Effectiveness of self-management interventions for long-term conditions in people experiencing socio-economic deprivation in high-income countries: a systematic review and meta-analysis.
Long-term conditions (LTCs) are prevalent in socio-economically deprived populations. Self-management interventions can improve health outcomes, but socio-economically deprived groups have lower participation in them, with potentially lower effectiveness. This review explored whether self-management interventions delivered to people experiencing socio-economic deprivation improve outcomes. We searched databases up to November 2022 for randomized trials. We screened, extracted data and assessed the quality of these studies using Cochrane Risk of Bias 2 (RoB2). We narratively synthesized all studies and performed a meta-analysis on eligible articles. We assessed the certainty of evidence using GRADE for articles included in the meta-analysis. The 51 studies included in this review had mixed findings. For the diabetes meta-analysis, there was a statistically significant pooled reduction in haemoglobin A1c (-0.29%). We had moderate certainty in the evidence. Thirty-eight of the study interventions had specific tailoring for socio-economically deprived populations, including adaptions for low literacy and financial incentives. Each intervention had an average of four self-management components. Self-management interventions for socio-economically deprived populations show promise, though more evidence is needed. Our review suggests that the number of self-management components may not be important. With the increasing emphasis on self-management, to avoid exacerbating health inequalities, interventions should include tailoring for socio-economically deprived individuals.


A step-wedge standard for the quantification of immunoperoxidase techniques.
This report describes the preparation and use of an artificial tissue containing differing amounts of an antigen covalently bound to gelatine (step wedge). The use of this step wedge enables the variables in the immunoperoxidase technique to be studied separately. The step wedge may be used as a standard in immunocytochemical quantification. By performing all the steps of the immunoperoxidase procedure on the step-wedge section and the tissue section simultaneously, valid comparisons can be made regarding changes in the amount of antigen in tissues. Absolute measurements of amounts of antigen in tissue cannot be made with this technique at present because of the loss of antigenicity involved in the preparation of the step wedge, differences of penetration by reagents between step wedge and tissue, and non-uniform distribution of antigens in this tissue. Use of the step wedge has shown that, under some circumstances, an increase in amount of antigen may be associated with a reduction in the amount of reaction product, demonstrating the impossibility of making any deductions about variations in the amount of antigens without control of the technique employed by a method such as the one presented here.


Transdiaphragmatic approach to the descending thoracic aorta for proximal control during surgery on the abdominal aorta.
A technic of mobilizing and clamping the lower descending thoracic aorta from the abdomen through the incision in the diaphragm is described. This technic is simple and may be useful when it is difficult to obtain proximal control of the abdominal aorta during surgery. In addition, certain surgical procedures on the upper abdominal aorta may be facilitated by the use of this technic.


The detection and management of attempted fraud during an online randomised trial.
Online studies offer an efficient method of recruiting participants and collecting data. Whilst delivering an online randomised trial, we detected unusual recruitment activity. We describe our approach to detecting and managing suspected fraud and share lessons for researchers. Our trial investigated the single and combined effects of different ways of presenting clinical audit and feedback. Clinicians and managers who received feedback from one of five United Kingdom national clinical audit programmes were emailed invitations that contained a link to the trial website. After providing consent and selecting their relevant audit, participants were randomised automatically to different feedback versions. Immediately after viewing their assigned feedback, participants completed a questionnaire and could request a financial voucher by entering an email address. Email addresses were not linked to trial data to preserve participant anonymity. We actively monitored participant numbers, questionnaire completions, and voucher claims. Following a rapid increase in trial participation, we identified 268 new voucher claims from three email addresses that we had reason to believe were linked. Further scrutiny revealed duplicate trial completions and voucher requests from 24 email addresses. We immediately suspended the trial, improved security measures, and went on to successfully complete the study. We found a peak in questionnaires completed in less than 20 seconds during a likely contamination period. Given that study and personal data were not linked, we could not directly identify the trial data from the 268 duplicate entries within the 603 randomisations occurring during the same period. We therefore excluded all 603 randomisations from the primary analysis, which was consequently based on 638 randomisations. A sensitivity analysis, including all 961 randomisations over the entire study except for questionnaire completions of less than 20 seconds, found only minor differences from the primary analysis. Online studies offering incentives for participation are at risk of attempted fraud. Systematic monitoring and analysis can help detect such activity. Measures to protect study integrity include linking participant identifiers to study data, balancing study security and ease of participation, and safeguarding the allocation of participant incentives. International Standard Randomised Controlled Trial Number: ISRCTN41584028. Registration date is August 17, 2017.


Psychiatric issues affecting long duration space missions.
As we move into the next Millennium, increasing numbers of people will travel into space. Psychological screening methods will be relaxed on near-Earth missions, such as might occur on a space station or a lunar colony. Crewmembers on interplanetary missions such as a trip to Mars will have to deal with psychiatric problems themselves with no possibility of evacuating an affected individual. For these reasons, it is important for support personnel on Earth and crewmembers in space to be knowledgeable about psychiatric difficulties that might occur and their appropriate treatments. Anecdotal reports from long duration manned space missions and studies from space analog environments on Earth were reviewed for information concerning these issues. Psychiatric problems pertinent to the space environment include adjustment and psychosomatic reactions, asthenia, mood and thought disorders, and post-mission personality changes and family problems. Counter-measures to ameliorate these difficulties involve pre-launch selection and training; monitoring, support, and counseling/psychotherapy during the mission; and post-return debriefings with crew members and their families. Psychoactive medications have been useful during space missions, although unclear pharmacokinetic issues related to microgravity need to be taken into account. Although much is known about psychiatric issues related to long duration manned space travel, more empirical work needs to be done during actual space missions.


A novel KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Marcus Gunn jaw-winking phenomenon.
To determine whether congenital fibrosis of the extraocular muscles (CFEOM) with Marcus Gunn jaw-winking phenomenon (MG) can result from mutations in the KIF21A gene encoding a kinesin motor protein. An individual with CFEOM1 (classic autosomal dominant CFEOM) and MG underwent a comprehensive ophthalmic examination. He and his healthy parents underwent screening for mutations in the KIF21A gene by direct DNA sequencing. The clinical records of our previously described patients with CFEOM and KIF21A mutations were reviewed for evidence of more extensive dysinnervation. A de novo and novel KIF21A mutation 2840T-->C (M947T) was present in the proband. In addition, among our previously described patients with CFEOM and KIF21A mutations, 3 individuals had MG and 1 had hypertropia during toothbrushing. This report introduces a new CFEOM1 KIF21A mutation and is, to our knowledge, the first report of a genetic defect associated with MG. The combination of CFEOM1 with MG supports a primary neurogenic etiology of CFEOM resulting from KIF21A mutations. These findings will increase understanding of the etiology of CFEOM and increase awareness of the affiliation of CFEOM with MG.


Effects of ultrasound-assisted H2O2 on the solubilization and antioxidant activity of yeast β-glucan.
Yeast β-glucan (YG) possess an extensive range of biological activities, such as the inhibition of oxidation, but the poor water solubility of macromolecular YG limits its application. In this study, through the combined degradation of ultrasonic waves and H2O2, and the optimization of the main process parameters for solubilizing YG by response surface methodology (RSM), a new product of YGUH was generated. The molecular weight, structural characteristics and degradation kinetics before and after solubilization were evaluated. The results showed that the optimal solubilization conditions were reaction time: 4 h, ultrasonic power: 3 W/mL, H2O2 concentration: 24 %. Under these conditions, ultrasound-assisted H2O2 increased the solubility (from 13.60 % to 70.00 %) and reduced molecular weight (from 6.73 × 106 Da to 1.22 × 106 Da). Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), Congo red (CR), scanning electron microscopy (SEM) revealed that ultrasound-assisted H2O2 increased the conformation's flexibility greatly, without changing the main structure of YG. More importantly, solubilization of YG improved free radical scavenging activity with YGUH exhibiting the highest levels of DPPH and ABTS+ free radical scavenging activity. These results revealed that ultrasound-assisted H2O2 degradation could be a suitable way to increase the solubility of YG for producing value-added YG.


Effect of the route of nutrition and L-alanyl-L-glutamine supplementation in amino acids' concentration in trauma patients.
Our purpose was to assess the amino acids' (AAs) profile in trauma patients and to assess the effect of the route of nutrition and the exogenous ALA-GLN dipeptide supplementation on plasma AAs' concentration. This is a secondary analysis of a previous randomized controlled trial. On day 1 and day 6 after trauma, plasma concentration of 25 AAs was measured using reverse phase high-performance liquid chromatography. Results were analyzed in relation to the route of nutrition and supplementation of ALA-GLN dipeptide. Differences between plasma AAs' concentrations at day 1 and day 6 were evaluated using the Student's t test or Mann-Whitney-Wilcoxon test. One-way ANOVA and the Kruskal-Wallis test were used to compare groups. A two-sided p value less than 0.05 was considered statistically significant. Ninety-eight patients were analyzed. Mean plasma concentrations at day 1 were close to the lower normal level for most AAs. At day 6 we found an increase in the eight essential AAs' concentrations and in 9 out of 17 measured non-essential AAs. At day 6 we found no differences in plasma concentrations for the sum of all AAs (p = .72), glutamine (p = .31) and arginine (p = .23) distributed by the route of nutrition. Administration of ALA-GLN dipeptide increased the plasma concentration of alanine (p = .004), glutamine (p < .001) and citrulline (p = .006). We found an early depletion of plasma AAs' concentration which partially recovered at day 6, which was unaffected by the route of nutrition. ALA-GLN dipeptide supplementation produced a small increase in plasma levels of glutamine and citrulline.


The Laughter Prescription: A Tool for Lifestyle Medicine.
Laughter is a normal and natural physiologic response to certain stimuli with widely acknowledged psychological benefits. However, current research is beginning to show that laughter may also have serious positive physiological effects for those who engage in it on a regular basis. Providers who prescribe laughter to their patients in a structured way may be able to use these natural, free, and easily distributable positive benefits. This article reviews the current medical understanding of laughter's physiologic effects and makes a recommendation for how physicians might best harness this natural modality for their patients.


Molecular detection of Chlamydophila abortus in post-abortion sheep at oestrus and subsequent lambing.
Enzootic abortion of ewes (EAE), resulting from infection with the bacterium Chlamydophila abortus (C. abortus), is a major cause of lamb loss in Europe. The purpose of this study was to assess the potential impact of the shedding of organisms in post-abortion ewes at oestrus and subsequent lambing on the epidemiology of EAE. Using a newly developed C. abortus specific real-time PCR assay, few chlamydial genomes could be detected in vaginal swabs taken from post-abortion ewes at oestrus. At subsequent parturition, all ewes lambed normally with no macroscopic or microbiological evidence of infection. Real-time PCR analysis of placental samples identified very few or no chlamydial genomes, which contrasted significantly with samples taken at the time of abortion, where an average of 2.7x10(7) chlamydial genomes per microgram of total tissue DNA was detected. Few genomes could also be detected from vaginal and cervical tissue samples and lymph nodes taken post-mortem. The results, although not discounting the possibility of a chronic low level persistent infection in post-abortion ewes, suggest that the low levels of chlamydial DNA detected during the periovulation period and at lambing do not significantly impact on the epidemiology of EAE. In terms of flock management, the products of abortion should be considered the major and principal source of infection for transmission to naïve ewes.


Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.
In patients with diabetic foot osteomyelitis (DFO) who underwent surgical debridement, we investigated whether a short (3 weeks) duration compared with a long (6 weeks) duration of systemic antibiotic treatment is associated with noninferior results for clinical remission and adverse events (AEs). In this prospective, randomized, noninferiority pilot trial, we randomized (allocation 1:1) patients with DFO after surgical debridement to either a 3-week or a 6-week course of antibiotic therapy. The minimal duration of follow-up after the end of therapy was 2 months. We compared outcomes using Cox regression and noninferiority analyses (25% margin, power 80%). Among 93 enrolled patients (18% females; median age 65 years), 44 were randomized to the 3-week arm and 49 to the 6-week arm. The median number of surgical debridements was 1 (range, 0-2 interventions). In the intention-to-treat (ITT) population, remission occurred in 37 (84%) of the patients in the 3-week arm compared with 36 (73%) in the 6-week arm (P = .21). The number of AEs was similar in the 2 study arms (17/44 vs 16/49; P = .51), as were the remission incidences in the per-protocol (PP) population (33/39 vs 32/43; P = .26). In multivariate analysis, treatment with the shorter antibiotic course was not significantly associated with remission (ITT population: hazard ratio [HR], 1.1 [95% confidence interval {CI}, .6-1.7]; PP population: HR, 0.8 [95% CI: .5-1.4]). In this randomized controlled pilot trial, a postdebridement systemic antibiotic therapy course for DFO of 3 weeks gave similar (and statistically noninferior) incidences of remission and AE to a course of 6 weeks. NCT03615807; BASEC 2016-01008 (Switzerland).


Immunosuppressive effects of recombinant interferon-alpha during long-term treatment of cancer patients.
Interferons (IFN) are known to modulate immune responses in an either stimulatory or inhibitory manner. Most of the knowledge about immunomodulatory activities of IFN comes from investigations of IFN effects on cells in vitro. This study examines the influence which long-term treatment with recombinant interferon-alpha 2 exerts on immune functions in cancer patients. Serial in vitro immune function studies of peripheral blood mononuclear cells were done to determine parameters of B-cell and T-cell functions as well as natural killer (NK)-cell activity. The authors detected profound suppression of in vitro immunoglobulin synthesis and lymphocyte proliferation as well as depression of NK-cell activity during IFN treatment. All suppressed immune functions normalized on discontinuation of IFN therapy. The authors conclude from these observations that, apart from their beneficial effects, IFN produce substantial immunosuppression.


The computer and stereotactic surgery in neurological surgery.
The technical aspects, current uses, and future clinical applications of stereotactic surgery and three-dimensional imaging in neurological surgery are reviewed.


Importance of patient history and physical examination in rheumatoid arthritis compared to other chronic diseases: results of a physician survey.
To survey physicians' opinions concerning the relative importance of 5 clinical encounter components-vital signs, patient history, physical examination, laboratory tests, and ancillary studies-in the diagnosis and management of 8 chronic diseases. A SurveyMonkey internet survey was e-mailed to 7,265 US physicians, including 3,542 rheumatologists and 3,723 nonrheumatologists, with the following query: "Please indicate the relative importance of 5 sources of information-vital signs, patient history, physical examination, laboratory tests, and ancillary studies-in diagnosis of congestive heart failure (CHF), diabetes mellitus, hypercholesterolemia, hypertension, lymphoma, pulmonary fibrosis, rheumatoid arthritis (RA), and ulcerative colitis." The response options were 0-20%, 21-40%, 41-60%, 61-80%, and 81-100%. A second query with an identical structure addressed management of the 8 diseases. The proportions of physicians who estimated each component as most (or tied for most) important in diagnosis or in management were computed. The survey was completed by 313 physicians (154 rheumatologists and 159 nonrheumatologists). More than 90% estimated vital signs as most important for hypertension, and laboratory tests for diabetes mellitus and hypercholesterolemia. More than 70% estimated ancillary studies as most important for lymphoma, pulmonary fibrosis, and ulcerative colitis. Patient history and physical examination were estimated as most important for RA and CHF by ≥50% of nonrheumatologists. RA and CHF were the only 2 of the 8 diseases studied for which ≥50% of nonrheumatologists estimated a patient history and physical examination as most important for diagnosis and management. Confirmation and extension of these observations in actual care may have implications for reimbursement and organization of clinical care.


A system for automatically extracting clinical events with temporal information.
The popularization of health and medical informatics yields huge amounts of data. Extracting clinical events on a temporal course is the foundation of enabling advanced applications and research. It is a structure of presenting information in chronological order. Manual extraction would be extremely challenging due to the quantity and complexity of the records. We present an recurrent neural network- based architecture, which is able to automatically extract clinical event expressions along with each event's temporal information. The system is built upon the attention-based and recursive neural networks and introduce a piecewise representation (we divide the input sentences into three pieces to better utilize the information in the sentences), incorporates semantic information by utilizing word representations obtained from BioASQ and Wikipedia. The system is evaluated on the THYME corpus, a set of manually annotated clinical records from Mayo Clinic. In order to further verify the effectiveness of the system, the system is also evaluated on the TimeBank _Dense corpus. The experiments demonstrate that the system outperforms the current state-of-the-art models. The system also supports domain adaptation, i.e., the system may be used in brain cancer data while its model is trained in colon cancer data. Our system extracts temporal expressions, event expressions and link them according to actually occurring sequence, which may structure the key information from complicated unstructured clinical records. Furthermore, we demonstrate that combining the piecewise representation method with attention mechanism can capture more complete features. The system is flexible and can be extended to handle other document types.


The combined spinal-epidural technique.
Epidural and spinal blocks are well-accepted regional techniques, but they have several disadvantages. The CSE technique can reduce or eliminate the risks of these disadvantages. CSE block combines the rapidity, density, and reliability of the subarachnoid block with the flexibility of continuous epidural block to extend duration of analgesia. The CSE technique is used routinely at many institutions, particularly for major orthopedic surgery and in obstetrics. It has been used in tens of thousands of patients without any reports of major problems. Although at first sight the CSE technique appears to be more complicated than epidural or spinal block alone, intrathecal drug administration and siting of the epidural catheter are both enhanced by the combined, single-space, needle-through-needle method. Concerns about the epidural catheter entering the theca via the small puncture hole are now considered to be unfounded, but as with all epidural catheter techniques, vigilant monitoring of the patient during and after any injection is paramount. CSE is an effective way to reduce the total drug dosage required for anesthesia or analgesia. The intrathecal injection achieves rapid onset with minimal doses of local anesthetics and opioids, and the block can be prolonged with low-dose epidural maintenance administration. In addition, the sequential CSE method can be used to extend the dermatomal block with minimal additional drugs or even saline. Reduction in total drug dosage has made truly selective blockade possible. Many studies have confirmed that low-dose CSE with local anesthetic and opioid, or low-dose epidural block alone, will provide effective analgesia with minimal motor and proprioceptive block. Such neurologic selective blockade has made it possible for most patients to walk and bear down normally in labor or postoperatively. There remains concern about the risk of infection being increased when the CSE technique is used in place of epidural block alone. Despite a recent flurry of reports of meningitis with CSE procedures, there is no evidence the CSE block is more hazardous than epidural or subarachnoid block alone. Arguably, the single-space, needle-through-needle CSE technique will continue to improve with new needle designs and other advances to improve further the success rate and reduce complications, such as neurotrauma, PDPH, and infection. Over the past decade it has become clear that the CSE technique is a significant advance in regional blockade.


Social deprivation and the public health risks of community drinking water supplies in New Zealand.
Quantitative evidence linking environmental exposures and social status at sub-national scales is surprisingly limited. This study investigated the public health risks associated with community water supplies in relation to social status in New Zealand. An ecological study using a Geographic Information System (GIS) to compare the grade of community water supplies with an index of social deprivation for small areas. New Zealand. The New Zealand population usually resident in meshblocks (census areas) with a community water supply (70% of the 1996 population of 3.6 million people). People living in deprived areas are exposed to greater public health risks from community water supplies. In urban areas, the odds of water supplies being high risk were 3.76 times greater for the most deprived decile compared with the least deprived decile (95% CI: 2.95 to 4.78). It is probable that deprived communities in New Zealand are experiencing a disproportionate burden of adverse health effects as a result of poor water quality.


Hirshfeld atom refinement based on projector augmented wave densities with periodic boundary conditions.
Hirshfeld atom refinement (HAR) is an X-ray diffraction refinement method that, in numerous publications, has been shown to give H-atom bond lengths in close agreement with neutron diffraction derived values. Presented here is a first evaluation of an approach using densities derived from projector augmented wave (PAW) densities with three-dimensional periodic boundary conditions for HAR. The results show an improvement over refinements that neglect the crystal environment or treat it classically, while being on a par with non-periodic approximations for treating the solid-state environment quantum mechanically. A suite of functionals were evaluated for this purpose, showing that the SCAN and revSCAN functionals are most suited to these types of calculation.


The prognostic role of extended preoperative hypercoagulability work-up in high-risk microsurgical free flaps: a single-center retrospective case series of patients with heterozygotic factor V Leiden thrombophilia.
Hypercoagulability is associated with an increased risk of microvascular complications and free flap failures. The authors present their experience and approach to diagnosing and treating patients with heterozygotic factor V Leiden (hFVL) thrombophilia undergoing free flap reconstruction. Between November 2009 and June 2018, 23 free flap surgeries were performed in 15 hypercoagulable patients with hFVL. According to the timing of perioperative hypercoagulability work-up, they were grouped into flaps with established diagnoses prior to surgery (Group A) versus flaps with unknown diagnoses prior to surgery (Group B). Baseline characteristics and perioperative complications were compared between both groups, including revision surgeries due to microvascular thromboses, acute bleedings, hematomas, flap necroses, and reconstructive failures. HFVL mutations had been confirmed preoperatively in 14 free flap surgeries (61%, Group A), whereas in 9 free flap surgeries (39%, Group B), mutations were only diagnosed postoperatively after the occurrence of microvascular thromboses had warranted extended hypercoagulability work-up. The overall rate of intraoperative flap thromboses was 9% (n = 2), whereas the overall rate of postoperative flap thromboses was 43% (n = 10). The corresponding salvage rates were 100% (n = 2/2) for intraoperative and 40% (n = 4/10) for postoperative pedicle thromboses. A total of five free flaps were lost (22%). Upon comparison, flaps with an unconfirmed diagnosis prior to surgery were at ten times higher risk for developing total necroses (flaps lost in Group B = 4/9 versus Group A = 1/14; OR: 10.4; 95% CI 1.0, 134.7; p = 0.03). Meticulous preoperative work-up of patients with any history of hypercoagulability can help reduce free flap loss rates, thus improving surgical outcomes and increasing patient safety.


Kinetics of cefatrizine penetration into gynaecological tissues after oral administration.
Twenty-four patients, hospitalized in order to undergo radical gynaecological surgery, were orally administered cefatrizine in a single dose of 1 g at different times before surgery. The tissue levels determined in the organs considered (uterus, ovary, tubae, vagina) proved that cefatrizine possesses good absorption in the genital tract, reaching concentrations near to the MICs of most gram-negative and gram-positive sensitive bacteria lasting even 12 h after administration.


Early diastolic filling dynamics in diastolic dysfunction.
The aim of the study was to determine the relationship between the rate of peak early mitral inflow velocity and the peak early diastolic mitral annular tissue velocities in normal controls and to compare them with subjects with diastolic dysfunction. The relationship between early passive diastolic transmitral flow and peak early mitral annular velocity in the normal and in diastolic dysfunction was studied. Two groups comprising 22 normal controls and 25 patients with diastolic dysfunction were studied. Compared with the normal group, those with diastolic dysfunction had a lower E/A ratio (0.7 +/- 0.2 vs. 1.9 +/- 0.5, p < 0.001), a higher time-velocity integral of the atrial component (11.7 +/- 3.2 cm vs. 5.5 +/- 2.1 cm, p < 0.0001), a longer isovolumic relaxation time 73 +/- 12 ms vs. 94 +/- 6 ms, p < 0.01 and a lower rate of acceleration of blood across the mitral valve (549.2 +/- 151.9 cm/sec2 vs. 871 +/- 128.1 cm/sec2, p < 0.001). They also had a lower mitral annular relaxation velocity (Ea) (6.08 +/- 1.6 cm/sec vs 12.8 +/- 0.67 cm/sec, p < 0.001), which was positively correlated to the acceleration of early diastolic filling (R = 0.66), p < 0.05. This investigation provides information on the acceleration of early diastolic filling and its relationship to mitral annular peak tissue velocity (Ea) recorded by Doppler tissue imaging. It supports not only the premise that recoil is an important mechanism for rapid early diastolic filling but also the existence of an early diastolic mechanism in normal.


[Differential gene expression in nasopharyngeal carcinoma cell with reduced and normal expression of 6A8 alpha-mannosidase].
To detect the differential display of mRNA expression between human nasopharyngeal carcinoma cell CNE-2L2 with reduced malignancy caused by transduction of a DNA antisense to 6A8 alpha-mannosidase cDNA (AS cell) and the wild type cell (W cell). Differential display of mRNA expression was analyzed using DNA microarray analysis. The datasets were confirmed by Northern blotting and RT-PCR. Out of the 1069 genes analyzed, 34 genes were up-regulated in AS cells relative to W cells. Conversely, 42 genes were down-regulated. The genes, up-regulation of which might have suppressive effect on tumor malignant behaviors, were P130 mRNA for 130K protein, TGF-betaIIR alpha, GABBR1, TGFBR1, TNFAIP1, STANIN, E-CADHERIN, CTNNA1 and 2, RFX2, TMPO, etc. The genes, down-regulation of which might have suppressive effect on tumor malignant behaviors, were CD44, NDRG1, TGFB1, RPS5, LEGUMAIIN, CBS, CD59, SNRPA1, etc. The microarray datasets were confirmed by Northern blot and RT-PCR analysis. In comparison to the W cell, AS cell has up-regulation of 34 genes and down-regulation of 42 genes. Changes of the gene expression may play a role in the malignancy reduction of AS cell.


Prophylactic intravesical chemotherapy to prevent bladder tumors after nephroureterectomy for primary upper urinary tract urothelial carcinomas: a systematic review and meta-analysis.
Intravesical recurrence after treatment of primary upper urinary tract urothelial carcinomas (UUT-UCs) is common. While intravesical instillation is widely used to prevent recurrence after transurethral resection for primary bladder tumors, there is still no consensus on the prophylactic capability of intravesical chemotherapy in preventing bladder tumor recurrence after surgery for UUT-UCs. A meta-analysis of the published results of clinical trials was performed to compare radical surgery alone or surgery plus postoperative intravesical chemotherapy. The primary end point was to determine the percentage of patients with recurrence in the different groups. Our study includes five trials with recurrence information on 614 patients. During follow-up, 55 of 268 (20.5%) patients who received postoperative instillation had bladder recurrence compared to 127 of 346 (36.7%) patients who had no adjuvant treatment--a decrease of 41% in the odds of recurrence with chemotherapy (odds ratio 0.48, 95% confidence interval 0.33-0.69, p = 0.0001). No serious adverse events were reported. Subgroup analyses were temporarily unavailable. Postoperative intravesical chemotherapy significantly decreases the risk of bladder recurrence after nephroureterectomy for primary UUT-UCs. Postoperative intravesical instillation is considered the treatment of choice after nephroureterectomy.


Does HIV adversely influence the outcome in advanced non-small-cell lung cancer in the era of HAART?
The objectives of the study are to assess the impact of HIV status on the outcome of patients with non-small-cell lung cancer (NSCLC) in the era of highly active antiretroviral therapy (HAART). Patients diagnosed with HIV-related NSCLC in the HAART era (since January 1996) were identified from a prospective single-centre lung cancer database. The clinicopathological characteristics and outcome of each HIV-positive patient were compared to three age- and stage-matched HIV-negative controls with NSCLC who were diagnosed over the same time period and treated in an identical manner. The results showed that the two groups had similar disease characteristics and received a similar amount of chemotherapy. The median overall survival of the two groups was the same (4 months, log rank P=0.55). None of the HIV-positive patients developed an AIDS defining illness or died of HIV during treatment or follow-up. In conclusion, in this cohort, HIV status does not influence the prognosis of advanced NSCLC. This suggests that the survival of patients with HIV-related NSCLC may have improved since the introduction of HAART, and this may be due to a decrease in HIV-related deaths.


Evaluation of external-beam radiation therapy plus 5-fluorouracil (5-FU) versus external-beam radiation therapy plus hycanthone (HYC) in confined, unresectable pancreatic cancer.
From March 1981 to November 1987, 87 patients with histologically confirmed pancreatic adenocarcinoma, unresectable but confined to the pancreatic region, were randomized to two treatments. The standard treatment was 40-50 Gy external-beam radiation therapy (RT) to gross tumor plus potential microscopic tumor with a 5 Gy boost to gross tumor plus a 1.5-2.0 cm margin, using multiple fields and 5-fluorouracil (5-FU) 500 mg/m2/d intravenously by rapid infusion. The 5-FU was given each of the initial 3 days of each of three 20 Gy radiation courses. The experimental treatment used identical radiation fields, but the two Gy daily radiation fractions were administered in a continuous course to a total dose of 50 Gy. Hycanthone was administered 60 mg/m2 intravenously within 2 to 4 hr during each day of the 5-day course of infusions during the first and fifth weeks of radiation therapy. There was no statistically significant difference between treatment arms in survival (p = 0.82) or disease-free survival (p = 0.27). Seven percent of hycanthone-treated patients demonstrated hepatic toxicity which was usually mild in nature. There was, however, one death due to hepatic toxicity.


The role of p-hydroxylation of amphetamine in its peripheral mode of action.
Desipramine completely abolished the blood pressure response to (+) amphetamine in the rat, whereas the tricyclic antidepressant iprindole did not reduce this response. Since both tricyclic drugs inhibit the aromatic hydroxylation of amphetamine, these studies do not support the hypothesis that hydroxylated metabolites of amphetamine, p-hydroxyamphetamine and p-hydroxynorephedrine are essential for the peripheral sympathomimetic effects of amphetamine.


In vitro and in vivo capacity of yeast-based products to bind to aflatoxins B1 and M1 in media and foodstuffs: A systematic review and meta-analysis.
The aflatoxins are hepatotoxic and carcinogenic metabolites produced by Aspergillus species during growth on crop products. In this regard, a systematic review to collect the quantitative data regarding the in vitro capacity of yeasts-based products to bind to aflatoxin B1 (AFB1) and/or aflatoxin M1 (AFM1) was performed. After screening, 31 articles which met the inclusion criteria was included and then the pooled decontamination of aflatoxins in the defined subgroups (the type of foods, pH, contact time, temperature, yeast species, and aflatoxin type) was calculated by the random effect model (REM). The overall binding capacity (BC) of aflatoxins by yeast was 52.05% (95%CI: 49.01-55.10), while the lowest and highest aflatoxins' BC were associated with Yeast Extract Peptone (2.79%) and ruminal fluid + artificial saliva (96.21%), respectively. Regarding the contact time, temperature, pH and type of aflatoxins subgroups, the binding percentages varied from 50.83% (>300 min) to 52.66% (1-300 min), 50.71% (0-40 °C) to 88.39% (>40 °C), 43.03% (pH: 3.1-6) to 44.56% (pH: 1-3) and 59.35% (pH > 6), and 48.47% (AFB1) to 69.03% AFM1, respectively. The lowest and highest aflatoxins' BC was related to C. fabianii (18.45%) and Z. rouxii (86.40%), respectively. The results of this study showed that variables such as temperature, yeast, pH and aflatoxin type can be considered as the effective factors in aflatoxin decontamination.


Evaluations of wasted mouse fibroblasts and SV-40 transformed human fibroblasts as models of ataxia telangiectasia in vitro.
Fibroblast cultures from wasted mice have been derived and the responses of these cultures to bleomycin treatment or gamma-irradiation have been examined. No differences were observed between wasted fibroblasts and littermate controls in the post-treatment inhibition of DNA replication. In contrast, a human SV-40 transformed ataxia telangiectasia fibroblast line mimicked the abnormal response of primary ataxia telangiectasia fibroblasts to gamma-rays or bleomycin and thus appears to be a useful in vitro model of ataxia telangiectasia.


Bilateral dural arteriovenous fistula in the region of the cavernous sinus.
The case of a patient with a fistula between the left internal carotid artery and the cavernous sinus, and another fistula between the right external carotid artery and the cavernous sinus, is reported. The clinical symptomatology, which was of spontaneous onset, was unilateral and consisted of exophthalmos and injection of the conjunctiva on the left side. Almost complete remission occurred after angiography.


High-Resolution Analysis of 5-Hydroxymethylcytosine by TET-Assisted Bisulfite Sequencing.
DNA cytosine modification is an important epigenetic mechanism that serves critical functions in a variety of biological processes in development and disease. 5-Methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are the two most common epigenetic marks found in the mammalian genome. 5hmC is generated from 5mC by the ten-eleven translocation (TET) family of dioxygenase enzymes. This modification can reach substantial levels in certain cell types such as embryonic stem cells and neurons. Standard bisulfite sequencing techniques cannot distinguish between 5mC and 5hmC. Therefore, the method of TET-assisted bisulfite sequencing has been developed for detecting 5hmC specifically. The method is based on protection of 5hmC by glycosylation followed by complete oxidation of both 5mC and 5fC to 5caC, which converts to uracil after bisulfite treatment leaving only 5hmC remaining as a cytosine signal after PCR and sequencing. The method requires a highly active TET protein for the conversion steps. Here, we present an efficient TET protein purification method and a streamlined TAB-sequencing protocol for 5hmC analysis at single base resolution.


Lipopolysaccharide exacerbates infarct size and results in worsened post-stroke behavioral outcomes.
A third of ischemic stroke cases have no traditional underlying causes such as hypertension, diabetes, atherosclerosis, obesity, or age. Moreover, thirty to forty percent of strokes occur during or acutely after an active infection and the incidence of stroke increases during flu season. We and others have shown that the combination of a minor bacterial infection mimic, 100 μg/kg of lipopolysaccharide (LPS) prior to a minor stroke-30 min transient middle cerebral artery occlusion (tMCAO)-exacerbates infarct volume in a mouse model. Thus, experimental and epidemiological data strongly suggest that infection and/or inflammation play a role in stroke occurrence and severity. However, to date, long-term outcomes of stroke during an active infection has not been studied. 3-4 month old C57Bl6/J mice were treated with saline or LPS 30 min prior to a 30 min tMCAO or sham surgery. A behavioral battery was administered to assess health status/sickness behavior, neurological deficits, motor, cognitive, and affective behaviors. We show for the first time that exposure to a low dose of LPS prior to a mild stroke significantly worsens neurological deficits and sickness scores. Motor, cognitive, and affective behaviors were assessed post-stroke and while stroke significantly affected motor behavior on rotarod, LPS did not increase the motor deficits. We did not observe any effects of stroke or LPS on cognitive and affective behaviors. Our observations of the association between infection, stroke, and worse sickness and neurological outcomes identify (1) a clinical need to aggressively treat infections in people with risk factors for stroke and (2) the need to understand the mechanism(s) of the association between infections and stroke.


Absent or low expression of the zeta chain in T cells at the tumor site correlates with poor survival in patients with oral carcinoma.
Immunohistology for expression of the CD3zeta and CD3epsilon chains in TIL was performed in 138 paraffin-embedded primary oral squamous cell carcinoma tissues and 10 nontumor, inflammatory lesions. Semiquantitative analysis of the staining intensity for zeta chain expression and number of zeta chain expression-positive cells distinguished tumors with absent or low zeta expression (42 of 132) from those with normal zeta expression (90 of 132). Zeta chain expression was inversely correlated with the tumor stage. Survival was significantly lower in patients whose TIL had absent or low zeta expression, controlling for stage (P = 0.003) and lymph node status (P = 0.0005). The prognostic value of zeta chain was restricted to patients with stage III or IV tumors (P = 0.003). The data indicate that absent or decreased zeta expression in TIL combined with tumor stage or nodal status defines a group of patients with oral squamous cell carcinoma who have an extremely poor prognosis.


[68-year-old female patient with dyspnea and hypokalemic hypertension].
Ectopic ACTH syndrome is a rare differential diagnosis of hypokalemic hypertension. Patients with ectopic ACTH syndrome due to small cell lung cancer have a poor prognosis. We report on a 68-year-old female patient who presented with dyspnea and hypokalemic hypertension. Endocrine testing was consistent with ectopic ACTH syndrome due to small cell lung cancer. After initiation of chemotherapy with etoposide and carboplatin ACTH and cortisol levels normalized and clinical symptoms impressively improved.


Morbidity and mortality factors in twins. An epidemiologic approach.
Some epidemiologic characteristics of twin pregnancies and twin infants have been reviewed. We found that twins are prone to be born prematurely and have lower birth weights than their singleton counterparts after 30 to 34 weeks of gestation. Twins are also more prone to birth asphyxia, hyaline membrane disease, respiratory disorders, and seizures. Congenital anomalies and nonrespiratory morbidity were not found to be increased in twins. Twins have a six times higher perinatal mortality rate than do singletons. This is accounted for by prematurity in the main. A part of the excess mortality in twins is accounted for by a higher mortality in larger, near-term twins. Efforts should be directed toward decreasing the incidence of prematurity in twins and understanding and managing the problems of near-term twins better.


Basic research on inflammatory bowel disease in China.
Since the etiology and the pathogenesis of inflammatory bowel disease (IBD) are still not well known, research on IBD often focuses on these topics. Investigative science papers about IBD in Chinese medical journals from 1989 to 2003 were viewed to understand the progress of basic IBD research in China. The basic science investigative papers about IBD from 1989 to 2003 in Chinese periodicals (VIP and CMCC) were reviewed and analyzed; the key words used were as follows: inflammatory bowel disease, ulcerative colitis, Crohn's disease, basic science investigation, and literature review. There were 3454 articles about IBD published in Chinese medical journals from 1989 to 2003, and during these 15 years, 508 papers focused on basic scientific investigations. There were 463 papers investigating the pathogenesis of IBD, 287 papers on immunological mechanisms, and 176 papers about other mechanisms. There were 142 papers investigating the mechanisms of Chinese traditional medicine on IBD from 1989 to 2003, which included 117 papers related to animal experiments and 25 papers related to clinical studies. There have been relatively few investigative scientific papers on IBD published in Chinese medical journals. However, the study of IBD has been emphasized in China. Research on the immunological mechanisms of IBD has been predominant. Furthermore, a large number of the research papers were about the mechanisms and effects of Chinese traditional medicine on IBD.


Pivotal advance: IgE accelerates in vitro development of mast cells and modifies their phenotype.
Antigen-dependent activation of IgE-bound mast cells is critical for immediate hypersensitivity and other allergic disorders. Recent studies have revealed the effects of monomeric IgEs on mast cell survival and activation. Furthermore, IgE molecules exhibit a wide range of heterogeneity in the ability to induce mast cell activation in the absence of antigen. Highly cytokinergic (HC) IgEs can induce a variety of activation events including cell survival, degranulation, cytokine production, and migration, whereas poorly cytokinergic (PC) IgEs can do so inefficiently. Here, we show that culture of bone marrow cells in the presence of monomeric IgEs results in an increased number of mast cells compared with cultures grown without IgE. Furthermore, time in culture required to generate > or =80% pure mast cells is decreased. IgE molecules can directly influence mast cell progenitors to differentiate into mast cells. mRNA expression of several mast cell proteases and mast cell-related transcription factors is higher in mast cells cultured with an HC IgE than those cultured with a PC IgE or without IgE. Expression of early growth response factor-1, a transcription factor that is involved in the production of TNF-alpha in mast cells, is enhanced in cultures containing high and low concentrations of HC IgE and a high concentration of PC IgE. Consistent with this, expression of TNF-alpha is higher in mast cells cultured with HC IgE than PC IgE. Therefore, our results suggest that monomeric IgEs, especially HC IgEs, not only promote mast cell development but also modulate the mast cell phenotype.


Immune-mediated diseases and subsequent risk of alopecia areata in a prospective study of US women.
Alopecia areata (AA) is the most common form of immune-mediated hair loss. Studies have begun to establish the most frequent comorbid diseases of AA; however, results have been inconsistent with few prospective studies. A total of 63,692 women in the Nurses' Health Study, 53-80 years, were prospectively followed from 2002 to 2014 to determine whether history of immune-mediated disease was associated with AA risk. Hazard ratios (HRs) and 95% confidence intervals (CIs) for AA in relation to immune-mediated conditions were computed using Cox proportional hazard models, adjusted for AA risk factors. 133 AA cases were identified during follow-up. Personal history of any immune-mediated disease was associated with increased AA risk (HR 1.72, 95% CI 1.24-2.37). History of systemic lupus erythematosus (HR 5.43, 95% CI 2.11-13.97), multiple sclerosis (HR 4.10, 95% CI 1.40-11.96), vitiligo (HR 3.13, 95% CI 1.08-9.10), psoriasis (HR 2.01, 95% CI 1.00-4.03), hypothyroidism (HR 1.88, 95% CI 1.30-2.71), and rheumatoid arthritis (HR 1.66, 95% CI 1.09-2.52) were associated with increased AA risk. History of inflammatory bowel disease or Graves' disease/hyperthyroidism was not significantly associated with AA risk. In this prospective study, personal history of immune-mediated diseases either individually or overall was associated with increased AA risk.


Neurobiological mechanisms of dialectical behavior therapy and Morita therapy, two psychotherapies inspired by Zen.
Psychotherapy is a learning process. Updating the prediction models of the brain may be the mechanism underlying psychotherapeutic changes. Although developed in different eras and cultures, dialectical behavior therapy (DBT) and Morita therapy are influenced by Zen principles, and both emphasize the acceptance of reality and suffering. This article reviews these two treatments, their common and distinct therapeutic factors, and their neuroscientific implications. Additionally, it proposes a framework that includes the predictive function of the mind, constructed emotions, mindfulness, therapeutic relationship, and changes enabled via reward predictions. Brain networks, including the Default Mode Network (DMN), amygdala, fear circuitry, and reward pathways, contribute to the constructive process of brain predictions. Both treatments target the assimilation of prediction errors, gradual reorganization of predictive models, and creation of a life with step-by-step constructive rewards. By elucidating the possible neurobiological mechanisms of these psychotherapeutic techniques, this article is expected to serve as the first step towards filling the cultural gap and creating more teaching methods based on these concepts.


Effect of maternal exposure to smoke on gas diffusion capacity in neonatal rat.
Offspring of control and experimental (chronically exposed to whole cigarette smoke) rats were sacrificed on 15th postnatal day. Pulmonary tissues were processed for quantitative electron microscopic analyses. Arithmetic and harmonic mean thicknesses were directly measured and diffusion capacity was derived for separate layers (tissue, plasma, erythrocyte) and the entire lung. Experimental offspring showed a greater volume density of interstitium in parenchyma (P less than 0.04), arithmetic (P less than 0.05) and harmonic (P less than 0.009) mean thicknesses. Diffusion capacities for lungs of both animal groups, however, were similar (0.00543 and 0.0054 cm3 O2.min-1.mm Hg-1.g body weight-1 for control and experimental lungs respectively). Experimental tissue appeared better adapted for optimal exchange of gases (P less than 0.05), as indicated by corrugation index (ratio between arithmetic and harmonic mean thicknesses) than for the control counterpart. In spite of induced alterations in several developmental processes by a presently used experimental procedure, tissue capacity for transport of gases was not significantly changed in either the alveolo-capillary membrane or the entire lung.


Instantaneous wave free ratio vs. fractional flow reserve and 5-year mortality: iFR SWEDEHEART and DEFINE FLAIR.
Guidelines recommend revascularization of intermediate epicardial artery stenosis to be guided by evidence of ischaemia. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are equally recommended. Individual 5-year results of two major randomized trials comparing FFR with iFR-guided revascularization suggested increased all-cause mortality following iFR-guided revascularization. The aim of this study was a study-level meta-analysis of the 5-year outcome data in iFR-SWEDEHEART (NCT02166736) and DEFINE-FLAIR (NCT02053038). Composite of major adverse cardiovascular events (MACE) and its individual components [all-cause death, myocardial infarction (MI), and unplanned revascularisation] were analysed. Raw Kaplan-Meier estimates, numbers at risk, and number of events were extracted at 5-year follow-up and analysed using the ipdfc package (Stata version 18, StataCorp, College Station, TX, USA). In total, iFR and FFR-guided revascularization was performed in 2254 and 2257 patients, respectively. Revascularization was more often deferred in the iFR group [n = 1128 (50.0%)] vs. the FFR group [n = 1021 (45.2%); P = .001]. In the iFR-guided group, the number of deaths, MACE, unplanned revascularization, and MI was 188 (8.3%), 484 (21.5%), 235 (10.4%), and 123 (5.5%) vs. 143 (6.3%), 420 (18.6%), 241 (10.7%), and 123 (5.4%) in the FFR group. Hazard ratio [95% confidence interval (CI)] estimates for MACE were 1.18 [1.04; 1.34], all-cause mortality 1.34 [1.08; 1.67], unplanned revascularization 0.99 [0.83; 1.19], and MI 1.02 [0.80; 1.32]. Five-year all-cause mortality and MACE rates were increased with revascularization guided by iFR compared to FFR. Rates of unplanned revascularization and MI were equal in the two groups.


Study of pristine and functionalized V2C and Mo2C MXenes as novel electrode material for supercapacitors.
The quantum capacitance (QC) of pristine and functionalized molybdenum carbide and vanadium carbide MXenes is determined using density functional theory to investigate their suitability as supercapacitor electrodes. The calculations are performed using Synopsys ATK package with PBE functional under generalized gradient approximation keeping the energy cut off at 540 eV and k-point sampling at 12 × 12 × 1. The calculated QC at Fermi level in case of V2C and Mo2C exhibit extremely high values of 3465.51 and 3243.99 μF/cm2 respectively. The values of QC remain high in both positive and negative bias region around Fermi level. The impact of functionalization is studied for functional groups OH, OCH3, F and O. For each functional group, two layers are added (one below and one above) to the pristine structure. Band structures of functionalized MXenes show that the metallic character of the MXenes is retained, except in the case of oxygen functionalized Mo2C, which turns out to be a semiconductor with band gap of 0.051 eV. Although some decrease in density of state (DOS) and QC is observed in functionalized MXenes with all functional groups. However, the values are still good enough for supercapacitor electrode applications. The effect of number of layers of pristine MXene is also studied up to three layers and an increase in QC is observed with increase in number of layers.


Visible-Light-Activated Divergent Reactivity of Dienones: Dimerization in Neat Conditions and Regioselective E to Z Isomerization in the Solvent.
2,4-Dienones undergo visible-light-promoted, photocatalyst-free dimerization in neat conditions to provide cyclohexene derivatives stereoselectively through cascade rearrangement pathways, whereas regioselective E → Z isomerization of the more dienophilic double bond takes place exclusively in nitromethane. On the basis of intermediate isolation and computational DFT studies, the dimerization reaction is proposed to proceed via s-trans to s-cis isomerization/regioselective E → Z isomerization/Diels-Alder cycloaddition.


Effect of clofibrate and gemfibrozil on the activities of mitochondrial carnitine acyltransferases in rat liver. Dose--response relations.
The effects of different doses of clofibrate and gemfibrozil on liver size, serum triglyceride concentration and the activities of hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and carnitine acyltransferases were studied in male rats. Both clofibrate and gemfibrozil treatment effectively decreased the fructose-induced hypertriglyceridaemia and increased the liver to body weight ratio. Clofibrate treatment also induced an increase of many times in the activities of mitochondrial alpha-GPD and carnitine acyltransferases, the effect increasing with the dose used. The effect of gemfibrozil on the activities of the enzymes was significantly smaller. There was no correlation between the decrease in serum triglyceride concentration and the changes in the activities of the enzymes. Only clofibrate increased the rate of fatty acylcarnitine oxidation in isolated mitochondria. It is concluded that both drugs increased the size of the rat liver, but that only clofibrate influenced the mitochondrial enzyme activities of mitochondrial carnitine acyltransferases and the accelerated mitochondrial oxidation of fatty acids are not the mechanisms by which these drugs lower serum lipid levels.


Prevalence of stroke-related sarcopenia: A systematic review and meta-analysis.
Although the skeletal muscle is the main effector of disability in stroke, evidence on post-stroke skeletal muscle is scarce; especially, the prevalence of stroke-related sarcopenia remains unclear. Thus, we aimed to systematically search the prevalence of sarcopenia in stroke survivors and synthesize pooled estimates of overall prevalence of stroke-related sarcopenia and prevalence stratified by sex, country, time since stroke onset, and diagnostic criteria of sarcopenia. We performed systematic searches in the MEDLINE, CINAHL, Embase, and Cochrane Library databases. English-language searches to identify included studies were completed August 25, 2019. Meta-analysis of data collected from cross-sectional or observational studies which were reported the prevalence of sarcopenia among stroke participants. All statistical analyses were performed using R version 3.5.2. A total of 855 articles were initially identified. Seven articles were included in this study. Total sample size across all included studies was 1695. Three studies were conducted in Japan, 2 in South Korea, 1 in Taiwan, and 1 in the U.S. Four included studies had a cross-sectional design, and 3 were retrospective cohort studies. Four and 3 studies included participants at <1 month and ≥6 months since stroke onset, respectively. The pooled prevalence estimate was 42% (95% confidence interval: 33%-52%), with a substantial heterogeneity (I2=91%). Sarcopenia is frequently observed in stroke survivors, and a higher prevalence of sarcopenia is noted during the early phase after stroke. This study would be useful for researchers to design sarcopenia studies in this population. Further prospective longitudinal studies for sarcopenia and their prognostic outcomes in stroke survivors are urgently needed to propose appropriate physical and nutritional strategies in geriatric rehabilitation.


Structural elucidation of hydroxylated metabolites of the isoflavan equol by gas chromatography-mass spectrometry and high-performance liquid chromatography-mass spectrometry.
Equol has, as have other isoflavonoids, recently gained considerable interest due to its possible health effects. However, detailed studies on the metabolism of equol are scarce. Therefore, we investigated the phase I metabolism of equol using liver microsomes from Aroclor-treated male Wistar rats as well as from a male human. The identification of the metabolites formed was elucidated using high performance liquid chromatography (HPLC) with diode array detection, HPLC/atmospheric pressure ionization electrospray mass spectrometry, and gas chromatography-mass spectrometry, as well as reference compounds. (+/-)-Equol was converted to 11 metabolites by the liver microsomes from Aroclor-pretreated rats comprising three aromatic monohydroxylated and four aliphatic monohydroxylated as well as four dihydroxylated products. The main metabolite was identified as 3'-hydroxy-equol. Using human liver microsomes, equol was converted to six metabolites with 3'-hydroxy- and 6-hydroxy-equol as main products. Furthermore, the aliphatic hydroxylated metabolite 4-hydroxyequol, which was recently detected in human urine after soy consumption, was formed. On the basis of these findings, it is suggested that phase I metabolism of equol is part of a complex biotransformation of the soy isoflavone daidzein in humans in vivo.


[Genomic imprinting and problem of parthenogenesis in mammals].
Genomic imprinting belongs by its nature to problems of epigenetics, which studies hereditary changes in gene expression not related to defective sequences of DNA nucleotides. Epigenetic mechanisms of control, including genomic imprinting, are involved in many processes of normal and pathological development of humans and animals. Disturbances of genomic imprinting may lead to various consequences, such as formation of developmental anomalies and syndromes in humans, appearance of the large offspring syndrome and increased mortality upon cloning of mammals, and death of parthenogenetic embryos soon after implantation and beginning of organogenesis. The death of diploid parthenogenetic or androgenetic mammalian embryos is determined by the absence of expression of the genes of imprinted loci of the maternal or paternal genome, which leads to significant defects in development of tissues and organs. A review is provided of the studies aimed at search of possible normalization of misbalanced gene activity and modulation of genomic imprinting effects during parthenogenetic development in mammals.


Transcriptome and WGCNA reveal hub genes in sugarcane tiller seedlings in response to drought stress.
Drought stress can severely affect sugarcane growth and yield. The objective of this research was to identify candidate genes in sugarcane tillering seedlings in response to drought stress. We performed a comparative phenotypic, physiological and transcriptomic analysis of tiller seedlings of drought-stressed and well-watered "Guire 2" sugarcane, in a time-course experiment (5 days, 9 days and 15 days). Physiological examination reviewed that SOD, proline, soluble sugars, and soluble proteins accumulated in large amounts in tiller seedlings under different intensities of drought stress, while MDA levels remained at a stable level, indicating that the accumulation of osmoregulatory substances and the enhancement of antioxidant enzyme activities helped to limit further damage caused by drought stress. RNA-seq and weighted gene co-expression network analysis (WGCNA) were performed to identify genes and modules associated with sugarcane tillering seedlings in response to drought stress. Drought stress induced huge down-regulated in gene expression profiles, most of down-regulated genes were mainly associated with photosynthesis, sugar metabolism and fatty acid synthesis. We obtained four gene co-expression modules significantly associated with the physiological changes under drought stress (three modules positively correlated, one module negatively correlated), and found that LSG1-2, ERF1-2, SHKA, TIL, HSP18.1, HSP24.1, HSP16.1 and HSFA6A may play essential regulatory roles as hub genes in increasing SOD, Pro, soluble sugar or soluble protein contents. In addition, one module was found mostly involved in tiller stem diameter, among which members of the BHLH148 were important nodes. These results provide new insights into the mechanisms by which sugarcane tillering seedlings respond to drought stress.


Effects of treatment with leuprolide acetate depot on working memory and executive functions in young premenopausal women.
The goal of this study was to assess the influence of sex steroid hormone suppression on performance on tests of prefrontal cortex (PFC) and working memory function (WM) in premenopausal women. Twenty-five women were treated with leuprolide acetate depot (LAD), a gonadotropin releasing hormone (GnRH) analog that chemically suppressed ovarian function as treatment of various benign gynecologic disorders. Performance on tests of PFC and WM of the LAD-treated women was assessed at pretreatment baseline and, again, following 4 weeks of treatment and their performance was compared to that of 25 healthy, control participants matched on age, education, and general intelligence. Following 4 weeks of LAD treatment, estrogen levels decreased to the postmenopausal range whereas progesterone levels fell to the lower limit of the menstrual cycle range of values. Furthermore, the LAD-treated women also experienced a significant deterioration in mood, in health-related symptoms and in performance on two tests of WM following 4 weeks of treatment. It was determined that only the post-treatment declines in estrogen, but not those in progesterone, in mood, or in health-related symptoms were associated with the worsening of performance on the WM tests. These findings provide new evidence that estrogen is influential in the maintenance of WM processes in premenopausal women.


Just Good Developmental Science: Trust, Identity, and Responsibility in Ethnic Minority Recruitment and Retention.
Given the noted difficulty of recruiting and retaining ethnic and racial minority populations into various kinds of research endeavors (e.g., basic, prevention, intervention, health), they remain underrepresented and thus underserved by the research community as compared to other US groups. As developmental scientists, we often ask questions that imply longitudinal research designs, and thus, issues of attentiveness and responsiveness are paramount to the successful engagement (i.e., recruitment) and sustainability (i.e., retention) of our research with ethnic/racial minority samples. The goal of this chapter is to advance an ongoing dialogue about much of the work researchers of ethnic/racial minority child and youth development do in order to effectually recruit and retain youth and families but that is not often obvious to colleagues and readers of the final products. We frame our discussion with three key broadly significant themes: the role of trust, researcher identity and insider/outsider status, and responsibility. Perhaps most importantly, throughout the chapter, we provide concrete examples of the ways in which developmental scientists are transforming potential recruitment and retention challenges into opportunities in their own research programs.


TPP-related mitochondrial targeting copper (II) complex induces p53-dependent apoptosis in hepatoma cells through ROS-mediated activation of Drp1.
In recent years, copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity. In this study, a novel mitochondrion-targeting copper (II) complex, [Cu (ttpy-tpp)Br2] Br (simplified as CTB), is first synthesized by our group. CTB with tri-phenyl-phosphine (TPP), a targeting and lipophilic group, can cross the cytoplasmic and mitochondrial membranes of tumor cells. The present study aims to investigate how CTB affects mitochondrial functions and exerts its anti-tumor activity in hepatoma cells. Multiple molecular experiments including Flow cytometry, Western blot, Immunofluorescence, Tracker staining, Transmission Electron Microscopy and Molecular docking simulation were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. CTB induced apoptosis via collapse of mitochondrial membrane potential (MMP), ROS production, Bax mitochondrial aggregation as well as cytochrome c release, indicating that CTB-induced apoptosis was associated with mitochondrial pathway in human hepatoma cells. Mechanistic study revealed that ROS-related mitochondrial translocation of p53 was involved in CTB-mediated apoptosis. Simultaneously, elevated mitochondrial Drp1 levels were also observed, and interruption of Drp1 activation played critical role in p53-dependent apoptosis. CTB also strongly suppressed the growth of liver cancer xenografts in vivo. In human hepatoma cells, CTB primarily induces mitochondrial dysfunction and promotes accumulation of ROS, leading to activation of Drp1. These stimulation signals accelerate mitochondrial accumulation of p53 and lead to the eventual apoptosis. Our research shows that CTB merits further evaluation as a chemotherapeutic agent for the treatment of Hepatocellular carcinoma (HCC).


DNA repair induced by various mutagens in rat hepatocyte primary cultures measured in the presence of hydroxyurea, guanazole or aphidicolin.
Guanazole and aphidicolin were chosen as candidates in the search for a selective, non-genotoxic inhibitor of DNA replication which could be used instead of hydroxyurea to measure DNA repair synthesis in rat hepatocyte primary cultures by liquid scintillation counting. The genotoxicity of these 3 chemicals was studied using the Salmonella/liver homogenate assay and the autoradiographic UDS test in hepatocytes. Hydroxyurea was positive in both of these assays. Guanazole and aphidicolin did not induce DNA repair in hepatocytes. Aphidicolin was not mutagenic for Salmonella typhimurium, whereas guanazole increased the revertant numbers of strain TA102 slightly. The incorporation of [3H]thymidine was measured by liquid scintillation to determine DNA repair induced by 2-acetylaminofluorene (2-AAF), aflatoxin B1, benzo[a]pyrene, cyclophosphamide, H2O2, 6-hydroxydopamine, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methylnitrosourea (MNU), 4-nitroquinoline-N-oxide and UV irradiation in the presence of either 10 mM hydroxyurea, 15 mM guanazole or 0.015 mM aphidicolin. Aphidicolin had an inhibitory effect on DNA repair. Except for the 3 chemicals mentioned below, the sensitivity of the DNA repair measurement was the same, no matter whether hydroxyurea or guanazole was used to inhibit replicative DNA synthesis. In the presence of hydroxyurea, DNA repair synthesis was found at lower concentrations in the case of aflatoxin B1, due to differences in the solvent control values, and in the case of H2O2, possibly due to a synergistic effect between hydroxyurea and H2O2. Guanazole allowed the detection of DNA repair induced by MNNG at lower concentrations, probably because of an antagonistic effect between hydroxyurea and MNNG. Based on these results, it was concluded that guanazole, but not aphidicolin, could be used instead of hydroxyurea to measure DNA repair synthesis by liquid scintillation in rat hepatocyte primary cultures. Although guanazole does not completely fulfill the criteria for an ideal DNA replication inhibitor, it has the advantage of being less genotoxic than hydroxyurea, and also appears to have a smaller potential to falsify the results by interacting with the test compounds.


Genomic selection for heterobothriosis resistance concurrent with body size in the tiger pufferfish, Takifugu rubripes.
Parasite resistance traits in aquaculture species often have moderate heritability, indicating the potential for genetic improvements by selective breeding. However, parasite resistance is often synonymous with an undesirable negative correlation with body size. In this study, we first tested the feasibility of genomic selection (GS) on resistance to heterobothriosis, caused by the monogenean parasite Heterobothrium okamotoi, which leads to huge economic losses in aquaculture of the tiger pufferfish Takifugu rubripes. Then, using a simulation study, we tested the possibility of simultaneous improvement of parasite resistance, assessed by parasite counts on host fish (HC), and standard length (SL). Each trait showed moderate heritability (square-root transformed HC: h2 = 0.308 ± 0.123, S.E.; SL: h2 = 0.405 ± 0.131). The predictive abilities of genomic prediction among 12 models, including genomic Best Linear Unbiased Predictor (GBLUP), Bayesian regressions, and machine learning procedures, were also moderate for both transformed HC (0.248‒0.344) and SL (0.340‒0.481). These results confirmed the feasibility of GS for this trait. Although an undesirable genetic correlation was suggested between transformed HC and SL (rg = 0.228), the simulation study suggested the desired gains index can help achieve simultaneous genetic improvements in both traits.


Effect of medium tonicity and dextran on neutrophil function in vitro.
Multiple investigations have demonstrated that hypertonic saline (HS) diminishes the response of polymorphonuclear leukocytes (PMNs) to stimulation. Recent meta-analysis suggests that hypertonic saline in dextran (HSD) is clinically superior to HS. No work to date has examined the effect of added dextran on this immunomodulatory property. Human PMNs were exposed to media of varying osmolarity (220-360 mOsm/L) and stimulated with f-met-leu-phe with or without dextran present in the medium. Cell volume, respiratory burst, PMN aggregation, and beta(2)-integrin (CD18) expression were measured. Stimulation with f-met-leu-phe increased cell volume, respiratory burst, aggregation, and CD18 expression. The increases in cell volume, respiratory burst, and aggregation were significantly attenuated by exposure to hypertonic medium. The addition of dextran to the media did not change the results. The alterations in PMN function associated with HS are not changed or attenuated by the addition of dextran, suggesting that the clinically superior HSD may have effects similar to HS in mitigating the tissue damage associated with activated PMNs.


Effect of immunization on HTLV-I infection in rabbits.
Two groups of 3 rabbits, each immunized with heat-inactivated HTLV-I or a synthetic env peptide (env175-196), developed antibodies to viral proteins including gp68 and gp46. These immunized rabbits were then challenged with a transfusion of blood from HTLV-I-infected rabbits of the opposite sex. After transfusion challenge, antibody titers further rose in both groups and antibodies to HTLV-I proteins p24 and p19 newly appeared in the env 175-196 group. In addition, 3 more rabbits were infused with hyperimmune rabbit anti-HTLV-I IgG and similarly challenged with virus-infected blood. Pre-challenge sera from these rabbits showed high anti-HTLV-I titers with antibodies to envelope and core proteins. Despite transfusion challenge, the antibody titers gradually declined to undetectable levels in all 3 rabbits over a period of 16 weeks. Virus isolation was attempted from peripheral lymphocytes harvested 1 to 6 months after challenge infection and cultured in the presence of interleukin-2 (IL-2). HTLV-I-carrying lymphoid cell lines of recipient origin were established from all 6 rabbits given active immunization, whereas HTLV-I could not be isolated from any of the 3 rabbits given passive immunization. Absence of virus infection in the latter group was confirmed by negative blood transfusion assay to normal rabbits. These results indicate that hyperimmune IgG, but neither heat-inactivated HTLV-I nor env 175-196, were protective against HTLV-I infection induced by blood transfusion.


Asthma in primary care: a case-based review of pharmacotherapy.
Asthma remains a significant public health burden in the United States. Primary care providers are in an ideal position to be able to target treatment for their patients on an individual basis. It is important to determine the level of control and then base treatment on both the severity and activity of disease and the ability of the patient to be adherent to the therapy regimen. Because prescription medications along with office visits represent most asthma expenses, it is imperative to choose wisely from among the quick-relief and the long-term control medications to find the right choice for your patient.


The acrylic tooth-denture base bond: effect of mechanical preparation and surface treatment.
The bond strength of acrylic teeth to denture base resins was tested using a widely-accepted technique. The pre-treatments included abrading and grooving the teeth, the application of monomer and the application of a proprietary bonding agent. Each of the 360 specimens was tensile-tested until fracture, using a universal testing machine. When bonded to heat-cured resin, the grooved teeth had the highest mean bond strength while the grooved monomer-treated group had the lowest. When bonded to cold cure resin, the unabraded monomer-treated teeth had the highest mean bond strength and the unabraded group the lowest.


Primary extranodal natural killer/T-cell nasal-type lymphoma of spine: A case report.
Primary Extranodal Natural Killer/T-Cell Nasal-Type Lymphoma (ENKTCL) of spine is rarely reported. This case study presents a rare case of ENKTCL originating from the sixth thoracic vertebra. Here, we present a case of 49-year-old Asian male with chest and back pain. Physical examination revealed the myodynamia of both lower limbs decreased from IV degree to 0 degree, reflexes of both lower limbs and a large area of cutaneous sensation below xiphoid process disappeared in 3 days. In immunophenotype analysis, CD2, CD3, CD7, and CD68 were positive and CD56 was suspiciously positive. Granzyme B and T-cell intracellular antigen (TIA-1) were also positive and in situ hybridization was positive for Epstein-Barr virus-encoded mRNA (EBER). Ki-67 was 60%+. Nuclide bone scan showed that the nuclide was unusually concentrated in the sixth thoracic vertebra which considered extremely active and slightly concentrated in the right sacrolilac joint. Magnetic resonance imaging detected an abnormal signal in the sixth thoracic vertebra with corresponding paravertebral and intraspinal occupying lesion. Based on the above features, a diagnosis of ENKTCL was made. This patient was treated with surgery and symptomatic supportive treatment. The myodynamia of patient's both lower limbs were elevated to I degree after the operation with chest and back pain partly relieved. However, the patient died about 3 months later. ENKTCL could originate from spine. Clinicians should be alert for early stage diagnose and distinguish it from some common spinal tumor such as neurofibroma and hemangioma.


Prospective controlled evaluation of auditory function in neonates given netilmicin or amikacin.
Longitudinal assessment of intensive care nursery infants given aminoglycoside antibiotics revealed no significant difference in the incidence of hearing impairment when compared with age- and sex-matched controls. Bilateral sensorineural impairment was confirmed in three (2%) infants, one each given netilmicin and amikacin and one untreated control infant. There was a high incidence of transient auditory abnormalities in this intensive care infant population. These findings emphasize the importance of long-term follow-up hearing evaluations in infants who require intensive care management in the neonatal period.


A contracting Intertropical Convergence Zone during the Early Heinrich Stadial 1.
Despite the fact that the response of tropical hydroclimate to North Atlantic cooling events during the Heinrich Stadial 1 (HS1) has been extensively studied in African, South American and Indonesia, the nature of such responses remains debated. Here we investigate the tropical hydroclimate pattern over the Indo-Asian-Australian monsoon region during the HS1 by integrating hydroclimatic records, and examining a δ18Oseawater record from Globigerinoides ruber (white) in the tropical Indian Ocean. Our findings indicate that tropical hydrological conditions were synchronously arid in both hemispheres during the early HS1 (~18.3-16.3 ka) in the Indo-Asian-Australian monsoon region, except for a narrow, wet hydrological belt in northern low latitudes, suggesting the existence of a contracted tropical precipitation belt at that time. This study reveals that the meltwater discharge and resulting changes in global temperatures and El Niño exerted a profound influence on the tropical hydroclimate in the Indo-Asian-Australian monsoon region during the early HS1.


The Autism Genome Project: goals and strategies.
Autism is a complex neurodevelopmental disorder with a broad spectrum of symptoms and varying severity. Currently, no biological diagnosis exists. Although there has been a significant increase in autism genetics research recently, validated susceptibility genes for the most common, sporadic forms of autistic disorder, as well as familial autism, have yet to be identified. The identification of autism-susceptibility genes will not only assist in the identification and/or development of better medications that can help improve the health and neurodevelopment of children with autism, but will also allow for better perinatal diagnosis. The Autism Genome Project (AGP) is a large-scale, collaborative genetics research project initiated by the National Alliance for Autism Research and the National Institutes of Health, and is aimed at sifting through the human genome in search of autism-susceptibility genes. Phase I of the AGP will consist of genome-wide scans utilizing both SNP array and microsatellite technologies. Linkage analysis will subsequently be performed on approximately 1500 pedigrees as will downstream fine-mapping and sequencing of the critical linkage intervals. Ultimately, the vision will be to identify the exact nucleotide variants within genes which give rise to predisposition. The AGP intends to move the field of autism clinical management forward by answering questions about the causal mechanisms underlying the pathophysiology of autism. From this knowledge, therapeutic targets for drug treatments, and ultimately, a newborn screening diagnostic that would allow for early intervention, can begin to be developed.


Bridging the gap between the emergency department and outpatient care: feasibility of a short-term psychiatric crisis intervention for children and adolescents.
Child and adolescent mental health systems are facing limited resources of available psychosocial interventions, often leading to long waiting lists for acceptance to treatment. We describe the feasibility of a short-term (8-10 sessions) psychological crisis intervention (CI) protocol for children and adolescents aged 8-17 years (n = 30, mean ± standard deviation 12.9 ± 2.4 years) who were referred to an outpatient mental health clinic due to suicidal ideation, aggression, severe anxiety, or extreme family conflict. The participants were assessed before and after the CI, and at a 3-6-months follow-up visit. The psychiatric assessments included clinical evaluation by a senior psychiatrist, and the completion of self-report questionnaires by both the participants and their parents. Following the establishment of the CI unit, the waiting lists for urgent cases were reduced from a median of 84 days in the two preceding years to 23 days in the following 3 years (H[2] = 18.5, p < 0.0001) for patients of the CI unit. A 1-year psychiatric follow-up after the end of the CI revealed that 72% did not require additional psychotherapy. The overall clinical evaluation measures (clinical evaluation, parents-report and child report) improved and had been preserved at the 3-6-months follow-up. Our results demonstrate the feasibility of a short-term CI protocol for expediting admission to treatment for urgent psychiatric cases.


Outcomes of laparoscopic and robotic radical cystectomy in the elderly patients.
To compare the perioperative outcomes of laparoscopic/robotic radical cystectomy (LRRC) for urothelial cancer of bladder (UCB) between elderly (≥ 70 years) and younger (<70 years) patients. A retrospective review of 146 patients who underwent LRRC between 2003 and 2010 at 2 academic institutions (Cleveland, Ohio, United States and Toulouse, France) was performed. Of these, 74 patients were classified as elderly (≥ 70 years) and 72 patients were considered younger (<70 years). Perioperative outcomes, final pathology results, overall survival (OS), and cancer specific survival (CSS) were compared between the 2 groups. Both groups had similar clinical stage at diagnosis, American Society of Anesthesiologists score, body mass index, and gender distribution. Ileal conduit-type diversion was favored in the older vs younger group, 84% vs 36%, respectively. Overall conversion rate to open procedures was 4% in both groups. Perioperative complication rate was not significantly different between the younger and older patients. Positive margin rate was 5% in both groups. The 5-year OS for older and younger patients was 75% and 87%, respectively (P = .03), and the 5-year CSS for the 2 groups was 51% and 54%, respectively (P = .7). Laparoscopic/robotic radical cystectomy in the elderly does not have worse perioperative complications or pathologic outcomes compared with younger patients and therefore can be offered as treatment option in select older patients.


Saccade selection when reward probability is dynamically manipulated using Markov chains.
Markov chains (stochastic processes where probabilities are assigned based on the previous outcome) are commonly used to examine the transitions between behavioral states, such as those that occur during foraging or social interactions. However, relatively little is known about how well primates can incorporate knowledge about Markov chains into their behavior. Saccadic eye movements are an example of a simple behavior influenced by information about probability, and thus are good candidates for testing whether subjects can learn Markov chains. In addition, when investigating the influence of probability on saccade target selection, the use of Markov chains could provide an alternative method that avoids confounds present in other task designs. To investigate these possibilities, we evaluated human behavior on a task in which stimulus reward probabilities were assigned using a Markov chain. On each trial, the subject selected one of four identical stimuli by saccade; after selection, feedback indicated the rewarded stimulus. Each session consisted of 200-600 trials, and on some sessions, the reward magnitude varied. On sessions with a uniform reward, subjects (n = 6) learned to select stimuli at a frequency close to reward probability, which is similar to human behavior on matching or probability classification tasks. When informed that a Markov chain assigned reward probabilities, subjects (n = 3) learned to select the greatest reward probability more often, bringing them close to behavior that maximizes reward. On sessions where reward magnitude varied across stimuli, subjects (n = 6) demonstrated preferences for both greater reward probability and greater reward magnitude, resulting in a preference for greater expected value (the product of reward probability and magnitude). These results demonstrate that Markov chains can be used to dynamically assign probabilities that are rapidly exploited by human subjects during saccade target selection.


High-fat diet aggravates experimental autoimmune pancreatitis through the activation of type I interferon signaling pathways.
Autoimmune pancreatitis (AIP) is an autoimmune disorder of the pancreas characterized by enhanced IgG4 antibody responses and multiple organ involvement. AIP is a pancreatic manifestation of the systemic IgG4-related disease (IgG4-RD). Although AIP and IgG4-RD predominantly occur in middle-aged and elderly men, the roles of eating habits and lifestyle in the pathogenesis of these conditions are poorly understood. In this study, we examined whether a high-fat diet (HFD), preferred by middle-aged and elderly men, increases sensitivity to experimental AIP. We modeled AIP in MRL/MpJ mice by repeated injections of polyinosinic:polycytidylic acid. HFD exacerbated AIP development and promoted pancreatic accumulation of interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs). However, HFD did not increase the severity of autoimmune sialadenitis, another disorder associated with AIP and IgG4-RD. Neutralization of type I IFN signaling pathways prevented the development of severe AIP induced by HFD. In contrast, leaky gut was less likely to be associated with the HFD-induced exacerbation of AIP, as was evidenced by the lack of significant alterations in the jejunal or ileal expression of tight junction proteins. These data suggest that HFD exacerbates experimental AIP through the activation of pDCs producing IFN-α.


Multimodality Management of Spetzler-Martin Grade 3 Brain Arteriovenous Malformations with Subgroup Analysis.
Spetzler-Martin grade 3 (SM3) lesions entail 4 distinct subtypes described based on size, eloquence, and deep venous drainage (3A-3D). The ideal management of each is contentious, and the results of A Randomized Trial of Unruptured Brain AVMs (ARUBA) introduced additional controversy and attention toward management strategies of unruptured brain arteriovenous malformations (bAVMs). We retrospectively reviewed 114 patients with treated SM3 bAVMs, including both ruptured and unruptured lesions. Primary outcomes included modified Rankin score at most recent follow-up, angiographic cure, and permanent treatment-related complications (morbidity). Other outcomes included mortality, bAVM recurrence or rebleed, and transient treatment-related complications. We used univariate and multivariate modeling to determine whether any specific features were predictive of outcomes. For unruptured bAVMs, an "ARUBA eligible" subgroup analysis was performed. We also reviewed the literature on management of ruptured and unruptured SM3 bAVMs. Of the 114 identified SM3 bAVMs, 40% were unruptured. Most (43.5%) lesions in the unruptured group were type 3C, whereas most ruptured bAVMs (66.2%) were type 3A. Unruptured lesions were mostly managed with radiosurgery (47.8%) and ruptured ones with preoperative embolization and surgery (36.7%). Surgical intervention was predictive of angiographic cure in multivariate modeling, even after controlling for ≥2 years of follow-up, although associated with a slightly higher rate of morbidity. Focal neurological deficit was the only predictor of a worse (modified Rankin score ≥2) functional outcome in follow-up for unruptured bAVMs. For ruptured bAVMs, superficial and cerebellar locations were predictive of better outcomes in multivariate models, in the absence of a focal neurological deficit at presentation and new after surgery deficit. ARUBA SM3 bAVMs specifically underwent more embolization as a monotherapy and less microsurgical resection than the present series. In spite of a heterogeneous array of angioarchitectural and anatomic features, SM3 bAVMs can be treated safely and effectively with surgery and radiosurgery either without or with pretreatment embolization. Ruptured lesions are more often type 3A, with smaller nidus, deep brain location, and deep venous drainage. Focal neurological deficit predicts worse clinical outcomes. Contemporary multimodality management of SM3 bAVMs is not adequately represented in the results of ARUBA, likely due to differences in treatment strategies.


Doxazosin lowers blood pressure and improves insulin responses to a glucose load with no changes in tyrosine kinase activity or insulin binding.
alpha-Adrenergic blockers have shown favorable metabolic effects. We evaluated the glucose and insulin responses to a glucose load and lipid profiles in 36 diabetic hypertensive patients before and after 8 weeks of doxazosin administration. To evaluate insulin action at the cellular level, erythrocyte insulin binding and tyrosine kinase (TK) activity were measured in 12 of these patients. Systolic and diastolic blood pressures decreased significantly (P < .0001) after 8 weeks of doxazosin therapy. Doxazosin administration significantly reduced the integrated insulin response (area under the curve [AUC]-insulin: 6093 +/- 894 to 5260 +/- 807; P = .04) and the insulin/glucose index (I/G) at 90 and 120 min after a glucose load (at 90 min, 0.230 +/- 0.055 v 0.180 +/- 0.04, P < .05; at 120 min, 0.275 +/- 0.071 v 0.173 +/- 0.036, P < .05). HDL3 level increased from 31.1 +/- 1.5 mg% to 34 +/- 1.6 mg% (P < .05) after doxazosin. Erythrocyte insulin binding and tyrosine kinase activity were not significantly altered after doxazosin. No significant correlation was found between the insulin or glucose responses and the insulin receptor binding or tyrosine kinase activity before and after treatment.


Exploration of Environmental DNA (eDNA) to Detect Kirtland's Snake (Clonophis kirtlandii).
Environmental DNA (eDNA) surveys utilize DNA shed by organisms into their environment in order to detect their presence. This technique has proven effective in many systems for detecting rare or cryptic species that require high survey effort. One potential candidate for eDNA surveying is Kirtland's Snake (Clonophis kirtlandii), a small natricine endemic to the midwestern USA and threatened throughout its range. Due to its cryptic and fossorial lifestyle, it is also a notoriously difficult snake to survey, which has limited efforts to understand its ecology. Our goal was to utilize eDNA surveys for this species to increase detection probability and improve survey efficiency to assist future conservation efforts. We conducted coverboard surveys and habitat analyses to determine the spatial and temporal activity of snakes, and used this information to collect environmental samples in areas of high and low snake activity. In addition, we spiked artificial crayfish burrows with Kirtland's Snake feces to assess the persistence of eDNA under semi-natural conditions. A quantitative PCR (qPCR) assay using a hydrolysis probe was developed to screen the environmental samples for Kirtland's Snake eDNA that excluded closely related and co-occurring species. Our field surveys showed that snakes were found in the spring during the first of two seasons, and in areas with abundant grass, herbaceous vegetation, and shrubs. We found that eDNA declines within a week under field conditions in artificial crayfish burrows. In environmental samples of crayfish burrow water and sediment, soil, and open water, a single detection was found out of 380 samples. While there may be physicochemical and biological explanations for the low detection observed, characteristics of assay performance and sampling methodology may have also increased the potential for false negatives. We explored these outcomes in an effort to refine and advance the successful application of eDNA surveying in snakes and groundwater microhabitats.


Formation of N-acyl-phosphatidylethanolamines by cytosolic phospholipase A2ε in an ex vivo murine model of brain ischemia.
N-Acyl-phosphatidylethanolamines (NAPEs), a minor class of membrane glycerophospholipids, accumulate along with their bioactive metabolites, N-acylethanolamines (NAEs) during ischemia. NAPEs can be formed through N-acylation of phosphatidylethanolamine by cytosolic phospholipase A2ε (cPLA2ε, also known as PLA2G4E) or members of the phospholipase A and acyltransferase (PLAAT) family. However, the enzyme responsible for the NAPE production in brain ischemia has not yet been clarified. Here, we investigated a possible role of cPLA2ε using cPLA2ε-deficient (Pla2g4e-/-) mice. As analyzed with brain homogenates of wild-type mice, the age dependency of Ca2+-dependent NAPE-forming activity showed a bell-shape pattern being the highest at the first week of postnatal life, and the activity was completely abolished in Pla2g4e-/- mice. However, liquid chromatography-tandem mass spectrometry revealed that the NAPE levels of normal brain were similar between wild-type and Pla2g4e-/- mice. In contrast, post-mortal accumulations of NAPEs and most species of NAEs were only observed in decapitated brains of wild-type mice. These results suggested that cPLA2ε is responsible for Ca2+-dependent formation of NAPEs in the brain as well as the accumulation of NAPEs and NAEs during ischemia, while other enzyme(s) appeared to be involved in the maintenance of basal NAPE levels.


Long-term potentiation in the dentate gyrus is preferentially induced at theta rhythm periodicity.
In urethane-anesthetized rats, high frequency stimulation was applied to the medial perforant pathway at various time intervals (50, 100, 200, 350 and 500 ms) following stimulation of the same pathway by a single pulse of equal intensity. Recordings of dentate gyrus granule cell evoked responses were made to investigate the range of stimuli that are effective in inducing long-term potentiation (LTP). LTP was induced almost exclusively at the 200 ms interval, corresponding to the periodicity of the theta rhythm. Taken in conjunction with similar findings reported in the CA1 field of the hippocampal slice, these results suggest that the correlation between theta rhythm periodicity and LTP is a general phenomenon within the hippocampal formation and lends further support to the hypothesis that the naturally occurring theta rhythm may play a modulatory role in the induction of LTP.


Cost analysis of office-based transnasal esophagoscopy.
Although office-based transnasal esophagoscopy has been investigated extensively, a cost analysis is still lacking. We performed a cost analysis combined with feasibility study for two diagnostic processes: patients with globus pharyngeus and/or dysphagia, and hypopharyngeal carcinoma. Prospective cohort study. Forty-one procedures were performed, of which 35 were fully completed. The procedure was well tolerated with mild complaints such as nasal or pharyngeal pain and burping. Four complications occurred: two minor epistaxis and two vasovagal reactions. In patients with globus pharyngeus and/or dysphagia, transnasal esophagoscopy resulted in a cost saving of €94.43 (p 0.026) per procedure, compared to our regular diagnostic process. In patients with suspicion of hypopharyngeal carcinoma, cost savings were €831.41 (p 0.000) per case. Cost analysis showed that office-based transnasal esophagoscopy can provide significant cost savings for the current standard of care. Furthermore, this procedure resulted in good patient acceptability and few complications.