Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms.
The calreticulin (CALR) exon 9 mutations that are identified in 20% of patients with Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) generate immunogenic antigens. Thus, therapeutic cancer vaccination against mutant CALR could be a new treatment modality in CALR-mutant MPN. The safety and efficacy of vaccination with the peptide CALRLong36 derived from the CALR exon 9 mutations was tested in a phase I clinical vaccination trial with montanide as adjuvant. Ten patients with CALRmut MPN were included in the trial and received 15 vaccines over the course of one year. The primary end point was evaluation of safety and toxicity of the vaccine. Secondary endpoint was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT03566446). Patients had a median age of 59.5 years and a median disease duration of 6.5 years. All patients received the intended 15 vaccines, and the vaccines were deemed safe and tolerable as only two grade three AE were detected, and none of these were considered to be related to the vaccine. A decline in platelet counts relative to the platelets counts at baseline was detected during the first 100 days, however this did not translate into neither a clinical nor a molecular response in any of the patients. Immunomonitoring revealed that four of 10 patients had an in vitro interferon (IFN)-γ ELISPOT response to the CALRLong36 peptide at baseline, and four additional patients displayed a response in ELISPOT upon receiving three or more vaccines. The amplitude of the immune response increased during the entire vaccination schedule for patients with essential thrombocythemia. In contrast, the immune response in patients with primary myelofibrosis did not increase after three vaccines. Therapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable. The vaccines did not induce any clinical responses. However, the majority of patients displayed a marked T-cell response to the vaccine upon completion of the trial. This suggests that vaccines directed against mutant CALR may be used with other cancer therapeutic modalities to enhance the anti-tumor immune response.


Recovery and time to growth of isolates in blood culture bottles: comparison of BD Bactec Plus Aerobic/F and BD Bactec Plus Anaerobic/F bottles.
This study was done to compare the growth of pathogens in paired aerobic/anaerobic blood culture bottles versus the use of only aerobic bottles, and to analyze the time to growth in both atmospheres. We retrospectively evaluated the results of all blood cultures collected over a 2-y period for the diagnosis of central venous catheter-related bloodstream infections or other severe infections in oncology patients. Among the 487 isolates, 174 (35.7%), all aerobic, grew only in the aerobic bottle; 250 (51.3%), all aerobic, grew in both bottles; and 63 (12.9%) grew only in the anaerobic bottle, of which 24 were anaerobic and 39 were aerobic microorganisms (8% of positive blood cultures). Of these 39 aerobic microorganisms, 12 were Gram-negative, 17 staphylococci (4 were Staphylococcus aureus), 5 streptococci, 2 Gram-positive bacilli, and 3 mixed growth. Though the mean time to positivity of pathogens grown in both atmospheres was significantly lower in the aerobic bottle than in the anaerobic bottle, in 71 cases (28.4%) the pathogens developed earlier in the anaerobic bottle than in the aerobic bottle - in 36 of these cases at least 1 h earlier, which is significant for starting targeted therapy. The use of paired aerobic/anaerobic blood culture bottles allowed the diagnosis of a percentage of bacteraemia due to either anaerobic or aerobic pathogens that would have been missed, as they grew only in the anaerobic atmosphere. Moreover in 8% of bacteraemia we identified a significant decrease in the time to detection, resulting in the opportunity to better manage the infections without an increase in costs.


Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets.
In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen human subjects. Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. The simulated skull efficiency using individual-specific heterogeneous models predicts well (R(2) = 0.84) the experimental energy efficiency. This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible.


A complexity drain on cells in the evolution of multicellularity.
A hypothesis has been advanced recently predicting that, in evolution, as higher-level entities arise from associations of lower-level organisms, and as these entities acquire the ability to feed, reproduce, defend themselves, and so on, the lower-level organisms will tend to lose much of their internal complexity (McShea 2001a). In other words, in hierarchical transitions, there is a drain on numbers of part types at the lower level. One possible rationale is that the transfer of functional demands to the higher level renders many part types at the lower level useless, and thus their loss in evolution is favored by selection for economy. Here, a test is conducted at the cell level, comparing numbers of part types in free-living eukaryotic cells (protists) and the cells of metazoans and land plants. Differences are significant and consistent with the hypothesis, suggesting that tests at other hierarchical levels may be worthwhile.


Emergency surgery for large bowel obstruction caused by cancer.
There are several options for surgical treatment of large bowel obstruction caused by cancer, depending on location of obstruction, intraoperative local findings (perforation, peritonitis, bowel dilatation proximal to obstruction) and patients' condition. Resection and anastomosis as one stage surgery would be prefered procedure. Anastomotic leakage, on the other hand, highly elevates risk of mortality and mobidity. The most important question is whether to, in resectable cases, perform primary resection with anastomosis or not. This study was retrospective and included 40 patients that have undergone emergency surgery for large bowel obstruction caused by cancer. According to whether resection and anastomosis was made at initial surgery or not, patients were grouped in group A (N = 18) and group B (N = 21), respectively. We have analysed the type of surgical procedure, days of hospitalization, mortality, anastomotic leakeage, wound infection and other postoperative complications. Our results show that there is no major difference in mortality and morbidity in these two groups, suggesting that for selected patients primary resection and anastomosis is a safe option of tratment with acceptable risk. Since there are no strict guidelines or scorring system which would point the tratment option the decision about the choice of procedure still remains the burden of surgeon and depends on its experience and subspeciality. Our experience recomends primary resection and anastomosis except in cases of bowel perforation on tumor site, in cases of extreme dilatation and atony of bowel proximal to obstruction site and severe hypoproteinemia and anemia.


Mediastinal lymphoma in dogs is homogeneous compared to thymic epithelial neoplasia and is more likely to envelop the cranial vena cava in CT images.
In order to identify CT signs that could be used to distinguish cranial mediastinal lymphoma and thymic epithelial neoplasia, a retrospective case-control study was done. Associations between CT signs and diagnosis were tested using binary logistic regression and results expressed as odds ratio and 95% confidence interval. Sixty-two dogs that had thoracic CT and confirmed diagnosis of lymphoma (n = 33) or thymic neoplasia (n = 29) were sampled. Thymic neoplasms included 24 thymomas and five thymic carcinomas. Dogs with thymic epithelial neoplasia were significantly older than dogs with lymphoma (median age 8.6 years versus 6.0 years, P = .007), but there were no significant differences in prevalence of clinical signs. Diagnosis of thymic epithelial neoplasia was associated with heterogeneous attenuation in pre- (odds ratio 23.3, 95% confidence interval, 4.5-121.1) and post-contrast (odds ratio 30.7, 95% confidence interval, 3.6-265.0) images. Conversely, envelopment of the cranial vena cava by the mass was less likely with thymic epithelial neoplasia than lymphoma (odds ratio 0.07, 95% confidence interval, 0.007-0.66). Greater standard deviation of Hounsfield unit values in post-contrast images was associated with thymic epithelial neoplasia (P = .005). Based on ROC analysis, SD > 17HU of the mass in post-contrast images had a sensitivity of 72% and specificity of 79% for thymic epithelial neoplasia. There were no significant differences in morphology, prevalence of calcification, mediastinal lymphadenopathy, cranial vena cava invasion, collateral vessels, or pleural fluid associated with these tumors. Thymic epithelial neoplasms tended to occur in older dogs and were heterogeneous in CT images, whereas mediastinal lymphoma was more homogeneous and more likely to envelop the cranial vena cava.


[Modulation of the intensity of fluorescence of aqueous solutions of proteins by magnetic field].
Effect of the constant magnetic field with up to 3.2 X 10(-4) A/m intensity on the fluorescence of papain aqueous solutions was investigated. It has been shown that depending on the magnetic field direction a reversible decrease or increase of fluorescence intensity takes place. The variation of fluorescence intensity under the influence of magnetic field is maximal under excitation at long wave ultra-violet light. The effect increases with the increase of temperature, increases linearly with the increase of magnetic field intensity but doesn't depend on protein concentration in diluted solutions. The examination of the data leads to the conclusion on the existence of two possible mechanisms: the variation of properties of surface tryptophan residues environment and paramagnetic orientation of protein globule under the influence of a magnetic field.


Controlled expression of an rpoS antisense RNA can inhibit RpoS function in Escherichia coli.
We show that an inducible rpoS antisense RNA complementary to the rpoS message can inhibit expression of RpoS in both exponential and stationary phases and can attenuate expression of the rpoS regulon in Escherichia coli. Plasmids containing rpoS antisense DNA expressed under the control of the T7lac promoter and T7 RNA polymerase were constructed, and expression of the rpoS antisense RNA was optimized in the pET expression system. rpoS antisense RNA levels could be manipulated to effectively control the expression of RpoS and RpoS-dependent genes. RpoS expression was inhibited by the expression of rpoS antisense RNA in both exponential and stationary phases in E. coli. RpoS-dependent catalase HPII was also downregulated, as determined by catalase activity assays and with native polyacrylamide gels stained for catalase. Induced RpoS antisense expression also reduced the level of RpoS-dependent glycogen synthesis. These results demonstrate that controlled expression of antisense RNA can be used to attenuate expression of a regulator required for the expression of host adaptation functions and may offer a basis for designing effective antimicrobial agents.


Network analysis of enzyme activities and metabolite levels and their relationship to biomass in a large panel of Arabidopsis accessions.
Natural genetic diversity provides a powerful resource to investigate how networks respond to multiple simultaneous changes. In this work, we profile maximum catalytic activities of 37 enzymes from central metabolism and generate a matrix to investigate species-wide connectivity between metabolites, enzymes, and biomass. Most enzyme activities change in a highly coordinated manner, especially those in the Calvin-Benson cycle. Metabolites show coordinated changes in defined sectors of metabolism. Little connectivity was observed between maximum enzyme activities and metabolites, even after applying multivariate analysis methods. Measurements of posttranscriptional regulation will be required to relate these two functional levels. Individual enzyme activities correlate only weakly with biomass. However, when they are used to estimate protein abundances, and the latter are summed and expressed as a fraction of total protein, a significant positive correlation to biomass is observed. The correlation is additive to that obtained between starch and biomass. Thus, biomass is predicted by two independent integrative metabolic biomarkers: preferential investment in photosynthetic machinery and optimization of carbon use.


Development of a targeted HPLC-ESI-QqQ-MS/MS method for the quantification of sulfolipids from a cyanobacterium, selected leafy vegetables, and a microalgae species.
The use of macro- and microalgae, as well as cyanobacteria, becomes increasingly important for human nutrition, even in Western diets. Health effects, positive as well as negative, are believed to result mainly from minor components in the food. In macro- and microalgae as well as in certain cyanobacteria, one class of such minor compounds is sulfolipids, more precisely sulfoquinovosylmonoacylglycerol (SQMG) and sulfoquinovosyldiacylglycerol (SQDG) derivatives. SQMGs and SQDGs consist of a diacylglycerol esterified with varying fatty acid combinations and a sulfoquinovose moiety. Sulfoquinovose is a sulfonated hexose analogous to D-glucose, but featuring a stable carbon-sulfur bond. With regard to their chemical structure, SQDGs can be distinguished according to their sn1- and sn2-bound fatty acids. Although there is great interest in SQDGs, because of their controversially discussed bioactivities, only a negligible number of comprehensive methods for identification and quantification has been published, so far. Within this work, a sample preparation including a quantitative isolation of SQDGs from selected raw materials, a clean-up with solid-phase extraction (SPE), and a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous identification and quantitation of different, intact SQMGs and SQDGs were developed and validated. The applicability of the method was further demonstrated by comparing a prominent cyanobacterium (Arthrospira sp.) with a microalgae preparation (Chlorella vulgaris), and selected leafy vegetables (spinach, basil).


Absorption after subarachnoid and subdural administration of iohexol, 51Cr-EDTA, and 125I-albumin to rabbits.
The absorption of the nonionic contrast medium iohexol, the clearance tracer 51Cr-ethylenediaminetetraacetic acid, and the blood-pool marker 125I-human serum albumin was studied after subarachnoid and subdural injection in rabbits. Subdural deposition of the contrast medium and 51Cr-ethylenediaminetetraacetic acid resulted in a faster absorption rate and higher achieved blood levels than a subarachnoid injection of the two substances, where a slow absorption to lower blood concentrations was observed. No significant differences in absorption rate could be shown after subdural and subarachnoid administration of iodine-labelled albumin. The excretion of iohexol was observed for 1 week after the intrathecal injection. For both the subdural and subarachnoid depositions, about 83% of the injected iohexol was found in urine within 24 hr after injection. The total recovery of iohexol after 1 week was 96% (range, 87%-101%).


Embryonal rhabdomyosarcoma of the female genital tract: 5 years' experience.
To present our single institution experience with 10 cases of embryonal rhabdomyosarcoma diagnosed over 5 years. Retrospective analysis of the medical records of 10 patients. The initial presenting data as age, complains and staging were analyzed. Surgical interference of all cases was studied. The follow up data regarding survival and recurrences were analyzed. The mean age at diagnosis was 4.3 years (range: 2-12). Six cases (60%) were subjected to "True Cut" biopsy and 4 cases (40%) were subjected to complete surgical excision of the tumor. All cases received chemotherapy. "Vincristine, Actinomycin D, Cyclophosphamide" combination was the most commonly used. Radiation therapy was used in 3 patients (30%) in the form of external beam radiation. The 5-year overall survival of our studied cases were 80%. The recurrence rate of our retrospectively studied 10 cases of embryonal rhabdomyosarcoma of vagina and cervix was high (70%). However, five-year survival was 80%. Combined modality treatment is essential to improve prognosis.


Actin-membrane interactions mediated by NETWORKED2 in Arabidopsis pollen tubes through associations with Pollen Receptor-Like Kinase 4 and 5.
During fertilization, Pollen Receptor-Like Kinases (PRKs) control pollen tube growth through the pistil in response to extracellular signals, and regulate the actin cytoskeleton at the tube apex to drive tip growth. We investigated a novel link between membrane-integral PRKs and the actin cytoskeleton, mediated through interactions between PRKs and NET2A; a pollen-specific member of the NETWORKED superfamily of actin-binding proteins. We characterize NET2A as a novel actin-associated protein that localizes to punctae at the plasma membrane of the pollen tube shank, which are stably associated with cortical longitudinal actin cables. NET2A was demonstrated to interact specifically with PRK4 and PRK5 in Nicotiana benthamiana transient expression assays, and associated at discreet foci at the shank membrane of Arabidopsis pollen tubes. Our data indicate that NET2A is recruited to the plasma membrane by PRK4 and PRK5, and that PRK kinase activity is important in facilitating its interaction with NET2A. We conclude that NET2A-PRK interactions mediate discreet sites of stable interactions between the cortical longitudinal actin cables and plasma membrane in the shank region of growing pollen tubes, which we have termed Actin-Membrane Contact Sites (AMCSs). Interactions between PRKs and NET2A implicate a role for NET2A in signal transduction to the actin cytoskeleton during fertilization.


Enhanced sensitivity to endotoxin induced by 6-sulfanilamidoindazole.
6-Sulfanilamidoindazole (6-SAI) is a sulfonamide that induces inflammation in the ankles and hind paws of older rats and sensitizes the animals to the lethal actions of endotoxin. Sensitization is associated with reductions in plasma glucose concentration but not changes in phagocytic function of the RES or increases in lysosomal or hepatic enzymes. Death in 6-SAI-pretreated but not control rats was associated with fibrin deposition in the glomerular capillaries (generalized Shwartzman reaction) and inflamed paws. Endotoxin shock in both 6-SAI-pretreated and control rats was associated with increases in activities of lysosomal and hepatic enzymes and hypoglycemia. Methylprednisolone but not desoxycorticosterone pretreatment protected 6-SAI-fed rats against endotoxin lethality and the generalized Shwartzman reaction and maintained the plasma glucose concentration but did not prevent loss of lysosomal integrity. Simultaneous administrations of small doses of phenylbutazone with 6-SAI suppressed inflammation but did not protect against endotoxin lethality or the generalized Shwartzman reaction.


Diagnostic and clinical significance of D2-40 expression in the normal human thymus and thymoma.
Human thymus development and thymoma behavior remain elusive, in spite of many acquisitions in the field in last decades. In the present paper, we analyzed the immunohistochemical expression of D2-40 in the normal human thymus and thymoma. In both fetal and postnatal normal thymus, we found a strong expression of D2-40 in the subcapsular and cortico-medullary epithelial cells, and lack of expression in the thymus of involution. These findings support a role for podoplanin in the proliferation of some subtypes of epithelial cells of the normal thymus stroma. In thymoma, the expression of D2-40 was detected in neoplastic cells in 18 from 26 cases (69.23%). No correlation was found between D2-40 expression and histological types of thymoma, but strong correlation was noticed with tumor stage. Based on these results, it is suggested that D2-40 expression is a good predictor of invasion and can be considered as a potential target for therapy in selected cases.


Acetylcholinesterase cDNA sequencing and identification of mutations associated with organophosphate resistance in Cochliomyia hominivorax (Diptera: Calliphoridae).
Altered acetylcholinesterase (AChE) has been identified in numerous arthropod species resistant to organophosphate (OP) and carbamate insecticides. The New World screwworm (NWS) Cochliomyia hominivorax (Coquerel), one of the most important myiasis-causing flies in the Neotropics, has been controlled mainly by the application of OP insecticides in its current geographical distribution. However, few studies have investigated insecticide resistance in this species. Based on previous studies about mutations conferring OP resistance in related dipteran species, AChE cDNA was sequenced allowing a survey for mutations (I298V, G401A, F466Y) in NWS populations. In addition, the G137D mutation in the carboxylesterase E3 gene, also associated with OP resistance, was analyzed in the same NWS populations. Only 2/135 individuals presented an altered AChE gene (F466Y). In contrast, a high frequency of the G137D mutation in the E3 gene was found in some localities of Brazil and Uruguay, while the mutant allele was not found in Cuba, Venezuela or Colombia. These findings suggest that the alteration in the carboxylesterase E3 gene may be one of the main resistance mechanisms selected in this ectoparasite. The knowledge of the frequency of these resistance-associated mutations in the NWS natural populations may contribute to the selection of appropriate chemicals for control as part of pest management strategies.


A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms.
We describe a map of 1.42 million single nucleotide polymorphisms (SNPs) distributed throughout the human genome, providing an average density on available sequence of one SNP every 1.9 kilobases. These SNPs were primarily discovered by two projects: The SNP Consortium and the analysis of clone overlaps by the International Human Genome Sequencing Consortium. The map integrates all publicly available SNPs with described genes and other genomic features. We estimate that 60,000 SNPs fall within exon (coding and untranslated regions), and 85% of exons are within 5 kb of the nearest SNP. Nucleotide diversity varies greatly across the genome, in a manner broadly consistent with a standard population genetic model of human history. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy.


Streptomyces sundarbansensis sp. nov., an actinomycete that produces 2-allyloxyphenol.
A novel actinomycete producing 2-allyloxyphenol, designated strain MS1/7(T), was isolated from sediments of the Sundarbans mangrove forest, India. Growth on International Streptomyces Project (ISP) media 2, 3, 4, 5 and 7 produced olive green to grey aerial hyphae that carried smooth-surfaced spores in a flexuous (Rectiflexibiles) arrangement. The strain contained ll-diaminopimelic acid, but no diagnostic sugars in whole-cell hydrolysates. Hexa-, octa- and a minor amount of tetra-hydrogenated menaquinones with nine isoprene units [MK-9 (H(4), H(6), H(8) and H(10))] were present as isoprene analogues. Diagnostic phospholipids were phosphatidylethanolamine and diphosphatidylglycerol. The predominant fatty acids were anteiso-C(15 : 0) (34.80 %), iso-C(16 : 0) (16.45 %), C(16) (10.53 %) and anteiso-C(17 : 0) (10.92 %). The strain showed greater than 99 % 16S rRNA gene sequence similarity to the type strains of several recognized species of the genus Streptomyces, but in the phylogenetic tree based on 16S rRNA gene sequences it formed a distinct phyletic line and demonstrated closest relationships to viomycin-producers (Streptomyces californicus NRRL B-1221(T), Streptomyces floridae MTCC 2534(T) and Streptomyces puniceus NRRL B-2895(T)). However, strain MS1/7(T) could be distinguished from these and other closely related species based on low levels of DNA-DNA relatedness (<44 %) and disparate physiological features, principally amino acid utilization and growth in NaCl. Strain MS1/7(T) is therefore suggested to represent a novel species of the genus Streptomyces, for which the name Streptomyces sundarbansensis sp. nov. is proposed. The type strain is MS1/7(T) ( = MTCC 10621(T) = DSM 42019(T)).


Effect of intrathecal fentanyl on the incidence, severity, and duration of postdural puncture headache in parturients undergoing caesarean section: A randomised controlled trial.
Postdural puncture headache (PDPH) is a side effect of spinal anaesthesia (SA). This study was conducted to investigate the effect of intrathecal fentanyl on the incidence, severity, and duration of PDPH. This was a prospective randomised controlled study including 220 parturients, who underwent Caesarean section (CS). They were divided into two groups for administration of SA with bupivacaine (bupivacaine group [B0], n = 111) or bupivacaine with fentanyl (bupivacaine fentanyl group [BF], n = 109). Haemodynamics, quality of anaesthesia, maternal side effects, and postoperative analgesia were noted. The neonatal Apgar score was recorded. The patients were followed up for 14 days after CS for the occurrence of PDPH, and its severity and duration. The collected data were statistically analysed, using the Statistical Package for the Social Sciences software version 25. Regarding haemodynamics, heart rate increased at 5 min post-induction and blood pressure decreased at 2min post-induction in both groups. Excellent intraoperative anaesthesia was obtained in 91.7% and 79.3% of cases in groups BF and B0, respectively (P < 0.01). Longer duration of postoperative analgesia was present in the BF group as compared to the B0 group (P < 0.001). The incidence of PDPH decreased in the BF group in a non-significant manner, whereas its severity and duration increased significantly in the B0 group. Although the addition of intrathecal fentanyl to bupivacaine for SA in CS patients did not reduce the incidence of PDPH significantly, its severity and duration decreased significantly.


Evaluation of the safety and reliability of the newly-proposed AO spine injury classification system.
To evaluate the safety and reliability of the new AO Classification, a recent classification system for Thoraco-Lumbar Spine Trauma (TLST). Retrospective study. We applied the new AO system in patients with TLST treated according to the TLICS. Two researchers classified injuries independently. Eight weeks later, the classification was repeated for intra and inter-observer agreement evaluation. To evaluate safety, we correlated the treatment performed based on the TLICS with the newer AO classification obtained. Fifty-four patients were included in this study, with a mean follow-up of 363.8 days. Twenty-three neurologically intact patients were initially treated conservatively. Their mean TLICS was 1.78 (1-4 points). Four patients underwent late surgery. Thirty-one patients were treated surgically. Their average TLICS was 7.22 points (4-10 points). Agreements in the four independent evaluations according to AO groups and subgroups were of 64.8% (35/54) and 55.5% (30/54) respectively. Kappa index for groups A, B and C was 0.75, 0.7 and 0.85 respectively. Kappa index for subgroups ranged from 0.16 to 0.85. Regarding safety, thirty (57.6%) patients with total subgroups agreement were analyzed. All patients with fracture in groups B and C underwent surgical treatment and patients in group A received surgery according to neurological status or failure of conservative treatment. The newer AO spine classification demonstrated good reliability at the level of groups. Subgroups demonstrated worse and varying reliability. Although the safety analysis was limited due to the low level of total concordance among all evaluations, patients from group A can be treated conservatively or surgically, whereas those from groups B and C are treated surgically.


Multi-Timescale Rhythmicity of Blood Glucose and Insulin Delivery Reveals Key Advantages of Hybrid Closed Loop Therapy.
Blood glucose and insulin exhibit coordinated daily and hourly rhythms in people without diabetes (nonT1D). Although the presence and stability of these rhythms are associated with euglycemia, it is unknown if they (1) are preserved in individuals with type 1 diabetes (T1D) and (2) vary by therapy type. In particular, Hybrid Closed Loop (HCL) systems improve glycemia in T1D compared to Sensor Augmented Pump (SAP) therapies, but the extent to which either recapitulates coupled glucose and insulin rhythmicity is not well described. In HCL systems, more rapid modulation of glucose via automated insulin delivery may result in greater rhythmic coordination and euglycemia. Such precision may not be possible in SAP systems. We hypothesized that HCL users would exhibit fewer hyperglycemic event, superior rhythmicity, and coordination relative to SAP users. Wavelet and coherence analyses were used to compare glucose and insulin delivery rate (IDR) within-day and daily rhythms, and their coordination, in 3 datasets: HCL (n = 150), SAP (n = 89), and nonT1D glucose (n = 16). Glycemia, correlation between normalized glucose and IDR, daily coherence of glucose and IDR, and amplitude of glucose oscillations differed significantly between SAP and HCL users. Daily glucose rhythms differed significantly between SAP, but not HCL, users and nonT1D individuals. SAP use is associated with greater hyperglycemia, higher amplitude glucose fluctuations, and a less stably coordinated rhythmic phenotype compared to HCL use. Improvements in glucose and IDR rhythmicity may contribute to the overall effectiveness of HCL systems.


Lymphocyte participation in wound healing. Morphologic assessment using monoclonal antibodies.
To investigate lymphocyte participation in wound healing, the migration of T lymphocyte subsets into healing wounds and subcutaneously implanted polyvinyl alcohol sponges was studied. Frozen sections of 5-, 7-, and 10-day-old incisional wounds and sponges from Lewis rats were stained with mouse anti-rat monoclonal antibodies. Cellular staining to OX1 (all leucocyte), W3/25 (helper/effector T lymphocytes), and OX8 (suppressor/cytotoxic T lymphocytes) was quantitated in two arbitrarily defined areas based on maximal cellular infiltration: the superficial wound, down to and including the papillary dermis, and the deep wound, the reticular dermis. Five-day wounds were significantly more cellular than 10-day wounds in the deep portion (p less than 0.05) and somewhat more cellular in the superficial section (p less than 0.10). Approximately 2:1 W3/25 to OX8 ratios were noted for wound strips on all days. At 5 and 10 days there are twice as many W3/25 and OX8 labeled cells in the deep wound as in the superficial portion. At 7 days there is a peak in surface W3/25 and OX8 lymphocytes, whereas the deep population remains constant. Seven- and 10-day sponge granulomas demonstrate ratios similar to the wound strips (5-day sponge lymphocytic infiltration was insufficient to count). The data demonstrate that lymphocyte subpopulation participation in wound healing is a dynamic and distinctive process.


Stereocontrolled Synthesis of α-3-Deoxy-d-manno-oct-2-ulosonic Acid (α-Kdo) Glycosides Using C3-p-Tolylthio-Substituted Kdo Donors: Access to Highly Branched Kdo Oligosaccharides.
3-Deoxy-d-manno-oct-2-ulosonic acid (Kdo) is an eight-carbon monosaccharide found widely in bacterial lipopolysaccharides (LPSs) and capsule polysaccharides (CPSs). We developed an indirect method for the stereoselective synthesis of α-Kdo glycosides with a C3-p-tolylthio-substituted Kdo phosphite donor. The presence of the p-tolylthio group enhanced the reactivity, suppressed the formation of elimination by-products (2,3-enes), and provided complete α-stereocontrol. A variety of Kdo α-glycosides were synthesized by our method in excellent yields (up to 98 %). After glycosylation, the p-tolylthio group can be efficiently removed by free-radical reduction. Subsequently, the orthogonality of the phosphite donor and thioglycoside donor was demonstrated by the one-pot synthesis of a trisaccharide in Helicobacter pylori and Neisseria meningitidis LPS. Moreover, an efficient total synthesis route to the challenging 4,5-branched Kdo trisaccharide in LPSs from several A. baumannii strains was highlighted. To demonstrate the high reactivity of our approach further, the highly crowded 4,5,7,8-branched Kdo pentasaccharide was synthesized as a model molecule for the first time. Additionally, the reaction mechanism was investigated by DFT calculations.


Prenatal education in a high-risk population: the effect on birth outcomes.
This case-control investigation examined the relationship between absence of specific educational content during prenatal care and risk of adverse birth outcomes. A total of 1484 women from three regions with high rates of low birthweight and infant mortality participated in structured postpartum interviews. Analyses were performed for both the full sample and three regional subsamples. For the full sample an adjusted risk ratio of 2.87 (95% CI = 1.75, 4.71) was noted between risk of preterm low birthweight and lack of advice to call the health provider if preterm labor were suspected. For one subsample an adjusted risk ratio of 2.50 (95% CI = 1.11, 5.60) was noted between the risk of preterm low birthweight and lack of education on the signs and symptoms of preterm labor. This study reinforces a body of literature that stresses the importance of appropriate prenatal care in preventing preterm low birthweight. It further suggests that adequacy measures of prenatal care should reflect quality and content as well as timing and number of prenatal visits.


[Decimeter radiothermometry in neurologic manifestations of lumbar osteochondrosis].
Using radiothermometry, a new noninvasive method based on recording the thermoradiation of tissues, the authors studied the in-depth temperature of tissues in 106 patients with lumbar osteochondrosis. A radiothermometer adjusted to a wave length of 30 cm was utilized. The accuracy of measurements was +/- 0.1 degree C. The findings showed an elevation of the in-depth temperature of lumbar tissues by 0.3 degree C as compared with the temperature of the mid-thoracic portion of the vertebral column. The elevation was maximal at the site of the involved intervertebral disc imaging. In the tissue of the leg on the side of pain the in depth temperature was 0.4-0.6 degrees C lower. The authors consider that temperature elevation in the lumbar tissue of the vertebral column is a manifestation of the attendant reactive inflammatory process while a decrease in the temperature of tissue on the side of pain is due to the neurodystrophic process with thermal disturbances. Decimetric radiothemometry may be used for the preoperative localization of intervertebral disk hernias.


Dietary strategies to improve the iron and zinc nutriture of young women following a vegetarian diet.
Dietary strategies to enhance the content and bioavailability of iron and zinc in vegetarian diets were compiled. Strategies included increasing promoters and decreasing antagonists of iron and zinc absorption, adopting food preparation and processing methods which hydrolyze the phytate content of cereals and legumes, and using iron cookware. These strategies were used to devise two vegetarian menus based on food consumption patterns derived from three day weighed food records of 78 Canadian lacto-ovo-vegetarian adolescents. The iron and zinc, as well as calcium, phosphorus, thiamin, riboflavin, niacin, vitamin A, protein and energy content of the devised menus were all higher than the actual intakes and the corresponding Canadian recommended nutrient intakes. Results show the overall nutrient adequacy of the recommended vegetarian menus and indicate that young lacto-vegetarian women can potentially meet their estimated dietary requirements for absorbed iron and zinc through modest modifications to the diet. Laboratory studies designed to measure the total amount of iron and zinc absorbed from these diets by young vegetarian women are needed to verify the efficacy of the devised menus.


Cola drinks consumption and oesophagitis.
For oesophageal epithelial changes to develop from gastro-oesophageal reflux disease (GORD), the character of the refluxate must be acid enough to cause injury. Experimentally, copious perfusion of the oesophagus with weak acid is quite harmless. However, hydrochloric acid alone with a pH below 3.0 may cause oesophageal injury. Cola drinks are strongly acidic (pH 2.5). This study analyses the influence of and possible interaction between cola consumption and oesophagitis. Twenty rats were divided into two groups of 10. The animals received saline (pH 7.0) or cola (pH 2.6) per OS with 24 h free access to these solutions. After the experiment the oesophagus was dissected. The mucosa was macroscopically and histopathologically examined, and flow cytometric analysis was used to look for proliferative activity. The histopathological analysis showed that there is no difference between saline and cola. But the findings of cell cycle analysis showed that the effects of cola and saline in inducing oesophageal mucosal damage are different. In the cola group the values were G0/G1, 7.33 +/- 2.88; S, 29.88 +/- 2.88; G2/M, 0.10 +/- 0.01; PI (proliferative-regenerative index), 29.76 +/- 2.88. The rat cell population g0/g1 phases were found to be low (p < 0.01), and the cell population S and PI phases were found to be significantly elevated compared with the control group (p < 0.01). (G0/G1, 79.30 +/- 5.97; S, 16.06 +/- 8.27; G2/M, 4.66 +/- 4.03; PI, 20.03 +/- 6.01). These results were reflected in the proliferative index, which is used as a measure of the regeneration index. The data show that cola has proliferative and regenerative effects on the oesophageal mucosa, and it is possible that its regenerative effect is caused as a result of an irritant effect.


A novel system to provide information via online YouTube videos and an evaluation of current online information about hereditary breast cancer.
The internet, especially YouTube, has become a prominent source of health information. However, the quality and accuracy of medical content on YouTube vary, posing concerns about misinformation. This study focuses on providing reliable information about hereditary breast cancer on YouTube, given its importance for decision-making among patients and families. The study examines the quality and accessibility of such content in Japanese, where limited research has been conducted. A nonprofit organization called BC Tube was established in May 2020 to create informative videos about breast cancer. The study analyzed 85 YouTube videos selected using the Japanese keywords "hereditary breast cancer" and "HBOC", categorized into six groups based on the source of upload: BC Tube, hospitals/governments, individual physicians, public-interest organizations/companies, breast cancer survivors, and others. The videos were evaluated based on various factors, including content length, view counts, likes, comments, and the presence of advertisements. The content was evaluated using the PEMAT and DISCERN quality criteria. BC Tube created high-quality videos with high scores on PEMAT understandability, significantly outperforming other sources. Videos from public-interest organizations/companies received the most views and likes, despite their lower quality. Videos from medical institutions and governments were of superior quality but attracted less attention. Our study emphasizes the importance of promoting accessible, easy-to-understand, and widely recognized medical information online. The popularity of videos does not always correspond to their quality, emphasizing the importance of quality evaluation. BC Tube provides a peer-reviewed platform to disseminate high-quality health information. We need to develop high-quality online health information and encourage the promotion of evidence-based information on YouTube.


Activation of MAP kinase signaling through ERK5 but not ERK1 expression is associated with lymph node metastases in oral squamous cell carcinoma (OSCC).
In an attempt to further elucidate the pathomechanisms in oral squamous cell carcinoma (OSCC), gene expression profiling was performed using a whole-transcriptome chip that contains 35,035 gene-specific 70 mere oligonucleotides (Human OligoSet 4.0; Operon, Cologne, Germany) to a set of 35 primary OSCCs. Altogether, 7390 genes were found differentially expressed between OSCC tumor samples and oral mucosa. To characterize the major biologic processes in this tumor collection, MAPPFinder, a component of GenMAPP version 2.1, was applied to this data set to generate a statistically ranked list of molecular signaling pathways. Among others, cancer-related pathways, such as mitogen-activated protein (MAP) kinase signaling (z score = 4.6, P < .001), transforming growth factor-beta signaling (z score = 3.0, P = .015), and signaling pathways involved in apoptosis (z score = 2.1, P = .037), were found deregulated in the OSCC collection analyzed. Focusing on the MAP kinase signaling pathway, subsequent tissue microarray analyses by immunohistochemistry revealed an increase in protein expression of MAP kinase-related proteins ERK1 in 22.8% (48 of 209) and ERK5 in 27.4% (76 of 277), respectively. An association of high ERK5 but not of high ERK1 expression with advanced tumor stage and the presence of lymph node metastases was found (P = .008 and P = .016, respectively). Our analysis demonstrates the reliability of the combined approach of gene expression profiling, signaling pathway analyses, and tissue microarray analysis to detect novel distinct molecular aberrations in OSCC.


Lack of relation of AKAP12 with p53 and Bcl-2 in colorectal carcinoma.
AKAP12 inhibits oncogenic proliferation, invasion, chemotaxis and neovascularization. Bcl-2 and p53 are two important apoptotic markers that play roles in apoptotic processes. It has been found that AKAP12 blocks the cell cycle and induces apoptosis in fibrosarcoma cells. In our study we assessed the relationship of AKAP12 with apoptotic markers, Bcl-2 and p53. Our study included 45 cases that were histopathologically diagnosed with colorectal carcinoma from the tissue samples acquired by surgical resection. AKAP 12, Bcl-2, and p53 expression was examined by immunohistochemistry. A total of 45 colorectal adenocarcinoma patients - 17 (37.8%) females and 28 (62.2%) males - were included in this study. AKAP12 expression was found to be negative in 8 patients (17.8%), and positive in 37 patients (82.2%). Bcl-2 was found positive in 6 patients (13.3%) and p53 in 29 patients (55.6%). AKAP12 expression had no significant relation with Bcl-2 and p53 expression (p:0.939, p:0.079, respectively). Although various studies have pointed to apoptotic activity of AKAP12, the literature is limited regarding relations with p53 or Bcl-2 expression. In the present study, we found no relation in colorectal carcinomas.


Measuring the burden and mortality of hospitalisation in Parkinson's disease: A cross-sectional analysis of the English Hospital Episodes Statistics database 2009-2013.
Patients with Parkinson's disease have higher hospital admission rates than the general population. We examined the reasons for admission, length of stay, costs, and in-hospital mortality in a national sample of Parkinson's disease patients. We used hospital admission data from the English Hospital Episodes Statistics database (2009-2013). Patients with Parkinson's disease or Parkinson's disease dementia and aged over 35 years were compared to all other admissions, excluding the above, with the same age criteria. We examined reasons for admissions (ICD-10), length of stay and in-hospital mortality. We used indirect standardisation and Poisson modelling to derive proportional ratios adjusting for age group and sex. There were 324,055 Parkinson's disease admissions in 182,859 patients over 4 years which included 232,905 non-elective admissions (72%). This resulted in expenditure of £907 million (£777 million for non-elective admissions). The main reasons for admission were pneumonia (13.5%), motor decline (9.4%), urinary tract infection (9.2%), and hip fractures (4.3%). These conditions occurred 1.5 to 2.6 times more frequently in patients than controls. Patients with Parkinson's disease were almost twice as likely to stay in hospital for more than 3 months (ratio 1.90, 95% CI 1.83, 1.97) and even more likely die in hospital (ratio 2.46, 95% CI 2.42, 2.49). Parkinson's disease patients in England have higher rates of emergency admissions with longer hospital stays, higher costs and in-hospital mortality. Urgent attention should be given to developing cost-effective interventions to reduce the burden of hospitalisation for patients, carers and healthcare systems.


Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father.
In humans, mutations in the testis-determining gene SRY result in XY sex reversal with pure gonadal dysgenesis (PGD). However, only about 10-15% of the cases of PGD can be explained by mutations within the SRY open reading frame, suggesting the existence of other sex-determining genes. Although SRY is known to bind and bend DNA, its target and mode of action remain elusive. Here, we describe a novel mutation in SRY at codon 127, resulting in a tyrosine (Y) to phenylalanine (F) substitution in the protein. This sequence variant was found not only in the XY female patient but also in her father, who is a phenotypically normal male. However, this Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggest that the Y127F variant is a novel mutation with functional consequences and not simply a polymorphism. The allelic variant of SRY transmitted in this family and shared by both a phenotypic female (proband) and a phenotypic male (proband's father) emphasizes the importance of modifier genes in the sex determination pathway.


Gradient static-strain stimulation in a microfluidic chip for 3D cellular alignment.
Cell alignment is a critical factor to govern cellular behavior and function for various tissue engineering applications ranging from cardiac to neural regeneration. In addition to physical geometry, strain is a crucial parameter to manipulate cellular alignment for functional tissue formation. In this paper, we introduce a simple approach to generate a range of gradient static strains without external mechanical control for the stimulation of cellular behavior within 3D biomimetic hydrogel microenvironments. A glass-supported microfluidic chip with a convex flexible polydimethylsiloxane (PDMS) membrane on the top was employed for loading the cells suspended in a prepolymer solution. Following UV crosslinking through a photomask with a concentric circular pattern, the cell-laden hydrogels were formed in a height gradient from the center (maximum) to the boundary (minimum). When the convex PDMS membrane retracted back to a flat surface, it applied compressive gradient forces on the cell-laden hydrogels. The concentric circular hydrogel patterns confined the direction of hydrogel elongation, and the compressive strain on the hydrogel therefore resulted in elongation stretch in the radial direction to guide cell alignment. NIH3T3 cells were cultured in the chip for 3 days with compressive strains that varied from ~65% (center) to ~15% (boundary) on hydrogels. We found that the hydrogel geometry dominated the cell alignment near the outside boundary, where cells aligned along the circular direction, and the compressive strain dominated the cell alignment near the center, where cells aligned radially. This study developed a new and simple approach to facilitate cellular alignment based on hydrogel geometry and strain stimulation for tissue engineering applications. This platform offers unique advantages and is significantly different from the existing approaches owing to the fact that gradient generation was accomplished in a miniature device without using an external mechanical source.


Alternate-day clonazepam treatment of intractable seizures.
Several investigations have demonstrated a reduction in benzodiazepine receptor binding after long-term exposure to this class of drugs. Such receptor alterations may contribute to the decreased efficacy of benzodiazepines in the management of convulsive disorders. To minimize receptor alterations, several patients with intractable seizures received alternate-day clonazepam therapy, resulting in improved seizure control. The favorable clinical responses suggest that alternative methods of benzodiazepine administration may circumvent receptor subsensitivity resulting from prolonged drug treatment.


Solution structure of the symmetric coiled coil tetramer formed by the oligomerization domain of hnRNP C: implications for biological function.
During active cell division, heterogeneous nuclear ribonucleoprotein (hnRNP) C is one of the most abundant proteins in the nucleus. hnRNP C exists as a stable tetramer that binds about 230 nucleotides of pre-mRNA and functions in vivo to package nascent transcripts and nucleate assembly of the 40 S hnRNP complex. Previous studies have shown that monomers lacking or possessing mutant oligomerization domains bind RNA with low affinity, strongly suggesting a cooperative protomer-RNA binding mode. In order to understand the role of the oligomerization domain in defining the biological functions and structure of hnRNP C tetramers, we have determined the high-resolution NMR structure of the oligomerization interface that is formed at the core of the complex, examining specific molecular interactions that drive assembly and contribute to the structural integrity of the tetramer. The determined structure reveals an antiparallel four-helix coiled coil, where classically described knobs-into-holes packing interactions at interhelical contact surfaces are optimized so that side-chains interdigitate to create an even distribution of hydrophobic surfaces along the core. While the stoichiometry of the complex appears to be primarily specified by occlusion of hydrophobic surfaces, particularly the interfacial residue L198, from solvent, helix orientation is primarily determined by electrostatic attractions across helix interfaces. The creation of potential interaction surfaces for other hnRNP C domains along the coiled coil exterior and the assembly of oligomerization interfaces in an antiparallel orientation shape the tertiary fold of full-length monomers and juxtapose RNA-binding elements at distal surfaces of the tetrameric complex in the quaternary assembly. In addition, we discuss the specific challenges encountered in structure determination of this symmetric oligomer by NMR methods, specifically in sorting ambiguous interatomic distance constraints into classes that define different elements of the coiled coil structure.


Altered Hox expression and increased cell death distinguish Hypodactyly from Hoxa13 null mice.
Hypodactyly (Hoxa13Hd) mice have a small deletion within the coding sequence of Hoxa13 and a limb phenotype that is more severe than that of mice with an engineered null allele of Hoxa13. We used whole-mount in situ hybridization, Nile blue sulfate staining and genetic crosses to determine the basis for the phenotypic differences between these two mutants. Expression of Hoxd13 was unaffected in Hoxa13-/- mice, but its domain was reduced at the anterior and posterior margins of the autopod in Hoxa13Hd/Hd limb buds. The maturation of Hoxd11 expression was delayed and expression of Hoxa11 failed to become restricted to the autopod/zeugopod junction in both Hoxa13Hd/Hd and Hoxa13-/- limb buds compared to wild-type mice. Fgf8 expression was normal in both Hoxa13Hd/Hd and Hoxa13-/- mice throughout limb development. A dramatic increase in cell death was observed in limb bud mesenchyme of Hoxa13Hd/Hd mice as early as E11.5 but not in mice homozygous for the null allele. Genetic background was excluded as the basisforthe phenotypic differences. Compound heterozygotes (Hoxa13-/Hd) displayed an intermediate phenotype relative to both homozygotes suggesting that Hoxa13Hd has an effect on the development of the autopod beyond that which may result from a loss of HOXA13 protein. These results showthat Hoxa13Hd has a negative effect on the survival of the mesenchyme in the autopod, unlike the Hoxa13 null mutation, that cannot be explained by a failure of the AER to express Fgfs. In addition, at least one target of HOXA13 may be Hoxa11.


Nitrosamine exposure causes insulin resistance diseases: relevance to type 2 diabetes mellitus, non-alcoholic steatohepatitis, and Alzheimer's disease.
The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies showed that streptozotocin, a nitrosamine-related com-pound, causes insulin resistance diseases including, T2DM, NASH, and AD-type neurodegeneration. We hypothesize that chronic human exposure to nitrosamine compounds, which are widely present in processed foods, contributes to the pathogenesis of T2DM, NASH, and AD. Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. (x3) or i.c. (x1) injection, and 2-4 weeks later, they were evaluated for cognitive-motor dysfunction, insulin resistance, and neurodegeneration using behavioral, biochemical, and molecular approaches. NDEA treatment caused T2DM, NASH, deficits in motor function and spatial learning, and neurodegeneration characterized by insulin resistance and deficiency, lipid peroxidation, cell loss, increased levels of amyloid-beta protein precursor/amyloid-beta, phospho-tau, and ubiquitin immunoreactivities, and upregulated expression of pro-inflammatory cytokine and pro-ceramide genes, which together promote insulin resistance. In conclusion, environmental and food contaminant exposures to nitrosamines play critical roles in the pathogenesis of major insulin resistance diseases including T2DM, NASH, and AD. Improved detection and prevention of human exposures to nitrosamines will lead to earlier treatments and eventual quelling of these costly and devastating epidemics.


Analysis of transcription factor network underlying 3T3-L1 adipocyte differentiation.
Lipid accumulation in adipocytes reflects a balance between enzymatic pathways leading to the formation and breakdown of esterified lipids, primarily triglycerides. This balance is extremely important, as both high and low lipid levels in adipocytes can have deleterious consequences. The enzymes responsible for lipid synthesis and breakdown (lipogenesis and lipolysis, respectively) are regulated through the coordinated actions of several transcription factors (TFs). In this study, we examined the dynamics of several key transcription factors (TFs) - PPARγ, C/EBPβ, CREB, NFAT, FoxO1, and SREBP-1c - during adipogenic differentiation (week 1) and ensuing lipid accumulation. The activation profiles of these TFs at different times following induction of adipogenic differentiation were quantified using 3T3-L1 reporter cell lines constructed to secrete the Gaussia luciferase enzyme upon binding of a TF to its DNA binding element. The dynamics of the TFs was also modeled using a combination of logical gates and ordinary differential equations, where the logical gates were used to explore different combinations of activating inputs for PPARγ, C/EBPβ, and SREBP-1c. Comparisons of the experimental profiles and model simulations suggest that SREBP-1c could be independently activated by either insulin or PPARγ, whereas PPARγ activation required both C/EBPβ as well as a putative ligand. Parameter estimation and sensitivity analysis indicate that feedback activation of SREBP-1c by PPARγ is negligible in comparison to activation of SREBP-1c by insulin. On the other hand, the production of an activating ligand could quantitatively contribute to a sustained elevation in PPARγ activity.


Words can hurt: The effects of physical and psychological partner violence on condom negotiation and condom use among young women.
Physical and psychological intimate partner violence (IPV) are prevalent on college campuses and may affect young women's condom use behavior. This study explored condom negotiation as a mediator of the relation of physical and psychological IPV to condom use among college women. A total of 235 heterosexual college women were recruited during September 2012-May 2013. Participants completed online questionnaires assessing lifetime history of IPV, frequency of condom negotiation, and use of condoms during the last 30 days. Specific forms of psychological IPV were related to less condom use. This association was mediated by condom negotiation, such that those who had experienced psychological IPV were less likely to negotiate condom use, and as a result, less likely to report using condoms in the past 30 days. Campus-based sexual health efforts should consider the relation of psychological IPV to condom negotiation and condom use and offer skills to promote condom negotiation among college women to increase condom use and reduce their risk of sexually transmitted infections.


Comparison of two dimensional and three dimensional radiotherapy treatment planning in locally advanced non-small cell lung cancer treated with continuous hyperfractionated accelerated radiotherapy weekend less.
Patients with inoperable non-small cell lung cancer being treated with continuous hyperfractionated accelerated radiotherapy weekend less (CHARTWEL) were planned and treated with a three dimensional (3D) conformal protocol and comparison made with two dimensional (2D) planning, as used previously, to compare past practice and methods. Twenty-four patients were planned initially using 3D and then replanned using a 2D system. The 2D plans were transferred onto the 3D system and recalculated. Dose volume histograms could then be constructed of planning target volumes for phases 1 and 2 (PTV 1 and 2, respectively), lung and spinal cord for the 2D plans and compared with the 3D plans. There was a significantly lower absolute dose to the isocentre with 2D compared to 3D planning with dose reductions of 3.9% for phase 1, 4.4% for phase 2 and 4.7% for those treated with a single phase. Maximum dose to spinal cord was greater in 17 of the 24 2D plans with a median dose reduction of 0.82 Gy for 3D (P=0.04). The percentage volume of whole lung receiving > or =20 Gy (V20) was greater in 16 of the 24 2D plans with a median reduction in V20 of 2.4% for 3D (P=0.03). A lower dose to tumour was obtained using 2D planning due to the method of dose calculation and spinal cord and lung doses were significantly higher.


Validation of a novel, objective measure of occupational sitting.
To test the validity of a sitting pad (SP) to measure desk based sitting time and transitions, against camera derived direct observation; and to compare the data with those from inclinometers in the ActivPAL(3) (AP) and ActiGraph GT3X+ (AG). Australian employees (n=13; 9 women; mean age 30 ± 6.5 years) were provided with a SP, AG and AP in 2011. A camera recorded chair based transitions during a prescribed and a free living protocol. Mean sitting time and transitions were calculated for each device and intra-class correlations (ICCs) and mean differences between (a) the SP and the camera and (b) the AP, AG and camera, were compared. During the prescribed protocol, the smallest mean differences compared with the camera were for the SP; sitting time 0.30 ± 0.21 minutes, transitions -0.46 ± 0.78. During free living, both the SP and AP (set to record events greater than 3 seconds) showed excellent levels of agreement with the camera for sitting time (0.999 and 0.990 respectively) and transitions (0.997 and 0.928 respectively). Agreement between the camera and the AG was poor for both sitting time and transitions (0.257 and 0.033 respectively). The SP is a highly accurate measure of desk based sitting time and transitions and provides novel measurement and intervention opportunities for research into occupational sitting.


Metagenomes Binning Using Proximity-Ligation Data.
Microbial communities are key components of all ecosystems, but characterization of their complete genomic structure remains challenging. Typical analysis tends to elude the complexity of the mixes in terms of species, strains, as well as extrachromosomal DNA molecules. Recently, approaches have been developed that bins DNA contigs into individual genomes and episomes according to their 3D contact frequencies. Those contacts are quantified by chromosome conformation capture experiments (3C, Hi-C), also known as proximity-ligation approaches, applied to metagenomics samples. Here, we present a simple computational pipeline that allows to recover high-quality Metagenomics Assemble Genomes (MAGs) starting from metagenomic 3C or Hi-C datasets and a metagenome assembly.


[Primary angiosarcoma of the spleen].
Primary spleen angiosarcoma is a malignant neoplasia based on vascular tissue and it is a rare tumor (65 cases published). The clinical aspects are obscure and the specific diagnosis is made by laparotomy. The prognosis is very poor in any case and survival isn't more than two years, whenever the spleen undergoes spontaneous rupture in which case the survival should be less than six months. The splenectomy before rupture could increase survival. Patients with or without metastatic disease may be treated by chemotherapy but with poor results. Radiotherapy is used for relief the pain produced for bone metastasis.


Strong Correlation between Ferromagnetic Superconductivity and Pressure-enhanced Ferromagnetic Fluctuations in UGe_{2}.
We have measured magnetization at high pressure in the uranium ferromagnetic superconductor UGe_{2} and analyzed the magnetic data using Takahashi's spin fluctuation theory. There is a peak in the pressure dependence of the width of the spin fluctuation spectrum in the energy space T_{0} at P_{x}, the phase boundary of FM1 and FM2 where the superconducting transition temperature T_{sc} is highest. This suggests a clear correlation between the superconductivity and pressure-enhanced magnetic fluctuations developed at P_{x}. The pressure effect on T_{Curie}/T_{0}, where T_{Curie} is the Curie temperature, suggests that the less itinerant ferromagnetic state FM2 is changed to a more itinerant one FM1 across P_{x}. Peculiar features in relations between T_{0} and T_{sc} in uranium ferromagnetic superconductors UGe_{2}, URhGe, and UCoGe are discussed in comparison with those in high-T_{c} cuprate and heavy fermion superconductors.


Progressive dystonia in a 12-year-old boy.
Pantothenate kinase-associated neurodegeneration (PKAN) (MIM 234200; Hallervorden-Spatz syndrome) is a degenerative, autosomal recessive disorder in childhood, currently without specific treatment. In contrast to variable clinical features, T2-weighted magnetic resonance images show a characteristic 'eye-of-the-tiger sign' in the globus pallidus due to excess iron deposition. Recently a defect in pantothenate kinase, the key regulatory enzyme in the synthesis of coenzyme A from pantothenate, has been identified as the cause of the disease. We report a 12-year-old boy with progressive rigidity, dystonia, impaired voluntary movement, dysarthria, and mental deterioration. Over 10 years the boy had been misdiagnosed with clumsiness, emotional and behavioural deficits, and attention deficit disorder, before neuroimaging was performed showing the characteristic 'eye-of-the-tiger sign'. Molecular analyses confirmed two mutations in the PANK2 gene [coding sequence of a gene that has homology to murine pantothenate kinase-1]. We conclude that in progressive childhood dystonia, PKAN should be considered and magnetic resonance imaging performed early. The newly described defect of the pantothenate kinase enzyme enables a novel therapeutic approach to be considered, based on the mutation analyses of the PANK2 gene, as well as the prenatal diagnosis of this disorder.


Quantitation of enantiomers of r-7,t-8,9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]-pyrene in human urine: evidence supporting metabolic activation of benzo[a]pyrene via the bay region diol epoxide.
Benzo[a]pyrene (BaP), a potent polycyclic aromatic hydrocarbon carcinogen, is widely distributed in the human environment. All humans are exposed to BaP through the diet and contact with the general environment; cigarette smokers have higher exposure. An important pathway of BaP metabolism proceeds through formation of diol epoxides including the 'bay region diol epoxide' 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [BaP-(7R,8S)-diol-(9S,10R)-epoxide] and the 'reverse diol epoxide' 9S,10R-dihydroxy-7R,8S-epoxy-7,8,9,10-tetrahydrobenzo [a]pyrene [BaP-(9S,10R)-diol-(7R,8S)-epoxide]. The bay region diol epoxide is considered a major ultimate carcinogen of BaP based on studies in cell culture and laboratory animals, but the available data in humans are less convincing. The bay region diol epoxide and the reverse diol epoxide react with H2O to produce enantiomeric BaP-tetraols that are excreted in the urine. We used chiral stationary-phase high-performance liquid chromatography and gas chromatography-negative ion chemical ionisation-tandem mass spectrometry to quantify these enantiomeric BaP-tetraols in the urine of 25 smokers and 25 non-smokers. The results demonstrated that the BaP-tetraol enantiomer representing the carcinogenic bay region diol epoxide pathway accounted for 68±6% (range 56-81%) of total BaP-tetraol in smokers and 64±6% (range 46-78%) in non-smokers. Levels of the major BaP-tetraol enantiomer decreased by 75% in smokers who quit smoking. These data provide convincing evidence in support of the bay region diol epoxide mechanism of BaP carcinogenesis in humans.


A κ Opioid Pharmacophore Becomes a Spinally Selective κ-δ Agonist When Modified with a Basic Extender Arm.
We have explored the concept of a molecular extender arm attached to a κ opioid agonist pharmacophore 3 (ICI-199,441) in an effort to potentially interact with a complementary group on a neighboring opioid receptor. The molecular arm containing a terminal amine group was lengthened incrementally from 11 up to 18 atoms. Increasing the number of atoms in the arm produced virtually no change in the mouse intracerebroventricular (i.c.v.) antinociceptive potency. In contrast, the intrathecal (i.t.) potency of 6 (KDA-16) with a 16-atom arm was dramatically increased, as reflected by its antinociceptive i.c.v./i.t. ED50 ratio of ∼130. Further lengthening led to a decreased ED50 ratio. In vivo selective antagonist studies of KDA-16 revealed that κ and δ opioid receptors were responsible for the greatly enhanced i.t. potency. Calcium release experiments in HEK-293 cells suggested that KDA-16 selectively activate κ-δ heteromers. These data are consistent with the reported possible presence of heteromeric κ-δ opioid receptors in mouse spinal cord but not in the brain. The use of a molecular extender arm may be useful for developing spinally selective analgesics.


Protocol for 'Resilient Caregivers': a randomised trial of a resilience-based intervention for psychologically distressed partner caregivers of patients with cancer.
Intimate partners of patients with cancer often experience significant distress, but there is a lack of psychological interventions that specifically target this population. 'Resilient Caregivers' is a novel resilience-based intervention for distressed partner cancer caregivers. The intervention was developed according to a resilience framework focusing on meta-reflective skills, coping strategies and value clarification. The aim of this study is to evaluate the effectiveness of this intervention in a randomised trial. Eighty participants will be invited through the Oncology Department at Herlev Hospital, Denmark and randomised to either the intervention or usual care. Participants are eligible if they are partners (married or unmarried) of patients diagnosed with cancer and experience distress (>4 on the distress thermometer). 'Resilient Caregivers' consists of seven manualised group sessions (2.5 hours each), focusing on resilience in relation to being a partner caregiver of a patient with cancer. The primary outcome is symptoms of anxiety, while secondary outcomes include distress, depression, quality of life, sleep quality and resilience. Data will be collected at baseline, 3, 6 and 12 months follow-up using validated scales, and analysed using mixed models for repeated measures. This study will follow the ethical principles in the Declaration of Helsinki and has been reviewed by the Ethics Committee of the Capital Region of Denmark (Journal no. 18055373). Written informed consent will be obtained from all participants. Results will be reported through scientific peer-reviewed journals and relevant conferences. NCT04610034.


Effect of yoga training on exercise tolerance in adolescents with childhood asthma.
Forty six young asthmatics with a history of childhood asthma were admitted for yoga training. Effects of training on resting pulmonary functions, exercise capacity, and exercise-induced bronchial lability index were measured. Yoga training resulted in a significant increase in pulmonary function and exercise capacity. A follow-up study spanning two years showed a good response with reduced symptom score and drug requirements in these subjects. It is concluded that yoga training is beneficial for young asthmatics.


Norepinephrine, the beta-adrenergic receptor, and immunity.
Over the past 20 years, a significant effort has been made to define a role for the neuroendocrine system in the regulation of immunity. It was expected that these experimental findings would help to establish a strategy for the development of clinical interventions to either suppress or augment immunological function for disease prevention. However, the translation of these basic experimental findings into clinical interventions has been difficult. Possible explanations for this difficulty are that the findings from human and animal studies do not agree and/or that the results obtained within one species are rarely verified in the other. Our goal in writing this review is to address this issue by summarizing the published findings from human studies and comparing them to published findings from animal studies. Although far from being exhaustive, this review summarizes and discusses at least the past 10 years of findings in which a change in immunity and a change in catecholamine levels and/or stimulation of the beta(2)-adrenergic receptor has been documented.


eIF5B gates the transition from translation initiation to elongation.
Translation initiation determines both the quantity and identity of the protein that is encoded in an mRNA by establishing the reading frame for protein synthesis. In eukaryotic cells, numerous translation initiation factors prepare ribosomes for polypeptide synthesis; however, the underlying dynamics of this process remain unclear1,2. A central question is how eukaryotic ribosomes transition from translation initiation to elongation. Here we use in vitro single-molecule fluorescence microscopy approaches in a purified yeast Saccharomyces cerevisiae translation system to monitor directly, in real time, the pathways of late translation initiation and the transition to elongation. This transition was slower in our eukaryotic system than that reported for Escherichia coli3-5. The slow entry to elongation was defined by a long residence time of eukaryotic initiation factor 5B (eIF5B) on the 80S ribosome after the joining of individual ribosomal subunits-a process that is catalysed by this universally conserved initiation factor. Inhibition of the GTPase activity of eIF5B after the joining of ribosomal subunits prevented the dissociation of eIF5B from the 80S complex, thereby preventing elongation. Our findings illustrate how the dissociation of eIF5B serves as a kinetic checkpoint for the transition from initiation to elongation, and how its release may be governed by a change in the conformation of the ribosome complex that triggers GTP hydrolysis.


Amino acids and peptides. XXIX. Synthesis of peptide fragments related to active center of eglin c and studies on the relationship between their structure and their inhibitory activity against cathepsin G and alpha-chymotrypsin.
H-Ser-Pro-Val-Thr-Leu-Asp-Leu-Arg-Tyr-OMe, corresponding to the sequence 41-49 of eglin c, inhibited human leukocyte cathepsin G and alpha-chymotrypsin. In order to gain further insight into the relationship between the structure and the inhibitory activity against cathepsin G and alpha-chymotrypsin, peptide fragments related to the above nonapeptide were synthesized by a conventional solution method and their inhibitory activities were examined. The smallest peptide which exhibited inhibitory effects on the above enzymes was H-Pro-Val-Thr-Leu-OMe, corresponding to the sequence 42-45 of eglin c.


Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis.
Understanding the host immune response during cryptococcal meningitis (CM) is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF) immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical outcome. CSF cytokine, chemokine, and macrophage activation marker concentrations were assayed at disease presentation, and associations between these parameters and microbiological and clinical outcomes were examined using principal component analysis (PCA). PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence of increased macrophage activation, more rapid clearance of Cryptococci from CSF, and survival at 2 weeks. The key components of this protective immune-response were interleukin (IL)-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive contribution to the PC1 score. A second component of co-correlated chemokines was identified by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). High CSF chemokine concentrations were associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive of immune reconstitution inflammatory syndrome (IRIS). In conclusion CSF cytokine and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS), more effective activation of CNS macrophages and microglial cells, and faster organism clearance; while high CNS chemokine levels may predispose to over recruitment or inappropriate recruitment of immune cells to the CNS and IRIS following peripheral immune reconstitution with ART. These results provide a rational basis for future studies of immune modulation in CM, and demonstrate the potential of baseline immune profiling to identify CM patients most at risk of mortality and subsequent IRIS.


Features of SLE in various ethnic groups in Israel.
To assess the association between the ethnic origin of patients with SLE living in Israel, and the clinical and laboratory features of SLE. A retrospective review of medical records was carried out. Patients were classified into 3 groups based on their ethnic origin: a) Ashkenazi Jews, b) Sepharadic Jews and c) Arabs. The study included 74 consecutive SLE patients, 69 (93%) women and 5 (7%) men. Their mean age at diagnosis was 32 years and their mean disease duration was 6.4 years. There were 21 (28%) Ashkenazi Jews, 31 (42%) Sepharadic Jews and 22 (30%) Arabs. The demographics, the frequency of various clinical and laboratory variables of SLE, and the mean disease activity index score (SLEDA1) of the three groups were not statistically different. The ethnic origin of SLE patients living in Israel is not associated with the clinical and laboratory features of the disease.


When a Psychometric Advance Falls in the Forest.
Borsboom (2006) attacks psychologists for failing to incorporate psychometric advances in their work, discusses factors that contribute to this regrettable situation, and offers suggestions for ameliorating it. This commentary applauds Borsboom for calling the field to task on this issue and notes additional problems in the field regarding measurement that he could add to his critique. It also chastises Borsboom for occasionally being unnecessarily perjorative in his critique, noting that negative rhetoric is unlikely to make converts of offenders. Finally, it exhorts psychometricians to make their work more accessible and points to Borsboom, Mellenbergh, and Van Heerden (2003) as an excellent example of how this can be done.


Hospice and assisted suicide: the structure and process of an inherent dilemma.
The hospice philosophy involves making terminal patients as comfortable as possible, empowering them with control of the time they have left, but neither hastening nor postponing death. The passage of Oregon's Death with Dignity Act in November of 1994, and the failure of the 1997 ballot measure to repeal it, made physician-assisted suicide another option for terminally ill people in that state, and focused increased attention on a conflict seemingly inherent in the hospice philosophy. We conducted interviews with 60 hospice providers, 43 in Oregon and, for comparison, 17 in the northeast, for their responses to this situation. The data reported here reflect some of the social and individual influences that come to bear as hospice providers attempt to resolve their dilemma.


Pyelonephritis treatment in the community emergency department: Cephalosporins vs. first-line agents.
The purpose of this study was to assess treatment with a fluoroquinolone or trimethoprim-sulfamethoxazole versus cephalosporins for pyelonephritis in discharged patients from a community hospital setting. A retrospective chart review was completed for adult female patients who received a prescription for a cephalosporin, fluoroquinolone or trimethoprim-sulfamethoxazole for the treatment of pyelonephritis within the network of a large healthcare system. The primary endpoint evaluated the failure rate of each treatment group. The secondary endpoint evaluated the difference between rates of resistance on culture and sensitivity reports for treatment groups. A total of 55 patients in the cephalosporin group and 43 patients in the fluoroquinolone and trimethoprim-sulfamethoxazole group were reviewed. The primary endpoint occurred in 0% of the patients in the cephalosporin group and in 23% of the patients in the fluoroquinolone and trimethoprim-sulfamethoxazole group, p < 0.001. Of the 98 urine samples collected, 71 samples were positive for pathogen growth. Upon evaluation of these isolates, 6% were resistant to cephalexin, 1% was resistant to cefdinir, 3% were resistant to ciprofloxacin and 23% were resistant to trimethoprim-sulfamethoxazole. Trimethoprim-sulfamethoxazole showed statistical significance for more bacterial resistance compared to the other agents, p < 0.01. Failure of therapy for pyelonephritis occurred more often in the fluoroquinolone and trimethoprim-sulfamethoxazole group than in the cephalosporin group. The findings in this study are most applicable to patients who are treated on an outpatient basis. A prospective, randomized clinical trial is necessary to confirm these results.


Determinants of bone mineral density in older men.
Although osteoporosis in men is increasingly recognized as an important health issue and bone mass appears to be a major determinant of fracture, there remain few data concerning the determinants of bone mass in men. To determine the correlates of bone density in men, we studied a large group of older subjects recruited from three rural communities in the northwestern United States. Three hundred and fifty-five men over the age of 60 years (mean 71.5 +/- 7.4 years) without known disorders of mineral metabolism were recruited by community advertising. Bone mineral density was measured at the lumbar spine, proximal femur and radius by dual-energy X-ray absorptiometry, and factors potentially related to skeletal status were assessed by direct measurements or questionnaire. In univariate analyses weight (positively) and age (negatively) were associated with bone density. After adjustment for these two factors, alcohol intake, osteoarthritis and thiazide use were associated with higher bone density, while previous fractures, gastrectomy, peptic ulcer disease, rheumatoid arthritis, glucocorticoid use, hypertension, previous hyperthyroidism, height loss since age 20 years, chronic lung disease and smoking were related to lower density. In multivariate models, only weight and a history of cancer were related to higher bone mass, and age, previous fracture, rheumatoid arthritis, gastrectomy and hypertension were associated with lower density. These data contribute to the emerging field of osteoporosis in men, and may help in the clinical identification of men at higher risk of osteopenia.


Laboratory earthquakes along inhomogeneous faults: directionality and supershear.
We report on the experimental observation of spontaneously nucleated ruptures occurring on frictionally held bimaterial interfaces with small amounts of wave speed mismatch. Rupture is always found to be asymmetric bilateral. In one direction, rupture always propagates at the generalized Rayleigh wave speed, whereas in the opposite direction it is subshear or it transitions to supershear. The lack of a preferred rupture direction and the conditions leading to supershear are discussed in relation to existing theory and to the earthquake sequence in Parkfield, California, and in North Anatolia.


T cell recognition of Mls. T cell clones demonstrate polymorphism between Mlsa, Mlsc, and Mlsd.
The determinants encoded by the minor lymphocyte stimulating locus (Mls) are defined as determinants that induce strong T cell proliferative responses in primary mixed lymphocyte reactions. Although the Mls locus was originally described as having four alleles, a, b, c, and d, a number of recent observations have led several investigators to challenge the idea that Mls is truly a polymorphic system. To better define this system of determinants recognized at high frequency by T cells, the present studies were undertaken to evaluate the polymorphism of Mls products. In the present study, the in vitro proliferative responses of Mlsa- and Mlsc-specific T cell clones were employed to analyze Mls products. The identification of determinants recognized by Mlsa- and Mlsc-reactive clones was established by the pattern of responses to stimulators derived from congenic strains, recombinant inbred strains, and backcross mice. T cell clones and unprimed T cells gave concordant responses that confirmed the Mlsa or Mlsc specificity of the cloned populations. With the use of these two sets of Mls-specific T cell clones, the existence or absence of polymorphism of Mls-encoded gene products was examined. It was found that Mlsa-specific cloned T cells responded to Mlsa but not Mlsc stimulators, whereas Mlsc-specific clones responded to Mlsc but not Mlsa. This reciprocal pattern of specificity indicates that the Mls system as currently defined is therefore truly polymorphic. In addition, it was observed that both Mlsa- and Mlsc-specific clones were stimulated by Mlsd stimulators. In particular, the possibility that Mlsa and Mlsc are not alleles but products of different loci and that Mlsd strains are those that express both Mlsa and Mlsc is considered.


Biodistribution of Liver-Derived Mesenchymal Stem Cells After Peripheral Injection in a Hemophilia A Patient.
With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver-derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthesis site, and mesenchymal stem cells have been shown to control joint bleeding in animal models of hemophilia. Adult-derived human liver stem cells (ADHLSCs) have mesenchymal characteristics and have been shown able to engraft in and repopulate both animal and human livers. Thus, the objectives were to evaluate the potency of ADHLSCs to control bleeding in a hemophilia A patient and assess the biodistribution of the cells after intravenous injection. A patient suffering from hemophilia A was injected with repeated doses of ADHLSCs via a peripheral vein (35 million In-oxine-labeled cells, followed by 125 million cells the next day, and 3 infusions of 250 million cells every 2 weeks thereafter; total infusion period, 50 days). After cell therapy, we found a temporary (15 weeks) decrease in the patient's FVIII requirements and severe bleeding complications, despite a lack of increase in circulating FVIII. The cells were safely administered to the patient via a peripheral vein. Biodistribution analysis revealed an initial temporary entrapment of the cells in the lungs, followed by homing to the liver and to a joint afflicted with hemarthrosis. These results suggest the potential use of ADHLSCs in the treatment of hemophilia A.


Rhythm perception and production predict reading abilities in developmental dyslexia.
Rhythm organizes events in time and plays a major role in music, but also in the phonology and prosody of a language. Interestingly, children with developmental dyslexia-a learning disability that affects reading acquisition despite normal intelligence and adequate education-have a poor rhythmic perception. It has been suggested that an accurate perception of rhythmical/metrical structure, that requires accurate perception of rise time, may be critical for phonological development and subsequent literacy. This hypothesis is mostly based on results showing a high degree of correlation between phonological awareness and metrical skills, using a very specific metrical task. We present new findings from the analysis of a sample of 48 children with a diagnosis of dyslexia, without comorbidities. These children were assessed with neuropsychological tests, as well as specifically-devised psychoacoustic and musical tasks mostly testing temporal abilities. Associations were tested by multivariate analyses including data mining strategies, correlations and most importantly logistic regressions to understand to what extent the different auditory and musical skills can be a robust predictor of reading and phonological skills. Results show a strong link between several temporal skills and phonological and reading abilities. These findings are discussed in the framework of the neuroscience literature comparing music and language processing, with a particular interest in the links between rhythm processing in music and language.


Predictors of Outcome in Patients with Pediatric Intracerebral Hemorrhage: Development and Validation of a Modified Score.
Purpose To propose and validate a modified pediatric intracerebral hemorrhage (PICH) (mPICH) score and to compare its association with functional outcome to that of the original PICH score. Materials and Methods Data from prospectively included patients were retrospectively analyzed. Consecutive patients with nontraumatic PICH who had undergone clinical follow-up were included. The study population was divided into a development cohort (2008-2012, n = 100) and a validation cohort (2013-2016, n = 43). An mPICH score was developed after variables associated with poor outcome were identified at multivariate analysis (King's Outcome Scale for Childhood Head Injury score < 5a) in the development cohort. The accuracy of the score for prediction of poor outcome was evaluated (sensitivity, specificity). Discrimination and calibration of associations between the mPICH score and poor outcome cohorts were assessed (C statistics, Hosmer-Lemeshow test). Results The mPICH score assessed as follows: brain herniation, four points; altered mental status, three points; hydrocephalus, two points; infratentorial PICH, two points; intraventricular hemorrhage, one point; PICH volume greater than 2% of total brain volume, one point. An mPICH score greater than 5 was associated with severe disability or worse, with sensitivity of 97% (95% confidence interval [CI]: 83%, 100%) and specificity of 61% (95% CI: 49%, 73%). The C statistic was 0.81 (95% CI: 0.73, 0.89). In the validation cohort, sensitivity and specificity were 95.2% (95% CI: 76%, 99%) and 77% (95% CI: 55%, 92%), respectively. There was no significant difference between the observed and predicted risks of poor outcome (P = .46). Conclusion An mPICH score was developed as a simple clinical and imaging grading scale for acute prognosis in patients with PICH. © RSNA, 2017.


Memory CD4+ T cells: beyond "helper" functions.
In influenza virus infection, antibodies, memory CD8+ T cells, and CD4+ T cells have all been shown to mediate immune protection, but how they operate and interact with one another to mediate efficient immune responses against virus infection is not well understood. In this issue of the JCI, McKinstry et al. have identified unique functions of memory CD4+ T cells beyond providing "help" for B cell and CD8+ T cell responses during influenza virus infection.


Amino acid adsorption on zeolite beta.
A thermodynamic equilibrium model has been developed to describe amino acid adsorption on microporous materials. The model addresses electrostatic, hydrophobic and steric interactions. A procedure for fitting the model's parameters is presented and should be applicable to the majority of the common 20 amino acids. The approach is demonstrated using experimental measurements of L-phenylalanine and L-arginine on zeolite beta. Between the adsorption mechanisms of ion exchange and physisorption, the first can contribute as much as two-thirds of the phenylalanine adsorbed at saturation. For the materials tested, ion exchange is maximized when the zeolite's silicon-to-aluminum ratio is 12. When this atom ratio is raised to 100, ion exchange no longer plays a significant role, but the amount physisorbed increases by 30%.


Communication in Pediatric Oncology: A Qualitative Study.
When children are seriously ill, parents rely on communication with their clinicians. However, in previous research, researchers have not defined how this communication should function in pediatric oncology. We aimed to identify these communication functions from parental perspectives. Semistructured interviews with 78 parents of children with cancer from 3 academic medical centers at 1 of 3 time points: treatment, survivorship, or bereavement. We analyzed interview transcripts using inductive and deductive coding. We identified 8 distinct functions of communication in pediatric oncology. Six of these functions are similar to previous findings from adult oncology: (1) building relationships, (2) exchanging information, (3) enabling family self-management, (4) making decisions, (5) managing uncertainty, and (6) responding to emotions. We also identified 2 functions not previously described in the adult literature: (7) providing validation and (8) supporting hope. Supporting hope manifested as emphasizing the positives, avoiding false hopes, demonstrating the intent to cure, and redirecting toward hope beyond survival. Validation manifested as reinforcing "good parenting" beliefs, empowering parents as partners and advocates, and validating concerns. Although all functions seemed to interact, building relationships appeared to provide a relational context in which all other interpersonal communication occurred. Parent interviews provided evidence for 8 distinct communication functions in pediatric oncology. Clinicians can use this framework to better understand and fulfill the communication needs of parents whose children have serious illness. Future work should be focused on measuring whether clinical teams are fulfilling these functions in various settings and developing interventions targeting these functions.


The difference in degree of conversion between light-cured and additional heat-cured composites.
This study was designed to determine the changes in the degree of conversion throughout composite resins of varying thicknesses after heat curing and to evaluate whether or not the thin wafer technique that was applied in this study was sensitive to changes in distance from the light source. A 5 mm-in-diameter hole was made in a 4 mm-thick Teflon plate, and composite resin was placed in the hole and light cured from the top for 60 seconds. Twenty samples were prepared; 10 of these were additionally heat cured in an inlay oven. After light curing or light and heat curing, the samples were sectioned into four parts and assigned to groups A, B, C, or D according to their distance from the light source. These sections were then thinned to 50-70 microns, and analyzed by use of a standard baseline technique with a Fourier Transform Infrared Spectrometer (FT-IR) to determine the degree of conversion. The degree of conversion diminished as the distance from the light source increased; however, once the samples were heat cured, significant increases in the degree of conversion were noted throughout the samples. In the heat-cured composites, the degree of conversion in the outer portion of the sample was higher than in the inner portion. The thin wafer technique with FT-IR is considered to be a reliable method for measuring the degree of conversion in a composite resin, because changes between groups were clearly noted.


CCR5 plays important roles in hepatitis B infection.
In humans, hepatitis B virus (HBV) is the most prevalent and the main infectious agent that leads to liver disease. Previous investigations identified that long-term HBV-infected patients are unable to eradicate HBV completely from hepatocytes. The main mechanisms responsible for long-term forms of the infections are yet to be clarified. However, researchers believe that the differences in genetic and immunological parameters in the patients in comparison to subjects who successfully clear HBV infections may be the causes for long-term infection. Previous studies demonstrated that chemokines play important roles in the regulation of immune cell migration and activation, which is crucial for a comprehensive immune response against HBV. RANTES, MIP-1α, and MIP-1β are important CC chemokines which act through CC chemokines receptor 5 (CCR5). This receptor is expressed on several effector immune cells including NK cells, T lymphocytes, and macrophages, and plays a crucial role in the regulation of activation and migration of the immune cells during immune responses against viruses, including HBV. Therefore, alterations in its expression or functions could be associated with attenuated immune responses against HBV. In addition, previous studies identified that a 32 base pair deletion (Δ32) in exon 1, as well as three polymorphisms in the promoter region of the CCR5 gene results in downregulation of the molecule. Previous studies revealed that CCR5 expression was altered in hepatitis B but the role of the CCR5 Δ32 mutation and CCR5 promoter polymorphisms in this disease is controversial. This review addresses the recent information regarding the status of CCR5 expression on immune cells and the association of CCR5 promoter polymorphisms with HBV-infected patients.