Malignant recurrent orbital solitary fibrous tumor.
Solitary fibrous tumor (SFT) is a rare mesenchymal tumor of fibroblastic origin commonly occurring in pleura. It can occur at many extrapleural sites but is rare in orbit. Most cases are benign and recurrence is not unusual in the head and neck and orbit and is usually due to incomplete surgical excision. However, malignant transformation (MT) in orbital SFT is extremely unusual. We present a case of orbital SFT in adult male who developed recurrence with MT eight years after initial surgical excision. He underwent left orbital exenteration. The recurrent tumor revealed features of malignancy with areas exhibiting morphology typical of SFT. The immunochemistry confirmed the diagnosis of SFT with MT. The patient was given adjuvant radiation and was disease free for the last 18 months. Identification of malignancy in orbital SFT is important for the patient to receive appropriate postoperative treatment, as seen in the present case.


Integer wavelet transform for embedded lossy to lossless image compression.
The use of the discrete wavelet transform (DWT) for embedded lossy image compression is now well established. One of the possible implementations of the DWT is the lifting scheme (LS). Because perfect reconstruction is granted by the structure of the LS, nonlinear transforms can be used, allowing efficient lossless compression as well. The integer wavelet transform (IWT) is one of them. This is an interesting alternative to the DWT because its rate-distortion performance is similar and the differences can be predicted. This topic is investigated in a theoretical framework. A model of the degradations caused by the use of the IWT instead of the DWT for lossy compression is presented. The rounding operations are modeled as additive noise. The noise are then propagated through the LS structure to measure their impact on the reconstructed pixels. This methodology is verified using simulations with random noise as input. It predicts accurately the results obtained using images compressed by the well-known EZW algorithm. Experiment are also performed to measure the difference in terms of bit rate and visual quality. This allows to a better understanding of the impact of the IWT when applied to lossy image compression.


Pharmacokinetics of articaine hydrochloride and its metabolite articainic acid after subcutaneous administration in red deer (Cervus elaphus).
To develop and validate a simple and sensitive method using liquid chromatography-mass spectrometry (LC-MS) for quantification of articaine, and its major metabolite articainic acid, in plasma of red deer (Cervus elaphus), and to investigate the pharmacokinetics of articaine hydrochloride and articainic acid in red deer following S/C administration of articaine hydrochloride as a complete ring block around the antler pedicle. The LC-MS method was validated by determining linearity, sensitivity, recovery, carry-over and repeatability. Articaine hydrochloride (40 mg/mL) was administered S/C to six healthy male red deer, at a dose of 1 mL/cm of pedicle circumference, as a complete ring block around the base of each antler. Blood samples were collected at various times over the following 12 hours. Concentrations in plasma of articaine and articainic acid were quantified using the validated LC-MS method. Pharmacokinetic parameters of articaine and articainic acid were estimated using non-compartmental analysis. Calibration curves were linear for both articaine and articainic acid. The limits of quantifications for articaine and articainic acid were 5 and 10 ng/mL, respectively. Extraction recoveries were >72% for articaine and >68% for articainic acid. After S/C administration as a ring block around the base of each antler, mean maximum concentrations in plasma (Cmax) of articaine were 1,013.9 (SD 510.1) ng/mL, detected at 0.17 (SD 0.00) hours, and the Cmax for articainic acid was 762.6 (SD 95.4) ng/mL at 0.50 (SD 0.00) hours. The elimination half-lives of articaine hydrochloride and articainic acid were 1.12 (SD 0.17) and 0.90 (SD 0.07) hours, respectively. The LC-MS method used for the quantification of articaine and its metabolite articainic acid in the plasma of red deer was simple, accurate and sensitive. Articaine hydrochloride was rapidly absorbed, hydrolysed to its inactive metabolite articainic acid, and eliminated following S/C administration as a ring block in red deer. These favourable pharmacokinetic properties suggest that articaine hydrochloride should be tested for efficacy as a local anaesthetic in red deer for removal of velvet antlers. Further studies to evaluate the safety and residues of articaine hydrochloride and articainic acid are required before articaine can be recommended for use as a local anaesthetic for this purpose.


Comparison of raloxifene and bisphosphonates based on adherence and treatment satisfaction in postmenopausal Asian women.
We evaluated adherence with raloxifene therapy compared with daily bisphosphonate in Asian postmenopausal women at increased risk of osteoporotic fractures. In this 12-month observational study conducted in Asia (Hong Kong, Malaysia, Pakistan, Philippines, Singapore, Taiwan), 984 postmenopausal women (aged 55 years or older) were treated with raloxifene 60 mg/day (n = 707; 72%) or daily bisphosphonate (alendronate 10 mg/day; n = 206; 21%, or risedronate 5 mg/day; n = 71; 7%) during their normal course of care. Patients were assessed at baseline, 6, and 12 months. Baseline characteristics (including age, race, education, menopausal status, and baseline fractures) were comparable between the raloxifene and bisphosphonate groups. More women on raloxifene completed the study compared with those on bisphosphonate (50.2% versus 37.5%; P < 0.001). Patients also took raloxifene for a longer period than bisphosphonate (median, 356 versus 348 days; P = 0.011). Compared with those taking bisphosphonate, significantly fewer patients taking raloxifene discontinued the study because of stopping treatment (5.7% versus 10.1%, P = 0.017) or changing treatment (2.8% versus 9.7%, P < 0.001). Inconvenient dosing was reported as a primary reason for discontinuation due to stopping or changing treatment in 19 (6.9%) bisphosphonate patients compared with 0 raloxifene patients. The percentage of patients who had consumed 80% or more of their study medication was similar for raloxifene patients (48-56 weeks; 95.2%) and bisphosphonate patients (48-56 weeks; 93.3%). More raloxifene patients responded that they were satisfied with their medication than bisphosphonate patients at 48-56 weeks (P = 0.002). We concluded that Asian postmenopausal women at increased risk of osteoporotic fractures showed a greater propensity to remain on raloxifene compared with bisphosphonate. The women on raloxifene exhibited lower discontinuation rates and higher treatment satisfaction.


A gender-specific association of CNV at 6p21.3 with NPC susceptibility.
Copy number variations (CNVs), a major source of human genetic polymorphism, have been suggested to have an important role in genetic susceptibility to common diseases such as cancer, immune diseases and neurological disorders. Nasopharyngeal carcinoma (NPC) is a multifactorial tumor closely associated with genetic background and with a male preponderance over female (3:1). Previous genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that are associated with NPC susceptibility. Here, we sought to explore the possible association of CNVs with NPC predisposition. Utilizing genome-wide SNP-based arrays and five CNV-prediction algorithms, we identified eight regions with CNV that were significantly overrepresented in NPC patients compared with healthy controls. These CNVs included six deletions (on chromosomes 3, 6, 7, 8 and 19), and two duplications (on chromosomes 7 and 12). Among them, the CNV located at chromosome 6p21.3, with single-copy deletion of the MICA and HCP5 genes, showed the highest association with NPC. Interestingly, it was more specifically associated with an increased NPC risk among males. This gender-specific association was replicated in an independent case-control sample using a self-established deletion-specific polymerase chain reaction strategy. To the best of our knowledge, this is the first study to explore the role of constitutional CNVs in NPC, using a genome-wide platform. Moreover, we identified eight novel candidate regions with CNV that merit future investigation, and our results suggest that similar to neuroblastoma and prostate cancer, genetic structural variations might contribute to NPC predisposition.


Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy.
Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.


Effects of estradiol benzoate and progesterone on superoxide dismutase activity in the thymus of rats.
The activity of mitochondrial superoxide dismutase (MnSOD) and cytosol superoxide dismutase (CuZnSOD) was measured in corresponding subcellular fractions prepared from the thymi of intact and chronically gonadectomized (GX) rats of both sexes, as well as of GX male and female rats injected subcutaneously with a single dose of 5 microg estradiol benzoate (EB) and/or 2 mg progesterone (P). Animals were sacrificed 2 h or 24 h following hormone treatment. In the females, the activity of MnSOD in the thymus was stable during the estrous cycle and did not change after ovariectomy. Treatment of GX females with estradiol benzoate resulted 2 h later in a significant elevation of MnSOD activity, whereas 24 h later the activity returned back to control values. On the other hand, treatment of GX females with progesterone had no effect on the MnSOD activity. However, combined hormone treatment, in which EB injection preceded progesterone injection by one hour, enhanced the effect on MnSOD activity similar to that of estradiol benzoate alone. The activity of CuZnSOD in cycling rats was increased in proestrus, whereas removal of the ovaries kept the values at low diestrus and estrus levels. Contrary to MnSOD, CuZnSOD activity did not change after EB treatment of GX females, while progesterone increased the enzyme activity at 2 h and 24 h after hormone treatment. However, combined EB+P treatment proved to be ineffective. In the males, neither MnSOD nor CuZnSOD activity was affected by the removal of testes or by progesterone treatment of GX animals. Only EB injection to GX rats significantly increased CuZnSOD activity 24 h later.


Effects of delay on the type and velocity of travelling pulses in neuronal networks with spatially decaying connectivity.
We study a one-dimensional model of integrate-and-fire neurons that are allowed to fire only one spike, and are coupled by excitatory synapses with delay. At small delay values, this model describes a disinhibited cortical slice. At large delay values, the model is a reduction of a model of thalamic networks composed of excitatory and inhibitory neurons, in which the excitatory neurons show the post-inhibitory rebound mechanism. The velocity and stability of propagating continuous pulses are calculated analytically. Two pulses with different velocities exist if the synaptic coupling is larger than a minimal value; the pulse with the lower velocity is always unstable. Above a certain critical value of the constant delay, continuous pulses lose stability via a Hopf bifurcation, and lurching pulses emerge. The parameter regime for which lurching occurs is strongly affected by the synaptic footprint (connectivity) shape. A bistable regime, in which both continuous and lurching pulses can propagate. may occur with square or Gaussian footprint shapes but not with an exponential footprint shape. A perturbation calculation is used in order to calculate the spatial lurching period and the velocity of lurching pulses at large delay values. For strong synaptic coupling, the velocity of the lurching pulse is governed by the tail of the synaptic footprint shape. Moreover, the velocities of continuous and lurching pulses have the same functional dependencies on the strength of the synaptic coupling strength gsyn: they increase logarithmically with gsyn for an exponential footprint shape, they scale like (In gsyn)1/2 for a Gaussian footprint shape, and they are bounded for a square footprint shape or any shape with a finite support. We find analytically how the axonal propagation velocity reduces the velocity of continuous pulses; it does not affect the critical delay. We conclude that the differences in velocity and shape between the front of thalamic spindle waves in vitro and cortical paroxysmal discharges stem from their different effective delays.


Leishmania amazonensis promastigotes evade complement killing by interfering with the late steps of the cascade.
During their growth in vitro, promastigotes of Leishmania amazonensis undergo differentiation from complement-susceptible to complement-resistant forms. Here, we demonstrate that both forms bind comparable amounts of C3 on their surfaces, with the predominant molecule species being the haemolytically active C3b. Likewise, equivalent amounts of C9 are deposited on both forms of promastigotes. However, while C9-bearing complexes are exposed on the cell surface of resistant promastigotes, they are cryptic in the susceptible stage of the parasites. The membrane fraction of complement-resistant promastigote lysates has the ability to inhibit complement-mediated haemolysis, blocking C9, but not C3 deposition to complement-activating complexes. Moreover, the membrane fraction of complement-resistant promastigote lysates can inhibit the late steps of guinea-pig erythrocyte lysis much more efficiently than complement-susceptible ones. Our results indicate that L. amazonensis promastigotes evade complement killing by inhibiting the cytolytic pathway of the complement cascade.


Essential Roles of Thyroid Hormone-Regulated Hyaluronan/CD44 Signaling in Adult Stem Cell Development During Xenopus laevis Intestinal Remodeling.
In the amphibian intestine during metamorphosis, thyroid hormone (TH) induces some larval epithelial cells to dedifferentiate into stem cells, which generate the adult epithelium analogous to the mammalian intestinal epithelium. We have previously shown that the canonical Wnt signaling pathway is involved in adult epithelial development in the Xenopus laevis intestine. To understand the function of this pathway more precisely, we here focused on CD44, a major Wnt target, which has been identified as a TH response gene in the X. laevis intestine. Our in situ hybridization analysis indicated that CD44 mRNA is detectable in adult epithelial primordia consisting of the adult stem/progenitor cells and is strongly expressed in the connective tissue (CT) cells surrounding them. Interestingly, when the expression of CD44 mRNA is the highest, hyaluronan (HA), a principle ligand of CD44, is newly synthesized and becomes most abundantly distributed in the CT just beneath the adult epithelial primordia that are actively proliferating. Thereafter, as the adult primordia differentiate into the simple columnar epithelium, the expression of CD44 mRNA is gradually downregulated. More importantly, using organ cultures of the X. laevis tadpole intestine in the presence of TH, we have experimentally shown that inhibition of HA synthesis by 4-methylumbelliferone suppresses development of not only the CT but also the epithelial stem cells, resulting in failure to generate the AE. Our findings strongly suggest that TH-upregulated HA/CD44 signaling plays an essential role in formation of the intestinal stem cell niche during vertebrate postembryonic development. Stem Cells 2017;35:2175-2183.


Tumor-Infiltrating Lymphocytes Improve Magee Equation-Based Prediction of Pathologic Complete Response in HR-Positive/HER2-Negative Breast Cancer.
Magee equation 3 (ME3) is predictive of the pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer but with insufficient predictive performance. This study was designed to improve predictive ability by combining ME3 with additional clinicopathologic markers. We retrospectively enrolled 460 patients with HR-positive/HER2-negative breast cancer from 2 centers. We obtained baseline characteristics, the ME3 score, and the number of stromal tumor-infiltrating lymphocytes (sTILs). After performing a logistic regression analysis, a predictive nomogram was built and validated externally. ME3 score (adjusted odds ratio [OR], 1.14 [95% confidence interval (CI), 1.10-1.17]; P < .001) and TILs (adjusted OR, 5.21 [95% CI, 3.33-8.14]; P < .001) were independently correlated with pCR. The nomogram (named ME3+) was established using ME3 and sTILs, and it demonstrated an area under the curve of 0.816 and 0.862 in internal and external validation, respectively, outperforming the ME3 score alone. sTILs and ME3 scores were also found to be positively correlated across the entire cohort (P < .001). The combination of sTILs and ME3 score potentially shows better performance for predicting pCR than ME3 alone. Larger validations are required for widespread application of ME3+ nomogram in NAC settings for HR-positive/HER2-negative breast cancer.


Nanovoid formation and mechanics: a comparison of poly(dicyclopentadiene) and epoxy networks from molecular dynamics simulations.
Protective equipment in civilian and military applications requires the use of polymer materials that are both stiff and tough over a wide range of strain rates. However, typical structural materials, like tightly cross-linked epoxies, are very brittle. Recent experiments demonstrated that cross-linked poly(dicyclopentadiene) (pDCPD) networks can circumvent this trade-off by providing structural properties such as a high glass transition temperature and glassy modulus, while simultaneously exhibiting excellent toughness and high-rate impact resistance. The greater performance of pDCPD was attributed to more facile plastic deformation and nano-scale void formation, but the chemical and structural mechanisms underlying this response were not clear. Here, we use atomistic molecular dynamics to compare the molecular- and chain-level properties of pDCPD and epoxy networks undergoing high strain rate deformation. We quantify the tensile modulus and yield strength of the networks as well as the prevalence and characteristics of nanovoids that form during deformation. Networks of similar molecular weight between cross-links are compared. Two key molecular-level properties are identified - monomer flexibility and polar chemistry - that influence the behavior of the networks. Increasing monomer flexibility reduces the modulus and yield strength, while strong non-covalent interactions (e.g., hydrogen bonds) that accompany polar moieties provide higher modulus and yield strength. The lack of strong non-covalent interactions in pDCPD was found to account for its lower modulus and yield strength compared to the epoxies. We examine the molecular-level properties of nanovoids, such as shape, alignment, and local stress distribution, as well as the local chemical environment, finding that nanovoid formation and growth are increased by the monomer rigidity but decreased by polar chemistry. As a result, the pDCPD network, which has a stiff chain backbone with nonpolar alkane chemistry, exhibits more and larger nanovoids that grow more readily during deformation, which could account for the higher toughness and more ductile behavior observed in pDCPD.


From cytosol to mitochondria: the beginning of a protein journey.
Mitochondrial protein import is one of the key processes during mitochondrial biogenesis that involves a series of events necessary for recognition and delivery of nucleus-encoded/cytosol-synthesized mitochondrial proteins into the organelle. The past research efforts have mainly unraveled how membrane translocases ensure the correct protein sorting within the different mitochondrial subcompartments. However, early steps of recognition and delivery remain relatively uncharacterized. In this review, we discuss our current understanding about the signals on mitochondrial proteins, as well as in the mRNAs encoding them, which with the help of cytosolic chaperones and membrane receptors support protein targeting to the organelle in order to avoid improper localization. In addition, we discuss recent findings that illustrate how mistargeting of mitochondrial proteins triggers stress responses, aiming to restore cellular homeostasis.


Prevalence of vitamin B12 deficiency in patients with plasma cell dyscrasias: a retrospective review.
To the authors' knowledge, the prevalence of vitamin B12 deficiency among patients with plasma cell dyscrasias (PCD) is largely unknown. Identifying this vitamin deficiency in such patients could help improve their anemia and increase their tolerance to potentially neurotoxic agents. The authors retrospectively reviewed the charts and laboratory results of 664 consecutive patients diagnosed with PCD who had their vitamin B12 and folate status evaluated between 1997 and 2001 at the Cleveland Clinic Multiple Myeloma Research Program. The patients were screened for vitamin B12 deficiency using serum vitamin B12 and methylmalonic acid. Of the 664 patients whose medical charts were reviewed, information on vitamin B12 status was available for 522 patients (78%). Among these 522 patients, 71 (13.6%) had laboratory-defined vitamin B12 deficiency and the remaining 451 patients (86.4%) did not. On univariate analysis, vitamin B12 deficiency correlated with immunoglobulin A (IgA) PCD (P = 0.04), higher mean corpuscular volume (P = 0.008), and longer follow-up (P = 0.048). In a covariate adjusted model, only the presence of IgA PCD was associated with an increased prevalence of vitamin B12 deficiency (P = 0.003). Vitamin B12 deficiency was prevalent in patients with PCD, especially in patients with the IgA subtype. Serum vitamin B12 measurements should be part of the initial evaluation and subsequent workups for anemia in patients with PCD.


Influence of irrigation approaches and spatial geolocation on tritium speciation, uptake and depuration.
Pine needles and tree cores from a tritium (T) contaminated phytoremediation forest at the Savannah River Site (SRS in Aiken, SC) Mixed Waste Management Facility (MWMF) were measured for total T and T speciation and compared to other locations at the SRS and the surrounding area. Tree core ages ranged from 9 to 14 years old, covering over half of the ∼20-year on-going remediation efforts, while pine needles represent more recent time periods of 1-to-2-year increments. Remedial irrigation efforts at the MWMF are found to directly influence the pine needle T concentrations. The T content in the MWMF samples is higher than non-irrigated needle samples from other locations around the SRS. Further, the different forms of organic bound T are preferentially stored in tree core tissue, compared to pine needles where tritiated water dominates.


Extrahepatic expression of NAD(P)H:menadione oxidoreductase, UDP glucuronosyltransferase-1A6, microsomal aldehyde dehydrogenase, and hepatic nuclear factor-1 alpha mRNAs in ch/ch and 14CoS/14CoS mice.
Oxidative stress-induced gene expression in liver of the untreated newborn c14CoS/c14CoS mouse, as compared with that in the cch/cch wild-type mouse, appears to be caused by homozygous loss of the fumarylacetoacetate hydrolase (Fah) gene on Chr 7 and absence of the FAH enzyme, which leads to increased levels of endogenous reactive oxygenated metabolites (ROMs) formed in the tyrosine degradative pathway. In these mice almost all studies to date have been carried out in liver. We have examined the extrahepatic expression of four genes. Two genes are members of the [Ah] battery and induced by ROM-mediated oxidative stress: NAD(P)H:menadione oxidoreductase (Nmo1) and UDP glucuronosyltransferase-1A6 (Ugt1a6). The other two genes are decreased in the livers of 14CoS/ 14CoS mice as compared with that in ch/ch mice: microsomal aldehyde dehydrogenase (Ahd3) and hepatocyte-specific nuclear factor-1 alpha HNF-1 alpha (Hnf1 alpha). In liver plus nine extrahepatic tissues of untreated newborn 14CoS/14CoS mutant and ch/ch wild-type mice, we compared NMO1, UGT1A6, AHD3 and HNF-1 alpha mRNA levels. Our results show a wide variation in extrahepatic tissue-specific expression of all four transcripts and indicate that numerous differences exist in the extrahepatic expression of these genes between 14CoS/14CoS and ch/ch mice.


[Nonspecific aortoarteritis (classification and surgical treatment)].
Three hundred cases of nonspecific aortoarteritis are reviewed. A new classification of the condition is proposed identifying 3 stages (acute inflammation, subacute recurrent inflammation and chronic condition), 3 types of morphologic changes (stenosing, deforming and aneurysmatic), 3 sites of lesion (aortic branches, the thoracoabdominal aorta and combined lesions) and 4 degrees of organ ischemia. Ten syndromes are distinguished in the clinical pattern, and their relative incidences are specified. A total of 253 operations, including 218 reconstructive ones, were performed: 83 on aortic branches, 87 on thoracoabdominal aorta, 40 on the abdominal aorta, and 11 for aortic aneurysms. Reconstructive surgery of renal arteries was performed in 89 patients, and of visceral arteries, in 55. The need for anti-inflammatory treatment is emphasized. Surgical treatment produces better results, as compared to conservative treatment alone.


[The improved method of portal decompression by liver cirrhosis in vivo].
The experimental study of liver cirrhosis with portal hypertension syndrome, modeled in 38 dogs, has been performed. Surgical treatment aimed on the portal decompression consisted of the implantation of the Celsite port-system. The reliable portal pressure decrease was observed in the first week of the experiment (from 269.3±17.8 to 157.4±26.5 millimeter of water). Portal decompression reasonably led to the improvement of the general state of the animals.


Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of the pregnane X receptor.
Heterotropic cooperativity of human cytochrome P450 (P450) 3A4/3A5 by the teratogen thalidomide was recently demonstrated by H. Yamazaki et al. ( ( 2013 ) Chem. Res. Toxicol. 26 , 486 - 489 ) using the model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver also displayed enhanced midazolam clearance upon pretreatment with orally administered thalidomide, presumably because of human P450 3A induction. In the current study, we further investigated the regulation of human hepatic drug metabolizing enzymes. Thalidomide enhanced levels of P450 3A4 and 2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes, indirectly suggesting the activation of upstream transcription factors involved in detoxication, e.g., the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). A key event after ligand binding is an alteration of nuclear receptor conformation and recruitment of coregulator proteins that alter chromatin accessibility of target genes. To investigate direct engagement and functional alteration of PXR and CAR by thalidomide, we utilized a peptide microarray with 154 coregulator-derived nuclear receptor-interaction motifs and coregulator and nuclear receptor boxes, which serves as a sensor for nuclear receptor conformation and activity status as a function of ligand. Thalidomide and its human proximate metabolite 5-hydroxythalidomide displayed significant modulation of coregulator interaction with PXR and CAR ligand-binding domains, similar to established agonists for these receptors. These results collectively suggest that thalidomide acts as a ligand for PXR and CAR and causes enzyme induction leading to increased P450 enzyme activity. The possibilities of drug interactions during thalidomide therapy in humans require further evaluation.


Development of Education and Research in Anesthesia and Intensive Care Medicine at the University Teaching Hospital in Lusaka, Zambia: A Descriptive Observational Study.
Data from 2006 show that the practice of anesthesia at the University Teaching Hospital in Lusaka, Zambia was underdeveloped by international standards. Not only was there inadequate provision of resources related to environment, equipment, and drugs, but also a severe shortage of staff, with no local capability to train future physician anesthetic providers. There was also no research base on which to develop the specialty. This study aimed to evaluate patient care, education and research to determine whether conditions had changed a decade later. A mix of qualitative data and quantitative data was gathered to inform the current state of anesthesia at the University Teaching Hospital, Lusaka, Zambia. Semistructured interviews were conducted with key staff identified by purposive sampling, including staff who had worked at the hospital throughout 2006 to 2015. Further data detailing conditions in the environment were collected by reviewing relevant departmental and hospital records spanning the study period. All data were analyzed thematically, using the framework described in the 2006 study, which described patient care, education, and research related to anesthetic practice at the hospital. There have been positive developments in most areas of anesthetic practice, with the most striking being implementation of a postgraduate training program for physician anesthesiologists. This has increased physician anesthesia staff in Zambia 6-fold within 4 years, and created an active research stream as part of the program. Standards of monitoring and availability of drugs have improved, and anesthetic activity has expanded out of operating theaters into the rest of the hospital. A considerable increase in the number of cesarean deliveries performed under spinal anesthetic may be a marker for safer anesthetic practice. Anesthesiologists have yet to take responsibility for the management of pain. The establishment of international partnerships to support postgraduate training of physician anesthetists in Zambia has created a significant increase in the number of anesthesia providers and has further developed nearly all aspects of anesthetic practice. The facilitation of the training program by a global health partnership has leveraged high-level support for the project and provided opportunities for North-South and international learning.


2-[5-(4-Fluoro-phen-yl)-3-(4-methyl-phen-yl)-4,5-dihydro-1H-pyrazol-1-yl]-4-phenyl-1,3-thia-zole.
In the title compound, C25H20FN3S, two independent mol-ecules comprise the asymmetric unit, which differ in the relative orientation of the fluoro-benzene ring with respect to the pyrazole ring to which it is attached [dihedral angles = 89.39 (17) and 75.23 (16)° in the two mol-ecules]. Each pyrazole ring adopts an envelope conformation with the methine C atom being the flap atom. There are additional twists in the mol-ecules, e.g. between the five-membered rings [dihedral angles = 18.23 (16) and 17.84 (16)°] and between the thia-zole and attached phenyl ring [10.26 (16) and 20.87 (15)°]. Overall, each mol-ecule has a T-shape. In the crystal, mol-ecules are connected into a three-dimensional architecture by weak C-H⋯π inter-actions.


Embedding of individual ferritin molecules in large, self-supporting silica nanofilms.
We report herein the fabrication of ferritin-embedded self-supporting silica nanofilms via a simple spin-coating process. Ferritin was employed as a template molecule, and solutions of ferritin and silica were spread on a polymer-coated silicon substrate, in this order. After dissolving the polymer underlayer by simply immersing ethanol, a centimeter-sized self-supporting nanofilm of ferritin/silica composite with a thickness of 15 nm was successfully transferred onto an alumina membrane without the film breaking. Ozone and hydrochloric acid solution treatment removed the template ferritin molecules from the composite film to produce corresponding transmembrane nanoholes. The reported method is very simple, and the fabrication of a protein-embedded self-supporting nanofilm enables the design of biomembrane-mimetic devices.


Prostate biopsy in Central Europe: results of a survey of indication, patient preparation and biopsy technique.
We surveyed urologists in Austria, Germany and Switzerland regarding their standard approach to prostate biopsy. Participants of Austrian and German urological meetings were asked to fill out a survey form; additionally, this was mailed to all Swiss urologists. 304 surveys are available for analysis. 97% of participants perform a biopsy if digital rectal examination is abnormal. 63% use 4 ng/ml PSA (prostate-specific antigen) as cut-off. Age-related reference ranges are used by 54%, free PSA by 57%. 22% use PSA density, 55% PSA velocity. Overall 61% require a written consent, with 85, 86 and 25% in Austria, Germany and Switzerland. 96% of the urologists prescribe a quinolone antibiotic with a wide range regarding the start and end of drug therapy. 77% offer some kind of anaesthesia. Periprostatic injection of a local anaesthetic drug is used by 36%, lidocaine gel by 27%. 91% perform the biopsies transrectally under ultrasound guidance. Digitally guided biopsies are used by 11%. Only 3 participants perform perineal biopsies. The mean number of cores per biopsy session is 9.2, the maximum number of cores is 15.3 as a mean. Participants will stop performing any further biopsies if the patient already had a mean of 3.5 biopsy sessions. The majority of urologists in Central Europe prescribe a quinolone antibiotic and recommend some type of analgesia. The majority has abandoned the sextant technique and increases the number of cores in the case of rebiopsy. Biopsies are stopped after a mean of 3.5 sessions.


Oncolytic Viruses-Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer.
Oncolytic viruses (OVs) are an emerging treatment option for many cancer types and have recently been the focus of extensive research aiming to develop their therapeutic potential. The ultimate aim is to design a virus which can effectively replicate within the host, specifically target and lyse tumor cells and induce robust, long lasting tumor-specific immunity. There are a number of viruses which are either naturally tumor-selective or can be modified to specifically target and eliminate tumor cells. This means they are able to infect only tumor cells and healthy tissue remains unharmed. This specificity is imperative in order to reduce the side effects of oncolytic virotherapy. These viruses can also be modified by various methods including insertion and deletion of specific genes with the aim of improving their efficacy and safety profiles. In this review, we have provided an overview of the various virus species currently being investigated for their oncolytic potential and the positive and negative effects of a multitude of modifications used to increase their infectivity, anti-tumor immunity, and treatment safety, in particular focusing on the interaction of tumor cells and OVs.


An X-ray spectromicroscopy study of protein adsorption to polystyrene-poly(ethylene oxide) blends.
Synchrotron-based X-ray photoemission electron microscopy (X-PEEM) and atomic force microscopy (AFM) were used to characterize the composition and surface morphology of thin films of a polystyrene-poly(ethylene oxide) blend (PS-PEO), spun cast from dichloromethane at various mass ratios and polymer concentrations. X-PEEM reveals incomplete segregation with ∼30% of PS in the PEO region and vice versa. Protein (human serum albumin) adsorption studies show that this partial phase separation leads to greater protein repellency in the PS region, whereas more protein is detected in the PEO region compared to control samples.


[Research progress on uranium induced human renal injury and its risk prediction].
Uranium has both radiotoxicity and chemical toxicity. Low enriched uranium is mainly chemically toxic, the kidney is the target organ of uranium chemical toxicity. However, due to the differences among species and the mixed effects of chemical toxicity and radiotoxicity, the dose effect relationship of uranium is not clear, and the current standards in China do not provide chemical toxicity limits for uranium workplaces. This paper reviews the data of acute and chronic human uranium exposure, dose effect relationship and renal injury risk prediction literature at home and abroad, providing reference for the health protection of uranium workers and the establishment of chemical limits in uranium workplaces.


Retrieval of placental blood from the umbilical vein to determine volume, sterility, and presence of clot formation.
From August 1988 to October 1989, 60 specimens of citrate-phosphate-dextrose-adenine anticoagulated blood were retrieved from the placental umbilical veins of newborns from three gestational age groups. The specimens were removed with a needle and syringe apparatus and placed directly into sterile transfusion packs. The specimens were evaluated for the volume obtained, sterility, and presence of macroscopic clots. A blood volume sufficient to provide at least one transfusion (10 mL/kg) for 87% of the premature infants studied was retrieved from the placenta. A greater blood volume per unit of birth weight was recovered from the placentas of the smaller newborns. A 12% positive culture frequency and a 7% frequency of detectable clots were identified. These rates of occurrence suggest the need for further studies to determine the origins of these complicating factors before the adoption of this technique in the clinical setting. These findings support the hypothesis that, with proper patient selection and with specimen culture and filtration, placental blood may be a viable option for the autologous transfusion of sick, premature infants.


Plasticity of motor behavior in monkeys with crossed forelimb nerves.
Monkeys in which nerves innervating the flexor muscles of the forearm and hand (the ulnar or the median nerve) had been surgically cross-united with the nerve innervating the extensor muscles (the radial nerve), and vice versa, showed excellent (ulnar-radial crosses) to moderate (median-radial crosses) control of movement performance after regeneration. Antagonistic movement responses were seen occasionally, but these were corrected almost immediately. Stimulation of the crossed nerves showed that they had innervated the antagonistic muscle groups. The results reveal the capacity of the primate central nervous system to adapt to gross disturbances imposed on the execution of movements by changes in peripheral innervation.


Interplay between mycoplasma surface proteins, airway cells, and the protean manifestations of mycoplasma-mediated human infections.
Adherence of mycoplasmas to specific tissue surfaces is a crucial step in the establishment of infection. Several pathogenic mycoplasmas are flask-shaped and possess specialized tips that permit a highly oriented surface parasitism of host target cells. Mycoplasma pneumoniae, which causes primary atypical pneumonia in humans, requires a network of interactive adhesins and accessory proteins to cytadhere. The adhesins must cluster at the mycoplasma tip organelle in close association with cytadherence-related accessory proteins and a naplike structure, which together appear to comprise a primitive cytoskeleton-like system. Proline-rich regions associated with these proteins play critical roles in the maintenance of the structural and functional integrity of the tip. Mycoplasma genitalium, originally isolated from the human urogenital tract of patients with nongonococcal urethritis, also colonizes airway cells along with M. pneumoniae. The molecular basis for cytadherence of these mycoplasmas is discussed in terms of the identification, cloning, and sequencing of the implicated mycoplasma genes, their common DNA and amino acid homologies and structural and functional domains, and the organizational similarities in their cytadherence-related operons. In addition, the multiorgan protean manifestations of mycoplasma infection are discussed in terms of the role that mycoplasma adhesins may play in molecular mimicry, postinfectious autoimmunity, and immune-mediated damage.


Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy.
We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection. We now show that this dystrophin expression was accompanied by an elevated expression of α-sarcoglycan, β-dystroglycan (BDG) and--in relevant cases--neuronal nitric oxide synthase (nNOS) at the sarcolemma, each of which is a component of a different subcomplex of the dystrophin-associated glycoprotein complex (DAPC). As expected, nNOS expression was relocalized to the sarcolemma in Duchenne patients in whom the dystrophin deletion left the nNOS-binding domain (exons 42-45) intact, whereas this did not occur in patients with deletions that involved this domain. Our results indicate that the novel internally deleted and shorter dystrophin induced by skipping exon 51 in patients with amenable deletions, can also restore the dystrophin-associated complex, further suggesting preserved functionality of the newly translated dystrophin.


Coordinate regulation of phospholipid biosynthesis by serine in Saccharomyces cerevisiae.
The addition of L-serine to inositol-containing growth medium repressed membrane-associated CDPdiacylglycerol synthase (CTP:phosphatidate cytidylyltransferase, EC 220.127.116.11) and phosphatidylserine synthase (CDPdiacylglycerol:L-serine O-phosphatidyltransferase, EC 18.104.22.168) activities and subunit levels in wild-type Saccharomyces cerevisiae. Enzyme activities and subunit levels were not repressed when inositol was absent from the growth medium. The addition of L-serine to the growth medium did not affect the phospholipid composition of wild-type cells. CDPdiacylglycerol synthase and phosphatidylserine synthase were not regulated in the S. cerevisiae inositol biosynthesis ino2, ino4, and opi1 regulatory mutants, suggesting that regulation by inositol plus L-serine is coupled to inositol synthesis. Inositol and L-serine did not affect the activities of purified CDPdiacylglycerol synthase and phosphatidylserine synthase. The addition of compounds structurally related to L-serine to the growth medium of wild-type cells also resulted in a repression of CDPdiacylglycerol synthase and phosphatidylserine synthase but only in the presence of inositol. Phosphatidylinositol synthase (CDPdiacylglycerol:myo-inositol 3-phosphatidyltransferase, EC 126.96.36.199) was not regulated by inositol plus L-serine.


Exploring the adaptive leisure activities of classified nursing model in elderly colon cancer patients: a perspective on interactive care.
The aims of the study were first to explore the adaptive leisure activities of classified nursing model from the perspective of nurse-patient interactive care, and to explore its impact on the physical and mental health of patients with colon cancer. From September 2017 to March 2022 as the observation time node, 82 patients with colon cancer who met the established inclusion and exclusion criteria were regarded as the research objects through the random number table as the grouping tool. The two groups of patients were named as the research group and the control group, with 41 patients in each group. The control group implemented routine nursing measures, and the research group implemented classified nursing mode and adaptive leisure activity mode. The two groups of patients received 4 weeks of nursing intervention. With the help of self-rating anxiety scale, self-rating depression scale, self-care ability evaluation scale and health status survey brief form, the two groups of patients were compared before intervention and at the end of the 4th week after intervention. After the intervention, the anxiety score (t = 6.656, p < 0.001) and depression score (t = 4.851, p < 0.001) of the research group were lower than those of the control group, and the difference was statistically significant. After the intervention, the self-concept (t = 4.845, p < 0.001), self-responsibility (t = 6.071, p < 0.001), self-care skills (t = 3.341, p < 0.001), health knowledge (t = 3.698, p < 0.001) and total score (t = 9.246, p < 0.001) of the research group were higher than those of the control group, and the difference was statistically significant. After the intervention, physical functioning (t = 8.141, p < 0.001), bodily pain (t = 6.083, p < 0.001), general health (t = 9.424, p < 0.001), role-physical (t = 8.057, p < 0.001), role-emotional (t = 13.252, p < 0.001), mental health (t = 12.565, p < 0.001), social functioning (t = 10.813, p < 0.001) and vitality score (t = 12.890, p < 0.001) of the research group were higher than those of the control group, with significant differences. Interactive care through adaptive leisure nursing improves mental well-being, self-management, and psychosocial functioning in elderly colon cancer patients, promoting overall health.


Undergraduate teaching on biological weapons and bioterrorism at medical schools in the UK and the Republic of Ireland: results of a cross-sectional study.
To determine if individual undergraduate schools of medicine in the UK and the Republic of Ireland provide any teaching to medical students about biological weapons, bioterrorism, chemical weapons and weaponised radiation, if they perceive them to be relevant issues and if they figure them in their future plans. A cross-sectional study utilising an internet-based questionnaire sent to key figures responsible for leading on the planning and delivery of undergraduate medical teaching at all schools of medicine in the UK and Ireland. All identified undergraduate schools of medicine in the UK and Ireland between August 2012 and December 2012. Numerical data and free text feedback about relevant aspects of undergraduate teaching. Of the 38 medical schools approached, 34 (28 in UK, 6 in Ireland) completed the questionnaire (89.47%). 4 (all in UK) chose not to complete it. 6/34 (17.65%) included some specific teaching on biological weapons and bioterrorism. 7/34 (20.59%) had staff with bioterrorism expertise (mainly in microbiological and syndromic aspects). 4/34 (11.76%) had plans to introduce some specific teaching on bioterrorism. Free text responses revealed that some felt that because key bodies (eg, UK's General Medical Council) did not request teaching on bioterrorism, then it should not be included, while others regarded this field of study as a postgraduate subject and not appropriate for undergraduates, or argued that the curriculum was too congested already. 4/34 (11.76%) included some specific teaching on chemical weapons, and 3/34 (8.82%) on weaponised radiation. This study provides evidence that at the present time there is little teaching at the undergraduate level in the UK and Ireland on the subjects of biological weapons and bioterrorism, chemical weapons and weaponised radiation and signals that this situation is unlikely to change unless there were to be high-level policy guidance.


Anatomical Variations of the Right Adrenal Vein: Concordance Between Multidetector Computed Tomography and Catheter Venography.
Adrenal venous sampling is the most reliable diagnostic procedure to determine surgical indications in primary aldosteronism. Because guidelines recommend multidetector computed tomography (CT) to evaluate the adrenal gland, some past reports used multidetector CT as a guide for adrenal venous sampling. However, the detailed anatomy of the right adrenal vein and its relationship with an accessory hepatic vein remains uncertain. The purpose of this study was to describe detailed anatomical variations of the right adrenal vein and to determine the concordance between CT and catheter venography in patients with primary aldosteronism. In total, 440 consecutive patients who underwent adrenal venous sampling were included. Four-phase dynamic CT was performed. Anatomical locations and variations of the right adrenal vein and its relationship with the accessory hepatic vein were compared with catheter venographic findings. Successful catheterization was achieved in 437 patients (99%). The right adrenal vein was visualized in the late arterial phase with CT in 420 patients (95%). The right adrenal vein formed a common trunk with the accessory hepatic vein in 87 patients (20%). CT identified the correct craniocaudal level of the orifice in 354 patients (84%). Anatomical variations, location, and angle of inflow of the right adrenal vein based on CT demonstrated high concordance with catheter venography. CT may provide useful information for preparation before adrenal venous sampling.


Real-life data regarding acute procedural success and 1-year clinical outcome of desolve bioresorbable scaffolds.
We aimed to evaluate the peri-procedural success of DESolve bio-resorbable scaffolds (BRSs) and analyzed real-life data about major cardiac events during 1-year follow-up. There is little information about real-life data of DESolve BRS which is a novel stent technology offering various advantages over drug eluting stents and commonly used in daily cardiology practice. We conducted this single-center and non-randomized cross-sectional study from June 2015 through August 2016 in Medipol University Department of Cardiology and included 117 patients undergoing single or multivessel percutaneous coronary interventions (PCI) with novolimus-eluting BRS devices (152 scaffolds) (Elixir Medical Corporation). Study end points were acute device and procedural success, scaffold thrombosis and major adverse cardiac event (MACE) rates of DESolve BRS. Device success was 96.7% and procedural success was 99.3%. We detected MACE rate as 0.9% while clinical-driven target lesion revascularization was performed in one patient. None of the patients experienced scaffold thrombosis or death. Peri-procedural complications were reported in three patients. High rates of successful scaffold implantations, low rates of peri-procedural complications, and major cardiac events in long-term suggest that DESolve scaffolds can safely and effectively be used in daily intervention practice by particularly experienced operators.


Endothelial dysfunction in hypercholesterolemia is reversed by a nutritional product designed to enhance nitric oxide activity.
The objective of this study was to investigate the vascular and biochemical effects of a formulated product in the form of a bar enriched with a combination of nutrients known to enhance the synthesis or activity of endothelium-derived nitric oxide (EDNO). Individuals with hypercholesterolemia manifest impaired flow-mediated vasodilation, which is largely due to a reduction in EDNO activity. Oral supplementation with large amounts (6-21 g/day) of L-arginine, the precursor of EDNO, have been shown to improve endothelium-mediated vasodilation in hypercholesterolemia. Such large doses are effective but may be impractical to take in capsule form. Accordingly, we have developed a nutrient bar enriched with L-arginine as well as other ingredients that additively enhance EDNO activity. A pilot study in 41 hypercholesterolemic individuals indicated that the bar was well tolerated, had no adverse effects on serum chemistries or lipid profile, and normalized endothelial vasodilator function. To definitively determine if the nutrient bar normalizes endothelial function, a double-blind, placebo-controlled study was performed. Flow-mediated endothelium-dependent vasodilation was assessed by high-resolution ultrasonography before and after 1 week of bar use (2 bars/day) in an additional group of 43 volunteer subjects (57 +/- 10 years old; 22 men, 21 women) with hypercholesterolemia. Subjects manifested an impaired flow-mediated vasodilation before the intervention. Vasodilator function in the active bar group improved to within a normal range (6.5 +/- 3% before to 10 +/- 5% after, P = 0.02; normal, 12 +/- 3%) and was significantly better (P < 0.01) than in the placebo bar group (7.1 +/- 3% before to 6.7 +/- 4% after). These findings reveal that use of a nutrient bar designed to enhance EDNO activity improves flow-mediated endothelium-dependent vasodilation in hypercholesterolemic individuals.


Late-onset globoid cell leucodystrophy (Krabbe's disease). Clinical and genetic delineation of two forms and their relation to the early-infantile form.
A girl is described with a late-onset form of globoid cell leucodystrophy (GLD, Krabbe's disease). Data of this patient and seventeen reported patients with late-onset GLD and cerebroside-beta-galactosidase deficiency were compared with those of patients with classical early-infantile GLD. Three phenotypes of GLD are proposed, an early-infantile form, and two late-onset forms. Biochemical studies demonstrated residual activities of cerebroside-beta-galactocerebrosidase in the late-onset forms. The KM values were identical in the three GLD phenotypes. Autosomal recessive inheritance is likely for each of the subtypes. Complementation studies by somatic cell hybridization suggest that the mutations in early-infantile and late-onset GLD are allelic.


Superior masenteric vein thrombosis.
A 43 year-old woman presented with severe non-specific abdominal pain of 1-week duration. She was on oral contraceptive pills for the past 6 years. Clinically patient appeared ill with no specific abnormal physical sign. Moderate amount of free fluid in the peritoneal cavity on ultrasound prompted an urgent abdominal computed tomography (CT) scan, which revealed thrombosis of the superior mesenteric vein. Further investigations revealed a hypercoagulable state with protein C deficiency. Patient responded well to anticoagulation and supportive therapy. One month later patient readmitted with vomiting and signs of intestinal obstruction. Barium study revealed a moderately long tight stricture at mid jejunum with proximal dilation. A by-pass surgery was carried out. She was well at 3 months follow-up.


Clinical outcome of internal stent for biliary anastomosis in liver transplantation.
This study analyzed the incidence and management of biliary complications after liver transplantation (LT) with or without internal stent. The medical record of all patients who underwent LT and were hospitalized from December 2009 to March 2013 were reviewed. Patients were grouped into 2 groups (internal stent group vs no stent group). There were 29 deceased-donor liver transplantations (58%) and 21 living-donor liver transplantations (42%). There were 2 perioperative mortalities, and those 2 patients were excluded from this study. The overall biliary complication rate was 6.45% in the internal stent group and 17.65% in the no stent group. The rate of anastomotic stricture was 3.23% (n = 1) in the stent group and 11.76% (n = 2) in the no stent group. The rate of bile leak was 3.23% (n = 1) in the stent group and 0% in the no stent group. The rate of biliary obstruction was 0% in the stent group and 5.88% (n = 1) in the no stent group. The overall rate of biliary complications in the internal stent group was lower than in the no stent group, and most of the biliary complications could be treated successfully with endoscopic or radiologic intervention.


Superior mesenteric arteriovenous fistula in vascularized whole organ pancreatic allografts.
Despite improved results in vascularized pancreatic transplantation, the incidence of technical complications continues to be high. Vascular complications are an important source of morbidity. Previously undescribed is the occurrence of an arteriovenous fistula (AVF) in the transplanted mesenteric bundle. We have identified this unusual complication in three of 90 consecutive recipients of pancreatic transplant. The first patient presented with severe and protracted endocrine insufficiency, which was effectively reversed by direct surgical ligation of the AVF. The second patient presented with hematuria, which likewise, resolved with correction of the AVF. The third instance was diagnosed immediately after transplant and was successfully corrected by direct surgical ligation. The operative approach with establishment of proximal vascular control differed in each instance. Clinical presentation was variable and diagnosis was suggested by physical examination, duplex ultrasonography and radionuclide perfusion scanning. Arteriography was confirmatory. Mesenteric AVF can be easily identified and corrected at the time of reoperation without compromising allograft function.


Ki67 measured after neoadjuvant chemotherapy for primary breast cancer.
The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described. Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0-15%), intermediate (15.1-35%), or high (35.1-100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively. Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P < 0.0001) and death (P < 0.0001) compared with patients with low or intermediate Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone-receptor-positive disease [hazard ratios (HR), 1.82-5.88] but not in hormone-receptor-negative disease (HR: 0.61-1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965). Posttreatment Ki67 levels provide prognostic information for patients with hormone-receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments.


[Experience with hernioplasty after Lichtenstein in inguinal hernias].
The presented method of hernioplasty was used in 1242 patients with different types of inguinal hernias. In 428 patients plasty of the inguinal canal was performed by the classical method of Lichtenstein, in 814 patients the method was modified. The method modified by the authors is described in detail. Improved results of treatment are associated by the authors with reduced ischemization of the sutured tissues with reticulate endoprosthesis. Recurrent hernias were noted in 0.2% in the main group, and 1.8% in the control group.


KIF18B promotes tumor progression in osteosarcoma by activating β-catenin.
Objective: Osteosarcoma is a common primary highly malignant bone tumor. Kinesin family member 18B (KIF18B) has been identified as a potential oncogene involved in the development and metastasis of several cancer types. While KIF18B overexpression in osteosarcoma tissue is clearly detected, its specific function in the disease process remains to be established. Methods:KIF18B expression was assessed in osteosarcoma tissues and cells. We additionally evaluated the effects of KIF18B on proliferation, migration, and invasion of osteosarcoma cells, both in vitro and in vivo. Results: Our results showed overexpression of KIF18B in osteosarcoma tissues and cells. Knockdown of KIF18B induced G1/S phase arrest and significantly inhibited proliferation, migration, and invasion of osteosarcoma cells, both in vitro and in vivo. KIF18B regulated β-catenin expression at the transcriptional level by controlling nuclear aggregation of ATF2 and at the post-transcriptional level by interacting with the adenomatous polyposis coli (APC) tumor suppressor gene in osteosarcoma cells. Conclusions: KIF18B plays a carcinogenic role in osteosarcoma by regulating expression of β-catenin transcriptionally via decreasing nuclear aggregation of ATF2 or post-transcriptionally through interactions with APC. Our collective findings support the potential utility of KIF18B as a novel prognostic biomarker for osteosarcoma.


aenmd: annotating escape from nonsense-mediated decay for transcripts with protein-truncating variants.
DNA changes that cause premature termination codons (PTCs) represent a large fraction of clinically relevant pathogenic genomic variation. Typically, PTCs induce transcript degradation by nonsense-mediated mRNA decay (NMD) and render such changes loss-of-function alleles. However, certain PTC-containing transcripts escape NMD and can exert dominant-negative or gain-of-function (DN/GOF) effects. Therefore, systematic identification of human PTC-causing variants and their susceptibility to NMD contributes to the investigation of the role of DN/GOF alleles in human disease. Here we present aenmd, a software for annotating PTC-containing transcript-variant pairs for predicted escape from NMD. aenmd is user-friendly and self-contained. It offers functionality not currently available in other methods and is based on established and experimentally validated rules for NMD escape; the software is designed to work at scale, and to integrate seamlessly with existing analysis workflows. We applied aenmd to variants in the gnomAD, Clinvar, and GWAS catalog databases and report the prevalence of human PTC-causing variants in these databases, and the subset of these variants that could exert DN/GOF effects via NMD escape. aenmd is implemented in the R programming language. Code is available on GitHub as an R-package (github.com/kostkalab/aenmd.git), and as a containerized command-line interface (github.com/kostkalab/aenmd_cli.git).


A descriptive study of a manual therapy intervention within a randomised controlled trial for hamstring and lower limb injury prevention.
There is little literature describing the use of manual therapy performed on athletes. It was our purpose to document the usage of a sports chiropractic manual therapy intervention within a RCT by identifying the type, amount, frequency, location and reason for treatment provided. This information is useful for the uptake of the intervention into clinical settings and to allow clinicians to better understand a role that sports chiropractors offer. All treatment rendered to 29 semi-elite Australian Rules footballers in the sports chiropractic intervention group of an 8 month RCT investigating hamstring and lower-limb injury prevention was recorded. Treatment was pragmatically and individually determined and could consist of high-velocity, low-amplitude (HVLA) manipulation, mobilization and/or supporting soft tissue therapies. Descriptive statistics recorded the treatment rendered for symptomatic or asymptomatic benefit, delivered to joint or soft tissue structures and categorized into body regions. For the joint therapy, it was recorded whether treatment consisted of HVLA manipulation, HVLA manipulation and mobilization, or mobilization only. Breakdown of the HVLA technique was performed. A total of 487 treatments were provided (mean 16.8 consultations/player) with 64% of treatment for asymptomatic benefit (73% joint therapies, 57% soft tissue therapies). Treatment was delivered to approximately 4 soft tissue and 4 joint regions each consultation. The most common asymptomatic regions treated with joint therapies were thoracic (22%), knee (20%), hip (19%), sacroiliac joint (13%) and lumbar (11%). For soft tissue therapies it was gluteal (22%), hip flexor (14%), knee (12%) and lumbar (11%). The most common symptomatic regions treated with joint therapies were lumbar (25%), thoracic (15%) and hip (14%). For soft tissue therapies it was gluteal (22%), lumbar (15%) and posterior thigh (8%). Of the joint therapy, 56% was HVLA manipulation only, 36% high-HVLA and mobilization and 9% mobilization only. Of the HVLA manipulation, 63% was manually performed and 37% mechanically assisted. The intervention applied was multimodal and multi-regional. Most treatment was for asymptomatic benefit, particularly for joint based therapies, which consisted largely of HVLA manipulation techniques. Most treatment was applied to non-local hamstring structures, in particular the knee, hip, pelvis and spine.


Enniatin B and beauvericin are common in Danish cereals and show high hepatotoxicity on a high-content imaging platform.
Mycotoxins are fungi-born metabolites that can contaminate foods through mould-infected crops. They are a significant food/feed-safety issue across the globe and represent a substantial financial burden for the world economy. Moreover, with a changing climate and fungal biota, there is now much discussion about emerging mycotoxins that are measurable at significant levels in crops world-wide. Unfortunately, we still know very little about the bioavailability and toxic potentials of many of these less characterized mycotoxins, including the large family of enniatins. In this study, we present new occurrence data for enniatin A, A1, B, B1 and beauvericin in four Danish crops: oat, wheat, and barley from the 2010 harvest, and rye from 2011 harvest. The occurrence of the four enniatins were B > B1 > A1 > A. Enniatin B was detected in 100% of tested samples regardless of crop type. In addition to occurrence data, we report a proof-of-concept study using a human-relevant high-content hepatotoxicity, or "quadroprobe," assay to screen mycotoxins for their cytotoxic potential. The assay was sensitive for most cytotoxic compounds in the 0.009-100 µM range. Among eight tested mycotoxins (enniatin B, beauvericin, altenariol, deoxynivalenol, aflatoxin B1, andrastin A, citrinin, and penicillic acid), enniatin B and beauvericin showed significant cytotoxicity at a concentration lower than that for aflatoxin B1, which is the archetypal acute hepatotoxic and liver-carcinogenic mycotoxin. Hence, the quadroprobe hepatotoxicity assay may become a valuable assessment tool for toxicity assessment of mycotoxins in the future. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1658-1664, 2017.


Cardioprotective mechanisms of phytochemicals against doxorubicin-induced cardiotoxicity.
Doxorubicin (DOX) is an anthracycline antibiotic, which is effectively used in the treatment of different malignancies, such as leukemias and lymphomas. Its most serious side effect is dose-dependent cardiotoxicity, which occurs through inducing oxidative stress apoptosis. Due to the myelosuppressive effect of dexrazoxane, a commonly-used drug to alleviate DOX-induced cardiotoxicity, researchers investigated the potential of phytochemicals for prophylaxis and treatment of this condition. Phytochemicals are plant chemicals that have protective or disease preventive properties. Preclinical trials have shown antioxidant properties for several plant extracts, such as those of Aerva lanata, Aronia melanocarpa, Astragalus polysaccharide, and Bombyx mori plants. Other plant extracts showed an ability to inhibit apoptosis, such as those of Astragalus polysaccharide, Azadirachta indica, Bombyx mori, and Allium stavium plants. Unlike synthetic agents, phytochemicals do not impair the clinical activity of DOX and they are particularly safe for long-term use. In this review, we summarized the results of preclinical trials that investigated the cardioprotective effects of phytochemicals against DOX-induced cardiotoxicity. Future human trials are required to translate these cardioprotective mechanisms into practical clinical implications.


Brown tumor of the spine in patients with primary hyperparathyroidism.
Retrospective case series and literature review. To describe our experience in diagnosis and management of patients with spine brown tumor (osteitis fibrosa cystica) as the initial manifestation of primary hyperparathyroidism and also to review the pertinent literature. The spine can be involved through reparative processes such as giant cell reparative granuloma and brown tumor, which lead to formation of lesions that can simulate tumors on neuroimaging. Brown tumor, an uncommon focal giant cell lesion, is a nonneoplastic and reactive process due to bone resorption and localized osseous lesion caused by primary or secondary hyperparathyroidism. Among the cases of spine giant cell lesions treated surgically by the authors (2000-2013), there were 4 cases of spine brown tumor in patients with primary hyperparathyroidism. Clinical, radiological, histopathologic, and surgical data of these 4 cases were collected, and the patients were followed from 5 to 7 years after the surgical intervention. There were 2 male and 2 female patients with age range of 16 to 52 years. The lesions were located in cervical (1 case), thoracic (1 case), and lumbar (2 cases) spine regions. Clinical presentations included neck and low back pain, radicular pain, paraparesis, and sphincter dysfunction. Surgical removal of the spine lesions was achieved in all cases. Spine fusion and instrumentation was done in 3 cases. Parathyroidectomy was performed in all 4 cases. Spine involvement with brown tumor in patients with primary hyperparathyroidism is rare and may be the first manifestation of hyperparathyroidism. Brown tumor should be differentiated from other giant cell lesions involving the spine. Long-term surgical outcome was satisfactory with no recurrence. 4.


Soluble antioxidant compounds regenerate the antioxidants bound to insoluble parts of foods.
This study aimed to investigate the regeneration potential of antioxidant capacity of an insoluble food matrix. Investigations were performed in vitro with several food matrices rich in dietary fiber (DF) and bound antioxidants. After removal of the soluble fraction, the antioxidant capacity (AC) of the insoluble fraction was measured by the QUENCHER procedure using ABTS(•+) or DPPH(•) radicals. After measurement, the insoluble residue was washed out to remove the excess of radicals and treated with pure antioxidant solution or antioxidant-rich beverage to regenerate depleted antioxidants on the fiber. Results revealed that the antioxidant capacity of compounds chemically bound to the insoluble moiety could be reconstituted in the presence of other hydrogen-donating substances in the liquid phase. Regeneration efficiency was found to range between 21.5 and 154.3% depending on the type of insoluble food matrix and regeneration agent. Among the food matrices studied, cereal products were found to have slightly higher regeneration efficiency, whereas antioxidant-rich beverages were more effective than pure antioxidants as regeneration agents. Taking wheat bran as reference insoluble material, the regeneration abilities of beverages were in the following order: green tea > espresso coffee > black tea > instant coffee > orange juice > red wine. These results highlighted the possible physiological relevance of antioxidants bound to the insoluble food material in the gastrointestinal tract. During the digestion process they could react with the free radicals and at the same time they can be regenerated by other soluble antioxidant compounds present in the meal.


Characteristics of nearly dry enzymes in organic solvents: implications for biocatalysis in the absence of water.
We have examined enzymes in nearly anhydrous organic solvents spanning a wide range of dielectric constants using a combination of electron paramagnetic resonance (EPR) spectroscopy, molecular dynamics simulations, high-pressure kinetic studies and the electrostatic model of Kirkwood. This approach enabled us to investigate the relationship between catalytic activity, protein flexibility and solvent polarity for an enzymatic reaction proceeding through a highly polar transition state in the near absence of water. Further insights into water-protein interactions and the involvement of water in enzyme structure and function have been obtained by EPR and multinuclear nuclear magnetic resonance studies of enzymes suspended and immobilized in organic solvents with and without added water. In these systems, correlations were observed between the water content and enzyme activity, flexibility, and active-site polarity, although the structural properties of suspended and immobilized enzymes differed markedly. These results have helped to elucidate the role of water in molecular events at the enzymic active site leading to improved biocatalysis in low-water environments.


The effect of mei-41 on rDNA redundancy in Drosophila melanogaster.
The recombination and repair defective mutant, mei-41, exhibits three rather striking effects on the genetic properties and chromosomal stability of rDNA in Drosophila. First, mei-41 inhibits rDNA magnification. However, mei-9, another recombination and repair defective mutation has no similar effect. This indicates that magnification requires some, but not all, of the gene products necessary for meiotic exchange. Second, under magnifying conditions, mei-41 induces interchanges between the X rDNA and either arm of the Ybb- chromosome. These interchanges occur at high frequency and are independent of rDNA orientation. Third, in mei-41 bb+/Ybb+ males, bobbed mutants in the X, but not the Y, also arise at high frequency. Evidence suggests that these events involve the rDNA type I insertion. The recombination and repair defective properties of mei-41 together with our results regarding its unusual and specific effects involving rDNA are explained in a simple model that has general implications for chromosome structure.


Comprehensive Molecular Characterization of Salivary Duct Carcinoma Reveals Actionable Targets and Similarity to Apocrine Breast Cancer.
Salivary duct carcinoma (SDC) is an aggressive salivary malignancy, which is resistant to chemotherapy and has high mortality rates. We investigated the molecular landscape of SDC, focusing on genetic alterations and gene expression profiles. We performed whole-exome sequencing, RNA sequencing, and immunohistochemical analyses in 16 SDC tumors and examined selected alterations via targeted sequencing of 410 genes in a second cohort of 15 SDCs. SDCs harbored a higher mutational burden than many other salivary carcinomas (1.7 mutations/Mb). The most frequent genetic alterations were mutations in TP53 (55%), HRAS (23%), PIK3CA (23%), and amplification of ERBB2 (35%). Most (74%) tumors had alterations in either MAPK (BRAF/HRAS/NF1) genes or ERBB2 Potentially targetable alterations based on supportive clinical evidence were present in 61% of tumors. Androgen receptor (AR) was overexpressed in 75%; several potential resistance mechanisms to androgen deprivation therapy (ADT) were identified, including the AR-V7 splice variant (present in 50%, often at low ratios compared with full-length AR) and FOXA1 mutations (10%). Consensus clustering and pathway analyses in transcriptome data revealed striking similarities between SDC and molecular apocrine breast cancer. This study illuminates the landscape of genetic alterations and gene expression programs in SDC, identifying numerous molecular targets and potential determinants of response to AR antagonism. This has relevance for emerging clinical studies of ADT and other targeted therapies in SDC. The similarities between SDC and apocrine breast cancer indicate that clinical data in breast cancer may generate useful hypotheses for SDC. Clin Cancer Res; 22(18); 4623-33. ©2016 AACR.


p53 in senescence - it's a marathon, not a sprint.
The tumour suppressor p53, a stress-responsive transcription factor, plays a central role in cellular senescence. The role of p53 in senescence-associated stable proliferative arrest has been extensively studied. However, increasing evidence indicates that p53 also modulates the ability of senescent cells to produce and secrete diverse bioactive factors (collectively called the senescence-associated secretory phenotype, SASP). Senescence has been linked with both physiological and pathological conditions, the latter including ageing, cancer and other age-related disorders, in part through the SASP. Cellular functions are generally dictated by the expression profile of lineage-specific genes. Indeed, expression of SASP factors and their regulators are often biased by cell type. In addition, emerging evidence suggests that p53 contributes to deregulation of more stringent lineage-specific genes during senescence. P53 itself is also tightly regulated at the protein level. In contrast to the rapid and transient activity of p53 upon stress ('acute-p53'), during senescence and other prolonged pathological conditions, p53 activities are sustained and fine-tuned through a combination of different inputs and outputs ('chronic-p53').


How to use articles about harm: the relationship between high tidal volumes, ventilating pressures, and ventilator-induced lung injury.
Intensivists commonly encounter patients who may be inadvertently harmed by critical care interventions. This article is designed to guide clinicians in the evaluations of an individual article assessing a question of harm, as well as the sum of multiple pieces of evidence. To assess the vaidity of a group of articles about the relationship between high tidal volumes and ventilating pressures on ventilator-induced lung injury; to interpret the results of these studies; and to consider whether they apply in practice. Issues of harm are sometimes measured in randomized trials, but are evaluated more often in myriad observational studies. We use critical appraisal guides for experimental studies (e.g., randomized trials) and observational studies (e.g., cohort studies, case-control studies and case series) that evaluate the potentially harmful exposure of high tidal volumes and ventilating pressures. This involves assessing the validity of the research, then determining the strength of association between the putative harmful exposure and adverse outcomes. These study designs and their interpretation using relative risks and odds ratios are reviewed. Finally, the relevance of this information (or lack thereof) to clinical practice needs to be determined. Examining these studies individually and in totality, there appears to be a relationship between high tidal volumes and ventilating pressures, although the strength of inference from this research is limited by design issues and sample sizes. Critically appraising a body of literature is more challenging than evaluating a single study, but often gives a broader view of the available evidence. Future large, rigorous, randomized trials of different approaches to mechanical ventilation will help to advance our understanding and to better inform our practice.


Kinesin-1 promotes chondrocyte maintenance during skeletal morphogenesis.
During skeletal morphogenesis diverse mechanisms are used to support bone formation. This can be seen in the bones that require a cartilage template for their development. In mammals the cartilage template is removed, but in zebrafish the cartilage template persists and the bone mineralizes around the cartilage scaffold. Remodeling of unmineralized cartilage occurs via planar cell polarity (PCP) mediated cell rearrangements that contribute to lengthening of elements; however, the mechanisms that maintain the chondrocyte template that supports perichondral ossification remain unclear. We report double mutants disrupting two zebrafish kinesin-I genes (hereafter kif5Blof) that we generated using CRISPR/Cas9 mutagenesis. We show that zygotic Kif5Bs have a conserved function in maintaining muscle integrity, and are required for cartilage remodeling and maintenance during craniofacial morphogenesis by a PCP-distinct mechanism. Further, kif5Blof does not activate ER stress response genes, but instead disrupts lysosomal function, matrix secretion, and causes deregulated autophagic markers and eventual chondrocyte apoptosis. Ultrastructural and transplantation analysis reveal neighboring cells engulfing extruded kif5Blof chondrocytes. Initial cartilage specification is intact; however, during remodeling, kif5Blof chondrocytes die and the cartilage matrix devoid of hypertrophic chondrocytes remains and impedes normal ossification. Chimeric and mosaic analyses indicate that Kif5B functions cell-autonomously in secretion, nuclear position, cell elongation and maintenance of hypertrophic chondrocytes. Interestingly, large groups of wild-type cells can support elongation of neighboring mutant cells. Finally, mosaic expression of kif5Ba, but not kif5Aa in cartilage rescues the chondrocyte phenotype, further supporting a specific requirement for Kif5B. Cumulatively, we show essential Kif5B functions in promoting cartilage remodeling and chondrocyte maintenance during zebrafish craniofacial morphogenesis.


A recessive circadian clock mutation at the frq locus of Neurospora crassa.
A circadian clock mutant of Neurospora crassa, the most distinctive characteristic of which is the complete loss of temperature compensation of its period length, maps to the frq locus where seven other clock mutants have previously been mapped. This mutant, designated frq-9, is recessive to the wild-type allele and to each of the other frq mutants; thus, it differs from the other mutants, which show incomplete dominance to wild type and to each other. Complementation analysis suggests either that the frq locus is a single gene or that frq-9 is a deletion that overlaps adjacent genes. Preliminary efforts at fine structure mapping have indicated that recombination between certain pairs of frq mutations is less than 0.005%, a distance consistent with the locus being a single gene. The recessive nature of frq-9, coupled with complete loss of temperature compensation, suggests that this mutant may represent the null phenotype of the locus and that the frq gene is involved in the temperature compensation mechanism of the clock.--Genetic mapping studies have placed the frq locus on linkage group VIIR, midway between oli (oligomycin resistance) and for (formate auxotrophy), about 2 map units from each, and clearly indicate that frq and oli are separate genes.


Cardiac responses to hypercapnia in larval zebrafish (Danio rerio): the links between CO2 chemoreception, catecholamines and carbonic anhydrase.
The ontogeny of carbon dioxide (CO2) sensing in zebrafish (Danio rerio) has not been examined. In this study, CO2-mediated increases in heart rate were used to gauge the capacity of zebrafish larvae to sense CO2. CO2 is thought to be detected via neuroepithelial cells (NECs), which are homologous to mammalian carotid body glomus cells. Larvae at 5 days post-fertilization (d.p.f.) exhibited tachycardia when exposed for 30 min to 0.75% CO2 (~5.63 mmHg); at 7 d.p.f., tachycardia was elicited by 0.5% CO2 (~3.75 mmHg). Based on pharmacological evidence using β-adrenergic receptor (β-AR) antagonists, and confirmed by β1-AR translational gene knockdown using morpholinos, the reflex tachycardia accompanying hypercapnia was probably mediated by the interaction of catecholamines with cardiac β1 receptors. Because the cardiac response to hypercapnia was abolished by the ganglionic blocker hexamethonium, it is probable that the reflex cardio-acceleration was mediated by catecholamines derived from sympathetic adrenergic neurons. Owing to its likely role in facilitating intracellular acidification during exposure to hypercapnia, it was hypothesized that carbonic anhydrase (CA) is involved in CO2 sensing, and that inhibition of CA activity would blunt the downstream responses. Indeed, the cardiac response to hypercapnia (0.75% CO2) was reduced in fish at 5 d.p.f. exposed to acetazolamide, a CA inhibitor, and in fish experiencing zCAc (CA2-like a) knockdown. Successful knockdown of zCAc was confirmed by CA activity measurements, western blotting and immunocytochemistry. Co-injection of embryos with zCAc morpholino and mRNA modified at the morpholino binding site restored normal levels of CA activity and protein levels, and restored (rescued) the usual cardiac responses to hypercapnia. These data, combined with the finding that zCAc is expressed in NECs located on the skin, suggest that the afferent limb of the CO2-induced cardiac reflex in zebrafish larvae is initiated by coetaneous CO2-sensing neuroepithelial cells.


Should Cooling Vests Be Used to Treat Exertional Heatstroke? A Critically Appraised Topic.
Clinical Scenario: Exercise performed in hot and humid environments increases core body temperature (TC). If TC exceeds 40.5°C for prolonged periods of time, exertional heat stroke (EHS) may occur. EHS is a leading cause of sudden death in athletes. Mortality and morbidity increase the longer the patient's TC remains above 40.5°C; thus, it is imperative to initiate cooling as quickly as possible. Acceptable cooling rates in EHS situations are 0.08-0.15°C/min, while ideal cooling rates are above 0.16°C/min. Cooling vests are popular alternatives for cooling hyperthermic adults. Most vests cover the anterior and posterior torso and have varying numbers of pouches for phase-change materials (eg, gel packs); some vests only use circulating water to cool. While cooling vests offer several advantages (eg, portability), studies demonstrating their effectiveness at rapidly reducing TC in EHS scenarios are limited. Are TC cooling rates acceptable (ie, >0.08°C/min) when hyperthermic humans are treated with cooling vests postexercise? No significant differences in TC cooling rates occurred between cooling vests and no cooling vests. Cooling rates across all studies were ≤0.053°C/min. Clinical Bottom Line: Cooling vests do not provide acceptable cooling rates of hyperthermic humans postexercise and should not be used to treat EHS. Instead, EHS patients should be treated with cold-water immersion within 30 min of collapse to avoid central nervous system dysfunction and organ failure. Strength of Recommendation: Strong evidence (eg, level 2 studies with PEDro scores ≥5) suggests that cooling vests do not reduce TC quickly and thus should not be used in EHS scenarios.


Use of amyloid PET across the spectrum of Alzheimer's disease: clinical utility and associated ethical issues.
Abstract Recent advances have made possible the in vivo detection of beta-amyloid (Aβ) pathology using positron emission tomography. While the gold standard for amyloid imaging, carbon-11 labeled Pittsburgh compound B is increasingly being replaced by fluorine-18 labeled radiopharmaceuticals, with three already approved for clinical use by US and European regulatory bodies. Appropriate use criteria proposed by an amyloid imaging taskforce convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging recommend restricting use of this technology to the evaluation of patients with mild cognitive impairment or atypical dementia syndromes. While use among asymptomatic individuals is currently viewed as inappropriate due prognostic uncertainty, elevated levels of brain Aβ among asymptomatic individuals may represent preclinical Alzheimer's disease. Amyloid imaging is likewise expected to play a role in the design of clinical trials. Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically. As the field moves toward adoption of a pro-disclosure stance for amyloid imaging findings, it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.


Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs.
The dopaminergic system originating in the midbrain ventral tegmental area (VTA) has been extensively studied over the past decades as a critical neural substrate involved in the development of alcoholism and addiction to other drugs of abuse. Accumulating evidence indicates that ethanol modulates the functional output of this system by directly affecting the firing activity of VTA dopamine neurons, whereas withdrawal from chronic ethanol exposure leads to a reduction in the functional output of these neurons. This chapter will provide an update on the mechanistic investigations of the acute ethanol action on dopamine neuron activity and the neuroadaptations/plasticities in the VTA produced by previous ethanol experience.


Trends in malaria research in 11 Asian Pacific countries: an analysis of peer-reviewed publications over two decades.
Quantitative data are lacking on published malaria research. The purpose of the study is to characterize trends in malaria-related literature from 1990 to 2009 in 11 Asian-Pacific countries that are committed to malaria elimination as a national goal. A systematic search was conducted for articles published from January 1990 to December 2009 in PubMed/MEDLINE using terms for malaria and 11 target countries (Bhutan, China, North Korea, Indonesia, Malaysia, Philippines, Solomon Islands, South Korea, Sri Lanka, Thailand and Vanuatu). The references were collated and categorized according to subject, Plasmodium species, and whether they contained original or derivative data. 2,700 articles published between 1990 and 2009 related to malaria in the target countries. The annual output of malaria-related papers increased linearly whereas the overall biomedical output from these countries grew exponentially. The percentage of malaria-related publications was nearly 3% (111/3741) of all biomedical publications in 1992 and decreased to less than 1% (118/12171; p < 0.001) in 2009. Thailand had the highest absolute output of malaria-related papers (n = 1211), followed by China (n = 609) and Indonesia (n = 346). Solomon Islands and Vanuatu had lower absolute numbers of publications, but both countries had the highest number of publications per capita (1.3 and 2.5 papers/1,000 population). The largest percentage of papers concerned the epidemiology and control of malaria (53%) followed by studies of drugs and drug resistance (47%). There was an increase in the proportion of articles relating to epidemiology, entomology, biology, molecular biology, pathophysiology and diagnostics from the first to the second decade, whereas the percentage of papers on drugs, clinical aspects of malaria, immunology, and social sciences decreased. The proportion of malaria-related publications out of the overall biomedical output from the 11 target Asian-Pacific countries is decreasing. The discovery and evaluation of new, safe and effective drugs and vaccines is paramount. In addition the elimination of malaria will require operational research to implement and scale up interventions.


Experimental quantification of electron spectral-diffusion under static DNP conditions.
Dynamic Nuclear Polarization (DNP) is an efficient technique for enhancing NMR signals by utilizing the large polarization of electron spins to polarize nuclei. The mechanistic details of the polarization transfer process involve the depolarization of the electrons resulting from microwave (MW) irradiation (saturation), as well as electron-electron cross-relaxation occurring during the DNP experiment. Recently, electron-electron double resonance (ELDOR) experiments have been performed under DNP conditions to map the depolarization profile along the EPR spectrum as a consequence of spectral diffusion. A phenomenological model referred to as the eSD model was developed earlier to describe the spectral diffusion process and thus reproduce the experimental results of electron depolarization. This model has recently been supported by quantum mechanical calculations on a small dipolar coupled electron spin system, experiencing dipolar interaction based cross-relaxation. In the present study, we performed a series of ELDOR measurements on a solid glassy solution of TEMPOL radicals in an effort to substantiate the eSD model and test its predictability in terms of electron depolarization profiles, in the steady-state and under non-equilibrium conditions. The crucial empirical parameter in this model is ΛeSD, which reflects the polarization exchange rate among the electron spins. Here, we explore further the physical basis of this parameter by analyzing the ELDOR spectra measured in the temperature range of 3-20 K and radical concentrations of 20-40 mM. Simulations using the eSD model were carried out to determine the dependence of ΛeSD on temperature and concentration. We found that for the samples studied, ΛeSD is temperature independent. It, however, increases with a power of ∼2.6 of the concentration of TEMPOL, which is proportional to the average electron-electron dipolar interaction strength in the sample.


Validity of self-report methods for measuring sedentary behaviour in older adults.
Sedentary behaviour (SB) is associated with a range of negative health outcomes, but little is known about the validity of self-report methods for measuring SB in older adults. Thus, the aim was to assess the reliability and validity of two instruments for measuring SB in older adults. Cross-sectional study. 41 community-dwelling older adults (14/27 male/female, 74.5 ± 7.6 years) wore an ActivPAL(3)™ (AP) for 7 consecutive days, then completed (1) a single question (SQ) to assess sitting time on a usual weekday, weekend day and yesterday (i.e. the last day of monitoring), and (2) a computer-delivered 24-h recall (MARCA) for the last two days. Intraclass correlation (ICC) and standard error of measurement (SEM) were used to assess test-retest reliability; validity was examined using Spearman's correlation, mean bias and limits of agreement, and kappa for classifying tertiles of time in SB, with AP as the reference standard. For the SQ, the ICC ranged from 0.64 to 0.79, with SEM 1.03-1.42 h/day. ICC for the MARCA ranged from 0.72 to 0.96, with SEM 0.47-1.18 h/day. The SQ showed modest correlation with AP (r = 0.13-0.33), with mean biases of about -3.5 h/day. The MARCA showed moderate correlation with AP (r = 0.49-0.67), with mean biases of about 1.4 h/day. When categorised into tertiles, agreement was significant but fair for the SQ, and moderate for the MARCA. Both measures have acceptable reliability, but the MARCA provides more valid estimates of SB than the SQ, which underestimates SB in this group of older adults.


Comparing years of healthy life, measured in 16 ways, for normal weight and overweight older adults.
Introduction. The traditional definitions of overweight and obesity are not age specific, even though the relationship of weight to mortality is different for older adults. Effects of adiposity on aspects of health beside mortality have not been well investigated. Methods. We calculated the number of years of healthy life (YHL) in the 10 years after baseline, for 5,747 older adults. YHL was defined in 16 different ways. We compared Normal and Overweight persons, classified either by body mass index (BMI) or by waist circumference (WC). Findings. YHL for Normal and Overweight persons differed significantly in 25% of the comparisons, of which half favored the Overweight. Measures of physical health favored Normal weight, while measures of mental health and quality of life favored Overweight. Overweight was less favorable when defined by WC than by BMI. Obese persons usually had worse outcomes. Discussion. Overweight older adults averaged as many years of life and years of healthy life as those of Normal weight. There may be no outcome based reason to distinguish Normal from Overweight for older adults. Conclusion. The "Overweight paradox" appears to hold for nonmortality outcomes. New adiposity standards are needed for older adults, possibly different by race and sex.