Leptin functions peripherally to regulate differentiation of mesenchymal progenitor cells.
Leptin functions through a well-documented central neuroendocrine pathway to regulate bone mass. However, the ability of leptin to modulate bone mass through a peripheral mechanism has been debated due to conflicting in vitro results and lack of sufficient in vivo models. We utilized mice with LoxP sites introduced into the long-form leptin receptor (ObRb) gene to determine how leptin regulates mesenchymal progenitor cell (MPC) differentiation and osteoblast function in vitro and in vivo. Rapid phosphorylation of Stat3 after leptin treatment of bone marrow stromal cells (BMSCs) from mice with conditional deletion of ObRb in macrophages (LysM(Cre+F/F)) confirmed expression of functional leptin receptors by BMSCs. Adenovirus-Cre mediated disruption of ObRb in primary stromal cells decreased mineralization and increased adipogenesis. In contrast, BMSCs harvested from leptin-signaling deficient Ob/Ob or Db/Db mice showed increased mineralization. To determine the physiologic relevance of these differences, mice with cell-specific deletion of ObRb in mesenchymal precursors (3.6(Cre+F/F)) or osteoblasts (2.3(Cre+F/F)) were generated. Although the 2.3(Cre+F/F) mice were grossly normal, the 3.6(Cre+F/F) mice displayed mild obesity that was not attributed to food intake. Femurs of 3.6(Cre+F/F) animals showed a 58%-61.9% increase in trabecular bone volume and a 65.5%-74% increase in bone mineral density. Cortical volume and mineral content were also increased 18%-22%. Primary 3.6(Cre+F/F) BMSCs recapitulated the high mineralization phenotype of Ob/Ob and Db/Db BMSCs. We conclude that leptin may have multiple peripheral roles depending on the differentiation state of MPC. Leptin (a) helps maintain MPCs in an undifferentiated state and (b) promotes mineralization of more differentiated osteoblasts.


A rat model for choroidal neovascularization using subretinal lipid hydroperoxide injection.
The purpose of this study was to develop and characterize a rat model of choroidal neovascularization (CNV) as occurs in age-related macular degeneration. The lipid hydroperoxide 13(S)-hydroperoxy-9Z,11E-octadecadienoic acid (HpODE) is found in submacular Bruch's membrane in aged humans and has been reported to generate neovascularization in a rabbit model. Three weeks after a single subretinal injection of 30 microg of HpODE, eyes of Sprague-Dawley rats were harvested. Follow-up fluorescein angiography was done on other animals until 5 weeks postinjection. Histological studies, immunohistochemical staining, and flatmount choroids for CNV measurements were performed. In addition, we used murine neuronal, bovine endothelial, and human ARPE19 cells for testing the in vitro effects of HpODE. CNV developed in 85.7% of HpODE-injected eyes. The neovascular areas were significantly greater in HpODE-injected eyes compared with those in control eyes (P = 0.023). The CNV had maximum dye leakage at 3 weeks, which subsided by the 5th week. Histologically, CNV extended from the choriocapillaris into the subretinal space. ED1-positive macrophages were recruited to the site. In vitro assays demonstrated that only 30 ng/ml HpODE induced cell proliferation and migration of endothelial cells. HpODE-induced CNV was highly reproducible, and its natural course seems to be ideal for evaluating therapeutic modalities. Because HpODE has been isolated from aged humans, the HpODE-induced rat model seems to be a relevant experimental model for CNV in age-related macular degeneration.


Government chief nursing officers' perceptions of barriers to using research on staffing.
Current global healthcare problems include nursing shortages contributing to low nurse staffing. Low nurse staffing is associated with poor patient and nurse outcomes, but research utilization using these findings especially at the policy level remains slow. To assess high-ranking government nurses' perceptions of barriers to using research on nurse staffing. An electronic information message about the impact of nurse staffing was presented to government chief nursing officers (CNOs) from 110 countries. The CNOs' perceptions of local barriers to utilizing these research findings were then assessed in an electronic survey. The four factors that influence the first two stages of Rogers's five-stage model of diffusion were examined. The factors, characteristics of the adopter, organization, innovation and communication, were measured using an adapted version of the BARRIERS scale. Barriers were present in all four characteristics. The top barrier was lack of reports and studies in one place. Other barriers were lack of cooperation within the organization and lack of awareness of the research findings. Differences according to Gross National Income were also noted. The CNOs and other health policy advisors can use the findings in planning for adequate nurse staffing. Development of electronic newsletters with summaries of pertinent research for CNOs and other policy advisors is needed. Future studies on nurse staffing are warranted. They should focus on other settings and how best to share research findings with policymakers.


An efficient surface modification using 2-methacryloyloxyethyl phosphorylcholine to control cell attachment via photochemical reaction in a microchannel.
This report describes a direct approach for cell micropatterning in a closed glass microchannel. To control the cell adhesiveness inside the microchannel, the application of an external stimulus such as ultraviolet (UV) was indispensible. This technique focused on the use of a modified 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer, which is known to be a non-biofouling compound that is a photocleavable linker (PL), to localize cells via connection to an amino-terminated silanized surface. Using UV light illumination, the MPC polymer was selectively eliminated by photochemical reaction that controlled the cell attachment inside the microchannel. For suitable cell micropatterning in a microchannel, the optimal UV illumination time and concentration for cell suspension were investigated. After selective removal of the MPC polymer through the photomask, MC-3T3 E1 cells and vascular endothelial cells (ECs) were localized only to the UV-exposed area. In addition, the stability of patterned ECs was also confirmed by culturing for 2 weeks in a microchannel under flow conditions. Furthermore, we employed two different types of cells inside the same microchannel through multiple removal of the MPC polymer. ECs and Piccells were localized in both the upper and down streams of the microchannel, respectively. When the ECs were stimulated by adenosine triphosphate (ATP), NO was secreted from the ECs and could be detected by fluorescence resonance energy transfer (FRET) in Piccells, which is a cell-based NO indicator. This technique can be a powerful tool for analyzing cell interaction research.


Acute heat-treatment disrupts inhibin-related protein production and gene expression in the adult rat testis.
Heat reversibly disrupts spermatogenesis, but the effects on Sertoli cell (SC) function and inhibin/activin-related proteins are less well-defined. Adult rat testis weights decreased by 40% within 2 weeks after heat-treatment (43 °C, 15 min), due to loss of pachytene spermatocytes and round spermatids. Coincident effects were reduced SC nuclear volume at one week and >50% reduction in expression of several critical SC genes (Inha, Cld11, Gja1, Tjp1, Cldn3) by 2 weeks. Leydig cell steroidogenic enzymes, Cyp11a1, Hsd3b1, were also reduced. Activin gene expression was unaffected at this time, but expression of the activin-binding protein, follistatin (Fst), increased >2-fold. At 4-8 weeks, coincident with the recovery of spermatocytes and early spermatids, but progressive loss of elongated spermatids, most SC genes had recovered; however, testicular activin A was reduced and activin B increased. At 8 weeks, serum inhibin was decreased and, consequently, serum FSH increased. Crucially, germ cell damage was not associated with a significant inflammatory response. At 14 weeks, most testicular parameters had returned to normal, but testis weights remained slightly reduced. These data indicate that, following acute heat-treatment, expression of several key Sertoli and Leydig cell genes declined in parallel with the initial loss of meiotic germ cells, whereas activins were responsive to the subsequent loss of mature spermatids, leading to an increase in testicular activin B production relative to activin A.


Adjuvant Human Papillomavirus Vaccine to Reduce Recurrent Cervical Dysplasia in Unvaccinated Women: A Systematic Review and Meta-analysis.
To perform a systematic review and meta-analysis evaluating the efficacy of adjuvant human papillomavirus (HPV) vaccination in preventing recurrent cervical intraepithelial neoplasia (CIN) 2 or greater after surgical excision. Electronic databases (Cochrane, PubMed, EMBASE, MEDLINE, Scopus, and ClinicalTrials.gov) were searched for studies comparing surgical excision alone to surgical excision with adjuvant HPV vaccination for CIN 2 or greater. Studies published from January 1990 to January 2019 were included. A total of 5,901 studies were reviewed. The primary outcomes evaluated included: recurrence of CIN 2 or greater, CIN 1 or greater, and HPV 16,18 associated CIN within 6-48 months. We used Covidence software to assist with screening, and meta-analysis was performed using Review Manager. Six studies met inclusion criteria and were included in the final analysis. In total 2,984 women were included; 1,360 (45.6%) received adjuvant HPV vaccination after surgical excision, and 1,624 (54.4%) received either placebo or surgical management alone for CIN 2 or greater. Recurrence of CIN 2 or greater occurred within 6-48 months in 115 women (3.9%) overall; however, recurrence was significantly lower for vaccinated women: 26 of 1,360 women (1.9%) vs 89 of 1,624 unvaccinated women (5.9%) (relative risk [RR] 0.36 95% CI 0.23-0.55). The risk of CIN 1 or greater was also significantly lower with adjuvant HPV vaccination, occurring in 86 of 1,360 vaccinated women (6.3%) vs 157 of 1,624 unvaccinated women (9.7%) (RR 0.67 95% CI 0.52-0.85). Thirty-five women developed recurrent CIN 2 or greater lesions specific to HPV 16,18; nine received adjuvant vaccination (0.9%) vs 26 who were unvaccinated (2.0%) (RR 0.41 95% CI 0.20-0.85). Adjuvant HPV vaccination in the setting of surgical excision for CIN 2 or greater is associated with a reduced risk of recurrent cervical dysplasia overall and a reduction in the risk of recurrent lesions caused by the most oncogenic strains (HPV 16,18). Human papillomavirus vaccination should therefore be considered for adjuvant treatment in patients undergoing surgical excision for CIN 2 or greater. PROSPERO, CRD42019123786.


Interactions of cholecystokinin and glucose in rat pancreatic islets.
The effects of sulfated cholecystokinin (CCK-8S) and glucose on insulin secretion and polyphosphoinositide (PPI) metabolism were studied in isolated rat islets. Both agonists stimulate PPI hydrolysis, inositol phosphate accumulation, 3H efflux from [3H]inositol-prelabeled tissue, and 45Ca efflux from prelabeled cells. However, the effects of CCK-8S on PPI metabolism are considerably greater than those of glucose. Furthermore, the effects of CCK-8S on PPI and Ca2+ metabolism are observed whether islets are incubated in either 2.75 or 7 mM glucose, but CCK-8S only stimulates insulin secretion (a biphasic response) when the higher glucose concentration is present. Addition of 1 microM forskolin to islets incubated in media containing 2.75 mM glucose does not influence basal insulin secretion but sensitizes the islets to the action of CCK-8S. In the presence of forskolin, CCK-8S induces a very marked first phase but no second phase of insulin secretion. We postulate that CCK-8S acts in this tissue via receptor-linked PPI hydrolysis, leading to an inositol trisphosphate-induced Ca2+ efflux. These receptor-mediated effects of CCK-8S are not altered either by the ambient glucose concentration or the cAMP content of the islets, but these two factors determine the responsiveness of the islets (in terms of insulin secretion) to a given CCK-8S signal.


Emotional and Neuropsychiatric Disorders Associated with Alzheimer's Disease.
Alzheimer's disease is associated with impairments in emotional communication including comprehension and production of facial emotional expressions, comprehension of affective prosody, and alexithymia. It is also associated with disorders of emotional experience including mood disorders (depression and anxiety), agitation/aggression, and psychosis. Agitation/aggression and psychosis are particularly disruptive, are associated with earlier institutionalization, and pose a major challenge to institutional management. Treatment of disorders of emotional experience has been primarily pharmacologic (reviewed here in detail) and has relied heavily on antipsychotic medications despite the small effect sizes demonstrated in a large number of randomized controlled trials and the prevalence of serious side effects associated with these drugs. Recent studies suggest that treatment with pimavanserin, an antipsychotic without activity at dopamine receptors, may represent an important advance for treatment of psychotic manifestations, even as the drug appears to pose significant risk. Dextromethorphan/quinidine may represent an important advance in the treatment of agitation/aggression. There is also compelling evidence that sleep disorders, which are common among patients with Alzheimer's disease and are readily treatable, may potentiate psychotic manifestations and agitation/aggression, but further studies are needed.


United States emergency department visits coded for intimate partner violence.
Limited information exists about medical treatment for victims of intimate partner violence (IPV). Our aim was to estimate the number of emergency department (ED) visits and subsequent hospitalizations that were assigned a code specific to IPV and to describe the clinical and sociodemographic features of this population. Data from the Nationwide Emergency Department Sample from 2006-2009 were analyzed. Cases with an external cause of injury code of E967.3 (battering by spouse or partner) were abstracted. From 2006-2009, there were 112,664 visits made to United States EDs with an e-code for battering by a partner or spouse. Most patients were female (93%) with a mean age of 35 years. Patients were significantly more likely to reside in communities with the lowest median income quartile and in the Southern United States. Approximately 5% of visits resulted in hospital admission. The mean charge for treat-and-release visits was $1904.69 and $27,068.00 for hospitalizations. Common diagnoses included superficial injuries and contusions, skull/face fractures, and complications of pregnancy. Females were more likely to experience superficial injuries and contusions, and males were more likely to have open wounds of the head, neck, trunk, and extremities. From 2006 to 2009, there were approximately 28,000 ED visits per year with an e-code specific to IPV. Although a minority, 7% of these visits were made by males, which has not been reported previously. Future prospective research should confirm the unique demographic and geographic features of these visits to guide development of targeted screening and intervention strategies to mitigate IPV and further characterize male IPV visits.


A model of host-microbial interactions in an open mammalian ecosystem.
The maintenance and significance of the complex populations of microbes present in the mammalian intestine are poorly understood. Comparison of conventionally housed and germ-free NMRI mice revealed that production of fucosylated glycoconjugates and an alpha1, 2-fucosyltransferase messenger RNA in the small-intestinal epithelium requires the normal microflora. Colonization of germ-free mice with Bacteroides thetaiotaomicron, a component of this flora, restored the fucosylation program, whereas an isogenic strain carrying a transposon insertion that disrupts its ability to use L-fucose as a carbon source did not. Simplified models such as this should aid the study of open microbial ecosystems.


A survey of the energy metabolism of nodulating symbionts reveals a new form of respiratory complex I.
A limiting factor in agriculture is the availability of nitrogen in the soil, which may be compensated by biological N2 fixation catalysed by bacteria. Most biological N2 fixation occurs in root nodules of plants that respond to bacterial infection by establishing symbiosis with selected prokaryotes. The plants provide energy metabolites and a microoxic environment to the bacterial symbionts to facilitate their capacity of N2 fixation. Despite enormous advances in the molecular genetics of this symbiosis between plants and nodulating bacteria, we still do not understand fundamental aspects which determine the efficiency of N2 fixation in the nodules, and therefore the capacity to biologically enrich agricultural soils. Here we provide an overview of the central features of the energy metabolism that sustains N2 fixation, with emphasis on the bacterial respiratory chain supplying the electrons and ATP required for the nitrogenase reaction. We discuss common trends and specific variations in the integrated process of respiratory electron transport and N2 fixation. Among such variations we introduce green complex I, an ancient version of NADH:ubiquinone oxidoreductase that is present in several Rhizobiaceae and may facilitate N2 fixation.


Penile augmentation with injectable hyaluronic acid gel: an alternative choice for small penis syndrome.
There is no well-established procedure for the management of small penis syndrome (SPS), especially when psychological interventions fail. This study aimed at systematically evaluating the physical and psychological benefits of penile augmentation (PA) using injectable hyaluronic acid (HA) gel. Thirty-eight patients receiving PA with HA gel from January 2017 to March 2020 were included and followed up for 1 year. Penile size, erectile function, and psychological burden measured by the Index of Male Genital Image (IMGI), Index of International Erectile Function (IIEF), and Beliefs about Penis Size (BPAS), respectively, were assessed at the beginning and at 1, 3, 6, and 12 months postinjection. The volume of HA gel injected was 21.5 ± 3.7 ml. Compared to baseline data, flaccid penile girth and length significantly increased by 3.41 ± 0.95 cm (P < 0.01) and 2.55 ± 0.55 cm (P < 0.01) at the 1st month postinjection, respectively. At the endpoint, despite attenuations, statistically significant improvements in flaccid penis size were still obtained, namely 2.44 ± 1.14 cm in girth (P < 0.01) and 1.65 ± 0.59 cm in length (P < 0.01). Similarly, erectile penile girth statistically increased by 1.32 ± 1.02 cm (P < 0.01) at the 1st month but were only 0.80 ± 0.54 cm bigger than baseline (P < 0.01) at the endpoint. At the 1st month, the average score of IMGI and the mean score of IIEF statistically increased by 46.2 ± 10.5 (P < 0.01) and 7.6 ± 6.2 (P < 0.01), respectively; the score of BAPS significantly decreased by 18.3 ± 4.5 (P < 0.01). These alterations remained steady during follow-up. Considering the significant penile size improvement, lasting psychological benefit, and low complication rate, PA with HA might serve as an appropriate alternative for patients with SPS.


Role of culture conditions and immunization in experimental nutritionally variant streptococcal endocarditis.
The nutritionally variant streptococci (NVS) are usually isolated from patients with NVS endocarditis and recently have been serotyped into three groups. In the past, studies on microbial endocarditis have not analyzed the effect of the growth medium or growth phase on the bacteria used to induce the disease in the experimental rabbit model. Therefore, in this study various bacterial growth parameters were examined, including growth in semisynthetic or complex medium to the exponential or stationary phase of growth. The 50% infective dose ranged from 3.7 X 10(5) to 8.5 X 10(6) CFU for representative strains from each of the three serotypes grown under these conditions, indicating that there was no significant difference. The role of immunization was also examined in this model using organisms grown to the exponential phase in semisynthetic medium. Rabbits were immunized with heat-killed whole cells, high titres of specific antibody were produced as demonstrated by enzyme-linked immunosorbent assay, and then the rabbits were challenged with 20- to 100-fold 50% infective dose of the homologous strain. A total of 90 to 100% of the rabbits were protected from the disease process, as shown by the absence of the organisms from the heart valve 3 days after the challenge. Rabbits immunized with the amphiphile that replaces lipoteichoic acid in these organisms were not protected from challenge, demonstrating that another surface component is responsible for adherence or colonization or both. Finally NVS were incubated with radioiodinated fibronectin, fibrinogen, or laminin to determine whether these molecules aided in the adherence of the organisms to the heart valve. Only minor amounts of these components were bound to NVS as compared with controls. Therefore, NVS bind directly to the damaged heart valve or through an unknown mechanism.


Effects of inhibitors of arachidonic acid metabolism and calcium entry on responses to acetylcholine, potassium and norepinephrine in the isolated canine saphenous vein.
The present study was designed to determine whether interference with the metabolism of arachidonic acid or the entry of extracellular calcium affects the responses of the canine saphenous vein to acetylcholine, potassium or norepinephrine. Rings of canine saphenous vein, with or without endothelium, were suspended in organ chambers filled with physiological salt solution and set at their optimal length for isometric tension recording. Removal of the endothelium, confirmed by the absence of the characteristic relaxation induced by thrombin in intact rings, did not affect concentration-response curves to acetylcholine or norepinephrine. The cyclooxygenase inhibitor, indomethacin, augmented the response to acetylcholine. This effect was comparable in rings with and without endothelium and in rings pretreated with phentolamine. Indomethacin did not alter the response to norepinephrine but augmented that to potassium. Similar results were obtained with the cyclooxygenase inhibitors, acetylsalicylic acid and meclofenamate. The antioxidant and lipoxygenase inhibitor nordihydroguaiaretic acid and the cyclooxygenase/lipoxygenase inhibitor phenidone blocked the ability of indomethacin to augment acetylcholine- and potassium-induced contractions. Arachidonic acid-induced contractions were not blocked by indomethacin but were inhibited by nordihydroguaiaretic acid, phenidone and the calcium entry blockers diltiazem and nimodipine. Diltiazem and nimodipine inhibited responses to potassium and acetylcholine without affecting those to norepinephrine. The augmentation by indomethacin of potassium- and acetylcholine-evoked contractions was inhibited by diltiazem and nimodipine. In rings of femoral artery denuded of endothelium, indomethacin had no effect on the responses to acetylcholine, norepinephrine or potassium. These results suggest that, in the canine saphenous vein but not in the femoral artery, activation of the lipoxygenase pathway for the metabolism of arachidonic acid augments preferentially contractions which depend upon the entry of extracellular calcium.


A technique for enhancing union of allograft to host bone.
The aim of limb-salvage surgery in malignant bone tumours in children is to restore function and eradicate local disease with as little morbidity as possible. Allografts are associated with a high rate of complications, particularly malunion at the allograft-host junction. We describe a simple technique which enhances union of allograft to host bone taking advantage of the discrepancy in size between the adult allograft and the child's bone. This involves lifting a flap of periosteum before resection from the host bone, which is then telescoped into the allograft medullary canal, which may require internal burring or splitting, for a distance of 1.5 to 2 cm and covering the bone junction with the periosteal flap. This is more stable than conventional end-to-end opposition. For each centimetre of telescoping the surface area available for bony union is increased more than three times. The periosteal flap also augments union. Additional surface fixation with a plate and screws is not necessary. We have used this technique in nine children, in eight of whom there was complete union at a mean of 16 weeks. Delayed union, associated with generalised limb osteoporosis, occurred in one. Early mobilisation, with weight-bearing by three weeks, was possible. There was only one fracture of the allograft.


Effect of bifidogenic factors on growth characteristics of bifidobacteria in infant formulas.
A bifidogenic factor, lactulose or fructooligosaccharides, was added (0.5%) into infant formula based on soy or infant formula with hydrolyzed casein. The infant formulas were then inoculated (2.5%) with Bifidobacterium bifidum (ATCC 15696), Bifidobacterium breve (ATCC 15700), Bifidobacterium infantis (ATCC 15697), or Bifidobacterium longum (ATCC 15708) or their mixture (mixed culture) and incubated at 37 degrees C for 24 h. Lactulose did not influence maximal counts or generation times in either formula for any species except B. infantis, which had lower counts. Trends of developed acidity and pH of the mixed culture in the infant formulas with or without lactulose were similar to those for B. breve. Maximal counts and generation times remained unchanged with or without fructooligosaccharides for all species and the mixed culture, except for B. bifidum in the formula based on soy, for which maximal counts did not occur. Growth in either formula was inhibited for B. infantis with lactulose and B. breve with fructooligosaccharides past 8 h of inoculation.


Does bariatric surgery prior to total hip or knee arthroplasty reduce post-operative complications and improve clinical outcomes for obese patients? Systematic review and meta-analysis.
Our aim was to determine whether, based on the current literature, bariatric surgery prior to total hip (THA) or total knee arthroplasty (TKA) reduces the complication rates and improves the outcome following arthroplasty in obese patients. A systematic literature search was undertaken of published and unpublished databases on the 5 November 2015. All papers reporting studies comparing obese patients who had undergone bariatric surgery prior to arthroplasty, or not, were included. Each study was assessed using the Downs and Black appraisal tool. A meta-analysis of risk ratios (RR) and 95% confidence intervals (CI) was performed to determine the incidence of complications including wound infection, deep vein thrombosis (DVT), pulmonary embolism (PE), revision surgery and mortality. From 156 potential studies, five were considered to be eligible for inclusion in the study. A total of 23 348 patients (657 who had undergone bariatric surgery, 22 691 who had not) were analysed. The evidence-base was moderate in quality. There was no statistically significant difference in outcomes such as superficial wound infection (relative risk (RR) 1.88; 95% confidence interval (CI) 0.95 to 0.37), deep wound infection (RR 1.04; 95% CI 0.65 to 1.66), DVT (RR 0.57; 95% CI 0.13 to 2.44), PE (RR 0.51; 95% CI 0.03 to 8.26), revision surgery (RR 1.24; 95% CI 0.75 to 2.05) or mortality (RR 1.25; 95% CI 0.16 to 9.89) between the two groups. For most peri-operative outcomes, bariatric surgery prior to THA or TKA does not significantly reduce the complication rates or improve the clinical outcome. This study questions the previous belief that bariatric surgery prior to arthroplasty may improve the clinical outcomes for patients who are obese or morbidly obese. This finding is based on moderate quality evidence. Cite this article: Bone Joint J 2016;98-B:1160-6.


Pulmonary complications in children with hematologic malignancies: accuracy of diagnosis with chest radiography and CT.
To determine the diagnostic accuracy of chest radiography and computed tomography (CT) in patients with complications during treatment for hematologic malignancies. CT scans were obtained 1 week or less before bronchoscopic sampling or biopsy in 48 pediatric patients (age range, 8 months to 18 years at diagnosis) undergoing treatment for leukemia, lymphoma, or myeloproliferative disease. Radiographs were obtained less than 1 week before CT. Pulmonary complications comprised fungal (n = 11), viral (n = 4), and bacterial (n = 5) pneumonias; cryptogenic organizing pneumonia ([COP] n = 4); and pulmonary tumor (n = 4). Chest radiographs and CT scans were rated independently by three radiologists who were unaware of these diagnoses. Satisfactory diagnostic accuracy, defined by the area under the receiver operating characteristic (ROC) curve, was noted for fungal pneumonia (radiography, ROC area = 0.82; CT, ROC area = 0.78), COP (radiography, ROC area = 0.75; CT, ROC area = 0.75), and pulmonary tumor (radiography, ROC area = 0.73; CT, ROC area = 0.83). Generalizability was good for fungal pneumonia (radiography, generalizability coefficient [GC] = 0.84; CT, GC = 0.84) and COP (radiography, GC = 0.75; CT, GC = 0.99). There was no statistically significant difference in diagnostic accuracy between radiography and CT for any of the diagnoses. Radiography and CT have satisfactory accuracies for fungal pneumonia and COP. For these conditions, CT identified more true-positive cases than did radiography.


Screening of newborn infants for cholestatic hepatobiliary disease with tandem mass spectrometry.
To assess the feasibility of screening for cholestatic hepatobiliary disease and extrahepatic biliary atresia by using tandem mass spectrometry to measure conjugated bile acids in dried blood spots obtained from newborn infants at 7-10 days of age for the Guthrie test. Three tertiary referral clinics and regional neonatal screening laboratories. Unused blood spots from the Guthrie test were retrieved for infants presenting with cholestatic hepatobiliary disease and from the two cards stored on either side of each card from an index child. Concentrations of conjugated bile acids measured by tandem mass spectrometry in the two groups were compared. Concentrations of glycodihydroxycholanoates, glycotrihydroxycholanoates, taurodihydroxycholanoates, and taurotrihydroxycholanoates. Receiver operator curves were plotted to determine which parameter (or combination of parameters) would best predict the cases of cholestatic hepatobiliary disease and extrahepatic biliary atresia. The sensitivity and specificity at a selection of cut off values for each bile acid species and for total bile acid concentrations for the detection of the two conditions were calculated. 218 children with cholestatic hepatobiliary disease were eligible for inclusion in the study. Two children without a final diagnosis and five who presented at <14 days of age were excluded. Usable blood spots were obtained from 177 index children and 708 comparison children. Mean concentrations of all four bile acid species were significantly raised in children with cholestatic hepatobiliary disease and extrahepatic biliary atresia compared with the unaffected children (P<0.0001). Of 177 children with cholestatic hepatobiliary disease, 104 (59%) had a total bile acid concentration >33 micromol/l (97.5th centile value for comparison group). Of the 61 with extrahepatic biliary atresia, 47 (77%) had total bile acid concentrations >33 micromol/l. Taurotrihydroxycholanoate and total bile acid concentrations were the best predictors of both conditions. For all cholestatic hepatobiliary disease, a cut off level of total bile acid concentration of 30 micromol/l gave a sensitivity of 62% and a specificity of 96%, while the corresponding values for extrahepatic biliary atresia were 79% and 96%. Most children who present with extrahepatic biliary atresia and other forms of cholestatic hepatobiliary disease have significantly raised concentrations of conjugated bile acids as measured by tandem mass spectrometry at the time when samples are taken for the Guthrie test. Unfortunately the separation between the concentrations in these infants and those in the general population is not sufficient to make mass screening for cholestatic hepatobiliary disease a feasible option with this method alone.


Hypopigmentation in an African patient treated with imatinib mesylate: a case report.
Imatinib mesylate (STI 571, Gleevec) is a potent bcr-abl tyrosine kinase inhibitor. It also inhibits c-kit tyrosine kinase. Imatinib mesylate is active in the treatment of cronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). It is considered by some authorities to be the standard of care in newly diagnosed CML as well as patients in chronic phase who do not have a related match. C-kit and its ligand stem-cell factor regulate melanocyte development and survival. Hypopigmentation in patients receiving imatinib mesylate for CML has been reported recently. In this article, we report a black Nigerian male with GIST, who developed hypopigmentation of distal parts of digits, as well as generalized lightening of skin on the body three months after receiving imatinib mesylate. We believe that this is the first case of hypopigmentation reported in a black patient with GIST.


Hearing and premorbid personality in paranoid states.
The author studied the hearing and premorbid personality of 79 patients whose illnesses began before they were 60 years old. Hearing was assessed by pure-tone audiometry and premorbid personality by interviewing relatives. Thirty-two patients had paranoid states, 32 matched patients had recurrent unipolar depression, and 15 patients had schizophrenia. Three paranoid patients and two depressed patients met DSM-III criteria for premorbid paranoid personality. There was no consistent difference in hearing loss between paranoid and depressed patients or between paranoid patients and a population control group. The author concludes that premorbid paranoid personality and hearing loss are not associated with paranoid states in middle age.


Quantification of 3-D coronary arterial motion using clinical biplane cineangiograms.
Speculation that the motion of the coronary arteries might be involved in the pathogenesis of coronary atherosclerosis has generated growing interest in the study of this motion. Accordingly, a system has been developed to quantify 3-D coronary arterial motion using clinical biplane cineangiograms. Exploiting the temporal continuity of sequential angiographic images, a template matching technique is designed to track the non-uniform frame-to-frame motion of coronary arteries without assuming that the vessels experience uniform axial strain. The implementation of the system is automated by a coarse-to-fine matching process, thus improving the efficiency and objectivity of motion analysis. The system has been validated and employed to characterize the in vivo motion dynamics of human coronary arteries; illustrative results show that this system is a promising tool for routine clinical and laboratory analysis of coronary arterial motion.


Does an Increased Critical Shoulder Angle Affect Re-tear Rates and Clinical Outcomes Following Primary Rotator Cuff Repair? A Systematic Review.
To determine if an increased critical shoulder angle (CSA) predisposes patients to higher re-tear rates and worse clinical outcomes after rotator cuff (RC) repair. A comprehensive search of the PubMed, MEDLINE, and EMBASE databases was performed in October 2018 for English-language studies pertaining to RC repair and an increased CSA in accordance with Preferred Reported Items for Systematic Reviews and Meta-analyses guidelines. Studies of all levels of evidence were included provided that any outcomes, including pain, patient-reported outcomes, and re-tear rates, were reported. Of a group of 1126 studies that satisfied the initial search criteria, 6 studies were included in the final analysis, comprising data from 473 patients. Three comparative studies were assessed for an association between increased CSA and RC re-tear rates. Among these 3 studies that compared RC re-tear rate in patients with larger and smaller CSAs, 22 of 97 patients (23%) with a larger CSA had a RC re-tear in comparison to 10 of 99 patients (10%) with a smaller CSA. All 3 studies demonstrated higher RC re-tear rates in patients with larger CSAs (risk ratio, 2.39-9.66, I2 = 7%.) The mean CSA in those patients who did not have RC re-tears ranged from 34.3° to 37°, and the mean CSA in those patients who had RC re-tears ranged from 37° to 40°. RC re-tear rates were higher in patients with larger CSAs among comparative, nonrandomized studies. However, the heterogeneity of the relevant literature limits the strength of his observation. Based on the current literature, it remains unclear as to whether lateral acromioplasty affects clinical outcomes as a function of a reduced postoperative CSA. Level IV, systematic review of Level II to IV studies.


Effects of mild head injury on postural stability as measured through clinical balance testing.
Although force-platform measures of postural stability provide objective information concerning mild head injury (MHI) resolution, their application has remained limited due to the high costs and impracticality for sideline use. Therefore, we investigated the efficacy of a clinical balance testing procedure for the detection of acute postural stability disruptions after MHI. We used a posttest control group design with repeated measures. Postural stability was tested at 3 postinjury time intervals (days 1, 3, and 5) using 2 procedures in a sports medicine laboratory: 1) a clinical balance battery consisting of 3 stances (double leg, single leg, and tandem) on 2 surfaces (firm and foam), and 2) the Sensory Organization Test using a sophisticated force-platform system. Sixteen MHI and 16 matched control subjects participated in this study. We measured performance with the Balance Error Scoring System for each of the clinical balance tests and the NeuroCom Smart Balance Master for Sensory Organization Testing. We found significantly higher postural instability in the MHI subjects revealed through the clinical test battery, with the 3 stances on the foam surface eliciting significant differences through day 3 postinjury. Results of the Sensory Organization Test revealed significant group differences on day 1 postinjury. Our results revealed that the Balance Error Scoring System may be a useful clinical procedure to assist clinicians in making return-to-play decisions in athletes with MHI in the absence of force-platform equipment.


Competition of nanoparticle-induced mobilization and immobilization effects on segmental dynamics of an epoxy-based nanocomposite.
The complex effects of nanoparticles on a thermosetting material based on an anhydride cured DGEBA/boehmite nanocomposite with different particle concentrations are considered. A combination of X-ray scattering, calorimetry, including fast scanning calorimetry and temperature modulated calorimetry, and dielectric spectroscopy was employed to study the structure, the vitrification kinetics and the molecular dynamics of the nanocomposites. For the first time in the literature, for an epoxy-based composite, a detailed analysis of the X-ray data was carried out. Moreover, the unfilled polymer was found to be intrinsically heterogeneous, showing regions with different crosslinking densities, indicated by two separate dynamic glass transitions. The glass transition temperature decreases with increasing nanoparticle concentration, resulting from a change in the crosslinking density. Moreover, on the one hand, for the nanocomposites, the incorporation of nanofiller increased the number of mobile segments for low nanoparticle concentrations, due to the altered crosslinking density. On the other hand, for higher loading degrees, the number of mobile segments decreased, resulting from the formation of an immobilized interphase (RAF). The simultaneous mobilization and immobilization of the segmental dynamics cannot be separated unambiguously. By taking the sample with the highest number of mobile segments as a reference state, it was possible to estimate the amount of RAF.


Orange-to-red tunable picosecond pulses by frequency doubling in a diode-pumped PPKTP waveguide.
A compact picosecond all-room-temperature orange-to-red tunable laser source in the spectral region between 600 and 627 nm is demonstrated. The tunable radiation is obtained by second-harmonic generation in a periodically poled potassium titanyl phosphate (PPKTP) multimode waveguide using a tunable quantum-dot external-cavity mode-locked laser. The maximum second-harmonic output peak power of 3.91 mW at 613 nm is achieved for 85.94 mW of launched pump peak power at 1226 nm, resulting in conversion efficiency of 4.55%.


Assessment of three in vitro tests and an in vivo test for chloroquine resistance in Plasmodium falciparum clinical isolates.
Three in vitro assays (the isotopic semimicrotest [700 microl per well; 24-well plates], the isotopic microtest [200 microl per well; 96-well plates], and the rapid in vitro test) and the standard in vivo test for chloroquine resistance were compared for 99 clinical isolates of Plasmodium falciparum obtained from symptomatic African patients. The 50% inhibitory concentrations determined by the two isotopic tests were similar and were highly correlated (r = 0.965; P < 0.05), showing a high concordance between the semimicrotest and the microtest. There was a moderate agreement between these two isotopic tests and the in vivo test. Most of the discordant results were probably due to host factors, including reinfections, pharmacokinetic variations, and immunologic response, which are eliminated in in vitro assays. The rapid in vitro test based on the inhibition of chloroquine efflux in the presence of verapamil was poorly concordant with the other tests. Despite some discordant results, isotopic in vitro assays are useful to characterize the phenotypes of individual isolates without the interference of host factors and are complementary to in vivo evaluation of drug efficacy. However, in vitro assays need to be standardized to allow direct comparison of results between different laboratories.


Caregiver characteristics and their relationship to health service utilization in minority patients with first episode stroke.
The purpose of the current study was to investigate the contribution of caregivers' characteristics to health service utilization by minority persons with first episode stroke. Participants were 61 primary caregivers of minority persons (41% African American; 59% Hispanic) with first episode symptomatic stroke consecutively admitted to an inpatient rehabilitation unit at a county hospital. Caregiver characteristics included resources for daily living, general health, social support, and health beliefs. Health service utilization was defined as the percentage of medical and therapy appointments attended for the first 6 months following discharge from inpatient rehabilitation. There was no difference in percentage of appointments attended between African American and Hispanic caregivers. There was a significant difference between caregivers on the External Control by Powerful Others subscale of the Multidimensional Health Locus of Control Scale (MHLC), with Hispanic caregivers reporting a greater belief that powerful others exerted control over their health. There was a trend for Hispanics to score higher on the External Control by Chance subscale of the MHLC. Results of logistic regression analyses indicated that persons with stroke were less likely to attend appointments if their caregiver believed that health was related to chance factors. These results suggest that caregiver health beliefs play an important role in patient adherence to medical recommendations. Education of caregivers may result in improved follow-through with medical recommendations.


Efficient free energy calculations on small molecule host-guest systems - a combined linear interaction energy/one-step perturbation approach.
Two efficient methods to calculate binding affinities of ligands with proteins have been critically evaluated by using sixteen small ligand host-guest complexes. It is shown that both the one-step (OS) perturbation method and the linear interaction energy (LIE) method have complementing strengths and weaknesses and can be optimally combined in a new manner. The OS method has a sound theoretical basis to address the free energy of cavity formation, whereas the LIE approach is more versatile and efficient to calculate the free energy of adding charges to such cavities. The off-term, which is neglected in the original LIE equation, can be calculated without additional costs from the OS, offering a powerful synergy between the two methods. The LIE/OS approach presented here combines the best of two worlds and for the model systems studied here, is more accurate than and as efficient as the original methods. It has a sound theoretical background and no longer requires any empirical parameters. The method appears very well suited for application in lead-optimization programmes in drug research, where the structure and dynamics of a series of molecules is of interest, together with an accurate calculation of the binding free energy.


Nazi indoctrination and anti-Semitic beliefs in Germany.
Attempts at modifying public opinions, attitudes, and beliefs range from advertising and schooling to "brainwashing." Their effectiveness is highly controversial. In this paper, we use survey data on anti-Semitic beliefs and attitudes in a representative sample of Germans surveyed in 1996 and 2006 to show that Nazi indoctrination--with its singular focus on fostering racial hatred--was highly effective. Between 1933 and 1945, young Germans were exposed to anti-Semitic ideology in schools, in the (extracurricular) Hitler Youth, and through radio, print, and film. As a result, Germans who grew up under the Nazi regime are much more anti-Semitic than those born before or after that period: the share of committed anti-Semites, who answer a host of questions about attitudes toward Jews in an extreme fashion, is 2-3 times higher than in the population as a whole. Results also hold for average beliefs, and not just the share of extremists; average views of Jews are much more negative among those born in the 1920s and 1930s. Nazi indoctrination was most effective where it could tap into preexisting prejudices; those born in districts that supported anti-Semitic parties before 1914 show the greatest increases in anti-Jewish attitudes. These findings demonstrate the extent to which beliefs can be modified through policy intervention. We also identify parameters amplifying the effectiveness of such measures, such as preexisting prejudices.


Nitric oxide production by spermatozoa and sperm characteristics in dogs with benign prostatic hyperplasia.
The aim of this study was to evaluate the effect of benign prostatic hyperplasia (BPH) on nitric oxide (NO) production by spermatozoa and sperm parameters in dogs. The study was conducted on 40 intact dogs of various breeds. The dogs were assigned to two groups: BPH group (n=20) and non-affected group (n=20). The sperm concentration and motility parameters of spermatozoa were assessed using computer-assisted sperm analysis. For the assessment of sperm morphology monochromatic Diff-Quick stain was used. Plasma membrane integrity, mitochondrial membrane potential and the spermatozoa producing nitric oxide and with apoptotic-like changes were determined using fluorescent stain methods. The percentages of motile sperm, sperm with progressive motility and normal sperm were statistically significantly (p<0.05) lower in dogs with BPH than in non-affected dogs. The proportion of sperm in motility subcategory RAPID was statistically significantly (p<0.05) lower in dogs with BPH than in control dogs, whereas in the STATIC motility subcategory the proportion was significantly (p<0.05) higher in dogs with BPH. The percentage of spermatozoa producing NO was significantly (p<0.05) higher in dogs with BPH than in control dogs. In conclusion, the results of this study showed that BPH adversely affects semen quality, especially motility, in dogs. The decreased semen quality was associated with an increased proportion of spermatozoa generating NO. Further research is needed to clarify the mechanisms by which BPH affects semen quality.


Analysis of standing droplets in rat proximal tubules.
Volume, osmolality, and concentrations for Na, Cl, and raffinose have been measured as a function of time in standing droplets within rat intermediate and late proximal tubules. Standing droplet reabsorption proceeds without the development of a measurable osmotic difference across the epithelium. After 140 s of tubular exposure, droplet-to-plasma concentration differences are observed for raffinose, Na, and Cl with the observed Na concentration difference, usually referred to as limiting gradient, being approximately 9 mM. It is possible that a smaller or even no limiting difference would be attained with longer exposure times. Previous values measured for the limiting Na concentration in the rat proximal tubule were determined before the attainment of constant concentrations. Assuming that the Na concentration we measured is the limiting value, we estimate that active NaCl transport accounts for a very small fraction, less than 6%, of the volume reabsorption; using an alternative approach of fitting a theoretical model to our experimental data, active NaCl transport is again estimated to account for only 6% of the total reabsorbate. The previous interpretation that a limiting Na concentration gradient constitutes the most direct evidence for active Na transport may be in error; the gradient we measure can be modeled without incorporating active NaCl transport.


A Novel Gene Underlies Bleomycin-Response Variation in Caenorhabditis elegans.
Bleomycin is a powerful chemotherapeutic drug used to treat a variety of cancers. However, individual patients vary in their responses to bleomycin. The identification of genetic differences that underlie this response variation could improve treatment outcomes by tailoring bleomycin dosages to each patient. We used the model organism Caenorhabditis elegans to identify genetic determinants of bleomycin-response differences by performing linkage mapping on recombinants derived from a cross between the laboratory strain (N2) and a wild strain (CB4856). This approach identified a small genomic region on chromosome V that underlies bleomycin-response variation. Using near-isogenic lines, and strains with CRISPR-Cas9 mediated deletions and allele replacements, we discovered that a novel nematode-specific gene (scb-1) is required for bleomycin resistance. Although the mechanism by which this gene causes variation in bleomycin responses is unknown, we suggest that a rare variant present in the CB4856 strain might cause differences in the potential stress-response function of scb-1 between the N2 and CB4856 strains, thereby leading to differences in bleomycin resistance.


The impact of socio-economic status on health related quality of life for children and adolescents with heart disease.
Socioeconomic status (SES) is known to influence children's health-related quality of life. Many SES indicators assess distinct dimensions of a family's position rather than measuring the same underlying construct. Many researchers, however, see SES indicators as interchangeable. The primary aim of this study was to determine which measure of SES had the strongest impact on health-related quality of life. This is a secondary analysis of the Pediatric Cardiac Quality of Life Inventory Validation Study. The SES variables were family income, Hollingshead Index (occupational prestige), and highest parent educational attainment level. Health-related quality of life was measured using the Pediatric Cardiac Quality of Life Inventory. Correlations tested the relationship among the three SES indicators. Regression-based modeling was used to calculate the strength of the association between SES measures and the Pediatric Cardiac Quality of Life Inventory. The correlations among the SES measures were moderately high, with the correlation between the Hollingshead Index and parental education being r = 0.62 (95% CI = 0.56-0.65). There were equally high correlations between family income and the Hollingshead (r = 0.61, 95% CI = 0.57-0.65) and a slightly lower correlation between family income and parental education (r = 0.55, 95% CI = 0.52-0.59). Family income had the highest explanatory value compared to the Hollingshead Index or parental educational attainment, while controlling for sex, race, current cardiac status, and original diagnosis, accounting for 4-5% of the variation in patient and parent Pediatric Cardiac Quality of Life Inventory Total score, respectively, compared to the other SES measures. Family income as an SES measure demonstrated the greatest fidelity with respect to health-related quality of life as measured by the Pediatric Cardiac Quality of Life Inventory across respondent groups and explained more of the variation compared to the Hollingshead Index or highest parental educational attainment.


Tolerability of mofebutazone in asthmatic patients.
Twenty-seven human volunteer asthmatic patients were each given one tablet of mofebutazone (300 mg) twice daily for 15 days. Pulmonary ventilatory function test (forced expiratory volume test) as well as bronchoalveolar lavage (BAL) were performed one day before initiation of treatment and one day after completion of the course; in the BAL, prostaglandin E2 (PGE2), prostaglandin F2alpha (PGF2alpha) and leukotrienes (LTs) were also estimated. It was found that there was no increase in the incidence or severity of the asthmatic attacks during the course of mofebutazone treatment. The drug tended to improve the tested pulmonary ventilatory functions or at least to leave them unchanged. All the mofebutazone-treated individuals showed a dramatic reduction in the concentrations of PGE2, PGF2alpha and LTs in their BAL, but there was no consistent correlation between the extent of reduction and the degree of benefit or worsening sustained by any individual patient. It is evident from the present study that mofebutazone has shown good tolerability which was associated with an improvement in the pulmonary ventilatory functions, a fact that would seem to advocate the use of this non-steroidal antiinflammatory drug (NSAID) in asthmatic patients whenever a need for such therapy becomes necessary.


Leiomyosarcoma metastases to the spine. Case series and review of the literature.
Leiomyosarcoma is a rare malignant smooth-muscle tumor that rarely metastasizes to bone. It is extremely uncommon for osseous metastasis to be the initial presentation of leiomyosarcoma or to be the initial manifestation of recurrence in patients with a history of leiomyosarcoma. The authors have treated four cases of metastatic leiomyosarcoma with the lesion initially presenting in the spine, and a fifth case of disseminated leiomyosarcoma that involved the spine. In their report, they highlight the cases of two of these patients and provide tabular data for the remaining three. The authors performed a comprehensive review of the literature on spinal leiomyosarcomas and retrospective chart reviews of five surgically treated patients in whom a spinal metastatic leiomyosarcoma was diagnosed. Their series consists of five women who ranged in age from 36 to 47 years (mean age 43.2 years). Four patients had known, or presumed, uterine primary lesions, whereas one harbored a retroperitoneal primary tumor. These lesions generally appear as lytic foci on imaging studies, but variable imaging characteristics were observed. All cases were managed aggressively: four patients underwent posterior/posterolateral decompression and fusion, and one underwent anterior-posterior en bloc resection and fusion. In all cases preoperative symptoms resolved. Two patients died 9 and 13 years after initial presentation. The remaining patients are alive and neurologically intact. Metastatic spinal leiomyosarcomas tend to symptomatically involve only one spinal level at the time of diagnosis and are known to recur locally. These lesions commonly affect women in early middle age, and long-term survival, even in those with systemic metastatic lesions, is better than that seen in individuals with more aggressive spinal metastases. Attempted gross-total resection with fusion, as opposed to minimal palliative decompression, is recommended.


A startling absence of emotion effects: Active attention to the startle probe as a motor task cue appears to eliminate modulation of the startle reflex by valence and arousal.
Research has shown that during emotional imagery, valence and arousal each modulate the startle reflex. Here, two imagery-startle experiments required participants to attend to the startle probe as a simple reaction time cue. In experiment 1, four emotional conditions differing in valence and arousal were examined. Experiment 2, to accentuate potential valence effects, included two negative high arousal, a positive high arousal and a negative low arousal condition. Imagery effectively manipulated emotional valence and arousal, as indicated by heart rate and subjective ratings. Compared to baseline, imagery facilitated startle responses. However, valence and arousal failed to significantly affect startle magnitude in both experiments and startle latency in Experiment 1. Results suggest that emotional startle modulation is eclipsed when the probe is significant for task completion and/or cues a motor response. Findings suggest that an active, rather than defensive, response set may interfere with affective startle modulation, warranting further investigation.


MRI Study of the Influence of Surface Coating Aging on the In Vivo Biodistribution of Iron Oxide Nanoparticles.
Medical imaging is an active field of research that fosters the necessity for novel multimodal imaging probes. In this line, nanoparticle-based contrast agents are of special interest, since those can host functional entities either within their interior, reducing potential toxic effects of the imaging tracers, or on their surface, providing high payloads of probes, due to their large surface-to-volume ratio. The long-term stability of the particles in solution is an aspect usually under-tackled during probe design in research laboratories, since their performance is generally tested briefly after synthesis. This may jeopardize a later translation into practical medical devices, due to stability reasons. To dig into the effects of nanoparticle aging in solution, with respect to their behavior in vivo, iron oxide stealth nanoparticles were used at two stages (3 weeks vs. 9 months in solution), analyzing their biodistribution in mice. Both sets of nanoprobes showed similar sizes, zeta potentials, and morphology, as observed by dynamic light scattering (DLS) and transmission electronic microscopy (TEM), but fresh nanoparticles accumulated in the kidneys after systemic administration, while aged ones accumulated in liver and spleen, confirming an enormous effect of particle aging on their in vivo behavior, despite barely noticeable changes perceived on a simple inspection of their structural integrity.


Toward Objective, Morphology-Based Taxonomy: A Case Study on the Malagasy Nesomyrmex sikorai Species Group (Hymenoptera: Formicidae).
Madagascar is one of the world's greatest biodiversity hotspots, meriting special attention from biodiversity scientists. It is an excellent testing ground for novel techniques in taxonomy that aim to increase classification objectivity and yield greater taxonomic resolving power. Here we reveal the diversity of a unique and largely unexplored fragment of the Malagasy ant fauna using an advanced combination of exploratory analyses on quantitative morphological data allowing for increased objectivity in taxonomic workflow. The diversity of the Nesomyrmex sikorai species-group was assessed via hypothesis-free nest-centroid-clustering combined with recursive partitioning to estimate the number of morphological clusters and determine the most probable boundaries between them. This combination of methods provides a highly automated and objective species delineation protocol based on continuous morphometric data. Delimitations of clusters recognized by these exploratory analyses were tested via confirmatory Linear Discriminant Analysis (LDA) and Multivariate Ratio Analysis (MRA). The final species hypotheses are corroborated by many qualitative characters, and the recognized species exhibit different spatial distributions and occupy different ecological regions. We describe and redescribe eight morphologically distinct species including six new species: Nesomyrmex excelsior sp. n., N. modestus sp. n., N. reticulatus sp. n., N. retusispinosus (Forel, 1892), N. rugosus sp. n., N. sikorai (Emery, 1896), N. striatus sp. n., and N. tamatavensis sp. n. An identification key for their worker castes using morphometric data is provided.


Short communication: prevalence, risk factors, and a field scoring system for udder cleft dermatitis in Dutch dairy herds.
Udder cleft dermatitis (UCD) is a well-known disorder in dairy cows. Veterinary literature about this subject, however, is scarce. The objectives of this study were to define a clinical scoring system for UCD, estimate the within-herd prevalence of UCD, and identify potential risk factors of UCD at cow and herd level. On 20 randomly selected dairy farms in the Netherlands, each lactating cow was photographed from a ventral, lateral, and caudal position. A scoring system with 6 categories of severity of UCD was proposed based on the ventral photographs. Cow measures such as udder width and depth, and front quarter attachment were determined from the lateral and caudal photographs. A questionnaire was conducted on each farm during farm visits. Udder cleft dermatitis, defined as a score 3 or higher, was detected in 5.2% of the 948 cows involved in this study. Within-herd prevalences of UCD ranged between 0 and 15% and UCD was found in 16 (80%) of the participating farms. Cows with a deep udder (relative to the hock), large front quarters, and a small angle between udder and abdominal wall were more likely to develop UCD. Production level and use of a footbath were identified as being positively associated with herd-level UCD prevalence. Herd size and average bulk milk somatic cell count did not seem to be associated with UCD prevalence. Because of the small herd sample size, no firm conclusions were drawn on herd-level risk factors. However, results from this study can be used in designing a future longitudinal UCD study. The prevalences of UCD found in the present study illustrate the current UCD situation in the Netherlands. Our results demonstrate that multiple potential risk factors of UCD could be identified at both the cow and herd level.


Platelet kinetics in patients with idiopathic thrombocytopenic purpura and moderate thrombocytopenia.
We studied ten normal subjects and 20 patients with stable, untreated idiopathic thrombocytopenic purpura (ITP) and platelet counts in the range of 35,000 to 110,000/microL. The diagnosis was made by clinical criteria. Platelet-associated IgG was increased in all nine of the nine patients studied. Autologous platelets were labeled with chromium 51 and reinfused for measurement of mean cell life and platelet production rate. Mean cell life was calculated by two methods, weighted mean and multiple hit, with excellent agreement between the two. As expected, mean cell life was significantly reduced in ITP patients as compared to the normal subjects (2.9 days v. 8.0 days, P less than .001). However, mean platelet production rates in ITP patients and normal subjects, 3.5 and 3.8 X 10(9) platelets/k/d respectively, were not significantly different. Platelet production rate was above and below the normal range (2 to 5.6 X 10(9) platelets/k/d) in two and four patients, respectively. We conclude that the rate of platelet production is not increased in most patients with ITP who have platelet counts greater than 35,000/microL. We did find that platelet size was increased in eight of the 12 patients in whom it was measured, including two of the patients with low platelet production.


Immortalization of human melanocytes does not alter the de novo properties of nitric oxide to induce cell detachment from extracellular matrix components via cGMP.
Nitric oxide (NO) is an important mediator in many (patho)physiological processes including inflammation and skin cancer. A key transducer in NO signaling is the soluble guanylyl cyclase (sGC) that catalyzes the formation of guanosine 3',5'-cyclic monophosphate (cGMP). The basic mechanism of NO-cGMP signaling in melanocytic cells is, however, not well elucidated. A setback for such studies is the limited availability of patient-derived melanocytes. Here, we report that immortalized human normal and vitiliginous cell lines generated via cell transfection with human papilloma virus 16 genes E6 and E7 express NO synthase and guanylyl cyclase isoforms and the multidrug resistance-associated proteins 4 and 5 as selective cGMP exporters. Donors of NO (e.g., the NONOate (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA-NO) and reactive nitrogen oxygen species (RNOS) like 3-morpholino-sydnonimine (SIN-1) as a donor of peroxynitrite as well as YC-1 as a NO-independent sGC stimulator increased intracellular cGMP levels in immortalized melanocytes (up to eightfold over controls), indicating the expression of functional sGC in these cells. PAPA-NO and SIN-1 also reduced the attachment of immortalized melanocytes to extracellular matrix (ECM) components like fibronectin which was dependent on cellular melanin content and cGMP. Such effects on melanoma cells were positively related to metastatic potential and were cGMP independent. Intriguingly, nonpigmented metastatic melanoma cells were more sensitive to exogenous sources of RNOS than of NO. Thus, immortalized melanocytes can be used as a tool for further research on differences in cell signaling between the different melanocytic lineages in particular towards impairment of cell-ECM adhesion by NO or RNOS, which may be important in metastasis and vitiligo pathogenesis.


Tracheostomy tube insertion in the pretracheal fascia.
A case of massive dissecting emphysema secondary to attempted emergency tracheostomy is reported. Malpositioning of the tube in the pretracheal fascia and positive pressure ventilation were the cause of the dissecting emphysema. This problem was recognized with subsequent removal of the tracheostomy tube, but unfortunately the skin was sutured which prevented air from escaping. The diagnosis was made by physical examination and chest roentgenogram. It was successfully treated by reopening of the wound and evacuation of clots. Careful technique performed under optimal conditions is of paramount importance in avoiding this complication.


Rehabilitation following rotator cuff repair: a survey of current UK practice.
Rotator cuff disorders, including rotator cuff tears, are common and can be treated conservatively or surgically. Data suggest that the incidence of surgery to repair the rotator cuff is rising. Despite this rise, the most effective approach to postoperative rehabilitation, a critical component of the recovery process, is not well developed. The present study aimed to describe current practice in the UK in relation to rehabilitation following rotator cuff repair. An electronic survey was developed and disseminated to UK based physiotherapists and surgeons involved with rotator cuff repair. One hundred valid responses were received. Although there is a degree of variation, current practice for the majority of respondents consists of sling immobilization for 4 weeks to 6 weeks. During this time, passive movement would be commenced before active movement is introduced towards the end of this phase. Resisted exercise begins 7 weeks to 12 weeks postoperatively, alongside return to light work. A progressive resumption of function, including manual work and sport, is advised from approximately 13 weeks. In the context of the current literature, it might be suggested that the current approach to rehabilitation following rotator cuff repair for the majority of respondents is somewhat cautious and has not progressed for over a decade.


[Retrospective evaluation of the safe reduction of surgical margins of resected stage-IIA cutaneous melanoma of the trunk and extremities].
The paper deals with analysis of 102 case histories locally-advanced 1.51-4.00 mm-thick cutaneous melanomas (CM) of the trunk and arms and legs operated on at the Center's Clinics and 52--at the Regional Oncological Dispensary, Samara. The effectiveness of relatively conservative procedures of treating CM of "medium" thickness and "intermediate" prognosis were assessed by histological analysis of resected material. CMs with such characteristics conform to the specifications of stage IIA of the criteria used by the American Joint Committee on Staging of Cancer (AJCC). The study of the time and frequency of relapse and dissemination of tumor in 154 patients provided the guide-lines for determining optimal extent of surgery to excise CM stage IIA of the trunk and arms and legs. Excision of 1.5-4.00 mm-thick CMs with 2 cm-wide margins left should be considered safe and less traumatic.


A study of stabilization of gluconeogenic activity in rat liver slices by calcium and manganese ions.
1. The effect of some bivalent cations on gluconeogenesis by the rat liver-slice preparation has been investigated. 2. Ca(2+) and Mn(2+) stimulated glucose production from a range of substrates but not from glycerol. Mg(2+) had no effect on the rate of glucose production. 3. Ca(2+) were required to maintain phosphoenolpyruvate carboxylase activity in the slice preparation. 4. Ca(2+) and Mn(2+), but not Mg(2+), retarded the release of lysosomal enzymes from the slice into the incubation medium. 5. It is proposed that Ca(2+) and Mn(2+) stimulate glucose production by stabilizing the lysosome system in the liver-slice preparation. 6. The value of the liver-slice preparation as a means of measuring hepatic gluconeogenesis is discussed.


UPD detection using homozygosity profiling with a SNP genotyping microarray.
Single nucleotide polymorphism (SNP) based chromosome microarrays provide both a high-density whole genome analysis of copy number and genotype. In the past 21 months we have analyzed over 13,000 samples primarily referred for developmental delay using the Affymetrix SNP/CN 6.0 version array platform. In addition to copy number, we have focused on the relative distribution of allele homozygosity (HZ) throughout the genome to confirm a strong association of uniparental disomy (UPD) with regions of isoallelism found in most confirmed cases of UPD. We sought to determine whether a long contiguous stretch of HZ (LCSH) greater than a threshold value found only in a single chromosome would correlate with UPD of that chromosome. Nine confirmed UPD cases were retrospectively analyzed with the array in the study, each showing the anticipated LCSH with the smallest 13.5 Mb in length. This length is well above the average longest run of HZ in a set of control patients and was then set as the prospective threshold for reporting possible UPD correlation. Ninety-two cases qualified at that threshold, 46 of those had molecular UPD testing and 29 were positive. Including retrospective cases, 16 showed complete HZ across the chromosome, consistent with total isoUPD. The average size LCSH in the 19 cases that were not completely HZ was 46.3 Mb with a range of 13.5-127.8 Mb. Three patients showed only segmental UPD. Both the size and location of the LCSH are relevant to correlation with UPD. Further studies will continue to delineate an optimal threshold for LCSH/UPD correlation.


Anti-IgM induces up-regulation and tyrosine-phosphorylation of heterogeneous nuclear ribonucleoprotein K proteins (hnRNP K) in a Ramos B cell line.
Heterogeneous nuclear ribonucleoprotein K protein (hnRNP K) has diverse molecular partners implicated in signal transduction pathways, and is tyrosine-phosphorylated in response to growth factors and oxidative stress. Among the structurally distinct domains of hnRNP K, an SH3-binding domain (SH3BD) has been known to promote the association of SH3-containing tyrosine kinases and protooncoprotein Vav, which are involved in B cell receptor (BCR) signalling. In this study, we analyzed proteins of Ramos B cell line that are altered upon BCR activation with anti-IgM antibody, revealing that a certain hnRNP K isoform is up-regulated in response to anti-IgM treatment. We also showed that hnRNP K is tyrosine-phosphorylated after BCR ligation. HnRNP K lacking the SH3BD is shown not to interact with phosphorylated Vav, and Ramos cells stably expressing this mutant protein are less susceptible to anti-IgM-induced apoptosis, indicating that hnRNP K is coupled to BCR-mediated signalling and its SH3BD is required for proper signal propagation. Our results provide the first evidence that hnRNP K is involved in BCR signalling pathway.


Evaluation of new film high-light system by comparison with conventional film.
The 3M "High Light System" has been used in a clinical environment for one and one-half years. The inherent advantages, as well as the disadvantages, of this system are discussed. An objective comparison of the blue based HL film and the conventional Type R film was made. This comparison indicates that image quality is similar with either film and, hence, radiographs produced with either system will be of diagnostic quality.


Quality control in diagnostic molecular pathology in the Netherlands; proficiency testing for patient identification in tissue samples.
To describe the evolution of proficiency testing for molecular diagnostic pathology with respect to determining unambiguously the patient identity of tissue samples by microsatellite analysis. Four rounds of quality control exchanges of samples from different patients were sent with the purpose of identifying the correct origin of these samples. The samples were either paraffin wax embedded sections on glass, sections in tubes, or isolated DNA. Blinded samples were distributed to all participating laboratories. No restrictions to the method and short tandem repeat markers used for identification were imposed. In four subsequent rounds the number of participating laboratories increased from three to 10. The numbers of samples tested increased in time from five to 12. The microsatellite markers used by the different laboratories showed little overlap. In the first three rounds, in which isolated DNA was provided, all samples were accurately classified irrespective of the microsatellite markers used. In the last round, which also included paraffin wax embedded sections, a small number of laboratories experienced problems, either with amplification or incorrect classification of a few samples. Proficiency testing was useful, and showed country wide high quality and correct identification of (patient) samples with molecular techniques for diagnostic purposes.


[A comparison of mean weights and the variability of weights of twelve bilateral muscles of the Japanese quail (Coturnix c. japonica) studied in four generations of consanguine crosses].
The influence of the increase of the degree of homozygosity, obtained by successive consanguine cross-breeding, on the mean weights and the variability of the weights of twelve muscles of the Japanese quail (Coturnix c. japonica) was studied in four generations of females and two generations of males. It was found that the mean weights of the twelve muscles in both sexes showed a progressive reduction in the consecutive generations of consanguine crosses, this reduction being more marked in the males than in the females. These results support the hypotheses of Haldane and Lerner that heterozygotes are at an advantage, having a more active metabolism and a greater rate of growth, because their richer biochemical system and greater number of alleles coding the enzymes enables them to benefit from their environment to a greater extent and within wider limits. The rates of decrease vary from one muscle to the other within the limits of 5.3 and 16.6%. For certain muscles there are also notable differences between males and females. Contrary to the hypothesis that could be formed at first sight, the variability in weight increases considerably, in almost all cases, when the degree of homozygosity increases. Here again quite considerable differences are found in the evolution of the variability with the degree of homozygosity, from one muscle to the other and also between the two sexes. Comparison of the mean weight of the left and right elements of the bilateral muscles shows no significant preponderance. It was found, however, that slight asymmetries observed in the different groups of different consanguinity tend to be in the same direction for a given muscle. The variability of the weights of the left and right elements does not seem to be influenced by the degree of homozygosity in the females; in the males, however, an increase in homozygosity increases the variability of the weights of the left and right elements in certain cases. The mean degree of humidity and the variability of the ratio wet weight/dry weight are not changed significantly by the degree of consanguinity in females. In the males, the variability in the degree of humidity is less in heterozygotes, an indication of their better capacity for homeostatic regulation. The reduction in the mean weights and the increase in variability as the degree of homozygosity increases shows the importance of the advantage of heterozygotes, which has a bearing on theories of the genetics of populations and their application in rearing, and particularly to selection techniques.


A Novel Method to Mitigate Real-Imaginary Image Imbalance in Microwave Tomography.
Typical microwave tomographic techniques reconstruct the real part of the permittivity with much greater accuracy as compared to the imaginary part. In this paper, we propose a method to mitigate the imbalance between the reconstructed complex permittivity components and increase the accuracy of the overall image recovery. To do so, the complex permittivity in the imaging domain is expressed as a weighted sum of a few preselected permittivities, close to the range of the expected values. To obtain the permittivity weights, a Gauss-Newton algorithm is employed. Image reconstructions from simulated and experimental data for different biomedical phantoms are presented. Results show that the proposed method leads to excellent reconstruction with balanced real and imaginary parts, across different scenarios.


Early versus late cardiac remodeling during right ventricular pressure load and impact of preventive versus rescue therapy with endothelin-1 receptor blockers.
Pulmonary artery banding (PAB) causes right ventricular (RV) dysfunction, biventricular fibrosis, and apoptosis, which are attenuated by endothelin-1 receptor blockade (ERB). Little is known about the time course of remodeling and whether early versus late ERB confers improved outcome. PAB was performed in five groups of rabbits: Shams, 3-wk PAB (3W), 6-wk PAB (6W), 6-wk PAB + ERB administered from day 1 (6WERB1), and 6-wk PAB + ERB administered from day 21 (6WERB21). Biventricular development of profibrotic molecular signaling, fibrosis, apoptosis, and conductance catheter and echocardiography function were studied. Thirty-three rabbits [ n = 6-7 per group; 3.00 (0.23) kg, mean (SD)] developed half to full systemic RV pressures. Biventricular profibrotic signaling and collagen deposition [RV collagen: Shams 3.8 (0.58) vs. 3W 8.69 (2.52) vs. 6W 8.83 (4.02)%, P < 0.005] and apoptosis [RV: Shams 8.32 (3.2) vs. 3W 55.95 (47.55) vs. 6W 38.85 (17.26) apoptotic cells per microfield, P < 0.0005] increased with PAB. Early and late ERB attenuated fibrosis [RV: 6WERB1 5.55 (1.18), 6WERB21 5.63 (0.72)%] and apoptosis [RV: 6WERB1 11.1 (5.25), 6WERB21 20.24 (7.16) apoptotic cells per microfield, P < 0.0001 vs. 6W]. RV dimensions progressively increased at 3W and 6W and decreased with early ERB [end-diastolic dimensions: Shams 0.4 (0.13) vs. 3W 0.55 (0.78) vs. 6W 0.78 (0.25) vs. 6WERB1 0.71 (0.26) vs. 6WERB21 0.49 (0.23) cm, P < 0.05]. Despite increased RV contractility with PAB [RV end-systolic pressure-volume relationship: Shams 3.76 (1.76) vs. 3W 12.21 (3.44) vs. 6W 19.4 (6.88) mmHg/ml], biventricular function and cardiac output [Shams 196.1 (39.73) vs. 3W 149.9 (34.82) vs. 6W 151 (31.69) ml/min] worsened in PAB groups and improved with early and late ERB [6WERB1 202.8 (26.8), 6WERB21 194.8 (36.93) ml/min, P < 0.05 vs. PAB]. In conclusion, RV pressure overload induces early biventricular fibrosis, apoptosis, remodeling, and dysfunction that worsens with persistent RV hypertension. This remodeling is attenuated by early and late ERB. NEW & NOTEWORTHY Our results in a rabbit model of progressive right ventricular (RV) pressure loading indicate that biventricular fibrosis, apoptosis, and dysfunction are already present when RV hypertension is reached at 3 wk of progressive pulmonary artery banding. These findings worsen with persistent RV hypertension to 6 wk and are attenuated with both early and late endothelin-1 receptor blockade, with some advantages to early therapy. These findings highlight the role of endothelin-1 in driving biventricular remodeling secondary to RV hypertension and suggest that early therapy with an endothelin-1 receptor blocker may be beneficial in attenuating biventricular remodeling but that late therapy is also effective.


Exposure and Recovery of the Gulf Toadfish (Opsanus beta) to Weathered Deepwater Horizon Slick Oil: Impacts on Liver and Blood Endpoints.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants that can be responsible for a variety of deleterious effects on organisms. These adverse outcomes are relatively well studied, but at concentrations rarely found in the environment. Among the documented effects of sublethal acute PAH exposure are reductions in osmoregulatory capacity and immune function, and changes in the function of critical metabolic organs such as the liver. Gulf toadfish (Opsanus beta) were exposed to control seawater (0.006 µg tPAH50 /L) or water accommodated fractions of Deepwater Horizon spill oil diluted to 3 flow-through exposure regimes (0.009, 0.059, and 2.82 µg tPAH50 /L) for 7 d, with a recovery period of equal duration. We hypothesized that these chronic exposures would induce the aryl hydrocarbon receptor (AhR)-mediated pathways and result in significant impacts on markers of osmoregulatory, immune, and metabolic function. We further hypothesized that measurable reversal of these impacts would be observed during the recovery period. Our results indicate that activation of cytochrome P 450 (CYP)1A1 was achieved during exposure and reversed during the recovery phase. The only significant deviations from controls measured were a reduction in plasma glucose in fish exposed to medium and high levels of PAH after 7 d of exposure and a reduction in plasma osmolality fish exposed to high levels of PAHs after 7 d of recovery, when CYP1A1 messenger (m)RNA levels had returned to control levels. Our study illustrates a disconnect between the activation of CYP1A1 in response to environmentally realistic PAHs concentrations and several physiological endpoints and supports the idea that the AhR might not be associated with mediating osmoregulatory, immune, and metabolic changes in Gulf toadfish. Environ Toxicol Chem 2021;40:1075-1086. © 2020 SETAC.


FosB transcription factor regulates COX-2 expression in colorectal cancer cells without affecting PGE2 expression.
The expression levels of cyclooxygenase (COX)-2 and the prostaglandin E2 (PGE2) content have been associated with poor prognosis in patients with colorectal cancer (CRC). There is a strong correlation between COX-2 expression and PGE2 production in tissues from CRC patients, suggesting an important role for COX-2 on the regulation of PGE2 production. Previous studies by the present authors, where CRC patients were divided into high- or low-COX-2 expressing tumors, displayed important differences in the expression levels of several transcription factors involved in carcinogenesis. Among them, FBJ murine osteosarcoma viral oncogene homolog B (FosB), which is a member of the activator protein-1 complex, was the highest upregulated transcription factor in patients with high expression levels of COX-2. The present study aimed to investigate the role of FosB on the COX-2/PGE2 axis in CRC cells with high COX-2 expression levels. Interference RNA technology was used to knockdown FosB expression in HCA-7 cells, and 72 h later the messenger (m)RNA expression levels of COX-1 and COX-2, as well as the PGE2 content, were measured. The results indicated that FosB knockdown decreased the expression levels of COX-2 but did not affect the PGE2 content or the mRNA expression levels of COX-1. The present findings suggest an important role for FosB on the regulation of COX-2 expression, but no effect on the regulation of the PGE2 levels. In addition, the present results imply independent regulatory mechanisms for COX-2 expression and PGE2 content.


Brainstem neuroimaging of nociception and pain circuitries.
The brainstem is known to be an important brain area for nociception and pain processing, and both relaying and coordinating signaling between the cerebrum, cerebellum, and spinal cord. Although preclinical models of pain have characterized the many roles that brainstem nuclei play in nociceptive processing, the degree to which these circuitries extend to humans is not as well known. Unfortunately, the brainstem is also a very challenging region to evaluate in humans with neuroimaging. The challenges for human brainstem imaging arise from the location of this elongated brain structure, proximity to cardiorespiratory noise sources, and the size of its constituent nuclei. These challenges can require dedicated approaches to brainstem imaging, which should be adopted when study hypotheses are focused on brainstem processing of nociception or modulation of pain perception. In fact, our review will highlight many pain neuroimaging studies that have reported some brainstem involvement in nociceptive processing and chronic pain pathology. However, we note that with recent advances in neuroimaging leading to improved spatial and temporal resolution, more studies are needed that take advantage of data collection and analysis methods focused on the challenges of brainstem neuroimaging.


Management of neonatal subglottic stenosis.
When considering management of subglottic stenosis, all conservative efforts to establish a satisfactory airway must be considered prior to surgical reconstruction. However, the approach which allows for the earliest possible decannulation is the one which is sought because of high morbidity and mortality of tracheostomy in the pediatric population.


Chemistry meets biology in the coordination dynamics of metalloproteins.
Metal sites in proteins are often presented in an idealized way that does not capture the intrinsic dynamic behavior of the protein or the extrinsic factors that affect changes in the coordination of the metal ion in biological space and time. The bioinorganic chemistry possible in healthy and diseased living organisms is limited by prevailing pH values, redox potentials, and availability and concentrations of metal ions and ligands. Changes in any of these parameters and protein-protein or protein-ligand interactions can result in differences in the type of metal ion bound, metal occupancy, and coordination number or geometry. This article addresses the plasticity and complexity of metal coordination in proteins when these parameters are considered. It uses three examples of zinc sites with sulfur donor atoms from cysteines in mammalian proteins: alcohol dehydrogenases, metallothioneins, and zinc transporters of the ZnT (SLC30A) family. Coordination dynamics of the metal sites in these proteins has different purposes; in alcohol dehydrogenases for the metal ion to perform its different roles in the catalytic cycle, in metallothioneins for serving as a metal buffer, and in ZnT zinc transporters for sensing metal ions and moving them through the protein and thus biological membranes. Defining the biological and chemical parameters that determine and affect coordination dynamics of metal ions in proteins will inform future investigations of metalloproteins.


MDCT evaluation of the growth kinetics of serous and benign mucinous cystic neoplasms of the pancreas.
We assessed the growth kinetics of pathologically proven benign neoplastic cystic lesions of the pancreas. The volume and longest axial diameter (LAD) of 20 pathologically proven pancreatic cystic lesions (12 mucinous cystic neoplasms (MCN) and 8 serous cystadenomas (SCN)) on 2 multidetector computed tomography scans, obtained before resection, were measured. Reciprocal of doubling time, doubling time and growth rate based on volume and LAD were calculated. A P value <0.05 was considered significant. For all cysts, growth kinetics based on volume were: reciprocal of doubling time (mean = 3.03, median=1.0), doubling time (mean = 644, median = 388 days) and growth rate (mean = 74.7, median = 5.7 ml/year). Results based on LAD were: reciprocal of doubling time (mean = 3.09, median = 1.3), doubling time (mean = 752, median = 273 days) and growth rate (mean = 24.5, median = 5.6 mm/year). These variables were not statistically different between MCNs and SCNs (P > 0.05 in all instances). Reciprocal of doubling time based on volume and LAD were comparable (P > 0.05). We concluded that the mean reciprocal of doubling time was 3.03 and 3.09 using volume and LAD, respectively. This may aid in designing follow-up guidelines for pancreatic cysts.


Site-directed spin labeling reveals a conformational switch in the phosphorylation domain of smooth muscle myosin.
We have used site-directed spin labeling and EPR spectroscopy to detect structural changes within the regulatory light chain (RLC) of smooth muscle myosin upon phosphorylation. Smooth muscle contraction is activated by phosphorylation of S19 on RLC, but the structural basis of this process is unknown. There is no crystal structure containing a phosphorylated RLC, and there is no crystal structure for the N-terminal region of any RLC. Therefore, we have prepared single-Cys mutations throughout RLC, exchanged each mutant onto smooth muscle heavy meromyosin, verified normal regulatory function, and used EPR to determine dynamics and solvent accessibility at each site. A survey of spin-label sites throughout the RLC revealed that only the N-terminal region (first 24 aa) shows a significant change in dynamics upon phosphorylation, with most of the first 17 residues showing an increase in rotational amplitude. Therefore, we focused on this N-terminal region. Additional structural information was obtained from the pattern of oxygen accessibility along the sequence. In the absence of phosphorylation, little or no periodicity was observed, suggesting a lack of secondary structural order in this region. However, phosphorylation induced a strong helical pattern (3.6-residue periodicity) in the first 17 residues, while increasing accessibility throughout the first 24 residues. We have identified a domain within RLC, the N-terminal phosphorylation domain, in which phosphorylation increases helical order, internal dynamics, and accessibility. These results support a model in which this disorder-to-order transition within the phosphorylation domain results in decreased head-head interactions, activating myosin in smooth muscle.


Effect of serotonin reuptake inhibitor on syndrome development in obese hyperglycemic mice (Umeå ob/ob).
These experiments tested the effect of 10 to 30 mg, citalopram/kg body weight on food intake, weight increase, and blood glucose levels in young obese hyperglycemic mice (Umeå ob/ob). A leptin defect in ob/ob mice results in hyperphagia, hyperglycemia, and increased body weight compared with normal mice. Citalopram had no effect on weight increase in ob/ob mice aged 3 to 10 weeks, when the weight increase is most rapid. Citalopram reduced the weight increase at the age 10 to 19 weeks. Food intake reaches a maximum at age 7 to 10 weeks and then decreases. The reduction was more rapid in citalopram-treated mice. The weight of feces paralleled the food intake. Citalopram treatment had no effect on serum insulin levels in 15-week-old mice. Blood sugar values in fed mice reached a peak at age 7 weeks (21.7 +/- 1.7 mmol/L in controls and 22.3 +/- 1 mmol/L in citalopram-treated mice). After that, blood sugar values decreased. The decrease was more pronounced in citalopram-treated mice (P < .01 compared with controls). Blood glucose levels were lower at ages 12 to 15 weeks in female ob/ob control mice (13.6 +/- 2.5 mmol/L v 19.0 +/- 0.6 mmol/L in male control mice; P < .05). The effect of citalopram was the same in male and female mice. There was a close correlation between accumulated food intake and blood glucose values in individual animals. At age 3 to 10 weeks, ob/ob mice have a high beta-cell proliferation rate, and they have large islets of Langerhans. This was not affected by citalopram treatment. Our findings show that the serotonergic system plays a role as a regulator of food intake over shorter periods, and this is also true in the absence of leptin.


Persistent primitive trigeminal artery: an unusual cause of vascular tinnitus.
Pulsatile tinnitus is generally of vascular origin and can be due to arterial, venous, or systemic causes. While certain congenital anatomical variants and arterial vascular loops have been commonly found in symptomatic patients undergoing imaging, persistent primitive trigeminal artery in association with isolated tinnitus is unusual. Thus we report a patient with unilateral isolated pulsatile tinnitus who was evaluated with magnetic resonance angiography and was found to have a persistent primitive trigeminal artery. We also briefly discuss vascular tinnitus as well as the embryology, imaging, and classification of persistent primitive trigeminal artery with the clinical implications.


Australian team sports athletes prefer dietitians, the internet and nutritionists for sports nutrition information.
To evaluate the information sources that are used and preferred by Australian athletes and to assess if preferences influence nutrition knowledge (NK). Elite and non-elite Australian team sport athletes, playing Australian football (AF), cricket, lawn bowls, soccer or hockey, were recruited via the sporting organisations' qualified sports dietitians or club presidents. Athletes completed one of two online, validated sports NK questionnaires. Frequency analysis on previous sources of advice, preferred sources of information and preferred type of support were assessed. Differences in NK scores (%) based on previous sources of dietary advice and preferences for obtaining information were assessed using t test or Mann-Whitney U test. Demographic and information source questions were completed by 410 athletes; 331 also completed NK questions. Athletes were mostly non-elite (76%) and AF players (79%). Forty-four per cent of athletes reported having previously received advice from a dietitian. Twenty per cent, 19% and 16% of athletes chose "dietitian," "internet" and "nutritionist" as their preferred source of nutrition information, respectively. Athletes preferred information on sports nutrition (35%), individual consultations (33%), and information on general healthy eating (33%), over cooking classes (4%) and group presentations (3%). There were no significant associations between preferred and previous information sources and NK scores. Australian athletes prefer dietitians, the internet and nutritionists for sports nutrition information. There is an interest in and need for access to a qualified sports dietitian and reputable internet-based nutrition information. Education programs and advice given to athletes need to be evaluated.


The neurobiological basis of cognitive impairment in Parkinson's disease.
The recent formalization of clinical criteria for Parkinson's disease with dementia (PDD) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PDD occurs on the background of severe dopamine deficits with, the main pathological drivers of cognitive decline being a synergistic effect between alpha-synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin, and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the α-synuclein gene, lead to a clear increased risk of PDD, whereas others, such as parkin mutations, are associated with a reduced risk of PDD. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD-MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low-dose MPTP treatment in primates recapitulates PD-MCI over time, enhancing the current biological concept of PD-MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. Whereas dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies, and genetic factors in PD-MCI remains to be fully elucidated.