Isolation and characterization of revertants from fourteen herpes simplex virus type 1 (strain 17) temperature-sensitive mutants.
The isolation of spontaneous non-temperature-sensitive revertants of herpes simplex virus type 1 (HSV-1) (strain 17) ts mutants, following a single round of selection at non-permissive temperature, is reported. The distinction between total and incomplete reversion was assessed by the wild-type performance of non-ts revertants in three aspects of HSV infection: (i) virus growth, (ii) induction of HSV-specified enzyme activities (where appropriate) and (iii) the gel profile of infected cell polypeptides. Wild-type behaviour was taken to indicate total reversion, while less than wild-type performance in any test indicated incomplete reversion. Only five of 19 HSV-1 mutants (ts L, U, X, R and G syn) examined for reversion of the ts lesion failed to yield non-ts revertants; these mutants may well contain multiple mutations. Total reversion was obtained with mutants ts K, F, E, S, M, N and I and incomplete reversion with the mutants ts D, T, B, P, A, W, F, H and possibly K. Thus, both total and incomplete revertants of ts F (and possibly ts K) were obtained. Some conclusions concerning the relative importance of individual polypeptide bands have been drawn from these studies. Within our sample in the revertant profiles Vmw 175, 155, 114, 65/64, 43, 40, 39, 30, 28, 21 and 16.5K always returned to wild-type levels; Vmw 273, 100, 67 and 38/37K almost always regained wild-type intensity but polypeptides Vmw 122, 117, 82/81, 57, 51, 27 and 12.5K were frequently not made in wild-type amounts.


Low utilisation of unactivated protein C in a patient with meningococcal septic shock and disseminated intravascular coagulation.
Activated protein C has recently been shown in a multicentre trial to significantly reduce mortality in patients with septic shock. There are also some case reports and minor studies demonstrating promising results with the unactivated form of protein C. However, in children with severe meningococcal infection, skin biopsies have demonstrated low expression of endothelial thrombomodulin and protein C receptors, suggesting low protein C activation capacity in severe meningococcal sepsis. A patient with meningococcal septic shock was treated with two doses of the unactivated form of protein C, the first during intense activation of the coagulation system and the second during a phase of low grade or no activation. Repeated plasma samples were analysed for protein C concentration, which made it possible to compare pharmacokinetics and half-lives of the two administrations. A shorter half-life during intense coagulation was expected if there was an activation and consumption of the protein C administered. The calculated half-lives of protein C during intense and low grade activation were 32 h and 19 h, respectively, a magnitude similar to that reported in protein C-deficient patients without infection. The result indicates that whole body utilisation of the unactivated protein C was low. Endothelial impairment of protein C activation does not seem to be restricted to the skin vessels only.


Transmembrane extension and oligomerization of the CLIC1 chloride intracellular channel protein upon membrane interaction.
Chloride intracellular channel proteins (CLICs) differ from most ion channels as they can exist in both soluble and integral membrane forms. The CLICs are expressed as soluble proteins but can reversibly autoinsert into the membrane to form active ion channels. For CLIC1, the interaction with the lipid bilayer is enhanced under oxidative conditions. At present, little evidence is available characterizing the structure of the putative oligomeric CLIC integral membrane form. Previously, fluorescence resonance energy transfer (FRET) was used to monitor and model the conformational transition within CLIC1 as it interacts with the membrane bilayer. These results revealed a large-scale unfolding between the C- and N-domains of CLIC1 as it interacts with the membrane. In the present study, FRET was used to probe lipid-induced structural changes arising in the vicinity of the putative transmembrane region of CLIC1 (residues 24-46) under oxidative conditions. Intramolecular FRET distances are consistent with the model in which the N-terminal domain inserts into the bilayer as an extended α-helix. Further, intermolecular FRET was performed between fluorescently labeled CLIC1 monomers within membranes. The intermolecular FRET shows that CLIC1 forms oligomers upon oxidation in the presence of the membranes. Fitting the data to symmetric oligomer models of the CLIC1 transmembrane form indicates that the structure is large and most consistent with a model comprising approximately six to eight subunits.


Oxidation of deuteroferrihaem by hydrogen peroxide.
1. The oxidation of deuteroferrihaem by H(2)O(2) to bile pigment and CO was studied both by stopped-flow kinetic spectrophotometry and mass spectrometry, at 25 degrees C, I=0.1m. 2. Spectrophotometric studies imply that, at constant pH, the rate of bile pigment formation is first-order with respect to [H(2)O(2)] and also proportional to [deuteroferrihaem monomer]. The effect of pH on the apparent second-order rate constant suggests that acid-ionization of deuteroferrihaem monomer is important in the reaction mechanism. 3. The relative rates of formation of O(2) (from catalytic decomposition of H(2)O(2)) and CO (from oxidation of ferrihaem) have been measured by mass spectrometry. The results are in excellent agreement with those obtained by combining kinetic data for catalytic decomposition (Jones et al., 1973, preceding paper) with the spectrophotometric results for deuteroferrihaem oxidation.


Evaluation of peptide-mediated transduction in human CD34+ cells.
Protein transduction domains (PTDs) have been used increasingly to deliver biologically active agents to a variety of cell types in vitro and in vivo. To define the most effective PTDs for transducing hematopoietic cells, we have screened a panel of PTD peptides in human CD34(+) cells for delivery of a 60-kd marker protein and assessed its impact on phenotypic maintenence in vitro. Compared to the HIV-TAT peptide, most peptide complexes displayed high efficiency in transducing the CD34(+) cells, except for those based on shorter peptides (4R, 4K, and 5RQ). In particular, the arginine homopolymers including 8R, 10R, and 12R, were internalized by the cells to a greater extent than the other PTDs. Transduction was significantly potentiated by preincubation of cells with dextran sulfate. Importantly, colony forming ability and CD34(+) CD38(-) primitive phenotype were not significantly altered in the presence of these peptides during a short-term liquid culture. Together, these data suggest the potential usefulness of arginine homopolymers in hematopoietic stem and progenitor cell manipulations.


SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models.
Emerging evidence demonstrates that a c-Met antibody-drug conjugate (ADC) has superior efficacy and safety profiles compared with those of currently available small molecules or antibody inhibitors for the treatment of c-Met-overexpressing cancers. Here we described both the in vitro and in vivo efficacies of SHR-A1403, a novel c-Met ADC composed of a humanized IgG2 monoclonal antibody against c-Met conjugated to a novel cytotoxic microtubule inhibitor. SHR-A1403 showed high affinity to c-Met proteins derived from human or monkey and potent inhibitory effects in cancer cell lines with high c-Met protein expression. In mice bearing tumors derived from cancer cell lines or patient HCC tissues with confirmed c-Met overexpression, SHR-A1403 showed excellent anti-tumor efficacy. Antibody binding with c-Met contributed to SHR-A1403 endocytosis; the subsequent translocation to lysosomes and cytotoxicity of the released toxin are speculated to be predominant mechanisms underlying the anti-tumor activity of SHR-A1403. In conclusion, SHR-A1403 showed significant anti-tumor activity in cancer cell lines, xenograft mouse models and an HCC PDX model, which all have high c-Met levels. These data provide references for SHR-A1403 as a potential therapy for the treatment of cancers with c-Met overexpression.


The protective effect of alpha-lipoic acid on the expression of collagen IV, renal function, and oxidative stress induced by diazinon in the renal parenchyma of rat.
Diazinon (DZN) is an organophosphate pesticide that is commonly used in agriculture worldwide, including in Iran, and unfortunately, it leads to a variety of negative effects on the environment, animals, and humans. Alpha-lipoic acid (ALA) is an antioxidant agent that acts via scavenging of oxygen-free radicals. Collagen IV is a component of the main base membrane structure and DZN may also affect the expression of this key protein. The aim of this study was to evaluate antioxidant properties of ALA on the expression of collagen IV, renal function, and oxidative stress induced by DZN in renal tissue. In this experimental study, 30 adult male Wistar rats were randomly divided into five groups (n = 6) including: the control group, DZN (40 mg/kg) group, ALA (100 mg/kg) group, ALA (100 mg/kg) + DZN (40 mg/kg) group, and sham group. On day 0 and after 6 weeks, the urine and blood samples were collected to measure glomerular filtration rate (GFR). After 6 weeks, the rats were anesthetized and the left kidney was used for immunohistochemistry study and the right kidney was used to evaluate the oxidative stress parameters. The results have shown that ALA significantly improved the biochemical parameters including superoxide dismutase, glutathione peroxidase, glutathione S-transferase, glutathione reductase, and GFR. In addition, ALA significantly prevented the expression of collagen IV that was changed by DZN administration in rats. We concluded that when exposed to DZN, depletion of antioxidant enzymes is accompanied by the induction of oxidative stress that might be beneficial in monitoring DZN toxicity and alpha-lipoic acid, as an antioxidant can overcome the toxicity induced by DZN in the kidney.


Effect of Iranian Ministry of Health protocols on cesarean section rate: a quasi-experimental study.
High Cesarean section rate is a major health problem in developing countries. This study was established to evaluate the effectiveness of Iranian Ministry of Health and Medical Education protocols on Cesarean section rate trend. Through a non-concurrent controlled quasi-experimental study, Cesarean section rate in Shohada-e-Tajrish and Taleghani hospitals in Tehran was compared during 2008-2009. Intervention group included 578 participants hospitalized because of premature rupture of membranes, prolonged pregnancy, pre-eclampsia, intra-uterine growth retardation, vaginal bleeding and premature labor in first and second trimester underwent interventions based on MOHME new protocol. On the other hand 594 cases as control group were selected during the same time before the intervention and underwent routine treatments. Descriptive statics, t-test, chi square and univariate analysis were used when appropriate. Basic characteristics in two groups had no statistically significant difference. Cesarean section applied for 360 (67.8%) women in case group and on the other hand, 270 (48.8%) Cesarean sections were done for control group (P<0.001). There was 19 % difference between intervention and control groups. Complication of pregnancies had increased by 6% in intervention group (P<0.001). Mortality rate in the study was zero in both groups. Applying clinical practice guidelines does not guarantee decreasing Cesarean section rate. Providing appropriate service may increase the ability of service providers to find more indications for Cesarean section.


Quorum sensing is a language of chemical signals and plays an ecological role in algal-bacterial interactions.
Algae are ubiquitous in the marine environment, and the ways in which they interact with bacteria are of particular interest in marine ecology field. The interactions between primary producers and bacteria impact the physiology of both partners, alter the chemistry of their environment, and shape microbial diversity. Although algal-bacterial interactions are well known and studied, information regarding the chemical-ecological role of this relationship remains limited, particularly with respect to quorum sensing (QS), which is a system of stimuli and response correlated to population density. In the microbial biosphere, QS is pivotal in driving community structure and regulating behavioral ecology, including biofilm formation, virulence, antibiotic resistance, swarming motility, and secondary metabolite production. Many marine habitats, such as the phycosphere, harbour diverse populations of microorganisms and various signal languages (such as QS-based autoinducers). QS-mediated interactions widely influence algal-bacterial symbiotic relationships, which in turn determine community organization, population structure, and ecosystem functioning. Understanding infochemicals-mediated ecological processes may shed light on the symbiotic interactions between algae host and associated microbes. In this review, we summarize current achievements about how QS modulates microbial behavior, affects symbiotic relationships, and regulates phytoplankton chemical ecological processes. Additionally, we present an overview of QS-modulated co-evolutionary relationships between algae and bacterioplankton, and consider the potential applications and future perspectives of QS.


Influence of hydroxyurea on fetal hemoglobin production in vitro.
Cytotoxic drugs increase circulating fetal hemoglobin levels. We examined the mechanism by measuring the fetal hemoglobin produced per BFU-E-derived erythroblast following hydroxyurea treatment in vivo and in vitro. Treatment of four sickle cell patients increased the percentage of circulating F reticulocytes. The frequencies of bone marrow or peripheral blood BFU-E or CFU-E-derived colonies and their fetal hemoglobin content were unaffected. In all cases, the number of erythroid cells/progenitor-derived colony increased. To explore further the effect of hydroxyurea on fetal hemoglobin production, we added 50 mumol/L hydroxyurea to cultures of peripheral blood BFU-E-derived erythroblasts on 1 of 9 days (day 5 through 13) to nine samples. These BFU-E were derived from the peripheral blood of normal donors, sickle trait donors, and sickle cell anemia patients and from the bone marrows of monkeys. This concentration of hydroxyurea was selected so that the frequency of BFU-E and their size was moderately decreased. Addition of hydroxyurea to these progenitor-derived erythroid cells had no effect on fetal hemoglobin content per cell. Neither did transient exposure of progenitors to hydroxyurea prior to culture in nontoxic concentrations (0 to 500 mumol/L) result in a significant increase in fetal hemoglobin content in progenitor-derived erythroblasts. These data suggest that hydroxyurea does not directly alter the HbF program expressed by progenitor-derived erythroid cells. Instead, it enhances hemoglobin F content secondarily, possibly by inducing alterations in erythropoiesis.


Purification and properties of phytate-specific phosphatase from Bacillus subtilis.
An enzyme which liberates Pi from myo-inositol hexaphosphate (phytic acid) was shown to be present in culture filtrates of Bacillus subtilis. It was purified until it was homogeneous by ultracentrifugation, but it still showed two isozymes on polyacrylamide gel electrophoresis. The enzyme differed from other previously known phytases in its metal requirement and in its specificity for phytate. It had a specific requirement for Ca2+ for its activity. The enzyme hydrolyzed only phytate and had no action on other phosphate esters tested. This B. subtilis phytase is the only known phytate-specific phosphatase. The products of hydrolysis of phytate by this enzyme were Pi and myo-inositol monophosphate. The enzyme showed optimum activity at pH 7.5. It was inhibited by Ba2+, Sr2+, Hg2+, Cd2+, and borate. Its activity was unaffected by urea, diisopropylfluorophosphate, arsenate, fluoride, mercaptoethanol, trypsin, papain, and elastase.


Lesions of central norepinephrine terminals with 6-OH-dopamine: biochemistry and fine structure.
Intracisternal injections of 6-hydroxydopamine produce rapid and long-lasting depletion of brain catecholamines without effects on serotonin concentrations. Depletion of norepinephrine is greatest in areas containing only nerve terminals and axons and least in areas containing monoamine cell bodies. The norepinephrine loss is accompanied by electron microscopic evidence of nerve terminal degeneration and decreased turnover. Dopamine loss is less marked and is not accompanied by degeneration or alteration of turnover rate.


Proteomic Profiling of Rhabdomyosarcoma-Derived Exosomes Yield Insights into Their Functional Role in Paracrine Signaling.
Exosomes are important intercellular communication vehicles, secreted into body fluids by multiple cell types, including tumor cells. They have been demonstrated to contribute to the metastatic progression of tumor cells through paracrine signaling. Tumor exosomes contain intact and functional proteins, mRNA and miRNA that may alter the cellular environment to favor tumor growth. We evaluated the protein cargo of exosomes derived from the childhood tumor rhabdomyosarcoma (RMS) and the molecular pathways they are implicated in to decipher their role in the progression of this aggressive disease. We conducted a mass spectrometry analysis of exosome content isolated from five RMS cell lines: three of embryonal RMS (ERMS) and two of alveolar RMS (ARMS) histology and verified results by multiple reaction monitoring and western blot analyses. Results revealed 161 common proteins in ERMS-derived exosomes and 122 common proteins in ARMS-derived exosomes, of which 81 proteins were common to both subtypes. Using both PANTHER gene classification and Pathway Studio software, we assessed the perturbed biological processes and altered pathways in which the exosomal proteins are involved. The 81 commonly expressed proteins included those involved in "cell-signaling," "cell-movement," and "cancer." Pathways engaging the identified proteins revealed 37 common pathways including "integrin signaling pathway," "inflammation mediated by chemokine and cytokine signaling pathway," and "angiogenesis." Finally, a comparison of exosomal proteins of RMS cells with publicly available datasets from other cancer cells revealed that 36 proteins are specific and endogenous to the RMS-exosomes. Taken together, our results reveal that RMS-derived exosomes carry a protein cargo that contributes to conserved cellular signaling networks across multiple cell lines, and we also identify RMS exosome-specific proteins that should be further evaluated as possible novel biomarkers for this tumor.


Childhood sexual abuse and adolescent pregnancy: a meta-analytic update.
Recent increases in adolescent pregnancies have sparked a renewed impetus to identify risk factors, such as childhood sexual abuse (CSA), associated with adolescent pregnancy. Given mixed evidence regarding the strength of the relationship between CSA and adolescent pregnancy (Blinn-Pike, Berger, Dixon, Kuschel, & Kaplan, 2002), our objective was to provide an estimate of the effect size of this relationship using updated literature and meta-analytic techniques. Meta-analyses of 21 studies were conducted using a random effects model of binary outcomes to determine aggregate effect-size estimates controlling for study heterogeneity. CSA significantly increased the odds of experiencing an adolescent pregnancy by 2.21-fold (95% CI: 1.94-2.51). A supplemental analysis suggested that 4.5 out of 10 pregnant adolescents may have a prior history of CSA. CSA places females at increased risk for subsequent adolescent pregnancy. Addressing conditions associated with CSA might impact the overall adolescent pregnancy rate.


Short-term Clinical and Radiographic Results of the Salto Mobile Total Ankle Prosthesis.
The mobile-bearing Salto total ankle prosthesis has been reported to have promising outcomes. However, clinical reports on this prosthesis are few, and most have been published by the inventors and disclosed consultants. We retrospectively reviewed 59 patients who received Salto prosthesis unilaterally. The average follow-up was 35.9 (range, 6-56) months. Clinical and radiologic results were evaluated. Clinical results were evaluated according to visual analog scale (VAS), American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score, Ankle Osteoarthritis Scale (AOS) pain and disability score, and ankle range of motion (ROM) in dorsiflexion/plantarflexion. In the radiographic evaluation, we measured the tibial angle (TA), talar angle (TAL), tibial slope, and talocalcaneal angle (TCA) on weightbearing radiographs. By the last follow-up, 7 of 59 patients (11.9%) had undergone reoperation, and 3 of 59 implants (5.1%) had been removed. The prosthesis survival was 94.9% (95% CI, 89.1%-100%). With any reoperation as the endpoint of follow-up, the clinical success rate was 88.1% (95% CI, 79.4%-96.9%). The mean postoperative visual analog scale score, AOFAS ankle-hindfoot score, and Ankle Osteoarthritis Scale pain and disability score improved significantly ( P < .001). The ankle range of motion also improved from preoperative 33.4 ± 16.6 to 40.3 ± 15.5 postoperatively ( P < .001); however, there was no statistically significant change in plantarflexion ( P = .243). Radiolucent areas and osteolysis were found in 28 (47.5%) and 27 (45.8%) patients, respectively. Heterotopic ossification was observed in 13 patients (22.0%). In this series, early clinical and radiographic outcomes of this prosthesis were promising. We believe the early radiolucent lines were probably due to the gap at the implant and bone interface, and they disappeared at the time of osseous integration. However, longer follow-up is necessary to determine the long-term durability and survivorship of this implant, particularly given the high incidence of postoperative osteolysis. Level IV, case series.


Complete experimental characterization of the influence of parametric four-wave mixing on stimulated Raman gain.
We present what is to our knowledge the first complete measurement of the dependence of Raman gain on chromatic dispersion, fully revealing the influence of parametric four-wave mixing on stimulated Raman scattering. In particular, a threefold increase of the Raman gain is observed under phase-matching conditions, in excellent agreement with theoretical predictions. Our experiments, which were performed in a photonic crystal fiber, demonstrate that these unique fibers can be exploited to boost the performances of fiber Raman amplifiers.


Effects of osthole on postmenopausal osteoporosis using ovariectomized rats; comparison to the effects of estradiol.
The purpose of this study was to examine effects of osthole on postmenopausal osteoporosis using ovariectomized (OVX) rats. All of the rats were divided into sham and OVX groups. At 2 weeks post-operation, the sham-operated rats received solvent vehicle (97% corn oil and 3% ethanol, 1.0 ml/kg, subcutaneously); the OVX rats were divided into three groups which were treated with solvent vehicle (same the sham rats, 1.0 ml/kg, subcutaneously), 17beta-estradiol (30 microg/kg, subcutaneously) or osthole (9.0 mg/kg, orally) 5 d/week for 4 weeks, respectively. In OVX rats, the increases of body weight, spleen and thymus weight were significantly decreased and the atrophy of uterus was preserved by 17beta-estradiol treatment, but not by osthole. Treatment with either 17beta-estradiol or osthole significantly protected cancellous bone loss owing to estrogen deficiency and significantly increased the maximal load in the femoral neck of OVX rats. In addition, the increases of serum osteocalcin (OC) and urinary deoxypyridinoline (DPD) levels caused by ovariectomy were all significantly suppressed by 17beta-estradiol. However, only urinary DPD was significantly reduced by osthole and no change was found in serum OC. Our results demonstrate that osthole may be just as effective as 17beta-estradiol in suppressing bone loss due to ovariectomy but osthole perhaps does not work through the estrogen pathway.


Client processing is altered by novel myopathy-causing mutations in the HSP40 J domain.
The misfolding and aggregation of proteins is often implicated in the development and progression of degenerative diseases. Heat shock proteins (HSPs), such as the ubiquitously expressed Type II Hsp40 molecular chaperone, DNAJB6, assist in protein folding and disaggregation. Historically, mutations within the DNAJB6 G/F domain have been associated with Limb-Girdle Muscular Dystrophy type 1D, now referred to as LGMDD1, a dominantly inherited degenerative disease. Recently, novel mutations within the J domain of DNAJB6 have been reported in patients with LGMDD1. Since novel myopathy-causing mutations in the Hsp40 J domain have yet to be characterized and both the function of DNAJB6 in skeletal muscle and the clients of this chaperone are unknown, we set out to assess the effect of these mutations on chaperone function using the genetically tractable yeast system. The essential yeast Type II Hsp40, Sis1, is homologous to DNAJB6 and is involved in the propagation of yeast prions. Using phenotypic, biochemical, and functional assays we found that homologous mutations in the Sis1 J domain differentially alter the processing of specific yeast prion strains, as well as a non-prion substrate. These data suggest that the newly-identified mutations in the J domain of DNAJB6 cause aberrant chaperone function that leads to the pathogenesis in LGMDD1.


Treatment of soft tissue defects in pediatric patients using the V.A.C. system.
Twenty-seven consecutive pediatric patients presenting to the orthopaedic surgery or plastic surgery services were reviewed after completion of wound care with the Vacuum Assisted Closure (V.A.C.) system. Each patient presented with complex soft tissue wounds requiring coverage procedures. Patients with acute wounds and wounds present after nonsuccessful attempts at surgical closure (dehisced incisions and failed flaps) were treated. All soft tissue defects healed without extensive coverage procedures using the V.A.C. system. In the majority of patients, use of the V.A.C. system produced a profuse bed of granulation tissue over all exposed bone, tendon, joint, and/or hardware, which could be covered with split thickness skin graft. Other patients were treated successfully with delayed primary closure, local flap advancement (one patient underwent a pedicled cross-leg flap), or by secondary intention. Use of the V.A.C. device is valuable in increasing the rate of granulation tissue formation and healing of extensive soft tissue injuries in pediatric patients. This vacuum system aids in the debridement of necrotic tissue and local soluble inflammatory mediators that may inhibit the proliferation of granulation tissue. These improvements in the local wound environment seem to accelerate wound healing compared with traditional methods. Before the development of the V.A.C. system, a minimum of nine patients within this group would have required free tissue transfer to obtain adequate coverage. The V.A.C. device seems to permit earlier coverage with local tissue or split-thickness skin grafting techniques, thereby decreasing the need for extensive microvascular tissue transfers in pediatric patients.


The development of a web-based resource to provide information and psychosocial support to informal cancer carers in hospitals in Vietnam.
Vietnam, like many low/middle income countries, lacks the infrastructure to provide information and psychosocial support to cancer patients and their carers. We undertook a codesign process to develop a web resource to inform and support carers. Cancer carers and health care professionals' perspectives regarding information and support needs and the content and delivery of web-based supports, were explored via five focus groups (n = 39) and semistructured interviews (n = 4) in Vietnam in 2018. Focus groups and interviews were transcribed verbatim and analyzed using thematic analysis. Resource components were verified at two joint stakeholder workshops attended by 40 participants. The development of a web-based resource was identified as an urgent need. A web-based resource was viewed as a suitable interface to provide support across regions in a sustainable way. The structure of the resource should include peer-led videoed advice, signposting to services and include official endorsement. The potential resource components identified includes (a) cancer causes and consequences; (b) hospital administration, treatment processes, and prices; (c) daily living; (d) emotional and supportive information; (e) skills training; and (f) nutrition and traditional medicine. The development of a web-based resource to deliver information and psychosocial supports to cancer carers and by-proxy patients is an urgent requirement in Vietnam. Next steps will include resource development and testing the resources ability to address the unmet needs of cancer carers and patients. A web-based resource to support cancer carers has the potential for application to other developing countries.


Antihypertensive effect of riboflavin analogs in rats with mineralocorticoid-induced hypertension.
This study investigated whether the riboflavin analogs, 7,8-dimethyl-10-formylmethyl isoalloxazine (FMI) and 7,8-dimethyl-10-(2'-hydroxyethyl) isoalloxazine (HEI), are effective antihypertensive agents in mineralocorticoid-induced or deoxycorticosterone acetate (DOCA)-salt hypertension. These studies are based on our previous observation tht aldosterone enhances the biosynthesis of renal flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) from riboflavin, and that FMI and HEI competitively inhibit conversion of riboflavin to FMN and reabsorption of Na+ in the kidney of adrenalectomized rats. When 1.6 mg of FMI or HEI were administered simultaneously with 3.0 mg of DOCA, the tail systolic blood pressure (SBP) of unanesthetized rats rose only to 136 +/- 5 mm Hg (standard error of the mean, SEM) compared to 163 +/- 5 mm Hg during DOCA therapy alone (p less than 0.0005). This hypotensive effect of FMI or HEI was noted after the fourth week of treatment and persisted through the ninth week. The rats tolerated the medication well and had no signs of riboflavin deficiency. DOCA administration alone resulted in a 24% increase in iliopsoas muscle Na+ concentration (p less than 0.0005), and a 0.8% increase in the water content of the muscle (p less than 0.025), suggesting a positive Na+ balance. Administration of FMI or HEI blunted the ability of DOCA to increase muscle Na+ concentration (p less than 0.025), water content (p less than 0.01). HEI treatment of the Kyoto strain of spontaneously hypertensive rats (SHR) did not lower their mean SBP. Thus it appears that the hypotensive actions of FMI or HEI are closely associated with their ability to modify the effects of mineralocorticoids on NA+ balance.


DynaCT imaging for intraprocedural evaluation of flow-diverting stent apposition during endovascular treatment of intracranial aneurysms.
The treatment of large, complex intracranial aneurysms is being increasingly performed using flow-diverting stents (FDS) such as the Pipeline Embolization Device (PED; ev3, Irvine, CA, USA). Malapposition of a FDS to the parent artery wall decreases the likelihood of aneurysm obliteration and increases the risk of both immediate and delayed complications. DynaCT scanning (Siemens Medical Solutions, Erlangen, Germany) is a novel imaging modality which uses a flat plane detector to generate CT images using the same C-arm employed for digital subtraction angiography. We present a 40-year-old woman with an unruptured, 11 mm cavernous internal carotid artery aneurysm who was treated with endovascular obliteration using a PED. Intraprocedural DynaCT scan performed after PED deployment demonstrated incomplete stent apposition to the parent vessel which could not be detected on digital subtraction angiography alone. Balloon angioplasty was performed to improve apposition of the stent to the vessel wall. There were no procedural or clinical complications. The aneurysm shrank in size at follow-up angiography 6 months after the procedure and will be monitored for progressive occlusion. While gross stent malapposition is readily evident after stent deployment, minor instances of malapposition may be undetectable by standard angiography. Therefore the use of DynaCT imaging may improve intraprocedural stent visualization and potentially avert long-term endovascular aneurysm treatment complications associated with inadequate stent apposition.


Genetically predicted waist circumference and risk of atrial fibrillation.
Observational studies have revealed an association between waist circumference (WC) and atrial fibrillation (AF). However, it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors. Therefore, the causal role of WC in AF is unclear. This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization (MR) analysis. In our two-sample MR analysis, the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study (GWAS) of WC (42 single nucleotide polymorphisms with a genetic significance of P <5 × 10-8). The data of WC (from the Genetic Investigation of ANthropometric Traits consortium, containing 232,101 participants) and the data of AF (from the European Bioinformatics Institute database, containing 55,114 AF cases and 482,295 controls) were used to assess the causal role of WC on AF. Three different approaches (inverse variance weighted [IVW], MR-Egger, and weighted median regression) were used to ensure that our results more reliable. All three MR analyses provided evidence of a positive causal association between high WC and AF. High WC was suggested to increase the risk of AF based on the IVW method (odds ratio [OR] = 1.43, 95% confidence interval [CI], 1.30-1.58, P = 2.51 × 10-13). The results of MR-Egger and weighted median regression exhibited similar trends (MR-Egger OR = 1.40 [95% CI, 1.08-1.81], P = 1.61 × 10-2; weighted median OR = 1.39 [95% CI, 1.21-1.61], P = 1.62 × 10-6). MR-Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF. Our findings suggest that greater WC is associated with an increased risk of AF. Taking measures to reduce WC may help prevent the occurrence of AF.


Sequential synthesis of small capped RNA transcripts in vitro by vesicular stomatitis virus.
Using purified viral or intracellular transcriptive complexes (RNP cores) of vesicular stomatitis virus (VSV), we have identified several small RNA species, ranging in size from 12 to 47 nucleotides in length that are synthesized in vitro by the genomic RNA. One group of small RNA transcripts is composed of three species that are capped at their 5' termini. Two of the capped species are from the start of the N gene and one is from the start of the NS gene. Unlike the previously described 5' triphosphated small RNAs, the templates encoding these small capped RNAs had uv target sizes greater than their respective lengths. In addition, these RNAs appeared sequentially during synchronized in vitro transcription reactions. Thus, these results provide evidence that sequences representing the 5'-capped termini of N and NS mRNAs are synthesized concomitantly with their respective mRNAs rather than simultaneously at the onset of transcription as proposed for the multiple entry, start-stop model (D. Testa, P. K. Chanda, and A. K. Banerjee, 1980, Cell 21, pp. 267-275). Together with the inability of the internally initiated 5'-triphosphated RNAs to be chased into mRNA (R. A. Lazzarini, I. Chien, F. Yang, and J. D. Keene, 1982, J. Gen. Virol. 58, 429-441), these results support a single entry model of VSV mRNA transcription.


Viral suppression and viral rebound among young adults living with HIV in Canada.
Describe the prevalence and covariates of viral suppression and subsequent rebound among younger (≤29 years old) compared with older adults.A retrospective clinical cohort study; eligibility criteria: documented HIV infection; resident of Canada; 18 years and over; first antiretroviral regimen comprised of at least 3 individual agents on or after January 1, 2000.Viral suppression and rebound were defined by at least 2 consecutive viral load measurements <50 or >50 HIV-1 RNA copies/mL, respectively, at least 30 days apart, in a 1-year period. Time to suppression and rebound were measured using the Kaplan-Meier method and Life Table estimates. Accelerated failure time models were used to determine factors independently associated with suppression and rebound.Younger adults experienced lower prevalence of viral suppression and shorter time to viral rebound compared with older adults. For younger adults, viral suppression was associated with being male and later era of combination antiretroviral initiation (cART) initiation. Viral rebound was associated with a history of injection drug use, Indigenous ancestry, baseline CD4 cell count >200, and initiating cART with a protease inhibitor (PI) containing regimen.The influence of age on viral suppression and rebound was modest for this cohort. Our analysis revealed that key covariates of viral suppression and rebound for young adults in Canada are similar to those of known importance to older adults. Women, people who use injection drugs, and people with Indigenous ancestry could be targeted by future health interventions.


Immunoaffinity purification and functional characterization of human transcription factor IIH and RNA polymerase II from clonal cell lines that conditionally express epitope-tagged subunits of the multiprotein complexes.
Purification of multiprotein complexes such as transcription factor (TF) IIH and RNA polymerase II (pol II) has been a tedious task by conventional chromatography. To facilitate the purification, we have developed an effective scheme that allows human TFIIH and pol II to be isolated from HeLa-derived cell lines that conditionally express the FLAG-tagged p62 subunit of human TFIIH and the RPB9 subunit of human pol II, respectively. An approximate 2000-fold enrichment of FLAG-tagged TFIIH and a 1000-fold enhancement of total pol II are achieved by a one-step immunoaffinity purification. The purified complexes are functional in mediating basal and activated transcription, regardless of whether TATA-binding protein or TFIID is used as the TATA-binding factor. Interestingly, repression of basal transcription by the positive cofactor PC4 is alleviated by increasing amounts of TFIID, TFIIH, and pol II holoenzyme, suggesting that phosphorylation of PC4 by these proteins may cause a conformational change in the structure of PC4 that allows for preinitiation complex formation and initiation of transcription. Furthermore, pol II complexes with different phosphorylation states on the carboxyl-terminal domain of the largest subunit are selectively purified from the inducible pol II cell line, making it possible to dissect the role of carboxyl-terminal domain phosphorylation in the transcription process in a highly defined in vitro transcription system.


Role of prophylactic surgical ligation of patent ductus arteriosus in extremely low birth weight infants: Systematic review and implications for clinical practice.
To investigate the effectiveness and safety of prophylactic surgical ligation of patent ductus arteriosus (PDA) on mortality and morbidity of preterm infants weighing less than 1000 g at birth. The study conducted a systematic search of available database from 1996-2008. Retrieved articles were assessed for eligibility and data was abstracted independently by two reviewers. Decisions to include studies for review and the methodological quality of included studies were asssessed in duplicate based on predetermined criteria. No language restrictions were applied. Only one eligible study that enrolled 84 extremely low birth weight infants was identified. Prophylactic surgical ligation of PDA resulted in a statistically significant reduction of severe stage II or III necrotizing enterocolitis, [RR 0.25, 95% CI (0.08, 0.83), P value 0.02, number needed to treat 5]. The study, however, found no statistically significant difference in mortality, intraventricular hemorrhage, bronchopulmonary dysplasia, and retinopathy of prematurity. Current evidence does not support the use of prophylactic surgical ligation of PDA in the management of the preterm infants.


Quo vadis blood protein adductomics?
Chemicals are measured regularly in air, food, the environment, and the workplace. Biomonitoring of chemicals in biological fluids is a tool to determine the individual exposure. Blood protein adducts of xenobiotics are a marker of both exposure and the biologically effective dose. Urinary metabolites and blood metabolites are short term exposure markers. Stable hemoglobin adducts are exposure markers of up to 120 days. Blood protein adducts are formed with many xenobiotics at different sites of the blood proteins. Newer methods apply the techniques developed in the field of proteomics. Larger adducted peptides with 20 amino acids are used for quantitation. Unfortunately, at present the methods do not reach the limits of detection obtained with the methods looking at single amino acid adducts or at chemically cleaved adducts. Therefore, to progress in the field new approaches are needed.


CD4⁺ and CD8⁺ T cell-dependent antiviral immunity requires STIM1 and STIM2.
Calcium signaling is critical for lymphocyte function, and intracellular Ca2+ concentrations are regulated by store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels. In patients, loss-of-function mutations in CRAC channel components ORAI1 and STIM1 abolish SOCE and are associated with recurrent and chronic viral infections. Here, using mice with conditional deletion of Stim1 and its homolog Stim2 in T cells, we determined that both components are required for the maintenance of virus-specific memory CD8+ T cells and recall responses following secondary infection. In the absence of STIM1 and STIM2, acute viral infections became chronic. Early during infection, STIM1 and STIM2 were required for the differentiation of naive CD8+ T cells into fully functional cytolytic effector cells and mediated the production of cytokines and prevented cellular exhaustion in viral-specific CD8+ effector T cells. Importantly, memory and recall responses by CD8+ T cells required expression of STIM1 and STIM2 in CD4+ T cells. CD4+ T cells lacking STIM1 and STIM2 were unable to provide "help" to CD8+ T cells due to aberrant regulation of CD40L expression. Together, our data indicate that STIM1, STIM2, and CRAC channel function play distinct but synergistic roles in CD4+ and CD8+ T cells during antiviral immunity.


Stereotactic Radiotherapy Increases Functionally Suppressive Regulatory T Cells in the Tumor Microenvironment.
Radiotherapy (RT) enhances innate and adaptive antitumor immunity; however, the effects of radiation on suppressive immune cells, such as regulatory T cells (Treg), in the tumor microenvironment (TME) are not fully elucidated. Although previous reports suggest an increased Treg infiltration after radiation, whether these Tregs are functionally suppressive remains undetermined. To test the hypothesis that RT enhances the suppressive function of Treg in the TME, we selectively irradiated implanted tumors using the small animal radiation research platform (SARRP), which models stereotactic radiotherapy in human patients. We then analyzed tumor-infiltrating lymphocytes (TIL) with flow-cytometry and functional assays. Our data showed that RT significantly increased tumor-infiltrating Tregs (TIL-Treg), which had higher expression of CTLA-4, 4-1BB, and Helios compared with Tregs in nonirradiated tumors. This observation held true across several tumor models (B16/F10, RENCA, and MC38). We found that TIL-Tregs from irradiated tumors had equal or improved suppressive capacity compared with nonirradiated tumors. Our data also indicated that after RT, Tregs proliferated more robustly than other T-cell subsets in the TME. In addition, after RT, expansion of Tregs occurred when T-cell migration was inhibited using Fingolimod, suggesting that the increased Treg frequency was likely due to preferential proliferation of intratumoral Treg after radiation. Our data also suggested that Treg expansion after irradiation was independent of TGFβ and IL33 signaling. These data demonstrate that RT increased phenotypically and functionally suppressive Tregs in the TME. Our results suggest that RT might be combined effectively with Treg-targeting agents to maximize antitumor efficacy. Cancer Immunol Res; 5(11); 992-1004. ©2017 AACR.


Assessing nutrition in elderly patients.
The nutritional status of elderly patients can have a significant bearing on their well-being. This article details how nurses can accurately assess the nutritional status and diet of elderly patients and plan appropriate care.


Benefit finding as a moderator of the relationship between spirituality/religiosity and drinking.
This study evaluated benefit finding as a moderator of the relationship between spiritual and religious attitudes and drinking. Previous research indicates that undergraduates who drink heavily experience negative alcohol-related consequences. Literature also suggests that spirituality and religiosity (S/R) are protective against heavy drinking (e.g., Yonker, Schnabelrauch, & DeHaan, 2012) and that finding meaning, which is conceptually related to benefit finding, is negatively associated with alcohol use (e.g., Wells, 2010). Seven hundred undergraduate students completed the study materials including measures of drinking, benefit finding, and S/R. Based on previous research, we expected that S/R and benefit finding would be negatively associated with drinking. Furthermore, we expected that benefit finding would moderate the association between S/R and drinking, such that S/R would be more negatively associated with drinking among those higher in benefit finding. Consistent with expectations, a negative association between S/R and drinking was present, and was stronger among those high in benefit finding. These findings extend previous research by demonstrating that the protective effect of S/R on drinking appears to be particularly true among those who find benefit following stressful experiences. This study extends previous research showing that S/R is negatively associated with drinking by evaluating benefit finding (measured via the Post-Traumatic Growth Inventory; Tedeschi & Calhoun, 1996) as a potential moderator of the relationship between S/R and drinking. This study contributes to the alcohol literature seeking to understand and identify individual factors in drinking and determine how S/R and benefit finding relate to drinking.


Development and Characterization of PLGA-Based Multistage Delivery System for Enhanced Payload Delivery to Targeted Vascular Endothelium.
Vascular-targeted drug delivery remains an attractive platform for therapeutic and diagnostic interventions in human diseases. This work focuses on the development of a poly-lactic-co-glycolic-acid (PLGA)-based multistage delivery system (MDS). MDS consists of two stages: a micron-sized PLGA outer shell and encapsulated drug-loaded PLGA nanoparticles. Nanoparticles with average diameters of 76, 119, and 193 nm are successfully encapsulated into 3-6 µm MDS. Sustained in vitro release of nanoparticles from MDS is observed for up to 7 days. Both MDS and nanoparticles arebiocompatible with human endothelial cells. Sialyl-Lewis-A (sLeA ) is successfully immobilized on the MDS and nanoparticle surfaces to enable specific targeting of inflamed endothelium. Functionalized MDS demonstrates a 2.7-fold improvement in endothelial binding compared to PLGA nanoparticles from human blood laminar flow. Overall, the presented results demonstrate successful development and characterization of MDS and suggest that MDS can serve as an effective drug carrier, which can enhance the margination of nanoparticles to the targeted vascular wall.


Artificial intelligence for automatic cerebral ventricle segmentation and volume calculation: a clinical tool for the evaluation of pediatric hydrocephalus.
Imaging evaluation of the cerebral ventricles is important for clinical decision-making in pediatric hydrocephalus. Although quantitative measurements of ventricular size, over time, can facilitate objective comparison, automated tools for calculating ventricular volume are not structured for clinical use. The authors aimed to develop a fully automated deep learning (DL) model for pediatric cerebral ventricle segmentation and volume calculation for widespread clinical implementation across multiple hospitals. The study cohort consisted of 200 children with obstructive hydrocephalus from four pediatric hospitals, along with 199 controls. Manual ventricle segmentation and volume calculation values served as "ground truth" data. An encoder-decoder convolutional neural network architecture, in which T2-weighted MR images were used as input, automatically delineated the ventricles and output volumetric measurements. On a held-out test set, segmentation accuracy was assessed using the Dice similarity coefficient (0 to 1) and volume calculation was assessed using linear regression. Model generalizability was evaluated on an external MRI data set from a fifth hospital. The DL model performance was compared against FreeSurfer research segmentation software. Model segmentation performed with an overall Dice score of 0.901 (0.946 in hydrocephalus, 0.856 in controls). The model generalized to external MR images from a fifth pediatric hospital with a Dice score of 0.926. The model was more accurate than FreeSurfer, with faster operating times (1.48 seconds per scan). The authors present a DL model for automatic ventricle segmentation and volume calculation that is more accurate and rapid than currently available methods. With near-immediate volumetric output and reliable performance across institutional scanner types, this model can be adapted to the real-time clinical evaluation of hydrocephalus and improve clinician workflow.


The effect of size of giant pancreatic pseudocysts on the outcome of internal drainage procedures.
Pancreatic pseudocysts (PP) that fail to resolve spontaneously are optimally treated by internal drainage to a viscus. Pseudocysts adherent to the stomach are usually drained by way of cystgastrostomy. Recent experience with giant pseudocysts (greater than 15 centimeters), however, challenges this approach. Fifty-two patients with pancreatic pseudocysts of various sizes were treated from 1982 to 1986 at the Massachusetts General Hospital. Twenty-eight PP were suitable for internal drainage. The postoperative complication rate was directly proportional to the size of the pseudocyst. Four patients had giant PP, three of which occurred after an attack of acute pancreatitis. All four were treated by cystgastrostomy. Three of four patients with giant pseudocysts had life-threatening postoperative complications as a result of incomplete emptying of the cyst, and two patients died. No evidence of anastomotic leakage could be demonstrated by upper gastrointestinal series or computed tomographic scans. Transgastric drainage tubes in these three instances were not protective. We conclude that cystgastrostomy may not be appropriate for the treatment of giant pancreatic pseudocysts because it fails to provide dependent drainage of a large cyst cavity. If internal drainage is performed, the cyst should be anastomosed to a defunctionalized loop of jejunum in a dependent position. In some instances, external drainage of giant pancreatic pseudocysts may be safer than cystgastrostomy.


Resin-based pit-and-fissure sealants: microleakage reduction and infiltration enhancement using a bonding agent.
To evaluate the marginal microleakage and the infiltration ability of pit-and-fissure sealants by applying the conventional sealing technique in comparison to using an additional bonding agent. Extracted non-carious permanent molars (n = 60) were first stored in sterile saline solution and then assigned to one of two groups: group C (control) was sealed (Helioseal F) by using the conventional technique, while in group BA (bonding agent), a bonding agent (OptiBond FL) was additionally applied prior to sealing. The teeth were thermocycled (1000 cycles, 5°C to 55°C, dwell time 30 s), then varnished and immersed in 5% methylene blue solution for 24 h. After embedding and sectioning each tooth into 6-12 slices, the presence of microleakage, unfilled areas, and air bubbles trapped in the sealant were assessed with a stereomicroscope. A higher proportion of microleakage was found under sealants applied without the additional use of the bonding agent. A statistically significant difference in microleakage was noted between the groups (p = 0.045). Regarding the presence of unfilled areas, a statistically significant difference between the groups was observed (p < 0.001), especially since no unfilled areas were found at all in the samples of the group using the bonding agent. Regarding the amount of air bubbles trapped in the sealant, no statistically significant difference was observed between the two groups (p = 0.829). Under these in vitro conditions, sealant procedures using an additional bonding agent applied beforehand significantly improved fissure infiltration and microleakage prevention significantly.


Acute upper gastrointestinal bleeding in patients with AIDS: a relatively uncommon condition associated with reduced survival.
To determine the cumulative incidence of acute upper gastrointestinal bleeding and its effect upon survival in patients with AIDS, 453 consecutive AIDS patients diagnosed in our hospital between June 1985 and March 1989 were followed for a median period of six months (maximum 42 months). The cumulative probability of acute gastrointestinal bleeding was 3% at six months and 6% at 14 months. This event was associated with significantly reduced survival. Independent risk factors for bleeding were: severe thrombocytopenia at the time of diagnosis and non-Hodgkin's lymphoma as the first clinical manifestation of AIDS. The potential causes of bleeding were investigated in all cases by emergency endoscopy or by necropsy examination in those patients whose clinical condition precluded the procedure. In nine of 15 patients, bleeding was due to lesions specifically associated with AIDS, but in the remainder the source of bleeding was not a direct consequence of HIV infection. We conclude that acute upper gastrointestinal bleeding rarely complicates the course of AIDS, but its occurrence is associated with decreased survival. As many of the causes are potentially treatable, a complete diagnostic approach is indicated in these patients, except those who are terminally ill.


Organizational development of biomedical engineering.
The evolution of biomedical engineering is traced, beginning with its roots in electrophysiology about 200 years ago. Significant research and professional developments during the 1940s, '50s, and '60s are sketched. Five major events that contributed to these developments are discussed. They are the split between biophysics and bioengineering (1957), S. Talbot's BME study grant (1958-60), the impact of the National Institutes of Health (since 1958), the IEEE ;BME-crisis' (1967/68), and the IEEE Bioengineering Society's founding (1968) and its BME view as an extension of physiology.


Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia.
Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5' untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5'UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.


Predictors of outcome after percutaneous treatment for cardiogenic shock.
To determine predictors of outcome after percutaneous coronary intervention (PCI) in patients with cardiogenic shock complicating acute myocardial infarction. Retrospective analysis of a cohort of 113 patients undergoing emergency coronary angiography and attempted PCI for cardiogenic shock complicating acute myocardial infarction in a regional cardiothoracic unit. In-hospital mortality was 51% (58 patients). Adverse outcome was associated with previous myocardial infarction, age over 70 years, cardiogenic shock complicating failure to respond to thrombolytic treatment (failed thrombolysis), and multivessel coronary artery disease. Multivariate logistic regression analysis showed that the first three factors were independent predictors of in-hospital death with odds ratios of 5.21 (95% confidence interval (CI) 1.85 to 14.69), 4.02 (95% CI 1.14 to 14.12), and 3.78 (95% CI 1.43 to 9.96), respectively. About 50% of patients with cardiogenic shock undergoing a strategy of urgent coronary angiography and PCI survive to hospital discharge. Survivors do well in the subsequent six months. Emergency PCI for cardiogenic shock reduces mortality from an expected 80% to about 50%. Clinical features can help determine which patients are most likely to gain from urgent coronary angiography and attempted PCI. Alternative strategies are needed to improve the outcome of patients who fare badly.


Electroacupuncture Pretreatment Attenuates Cerebral Ischemia-Reperfusion Injury in Rats Through Transient Receptor Potential Vanilloid 1-Mediated Anti-apoptosis via Inhibiting NF-κB Signaling Pathway.
Our previous study showed that electroacupuncture (EA) pretreatment elicited protective effect on cerebral ischemia-reperfusion injury (CIRI) in rats, at least partly, which was associated with transient receptor potential vanilloid 1 (TRPV1)-regulated anti-oxidant stress and anti-inflammation. In this study, we further investigated the possible contribution of TRPV1-mediated anti-apoptosis in EA pretreatment-evoked neuroprotection in CIRI. After EA pretreatment at Baihui (GV20), bilateral Shenshu (BL23) and Sanyinjiao (SP6) acupoints, transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 6 h in rats. Then, infarct volume, nerve cell injury, neuronal apoptosis, NF-κB signaling activation, and expression of TRPV1 were evaluated by TTC staining, Hematoxylin-Eosin staining, transmission electron microscopy, immunochemistry, immunofluorescence, and Western blot, respectively. The presented data showed that EA pretreatment significantly reduced infarct volume, relieved nerve cell injury, decreased the expression of pro-apoptotic proteins Bax and cleaved caspase-3, increased the level of anti-apoptotic protein Bcl-2, inhibited NF-κB (p65) transcriptional activity, and curbed TRPV1 expression in MCAO rats. By contrast, enhancement of TRPV1 expression accompanying capsaicin application, the specific TRPV1 agonists, markedly accelerated nerve cell damage, aggravated neuronal apoptosis, prompted nuclear translocation of NF-κB (p65), resulting in the reversion of EA pretreatment-evoked neuroprotective effect in MCAO rats. Thus, we conclude that EA pretreatment-induced downregulation of neuronal TRPV1 expression plays an anti-apoptosis role through inhibiting NF-κB signaling pathway, thereby protecting MCAO rats from cerebral ischemia-reperfusion injury.


The neurological illness of Friedrich Nietzsche.
Friedrich Nietzsche (1844-1900), one of the most profound and influential modern philosophers, suffered since his very childhood from severe migraine. At 44 he had a mental breakdown ending in a dementia with total physical dependence due to stroke. From the very beginning, Nietzsche's dementia was attributed to a neurosyphilitic infection. Recently, this tentative diagnosis has become controversial. To use historical accounts and original materials including correspondence, biographical data and medical papers to document the clinical characteristics of Nietzsche's illness and, by using this pathography, to discuss formerly proposed diagnoses and to provide and support a new diagnostic hypothesis. Original letters from Friedrich Nietzsche, descriptions by relatives and friends, and medical descriptions. Original German sources were investigated. Biographical papers published in medical journals were also consulted. Nietzsche suffered from migraine without aura which started in his childhood. In the second half of his life he suffered from a psychiatric illness with depression. During his last years, a progressive cognitive decline evolved and ended in a profound dementia with stroke. He died from pneumonia in 1900. The family history includes a possible vascular-related mental illness in his father who died from stroke at 36. Friedrich Nietzsche's disease consisted of migraine, psychiatric disturbances, cognitive decline with dementia, and stroke. Despite the prevalent opinion that neurosyphilis caused Nietzsche's illness, there is lack of evidence to support this diagnosis. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) accounts for all the signs and symptoms of Nietzsche's illness. This study adds new elements to the debate and controversy about Nietzsche's illness. We discuss former diagnoses, comment on the history of a diagnostic mistake, and integrate for the first time Nietzsche's medical problems.


Report of the symposium on Cutaneous Lymphomas: Sixth International Conference on Malignant Lymphoma.
The symposium discussed the pathobiology, classification, and treatment of cutaneous lymphomas. Drs. Burg and Kadin commented on the pathophysiology of mycosis fungoides/Sézary syndrome and cutaneous CD30+ lymphoproliferative disorders, respectively. A proposed classification of primary cutaneous lymphomas from the EORTC was presented by Drs. Kerl and Sterry. Dr. Jaffe presented a classification of cutaneous lymphomas based on the REAL classification. All speakers agreed that primary cutaneous lymphomas are usually distinctive in their clinical behavior and biology, and differ from their nodal counterparts. The symposium concluded with remarks from Drs. Vonderheid and Hoppe on the therapeutic approach to primary cutaneous lymphoid malignancies.


Impact of Precision Medicine on Drug Repositioning and Pricing: A Too Small to Thrive Crisis.
The pricing of targeted medicines continues to be a major area of contention in healthcare economics. This issue is further complicated by redefining the role of molecular testing in precision medicine. Currently, whilst pricing of clinical laboratory diagnostics is cost-based, drug pricing is value-based. The pricing for molecular testing is under pressure to change the traditional business model, for it has a critical subsidiary role in determining the final value of targeted medicines. The market size for drugs is reduced by molecular testing when patients with the same disease are stratified based on their genetics, it is critical to determine the value of this new enhanced drug specificity to realize its full pricing potential. However, these value-based pricing strategies require a careful understanding of changing market conditions, especially, in the context of stratified patient segments made possible by precision medicine. In this article, we discuss the various factors impacting pricing decisions, and consider evolving economic trends in precision medicine.


Insights from exemplar practices on achieving organizational structures in primary care.
Interprofessional practice (IPP) is associated with better patient care outcomes and patient and provider satisfaction, yet little is known about the organizational structures that support effective IPP. We selected 9 diverse clinical practice sites with exemplary IPP and conducted site visits with nonparticipant observations and interviewed 80 physicians, nurses, pharmacists, dieticians, medical and hospital assistants, nurse practitioners, physician assistants, clinic managers, physical and occupational therapists, respiratory therapists, social workers, psychologists, and others. We independently coded field notes and interviews and identified themes and trends using a grounded theory approach. Sites were evaluated for IPP using key features identified by the 2011 Interprofessional Education Collaboration Expert Panel. The primary themes at sites with high IPP were coordination of care and mutual respect. Four key organizational features were associated with these 2 themes: independent responsibilities for each professional; organizational structures for providers to learn about each other's roles; a structure and culture promoting accessible, frequent communication about patients; and strong leadership in IPP-supportive values. To achieve interprofessional collaboration, practice teams require structural supports that facilitate coordination of care and mutual respect.


Sensitization of dog and guinea pig heart myofilaments to Ca2+ activation and the inotropic effect of pimobendan: comparison with milrinone.
We compared the effects of the newer inotropic drugs, pimobendan (UD-CG 115 BS) and milrinone (Win 47203), on the electrical, mechanical and biochemical activity of intact and detergent-skinned preparations of cardiac muscle. Both of these agents increased contractile force of guinea pig papillary muscle preparations bathed under physiological conditions or depolarized with 25 mM K+o. The positive inotropic action was associated with potentiation of the Ca2+-dependent slow action potentials (APS). Contractile force developed in the presence of 25 mM [K]o and 1 microM isoproterenol was increased further by addition of 50 microM pimobendan with no effect on the slow action potential. Milrinone (50 microM) did not produce a further increase in the force or potentiate the slow APs. Pimobendan, in a dose-dependent manner, increased active tension developed by chemically-skinned dog heart muscle fibers at submaximally activating concentrations of Ca2+, whereas milrinone did not. At pCa 6.25, the half-maximal concentration of pimobendan for stimulation of force development was about 40 microM. At maximally activating levels of Ca2+ (pCa 4.5), pimobendan had little or no effect on force development. The effect of pimobendan on force was paralleled by changes in the Ca2+-activated Mg-ATPase activity of the isometric skinned fiber preparations. Moreover, the tension-cost (unit increase in ATPase rate/unit increase in force) was unchanged in the presence of pimobendan. Milrinone did not affect ATP hydrolysis by the skinned fiber preparations. Force-pCa and ATPase-pCa relations of skinned fiber preparations contracting isometrically were shifted to the left by 0.15-0.20 pCa units in the presence of 50 microM pimobendan. In contrast, there was no effect of pimobendan on the ATPase activity of unloaded myofibrillar preparations. The stimulation of force and ATPase activity of the skinned heart muscle fibers could be accounted for by an effect of pimobendan on the affinity of the regulatory (low affinity, Ca2+-specific) binding sites of cardiac troponin C. Ca2+ binding to the "structural" high affinity sites of troponin C was slightly inhibited. The results indicate that the positive inotropic actions of pimobendan, but not milrinone, may involve activation of the cardiac myofilaments by a direct effect involving an increased affinity of the regulatory site on troponin C for Ca2+.


[MicroRNAs As An Important Precursors of Diagnostic Obstetric Pathology].
MicroRNAs (miRs) are the class of short nucleotide sequences (21-27 nucleotides) RNA, non-coding protein synthesis. miRs are known as effective posttranscriptional negative regulators of gene expression with specific binding sites of targeted messenger RNA (mRNA) in the cytoplasm, providing translational repression or degradation of the target miR transcript. In this review we studied the role of miRNAs in the development of a physiological pregnancy and obstetric complications. The placenta is a unique organ which provides modulation of the immune system of the maternal organism during pregnancy including miRs which determine immunological tolerance of the body to the tissues of the fetus. Thus the "placental" miRs in maternal circulation may be the potential biomarker revealed at various obstetric pathology on the early stages before clinical manifestation of the diseases.


Clinicopathological features of extranodal lymphomas: Kuwait experience.
A total of 935 patients with extranodal non-Hodgkin lymphoma (NHL) diagnosed in the period between January 1985 and December 2000 in Kuwait Cancer Center, serving the whole population of Kuwait, were used to describe the clinicopathological and epidemiological features of extranodal lymphomas in Kuwait. Extranodal lymphomas accounted for 45% of all NHL observed during this time. All NHL cases from Kuwait Cancer registry were analyzed and pathologically reclassified using the latest WHO (2000) classification. The most common lymphoma observed was diffuse large B-cell lymphoma (58.60%) followed by Burkitt s lymphoma (BL) (3.80%). In the pediatric group, BL comprises more than two thirds of all patients (77.20%). The most common extranodal sites were stomach (19.70%) and skin (17.80%) in the adult group, large intestine (29.80%) and small intestine (19.30%) in the pediatric age group. The majority (73.40%) of adult extranodal lymphomas was in stage IE-IIE and had a very good prognosis. On the contrary, the majority of pediatric extranodal lymphomas were found to be in stage III and IV. Variations in treatment policies (single agent or combined chemotherapy, radiotherapy, combined modality treatment) adopted and changed during the time period of 16 years of this retrospective study were documented.


Glucagon does not affect catecholamine release in primary cultures of bovine adrenal chromaffin cells.
Human pheochromocytoma tumor cells express glucagon receptors, and bolus i.v. glucagon injection rapidly increases plasma epinephrine levels, suggesting that glucagon can directly stimulate adrenomedullary secretion. In this study, we tested whether the catecholamine secretory response to glucagon was present in bovine chromaffin cells or exclusive to the tumor cells. Adrenomedullary cells were cultured in 24-well plates (10(6) cells per well). After 48-72 hours, wells were incubated for 1-20 minutes with (1) incubation medium (control), (2) catecholamine secretagogues (nicotine or potassium ion), or (3) glucagon (10(-8) to 10(-5) M). After incubation, catecholamine contents in medium and cells were assayed by high-pressure liquid chromatography with electrochemical detection. Fractional release rates of epinephrine, norepinephrine, and dopamine were calculated and compared to controls. Reverse-transcriptase PCR was performed to compare expression of mRNA of the glucagon receptor in chromaffin cells and pheochromocytoma cells. Nicotine and potassium evoked time-dependent release of epinephrine, norepinephrine, and dopamine. Glucagon did not affect catecholamine secretion at any concentration. Reverse-transcriptase PCR failed to detect mRNA for glucagon receptor in bovine adrenomedullary cells, but did detect it in human pheochromocytoma cells. In contrast to pheochromocytoma tumor cells, bovine adrenomedullary chromaffin cells do not express the glucagon receptor, and therefore do not secrete catecholamines in response to glucagon.


Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.
It is uncertain whether modest benefits from adjuvant chemotherapy in stage II colorectal cancer justify the toxicity, cost, and inconvenience. We investigated the usefulness of defective mismatch repair (dMMR), BRAF, and KRAS mutations in predicting tumor recurrence and sensitivity to chemotherapy. Immunohistochemistry for dMMR and pyrosequencing for KRAS/BRAF were performed for 1,913 patients randomly assigned between fluorouracil and folinic acid chemotherapy and no chemotherapy in the Quick and Simple and Reliable (QUASAR) trial. Twenty-six percent of 695 right-sided colon, 3% of 685 left-sided colon, and 1% of 407 rectal tumors were dMMR. Similarly, 17% of right colon, 2% of left colon, and 2% of rectal tumors were BRAF mutant. KRAS mutant tumors were more evenly distributed: 40% right colon, 28% left colon, and 36% rectal tumors. Recurrence rate for dMMR tumors was half that for MMR-proficient tumors (11% [25 of 218] v 26% [438 of 1,695] recurred; risk ratio [RR], 0.53; 95% CI, 0.40 to 0.70; P < .001). Risk of recurrence was also significantly higher for KRAS mutant than KRAS wild-type tumors (28% [150 of 542] v 21% [219 of 1,041]; RR, 1.40; 95% CI, 1.12 to 1.74; P = .002) but did not differ significantly between BRAF mutant and wild-type tumors (P = .36). No marker predicted benefit from chemotherapy with efficacy not differing significantly by MMR, KRAS, or BRAF status. The prognostic value of MMR and KRAS was similar in the presence and absence of chemotherapy. MMR assays identify patients with a low risk of recurrence. KRAS mutational analysis provides useful additional risk stratification to guide use of chemotherapy.


The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants.
Complications of vascular diseases, including atherosclerosis, are the number one cause of death in Western societies. Dysfunction of endothelial cells is a critical underlying cause of the pathology of atherosclerosis. Lipid rafts, and especially caveolae, are enriched in endothelial cells, and down-regulation of the caveolin-1 gene may provide protection against the development of atherosclerosis. There is substantial evidence that exposure to environmental pollution is linked to cardiovascular mortality, and that persistent organic pollutants can markedly contribute to endothelial cell dysfunction and an increase in vascular inflammation. Nutrition can modulate the toxicity of environmental pollutants, and evidence suggests that these affect health and disease outcome associated with chemical insults. Because caveolae can provide a regulatory platform for pro-inflammatory signalling associated with vascular diseases such as atherosclerosis, we suggest a link between atherogenic risk and functional changes of caveolae by environmental factors such as dietary lipids and organic pollutants. For example, we have evidence that endothelial caveolae play a role in uptake of persistent organic pollutants, an event associated with subsequent production of inflammatory mediators. Functional properties of caveolae can be modulated by nutrition, such as dietary lipids (e.g. fatty acids) and plant-derived polyphenols (e.g. flavonoids), which change activation of caveolae-associated signalling proteins. The following review will focus on caveolae providing a platform for pro-inflammatory signalling, and the role of caveolae in endothelial cell functional changes associated with environmental mediators such as nutrients and toxicants, which are known to modulate the pathology of vascular diseases.


Immunohistological study of involucrin expression in Darier's disease skin.
Darier's disease (DD) is an autosomal dominant skin disorder characterized by acantholysis and abnormal keratinization. The gene responsible for DD, ATP2A2 encodes for the sarco/endoplasmic reticulum (ER) Ca2+-ATPase isoform 2 protein. Involucrin, considered as a marker of terminal epidermal differentiation, could be altered in some keratinization disorders including DD. An immunohistochemical staining using anti-involucrin antibody was carried out on 16 DD patients epidermis. Involucrin staining was compared with biopsies from cutaneous lesions of three healthy individuals and of patients with Hailey-Hailey disease (five cases) and Mal de Meleda (four cases). A semi-quantitative analysis was performed in order to evaluate involucrin immunostaining on the basis of intensity, extension and epidermal distribution. The involucrin expression was examined afterward with confocal laser scanning microscopy. In contrast to normal skin, all DD cases showed premature expression of involucrin in the lower epidermal layers in four cases with a strong labeling in both keratinocytes cell membrane and cytoplasm. Other keratinization disorders share premature expression of involucrin but displayed differences in cytoplasm/cell membrane labeling. DD skin displayed a constant immunohistochemical involucrin pattern characterized by both premature expression and a particular cytoplasmic/cell membrane localization distribution.


Clinical outcomes of oropharyngeal squamous cell carcinoma stratified by human papillomavirus subtype: A systematic review and meta-analysis.
We aim to determine if there is a survival difference between patients with oropharyngeal squamous cell carcinoma (OPSCC) associated with human papillomavirus (HPV) 16 versus HPV-non16 subtypes. Databases were queried for full length, peer-reviewed, English language, articles published between 01/01/1980 and 06/08/2022. Studies reporting clinical outcomes of OPSCC associated with HPV16 and HPV-non16 subtypes with at least 10 patients were included. Primary outcome was the overall survival (OS) of patients with HPV16- versus HPV-non16-associated OPSCC. Secondary outcomes were recurrence-free survival (RFS) and pooled rate of p16 positivity by immunohistochemistry (IHC). A total of 9 studies met inclusion criteria and included 1,310 patients with HPV16 and 219 with HPV-non16 subtypes of OPSCC. The prevalence of HPV-non16 was 14.3 %. The pooled 5-year OS rates for patients with HPV16 and HPV-non16 were 83.4 %(95 % CI 77.8-89.0 %) and 69.3 %(95 % CI 58.5-80.1 %), respectively. OS at 5 years was significantly worse for HPV-non16 subtype, compared to HPV16 (log odds ratio [OR] -0.54, p = 0.008). There was a trend towards worse 5-year RFS with HPV-non16 compared to HPV16 (log OR -0.55, p = 0.063). Patients with HPV-non16 disease were less likely to be p16 positive by IHC (log OR -0.91, p = 0.02). Patients with HPV-non16OPSCC may experience worse OS and were less likely to be p16 positive compared to patients with HPV16 disease. While future prospective validation is warranted, routine assessment of both p16 IHC and HPV subtype could be considered prior to pursuing treatment de-escalation for HPV-associated OPSCC.


The decline of venture capital investment in early-stage life sciences poses a challenge to continued innovation.
A key element required for translating new knowledge into effective therapies is early-stage venture capital that finances the work needed to identify a lead molecule or medical device prototype and to develop it to the proof-of-concept stage. This early investment is distinguished by great uncertainty over whether the molecule or prototype is safe and effective, the stability of the regulatory standards to which clinical trials are designed, and the likelihood that large follow-on investments for commercial development can be secured. Regulatory and reimbursement policies have a profound impact on the amount of capital and the types of life science projects that investors pursue. In this article I analyze several recent trends in early-stage venture capital funding, describe how these trends are influenced by regulatory and reimbursement policies, and discuss the role of policy makers in bringing new treatments to market. Policy makers can foster renewed private investment into critically needed early-stage products by increasing Small Business Innovation Research (SBIR) funding and public support for clinical trials in targeted areas of interest; creating regulatory pathways to enable early testing of experimental compounds in limited populations; and offering economic incentives for investors and developers in designated therapeutic areas.


The first metatarsal web space: its applied anatomy and usage in tracing the first dorsal metatarsal artery in thumb reconstruction.
To clarify the anatomical relationship of the structures in the first toe webbing space for better dissection of toes in thumb reconstruction. The first dorsal metatarsal artery, the first deep transverse metatarsal ligament and the extensor expansion were observed on 42 adult cadaveric lower extremities. Clinically the method of tracing the first dorsal metatarsal artery around the space of the extensor expansion was used in 36 cases of thumb reconstruction. The distal segments of the first dorsal metatarsal artery of Gilbert types I and II were located superficially to the extensor expansion. The harvesting time of a toe was shortened from 90 minutes to 50 minutes with 100% survival of reconstructed fingers. The distal segment of the first dorsal metatarsal artery lies constantly at the superficial layer of the extensor expansion. Most of the first metatarsal arteries of Gilbert types I and II can be easily located via the combined sequential and reverse dissection around the space of the extensor expansion.


An Atoh1-S193A Phospho-Mutant Allele Causes Hearing Deficits and Motor Impairment.
Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor that is essential for the genesis, survival, and maturation of a variety of neuronal and non-neuronal cell populations, including those involved in proprioception, interoception, balance, respiration, and hearing. Such diverse functions require fine regulation at the transcriptional and protein levels. Here, we show that serine 193 (S193) is phosphorylated in Atoh1's bHLH domain in vivo Knock-in mice of both sexes bearing a GFP-tagged phospho-dead S193A allele on a null background (Atoh1S193A/lacZ) exhibit mild cerebellar foliation defects, motor impairments, partial pontine nucleus migration defects, cochlear hair cell degeneration, and profound hearing loss. We also found that Atoh1 heterozygous mice of both sexes (Atoh1lacZ/+) have adult-onset deafness. These data indicate that different cell types have different degrees of vulnerability to loss of Atoh1 function and that hypomorphic Atoh1 alleles should be considered in human hearing loss.SIGNIFICANCE STATEMENT The discovery that Atonal homolog 1 (Atoh1) governs the development of the sensory hair cells in the inner ear led to therapeutic efforts to restore these cells in cases of human deafness. Because prior studies of Atoh1-heterozygous mice did not examine or report on hearing loss in mature animals, it has not been clinical practice to sequence ATOH1 in people with deafness. Here, in seeking to understand how phosphorylation of Atoh1 modulates its effects in vivo, we discovered that inner ear hair cells are much more vulnerable to loss of Atoh1 function than other Atoh1-positive cell types and that heterozygous mice actually develop hearing loss late in life. This opens up the possibility that missense mutations in ATOH1 could increase human vulnerability to loss of hair cells because of aging or trauma.


Evaluation of the dual route theory of reading: a metanalysis of 35 neuroimaging studies.
Numerous studies concerned with cerebral structures underlying word reading have been published during the last decade. A few controversies, however, together with methodological or theoretical discrepancies between laboratories, still contribute to blurring the overall view of advances effected in neuroimaging. Carried out within the dual route of reading framework, the aim of this metanalysis was to provide an objective picture of these advances. To achieve this, we used an automated analysis method based on the inventory of activation peaks issued from word or pseudoword reading contrasts of 35 published neuroimaging studies. A first result of this metanalysis was that no cluster of activations has been found more recruited by word than pseudoword reading, implying that the first steps of word access may be common to word and word-like stimuli and would take place within a left occipitotemporal region (previously referred to as the Visual Word Form Area-VWFA) situated in the ventral route, at the junction between inferior temporal and fusiform gyri. The results also indicated the existence of brain regions predominantly involved in one of the two routes to access word. The graphophonological conversion seems indeed to rely on left lateralized brain structures such as superior temporal areas, supramarginal gyrus, and the opercular part of the inferior frontal gyrus, these last two regions reflecting a greater load in working memory during such an access. The lexicosemantic route is thought to arise from the coactivation of the VWFA and semantic areas. These semantic areas would encompass a basal inferior temporal area, the posterior part of the middle temporal gyrus, and the triangular part of inferior frontal gyrus. These results confirm the suitability of the dual route framework to account for activations observed in nonpathological subjects while they read.


De Novo Genome Assembly of the Meadow Brown Butterfly, Maniola jurtina.
Meadow brown butterflies (Maniola jurtina) on the Isles of Scilly represent an ideal model in which to dissect the links between genotype, phenotype and long-term patterns of selection in the wild - a largely unfulfilled but fundamental aim of modern biology. To meet this aim, a clear description of genotype is required. Here we present the draft genome sequence of M. jurtina to serve as a founding genetic resource for this species. Seven libraries were constructed using pooled DNA from five wild caught spotted females and sequenced using Illumina, PacBio RSII and MinION technology. A novel hybrid assembly approach was employed to generate a final assembly with an N50 of 214 kb (longest scaffold 2.9 Mb). The sequence assembly described here predicts a gene count of 36,294 and includes variants and gene duplicates from five genotypes. Core BUSCO (Benchmarking Universal Single-Copy Orthologs) gene sets of Arthropoda and Insecta recovered 90.5% and 88.7% complete and single-copy genes respectively. Comparisons with 17 other Lepidopteran species placed 86.5% of the assembled genes in orthogroups. Our results provide the first high-quality draft genome and annotation of the butterfly M. jurtina.


Paraneoplastic hypertrophic osteopathy in 30 dogs.
Paraneoplastic hypertrophic osteopathy (pHO) is known to occur in both canine and human cancer patients. While the pathology of pHO is well-described in the dog, very little information exists regarding the true clinical presentation of dogs affected with pHO. The primary objective of this study was to provide a more comprehensive clinical picture of pHO. To this end, we retrospectively identified 30 dogs and recorded data regarding presenting complaints and physical examination (PE) findings on the date of pHO diagnosis. As a secondary objective, any blood test results were also collected from the computerized records. The most common clinical signs included leg swelling, ocular discharge and/or episcleral injection, lameness, and lethargy. The most common haematological and serum biochemical abnormalities included anaemia, neutrophilia and elevated alkaline phosphatase. In addition to presenting a more detailed clinical description of pHO in the dog, these data support the previously described haematological, serum biochemical and PE abnormalities published in individual case reports.


Sensory Patterns, Obesity, and Physical Activity Participation of Children With Autism Spectrum Disorder.
Obesity is a public health concern for the population in general and for children with autism spectrum disorder (ASD) specifically. The purpose of this study was to understand relationships between sensory patterns, obesity, and physical activity engagement of children with ASD (N = 77) sampled from a specialized community-based swimming program. This retrospective correlational study analyzed program data. Results show that almost half (42.2%) of the children were overweight or obese, and sensory avoiding behaviors were related to higher body mass index (BMI). Children participated in few formal and informal physically active recreation activities. Sensory seeking behaviors were associated with increased participation in informal activities, and higher BMI was associated with less participation in both formal and informal activities. Practitioners should consider sensory processing patterns and BMI when developing community-based programs to promote physical activity of children with ASD.


Nephropathia epidemica and Puumala virus in Austria.
To study the epidemiology of hantavirus infections in Austria, 1215 humans and 596 rodents of different species were tested for the presence of antibodies against Puumala and Hantaan virus. Direct virus identification by polymerase chain reaction in lung tissue of serologically positive rodents was performed to verify antibody results and to determine the genetic identity of viral RNA by phylogenetic analysis of a part of the hantavirus M segment. For 32 of the 37 cases of nephropathia epidemica diagnosed in Austria, the location where transmission took place could be traced to specific areas in the Austrian federal states of Carinthia and Styria. The overall seroprevalence in humans was 1.2% and ranged from 0.02% in Villach, Carinthia, to 0.8% in Korneuburg, Lower Austria, and 1.8% in Wolfsberg, Carinthia. Virus RNA could be amplified from three Clethrionomys glareolus voles collected in Klippitztörl, Carinthia, and from one collected in Ernstbrunn, Lower Austria. The sequences were all identified as Puumala virus by phylogenetic analysis and were found to be most closely related to the western European Puumala viruses from Germany and France. No evidence of the existence of Hantaan-like infections and viruses in Austria was found.


A new technique of scarless expanded forehead flap for reconstructive surgery.
The forehead flap is an ideal flap for reconstructive surgery, especially for that involving reconstruction of the face and neck. However, it is usually limited to use in nasal reconstruction, even when performed in conjunction with tissue expansion, because of the severe visible morbidity of the donor site. In this article, the author discusses his development of a new technique of forehead flap, performed in conjunction with tissue expansion, for reconstructive surgery without visible scarring at the donor site. The technique involved positioning a tissue expander in the forehead pocket under the occipitofrontal muscle and serially inflating the expander over a period of approximately 4 to 6 weeks. Thereafter, an expanded forehead flap was created from the frontal hairline area on the basis of the location of the superficial temporal vessels and transferred into 16 recipient sites in 13 patients as an island flap (n = 8), a free flap (n = 1), or a local random flap (n = 7). The donor site was closed directly into the frontal hairline, without any visible scar. With the author's experience in the use of the island flap for nasal, facial, and neck reconstruction and of the free flap for reconstruction in the extremities, the flap could be as large as 8 x 18 cm without inducing flap necrosis or problems with donor-site closure. All patients (n = 13) had acceptable donor-site aesthetic results, without visible scarring. The results indicate that the flap could be a safe, ample, and color-matched flap for reconstruction of the face and neck and could also diminish donor-site morbidity to a minimum, without an unsightly visible scar. Furthermore, the flap could be formed into a customized free flap, with the above-mentioned advantages, to be transferred to any part of the body.


Prevalence of autoantibodies in pediatric patients with idiopathic pulmonary hemosiderosis: a scoping review of the literature in the period 1980-2021.
Idiopathic pulmonary hemosiderosis (IPH) is a rare disease of unknown etiology. Due to the frequent findings of autoimmune antibodies - autoantibodies, immunologic causation of the diffuse alveolar hemorrhage in IPH has been proposed, to assess the prevalence/frequency and type of autoantibodies in pediatric patients with IPH. In addition, the patient demographics, diagnostic modalities used to diagnose IPH, treatment, and outcomes were also evaluated. Scoping review: The PubMed, Medline, and Embase databases were searched with appropriate MeSH terms to identify relevant papers consistent with the defined inclusion criteria. Thirteen observational studies comprising a total of 352 pediatric patients were included in this review. The majority of subjects were girls 217 out of 352 (61.6%). The mean and median ages of patients ranged from 3.1-6.5 years to 2.3-7 years, respectively. In the 10 studies that specified the number of patients in their cohorts with either at least one positive autoantibody or no antibody, the overall prevalence of autoantibodies was 76 out of 288 patients (26.4%). The prevalence of specific antibodies was as follows: ANA, 20.3%; ANCA, 17%; anti-dsDNA, 9.1%; RF, 12%; anti-SMA, 23.2%; and celiac antibodies, 25.9%. Cow's milk protein allergy was present in 16.2% of the children. The significance of an association between IPH and the presence of autoantibodies has not been clarified. The autoantibodies could be suggestive of an overall immune dysregulation rather than causation. However, limited evidence based on a single study suggests that the presence of ANA may be associated with a higher risk of recurrence and worse outcomes. Further research, including prospective studies, will be crucial to explore a possible genetic linkage between vasculitides, systemic rheumatologic diseases, and IPH.


Effect of carnosine on gentamicin-induced nephrotoxicity.
Gentamicin (GM) is an antibiotic whose clinical use is limited by its nephrotoxicity. Thus the present study was undertaken to investigate if carnosine, an antioxidant, could protect the kidney in this experimental model. The animals were divided into seven groups each of 10 animals: one control group, two healthy carnosine groups (10 mg/kg/day), two GM groups (80 mg/kg/day), and two carnosine-GM groups. Kidney function tests, histopathological, ultrastructural, and enzymatic histochemical studies clarified GM nephrotoxicity. GM rat showed early kidney function failure as blood creatinine and blood urea were significantly increased after one and two weeks. Experimental evidence suggested a role of reactive oxygen species in GM-induced nephrotoxicity. Histopathological examination revealed degenerative changes in glomeruli and tubules. Ultrastructural study showed glomerular changes, some degeneration of both distal and collecting tubules. The proximal tubules showed marked degrees of changes and necrosis. Enzymatic histochemical studies of GM rats revealed marked elevation of lactate dehydrogenase (LDH) and inhibition of succinic dehydrogenase (SDH), alkaline phosphatases (ALP), acid phosphatases (ACP), and adenosine triphosphatase (ATPase). Blood creatinine and urea were normalized in the carnosine-GM group after one and two weeks. Structural and enzymatic histochemical pictures were greatly ameliorated. The mechanism by which carnosine has a protective effect on GM-induced nephrotoxicity was attributed to its many actions: double antioxidant action, protein molecule protection, removal of harmfully modified ones, activation of immune system, preservation of membrane fluidity, and cytosolic buffering. Carnosine thus offers a promise of ameliorating GM nephrotoxicity.


FR149175, a beta 3-adrenoceptor-selective agonist, is a possible therapeutic agent for non-insulin-dependent diabetes mellitus.
We examined whether FR149175 (ethyl-[(S)-8-[(R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-6,7,8,9 - tetrahydro-5H-benzocyclohepten-2-yloxy]acetate monohydrochloride monohydrate), a selective agonist for the beta 3-adrenoceptor, is a possible therapeutic agent for non-insulin-dependent diabetes mellitus (NIDDM). FR149175 had hypoglycemic effects with an increase in the level of plasma insulin in normal rats. In Zucker fatty rats, an animal model of NIDDM, repeated administration of the drug improved hyperinsulinemia and showed a tendency to decrease the area under the curve (AUC) for plasma glucose levels in the glucose tolerance test. Moreover, FR149175 decreased plasma triglyceride, free fatty acid and total cholesterol levels in the rats. Body weight gain in the rat was suppressed by FR149175 as well. These results suggest that FR149175 has antiobesity and antidiabetic effects and that this drug may be useful for treating NIDDM.