Calculation of limits for significant unidirectional changes in two or more serial results of a biomarker based on a computer simulation model.
Reference change values (RCVs) were introduced more than 30 years ago and provide objective tools for assessment of the significance of differences in two consecutive results from an individual. However, in practice, more results are usually available for monitoring, and using the RCV concept on more than two results will increase the number of false-positive results. Therefore, a simple method is needed to interpret the significance of a difference when all available serial biomarker results are considered. A computer simulation model using Excel was developed. Based on 10,000 simulated data from healthy individuals, a series of up to 20 results from an individual was generated using different values for the within-subject biological variation plus the analytical variation. Each new result in this series was compared to the initial measurement result. These successive serial relative differences were computed to give limits for significant unidirectional differences with a constant cumulated maximum probability of both 95% (P < 0.05) and 99% (P < 0.01). Factors used to multiply the first result from an individual were calculated to create the limits for constant cumulated significant differences. The factors were shown to become a simple function of the number of results and the total coefficient of variation. To interpret unidirectional differences in two or more serial results of a biomarker, the limits for significances are easily calculated using the presented factors. The first result is multiplied by the appropriate factor for increase or decrease, which gives the limits for a significant difference.


Motivational interviewing in dental hygiene education: curriculum modification and evaluation.
Motivational interviewing (MI) is a person-centered, goal-directed method of communication for eliciting and strengthening intrinsic motivation for behavior change. Originally developed in the field of addiction therapy, MI has been increasing applied in the health professions with a growing body of successful outcomes for tobacco cessation and diabetic control, which can significantly impact oral health. MI has shown preliminary value for impacting oral behaviors that reduce early childhood caries, plaque, and gingival inflammation. While the training in and use of MI by oral health providers is emerging, full integration into dental and dental hygiene curricula has yet to be explored. Therefore, the purpose of this project was to evaluate the full implementation of MI in the classroom and clinic of a dental hygiene curriculum.


Surgical Management of Parotid Duct Injury Using a Feeding Tube.
The parotid duct (Stenson's duct) can be damaged during traumatic injuries and surgical interventions. Early diagnosis and treatment of a duct injury is of great importance because complications such as sialocele and salivary gland fistula may develop if the duct is not surgically repaired. We think that the feeding tube is an ideal material in the parotid duct repair because of its technical characteristics, availability, and low cost. In this article, we described the use of a feeding tube for the treatment of a parotid duct rupture in a facial stab wound laceration, as it is a low-cost and easy-to-access material readily available in every operating room.


Prenatal diagnosis of dominant and recessive dystrophic epidermolysis bullosa: application and limitations in the use of KF-1 and LH 7:2 monoclonal antibodies and immunofluorescence mapping technique.
Prenatal diagnosis is now possible for junctional and recessive dystrophic forms of epidermolysis bullosa (EB); however, there is no similar published experience for dominant dystrophic EB, although data with KF-1 monoclonal antibody suggests that both forms of dystrophic EB can be identified at least postnatally with this unique probe. We now report our experience with light microscopy, electron microscopy, immunofluorescence mapping, and KF-1 and LH 7:2 monoclonal antibodies, in both a mother with dominant dystrophic EB and her fetus at risk, and in a fetus previously shown to be affected with recessive dystrophic EB. KF-1 and LH 7:2 antigens were absent in recessive dystrophic EB fetal skin, identical to findings observed postnatally. LH 7:2 was normally expressed in a mother with dominant dystrophic EB and in her fetus at risk for this disease. In contrast, while KF-1 antigen was abnormally expressed in the affected mother, it was normally expressed in only 1/7 fetal biopsies despite the fact that this fetus was shown by light and electron microscopy and immunofluorescence mapping to be unaffected with dominant dystrophic EB. We conclude that 1) transmission electron microscopy can be used to prenatally exclude the diagnosis of dominant dystrophic EB (Cockayne-Touraine variety), 2) immunofluorescence mapping is an accurate technique for prenatal as well as postnatal diagnosis of EB, and 3) KF-1 cannot by itself be used as an accurate probe for the prenatal diagnosis of dominant dystrophic EB, due to the apparent variability in the time for the normal expression of KF-1 in fetal skin during the second trimester.


Effects of a frequent double-nucleotide basal core promoter mutation and its putative single-nucleotide precursor mutations on hepatitis B virus gene expression and replication.
The basal core promoter (BCP) of hepatitis B virus (HBV) directs the transcription of both precore RNA and core RNA which code for e antigen (HBeAg) and core antigen, respectively. A double mutation in the BCP which converts nucleotide (nt) 1762 from A to T and nt 1764 from G to A is frequently observed in patients with chronic hepatitis B. We recently demonstrated that this double mutation prevented the binding of a liver-enriched factor (LEF) to the BCP, suppressed only precore RNA transcription (and hence HBeAg expression), and enhanced progeny virus production. In order to understand the mechanism for the selection of this frequent double mutation, we have extended our previous studies to further characterize LEF and to compare the effects of this double-nucleotide mutation (M1) with each single-nucleotide mutation at nt 1762 (M2) and nt 1764 (M3). Our results indicate that LEF is likely composed of a heterodimer formed between the transcription factor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and an unidentified liver-enriched factor. Further studies reveal that both M1 and M2 prevent the binding of LEF to the BCP, suppress only precore RNA transcription, and increase the efficiency of progeny virus synthesis. In contrast, M3 retains some LEF binding activity, does not suppress HBV RNA transcription, and reduces slightly the efficiency of virus progeny synthesis. The reduced ability of M3 to replicate indicates that it has no selection advantage in itself at the level of the infected hepatocyte. In spite of its enhanced replication rate, M2 is rarely detected in HBV patients. This indicates the involvement of factors other than intracellular replication rates in the selection of these virus variants in the infected individual.


Genome sequence of Microbacterium foliorum bacteriophage DumpQuist isolated from soil in Clarksville, Tennessee.
Bacteriophage DumpQuist was isolated from soil collected in Clarksville, TN, using the bacterium Microbacterium foliorum. Electron microscopy revealed that DumpQuist has a podovirus morphology. DumpQuist has a 53,924-bp genome that contains 54 predicted protein-coding genes and is most similar to phages in actinobacteriophage cluster EK1.


Acute neuropathic pain: diagnosis and treatment.
Acute neuropathic pain (ANP) is a condition that is under-recognized, often difficult to treat and one that may progress to persistent pain and disability. This review examines the diagnosis and treatment in order to assist clinicians in providing better care to patients with this debilitating pain. The recent development of psychometric scales for the detection of neuropathic pain may assist in diagnosing ANP, though this is yet to be tested. Specific research into the treatment of ANP is sparse. However, several recent trials have shown that both tramadol and gabapentin are useful in mitigating neuropathic cancer pain. In addition, a recent trial suggests a combination of neural blockade with memantine may be useful in reducing ANP. The diagnosis of ANP is assisted by knowledge of the medical circumstances that have a higher risk of the condition developing, a detailed pain history with a directed examination and use of neuropathic pain scales. Although the data are lacking, agents that have demonstrated efficacy in persistent neuropathic pain states should be used in ANP. Refractory ANP could be treated with either intravenous lidocaine or calcitonin. Future research should be directed at validating a scale of neuropathic pain in ANP and conducting more therapeutic trials.


Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia.
In KMT2A-rearranged acute lymphoblastic leukemia (ALL), an aggressive malignancy, oncogenic KMT2A-fusion proteins inappropriately recruit DOT1L to promote leukemogenesis, highlighting DOT1L as an attractive therapeutic target. Unfortunately, treatment with the first-in-class DOT1L inhibitor pinometostat eventually leads to non-responsiveness. To understand this we established acquired pinometostat resistance in pediatric KMT2A::AFF1+ B-ALL cells. Interestingly, these cells became mostly independent of DOT1L-mediated H3K79 methylation, but still relied on the physical presence of DOT1L, HOXA9 and the KMT2A::AFF1 fusion. Moreover, these cells selectively lost the epigenetic regulation and expression of various KMT2A-fusion target genes such as PROM1/CD133, while other KMT2A::AFF1 target genes, including HOXA9 and CDK6 remained unaffected. Concomitantly, these pinometostat-resistant cells showed upregulation of several myeloid-associated genes, including CD33 and LILRB4/CD85k. Taken together, this model comprehensively shows the adaptive potential of KMT2A-rearranged ALL cells upon losing dependency on one of its main oncogenic properties.


The effect of recombinant human erythropoietin therapy on red cell expansion during autologous blood donation.
As the result of the institution of coordinated programs involving regional blood centers, hospital blood banks, information services, and physicians, preoperative autologous blood donation, a previously underutilized practice, has become a standard of care in a number of elective surgical procedures. In addition, the administration of recombinant human erythropoietin has been shown to facilitate the collection of autologous blood from patients scheduled for elective orthopaedic surgery. An analysis of the findings in a study of 263 orthopaedic surgical patients in which the relationship between autologous blood ordering, collection and storage, and subsequent blood transfusion was studied indicates that both blood ordering and blood procurement practices are significant factors with regard to allogeneic blood exposure.


Indexing powder patterns in physical form screening: instrumentation and data quality.
Two multisample laboratory powder diffractometers have been evaluated for the purpose of pattern indexing in the context of physical form screening. Both diffractometers utilise foil transmission geometry, primary monochromated radiation, and a position-sensitive detector. Data collected from six compounds (sotalol hydrochloride, hydroflumethiazide, verapamil hydrochloride, captopril, clomipramine hydrochloride, and famotidine) showed good angular resolution (FWHM as small as ca. 0.06 degrees ) and lattice parameters were easily obtained using the indexing program DICVOL-91. The extent of preferred orientation in each pattern was estimated using the DASH implementation of the March-Dollase function and is most evident with clomipramine hydrochloride and famotidine. Otherwise, the data compare favorably with reference capillary data sets. In conclusion, where there is a requirement to analyze 20-30 samples per day, with an emphasis on obtaining the high-quality data that are important in pattern recognition and imperative in indexing, the combination of foil transmission geometry, primary monochromated radiation, plus a position-sensitive detector is highly effective. The data also afford opportunities for crystal structure determination.


Epitaxial Single-Layer MoS2 on GaN with Enhanced Valley Helicity.
Engineering the substrate of 2D transition metal dichalcogenides can couple the quasiparticle interaction between the 2D material and substrate, providing an additional route to realize conceptual quantum phenomena and novel device functionalities, such as realization of a 12-time increased valley spitting in single-layer WSe2 through the interfacial magnetic exchange field from a ferromagnetic EuS substrate, and band-to-band tunnel field-effect transistors with a subthreshold swing below 60 mV dec-1 at room temperature based on bilayer n-MoS2 and heavily doped p-germanium, etc. Here, it is demonstrated that epitaxially grown single-layer MoS2 on a lattice-matched GaN substrate, possessing a type-I band alignment, exhibits strong substrate-induced interactions. The phonons in GaN quickly dissipate the energy of photogenerated carriers through electron-phonon interaction, resulting in a short exciton lifetime in the MoS2 /GaN heterostructure. This interaction enables an enhanced valley helicity at room temperature (0.33 ± 0.05) observed in both steady-state and time-resolved circularly polarized photoluminescence measurements. The findings highlight the importance of substrate engineering for modulating the intrinsic valley carriers in ultrathin 2D materials and potentially open new paths for valleytronics and valley-optoelectronic device applications.


Selective retention of essential fatty acids: the role of hepatic monoacylglycerol acyltransferase.
In the suckling rat, chick embryo, and hibernating marmot, fatty acids provide the major source of energy, and despite the high rate of hepatic beta-oxidation, these animals selectively retain long-chain polyunsaturated derivatives of C18:2n-6 and C18:3n-3. To determine whether the hepatic microsomal activity monoacylglycerol acyltransferase (MGAT) (EC 18.104.22.168) could provide a mechanism to selectively acylate monoacylglycerols that contain essential fatty acids, we tested the ability of MGAT activity from each of the three species to acylate sn-2-monoC18:1-, sn-2-monoC18:2-, sn-2-monoC18:3-, and sn-2-monoC20:4-glycerols. Hepatic MGAT activity acylated sn-2-monoC18:3-glycerol and sn-2-monoC18:2-glycerol in preference to sn-2-monoC18:1-glycerol in each of the three different lipolytic animals. MGAT's acyl group specificity could not be explained by invoking differences in membrane fluidity because the apparent affinity for sn-2-monoC20:4-glycerol was not increased. Further, sn-2-monoC18:3-glycerol remained a preferred substrate under assay conditions when both the C18:3 and C18:1 species were present in equal amounts. As would be predicted in the presence of high activity of a selective MGAT, the hepatic glycerolipids from neonatal rats showed increases in dienoic, trienoic, and C22:6 fatty acids and relative decreases in monoenoic, saturated, and C20:4 fatty acids. We hypothesize that, during lipolysis, the reacylation of sn-2-monoacylglycerols by MGAT may provide a mechanism by which essential fatty acids are retained within specific tissues.


[The mechanisms of action of extracorporeal helium-neon laser irradiation in acute exogenous poisonings].
Extracorporeal exposure to LG-79 He-Ne laser of 12 mWt power was used in 57 patients hospitalized at the intoxication reanimation department with acute poisonings with psychotropic drugs. The clinical result was a decrease of the incidence of pneumonia in the patients with x-ray signs of venous congestion from 52% among those administered to physiochemotherapy to 24% after this treatment modality. Laser hemotherapy brought about a temporary normalization of the erythrocyte membrane permeability, which was changed biophysically by means of a diffractometer. Red cell aggregation was approximating the norm, decreasing by 20%, and platelet aggregation decreased by 17%. Analysis of the results brought as to a conclusion that He-Ne laser exposure is an effective source of singlet stimulation of molecular O2 evenly dissolved in the blood, which causes resonance oscillations of water difields. This leads to membrane depolarization, which is probably responsible for purification of polarized membranes from toxic agents fixed by them.


[Quality of life of the elderly in the community: application of the Flanagan scale].
The aim of this study was to evaluate the satisfaction degree of the elderly people regarding their quality of life. Data were obtained by a questionnaire characterizing the sample with a scale of quality proposed by Flanagan, using the interview technique. Among 128 elderly people, authors verified a insufficient degree of satisfaction. The dimensions of the quality of life pointed out by the Flanagan's scale were: personal development and fulfillment; family relations; social participation; welfare and material support; learning and friendship. The authors concluded that the Flanagan's scale presents limitations as a result of the subjectivity of the concept of quality.


Emerging antibiotic resistance in Salmonella typhimurium in Norway.
The antimicrobial resistance of 809 Salmonella Typhimurium isolates collected from humans in Norway between 1975 and 1998 was studied. The material was subdivided into domestic and foreign isolates according to whether the patient had recently travelled abroad or not. In imported isolates the largest increase in resistance was in 1996 when 35% of the isolates were multi-resistant. The first multi-resistant isolate acquired in Norway appeared in 1994, but already in 1998 23% of the isolates domestically acquired were multi-resistant, and a majority were S. Typhimurium DT104. We found no ciprofloxacin resistance in domestically acquired isolates. Amplified fragment length polymorphism analysis was performed on selected multi-resistant isolates. The method discriminated well between different multi-resistant isolates, but not between DT104 isolates. Resistant and multi-resistant S. Typhimurium were until 1998 essentially recovered from patients who had travelled abroad, but multi-resistant isolates, mainly DT104, are now also being transmitted within the country.


Cryopreservation of human cadaver corneas regenerated at 31 degrees C in a modified tissue culture medium.
Human corneas were obtained 2-82 h post mortem, cultured for 20-28 h, in a modified tissue culture medium, frozen at a controlled rate, and thawed rapidly. The thawed corneas were subjected to 20-28 h of additional culture. Immediately after thawing, a mean endothelial cell damage of 11% was indicated by trypane blue staining. The mean endothelial cell loss during the subsequent culture was 34%. This cell loss was not related to post mortem time, to donor age, to cell loss during the primary culture, or to endothelial cell density.


Does anterolateral ligament internal bracing improve the outcomes of anterior cruciate ligament reconstruction in patients with generalized joint hypermobility?
Generalized joint hypermobility (GJH) is a risk factor for anterior cruciate ligament (ACL) injury and ACL graft failure and is considered an indication for anterolateral ligament (ALL) reconstruction. The aim of this retrospective study was to compare functional outcomes, rupture rates, and residual instability in patients with GJH undergoing isolated ACL reconstruction or combined ACL reconstruction and ALL augmentation with internal bracing (ALL-IB). Sixty-eight patients with GJH and unilateral ACL injury were randomly assigned to undergo either isolated ACL reconstruction (Group 1) or combined ACL reconstruction and ALL-IB (Group 2). The patients were evaluated pre- and postoperatively; their medical histories; physical examination results; anterior knee translation, as measured using the KT-1000 arthrometer; and scores of validated knee assessments were recorded. Groups 1 and 2 consisted of 37 and 31 patients, respectively. The mean follow-up was 30.1±4.1 and 28.1±2.9 months, respectively. In the final evaluation, the patients in Group 2 showed better rotational stability, as evaluated by the pivot-shift test (p=0.013); better anteroposterior stability, as evaluated by KT-1000 arthrometry (p=0.001); similar function (p=0.14 for the Lysholm, p=0.11 for the Cincinnati, and p=0.19 for the International Knee Documentation Committee subjective score); and failure rate (p=0.41). The functional outcomes were similar between the groups. The stability outcomes after combined ACL and ALL-IB were better than those after isolated ACL reconstruction in patients with GJH. However, the technique and its results need to be validated in larger patient series and prospective randomized controlled trials.


p53 mutations in mammary ductal carcinoma in situ but not in epithelial hyperplasias.
The development and progression of human breast neoplasia is characterized by the accumulation of numerous somatic genetic alterations. Although mutation of the p53 tumor suppressor gene is one of the most common alterations identified in invasive carcinomas, it is not clear whether mutations usually occur in noninvasive lesions before the development of invasion. To investigate the presence and heterogeneity of p53 mutations in breast neoplasia, we studied a morphological spectrum of paired lesions including invasive carcinomas and adjacent noninvasive epithelial lesions. Using 18 invasive ductal carcinomas with known p53 mutations, tissue samples were microdissected from formalin-fixed, paraffin-embedded tissue sections, and mutations in exons 4-8 of the p53 gene were identified by PCR amplification, single-strand conformational polymorphism, and direct sequencing. Multiple geographically distinct foci of invasive carcinoma were microdissected from six different invasive carcinomas, and all samples from each case had the same mutation. The absence of mutation heterogeneity provides evidence that p53 mutations occurred at the time of, or before, the clonal selection of the dominant component of the invasive carcinoma. To delineate the timing of p53 inactivation further in these cases, histological slides were reviewed to identify all noninvasive epithelial lesions. There were eight cases with associated ductal carcinoma in situ (DCIS), and in total, 27 distinct tissue samples representing a spectrum of histological subtypes and grades of DCIS were microdissected. In all 27 samples, the identical p53 mutation was identified in the DCIS as was present in the invasive carcinoma. In contrast, no p53 mutations were identified in any of the 21 microdissected foci of epithelial hyperplasia analyzed, including one sample with atypia. Together, these findings provide support that p53 mutations commonly occur early in breast neoplasia, usually at the stage of DCIS, but are not often identified in foci of hyperplasia. These findings support an important biological role for p53 mutation in progression from noninvasive precursors in breast neoplasia and provide further evidence that p53 mutation could have potential use as a molecular marker.


3-D scalable medical image compression with optimized volume of interest coding.
We present a novel 3-D scalable compression method for medical images with optimized volume of interest (VOI) coding. The method is presented within the framework of interactive telemedicine applications, where different remote clients may access the compressed 3-D medical imaging data stored on a central server and request the transmission of different VOIs from an initial lossy to a final lossless representation. The method employs the 3-D integer wavelet transform and a modified EBCOT with 3-D contexts to create a scalable bit-stream. Optimized VOI coding is attained by an optimization technique that reorders the output bit-stream after encoding, so that those bits belonging to a VOI are decoded at the highest quality possible at any bit-rate, while allowing for the decoding of background information with peripherally increasing quality around the VOI. The bit-stream reordering procedure is based on a weighting model that incorporates the position of the VOI and the mean energy of the wavelet coefficients. The background information with peripherally increasing quality around the VOI allows for placement of the VOI into the context of the 3-D image. Performance evaluations based on real 3-D medical imaging data showed that the proposed method achieves a higher reconstruction quality, in terms of the peak signal-to-noise ratio, than that achieved by 3D-JPEG2000 with VOI coding, when using the MAXSHIFT and general scaling-based methods.


Scale-up of microdroplet reactions by heated ultrasonic nebulization.
Dramatically higher rates for a variety of chemical reactions have been reported in microdroplets compared with those in the liquid bulk phase. However, the scale-up of microdroplet chemical synthesis has remained a major challenge to the practical application of microdroplet chemistry. Heated ultrasonic nebulization (HUN) was found as a new way for scaling up chemical synthesis in microdroplets. Four reactions were examined, a base-catalyzed Claisen-Schmidt condensation, an oximation reaction from a ketone, a two-phase oxidation reaction without the use of a phase-transfer-catalyst, and an Eschenmoser coupling reaction. These reactions show acceleration of one to three orders of magnitude (122, 23, 6536, and 62) in HUN microdroplets compared to the same reactions in bulk solution. Then, using the present method, the scale-up of the reactions was achieved at an isolated rate of 19 mg min-1 for the product of the Claisen-Schmidt condensation, 21 mg min-1 for the synthesis of benzophenone oxime from benzophenone, 31 mg min-1 for the synthesis of 4-methoxybenzaldehyde from 4-methoxybenzyl alcohol, and 40 mg min-1 for the enaminone product of the Eschenmoser coupling reaction.


Control of attention shifts between vision and audition in human cortex.
Selective attention contributes to perceptual efficiency by modulating cortical activity according to task demands. Visual attention is controlled by activity in posterior parietal and superior frontal cortices, but little is known about the neural basis of attentional control within and between other sensory modalities. We examined human brain activity during attention shifts between vision and audition. Attention shifts from vision to audition caused increased activity in auditory cortex and decreased activity in visual cortex and vice versa, reflecting the effects of attention on sensory representations. Posterior parietal and superior prefrontal cortices exhibited transient increases in activity that were time locked to the initiation of voluntary attention shifts between vision and audition. These findings reveal that the attentional control functions of posterior parietal and superior prefrontal cortices are not limited to the visual domain but also include the control of crossmodal shifts of attention.


Study of the uncertainty in estimation of the exposure of non-human biota to ionising radiation.
Uncertainty in estimations of the exposure of non-human biota to ionising radiation may arise from a number of sources including values of the model parameters, empirical data, measurement errors and biases in the sampling. The significance of the overall uncertainty of an exposure assessment will depend on how the estimated dose compares with reference doses used for risk characterisation. In this paper, we present the results of a study of the uncertainty in estimation of the exposure of non-human biota using some of the models and parameters recommended in the FASSET methodology. The study was carried out for semi-natural terrestrial, agricultural and marine ecosystems, and for four radionuclides (137Cs, 239Pu, 129I and 237Np). The parameters of the radionuclide transfer models showed the highest sensitivity and contributed the most to the uncertainty in the predictions of doses to biota. The most important ones were related to the bioavailability and mobility of radionuclides in the environment, for example soil-to-plant transfer factors, the bioaccumulation factors for marine biota and the gut uptake fraction for terrestrial mammals. In contrast, the dose conversion coefficients showed low sensitivity and contributed little to the overall uncertainty. Radiobiological effectiveness contributed to the overall uncertainty of the dose estimations for alpha emitters although to a lesser degree than a number of transfer model parameters.


Modelling acute and lasting effects of tDCS on epileptic activity.
Transcranial Direct brain stimulation (tDCS) is commonly used in order to modulate cortical networks activity during physiological processes through the application of weak electrical fields with scalp electrodes. Cathodal stimulation has been shown to decrease brain excitability in the context of epilepsy, with variable success. However, the cellular mechanisms responsible for the acute and the long-lasting effect of tDCS remain elusive. Using a novel approach of computational modeling that combines detailed but functionally integrated neurons we built a physiologically-based thalamocortical column. This model comprises 10,000 individual neurons made of pyramidal cells, and 3 types of gamma-aminobutyric acid (GABA) -ergic cells (VIP, PV, and SST) respecting the anatomy, layers, projection, connectivity and neurites orientation. Simulating realistic electric fields in term of intensity, main results showed that 1) tDCS effects are best explained by modulation of the presynaptic probability of release 2) tDCS affects the dynamic of cortical network only if a sufficient number of neurons are modulated 3)VIP GABAergic interneurons of the superficial layer of the cortex are especially affected by tDCS 4) Long lasting effect depends on glutamatergic synaptic plasticity.


Functional analysis of the glucocorticoid regulatory elements present in the mouse mammary tumor virus long terminal repeat. A synthetic distal binding site can replace the proximal binding domain.
Transcription of mouse mammary tumor virus DNA is stimulated by steroid hormones. The DNA sequences involved in this regulation are located in the viral long terminal repeat between positions -200 and -50 with respect to the transcription initiation site. In this region four, one distal and three proximal, in vitro binding sites for the glucocorticoid hormone-receptor complexes have been identified. We have prepared a series of 5' and 3' deletions of this region, using the exonuclease ExoIII. Combination of suitable 5' and 3' fragments enabled us to reconstitute the entire long terminal repeat with small internal deletions. The mutated long terminal repeats linked to the coding region of the Herpes simplex virus thymidine kinase gene were introduced into LTK- aprt- cells by transfection. Transcription from the mouse mammary tumor virus promoter in the presence or absence of hormone was assayed by nuclease S1 mapping. Deletion of the proximal in vitro binding sites resulted in a decrease in hormonal inducibility. When a synthetic oligonucleotide harboring the sequence of the distal in vitro binding site was inserted at the site of the proximal ones, hormone response was restored. This indicated that the distal binding site can replace the proximal ones in their hormone-regulatory function. However, insertion at the same site of an oligonucleotide containing the sequence 5' TGTTCT 3' found in all four binding sites, did not restore the hormone response, indicating that sequences flanking the TGTTCT motif are required for hormone response. Insertion of an unrelated DNA fragment at the site of the proximal binding element deletion completely abolished the hormone response. Analyses of different proximal binding-site deletion and insertion mutants suggested the presence of a transcriptional element located downstream from the most proximal hormone-receptor binding site.


Parallel analyses of Alexandrium catenella cell concentrations and shellfish toxicity in the Puget Sound.
Alexandrium catenella is widespread in western North America and produces a suite of potent neurotoxins that cause paralytic shellfish poisoning (PSP) in humans and have deleterious impacts on public health and economic resources. There are seasonal PSP-related closures of recreational and commercial shellfisheries in the Puget Sound, but the factors that influence cell distribution, abundance, and relationship to paralytic shellfish toxins (PSTs) in this system are poorly described. Here, a quantitative PCR assay was used to detect A. catenella cells in parallel with state shellfish toxicity testing during the 2006 bloom season at 41 sites from April through October. Over 500,000 A. catenella cells liter(-1) were detected at several stations, with two main pulses of cells driving cell distribution, one in June and the other in August. PSTs over the closure limit of 80 mug of PST 100 per g of shellfish tissue were detected at 26 of the 41 sites. Comparison of cell numbers and PST data shows that shellfish toxicity is preceded by an increase in A. catenella cells in 71% of cases. However, cells were also observed in the absence of PSTs in shellfish, highlighting the complex relationship between A. catenella and the resulting shellfish toxicity. These data provide important information on the dynamics of A. catenella cells in the Puget Sound and are a first step toward assessing the utility of plankton monitoring to augment shellfish toxicity testing in this system.


Quality improvement in clinical teaching through student evaluations of rotations and feedback to departments.
Clinical teaching at medical schools needs continual improvement. We used a new evaluation instrument to gather student ratings on a departmental level across all clinical rotations. The ratings were used to enable cross comparison of departmental clinical teaching quality, official ranking and feedback as a method to improve teaching quality. This study was designed to evaluate whether these interventions increased the quality of clinical teaching. A web-based questionnaire consisting of 10 questions (Likert scale 1-6) was introduced into all hospital departments at Uppsala University Hospital, Sweden. Specific feedback was given to participating departments based on the assessments collected. Action plans were created in order to address areas for departmental improvement. Questionnaire scores were used as a measure of clinical teaching quality. Mean follow-up time was 2.5 semesters. The student response rate was 70% (n = 1981). The departments' median ratings (25th-75th percentile) for the baseline were 4.05 (3.80-4.30). At follow-up, the median rating had increased to 4.56 (4.29-4.72) (p < 0.001). The introduction of a uniform clinical teaching evaluation instrument enabled cross comparison between clinical departments. Specific feedback enabled the development of action plans in the departments. This caused a rapid and substantial increase in the quality of clinical teaching.


Has COVID19 derailed Bhutan's national malaria elimination goal? A commentary.
The COVID-19 pandemic has resulted in massive global disruptions with considerable impact on the delivery of health services and national health programmes. Since the detection of the first COVID-19 case on 5th March 2020, the Royal Government of Bhutan implemented a number of containment measures including border closure and national lockdowns. Against the backdrop of this global COVID-19 pandemic response, there was a sudden surge of locally-transmitted malaria cases between June to August 2020. There were 20 indigenous cases (zero Plasmodium falciparum and 20 Plasmodium vivax) from a total of 49 cases (seven P. falciparum and 42 P. vivax) in 2020 compared to just two from a total of 42 in 2019. Over 80% of the cases were clustered in malaria endemic district of Sarpang. This spike of malaria cases was attributed to the delay in the delivery of routine malaria preventive interventions due to the COVID-19 pandemic. As a result, Bhutan is unlikely to achieve the national goal of malaria elimination by 2020.


Factors influencing malnutrition in children waiting for liver transplants.
Nutrition deficiencies are common in children with chronic liver disease. To determine whether age, hepatic dysfunction, or energy intake influences this malnutrition, we evaluated the nutritional status of 49 children aged 2.5 mo to 13 y (mean: 35 mo; median: 12 mo). The children were divided into two groups according to age: group 1-29 patients aged < or = 1 y (mean: 7 mo; median: 7 mo); and group 2-20 patients > 1 y (mean: 75 mo; median: 59 mo). Hepatic dysfunction was defined according to the Malatack criteria. Seventy-two-hour dietary intakes were recorded by a nutritionist. Nutritional status was assessed by anthropometric measures when the patients were enrolled on the waiting list for liver transplants. We evaluated the following indexes: weight, height, fat body mass, and lean body mass on the basis of height-age (age at which height reached 50th Italian height percentile). Mean height Z scores were low in both groups, but the difference was not significant. Mean weight Z scores and mean percentages of fat body mass were significantly lower (P < 0.001) in group 1 than in group 2 patients. In group 2, lean body mass and fat body mass were significantly lower (P < 0.05) in patients with moderate-to-severe hepatic failure than in patients with mild hepatic dysfunction. The mean energy intake was in the range of the recommended daily allowances for age but was insufficient for both groups of patients. The evidence of significant acute and chronic malnutrition confirmed the need for nutritional support, especially for younger and older children with moderate-to-severe hepatic dysfunction. We emphasize the necessity of accurate assessment of nutritional status by simple anthropometric measurements to be sure of the effects and adequacy of the nutritional intervention.


Effect of numbering of return envelopes on participation, explicit refusals, and bias: experiment and meta-analysis.
Tracing mail survey responses is useful for the management of reminders but may cause concerns about anonymity among prospective participants. We examined the impact of numbering return envelopes on the participation and the results of a survey on a sensitive topic among hospital staff. In a survey about regrets associated with providing healthcare conducted among hospital-based doctors and nurses, two randomly drawn subsamples were provided numbered (N = 1100) and non-numbered (N = 500) envelopes for the return of completed questionnaires. Participation, explicit refusals, and item responses were compared. We also conducted a meta-analysis of the effect of questionnaire/envelope numbering on participation in health surveys. The participation rate was lower in the "numbered" group than in the "non-numbered" group (30.3% vs. 35.0%, p = 0.073), the proportion of explicit refusals was higher in the "numbered" group (23.1% vs 17.5%, p = 0.016), and the proportion of those who never returned the questionnaire was similar (46.6% vs 47.5%, p = 0.78). The means of responses differed significantly for 12 of 105 items (11.4%), which did not differ significantly from the expected frequency of type 1 errors, i.e., 5% (permutation test, p = 0.078). The meta-analysis of 7 experimental surveys (including this one) indicated that numbering is associated with a 2.4% decrease in the survey response rate (95% confidence interval 0.3% to 4.4%). Numbered return envelopes may reduce the response rate and increase explicit refusals to participate in a sensitive survey. Reduced participation was confirmed by a meta-analysis of randomized health surveys. There was no strong evidence of bias.


Reliability of GFR formulas based on serum creatinine, with special reference to the MDRD Study equation.
Estimation of glomerular filtration rate (GFR) is central to the diagnosis, evaluation and management of chronic kidney disease (CKD). This review summarizes data on the performance of equations using serum creatinine to estimate GFR, particularly the Modification of Diet in Renal Disease (MDRD) Study equation. The size of studies evaluating GFR estimation equations and their level of sophistication in estimating bias, precision, validity and sensitivity to the source population have improved over the past decade. We update our review from 2006, which included 7 studies with over 500 individuals and 12 studies with 50-499 individuals with measured GFR evaluating the MDRD Study and Cockcroft-Gault equations. More recent studies include an individual level pooling analysis of 5504 participants in 10 studies which showed that creatinine calibration to reference methods improved the performance of the MDRD Study equation but increased bias for the Cockcroft-Gault equation. The MDRD Study equation had a bias of 3.0 %, interquartile range of 29.0 % and percentage of estimates within 30 % of the measured GFR value (P(30)) of 82 % for estimates below 60 mL/(min x 1.73 m(2)). Above this value, the bias was greater (8.7 %) and estimates are less useful since 30 % error is a large absolute error in GFR. Results vary across studies but are generally similar with disappointing performance in the high GFR range, which is of particular interest in early diabetic nephropathy. New equations using serum creatinine can reduce the bias present in the high GFR range but are unlikely to dramatically improve precision, suggesting a need for additional markers. Finally, algorithms are needed to tailor clinical practice based on data from GFR estimates and other participant characteristics, including the source population and level of proteinuria.


Preventive Effect of Arctium lappa Polysaccharides on Acute Lung Injury through Anti-Inflammatory and Antioxidant Activities.
The objective of this study was to investigate the preventive effects of polysaccharides extracted from the roots of Arctium lappa (ALP) against acute lung injury (ALI) models induced by lipopolysaccharide (LPS). The polysaccharides were extracted and characterized, and their anti-inflammatory and antioxidant capacities were assessed. The findings demonstrated that ALP could mitigate the infiltration of inflammatory cells and reduce alveolar collapse in LPS-induced ALI in mice. The expression levels of the pro-inflammatory factor TNF-α decreased, while the anti-inflammatory factor IL-10 increased. Furthermore, the administration of ALP improved the activities of lung antioxidant enzymes, including SOD, GSH, and CAT, and lowered MDA levels. These results suggest that ALP exhibits a preventive effect on ALI and has potential as an alternative treatment for lung injury.


Evaluation of Changes in the Motor Network Following BCI Therapy Based on Graph Theory Analysis.
Despite the established effectiveness of the brain-computer interface (BCI) therapy during stroke rehabilitation (Song et al., 2014a, 2015; Young et al., 2014a,b,c, 2015; Remsik et al., 2016), little is understood about the connections between motor network reorganization and functional motor improvements. The aim of this study was to investigate changes in the network reorganization of the motor cortex during BCI therapy. Graph theoretical approaches are used on resting-state functional magnetic resonance imaging (fMRI) data acquired from stroke patients to evaluate these changes. Correlations between changes in graph measurements and behavioral measurements were also examined. Right hemisphere chronic stroke patients (average time from stroke onset = 38.23 months, standard deviation (SD) = 46.27 months, n = 13, 6 males, 10 right-handed) with upper-extremity motor deficits received interventional rehabilitation therapy using a closed-loop neurofeedback BCI device. Eyes-closed resting-state fMRI (rs-fMRI) scans, along with T-1 weighted anatomical scans on 3.0T MRI scanners were collected from these patients at four test points. Immediate therapeutic effects were investigated by comparing pre and post-therapy results. Results displayed that th average clustering coefficient of the motor network increased significantly from pre to post-therapy. Furthermore, increased regional centrality of ipsilesional primary motor area (p = 0.02) and decreases in regional centrality of contralesional thalamus (p = 0.05), basal ganglia (p = 0.05 in betweenness centrality analysis and p = 0.03 for degree centrality), and dentate nucleus (p = 0.03) were observed (uncorrected). These findings suggest an overall trend toward significance in terms of involvement of these regions. Increased centrality of primary motor area may indicate increased efficiency within its interactive network as an effect of BCI therapy. Notably, changes in centrality of the bilateral cerebellum regions have strong correlations with both clinical variables [the Action Research Arm Test (ARAT), and the Nine-Hole Peg Test (9-HPT)].


Inositol 1,4,5-trisphosphate receptors are downregulated in mouse oocytes in response to sperm or adenophostin A but not to increases in intracellular Ca(2+) or egg activation.
Fertilization in mammals stimulates a series of Ca(2+) oscillations that continue for 3-4 h. Cell-cycle-dependent changes in the ability to release Ca(2+) are one mechanism that leads to the inhibition of Ca(2+) transients after fertilization. The downregulation of InsP(3)Rs at fertilization may be an additional mechanism for inhibiting Ca(2+) transients. In the present study we examine the mechanism of this InsP(3)R downregulation. We find that neither egg activation nor Ca(2+) transients are necessary or sufficient for the stimulation of InsP(3)R downregulation. First, parthenogenetic activation fails to stimulate downregulation. Second, downregulation persists when fertilization-induced Ca(2+) transients and egg activation are inhibited using BAPTA. Third, downregulation can be induced in immature oocytes that do not undergo egg activation. Other than fertilization, the only stimulus that downregulated InsP(3)Rs was microinjection of the potent InsP(3)R agonist adenophostin A. InsP(3)R downregulation was inhibited by the cysteine protease inhibitor ALLN but MG132 and lactacystin were not effective. Finally, we have injected maturing oocytes with adenophostin A and produced MII eggs depleted of InsP(3)Rs. We show that sperm-induced Ca(2+) signaling is inhibited in such InsP(3)R-depleted eggs. These data show that InsP(3)R binding is sufficient for downregulation and that Ca(2+) signaling at fertilization is mediated via the InsP(3)R.


Student's Corner.
An undergraduate student at Rensselaer Polytechnic Institute has learned very quickly that a spoonful of sugar really does help the medicine go down. In fact, with his invention, the sugar may actually be the medicine!


Hepatic sinusoidal obstruction syndrome in patients undergoing hematopoietic stem cell transplant.
To provide a comprehensive review of hepatic sinusoidal obstruction syndrome (HSOS) in patients receiving a hematopoietic stem cell transplant and to describe the implications for nursing care. Published research articles, reviews, case reports, and books. Disagreement exists regarding the precise cause of HSOS. Prevention and treatment strategies have emerged based on these causative theories. Few published resources are available for nursing assessment and intervention specific to HSOS, although symptom management strategies derived from other disease etiologies can be used successfully. HSOS is a complex consequence of myeloablative chemoradiotherapy. Although the overall incidence is declining, research continues to explore better methods for prophylaxis and develop more efficacious treatment options. Nurses caring for patients receiving a hematopoietic stem cell transplant must comprehend the proposed etiologies for HSOS and be familiar with the manifestations of the syndrome. Symptom management requires a thorough understanding of affected organ systems.


Oral therapy for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: a revolution in progress.
Patients with myeloid neoplasms such as myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) are generally older, and many are not eligible for curative intent intensive therapies and/or allogeneic hematopoietic stem cell transplantation. While lower intensity, hypomethylating agent (HMA)-based therapies such as azacitidine+venetoclax have improved patient outcomes significantly, responses are not durable, and most patients die from disease-related complications. The approvals of oral HMAs such as cedazuridine-decitabine (C-DEC) and oral azacitidine (CC-486) have kindled the hope that myeloid malignancies may soon be treated with total oral therapy. We review all-oral therapies including the approvals of C-DEC and CC-486 in MDS and AML, respectively, in addition to emerging all-oral therapies, both monotherapy and combination, in higher-risk (HR) MDS and AML. Oral HMAs have the potential to be a convenient and efficacy-equivalent treatment option for patients with HR-MDS or AML and improve their quality of life by reducing clinic visits for medication administration. Total-oral therapy combinations, largely including an oral HMA 'backbone,' are in the early phases of clinical development, and it is our hope that well-designed trials employing these agents may soon allow the identification of optimal regimens that deliver effective disease-directed therapy with good tolerability.


Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease.
Semaphorin 7a regulates transforming growth factor β1 (TGFβ1)-induced fibrosis. This study was undertaken to test the hypothesis that semaphorin 7a exerts its profibrotic effects in part by promoting the tissue accumulation of CD45+ fibrocytes. A murine model of pulmonary fibrosis in which an inducible, bioactive form of the human TGFβ1 gene is overexpressed in the lung was used. Fibrosis and fibrocytes were evaluated in TGFβ1-transgenic mice in which the semaphorin 7a locus had been disrupted. The effect of replacement or deletion of semaphorin 7a on bone marrow-derived cells was ascertained using bone marrow transplantation. The role of the semaphorin 7a receptor β1 integrin was assessed using neutralizing antibodies. The applicability of these findings to TGFβ1-driven fibrosis in humans was examined in patients with scleroderma-related interstitial lung disease (ILD). The appearance of fibrocytes in the lungs of TGFβ1-transgenic mice required semaphorin 7a. Replacement of semaphorin 7a on bone marrow-derived cells restored lung fibrosis and fibrocytes. Immunoneutralization of β1 integrin reduced pulmonary fibrocytes and fibrosis. Peripheral blood mononuclear cells (PBMCs) from patients with scleroderma-related ILD showed increased levels of messenger RNA for semaphorin 7a and its receptors, with semaphorin 7a located on collagen-producing fibrocytes and CD19+ lymphocytes. Peripheral blood fibrocyte outgrowth was enhanced in these patients. Stimulation of normal human PBMCs with recombinant semaphorin 7a enhanced fibrocyte differentiation; these effects were attenuated by β1 integrin neutralization. Our findings indicate that interventions that reduce semaphorin 7a expression or prevent the semaphorin 7a-β1 integrin interaction may ameliorate TGFβ1-driven or fibrocyte-associated autoimmune fibroses.


Evidence for the Misfolding of the A1 Domain within Multimeric von Willebrand Factor in Type 2 von Willebrand Disease.
Von Willebrand factor (VWF), an exceptionally large multimeric plasma glycoprotein, functions to initiate coagulation by agglutinating platelets in the blood stream to sites of vascular injury. This primary hemostatic function is perturbed in type 2 dysfunctional subtypes of von Willebrand disease (VWD) by mutations that alter the structure and function of the platelet GPIbα adhesive VWF A1 domains. The resulting amino acid substitutions cause local disorder and misfold the native structure of the isolated platelet GPIbα-adhesive A1 domain of VWF in both gain-of-function (type 2B) and loss-of-function (type 2M) phenotypes. These structural effects have not been explicitly observed in A1 domains of VWF multimers native to blood plasma. New mass spectrometry strategies are applied to resolve the structural effects of 2B and 2M mutations in VWF to verify the presence of A1 domain structural disorder in multimeric VWF harboring type 2 VWD mutations. Limited trypsinolysis mass spectrometry (LTMS) and hydrogen-deuterium exchange mass spectrometry (HXMS) are applied to wild-type and VWD variants of the single A1, A2, and A3 domains, an A1A2A3 tridomain fragment of VWF, plasmin-cleaved dimers of VWF, multimeric recombinant VWF, and normal VWF plasma concentrates. Comparatively, these methods show that mutations known to misfold the isolated A1 domain increase the rate of trypsinolysis and the extent of hydrogen-deuterium exchange in local secondary structures of A1 within multimeric VWF. VWD mutation effects are localized to the A1 domain without appreciably affecting the structure and dynamics of other VWF domains. The intrinsic dynamics of A1 observed in recombinant fragments of VWF are conserved in plasma-derived VWF. These studies reveal that structural disorder does occur in VWD variants of the A1 domain within multimeric VWF and provides strong support for VWF misfolding as a result of some, but not all, type 2 VWD variants.


Coloration of silver-stained protein bands in polyacrylamide gels is caused by light scattering from silver grains of characteristic sizes.
This study investigates the physical basis of color effects in the detection of proteins in polyacrylamide gels by silver staining. Specifically, the hypothesis that different colors may correlate with the development of silver grains of characteristic sizes was investigated by electron microscopy. Protein bands that stained brown, yellow, and blue were excised from stained gels and prepared for electron microscopy by thin-sectioning. In each case, the size distributions of globular silver grains were determined directly from the electron micrographs. We found that blue bands have larger silver grains (with diameters of 40-100 nm) than yellow (21-39 nm) or brown bands (17-35 nm). On the basis of these and other observations, a general mechanism is proposed whereby chemical specificity of electrophoretically separated proteins is expressed in color-specific silver staining.


Generalized railway tank car safety design optimization for hazardous materials transport: addressing the trade-off between transportation efficiency and safety.
North America railways offer safe and generally the most economical means of long distance transport of hazardous materials. Nevertheless, in the event of a train accident releases of these materials can pose substantial risk to human health, property or the environment. The majority of railway shipments of hazardous materials are in tank cars. Improving the safety design of these cars to make them more robust in accidents generally increases their weight thereby reducing their capacity and consequent transportation efficiency. This paper presents a generalized tank car safety design optimization model that addresses this tradeoff. The optimization model enables evaluation of each element of tank car safety design, independently and in combination with one another. We present the optimization model by identifying a set of Pareto-optimal solutions for a baseline tank car design in a bicriteria decision problem. This model provides a quantitative framework for a rational decision-making process involving tank car safety design enhancements to reduce the risk of transporting hazardous materials.


Experimental evidence for improved neuroimaging interpretation using three-dimensional graphic models.
Three-dimensional (3D) or volumetric visualization is a useful resource for learning about the anatomy of the human brain. However, the effectiveness of 3D spatial visualization has not yet been assessed systematically. This report analyzes whether 3D volumetric visualization helps learners to identify and locate subcortical structures more precisely than classical cross-sectional images based on a two dimensional (2D) approach. Eighty participants were assigned to each experimental condition: 2D cross-sectional visualization vs. 3D volumetric visualization. Both groups were matched for age, gender, visual-spatial ability, and previous knowledge of neuroanatomy. Accuracy in identifying brain structures, execution time, and level of confidence in the response were taken as outcome measures. Moreover, interactive effects between the experimental conditions (2D vs. 3D) and factors such as level of competence (novice vs. expert), image modality (morphological and functional), and difficulty of the structures were analyzed. The percentage of correct answers (hit rate) and level of confidence in responses were significantly higher in the 3D visualization condition than in the 2D. In addition, the response time was significantly lower for the 3D visualization condition in comparison with the 2D. The interaction between the experimental condition (2D vs. 3D) and difficulty was significant, and the 3D condition facilitated the location of difficult images more than the 2D condition. 3D volumetric visualization helps to identify brain structures such as the hippocampus and amygdala, more accurately and rapidly than conventional 2D visualization. This paper discusses the implications of these results with regards to the learning process involved in neuroimaging interpretation.


Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.


Neuropsychological profiles associated with subcortical white matter alterations and Parkinson's disease: implications for the diagnosis of dementia.
Despite the emergence of a number of new classification systems, the diagnosis of cerebrovascular dementia remains controversial. Also controversial is the significance of periventricular and deep white matter alterations (WMA) as seen on magnetic resonance imaging (MRI). To further clarify this issue, MRI scans were used to regroup patients clinically diagnosed with Alzheimer's disease (AD) or subcortical ischemic vascular dementia (IVD) into cohorts presenting with either little versus significant WMA on MRI. These two groups were then compared to demented patients diagnosed with idiopathic Parkinson's disease (PD) using a comprehensive neuropsychological protocol. Neuropsychological assessment failed to distinguish between patients with PD and significant WMA. By contrast, both of these patient groups exhibited disproportionate impairment on tests of executive systems functioning, whereas patients with little WMA showed greater impairment on tests of declarative memory and semantic knowledge. These findings constitute further evidence that the pattern of cognitive impairment associated with significant WMA is distinctly different when compared to AD. These results are discussed within the context of a growing body of literature suggesting that elements of the underlying neuropathologies in AD and IVD are linked. Implications for the diagnosis of dementia are also discussed.


Do we all mean the same thing by "problem-based learning"? A review of the concepts and a formulation of the ground rules.
Problem-based learning (PBL) has emerged as a useful tool of epistemological reform in higher education, particularly in medical schools. Indeed, PBL has spent most of its career inducing revolutionary undergraduate medical reform. Nevertheless, obtaining informed agreement on the characteristics of the PBL "genus" is a challenge when the label is vulnerable to being borrowed for prestige or subversion. Many "PBL" single-subject courses within traditional curricula do not use PBL at all. Such semantic uncertainty compromises the evidence-base on the added value of problem-based versus traditional approaches and the main messages for good practice. This literature review explores what is meant by the term PBL by aiming to answer the following questions: What difficulties are inherent in the "problem-based" tag? What does the term "problem-based curriculum" imply? How has PBL been characterized and validated by focusing on its purpose? How else has PBL been characterized? How does PBL relate to problem solving? How does PBL relate to epistemological reform? In conclusion, what ground rules can be formulated for PBL? Despite much conceptual fog lingering over the PBL literature, useful ground rules can be formulated.


Chronic wounds treated with a physiologically relevant concentration of platelet-rich plasma gel: a prospective case series.
Chronic wounds are characterized by a long inflammatory phase that hinders regenerative wound healing. The purpose of this prospective case series was to evaluate how a physiologically relevant concentration of an autologous platelet-rich plasma (PRP) gel affects initial wound healing trajectories of chronic, nonhealing wounds of various etiologies and in different care settings. Using convenience sampling methods, 49 patients (average age: 60.6 years, SD 14.7) with 65 nonhealing wounds (mean duration 47.8 weeks, range 3 to 260) at eight long-term acute care (LTAC) hospitals and three outpatient foot or wound clinics who were prescribed PRP gel for their nonhealing wound were enrolled. The majority of patients had low albumin, hematocrit, and/or hemoglobin levels. After wound assessments and measurements were obtained and the gel prepared, a skin barrier was applied to the periwound skin and the gel applied and protected with cover dressings. The most common wounds were pressure ulcers (n = 21), venous ulcers (n = 16) and diabetic foot ulcers (n = 14). Mean wound area and volume were 19 cm2 (SD 29.4) and 36.2 cm3 (SD 77.7), respectively. Following a mean of 2.8 (SD 2.4) weeks with 3.2 (SD 2.2) applications, reductions in wound volume (mean 51%, SD 43.1), area (39.5%, SD 41.2), undermining (77.8%, SD 28.9), and sinus tract/tunneling (45.8%, SD 40.2) were observed. For all wound etiologies, 97% of wounds improved. The results of this study suggest the application of this PRP gel can reverse nonhealing trends in chronic wounds.


Differential treatment intensity research: a missing link to creating optimally effective communication interventions.
Research over the past 50 years has yielded several promising approaches and many specific intervention techniques designed to enhance the communication and language development of young children with intellectual and developmental delays and disabilities. Yet virtually no systematic research has been conducted on the effects of different treatment intensities. We review how intervention intensity has been defined in the literature and propose a set of terms borrowed from medicine that are intended to capture the dynamic aspects of this concept as an aid to further investigation. On the basis of this approach, we propose four types of knowledge that can be generated through the systematic study of treatment intensity and discuss appropriate methods for investigating the effects of differential treatment intensities. We conclude with three recommendations for the field.


Vitrectomy Due to Vitreous Hemorrhage and Tractional Retinal Detachment Secondary to Eales' Disease
To investigate visual and anatomical outcomes of vitreoretinal surgeries in patients with Eales' disease. In this retrospective study, 22 eyes of 21 patients with vitreous hemorrhage (VH) or tractional retinal detachment (TRD) secondary to Eales' disease who underwent vitreoretinal surgery between January 1997 and December 2015 and had at least 1 year of follow-up were included. The mean best corrected visual acuity (BCVA) was significantly higher at final visit (0.6±0.9 logMAR) than the preoperative values (1.8±1.1 logMAR) (p<0.001). After surgery, BCVA was stable in 4 eyes (18.2%), increased in 16 eyes (72.7%), and decreased in 2 eyes (9.1%). Although the mean BCVA was better in the VH group (0.3±0.34 logMAR) than the TRD group (0.9±1.1 logMAR), the difference was not statistically significant (p=0.1). Multivariable linear regression analyses revealed that final BCVA was negatively associated with preoperative or postoperative proliferative vitreoretinopathy grade C (PVR-C), preoperative retinal detachment involving the macula, postoperative neovascular glaucoma, and long preoperative duration of disease, and positively associated with preoperative BCVA. Final BCVA was not associated with preoperative retinal and disc neovascularization, rubeosis iridis, total posterior hyaloid detachment, preoperative retinal laser photocoagulation, indication of surgery, diameter of sclerotomy (20 or 23 gauge), preoperative lens status, preoperative or postoperative epimacular membrane, peroperative iatrogenic retinal breaks, postoperative hypotony, cystoid macular edema, and new or recurrent retinal detachment. The primary anatomic success rate was 81.8% and the final anatomic success rate was 90.9%. In Eales' disease, good visual results can be obtained with vitreoretinal surgery if the detachment area does not involve the macula and PVR-C does not develop pre- or postoperatively.


Cerebrospinal Fluid Analysis in Multiple Sclerosis Diagnosis: An Update.
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) with brain neurodegeneration. MS patients present heterogeneous clinical manifestations in which both genetic and environmental factors are involved. The diagnosis is very complex due to the high heterogeneity of the pathophysiology of the disease. The diagnostic criteria have been modified several times over the years. Basically, they include clinical symptoms, presence of typical lesions detected by magnetic resonance imaging (MRI), and laboratory findings. The analysis of cerebrospinal fluid (CSF) allows an evaluation of inflammatory processes circumscribed to the CNS and reflects changes in the immunological pattern due to the progression of the pathology, being fundamental in the diagnosis and monitoring of MS. The detection of the oligoclonal bands (OCBs) in both CSF and serum is recognized as the "gold standard" for laboratory diagnosis of MS, though presents analytical limitations. Indeed, current protocols for OCBs assay are time-consuming and require an operator-dependent interpretation. In recent years, the quantification of free light chain (FLC) in CSF has emerged to assist clinicians in the diagnosis of MS. This article reviews the current knowledge on CSF biomarkers used in the diagnosis of MS, in particular on the validated assays and on the alternative biomarkers of intrathecal synthesis.


The role of D-dimer in the diagnosis of venous thromboembolism.
The diagnosis of venous thromboembolism remains a clinical challenge. D-dimer, a specific breakdown product of crosslinked fibrin, is a sensitive marker for acute thrombosis. Recent studies have demonstrated that D-dimer testing has a promising role as an exclusionary test in patients with suspected deep vein thrombosis or pulmonary embolism. However, a wide range of sensitivities and specificities has been reported for D-dimer assays because of inter- and intra-assay variations and differences in patient populations. New rapid D-dimer enzyme-linked immunosorbent assays and the whole blood agglutination assay SimpliRED (Agen Biomedical, Brisbane, Australia) D-dimer have high negative predictive values. Recent studies have shown that a normal result on a SimpliRED assay combined with a low pre-test probability or normal result on impedance plethysmography reliably excludes venous thrombosis. Latex agglutination assays are relatively insensitive as screening tests and should not be used. Management studies are underway and will further delineate the role of D-dimer testing in patients with suspected venous thromboembolism.


Brass instruments as a cascade of two-port networks: Transfer functions, chain parameters, and power efficiency in theory and practice.
This paper investigates how two-port network theory as a means for system identification can be applied to the analysis of brass instruments. A special focus is placed on the energy conversion efficiency as this is limited by inner damping, which receives much attention by expert players and makers of brasses. Theory suggests that a reconstruction of the 2 × 2 matrix representing the network requires input impedance and transfer function for two different boundary conditions. Besides the normal case of free sound radiation, instruments are also analyzed with the bell closed by a spherical cap. For this purpose, a customized 3D-printed spherical cap was fabricated and attached to the bell. Four measured spectra and the passivity condition over-determine the set of system equations. It is shown how to take advantage of this freedom when analyzing wind instruments. Measurements and simulations of a trumpet and a trombone are presented and compared.


Are burnout levels increasing? The experience of Israeli primary care physicians.
Burnout is a professional occupational disease that puts both physicians and patients at risk. Triggered by the increase in burnout levels among physicians, the European Forum of Medical Associations and the World Health Organization issued a statement in February 2003 expressing serious concerns about the situation, urging all national medical associations to increase awareness of the problem, monitor it and study its causes in order to develop preventive strategies. To compare burnout levels in two separate samples of primary care physicians measured in the mid-1990s, with burnout levels in a similar but small and independent sample, assessed in 2001; and to outline the theoretical bases of burnout. Altogether, 508 primary care physicians employed by Clalit Health Services responded anonymously to a self-report questionnaire. The samples were not representative and included family physicians, pediatricians and clinic directors. Burnout levels were significantly higher in the 2001 sample than in the mid-1990s samples, especially among clinic directors. Despite methodologic limitations of the study, the findings suggest that burnout levels may be increasing among primary care physicians in Israel. This may be due to substantial increases in workload and role conflicts following implementation of the Health Insurance Law and Patients' Rights Act. Because these findings are consistent with the trend in Europe, this situation cannot be ignored and systematic studies of burnout among all medical specialties should be carried out to uncover current sources of the syndrome and to devise measures of prevention and treatment.


Xeno-kidney transplantation: from idea to reality.
Although kidney transplantation is a widely used therapy for chronic renal failure, not all patients can be transplanted due to the limited numbers of organ donations. A possible solution could be xenogenic kidney transplantation. Herein we have described the present state, problems and possible solutions using xenograft treatments.


Melatonin protects against pancreaticobiliary inflammation and associated remote organ injury in rats: role of neutrophils.
Although the role of oxidative stress in acute pancreatitis (AP) has been studied in several animal models, little data are available regarding AP induced by pancreatic duct obstruction. We characterized the protective effects of melatonin on pancreaticobiliary inflammation and associated remote organ injury. In Sprague-Dawley rats, either the common pancreaticobiliary duct (PBDL; n = 28) or bile duct (BDL; n = 28) was ligated or a sham operation was applied (n = 14). Either melatonin (10 mg/kg) or vehicle (saline; 1 mL/kg) was administered intraperitoneally (i.p.) immediately before the surgery and twice a day until the rats were decapitated at 6 or 72 h. The pancreas, liver, kidneys and lungs were removed and tissue samples were stored for the determination of malondialdehyde (MDA) and glutathione (GSH) levels and myelopreoxidase activity. The results demonstrate that pathogenesis of acute obstructive pancreatitis involves not only the oxidative damage of the pancreatic and hepatic tissues, as assessed by increased MDA and reduced GSH levels, but the lungs and kidneys are also challenged by oxidant injury. Similarly, hepatic oxidative injury caused by cholestasis was also accompanied by pulmonary, renal and even pancreatic damage. The biochemical findings were also verified histologically. Melatonin, probably because of its free-radical scavenging and antioxidant activity, which involves an inhibitory effect on tissue neutrophil infiltration, protected all the affected tissues.


Response of age forty and over military personnel to an unsupervised, self-administered aerobic training program.
The Army recently extended mandatory physical training and testing to include personnel 40 yrs of age and older. The purpose of this study was to describe the profile of aerobic fitness in a representative group from this age population and to evaluate the response of such a group to a self-administered, unsupervised training program. Maximal oxygen uptake (Vo2 max) and percent body fat (%BF) were assessed in 260 military personnel (40-53 yrs of age) before and after 6 mo of physical training consisting of a progressive walk/run mode of exercise. Before training the mean +/- S.D. for Vo2 max and %BF for all subjects was 38.1 +/- 6.2 ml/kg . min and 26.1 +/- 4.7%, respectively. Subjects were divided into three groups based upon their initial level of physical activity determined by interview as follows: inactive, moderately active and active. Upon retesting after 6 mo, 40% of the inactive group had not participated to any appreciable degree in the program and subjects of this group who did participate showed only a slight and insignificant increase (4.4%) in Vo2 max. The pretraining level of Vo2 max for the total population studied was similar to that reported in other studies on comparably aged subjects. However, changes with training were well below those seen with supervised group programs of 6 mo duration.


Osseous stress reaction in a rower diagnosed with positron emission tomography (PET): a case report.
Back injury is one of the most frequently encountered injuries in the collegiate rower. The differential diagnosis of back pain in the competitive rower includes muscle strain, ligament/tendon injury, stress reaction, stress fracture, and a tear in the annulus fibrosis. Endurance sports, such as rowing, have an increased frequency of stress injury The diagnosis of stress reaction cannot be made with plain radiographs. Many studies have firmly established the efficacy of single photon emission computed tomography (SPECT) bone scans and magnetic resonance imaging in establishing the diagnosis of a stress reaction We present a case of a collegiate rower with mid back pain secondary to a stress reaction of the endplates of the costotransverse articulation at the T8 level diagnosed by a positive positron emission tomogram study in the setting of a negative SPECT scan.


Pseudo-outbreak of rotavirus infection in a neonatal intensive care unit.
A rotavirus outbreak in a neonatal intensive care unit (NICU) may have catastrophic consequences for young infants receiving critical care. From May 13, 2011 to July 11, 2011, a significant increase in stool samples testing positive for rotavirus antigens in the NICU of a university affiliated hospital was observed. Due to lack of clinical presentations suggestive of rotavirus infection in the patients and the rarity of rotavirus infection in the NICU in the past, a pseudo-outbreak was suspected. Infection control measures were reinforced initially. To investigate the outbreak, a prospective laboratory-based active surveillance of all infants in the NICU was conducted right after the cluster was identified. Repeated testing using a modified enzyme immunoassay (EIA) kit, rotavirus RNA polyacrylamide gel electrophoresis (PAGE), reverse transcription polymerase chain reaction (RT-PCR), and retrospective chart review methods were used to confirm the pseudo-outbreak. Seven infants in the NICU, with or without gastrointestinal symptoms, tested positive for the rotavirus antigen using the old version of an EIA kit, which indicated a possible outbreak. Active surveillance with repeated tests for recollected stool samples using a modified EIA kit showed negative results in all 24 infants in the NICU. Seven stored stool samples from four infants, which previously tested positive for the rotavirus antigen, tested negative for rotavirus using the modified EIA kit, PAGE, and RT-PCR. Chart reviews showed no clinical difference between index cases and controls. False positivity might arise from unsatisfactory specificity of the old EIA kit. After the introduction of the modified EIA kit, no rotavirus was detected in the NICU for at least 7 months. This cluster of patients who tested positive for the rotavirus antigen in stools was confirmed to be a pseudo-outbreak. Interpretation of the old EIA for rotavirus in an NICU setting should be done with caution until the mechanism of the false-positive reaction is elucidated.


Drug treatment in the elderly: an intervention in primary care to enhance prescription quality and quality of life.
The aim of the study was to assess the effect on prescription quality and quality of life after intervention with prescription reviews and promotion of patient participation in primary care. A randomized controlled study with three groups: (A) controls, (B) prescription review sent to physician, and (C) as in B and with a current comprehensive medication record sent to the patient. The municipality of Örebro, Sweden (130 000 inhabitants). The study focused on the easiest possible intervention to increase prescription quality and thereby increase quality of life. The intervention should be cost-efficient, focus on colleague-to-colleague advice, and be possible to perform in the primary health care centre without additional resources such as a pharmacist. 150 patients recently discharged from hospital. Inclusion criteria were: ≥ 75 years, ≥ five drugs and living in ordinary homes. Quality of life (EQ-5D index, EQ VAS) and quality of prescriptions. Extreme polypharmacy was common and persistent in all three groups and this was accompanied by an unchanged frequency of drug-risk indicators. There was a low EQ-5D index and EQ VAS in all three groups throughout the study. No statistically significant differences were found anywhere between the groups. The intervention seems to have had no effect on quality of prescriptions or quality of life. This underlines the major challenge of finding new strategies for improving prescription quality to improve patient outcome measures such as quality of life and reduce the known risks of polypharmacy for the elderly.


1 -Antitrypsin deficiency and neonatal hepatitis.
Five out of 28 infants investigated in a regional survey of neonatal hepatitis were found to have genetically-determined deficiency of alpha(1)-antitrypsin (ZZ phenotype). The clinical course and pathological changes varied considerably. All five infants had an acute hepatitis-like illness, and although this subsided cirrhosis later developed in three cases. The remaining two infants had minimal abnormalities of the liver function tests at 12 and 18 months of age, and one had increased hepatic fibrosis. Australia antigen was found in the serum of three infants, and Australia antigen or antibody in one or both parents of these and of one further case whose serum was negative. It is suggested that the association of neonatal hepatitis with alpha(1)-antitrypsin deficiency may be commoner than previously realized and that Australia antigen acts as a trigger factor in these cases.


Integration of bioenergetics in the ADM1 and its impact on model predictions.
In this work, the integration of dynamic bioenergetic calculations in the IWA Anaerobic Digestion Model No. 1 (ADM1) is presented. The impact of bioenergetics on kinetics was addressed via two different approaches: a thermodynamic-based inhibition function and variable microbial growth yields based on dynamic Gibbs free energy calculations. The dynamic bioenergetic calculations indicate that the standard ADM1 predicts positive reaction rates under thermodynamically unfeasible conditions. The dissolved hydrogen inhibition approach used in ADM1 is, however, deemed as adequate, offering the trade-off of not requiring dynamic bioenergetics computation despite the need of hydrogen inhibition parameters. Simulations of the model with bioenergetics showed the low amount of energy available in butyrate and propionate oxidation, suggesting that microbial growth on these substrates must be very limited or occur via alternative mechanisms rather than dissolved hydrogen.


The effect of an applied potential on the activity of carbonic anhydrase immobilized on graphite rods.
The effect of both a positive and a negative applied potential on the p-NPA hydrolysis activity of bovine carbonic anhydrase (BCA) immobilized on graphite rods has been investigated. Background experiments show that the pH-activity profile for BCA free in solution is not affected by either a negative or a positive potential applied to graphite rods placed in the same solution. However, the activity of BCA immobilized by covalent attachment to a graphite rod is influenced by a potential externally applied to the graphite rod. An overall increase in activity (as determined by the initial rate of the p-NPA hydrolysis reaction) is observed in the presence of a -0.2 V (Ag/AgCl) applied potential, while decreased activity is evident at +0.6 V (Ag/AgCl). This is indicative of an electrolyte anion effect rather than a local pH effect. In the presence of the specific anion inhibitors Cl(-) and SCN(-), the relative BCA activity increases at -0.2 V (Ag/AgCl) and decreases at +0.6 V (Ag/AgCl) are consistent with the different BCA inhibition constants for Cl(-) and SCN(-). Accelerated loss of immobilized BCA activity also accompanies the application of the external potentials, particularly at +0.6 V (Ag/AgCl). Results described here represent an early example of potentiostatic control of nonredox enzyme activity. Several possible mechanisms are discussed including specific anion inhibition, enzyme surface charge/charged support material interactions, and charged product inhibition. It is likely that a combination of such mechanisms is operational in this system. The implications of external potentials affecting the activity of immobilized enzymes in the design of stable immobilized enzyme electrodes are also discussed.


Position of synaptotagmin I at the membrane interface: cooperative interactions of tandem C2 domains.
Synaptotagmin I is a synaptic vesicle associated membrane protein that appears to regulate Ca(2+)-mediated exocytosis. Here, the Ca(2+)-dependent membrane interactions of a water soluble fragment of synaptotagmin I (C2AB) that contains its two C2 domains (C2A and C2B) were determined using site-directed spin labeling. Membrane depth parameters were obtained for 19 spin-labeled mutants of C2AB when bound to phosphatidylcholine and phosphatidylserine membranes, and these distance constraints were used in combination with the high-resolution structures of C2A and C2B to generate a model for the membrane orientation and position of synaptotagmin at the bilayer interface. Both C2A and C2B bind to the membrane interface with their first and third Ca(2+) binding loops penetrating the membrane interface. The polybasic face of C2B does not interact with the membrane lipid but is available for electrostatic interaction with other components of the fusion machinery. When compared to positions determined previously for the isolated domains, both C2A and C2B have similar orientations; however, the two domains are positioned deeper into the bilayer interior when present in the tandem construct. These data indicate that C2A and C2B do not act independently but influence their mutual membrane penetration. This may explain the occurrence of multiple C2 domains in proteins that function in membrane trafficking and repair.


p53 status does not affect sensitivity of human ovarian cancer cell lines to paclitaxel.
Nine human ovarian cancer cell lines that express wild-type (wt) or mutated p53 were used to evaluate the cytotoxicity induced by paclitaxel. The IC50 calculated in the five mutated p53-expressing cell lines was not different from the four wt p53-expressing cell lines. The introduction of wt p53, by using a temperature-sensitive mutant murine p53 or the human p53 under the control of a tetracycline-dependent promoter, did not change the cytotoxicity of paclitaxel as compared to mock-transfected cells. By using for each cell line the paclitaxel IC50, we found that these concentrations were sufficient to induce an increase in p53 levels in all of the four wt p53-expressing cells, whereas in the mutated p53-expressing cells, the levels were unaffected. This increase in p53 levels led to an increase in the mRNA and protein levels of p53 downstream genes (WAF1, GADD45, and bax). In none of the cell lines examined was paclitaxel able to induce apoptosis, evaluated by terminal deoxynucleotidyl transferase-mediated nick end labeling staining and filter binding assay at concentrations closed to the IC50. By increasing the concentration of paclitaxel in the filter binding assay, we could see fragmentation of DNA in the different cell lines. We conclude that the presence of p53 is not a determinant for the cytotoxicity induced by paclitaxel in human ovarian cancer cell lines. Differences in the activation of p53 downstream genes could be observed in wt versus mutated p53-expressing cells, but this does not account either for a differential induction of apoptosis or for a change in cytotoxicity induced by paclitaxel.


Immune disorders in hemodialysis patients.
Immunologically, End Stage renal Disease (ESRD) is associated with some disorders in both innate and adaptive immune system in such a form that there is a coexistence of both immune activation and immune suppression. Although these disorders are complex yet thoroughly unknown, there is a close relation between the progressively defective immune system with side effects as well as mortality causes including cardiovascular problems, infections, and malignancies. From the other point, chronic inflammation as a major determinant of "dialysis syndrome" (including malnutrition, cachexia, and vasculopathy) is considered as the main factor of inability and mortality in dialysis patients. Such inflammation is generally arisen from immune system response to uremia and individual's repetitive contact with dialysis instruments and, in the long term, leads to premature aging via intensifying tissue degeneration. Therefore, the immune system is known as one of the most important therapeutic targets to reduce morbidity and mortality in uremic and dialysis patients. This review addresses different aspects as well as mechanisms of immune system dysfunction and possible therapeutics in dialysis patients.


Increased release of prostaglandins from the mesenteric vascular bed of diabetic animals: the effects of glucose and insulin.
To study prostaglandin (PG) metabolism in peripheral vascular beds, PGs and TxB2 released from perfused mesenteric tissues were measured in both normal and streptozotocin (STZ)-induced diabetic rats. The release of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) was significantly increased in mesenteric vascular beds from diabetics in comparison with control rats. The 6-keto-PGF1 alpha/TxB2 ratio was decreased in diabetics. In order to clarify the mechanism of this imbalanced synthesis of eicosanoids, we infused buffer with 500 mg/dl glucose which was similar to the concentration of blood glucose in the diabetic rats. In response to this high glucose concentration, TxB2 released into the effluent from the mesenteric beds of normal animals was increased to the diabetic level. The release of the other PGs was not changed significantly. The 6-keto-PGF1 alpha/TxB2 ratio was decreased in control rats perfused with buffer containing 500 mg/dl glucose. We also investigated the effect of insulin (50 and 100 microU/ml) in the diabetic mesenteric vascular beds, but there were no changes in prostaglandin or TxB2 release. These data suggest that a high glucose level may have an important role in regulating TxA2 synthesis and in modulating the balance between PGI2 and TxA2 in diabetes. It is postulated that an increase in the micro-circulation of PGI2 may partially be protective against the progression of angiopathy.


Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.
To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter. Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.


Longitudinal Associations between Monetary Value of the Diet, DASH Diet Score and the Allostatic Load among Middle-Aged Urban Adults.
Lower cost can lead to poorer-quality diets, potentially worsening metabolic profiles. We explored these pathways among urban adults. Longitudinal data were extracted from 1224-1479 participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. DASH(mean) (Dietary Approaches to Stop Hypertension) score was computed using four 24 h recalls (v1/v2: 2004-2013) linked with a national food price database to estimate monetary value of the diet [MVD(mean)]. Allostatic load (AL) was measured at visits 2 (v2) and 3 (v3) in 2009-2018. Mixed-effects regression and structural equation modeling (SEM) were conducted, linking MVD(mean)/DASH(mean) to AL [v2 and annual change(v3-v2)] and exploring mediating pathways between MVD(mean) and AL(v3) through DASH(mean), stratifying by sex, race and poverty status. MVD(mean) tertiles were linearly associated with contemporaneous DASH(mean), after energy adjustment. In mixed-effects regression models, DASH(mean) was consistently linked to lower AL(v2). DASH(mean) and MVD(mean) were positively associated with higher serum albumin(v2). In SEM, MVD(mean) was linked to AL(v3) through DASH(mean), mainly among Whites and specifically for the cholesterol and Waist-Hip-Ratio AL components. In summary, energy and other covariate-adjusted increase in MVD may have a sizeable impact on DASH which can reduce follow-up AL among urban White middle-aged adults. More studies are needed to replicate findings in comparable samples of urban adults.


Risk factors for venous thromboembolism.
Venous thromboembolism is a common and potentially lethal disease. Patients who have pulmonary embolism are at especially high risk for death. Death owing to pulmonary embolism is independent of other comorbid conditions (e.g., cancer, chronic heart disease, or lung disease). Sudden death is often the first clinical manifestation. Only a reduction in the incidence of venous thromboembolism can reduce sudden death owing to pulmonary embolism and venous stasis syndrome owing to deep vein thrombosis. The incidence of venous thromboembolism has been relatively constant since about 1980. Improvement in the incidence of venous thromboembolism will require better recognition of persons at risk, improved estimates of the magnitude of risk, the avoidance of risk exposure when possible, more widespread use of safe and effective prophylaxis when risk is unavoidable, and targeting of prophylaxis to those persons who will benefit most. Recognition of venous thromboembolism as a multifactorial disease with genetic and genetic-environmental interaction has provided significant insights into its epidemiology and offers the possibility of improved identification of persons at risk for incident and recurrent venous thromboembolism.


Co-creating physical activity interventions: a mixed methods evaluation approach.
Co-creation strategies, such as cooperative planning, are promising as a means to ensure that physical activity interventions address real-world problems and are tailored to the target group. This has already been validated in diverse settings. However, questions targeting the transferability of cooperative planning to new settings and the key factors influencing its success or failure remain unclear. At the same time, co-creation processes are complex, and evaluation can be challenging. Following calls for detailed reporting, this paper describes the programme activities, the underlying logic, and methodological design of a study that aims to evaluate the transfer of cooperative planning to new settings and to explore the associated key determinants. Cooperative planning was utilized as a strategy to target physical activity promotion in three real-world German settings in the nursing care and automotive mechatronics sectors. This involved researchers working alongside stakeholders from practice and policy to conjointly develop new interventions to promote physical activity in physically demanding jobs. A pragmatic approach is used to evaluate both the transferability and key determinants of this strategy. We developed a logic model for this co-creation process that describes the underlying assumptions and guides the evaluation. The evaluation outcomes of this study include planning meetings, newly developed interventions, and the determinants that are likely to affect cooperative planning. Quantitative and qualitative data will be collected using questionnaires, documents, and interviews. The quantitative data will be analysed descriptively, while the qualitative data will mainly be analysed using qualitative content analysis, split by settings. Subsequently, data triangulation will be used to integrate the quantitative and qualitative findings, which will then be compared across all three settings. The study findings will contribute to a better understanding of co-creation strategies, their transferability, and key determinants. The practical implications can include a checklist for assessing key determinants and a guideline for transferring cooperative planning into new settings to benefit more people. Ultimately, this study will help to advance co-creation strategies and may be relevant for researchers, practitioners, and policy-makers targeting physical activity promotion in various contexts. Open Science Framework: https://osf.io/r6xnt/ (retrospectively registered).