zinc in the growth medium also influenced the phenotypes of Delta yfh1 cells. It prevented the accumulation of iron in the mitochondria of Delta yfh1 cells and increased the growth rate of these cells and their resistance to oxidative stress. However, zinc did not restore the deficiency of Fe-S and haem proteins of Delta yfh1 cells. Zinc inhibited mitochondrial respiration and protected Yah1p, the mitochondrial ferredoxin. These results suggest that zinc nutrition may be important in the aetiology of Friedreich's ataxia.


cAMP signaling regulates platelet myosin light chain (MLC) phosphorylation and shape change through targeting the RhoA-Rho kinase-MLC phosphatase signaling pathway.
Cyclic adenosine monophosphate (cAMP)-dependent signaling modulates platelet shape change through unknown mechanisms. We examined the effects of cAMP signaling on platelet contractile machinery. Prostaglandin E1 (PGE1)-mediated inhibition of thrombin-stimulated shape change was accompanied by diminished phosphorylation of myosin light chain (MLC). Since thrombin stimulates phospho-MLC through RhoA/Rho-associated, coiled-coil containing protein kinase (ROCK)-dependent inhibition of MLC phosphatase (MLCP), we examined the effects of cAMP on this pathway. Thrombin stimulated the membrane localization of RhoA and the formation of a signaling complex of RhoA/ROCK2/myosin phosphatase-targeting subunit 1 (MYPT1). This resulted in ROCK-mediated phosphorylation of MYPT1 on threonine 853 (thr(853)), the disassociation of the catalytic subunit protein phosphatase 1δ (PP1δ) from MYPT1 and inhibition of basal MLCP activity. Treatment of platelets with PGE1 prevented thrombin-induced phospho-MYPT1-thr(853) in a protein kinase A (PKA)-dependent manner. Examination of the molecular mechanisms revealed that PGE1 induced the phosphorylation of RhoA on serine(188) through a pathway requiring cAMP and PKA. This event inhibited the membrane relocalization of RhoA, prevented the association of RhoA with ROCK2 and MYPT1, attenuated the dissociation of PP1δ from MYPT1, and thereby restored basal MLCP activity leading to a decrease in phospho-MLC. These data reveal a new mechanism by which the cAMP-PKA signaling pathway regulates platelet function.


Female genital tuberculosis in Pakistan - A retrospective review of 10-year laboratory data and analysis of 32 cases.
Female genital tuberculosis (FGTB) is an underobserved clinical entity owing to diagnostic challenges stemming from difficulty of obtaining diagnostic specimens and paucibacillary nature of the disease. Yet, FGTB is a cause of infertility, pelvic pain, or menstrual irregularities in high-burden countries. To assess laboratory and microbiology diagnostic utilization for FGTB in Pakistan, we have collected data from 2007 to 2016 to inform the need for improved laboratory diagnostics. The objectives of this study were to determine the proportion of FGTB as culture-confirmed extrapulmonary tuberculosis (EPTB) and to describe the characteristics of women with culture-confirmed FGTB in a nationwide laboratory network in Pakistan. A retrospective database was established by accessing laboratory archives and analyzed by sex and source to determine extrapulmonary cases among women. Data were checked for quality, and after removing patient identifiers and duplicate samples, frequencies were calculated in MS Excel. Clinical characteristics of patients were derived from a linked hospital database for those patients who were diagnosed and managed at the affiliated university hospital in Karachi, Pakistan. Over 10 years, 410,748 mycobacterial cultures were received from multiple geographic sites throughout Pakistan and processed at the study laboratory. The overall mean culture positivity rate was 5.9% ± 3.5%, while the mean culture positivity rate among females was 2.8% ± 0.8%. Among female culture-confirmed tuberculosis cases, the pulmonary-to-EPTB ratio of infection was 5. Over 10 years, a total of 32 FGTB cases were reported on the basis of positive cultures for Mycobacterium tuberculosis; 3 (9.4%) were rifampin resistant. FGTB currently constitutes a small but significant proportion of culture-confirmed EPTB. A fewer number of laboratory requisitions suggest the need to increase awareness and testing. The advent of high-sensitivity molecular testing on extrapulmonary specimens has the potential to improve diagnostic accuracy and improved detection of FGTB cases in high-burden regions.


Effectiveness of switching from baricitinib 4 mg to upadacitinib 30 mg in patients with moderate-to-severe atopic dermatitis: a real-world clinical practice in Japan.
Atopic dermatitis (AD) is a chronic eczematous disease with severe pruritus. Janus kinase (JAK) inhibitors, upadacitinib, baricitinib, and abrocitinib, are systemic treatments for AD. The outcomes of switching from one JAK inhibitor to another have not been examined. We assessed the outcomes of switching from baricitinib 4 mg to upadacitinib 30 mg in Japanese patients with moderate-to-severe AD. Twenty patients treated with baricitinib 4 mg, showing insufficient response or adverse events, were switched to treatment with upadacitinib 30 mg. We evaluated total eczema area and severity index (EASI), EASI at head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and peak pruritus numerical-rating scale (PP-NRS) at baseline (start of baricitinib), weeks 0 (time of switching), and 4 and 12 after switching. Total EASI, EASI at each anatomical site, EASI of each clinical sign, and PP-NRS were markedly reduced at weeks 4 or 12 compared to week 0. Achievement rates of more than 75% or 90% reduction of EASI from baseline significantly improved after switching. Switching from baricitinib 4 mg to upadacitinib 30 mg effectively improved rash and pruritus.


Caspase-6-Resistant Mutant Huntingtin Does not Rescue the Toxic Effects of Caspase-Cleavable Mutant Huntingtin in vivo.
The amelioration of behavioral and neuropathological deficits in mice expressing caspase-6-resistant (C6R) mutant huntingtin (mhtt), despite the presence of an expanded polyglutamine tract, highlights proteolysis of htt at the 586aa caspase-6 (casp6) site may be an important mechanism in the pathogenesis of Huntington disease (HD). One possible explanation of these effects is that C6R mhtt could act as a dominant negative on mhtt. To determine if the neuroprotective effect observed in the C6R mice is due to dominant negative effects, we crossed the C6R mice to the YAC128 HD mouse model to generate mice expressing both caspase-cleavable and C6R mhtt (YAC/C6R) concurrently and assessed previously defined behavioral and neuropathological endpoints. Our results demonstrate that YAC/C6R animals exhibit similar motor abnormalities and learning deficits as the YAC128 mice. Neuropathological analysis reveals a significant decrease in brain weight and striatal volume in the YAC/C6R mice comparable to the YAC128 mice. In contrast, and similar to previous findings, C6R mice demonstrate preserved brain weight and striatal volume. As expected, body weight is significantly increased in the YAC/C6R mice due to the increased levels of htt. The results of this study suggest that the lack of an HD phenotype in the C6R mice is most likely due to the absence of cleavage of htt and not due to suppression of expression of mhtt.


Hypoxia Reduces the Pathogenicity of Pseudomonas aeruginosa by Decreasing the Expression of Multiple Virulence Factors.
Our understanding of how the course of opportunistic bacterial infection is influenced by the microenvironment is limited. We demonstrate that the pathogenicity of Pseudomonas aeruginosa strains derived from acute clinical infections is higher than that of strains derived from chronic infections, where tissues are hypoxic. Exposure to hypoxia attenuated the pathogenicity of strains from acute (but not chronic) infections, implicating a role for hypoxia in regulating bacterial virulence. Mass spectrometric analysis of the secretome of P. aeruginosa derived from an acute infection revealed hypoxia-induced repression of multiple virulence factors independent of altered bacterial growth. Pseudomonas aeruginosa lacking the Pseudomonas prolyl-hydroxylase domain-containing protein, which has been implicated in bacterial oxygen sensing, displays reduced virulence factor expression. Furthermore, pharmacological hydroxylase inhibition reduces virulence factor expression and pathogenicity in a murine model of pneumonia. We hypothesize that hypoxia reduces P. aeruginosa virulence at least in part through the regulation of bacterial hydroxylases.


Characterization of TEM-, SHV- and AmpC-type beta-lactamases from cephalosporin-resistant Enterobacteriaceae isolated from swine.
Extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacteriaceae are an increasing problem in human medicine and an emerging problem in the veterinary field. Our study, therefore, focused on assessing the prevalence of beta-lactamases isolated from swine. Sixty-six Salmonella enterica serovar Typhimurium (S. Typhimurium), 33 Salmonella enterica serovar Enteritidis (S. Enteritidis), 26 Klebsiella pneumonia (K. pneumoniae) and 130 Escherichia coli (E. coli) pig isolates collected from 1999-2006 were screened for beta-lactam resistance by the disk diffusion test (DDT) and micro-broth dilution. Among the isolates, five E. coli and five K. pneumoniae exhibited reduced susceptibility to the cephalosporins tested. PCR, plasmid profiling and Southern blot hybridization showed the presence of multiple beta-lactamases in these isolates of animal origin. Hybridization patterns of the DHA-1 specific probe indicated that dissemination of DHA-1 related beta-lactamases could be attributed to plasmids of one common size among the enteric microbes of animal origin. To the best of our knowledge, this study reports the first identification of SHV-28 and DHA-1 from microbes of animal origin.


Cytokines involved in the augmentation of murine natural killer cell activity by pyrimidinones in vivo.
Therapeutically active pyrimidinones such as 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP, Bropirimine) are known to be potent immuno-modulators. This includes their ability to markedly augment murine natural killer (NK) cell activity as measured in ex vivo NK assays. We now report the use of a murine in vivo NK assay, based on the rate of NK-cell mediated clearance of radiolabeled tumor cells from the lungs, to directly demonstrate in vivo NK augmentation by several pyrimidinones, including ABPP. In order to evaluate the involvement of the cytokines interferon (IFN), interleukin-1 (IL-1), and interleukin-2 (IL-2) in ABPP-induced NK augmentation, we first showed that injection of purified IFN or IL-1, but not IL-2, resulted in significant enhancement of in vivo NK activity. However, the mixture of IFN, IL-1, and IL-2 synergistically enhanced NK activity more than with any of the cytokines alone. We then showed that ABPP induced significant serum levels of IFN and IL-1, but not IL-2. The induction of IL-1 by ABPP in vivo was further verified by demonstration of increased serum levels of the acute phase protein serum amyloid P in ABPP-treated mice. The possible induction of IL-2 by ABPP was further investigated by using cyclosporin A (CsA) to inhibit IL-2 production in vivo. No diminution of ABPP-induced NK augmentation was seen, however, in CsA treated mice. These results suggest a role for IFN and IL-1 in the augmentation of NK activity in vivo by ABPP, but no evidence for a role for IL-2 was found.


Underneath the unconventional: philosophies & paradigms of special operations forces clinical science.
Special Operations Forces (SOF) medical personnel (clinicians) directly impact their patients' outcomes, regardless if the patient is a Soldier, civilian, or indigenous person. Any health practitioner who specializes in trauma, Soldiers' healthcare, or tactical and/or operational healthcare must have a working knowledge of SOF medicine and its philosophical, political, and contextual origins. SOF clinical evidence and knowledge base is extensive and inextricably linked to SOF clinicians' underlying warrior philosophy and worldview. This submission will argue the point that SOF healthcare is a discipline and mature science in its own right, as evidenced by SOF's utilization and/or rejection of other disciplines' (nursing, medicine, conventional military) paradigms, community-wide adoption of its own specific paradigms, disciplinary matrix, and language. Peer-reviewed articles relevant to SOF and military healthcare from 2009-2011 are reviewed to determine possible philosophical frameworks, identify extant methodologies, and demonstrate underlying philosophical constructs.


Adipocyte DIO2 Expression Increases in Human Obesity but Is Not Related to Systemic Insulin Sensitivity.
Deiodinase type II (D2), encoded by DIO2, catalyzes the conversion of T4 to bioactive T3. T3 not only stimulates adaptive thermogenesis but also affects adipose tissue (AT) lipid accumulation, mitochondrial function, inflammation, and potentially systemic metabolism. Although better defined in brown AT, the precise role of DIO2 expression in white AT remains largely unknown, with data derived only from whole fat. Therefore, the purpose of this study was to determine whether subcutaneous (SAT) and visceral (VAT) adipocyte-specific gene expression of DIO2 differs between obese and lean patients and whether these differences relate to alterations in mitochondrial function, fatty acid flux, inflammatory cytokines/adipokines, and ultimately insulin sensitivity. Accordingly, adipocytes of 73 obese and 21 lean subjects were isolated and subjected to gene expression analyses. Our results demonstrate that obese compared to lean human individuals have increased adipocyte-specific DIO2 expression in both SAT and VAT. Although higher DIO2 was strongly related to reduced fatty acid synthesis/oxidation and mitochondrial function, we found no relationship to proinflammatory cytokines or insulin resistance and no difference based on diabetic status. Our results suggest that adipocyte-derived DIO2 may play a role in weight maintenance but is likely not a major contributor to obesity-related insulin resistance.


Cleavage of arginyl-arginine and lysyl-arginine from the C-terminus of pro-hormone peptides by human germinal angiotensin I-converting enzyme (ACE) and the C-domain of human somatic ACE.
Mammalian germinal angiotensin I-converting enzyme (gACE) is a single-domain dipeptidyl carboxypeptidase found exclusively in male germ cells, which has almost identical sequence and enzymic properties with the C-domain of the two-domain somatic ACE. Mutant mice that do not express gACE are infertile, suggesting a role for the enzyme in the processing of undefined peptides involved in fertilization. A number of spermatid peptides [e.g. cholecystokinin (CCK) and gastrin] are processed from pro-hormones by endo- and exo-proteolytic cleavages which might generate substrates for gACE. We have shown that peptide hormone intermediates with Lys/Arg-Arg at the C-terminus are high-affinity substrates for human gACE. gACE from human sperm cleaved Arg-Arg from the C-terminus of the CCK5-GRR (GWMDFGRR), a peptide corresponding to the C-terminus of a CCK-gastrin prohormone intermediate. Hydrolysis of CCK5-GRR by recombinant human C-domain ACE was Cl- dependent, with maximal activity achieved in 5-10 mM NaCl at pH 6.4. C-Domain ACE cleaved Lys/Arg-Arg from the C-terminus of dynorphin-(1-7), a pro-TRH peptide KRQHPGKR, and two insect peptides FSPRLGKR and FSPRLGRR. C-Domain ACE displayed high affinity towards all these substrates with Vmax/Km values between 14 and 113 times greater than the Vmax/Km for the conversion of the best known ACE substrate, angiotensin I, into angiotensin II. In conclusion, we have identified a new class of substrates for human gACE, and we suggest that gACE might be an alternative to carboxypeptidase E for the trimming of basic dipeptides from the C-terminus of intermediates generated from pro-hormones by subtilisin-like convertases in human male germ cells.


Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells.
Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing myocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1-7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.


Ofatumumab for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab: a critique of the submission from GSK.
This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of ofatumumab for the treatment of refractory chronic lymphocytic leukaemia (CLL), based upon the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included one study: a non-randomised, single-arm study. Two other studies were identified but both were non-comparative and provided evidence for therapies other than ofatumumab. For this reason these studies were not discussed in full in the main body of the submission. In the Hx-CD20-406 study, the overall response rate was 58% (99% confidence interval 40% to 74%, p < 0.001). Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression-free survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The MS concluded that ofatumumab provides a new, effective and well-tolerated therapy for patients with CLL who are refractory to both fludarabine and alemtuzumab [double refractory (DR)]. The ERG undertook a critical appraisal of the submission. The ERG had a number of concerns regarding the manufacturer's estimates of effectiveness based on evidence from a single-arm, non-randomised study. An 'area-under-the-curve' or 'partitioned-survival' model was used to project expected clinical and economic outcomes for patients with DR CLL who were assumed to receive ofatumumab or best supportive care (BSC). The model had a three-state structure: 'alive pre-progression', 'alive post progression' and 'dead'. Overall, the modelling approach is reasonable given the limited evidence available for the drug in the patient population under review. However, a number of uncertainties were identified in the economic evaluation; for example, the BSC arm used data from patients in the Hx-CD20-406 study who did not respond to ofatumumab treatment - 'non-responders' - and the ofatumumab arm used data from all of those treated in the Hx-CD20-406 study. Further uncertainty arose regarding the choice of utilities, the omission of 17p and 11q chromosomal deletions as factors in the Cox proportional hazards models for PFS and OS, and the omission of the costs of drugs in progressive disease. It was felt that these factors biased cost-effectiveness in favour of ofatumumab. When revisions were made to the assumptions in the model based on the ERG's review of the published and submitted evidence, the revised base-case incremental cost-effectiveness ratio for ofatumumab increased to £ 81,500 per quality-adjusted life-year. The final appraisal determination was issued by NICE in September 2010 (www.nice.org.uk/nicemedia/live/12264/50758/50758.pdf).