Autoimmunity to a liver membrane lipoprotein and liver damage in alcoholic liver disease.
Antibodies reacting with a liver membrane lipoprotein (LSP) have been detected by radioimmunoassay in the sera of 15 (27%) of 55 patients with alcohol-related liver lesions. There was a close association between the presence of the anti-LSP antibody and the findings on liver biopsy of a lymphocytic infiltrate in the portal tracts together with piecemeal necrosis of periportal hepatocytes. These histological features are characteristically found in the autoimmune disorder of chronic active hepatitis, in which anti-LSP antibodies are almost invariably present. It is suggested that in these cases of alcoholic liver disease there is loss of tolerance, and continued production of anti-LSP could promote periportal inflammation and accelerate the progression to cirrhosis. In the cases of acute alcoholic hepatitis without periportal inflammation studied, anti-LSP was not detected demonstrating that production of this autoantibody is not simply secondary to liver damage.


Immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix(®)) in renal transplant recipients.
In the course of the influenza A H1N1 pandemic, transplanted patients were recommended to receive vaccination. In the present study, we evaluated the immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix®) in renal allograft recipients. Sixty patients and 22 healthy controls participated in a prospective observational study and received a single dose of Pandemrix®. H1N1 antibody titres as well as anti-HLA antibodies were determined before and after vaccination. In 19 patients, a booster vaccination was performed and the outcome of all vaccinated renal allograft recipients (n = 107) in our clinic was reviewed. Two out of sixty patients had an elevated influenza A H1N1 titre before vaccination. Of the remaining 58 patients, only 20/58 (34.5%) developed a protective immune response in contrast to 20/22 (91%) of the control group. After booster vaccination, a protective titre was present in 8/19 (42%) of patients. Of the 107 patients, 6 (5.6%) developed new donor-specific HLA antibodies after vaccination. These data suggest that Pandemrix® does not provide a protective immune response in the majority of kidney transplant recipients. Therefore, for new vaccines, efficacy as well as safety profiles should be evaluated in this subgroup of patients.


Photocoagulation Up to Ora Serrata in Diabetic Vitrectomy to Prevent Recurrent Vitreous Hemorrhage.
To evaluate the role of performing photocoagulation up to ora serrata during vitrectomy in preventing recurrent vitreous hemorrhage (VH) in patients undergoing pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR). This retrospective, nonrandomized study included 60 eyes from 60 patients who had undergone PPV for VH due to PDR. These patients were divided into two groups: group 1, those who underwent photocoagulation up to ora serrata using the scleral indentation technique during surgery; and group 2, those who did not undergo scleral indentation when photocoagulation and underwent photocoagulation up to vortex veins. Their hospital records were analyzed to investigate the recurrence rate of VH, the time until recurrence of VH after surgery, logarithm of the minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) measured before surgery and at 1, 2, and 3 years after surgery, and the occurrence of complications such as neovascular glaucoma (NVG) during follow-up. Group 1 exhibited lower recurrence rate of VH (2 of 30 [6.7%] vs. 10 of 30 [33.3%], p = 0.01) and lower occurrence of postoperative NVG (2 of 30 [6.7%] vs. 8 of 30 [26.7%], p = 0.038) compared with group 2. There were no statistically significant differences in logMAR BCVA measured at 1, 2, and 3 years between the two groups (at 1 year: 0.54 ± 0.43 vs. 0.54 ± 0.44, p = 0.954; at 2 years: 0.48 ± 0.47 vs. 0.55 ± 0.64, p = 0.235; at 3 years: 0.51 ± 0.50 vs. 0.61 ± 0.77, p = 0.200). Logistic regression analysis showed that among several factors that could affect recurrence rate of VH, only range of photocoagulation performed was a statistically significant factor (odds ratio, 0.119; 95% confidence interval, 0.022-0.659; p = 0.015). Photocoagulation treatment over a wider range with scleral indentation could be a beneficial adjunct procedure for preventing postoperative recurrent VH following diabetic vitrectomy.


Racial/Ethnic Differences in Childhood Blood Lead Levels Among Children <72 Months of Age in the United States: a Systematic Review of the Literature.
Childhood lead poisoning is a serious public health problem with long-term adverse effects. Healthy People 2020's environmental health objective aims to reduce childhood blood lead levels; however, efforts may be hindered by potential racial/ethnic differences. Recent recommendations have lowered the blood lead reference level. This review examined racial/ethnic differences in blood lead levels among children under 6 years of age. We completed a search of PubMed, CINAHL, and PsycINFO databases for published works from 2002 to 2012. We identified studies that reported blood lead levels and the race/ethnicity of at least two groups. Ten studies met inclusion criteria for the review. Blood lead levels were most frequently reported for black, white, and Hispanic children. Six studies examined levels between blacks, whites, and Hispanics and two between blacks and whites. Studies reporting mean lead levels among black, whites, and Hispanics found that blacks had the highest mean blood lead level. Additionally, studies reporting blood lead ranges found that black children were more likely to have elevated levels. Studies suggest that black children have higher blood lead levels compared to other racial/ethnic groups. Future studies are warranted to obtain ample sample sizes for several racial/ethnic groups to further examine differences in lead levels.


Carbon dioxide reactivity of computed tomography functional parameters in rabbit VX2 soft tissue tumour.
Tumour blood flow is one of the important factors limiting the efficacy of radiation therapy (hypoxic radioresistance), chemotherapy (drug delivery) and thermal therapy (heat dissipation) in treating cancer. The modification of tumour blood flow has been an area of intense investigation. In the current study, the arterial carbon dioxide tension (PaCO2) was changed in order to investigate the tumour vascular response to carbon dioxide. Functional maps of blood flow, blood volume and mean transit time were generated at four PaCO2 levels in VX2 tumour in the rabbit thigh and normal soft tissue. The PaCO2 levels investigated were normocapnia (PaCO2 = 40.9 +/- 1.2 mmHg), hypocapnia (27.2 +/- 2.3 and 33.5 +/- 2.3 mmHg) and hypercapnia (54.9 +/- 4.4 mmHg). The carbon dioxide reactivity of the global tumour blood flow and mean transit time showed significant differences between normocapnia and the two levels of hypocapnia, but not between normocapnia and hypercapnia. The average fractional change of blood flow from normocapnia for the two levels of hypocapnia was -0.41 +/- 0.06 and -0.29 +/- 0.08, respectively (P < 0.05). In the case of mean transit time the fractional change was +0.39 +/- 0.30 and +0.23 +/- 0.24, respectively (P < 0.05). The fractional change of blood volume from normocapnia, however, was not significantly different at any capnic level, as was the case with respect to each of the functional parameters in normal tissue. The ability to reduce blood flow and increase mean transit time through hypocapnia has significant implications in thermal therapy, since heat dissipation is a major factor in limiting the effectiveness of treatment.


Heterogeneity of the tumor vasculature.
The blood vessels supplying tumors are strikingly heterogeneous and differ from their normal counterparts with respect to organization, structure, and function. Six distinctly different tumor vessel types have been identified, and much has been learned about the steps and mechanisms by which they form. Four of the six vessel types (mother vessels, capillaries, glomeruloid microvascular proliferations, and vascular malformations) develop from preexisting normal venules and capillaries by angiogenesis. The two remaining vessel types (feeder arteries and draining veins) develop from arterio-venogenesis, a parallel, poorly understood process that involves the remodeling of preexisting arteries and veins. All six of these tumor vessel types can be induced to form sequentially in normal mouse tissues by an adenoviral vector expressing vascular endothelial growth factor (VEGF)-A164. Current antiangiogenic cancer therapies directed at VEGF-A or its receptors have been of only limited benefit to cancer patients, perhaps because they target only the endothelial cells of the tumor blood vessel subset that requires exogenous VEGF-A for maintenance. A goal of future work is to identify therapeutic targets on tumor blood vessel endothelial cells that have lost this requirement.


Effects of intravenous glucocorticoids on postoperative delirium in adult patients undergoing major surgery: a systematic review and meta-analysis with trial sequential analysis.
The effects of intravenous glucocorticoids on postoperative delirium (POD) in adult patients undergoing major surgery remain controversial. Therefore, we conducted this meta-analysis to assess whether intravenous glucocorticoids can decrease POD incidence in the entire adult population undergoing major surgery and its association with patients age, type of surgery, and type of glucocorticoid. We searched the relevant literature published before November 3, 2023, through Cochrane Library, PubMed, Embase, and Web of Science. The primary outcome was POD incidence. The risk ratio for the primary outcome was calculated using the Mantel-Haenszel method. The secondary outcomes included 30-day mortality, length of hospital stay, ICU duration, mechanical ventilation duration, and occurrence of glucocorticoid-related adverse effects (e.g., infection and hyperglycemia). This meta-analysis was registered in PROSPERO: CRD42022345997. We included eight randomized controlled studies involving 8972 patients. For the entire adult population undergoing major surgery, intravenous glucocorticoids reduced the POD incidence (risk ratio = 0.704, 95% confidence interval, 0.519-0.955; P = 0.024). However, subgroups defined by type of surgery showed differential effects of glucocorticoids on POD. Intravenous glucocorticoids can not reduce POD incidence in adult patients undergoing cardiac surgery (risk ratio = 0.961, 95% confidence interval, 0.769-1.202; P = 0.728), with firm evidence from trial sequential analysis. However, in major non-cardiac surgery, perioperative intravenous glucocorticoid reduced the incidence of POD (risk ratio = 0.491, 95% confidence interval, 0.338-0.714; P < 0.001), which warrants further studies due to inconclusive evidence by trial sequence analysis. In addition, the use of glucocorticoids may reduce the mechanical ventilation time (weighted mean difference, -1.350; 95% confidence interval, -1.846 to -0.854; P < 0.001) and ICU duration (weighted mean difference = -7.866; 95% confidence interval, -15.620 to -0.112; P = 0.047). For the entire adult population undergoing major surgery, glucocorticoids reduced the POD incidence. However, the effects of glucocorticoids on POD appear to vary according to the type of surgery. In patients receiving major non-cardiac surgery, glucocorticoid may be an attractive drug in the prevention of POD, and further studies are needed to draw a definitive conclusion. In cardiac surgery, intravenous glucocorticoids have no such effect.


Medical student perceptions of research training on patient care during clerkship.
This article was migrated. The article was marked as recommended. Background Health Science Research (HSR) is a pre-clerkship component of the University of Toronto (U of T) MD Program. Through online modules and tutorials, students learn to understand and apply research, and write an original research protocol. This study explored students' perceptions on how HSR prepared them to identify, critically appraise and consume research during clerkship. Methods An online 12-item questionnaire surveyed U of T medical students (Class of 2018) who completed HSR in 2016. Basic descriptive statistics were performed; free text responses were analysed via descriptive thematic analysis. Results Twenty six percent (67/262) of students participated. Approximately half either agreed/strongly agreed that HSR helped them to critically appraise research articles (50.7%, 32/63) and assess applicability of results to patient care (50.8%, 32/63). Three themes emerged: i) desire for increased critical appraisal, ii) producing research less important than consuming research, iii) developing a greater appreciation of research during clerkship. Conclusions Students' perceptions on HSR's value during clerkship were modest; they desired greater focus on learning to be consumers of research. These results will refine HS, and our observations may be useful to other educators, as this type of intervention is not represented in existing literature.


A cystic amelanotic melanoma metastasis to the brain: case report.
As far as we know, cyst formation in intracranial melanoma is rare, and only 15 cases of intracranial amelanotic melanoma have been reported until now. A yellowish mass was observed in the frontal lobe. The content of the cyst consisted of old hematoma, xanthochromic fluid and necrotic tissue, was evacuated and the cyst wall was totally resected. No abnormal pigmentation was noted in the cyst wall and surrounding brain tissue. The imaging features of metastatic melanomas are distinctive due to the presence of melanin and the propensity for hemorrhage. Both hemorrhage and melanin can produce T1-weighted hyperintensity and T2-weighted signal intensity loss.


Cotreatment of IGF1 and Fadrozole Upregulates the Expression of RSPO1, SOX9, and AMH in Chicken Embryos.
Insulin-like growth factor-1 (IGF1) and anti-aromatase synergistically increase the rate and stability of female-to-male sex reversal as well as pre- and postnatal weight gains in hatched chickens. This study aimed at assessing gene expression profiles of chicken embryos treated with IGF1 and fadrozole. Day 3.5 fertile eggs were in ovo injected with one of IGF1, fadrozole anti-aromatase, combined IGF1 and fadrozole, or sham injection. The expression profile was studied on day 6 and day 11 of the embryonic development following gonadal differentiation. On day 6 of embryonic development, simultaneous injection of IGF1 and fadrozole significantly upregulated the expression of RSPO1, AMH, and SOX9 in genetically female embryos compared to single injections and control groups. Also, a higher expression of ESR1 and BMP4 was observed in genetically male embryos on day 6 compared to the control group. In day 11 embryos, a higher expression of BMP4 was detected in both males and females of the IGF1 and fadrozole-administered group compared to the sham injection cohort. In conclusion, the results of this study indicate that combined effects of IGF1 and fadrozole induce female-to-male sex reversal by increasing the expression of testis developmental factors rather than attenuating ovary developmental factors.


Opinions and Attitudes of Pulmonologists About Augmentation Therapy in Patients with Alpha-1 Antitrypsin Deficiency. A Survey of the EARCO Group.
Augmentation therapy (AT) is the only specific treatment licensed for patients with alpha-1 antitrypsin deficiency (AATD) associated lung disease. Since patients with severe AATD may have a very different prognosis and AT requires intravenous infusions for life, the decision to initiate AT may be challenging. This survey was conducted on 63 experts in AATD from 13 European countries about their opinions and attitudes regarding AT. Participants were asked to rank the importance of 11 identified factors related with the prescription of AT. In addition, each participant was asked to respond to the indication of AT for 30 out of 500 hypothetical cases developed with the combinations of the 11 factors. Each case was evaluated by 3 experts to check the concordance. The variables that scored higher on preferences for initiating AT were AAT genotype (score 8.6 from a Likert scale 0-10 (SD: 1.7)), AATD serum level (8.2 (SD:2.4)) and FEV1 (%) decline (7.9 (SD:2.4)). Among the 500 different cases, there was an agreement in indication of AT among the 3 experts in 291 (58.2%). Regarding the variables associated with AT, it was indicated to 81.9% of Pi*ZZ, 52.4% of Pi*SZ and 9.8% of Pi*MZ (p < 0.0001). For Pi*ZZ patients, multivariate analysis identified younger age, reduced FEV1 (%), higher FEV1 decline and worse emphysema as significantly associated with prescription (AUC = 0.8114); for Pi*SZ variables were younger age, worse FEV1 (%) and worse emphysema (AUC = 0.7414); and for Pi*MZ younger age, worse DLCO (%), higher DLCO decline and dyspnea (AUC = 0.8387). There is a high variability in the criteria for prescription of AT among European experts. Most cases were recommended AT according to guidelines, but a significant number of patients with genotype Pi*SZ and almost 10% Pi*MZ were recommended to initiate AT despite the lack of evidence of efficacy in these genotypes.


Cell based functional assays for IDO1 inhibitor screening and characterization.
Indoleamine 2,3-dioxygenase 1 (IDO1) is a new immune-oncology target and its inhibitors have shown promise in the clinic especially in combination with other immune-stimulating agents. Here we describe two robust cell-based assays for screening IDO1 inhibitors. Both assays can be easily adopted by most laboratories and utilized for screening of IDO1 inhibitors. Endogenous IDO1 expression is induced in a cancer cell line with interferon gamma and its activity is assessed by measuring kynurenine secreted into the media. The effect of cancer cell IDO1 induction and inhibition on T cell activation is evaluated in a co-culture assay using Jurkat T cell line. Additional readouts assessing cell viability are employed for early detection of false positive IDO1 inhibitors and toxic compounds. Clinical candidates epacadostat and BMS-986205 were evaluated in the assays as control compounds, the former can completely inhibit IDO1 activity while the maximum effect of the later is limited (to about 80% in our system) consistent with the differences in their interaction with IDO1. Nanomolar concentrations of both compounds rescued IDO1 mediated inhibition of T cell activation. However, treatment with micromolar concentrations of BMS-986205 blocked Jurkat T cell activation and after prolonged incubation induced cell death.


Implementation of a prostate cancer-specific targeted sequencing panel for credentialing of patient-derived cell lines and genomic characterization of patient samples.
Primary and metastatic prostate cancers have low mutation rates and recurrent alterations in a small set of genes, enabling targeted sequencing of prostate cancer-associated genes as an efficient approach to characterizing patient samples (compared to whole-exome and whole-genome sequencing). For example, targeted sequencing provides a flexible, rapid, and cost-effective method for genomic assessment of patient-derived cell lines to evaluate fidelity to initial patient tumor samples. We developed a prostate cancer-specific targeted next-generation sequencing (NGS) panel to detect alterations in 62 prostate cancer-associated genes as well as recurring gene fusions with ETS family members, representing the majority of common alterations in prostate cancer. We tested this panel on primary prostate cancer tissues and blood biopsies from patients with metastatic prostate cancer. We generated patient-derived cell lines from primary prostate cancers using conditional reprogramming methods and applied targeted sequencing to evaluate the fidelity of these cell lines to the original patient tumors. The prostate cancer-specific panel identified biologically and clinically relevant alterations, including point mutations in driver oncogenes and ETS family fusion genes, in tumor tissues from 29 radical prostatectomy samples. The targeted panel also identified genomic alterations in cell-free DNA and circulating tumor cells (CTCs) from patients with metastatic prostate cancer, and in standard prostate cancer cell lines. We used the targeted panel to sequence our set of patient-derived cell lines; however, no prostate cancer-specific mutations were identified in the tumor-derived cell lines, suggesting preferential outgrowth of normal prostate epithelial cells. We evaluated a prostate cancer-specific targeted NGS panel to detect common and clinically relevant alterations (including ETS family gene fusions) in prostate cancer. The panel detected driver mutations in a diverse set of clinical samples of prostate cancer, including fresh-frozen tumors, cell-free DNA, CTCs, and cell lines. Targeted sequencing of patient-derived cell lines highlights the challenge of deriving cell lines from primary prostate cancers and the importance of genomic characterization to credential candidate cell lines. Our study supports that a prostate cancer-specific targeted sequencing panel provides an efficient, clinically feasible approach to identify genetic alterations across a spectrum of prostate cancer samples and cell lines.


Multiple health disparities among minority adults with mobility limitations: san application of the ICF framework and codes.
To examine the interface between mobility limitations and minority status and its effect on multiple health and health-related domains among adults, using the framework of the International Classification of Functioning, Disability and Health (ICF). We combined 8 years of data from the 1997-2004 US National Health Interview Survey to investigate health disparities among minorities with mobility limitations as defined by the ICF. A total of 79,739 adults surveyed met these criteria. Adults with both mobility limitations and minority status experienced the greatest disparities (p<0.001) in worsening health (adjusted odds ratio [AOR]=8.5), depressive symptoms (AOR=17.2), diabetes (AOR=5.5), hypertension (AOR=3.4), stroke (AOR=7.2), visual impairment (AOR=4.6), difficulty with activities of daily living (AOR=42.7) and instrumental activities of daily living (AOR=27.7), use of special equipment (AOR = 28.1), obesity (AOR=3.3), physical inactivity (AOR=2.7), and low workforce participation (AOR=0.35). For most outcome measures, findings supported our hypothesis that persons with both mobility limitations and minority status experience greater health disparities than do adults with minority status or mobility limitations alone.


Clinical and antimicrobial susceptibility profile of typhoid fever in children in the era of antibiotic resistance.
Enteric fever remains a significant public health problem in low- and middle-income countries with further challenges from emerging antimicrobial resistance. Our prospective study evaluated the current clinical and antimicrobial susceptibility profile of enteric fever in 88 children and compared it to previously established literature. Enteric fever usually presents with nonspecific signs and symptoms, with predominant respiratory complaints. A paradigm shift in the antimicrobial sensitivity pattern has been noted, with increasing resistance for first-line antibiotics and older antibiotics such as ampicillin, cotrimoxazole, and chloramphenicol showing good sensitivity. Thus, the introduction of the latter merits consideration.


Increased cyanophage infection at the bottom of the euphotic zone, especially in the fall.
Picocyanobacteria contribute greatly to offshore primary production with cells extending through the deep euphotic zone. Literature indicates high viral infection of cyanobacteria in ocean transition zones. We postulate that the bottom of the euphotic zone is a transition zone, where communities transition from phototrophic to aphotic processes. We use single-copy core genes to examine cyanophage to cyanobacteria ratios in cellular metagenomes in the subtropical North Atlantic and Pacific. Cyanophage to cyanobacteria terL/rpoB ratios generally increase to >10 in the deep euphotic zone. As light levels decrease in the fall, Prochlorococcus in the deep euphotic zone experience reduced light levels. We find clear differences between spring (Geotraces GA02) and fall (GA03) in the North Atlantic, with terL/rpoB ratios increasing to >40 in the fall. When examining 23 months of the North Pacific Hawaii Ocean Timeseries, the depth of elevated cyanophage to cyanobacteria ratios in cellular metagenomes negatively correlated with surface photosynthetic radiation (PAR), particularly with the change in PAR, which reflected the season. In fall, all picocyanobacteria ecotypes were found at depths enriched with viruses, while in summer, only low light ecotypes were affected. Thus, we find high cyanophage infection both in the deep euphotic zone and during seasonal transitions.


Spacing and the transition from calculation to retrieval.
Many arithmetic problems can be solved in two ways--by a calculation involving several steps and by direct retrieval of the answer. With practice on particular problems, memory retrieval tends to supplant calculation--an important aspect of skill learning. We asked how the distribution of practice on particular problems affects this kind of learning. In two experiments, subjects repeatedly worked through sets of multiple-digit multiplication problems. The size of the trained problem set was varied. Using a smaller set size (with shorter average time between problem repetitions) showed faster responses and an earlier transition to retrieval during training. However, in a test session presented days later, the pattern reversed, with faster responses and more retrieval for the large set size. Evidently, maximizing the occurrence of direct retrieval within training is not the best way to promote learning to retrieve the answer. Practical implications are discussed.


Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome.
Hereditary long QT syndrome (hLQTS) is a heterogeneous genetic disease characterized by prolonged QT interval in the electrocardiogram, recurrent syncope, and sudden cardiac death. Mutations in the cardiac potassium channel HERG (KCNH2) are the second most common form of hLQTS and reduce the delayed rectifier K(+) currents, thereby prolonging repolarization. We studied a novel COOH-terminal missense mutation, HERG R752W, which segregated with the disease in a family of 101 genotyped individuals. When the mutant cRNA was expressed in Xenopus oocytes it produced enhanced rather than reduced currents. Simulations using the Luo-Rudy model predicted minimal shortening rather than prolongation of the cardiac action potential. Consequently, a normal or shortened QT interval would be expected in contrast to the long QT observed clinically. This anomaly was resolved by our observation that the mutant protein was not delivered to the plasma membrane of mammalian cells but was retained intracellularly. We found that this trafficking defect was corrected at lower incubation temperatures and that functional channels were now delivered to the plasma membrane. However, trafficking could not be restored by chemical chaperones or E-4031, a specific blocker of HERG channels. Therefore, HERG R752W represents a new class of trafficking mutants in hLQTS. The occurrence of different classes of misprocessed channels suggests that a unified therapeutic approach for altering HERG trafficking will not be possible and that different treatment modalities will have to be matched to the different classes of trafficking mutants.


Cryoultramicrotomy and immunocytochemistry in the analysis of muscle fine structure.
Cryoultramicrotomy, which avoids the use of harsh fixation procedures, deleterious dehydration and plastic embedding can be combined with immunocytochemistry to determine the ultrastructural localization of cellular proteins. Our attempts to use the cryosectioning technique in combination with immunolabelling to bridge the gap between light and electron microscopic analysis of muscle morphology have enabled us to obtain new information on fibre typing at the ultrastructural level. Furthermore, we have obtained a marked improvement in the resolution of myofibrillar structures by using semithin cryosections for fluorescence microscopy. Data are also presented on correlated light and electron microscope immunocytochemistry of myocardial intermediate filaments confirming the presence of longitudinally oriented intermediate filaments of desmin in the region of the intercalated discs of mammalian cardiac myocytes, whereas elsewhere in the myocyte the bulk of intermediate filaments of desmin is concentrated in the intermyofibrillar space at the level of the Z disc.


Two double blind trials of diclofenac sodium with aspirin and with naproxen in the treatment of patients with rheumatoid arthritis.
In 2 multicenter, double blind studies, the efficacy and safety of diclofenac, 150 mg/day, were compared with those of aspirin, 3.6 g/day, in 194 patients with rheumatoid arthritis (RA) in Study 1 and with those of naproxen, 1000 mg/day, in 223 patients with RA in Study 2. After single blind, placebo washout periods of 2 days to 2 weeks, patients entered 12-week treatment periods in each study. In both studies, diclofenac, aspirin, and naproxen produced statistically significant improvement (p less than or equal to 0.01) from baseline in all primary efficacy variables at each assessment visit. There were no significant differences between treatments. In both studies, significantly fewer (p less than or equal to 0.05) patients receiving diclofenac experienced adverse effects compared to the aspirin and naproxen groups. Significantly fewer (p less than 0.05) patients in the diclofenac group compared to the aspirin group discontinued the trial due to side effects (primarily tinnitus and deafness). In Study 2, fewer patients in the diclofenac group discontinued the trial due to adverse effects than in the naproxen group. In conclusion, diclofenac, aspirin, and naproxen demonstrated similar efficacy; however, diclofenac was significantly better tolerated than either aspirin or naproxen.


Selection against spermatozoa with fragmented DNA after postovulatory mating depends on the type of damage.
Before ovulation, sperm-oviduct interaction mechanisms may act as checkpoint for the selection of fertilizing spermatozoa in mammals. Postovulatory mating does not allow the sperm to attach to the oviduct, and spermatozoa may only undergo some selection processes during the transport through the female reproductive tract and/or during the zona pellucida (ZP) binding/penetration. We have induced DNA damage in spermatozoa by two treatments, (a) a scrotal heat treatment (42 degrees C, 30 min) and (b) irradiation with 137Cs gamma-rays (4 Gy, 1.25 Gy/min). The effects of the treatments were analyzed 21-25 days post heat stress or gamma-radiation. Postovulatory females mated either with treated or control males were sacrificed at Day 14 of pregnancy, and numbers of fetuses and resorptions were recorded. Both treatments decreased significantly implantation rates however, the proportion of fetuses/resorptions was only reduced in those females mated to males exposed to radiation, indicating a selection favoring fertilization of sperm with unfragmented DNA on the heat treatment group. To determine if DNA integrity is one of the keys of spermatozoa selection after postovulatory mating, we analyzed sperm DNA fragmentation by COMET assay in: a) sperm recovered from mouse epididymides; b) sperm recovered from three different regions of female uterine horns after mating; and c) sperm attached to the ZP after in vitro fertilization (IVF). Similar results were found for control and both treatments, COMET values decreased significantly during the transit from the uterine section close to the uterotubal junction to the oviduct, and in the spermatozoa attached to ZP. However, fertilization by IVF and intracytoplasmatic sperm injection (ICSI) showed that during sperm ZP-penetration, a stringent selection against fragmented-DNA sperm is carried out when the damage was induced by heat stress, but not when DNA fragmentation was induced by radiation. Our results indicate that in postovulatory mating there is a preliminary general selection mechanism against spermatozoa with low motility and fragmented-DNA during the transport through the female reproductive tract and in the ZP binding, but the ability of the ZP to prevent fertilization by fragmented-DNA spermatozoa is achieved during sperm-ZP penetration, and depends on the source of damage.


A natural association of a yeast with Aspergillus terreus and its impact on the host fungal biology.
Several fungi have been shown to harbor microorganisms that regulate the key components of fungal metabolism. We explored the symbiotic association of an endophyte, Aspergillus terreus, which led to the isolation of a yeast, Meyerozyma caribbica, as its symbiont. An axenic fungal culture, free of the symbiont, was developed to study the effect of this association on the endophytic fungus. The symbiotic yeast partner was found to play an important role in the adaptation of A. terreus to thermal as well as osmotic stress. Under these stress conditions, the symbiont enhanced the production of lovastatin and the growth of the host fungus. The symbiotic yeast was found to induce the expression of the global regulator gene, the key genes involved in the lovastatin biosynthetic pathway as well as those involved in general growth and development, under stress conditions, in the fungal partner. Analysis by PCR and fluorescent in situ hybridization microscopy indicated that the yeast may be present inside the hyphae of the fungus. However, a direct method like transmission electron microscopy may help to better understand the dynamics of this association, including the distribution of the yeast cells in/on the fungal hyphae and spores.


The gas-phase ligand exchange of copper and nickel acetylacetonate, hexafluoroacetylacetonate and trifluorotrimethylacetylacetonate complexes.
The gas-phase ligand-exchange reactions between Cu(II) and Ni(II) complexes containing the acetylacetonate (acac), hexafluoroacetylacetonate (hfac), and trifluorotrimethylacetylacetonate (tftm) ligands were investigated using a triple quadrupole mass spectrometer. The gas-phase mixed-ligand products of [Cu(acac)(tftm)](+), [Ni(acac)(tftm)](+), [Cu(hfac)(tftm)](+), and [Ni(hfac)(tftm)](+) were formed following the co-sublimation of either homo-metal or hetero-metal precursors. The gas-phase formation of [Cu(acac)(tftm)](+), [Cu(hfac)(tftm)](+), [Ni(acac)(tftm)](+), and [Ni(hfac)(tftm)](+) complexes is reported herein for the first time. The corresponding fragmentation patterns of these species along with those of Cu(tftm)(2) and Ni(tftm)(2) are also presented. Mass-selected ion-neutral reactions were investigated.


High prevalence of fragility vertebral fractures in patients hospitalised in Internal Medicine Units. Results of the POINT (Prevalence of Osteoporosis in INTernal medicine) study.
Osteoporotic vertebral fractures (VFs) often go unrecognised in both healthy individuals and in pathological conditions. Few data exist on VFs in patients hospitalised in Internal Medicine Units (IMUs), who often suffer from multiple concomitant chronic disorders. This multicentre cross-sectional study was aimed at assessing the prevalence of VFs in an unselected population of patients referring to IMUs. Correlations between VFs and the main coexisting diseases were also investigated. Information on demographic, clinical and laboratory findings, and on the presence of known risk factors for osteoporosis was recorded. The Genant's semi-quantitative method was used to evaluate, in a central reading centre, the presence and severity of VFs in the thoracic and lumbar spine. A cohort of 995 patients was evaluated. At least one VF of any grade was found in 47.5% of patients, with similar prevalence between females (48.1%) and males (46.7%). Older age, chronic obstructive pulmonary disease, and previous diagnosis of osteoporosis showed a significant association with VFs in multivariable analysis. However, 79.7% of the VFs were observed in patients without previous diagnosis of osteoporosis. Moreover, a VF of grade 2 or greater was found in 20.8% of patients. Fragility VFs is a very frequent finding in patients hospitalised in IMUs. Consequently, more attention should be devoted in this clinical setting to this comorbidity, which is known to be an additional factor for mortality and, when localised in the thoracic part of the spine, may negatively influence a concomitant respiratory insufficiency.


Mixtures of t $$ t $$ factor analysers with censored responses and external covariates: An application to educational data from Peru.
Analysing data from educational tests allows governments to make decisions for improving the quality of life of individuals in a society. One of the key responsibilities of statisticians is to develop models that provide decision-makers with pertinent information about the latent process that educational tests seek to represent. Mixtures of t $$ t $$ factor analysers (MtFA) have emerged as a powerful device for model-based clustering and classification of high-dimensional data containing one or several groups of observations with fatter tails or anomalous outliers. This paper considers an extension of MtFA for robust clustering of censored data, referred to as the MtFAC model, by incorporating external covariates. The enhanced flexibility of including covariates in MtFAC enables cluster-specific multivariate regression analysis of dependent variables with censored responses arising from upper and/or lower detection limits of experimental equipment. An alternating expectation conditional maximization (AECM) algorithm is developed for maximum likelihood estimation of the proposed model. Two simulation experiments are conducted to examine the effectiveness of the techniques presented. Furthermore, the proposed methodology is applied to Peruvian data from the 2007 Early Grade Reading Assessment, and the results obtained from the analysis provide new insights regarding the reading skills of Peruvian students.


Effects of aqueous extracts of PM(10) filters from the Utah valley on human airway epithelial cells.
We hypothesized that the reduction in hospital respiratory admissions in the Utah Valley during closure of a local steel mill in 1986-1987 was attributable in part to decreased toxicity of ambient air particles. Sampling filters for particulate matter < 10 micrometer (PM(10)) were obtained from a Utah Valley monitoring station for the year before (year 1), during (year 2), and after (year 3) the steel mill closure. Aqueous extracts of the filters were analyzed for metal content and oxidant production and added to cultures of human respiratory epithelial (BEAS-2B) cells for 2 or 24 h. Year 2 dust contained the lowest concentrations of soluble iron, copper, and zinc and showed the least oxidant generation. Only dust from year 3 caused cytotoxicity (by microscopy and lactate dehydrogenase release) at 500 microgram/ml. Year 1 and year 3, but not year 2, dust induced expression of interleukin-6 and -8 in a dose-response fashion. The effects of ambient air particles on human respiratory epithelial cells vary significantly with time and metal concentrations.


Constitutive turnover of cyclin E by Cul3 maintains quiescence.
Two distinct pathways for the degradation of mammalian cyclin E have previously been described. One pathway is induced by cyclin E phosphorylation and is dependent on the Cul1/Fbw7-based E3 ligase. The other pathway is dependent on the Cul3-based E3 ligase, but the mechanistic details of this pathway have yet to be elucidated. To establish the role of Cul3 in the degradation of cyclin E in vivo, we created a conditional knockout of the Cul3 gene in mice. Interestingly, the biallelic loss of Cul3 in primary fibroblasts derived from these mice results in increased cyclin E expression and reduced cell viability, paralleling the loss of Cul3 protein expression. Cell cycle analysis of viable, Cul3 hypomorphic cells shows that decreasing the levels of Cul3 increases both cyclin E protein levels and the number of cells in S phase. In order to examine the role of Cul3 in an in vivo setting, we determined the effect of deletion of the Cul3 gene in liver. This gene deletion resulted in a dramatic increase in cyclin E levels as well as an increase in cell size and ploidy. The results we report here show that the constitutive degradation pathway for cyclin E that is regulated by the Cul3-based E3 ligase is essential to maintain quiescence in mammalian cells.


Distributed population coding of multisensory spatial information in the associative cortex.
This study describes a possible mechanism of coding of multisensory information in the anterior ectosylvian visual area of the feline cortex. Extracellular microelectrode recordings on 168 cells were carried out in the anterior ectosylvian sulcal region of halothane-anaesthetized, immobilized, artificially ventilated cats. Ninety-five neurons were found to respond to visual stimuli, 96 responded to auditory stimuli and 45 were bimodal, reacting to both visual and auditory modalities. A large proportion of the neurons exhibited significantly different responses to stimuli appearing in different regions of their huge receptive field. These neurons have the ability to provide information via their discharge rate on the site of the stimulus within their receptive field. This suggests that they may serve as panoramic localizers. The ability of the bimodal neurons to localize bimodal stimulus sources is better than any of the unimodal localizing functions. Further, the sites of maximal responsivity of the visual, auditory and bimodal neurons are distributed over the whole extent of the large receptive fields. Thus, a large population of such panoramic visual, auditory and multisensory neurons could accurately code the locations of the sensory stimuli. Our findings support the notion that there is a distributed population code of multisensory information in the feline associative cortex.


Expression of the Medicago truncatula DM12 gene suggests roles of the symbiotic nodulation receptor kinase in nodules and during early nodule development.
The Medicago truncatula DMI2 gene encodes a receptorlike kinase required for establishing root endosymbioses. The DMI2 gene was shown to be expressed much more highly in roots and nodules than in leaves and stems. In roots, its expression was not altered by nitrogen starvation or treatment with lipochitooligosaccharidic Nod factors. Moreover, the DMI2 mRNA abundance in roots of the nfp, dmil, dmi3, nsp1, nsp2, and hcl symbiotic mutants was similar to the wild type, whereas lower levels in some dmi2 mutants could be explained by regulation by the nonsense-mediated decay, RNA surveillance mechanism. Using pDMI2::GUS fusions, the expression of DMI2 in roots appeared to be localized primarily in the cortical and epidermal cells of the younger, lateral roots and was not observed in the root apices. Following inoculation with Sinorhizobium meliloti, the DMI2 gene was induced in the nodule primordia, before penetration by the infection threads. No increased expression was seen in lateral-root primordia. In nodules, expression was observed primarily in a few cell layers of the pre-infection zone. These results are consistent with the DMI2 gene mediating Nod factor perception and transduction leading to rhizobial infection, not only in root epidermal cells but also during nodule development.


[Resistant atrial fibrillation: how far does one go in its treatment?].
Resistant atrial fibrillation consists in recurrent or persistent fibrillation despite a conventional treatment persistent. When conventional treatments (drugs, external defibrillation) fails, we have the following options: internal defibrillation, pacemaker implantation either standard or with biatrial pacing, curative or palliative radiofrequency ablation techniques, antiarrhythmic surgery, atrial defibrillator implantation. These different treatment modalities, isolated or combined will frequently be able to reduce the patient symptoms and some of at them may suppress the majority of atrial fibrillation episodes. Not all these treatments are widely used at the present time but a lot of research is being done about them. The purpose of this article is to describe their use in resistant patients.


Overweight and obesity prevalence among Indian women by place of residence and socio-economic status: Contrasting patterns from 'underweight states' and 'overweight states' of India.
Evidence from developing countries demonstrates a mixed relationship of overweight/obesity with socioeconomic status (SES) and place of residence. Theory of nutrition transition suggests that over the course of development, overweight first emerges among rich and urban people before spreading among rural and poor people. India is currently experiencing a rapid rise in the proportion of overweight and obese population especially among adult women. Under the backdrop of huge socio-economic heterogeneity across the states of India, the inter-state scenario of overweight and obesity differs considerably. Hence, this paper investigates the evolution over time of overweight and obesity among ever-married Indian women (15-49 years) from selected 'underweight states' (Bihar, Orissa and Madhya Pradesh, where underweight proportion is predominant) and 'overweight states' (Kerala, Delhi and Punjab, where overweight is the prime concern), in relation to a few selected socio-economic and demographic indicators. This study analysed National Family Health Surveys- NFHS-2 (1998-99) and NFHS-3 (2005-06) following Asian population specific BMI cut-offs for overweight and obesity. The results confirm that within India itself the relationship of overweight and obesity with place of residence and SES cannot be generalized. Results from 'overweight states' show that the overweight problem has started expanding from urban and well-off women to the poor and rural people, while the rural-urban and rich-poor difference has disappeared. On the other hand in 'underweight states' overweight and obesity have remained socially segregated and increasing strongly among urban and richer section of the population. The rate of rise of overweight and obesity has been higher in rural areas of 'OW states' and in urban areas of 'UW states'. Indian policymakers thus need to design state-specific approaches to arrest the rapid growth of overweight and its penetration especially towards under-privileged section of the society.


Antiproliferative effect of adiponectin on rat uterine leiomyoma ELT-3 cells.
Although fibroids greatly affect reproductive health, the pathophysiology and epidemiology are not well known. Recently, we have reported the relationship between uterine leiomyoma and metabolic syndrome. Many studies have indicated that reductions in plasma adiponectin levels play major roles in the development of metabolic syndrome. In this study, we investigated the significant repressive effect of adiponectin on rat uterine leiomyoma ELT-3 cells proliferation. Expression of adiponectin receptor 1 and receptor 2 was evaluated by RT-PCR and Western blot analysis. Cell proliferation was assessed by the MTS assay and cell counting. Apoptosis was evaluated by Hoechst staining and cleaved poly (ADP-ribose) polymerase (PARP). Adiponectin receptor 1 and receptor 2 were expressed in ELT-3 cells. Adiponectin repressed rat uterine leiomyoma ELT-3 cells cell proliferation without inducing apoptosis. The repression of adiponectin on leiomyoma cell proliferation in the rat may explain a crucial role of adiponectin in the association of metabolic syndrome with uterine leiomyoma.


Trastuzumab and chemotherapeutics: drug interactions and synergies.
Previous studies have shown a synergistic interaction between trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) and the cytotoxic drug cisplatin in human breast cancer cells. To define the nature of the interaction between trastuzumab and other classes of cytotoxic drugs, we applied multiple drug effect/combination index isobologram analysis to a variety of chemotherapeutic drug/trastuzumab combinations in vitro. Synergistic interactions at clinically relevant drug concentrations were observed for trastuzumab in combination with cisplatin, docetaxel, thiotepa, 4-OH cyclophosphamide, vinorelbine, and etoposide. Additive cytotoxic effects were observed with trastuzumab plus doxorubicin, paclitaxel, methotrexate, and vinblastine. One drug, 5-fluorouracil was found to be antagonistic with trastuzumab in vitro. In vivo drug/trastuzumab studies were conducted with HER-2/neu-transfected MCF7 human breast cancer xenografts in athymic mice. Combinations of trastuzumab plus cisplatin, docetaxel, cyclophosphamide, doxorubicin, paclitaxel, methotrexate, etoposide, and vinblastine in vivo resulted in a significant reduction in xenograft volume compared to chemotherapy-alone controls (P < .05). The synergistic interaction of trastuzumab with specific chemotherapeutic agents suggests rational combinations for testing in human clinical trials.


A longitudinal twin study of general cognitive ability over four decades.
In this longitudinal study we examined the stability of general cognitive ability (GCA), as well as heterogeneity and genetic and environmental influences underlying individual differences in change. We investigated GCA from young adulthood through late midlife in 1,288 Vietnam Era Twin Study of Aging participants at ages ∼20, ∼56, and ∼62 years. The correlations among the 3 occasions ranged from .73 to .85, reflecting substantial stability. The heritability was significant on each of the 3 occasions and ranged from .59 to .66. The influence of the shared environment was not significant at any of the ages. The genetic correlations across the 3 occasions ranged from .95 to .99 and did not differ significantly from 1.0. The nonshared environmental correlations ranged from .21 to .47. Latent growth curve analysis was applied to characterize trajectories over the 42-year period. Slope was significantly different from 0 and indicated that there was modest change over time. There was a significant genetic influence on initial level of GCA (h2 = .67), but not change (h2 = .23). Genetic factors primarily contribute to stability, while change reflects the influence of nonshared environmental influences. There was a significant negative correlation between initial level of GCA and change (r = -.31). Latent class growth analysis identified 4 trajectories. In general, the 4 groups followed parallel trajectories and were differentiated mainly by differences in AFQT performance level at the time of military induction. (PsycINFO Database Record


A critical analysis of the current surgical concepts for lower blepharoplasty.
This article discusses the new trends in lower blepharoplasty. Many different techniques have been described for the treatment of lower lid deformities, some favoring the transconjunctival approach that avoids touching the orbicularis oculi muscle, others recommending the muscle cutaneous flap. In some cases, maintenance of the fat is indicated, whereas in others its removal is recommended. To clarify such divergences, the author performed 100 blepharoplasties. The transconjunctival approach was performed with or without skin removal and with or without canthopexy, and the muscle cutaneous flap method was performed with or without fat removal and with or without canthopexy. The patients were followed up and observed for 6 months. The preoperative, intraoperative, and postoperative periods were analyzed. The patient, the surgeon, and a third person evaluated the results. Preoperative and postoperative photographs illustrate this article.


Augmentation of the mandible via a "tent-pole" procedure and implant treatment in a patient with type III osteogenesis imperfecta: clinical and histologic considerations.
The present report describes the oral rehabilitation of a female patient suffering from type III osteogenesis imperfecta. Agenesis of the mandibular anterior teeth and malocclusion caused partly by heavily worn teeth made dental rehabilitation necessary. Before a decision to use implants following a grafting procedure, the osseointegration of microimplants was tested. After 4 and 12 months, bone plugs containing two microimplants were retrieved from the patient. Histologic evaluation showed very sparse/poor osseointegration, and the healing time seemed to be much longer than normal. A decision was made to use the "tent-pole" procedure described by Marx et al, followed by prolonged healing. Surgery was uneventful, and the patient was provided with four implants that were partly covered with bone obtained from the iliac crest. Platelet-rich plasma was used to accelerate bone healing. After 9 months, the implants were uncovered and the prosthetic construction was completed. The implant-supported metal-ceramic restoration was serving well at the 1-year and 3-year follow-ups. Minimal resorption of marginal bone was detected during the first year.


Developmental venous anomaly in the newborn brain.
Cerebral developmental venous anomaly (DVA) is considered a benign anatomical variant of parenchymal venous drainage; it is the most common vascular malformation seen in the adult brain. Despite its assumed congenital origin, little is known about DVA in the neonatal brain. We report here the first cohort study of 14 neonates with DVA. Fourteen infants (seven preterm) with DVA diagnosed neonatally using cranial ultrasound (cUS) and magnetic resonance imaging (MRI) from three tertiary neonatal units over 14 years are reviewed. DVA was first detected on cUS in 6 and on MRI in 8 of the 14 infants. The cUS appearances of DVA showed a focal fairly uniform area of increased echogenicity, often (86 %) adjacent to the lateral ventricle and located in the frontal lobe (58 %). Blood flow in the dilated collector vein detected by Doppler ultrasound (US) varied between cases (venous flow pattern in ten and arterialized in four). The appearance on conventional MRI was similar to findings in adults. Serial imaging showed a fairly constant appearance to the DVAs in some cases while others varied considerably regarding anatomical extent and flow velocity. This case series underlines that a neonatal diagnosis of DVA is possible with carefully performed cUS and MRI and that DVA tends to be an incidental finding with a diverse spectrum of imaging appearances. Serial imaging suggests that some DVAs undergo dynamic changes during the neonatal period and early infancy; this may contribute to why diagnosis is rare at this age.


Effects of intensive lipid-lowering therapy on the coronary arteries of asymptomatic subjects with elevated apolipoprotein B.
Do the benefits of intensive lipid-lowering therapy seen in symptomatic patients extend to high-risk subjects who have never had symptoms? Of 120 men completing the FATS trial, 91 were symptomatic and 29 asymptomatic. All had apolipoprotein B > or = 125 mg/dL, a positive family history, and coronary atherosclerosis. All were counseled in diet and randomized to intensive therapy: colestipol 10 g TID plus either niacin 1 g QID or lovastatin 20 mg BID or to conventional therapy: placebos, or colestipol if low-density lipoprotein cholesterol was elevated. End points included quantitative arteriographic disease change and clinical events over a 2.5-year interval. At baseline, symptomatic and asymptomatic patients had comparable risk profiles, but proximal stenosis severity averaged 36% for symptomatic and 23% for asymptomatic patients (P < .001). Among the 91 symptomatic patients, those in the intensive group experienced definite (> or = 10%S) proximal lesion progression less frequently than conventional (24% of intensive versus 48% of conventional) and definite regression more frequently (36% of intensive versus 15% of conventional) (P = .009). Similarly, among the 29 asymptomatic patients, 19% of intensive versus 38% of conventional had progression and 31% of intensive versus 0% of conventional, regression (P = .04). Ischemia on baseline exercise tolerance testing was associated with significantly greater proximal disease progression among the asymptomatic patients. Clinical cardiovascular events (death, infarction, or revascularization) occurred in 10 of 38 symptomatic patients originally assigned to conventional therapy, compared with 5 of 76 symptomatic patients assigned to intensive (P < .01); no asymptomatic patient had an event. Asymptomatic subjects with this high-risk profile have less coronary disease at baseline than comparable symptomatic patients, and they have an excellent short-term clinical prognosis. However, asymptomatic subjects are indistinguishable from symptomatic patients in terms of their arterial disease progression with conventional therapy and their regression with intensive. These findings may justify an active treatment strategy in such subjects, particularly those with provokable ischemia.


SuperCam Calibration Targets: Design and Development.
SuperCam is a highly integrated remote-sensing instrumental suite for NASA's Mars 2020 mission. It consists of a co-aligned combination of Laser-Induced Breakdown Spectroscopy (LIBS), Time-Resolved Raman and Luminescence (TRR/L), Visible and Infrared Spectroscopy (VISIR), together with sound recording (MIC) and high-magnification imaging techniques (RMI). They provide information on the mineralogy, geochemistry and mineral context around the Perseverance Rover. The calibration of this complex suite is a major challenge. Not only does each technique require its own standards or references, their combination also introduces new requirements to obtain optimal scientific output. Elemental composition, molecular vibrational features, fluorescence, morphology and texture provide a full picture of the sample with spectral information that needs to be co-aligned, correlated, and individually calibrated. The resulting hardware includes different kinds of targets, each one covering different needs of the instrument. Standards for imaging calibration, geological samples for mineral identification and chemometric calculations or spectral references to calibrate and evaluate the health of the instrument, are all included in the SuperCam Calibration Target (SCCT). The system also includes a specifically designed assembly in which the samples are mounted. This hardware allows the targets to survive the harsh environmental conditions of the launch, cruise, landing and operation on Mars during the whole mission. Here we summarize the design, development, integration, verification and functional testing of the SCCT. This work includes some key results obtained to verify the scientific outcome of the SuperCam system.


Current State of Functional MRI in the Presurgical Planning of Brain Tumors.
Surgical resection of brain tumors is challenging because of the delicate balance between maximizing tumor removal and preserving vital brain functions. Functional MRI (fMRI) offers noninvasive preoperative mapping of widely distributed brain areas and is increasingly used in presurgical functional mapping. However, its impact on survival and functional outcomes is still not well-supported by evidence. Task-based fMRI (tb-fMRI) maps blood oxygen level-dependent (BOLD) signal changes during specific tasks, while resting-state fMRI (rs-fMRI) examines spontaneous brain activity. rs-fMRI may be useful for patients who cannot perform tasks, but its reliability is affected by tumor-induced changes, challenges in data processing, and noise. Validation studies comparing fMRI with direct cortical stimulation (DCS) show variable concordance, particularly for cognitive functions such as language; however, concordance for tb-fMRI is generally greater than that for rs-fMRI. Preoperative fMRI, in combination with MRI tractography and intraoperative DCS, may result in improved survival and extent of resection and reduced functional deficits. fMRI has the potential to guide surgical planning and help identify targets for intraoperative mapping, but there is currently limited prospective evidence of its impact on patient outcomes. This review describes the current state of fMRI for preoperative assessment in patients undergoing brain tumor resection. Keywords: MR-Functional Imaging, CNS, Brain/Brain Stem, Anatomy, Oncology, Functional MRI, Functional Anatomy, Task-based, Resting State, Surgical Planning, Brain Tumor © RSNA, 2023.


An ethics curriculum for the pediatric residency program. Confronting barriers to implementation.
The 1997 Residency Review Committee requirements in pediatrics mandate a structured curriculum in medical ethics for all accredited pediatric residency programs. To our knowledge, there are no published models for the development of an ethics curriculum for pediatric residents. Several obstacles may confront those attempting to begin an ethics teaching program. To describe the successful implementation of a structured ethics curriculum for pediatric residents. Our program was designed to overcome the following obstacles: (1) time constraints of faculty and residents, (2) scheduling difficulties and lack of continuity, (3) attitudes of residents toward the material, and (4) inadequate ethics training among faculty. In addition to traditional topics in medical ethics, the curriculum focuses on issues that confront residents primarily during their training, issues that may shape their professional values in important ways. This ethics curriculum has been successfully implemented in our own program and offers solutions to common barriers faced by those seeking to implement an ethics curriculum for pediatric residents. We present the ethics curriculum currently in use at our institution as a tool that may be adopted as it stands or as altered by others as they develop their own program's ethics curriculum. We believe the proposed curriculum directly confronts many of the barriers to successful ethics education of pediatric residents.


Cardiovascular disease risk of dietary stearic acid compared with trans, other saturated, and unsaturated fatty acids: a systematic review.
High stearic acid (STA) soybean oil is a trans-free, oxidatively stable, non-LDL-cholesterol-raising oil that can be used to replace trans fatty acids (TFAs) in solid fat applications. The objective was to assess the cardiovascular health effects of dietary STA compared with those of trans, other saturated, and unsaturated fatty acids. We reviewed epidemiologic and clinical studies that evaluated the relation between STA and cardiovascular disease (CVD) risk factors, including plasma lipids and lipoproteins, hemostatic variables, and inflammatory markers. In comparison with other saturated fatty acids, STA lowered LDL cholesterol, was neutral with respect to HDL cholesterol, and directionally lowered the ratio of total to HDL cholesterol. STA tended to raise LDL cholesterol, lower HDL cholesterol, and increase the ratio of total to HDL cholesterol in comparison with unsaturated fatty acids. In 2 of 4 studies, high-STA diets increased lipoprotein(a) in comparison with diets high in saturated fatty acids. Three studies showed increased plasma fibrinogen when dietary STA exceeded 9% of energy (the current 90th percentile of intake is 3.5%). Replacing industrial TFAs with STA might increase STA intake from 3.0% (current) to approximately 4% of energy and from 4% to 5% of energy at the 90th percentile. One-to-one substitution of STA for TFAs showed a decrease or no effect on LDL cholesterol, an increase or no effect on HDL cholesterol, and a decrease in the ratio of total to HDL cholesterol. TFA intake should be reduced as much as possible because of its adverse effects on lipids and lipoproteins. The replacement of TFA with STA compared with other saturated fatty acids in foods that require solid fats beneficially affects LDL cholesterol, the primary target for CVD risk reduction; unsaturated fats are preferred for liquid fat applications. Research is needed to evaluate the effects of STA on emerging CVD risk markers such as fibrinogen and to understand the responses in different populations.


Genetic recombinational and physical linkage analyses on slash pine.
Slash pine is native to the southeastern USA, but is commercially valuable world-wide as a timber-, fiber- and resin-producing species. Breeding objectives emphasize selection for fusiform rust disease resistance. Identification of markers linked to genetic factors conditioning specificity should expand our knowledge of disease development. Towards this end, random amplified polymorphic DNA (RAPD) markers were identified and mapped in a tree hypothesized to be homozygous dominant for resistance at one locus and homozygous recessive at another. Because the DNA prepared for analysis was from haploid maternally-inherited, megagametophyte tissue of seeds, RAPD markers were observed as either present or absent. The analysis revealed 13 linkage groups of three or more loci, ranging in size from 28 to 68 cM, and nine linked pairs. The 22 groups and pairs included 73 RAPD markers and covered a genetic map distance of approximately 782 cM. Genome size estimates, based on linkage data, range from 2,880 to 3,360 cM, and equal 6.0-6.9 x 10(6) bp/cM (physical size > 20,000 Mbp). Using a 30 cM map scale and including unlinked markers, ends of linkage groups, and linked pairs, the RAPD markers account for approximately 2,160 cM or 64-75% of the genome. Mapping 80 additional RAPD markers placed 131 loci total in 20 linkage groups of three or more loci, nearly doubling the coverage in the groups to a genetic map distance of approximately 1,347 cM. Two other slash pine trees also have been RAPD mapped. DNA-DNA in situ hybridization and cytochemical staining are being used to integrate the genetic recombinational maps. A karyotype and ideogram have been prepared for slash pine (2n = 2x = 24); metaphase chromosome preparations show 11 pairs of long metacentric chromosomes and one shorter pair of submetacentric chromosomes. Patterns of fluorescence in situ hybridization to genes for the large and small rRNA subunits and fluorochrome banding patterns using the GC-base-specific chromomycin A3 (CMA) and AT-base-specific 4',6-diamidino-2-phenylindole (DAPI) allowed all twelve pairs of chromosomes to be identified and a standard karyotype established. A family of sequences associated with (TTTAGGG)n related repeats has been identified in slash pine using a labeled synthetic oligonucleotide probe. Fluorescence in situ hybridization shows a weak signal at telomeres and significantly stronger intensity at non-telomeric sites. The most common non-telomeric location was in the pericentric regions of chromosomes; interstitial sites of hybridization were relatively common. Microsatellite DNAs, an abundant retrotransposon-like element, and total genomic in situ hybridization and species and chromosome specific DNAs are being evaluated for analyses of interspecific hybrids and chromosome evolution between related species. Interest in low and single copy sequences is increasing.


Genome structure of Abelson murine leukemia virus variants: proviruses in fibroblasts and lymphoid cells.
We have prepared full-length DNA clones of the Abelson murine leukemia virus (A-MuLV) genome. A specific probe homologous to the central portion of the A-MuLV genome was prepared by nick translation of a subcloned restriction fraction from the cloned DNA. The probe was used to examine the genome structure of several A-MuLV variants. The conclusions are: (i) three viruses coding for Abelson-specific proteins of molecular weight 120,000, 100,000, and 90,000 had genomes indistinguishable in size, suggesting that the shorter proteins are the result of early translational termination; (ii) compared with the genome encoding the 120,000-dalton (120K) protein, a genome coding for a 160K protein was 0.8 kilobase larger in the A-MuLV-specific region; and (iii) a genome coding for a 92K protein had a 700-base pair deletion internal to the coding region. This mutant was transformation defective: its 92K protein lacked the protein kinase activity normally associated with the A-MuLV protein, and cells containing the virus were not morphologically transformed. In addition, we determined the number of A-MuLV proviruses in each of several transformed fibroblast and lymphoid cells prepared by infection in vitro. These experiments show that a single copy of the A-MuLV provirus is sufficient to transform both types of cells and that nonproducer cells generally have only one integrated provirus.


Testing the reproducibility of multiple displacement amplification on genomes of clonal endosymbiont populations.
The multiple displacement amplification method has revolutionized genomic studies of uncultured bacteria, where the extraction of pure DNA in sufficient quantity for next-generation sequencing is challenging. However, the method is problematic in that it amplifies the target DNA unevenly, induces the formation of chimeric reads and also amplifies contaminating DNA. Here, we have tested the reproducibility of the multiple displacement amplification method using serial dilutions of extracted genomic DNA and intact cells from the cultured endosymbiont Bartonella australis. The amplified DNA was sequenced with the Illumina sequencing technology, and the results were compared to sequence data obtained from unamplified DNA in this study as well as from a previously published genome project. We show that artifacts such as the extent of the amplification bias, the percentage of chimeric reads and the relative fraction of contaminating DNA increase dramatically for the smallest amounts of template DNA. The pattern of read coverage was reproducibly obtained for samples with higher amounts of template DNA, suggesting that the bias is non-random and genome-specific. A re-analysis of previously published sequence data obtained after amplification from clonal endosymbiont populations confirmed these predictions. We conclude that many of the artifacts associated with the use of the multiple displacement amplification method can be alleviated or much reduced by using multiple cells as the template for the amplification. These findings should be particularly useful for researchers studying the genomes of endosymbionts and other uncultured bacteria, for which a small clonal population of cells can be isolated.


Stem cells for retinal degenerative disorders.
Many systemic and eye-specific genetic disorders are accompanied by retinal degenerations that lead to blindness. In some of these diseases retinal degeneration occurs early in life and is quite rapid, whereas in other disorders, retinal degeneration starts later and progresses very slowly. At present, no therapies are available to patients for preventing or reversing the retinal degeneration that occurs in these diseases. Implantation of neural progenitor cells into the eye may be a means by which to retard or even reverse degeneration of the retina. To evaluate the potential of neural precursor cell implantation for treating retinal degenerative disorders, neuralized mouse embryonic stem cells from green fluorescent protein (GFP) transgenic mice were administered intravitreally to normal mice, mice with early retinal degeneration, and mice with slowly progressing retinal degeneration. In normal mice, the donor cells remained in the vitreous cavity and did not associate with the host retina. In mice with early retinal degeneration, implantation of the neural precursors was performed after the degeneration was almost complete. In these animals, the donor cells primarily associated closely with the inner surface of the retina, although a small fraction of donor cells did integrate into the host retina. Donor cells implanted in mice with slowly progressing retinal degeneration also associated with the inner retinal surface, but many more of the cells integrated into the retina. These findings indicate the importance of host tissue-donor cell interactions in determining the fate of implanted neural precursor cells. These interactions will be a major consideration when devising strategies for using cell implantation therapies for neurodegenerative disorders.


Combination therapy of levetiracetam and gabapentin against nonconvulsive seizures induced by penetrating traumatic brain injury.
Posttraumatic seizures are a medical problem affecting patients with traumatic brain injury. Yet effective treatment is lacking owing to the limitations of antiepileptic drugs (AEDs) applicable to these patients. In this study, we evaluated the dose-response efficacy of levetiracetam (12.5-100.0 mg/kg) and gabapentin (1.25-25.0 mg/kg) administered either individually or in pairs at fixed-dose ratios as a combination in mitigating posttraumatic nonconvulsive seizures induced by severe penetrating ballistic-like brain injury (PBBI) in rats. Seizures were detected by continuous electroencephalogram (EEG) monitoring for 72 hours postinjury. Animals were treated twice per day for 3 days by intravenous injections. Both levetiracetam (25-100 mg/kg) and gabapentin (6.25-25 mg/kg) significantly reduced PBBI-induced seizure frequency by 44% to 73% and 61% to 69%, and seizure duration by 45% to 64% and 70% to 78%, respectively. However, the two drugs manifested different dose-response profiles. Levetiracetam attenuated seizure activity in a dose-dependent fashion, whereas the beneficial effects of gabapentin plateaued across the three highest doses tested. Combined administration of levetiracetam and gabapentin mirrored the more classic dose-response profile of levetiracetam monotherapy. However, no additional benefit was derived from the addition of gabapentin. Furthermore, isobolographic analysis of the combination dose-response profile of levetiracetam and gabapentin failed to reach the expected level of additivity, suggesting an unlikelihood of favorable interactions between these two drugs against spontaneously occurring posttraumatic seizure activities at the particular set of dose ratios tested. This study was the first attempt to apply isobolographic approach to studying AED combination therapy in the context of spontaneously occurring posttraumatic seizures. Despite the failure to achieve additivity from levetiracetam and gabapentin combination, it is important to recognize the objectivity of the isobolographic approach in the evaluation of AED combination therapy against seizures directly associated with brain injuries.


Phasic mechanoreceptor stimuli can induce phasic activation of upper airway muscles in humans.
1. Upper airway dilator muscles are phasically activated throughout breathing by respiratory pattern generator neurons. Studies have shown that non-physiological upper airway mechanoreceptive stimuli (e.g. rapidly imposed pulses of negative pressure) also activate these muscles. Such reflexes may become activated during conditions that alter airway resistance in order to stabilise airway patency. 2. To determine the contribution of ongoing mechanoreceptive reflexes to phasic activity of airway dilators, we assessed genioglossal electromyogram (GG EMG: rectified with moving time average of 100 ms) during slow (physiological) oscillations in negative pressure generated spontaneously and passively (negative pressure ventilator). 3. Nineteen healthy adults were studied while awake, during passive mechanical ventilation across normal physiological ranges of breathing rates (13-19 breaths min-1) and volumes (0.5-1.0 l) and during spontaneous breathing across the physiological range of end-tidal carbon dioxide (PET,CO2; 32-45 mmHg). 4. Within-breath phasic changes in airway mechanoreceptor stimuli (negative pressure or flow) were highly correlated with within-breath phasic genioglossal activation, probably representing a robust mechanoreceptive reflex. These reflex relationships were largely unchanged by alterations in central drive to respiratory pump muscles or the rate of mechanical ventilation within the ranges studied. A multivariate model revealed that tonic GG EMG, PET,CO2 and breath duration provided no significant independent information in the prediction of inspiratory peak GG EMG beyond that provided by epiglottic pressure, which alone explained 93 % of the variation in peak GG EMG across all conditions. The overall relationship was: Peak GG EMG = 79.7 - (11.3 X Peak epiglottic pressure), where GG EMG is measured as percentage of baseline, and epiglottic pressure is in cmH2O. 5. These data provide strong evidence that upper airway dilator muscles can be activated throughout inspiration via ongoing mechanoreceptor reflexes. Such a feedback mechanism is likely to be active on a within-breath basis to protect upper airway patency in awake humans. This mechanism could mediate the increased genioglossal activity observed in patients with obstructive sleep apnoea (i.e. reflex compensation for an anatomically smaller airway).


Evaluation of a possible role of Stigmatella aurantiaca ACE in Aβ peptide degradation: a molecular modeling approach.
Amyloid-β (Aβ)-degrading enzymes are known to degrade Aβ peptides, a causative agent of Alzheimer's disease. These enzymes are responsible for maintaining Aβ concentration. However, loss of such enzymes or their Aβ-degrading activity because of certain genetic as well as nongenetic reasons initiates the accumulation of Aβ peptides in the human brain. Considering the limitations of the human enzymes in clearing Aβ peptide, the search for microbial enzymes that could cleave Aβ is necessary. Hence, we built a three-dimensional model of angiotensin-converting enzyme (ACE) from Stigmatella aurantiaca using homology modeling technique. Molecular docking and molecular dynamics simulation techniques were used to outline the possible cleavage mechanism of Aβ peptide. These findings suggest that catalytic residue Glu 434 of the model could play a crucial role to degrade Aβ peptide between Asp 7 and Ser 8. Thus, ACE from S. aurantiaca might cleave Aβ peptides similar to human ACE and could be used to design new therapeutic strategies against Alzheimer's disease.


Accumulation of perfluoroalkyl compounds in tibetan mountain snow: temporal patterns from 1980 to 2010.
The use of snow and ice cores as recorders of environmental contamination is particularly relevant for per- and polyfluoroalky substances (PFASs) given their production history, differing source regions and varied mechanisms driving their global distribution. In a unique study perfluoroalkyl acids (PFAAs) were analyzed in dated snow-cores obtained from high mountain glaciers on the Tibetan Plateau (TP). One snow core was obtained from the Mt Muztagata glacier (accumulation period of 1980-1999), located in western Tibet and a second core from Mt. Zuoqiupo (accumulation period: 1996-2007) located in southeastern Tibet, with fresh surface snow collected near Lake Namco in 2010 (southern Tibet). The higher concentrations of ∑PFAAs were observed in the older Mt Muztagata core and dominated by perfluorooctanesulfonic acid (PFOS) (61.4-346 pg/L) and perfluorooctanoic acid (PFOA) (40.8-243 pg/L), whereas in the Mt Zuoqiupu core the concentrations were lower (e.g., PFOA: 37.8-183 pg/L) with PFOS below detection limits. These differences in PFAA concentrations and composition profile likely reflect the upwind sources affecting the respective sites (e.g., European/central Asian sources for Mt Muztagata and India sources for Mt Zuoqiupu). Perfluorobutanoic acid (PFBA) dominated the recent surface snowpack of Lake Namco which is mainly associated with India sources where the shorter chain volatile PFASs precursors predominate. The use of snow cores in different parts of Tibet provides useful recorders to examine the influence of different PFASs source regions and reflect changing PFAS production/use in the Northern Hemisphere.


High-dose intra-arterial nicardipine results in hypotension following vasospasm treatment in subarachnoid hemorrhage.
Intra-arterial (IA) nicardipine is often used to treat cerebral vasospasm associated with subarachnoid hemorrhage (SAH). While hypotension has been noted to be a dose-limiting side effect of intravenous infusions, this has seldom been reported for IA administration. We reviewed a consecutive series of patients who received IA nicardipine for SAH-associated vasospasm. Nicardipine was titrated to angiographic response, with blood pressure and intracranial pressure monitoring. We analyzed data using Wilcoxon signed rank, Student's t-test, Spearman's correlation, and χ(2) statistics as appropriate. A P value <0.05 was considered significant. Thirty patients underwent 50 procedures in which nicardipine was the sole chemical vasodilator (median dose, 15 mg). Median mean arterial pressures (MAP) decreased from 118 to 100 mmHg (P < 0.001), with an intra-operative low of 80 mmHg. Both intra-operative and post-operative decreases in MAP were directly related to nicardipine dose (r (s) = 0.352, P = 0.022 and r (s) = 0.308, P = 0.047, respectively). Hypotension (MAP < 70 mmHg) occurred in 22%, and 44% required initiation of or increases in vasopressor therapy. After the first treatment, 11 of 16 patients treated with vasodilator therapy alone, and 5 of 14 patients who underwent additional balloon angioplasty (68.8 vs. 35.7%, P = 0.141), required further endovascular treatments due to recurrent vasospasm on subsequent days. Intra-arterial nicardipine is associated with significant intra-operative blood pressure lowering, an increased requirement for intra-operative vasopressor therapy, and a tendency toward re-treatment when used as initial monotherapy for vasospasm.


Monotony of surprise and large-scale quest for unusual words.
The problem of characterizing and detecting recurrent sequence patterns such as substrings or motifs and related associations or rules is variously pursued in order to compress data, unveil structure, infer succinct descriptions, extract and classify features, etc. In molecular biology, exceptionally frequent or rare words in bio-sequences have been implicated in various facets of biological function and structure. The discovery, particularly on a massive scale, of such patterns poses interesting methodological and algorithmic problems and often exposes scenarios in which tables and synopses grow faster and bigger than the raw sequences they are meant to encapsulate. In previous study, the ability to succinctly compute, store, and display unusual substrings has been linked to a subtle interplay between the combinatorics of the subword of a word and local monotonicities of some scores used to measure the departure from expectation. In this paper, we carry out an extensive analysis of such monotonicities for a broader variety of scores. This supports the construction of data structures and algorithms capable of performing global detection of unusual substrings in time and space linear in the subject sequences, under various probabilistic models.


Cholecystokinin activates area postrema neurons in rat brain slices.
Peripheral cholecystokinin (CCK) reduces food intake and triggers the secretion of both oxytocin and corticotropin-releasing hormone. These responses are partially initiated by activation of receptors in the peripheral endings of the vagus nerve. However, in vivo studies showing that after vagotomy systemic CCK induces fos activation of neurons in the area postrema (AP) suggest that circulating CCK may directly influence the activity of neurons in this structure. The present study was therefore designed to investigate the responsiveness of AP neurons to CCK using in vitro extracellular single-unit recording techniques. Bath application of 100 nM CCK for 200 s resulted in excitatory responses in 41% and inhibitory effects in 6% of 143 AP neurons tested. Application of multiple doses of CCK (1-100 nM) to single neurons demonstrated that CCK effects were dose dependent. The firing rate of tested neurons increased by 48 +/- 15% in response to 1 nM, by 89 +/- 22% in response to 10 nM, and by 242 +/- 77% in response to 100 nM CCK. After we blockaded synaptic transmission with a low-Ca2+/high-Mg2+ artificial cerebrospinal fluid, the excitatory effects of CCK remained in all nine neurons tested. The CCK-receptor antagonist L-364,718 had no significant effect on the responses to CCK (P > 0.1, n = 4), whereas, after perfusion of slices with the CCKB-receptor antagonist L-365,260, mean responses to CCK were significantly reduced to 12.6 +/- 4.7% of the control value (P < 0.001, n = 4). These results demonstrate a direct and dose-dependent excitatory action of CCK on AP neurons that is abolished by CCKB-receptor antagonists. These data emphasize the potential role of AP in processing afferent information derived from circulating peptide concentrations that could be involved in the regulation of food intake.


The appropriateness of treating psychopathic disorders.
The received wisdom is that there is no known effective treatment for psychopathic disorders. Although outcome studies have not identified an effective programmatic treatment for psychopathic disorders, such studies tend to leave the question open. If behavioral science has not established that psychopathic disorders respond to a particular programmatic approach, neither are psychopathic disorders convincingly proven to be absolutely resistant to treatment. If no treatment is known to be effective in psychopathic disorders, then any treatment seems to squander resources. What is often missing from the discussion is effective therapeutic measures to treat other behaviors that often co-occur, if they do not represent a domain of pathology of psychopathic disorders, such as impulsive aggression. After a brief summary of results of programmatic treatment of psychopathic offenders, this review focuses on the pharmacotherapy of impulsive aggression in psychopathic disorders. If the impulsive aggression that occurs with psychopathic disorders can be better controlled, treatment can have substantial benefits and would be most appropriate.


The Domestic Violence Fatality Review: Can It Mobilize Community-Level Change?
Domestic Violence Fatality Review (DVFR) teams are a means of identifying systems' gaps in the coordinated response to domestic violence. While the number of homicide reviews has grown, little is known about whether DVFRs facilitate change in the community-level response to domestic violence. This research evaluated whether the recommendations made by one state-level DVFR had an effect on community and organizational priorities and practices. The results indicate that the recommendations influence countywide priorities, but less was done to implement the recommendations. DVFRs have the capacity to influence community-level change agendas; however, organizations need support moving from issue prioritization to implementation.


The first triple gene block protein of peanut clump virus localizes to the plasmodesmata during virus infection.
The subcellular localization of the first triple gene block protein (TGBp1) of peanut clump pecluvirus (PCV) was studied by subcellular fractionation and immunogold cytochemistry using TGBp1-specific antibodies raised against a fusion protein expressed in and purified from bacteria. In the inoculated and apical leaves of virus-infected Nicotiana benthamiana, TGBp1 localized to the cell wall and P30 fractions. Electron microscopy of immunogold-decorated ultrathin sections of the infected leaf tissue revealed TGBp1-specific labeling of the plasmodesmata joining mesophyll cells. In longitudinal sections of the plasmodesmata, the TGBp1-specific labeling was most commonly associated with the plasmodesmal collar region. In transgenic N. benthamiana, which constitutively expressed TGBp1, no TGBp1-specific immunogold labeling of plasmodesmata was observed, but plasmodesmata were gold decorated when the transgenic plants were infected with a TGBp1-defective PCV mutant, indicating that factors induced by the virus infection target and/or anchor the transgene TGBp1 to the plasmodesmata.


Adjuvant therapies in venous leg ulcer management: A scoping review.
Compression therapy is the current evidence-based approach to manage venous leg ulcers (VLU); however, adherence is a major barrier to successful treatment. Combination approaches may relieve the burden of treatment by shortening the time to ulcer healing. This scoping review conducted by Australian researchers aimed to establish the evidence of effectiveness of various adjuvant methods on wound healing and recurrence. Randomized Controlled Trials (RCTs), and Systematic Reviews (SR) and Meta-Analyses (MA) on VLU management approaches published from January 2015 to December 2018 were included in this review. The articles included in the scoping review were grouped according to the management approaches, including (1) pharmaceutical interventions, (2) surgical interventions, (3) topical agents, (4) the use of devices, and (5) other, such as physiotherapy and psychological interventions. Results of this scoping review indicate that there is a limited high-quality evidence of effectiveness in most adjuvant therapies on wound healing and recurrence. Given the low-quality evidence observed in this scoping review for adjuvant treatments, the implication for practice is that current management guidelines be followed. Further rigorous studies have the potential to produce better quality evidence. Quality of evidence can be improved by ensuring large sample sizes of a single etiology wounds, standardizing reporting outcomes, and maintaining detailed and evidence-based protocols in physiological or psychological interventions.


Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas.
We conducted a randomized trial to evaluate primarily the cardioprotective effect of dexrazoxane (DEX) in patients with advanced breast cancer and soft tissue sarcomas (STS) treated with high-dose epirubicin (EPI). We wished also to determine the value of radioimmunoscintigraphy (RIS) in the assessment of anthracycline cardiotoxicity. Patients with breast cancer (n = 95) or STS (n = 34) received EPI 160 mg/m2 by intravenous (I.V.) bolus every 3 weeks with or without DEX 1,000 mg/m2 I.V. Cardiac monitoring included multigated radionuclide (MUGA) scans with determination of resting left ventricular ejection fraction (LVEF), and RIS with indium 111 antimyosin monoclonal antibodies. In either disease, antitumor response rates, time to progression, and survival did not significantly differ between the two arms. There was little difference in noncardiac toxicity for the two treatment groups. All methods of cardiac evaluation clearly documented the cardioprotective effect of DEX. Four patients developed congestive heart failure (CHF), all in the EPI arm. The decrease in LVEF from baseline was significantly greater in the control group. An abnormal antimyosin uptake was observed early in both arms and progressively increased during treatment. However, this increase was significantly higher in the EPI group (P = .004). DEX significantly protects against the development of cardiotoxicity when high single doses of EPI are used. Apparently, there was no evidence of an adverse impact of DEX on antitumor activity. Although RIS is a sensitive technique in detecting anthracycline cardiac damage, its specificity is low and it cannot be considered a primary test for guiding anthracycline treatment.


Inferring Adaptive Introgression Using Hidden Markov Models.
Adaptive introgression-the flow of adaptive genetic variation between species or populations-has attracted significant interest in recent years and it has been implicated in a number of cases of adaptation, from pesticide resistance and immunity, to local adaptation. Despite this, methods for identification of adaptive introgression from population genomic data are lacking. Here, we present Ancestry_HMM-S, a hidden Markov model-based method for identifying genes undergoing adaptive introgression and quantifying the strength of selection acting on them. Through extensive validation, we show that this method performs well on moderately sized data sets for realistic population and selection parameters. We apply Ancestry_HMM-S to a data set of an admixed Drosophila melanogaster population from South Africa and we identify 17 loci which show signatures of adaptive introgression, four of which have previously been shown to confer resistance to insecticides. Ancestry_HMM-S provides a powerful method for inferring adaptive introgression in data sets that are typically collected when studying admixed populations. This method will enable powerful insights into the genetic consequences of admixture across diverse populations. Ancestry_HMM-S can be downloaded from https://github.com/jesvedberg/Ancestry_HMM-S/.


Adrenal Suppression in Children During the Treatment for Acute Lymphoblastic Leukemia Beyond Induction.
Adrenal suppression (AS) is an iatrogenic, life-threatening condition that can occur after glucocorticoid exposure. Despite recognition that AS occurs after induction phase treatment in children with acute lymphoblastic leukemia (ALL), the risk of AS in phases beyond induction is unknown. We conducted a pilot study in pediatric patients with ALL to ascertain whether the risk of AS persists in post-induction phases of treatment. Patients diagnosed between 12 months to younger than 18 years with B or T-ALL and starting any new phase of treatment were eligible for the study. Relapsed or infant ALL were excluded. Low dose ACTH stimulation testing (LDST), measurement of albumin and cortisol binding globulin were performed in all patients. Screening for symptoms of AS was done. Twenty-four patients enrolled in the study. One was diagnosed with clear AS. Five others had a borderline cortisol peak, representing possible mild AS. Symptoms were nonspecific and did not help distinguish patients with normal LDST from those with borderline or abnormal results. Patients on treatment for ALL continue to be at risk of AS beyond induction treatment. Although this risk appears small, physicians must be vigilant as patients may be asymptomatic but could develop adrenal crisis during treatment.


Determination of selected endocrine disrupting chemicals in Lake Van, Turkey.
In the present study, we investigated the distribution of 17β-estradiol (E2), 17α-ethynylestradiol (EE2), alkylphenol ethoxylates (APEs) and organochlorine pesticides (DDE/DDT) in water and sediment samples in the Eastern Anatolia of Turkey, Lake Van, which is the largest soda lake in the world. The procedure consisted of solid phase extraction performed with OASIS HLB cartridges followed by non-competitive enzyme-linked immunosorbent assays (ELISA). The endocrine disrupting compounds E2, EE2, and DDT/DDE were detected in most of the lake samples with mean concentrations of 0.996 ± 0.304, 0.050 ± 0.022, and 0.749 ± 0.658 ng/L in water, respectively. Mean concentrations of E2, EE2 and DDT/DDE in sediment were 0.098 ± 0.053, 0.091 ± 0.072, and 1.281 ± 0.754 ng/g, respectively. APEs were not measured in the sediment samples. The EDCs levels in surface water and sediment samples were lower than that of other countries. The EDCs were also found in effluent and influent municipal sewage samples. Van city municipal wastewater treatment plant has no removal efficiency for EDCs.


When is it safe to return to driving following first-ever seizure?
The risk of recurrence following a first-ever seizure is 40-50%, warranting driving restriction during the early period of highest risk. This restriction must be balanced against the occupational, educational and social limitations that result from patients being ineligible to drive. The recommended duration of non-driving after a first seizure varies widely between jurisdictions, influenced by various factors including the community perception of an acceptable relative level of risk for an accident (the accident risk ratio; ARR). Driving restrictions may be based on individualised risk assessments or across-the-board guidelines, but these approaches both require accurate data on the risk of seizure recurrence. 1386 patients with first-ever seizure were prospectively analysed. Seizure recurrence was evaluated using survival analysis. The duration of non-driving required for a range of risks of seizure recurrence and ARRs was calculated. Additionally, the actual occurrence of seizures while driving was prospectively determined during follow-up. For a risk of seizure recurrence to fall to 2.5% per month, corresponding to a monthly risk of a seizure while driving of 1.04 per thousand and an ARR of 2.6, non-driving periods of 8 months are required for unprovoked first-ever seizure, and 5 months for provoked first-ever seizure. Of patients with a seizure recurrence, 14 (2%) occurred while driving, with the monthly risk falling to less than 1/1000 after 6 months. Our data provide a quantitative approach to decisions regarding a return to driving in patients with first-ever provoked or unprovoked seizure.