The Bubble of Normalisation: A Qualitative Study of Carers of People With Dementia Who Do Not Seek Help for a Diagnosis.
Improving dementia diagnosis rates are a key feature of dementia strategy and policy worldwide. This study aimed to explore the experience of carers of people diagnosed with dementia during or following a hospital admission in order to identify factors that had prevented them from seeking help beforehand. Semi-structured interviews were conducted with 12 informal carers including adults caring for a parent, a friend or a spouse diagnosed with dementia between 2010-2019, following an acute hospital admission for a physical health problem, having not sought help previously. Carers created a 'bubble of normalisation' around themselves and the person living with dementia (PLWD) to reject the label of dementia and protect the PLWD from a loss of independence, discrimination and prejudice they felt would be the result of a diagnosis. Carers struggled to talk to the PLWD about dementia reinforcing denial and stigma. Post-diagnosis carers felt unsupported and questioned the value of diagnosis. Stigma related to images of dementia as a disease that takes away independence and identity prevented discussion about dementia between carers and the PLWD. A lack of open discussion about memory concerns between health care professionals and carers also served to delay diagnosis.


Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation.
The role that transforming growth factor-α (TGF-α) has in chronic pancreatitis and pancreatic cancer has not been fully elucidated. We evaluated the effects of TGF-α on the human pancreatic stellate cell (PSC) line RLT-PSC and primary human PSCs, and the expression levels of TGF-α and metalloproteinase-1 (MMP-1) in human chronic pancreatitis and pancreatic cancer tissues. TGF-α stimulated the proliferation and migration of PSCs. Although the mRNA expression levels of tissue inhibitor of metalloproteinase-1 and α1(I) collagen were unchanged, the mRNA expression levels of MMP-1 increased concomitant with increases in MMP-1 protein levels and collagenase activity. TGF-α-stimulated migration of RLT-PSC cells was partially blocked by tissue inhibitor of metalloproteinase-1 protein and MMP-1 small interfering RNA. MMP-1 was also observed to stimulate the migration of PSCs. TGF-α-induced MMP-1 expression was completely blocked by gefitinib in PSCs. The Ras-ERK and PI3/Akt pathways appear to be involved in the activation of MMP-1 in PSCs. Immunohistochemical analyses showed that MMP-1 expression was significantly increased in the pancreatic interstitial tissues in case of chronic pancreatitis or pancreatic cancer compared with those in case of normal pancreas. In conclusion, TGF-α increased proliferation and migration of PSCs. TGF-α-induced migration of cells may be partly due to upregulation of MMP-1. TGF-α and MMP-1 upregulation may contribute to the pathogenesis of chronic pancreatitis and pancreatic cancer.


Genetic Variations in the Serotonergic System Mediate a Combined, Weakened Response to SSRI Treatment: A Proposed Model
Individuals with the short (S) allele in the promoter region of the serotonin transporter gene (5-HTTLPR) show a less favorable response to selective serotonin reuptake inhibitor (SSRI) treatment than individuals with the long (L) allele. Similarly, individuals with the C(-1019)G allele for the mutation found in the promoter region of the serotonin 1A receptor gene (5-HTR1A) have shown blunted responses to SSRI treatment when compared with individuals lacking this polymorphism. While these findings have been replicated across multiple studies, only two studies to date have reported data for a gene-gene interaction associated with response to SSRI treatment. Both of these studies reported a combined effect for these genotypes, with individuals homozygous for the L allele and the C allele (5-HTT(L/L)-1A(C/C)) reporting the most favorable response to SSRI treatment, and individuals homozygous for the S allele and the G allele (5-HTT(S/S)-1A(G/G)) reporting the least favorable response to SSRI treatment. Additionally, no neural mechanisms have been proposed to explain why this gene-gene interaction has been observed. To that end, this article provides a review of the relevant literature associated with these polymorphisms and proposes a feasible model that describes a genotype-dependent modulation of postsynaptic serotonin signaling associated with the 5-HTT and 5-HTR1A genes.


The efficacy of the Self-Adjusting File versus WaveOne in removal of root filling residue that remains in oval canals after the use of ProTaper retreatment files: A cone-beam computed tomography study.
The current ex vivo study compared the efficacy of removing root fillings using ProTaper retreatment files followed by either WaveOne reciprocating file or the Self-Adjusting File (SAF). Forty maxillary canines with single oval root canal were selected and sectioned to obtain 18-mm root segments. The root canals were instrumented with WaveOne primary files, followed by obturation using warm lateral compaction, and the sealer was allowed to fully set. The teeth were then divided into two equal groups (N = 20). Initial removal of the bulk of root filling material was performed with ProTaper retreatment files, followed by either WaveOne files (Group 1) or SAF (Group 2). Endosolv R was used as a gutta-percha softener. Preoperative and postoperative high-resolution cone-beam computed tomography (CBCT) was used to measure the volume of the root filling residue that was left after the procedure. Statistical analysis was performed using t-test. The mean volume of root filling residue in Group 1 was 9.4 (±0.5) mm(3), whereas in Group 2 the residue volume was 2.6 (±0.4) mm(3), (P < 0.001; t-test). When SAF was used after ProTaper retreatment files, significantly less root filling residue was left in the canals compared to when WaveOne was used.


Tertiary Lymphoid Structures Are Related to Inflammatory Progression and Bone Loss in Human Apical Periodontitis.
Bone loss is strongly associated with the immunologic milieu in apical periodontitis (AP). Tertiary lymphoid structures (TLSs) are organized lymphoid cell aggregates that form in nonlymphoid tissues under persistent inflammatory circumstances. To date, there has been no relevant report of TLSs in periapical lesions. This work aimed to investigate the formation and potential function of TLSs in AP. Tissues from human apical lesions (n = 61) and healthy oral mucosa (n = 5) were collected. Immunohistochemistry and multiplex immunofluorescence were used to detect the formation of TLSs. Correlation analyses were performed between clinical variables and TLSs. In addition, immunohistochemistry was used to evaluate the expression of interleukin-1 beta, interleukin-6, receptor activator of nuclear factor kappa-B ligand, and macrophage subsets in the apical lesions. Periapical granulomas (n = 24) and cysts (n = 37) were identified by histologic evaluation. TLSs, composed of B-cell and T-cell clusters, developed in periapical granulomas and radicular cysts. The CXC-chemokine ligand 13, its receptor CXC-chemokine receptor 5, follicular dendritic cells, and high endothelial venules were localized in TLSs. The quantity and size of TLSs were positively associated with bone loss in AP. Moreover, proinflammatory cytokines and macrophage subsets were also substantially elevated in TLS regions of apical lesions. The formation of TLSs in periapical granulomas and cysts was closely associated with persistent immune responses and bone loss in apical lesions. TLSs provide an updated insight into the complicated immune response process in AP.


Risk of acute thromboembolic events with oral contraceptive use: a systematic review and meta-analysis.
To estimate the risk of venous thromboembolism, stroke, or myocardial infarction (MI) associated with the use of oral contraceptive pills (OCPs) and to describe how these risks vary by dose or formulation. We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published from January 1995 through June 2012 that evaluated the association between OCP use and risk of venous thromboembolism, stroke, or MI. We reviewed 6,476 citations. We included English-language, controlled studies with human participants reporting a quantitative association between exposure to OCPs and outcomes of venous thromboembolism, stroke, or MI. Two investigators independently reviewed articles for inclusion or exclusion; discordant decisions were resolved by team review and consensus. Random-effects meta-analysis was used to generate summary odds ratios (ORs). Fifty studies met inclusion criteria. There were no randomized clinical trials. We found threefold increased odds of venous thromboembolism among current compared with noncurrent OCP users (14 studies; OR 2.97, 95% confidence interval [CI] 2.46-3.59). We found twofold increased odds of ischemic stroke (seven studies; OR 1.90, 95% CI 1.24-2.91). There was no evidence of increased risk of hemorrhagic stroke (four studies; OR 1.03, 95% CI 0.71-1.49) or MI (eight studies; OR 1.34, 95% CI 0.87-2.08). Current use of combined OCPs is associated with increased odds of venous thromboembolism and ischemic stroke but not hemorrhagic stroke or MI.


Is acute recurrent pancreatitis in children a precursor of chronic pancreatitis? A long-term follow-up study of 93 cases.
In view of paucity of literature we analyzed our experience of acute recurrent pancreatitis (ARP) to study clinical profile and long-term outcome. Over 13 years, 93 consecutive children (≤18 years) diagnosed to have ARP were included in this study. Magnetic resonance cholangiopancreatography was done at baseline and on follow-up. Common mutations for serine-protease-inhibitor (SPINK1 N34S), protease inhibitor (PRSS1 R122S) and cystic fibrosis transmembrane conductance regulator (CFTR deltaF508, 5T) were studied in 22 idiopathic cases. The median age of the children with ARP was 13 (10-14.5) years, 53 were males. Etiology included biliary in 14 (15%), pancreas divisum in 6 (7%), others in 3 (3.5%) and idiopathic in the remaining 70 (75%). SPINK1 mutation was found in 10/22 (45%) cases. Over a median follow-up of 25.5 (8.25-48) months, 37 (42%) of 88 (5 lost to follow-up) developed chronic pancreatitis (CP). On multivariate analysis idiopathic etiology (p<0.03), presence of SPINK1 mutation (p=0.01), longer follow-up (p<0.001) were associated with progression to CP. Biliopancreatic structural/obstructive causes should always be looked for. It seems ARP is a precursor of CP and progression is associated with idiopathic etiology and presence of genetic mutations. Hence, patients with ARP should be kept on regular follow-up to detect CP.


Direct measurement of antibody production in cell suspensions using an enzyme-linked immunosorbent assay.
We have developed an enzyme-linked immunosorbent assay (ELISA) to measure antibody production in cell suspensions using highly sensitive avidin-biotinylated peroxidase (ABC) reagents. The cells are serially diluted in media and placed directly on a standard antigen-coated microtiter plate for 6 h, and the plate is then washed and processed to determine the bound antibody. The amount of antibody detected is reduced by puromycin indicating in vitro synthesis. Standard errors of the means of optical density readings of replicate samples are less than 10%. The background readings and readings obtained using non-immune cells are negligible, demonstrating no significant contamination by endogenous peroxidases.


Reconstructive procedure for unstable radial-sided triangular fibrocartilage complex avulsions.
Radial-sided avulsions of the triangular fibrocartilage complex (TFCC) (Palmer 1D) with distal radioulnar joint (DRUJ) instability remain a challenging pathology to treat. We tested an intra-articular reconstruction that addresses unstable radial-sided TFCC avulsions. Ten preserved, dissected, cadaveric forearm specimens with intact TFCC and without ulnar-positive variance had biomechanical testing using a hydraulic testing device. The measurement of total displacement of the ulna relative to the radius was performed with an applied load ranging from 20 N in a volar direction to 20 N in a dorsal direction. Specimens were tested sequentially with intact TFCC, with surgically induced Palmer 1D lesions, and after reconstruction of the TFCC. All tests were performed at neutral, maximal pronation, and maximal supination. The mean total displacements of the DRUJ of the specimens at neutral rotation were as follows: 4.1 +/- 0.4 mm for the intact specimens compared with 11.8 +/- 0.8 mm after creation of the tear and 3.9 +/- 0.7 mm for the reconstructed specimens. In maximal pronation the mean total displacements were as follows: 2.4 +/- 0.3 mm intact versus 4.9 +/- 0.7 mm for torn and 2.1 +/- 0.3 mm after reconstruction. In maximal supination the mean total displacements were as follows: 1.4 +/- 0.2 mm intact versus 5.7 +/- 1.3 mm for torn and 1.0 +/- 0.1 mm after reconstruction. All specimens obtained the preoperative pronation and supination motion after the reconstruction. Current procedures are unable to restore DRUJ stability without a significant limitation of pronation and supination. This intra-articular reconstruction of radial-sided TFCC avulsions succeeded in restoring baseline stability to the DRUJ without interfering with pronation/supination.


Early walking time is associated with recovery of activities of daily living during hospitalization in older patients with community-acquired pneumonia: A single-center prospective study.
Pneumonia is a common disease with a high mortality rate among older adults that is associated with a decline in activities of daily living (ADL) during hospitalization. The aims of this study were to investigate the following: (i) early physical activity time among older patients hospitalized with community-acquired pneumonia; and (ii) the association of physical activity time with the recovery of ADL. A prospective observational study was carried out in patients aged ≥65 years hospitalized with community acquired pneumonia. We measured the time spent standing and walking as physical activity time using the activPAL accelerometer from the third to the ninth day of admission. Patients underwent rehabilitation during their hospitalization, and rehabilitation effectiveness was calculated using the motor Functional Independence Measure on admission and at day 10. We used stepwise multiple regression to examine the relationship between physical activity time and rehabilitation effectiveness. A total of 87 patients were included in the analysis. Median (interquartile range) physical activity time was 69 min/day (43-103 min/day). In the multiple regression model, a greater daily walking time, higher cognitive and physical function, and ADL at admission were independently associated with rehabilitation effectiveness (adjusted R2 = 0.32, P < 0.0001). For every increase of 10 min/day of walking time, ADL improved by 7.8% (B = 7.8, 95% CI 1.3-14.2, P = 0.02). Older patients hospitalized with community-acquired pneumonia have low levels of physical activity, and increasing early walking time might be an effective strategy to accelerate the recovery of ADL. Geriatr Gerontol Int 2021; 21: 1099-1104.


Potential application of gaseous nitric oxide as a topical antimicrobial agent.
The presence of bacterial colonization in non-healing wounds and burn injuries interferes significantly with the normal process of healing. Recent evidence suggests that nitric oxide (NO) plays an important role in host defense against infection and regulates wound healing and angiogenesis. We investigated the potential application of a medical-grade gaseous form of NO (gNO) as a novel antibacterial agent in wound infection. Using a continuous horizontal-flow delivery system, the antibacterial activity of gNO was tested in vitro against a range of pathogens, including clinical isolates of Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Group B Streptococcus, Pseudomonas aeruginosa, and Candida albicans. To probe the effect of topical application of gNO on the human skin, the proliferation and extracellular matrix gene expression of human dermal fibroblasts in culture were also analyzed by (3)H-thymidine incorporation assay and Northern blot techniques, respectively. Potent bacteriocidal activity was observed at 200 ppm gNO with an average of 4.1 +/- 1.1 h to completely stop bacterial growth. Interestingly, this dose of gNO did not show any cytotoxic effect in human dermal fibroblasts in culture exposed for up to 48 h. Analysis of gene transcription in fibroblasts revealed a significant increase in MMP-1 mRNA expression as early as 2 h post-exposure to gNO. Although to a lesser degree, a significant reduction in type I procollagen was also observed in the same fibroblasts. The results of this study suggest that exogenous gaseous NO has potent significant antibacterial properties that can be beneficial in reducing bacterial burden in infected wound in burn injuries or non-healing ulcers.


The content of docosahexaenoic acid in the maternal diet differentially affects the immune response in lactating dams and suckled offspring.
The objective of this study was to determine the effect of feeding a maternal diet supplemented with docosahexaenoic acid (DHA) while also containing adequate amounts of arachidonic acid on immune system development and function in suckled offspring and lactating rats. Sprague-Dawley dams were randomized to one of the two nutritionally adequate experimental diets 24-48 h prior to parturition: control diet (N = 12, 0 % DHA) or high DHA diet (N = 8, 0.9 % DHA of total fatty acids). Diets were fed throughout the lactating/suckling period (21 days), and then, dams and pups were terminated, and immune cell phenotypes and cytokine production by mitogen- or ovalbumin-stimulated splenocytes were measured. Feeding dams a high DHA diet resulted in a higher proportion of 18:3n-3, 22:5n-3 and 22:6n-3 found in pup's stomach content (breast milk; P < 0.01). Feeding the high DHA diet had no impact on growth parameters or the ex vivo cytokine production by mitogen-stimulated splenocytes in both dams and pups. There was a higher proportion of OX12+CD80+ cells and a lower production of TGF-β by splenocytes after ovalbumin stimulation in pups from dams fed the DHA diet (both P < 0.05) while maintaining a similar IL-2 production. LPS-stimulated splenocytes from dams fed the high DHA diet produced more TNF-α versus control diet (P < 0.05). Overall, our results suggest that DHA supplementation in the maternal diet does not change the immune response to mitogens but positively affects the activation of B cells as well as the response to a potential food antigen upon challenge in suckled offspring.


Medicinal plants used for neurological and mental disorders in Navarra and their validation from official sources.
This paper provides important ethnopharmacological information on plants used in neurological and mental disorders in Navarra. Information was collected using semi-structured ethnobotanical interviews with 667 informants in 265 locations. In order to confirm the pharmacological validation of the uses claimed by the informants, monographs from Official International Agencies (ESCOP, Commission E, WHO and EMA) were reviewed. A literature review was conducted focusing on the plants that were widely used but had no published monograph. A total of 172 pharmaceutical uses were reported, for 46 plants and 26 families, mainly represented by Lamiaceae (15%), Asteraceae (13%), Rosaceae and Rutaceae (7%, each one), and Clusiaceae, Malvaceae, Papaveraceae and Urticaceae (4%, each one). The most frequently used parts were inflorescence (39%), flowered aerial parts (16%), and aerial parts (13%), followed by inflorescence bract (8%) and leaves (7%). Nine out of 46 plants (20%) and 81 of 172 uses (47%), have already been pharmacologically validated. The remaining 37 plants (of total 46, 80%) have been reported for neurological and mental disorders and need to be screened through standard pharmacological and clinical procedures for their activities. The most used species are Chamaemelum nobile (L.) All., Jasonia glutinosa (L.) DC., and Santolina chamaecyparissus L. ssp. squarrosa (DC.) Nyman, in all cases the administration as infusion. Data indicate a high degree of plants knowledge in Navarra regarding neurological and mental disorders. The present study constitutes a good basis for further phytochemical and pharmacological research of C. nobile, J. glutinosa and S. chamaecyparissus, which could be of interest in the design of new inexpensive, effective and safe drugs.


Nicotine pre-exposure reduces stroke-induced glucose transporter-1 activity at the blood-brain barrier in mice.
With growing electronic cigarette usage in both the smoking and nonsmoking population, rigorous studies are needed to investigate the effects of nicotine on biological systems to determine long-term health consequences. We have previously shown that nicotine exerts specific neurovascular effects that influence blood brain barrier (BBB) function in response to stroke. In this study, we investigated the effects of nicotine on carrier-mediated glucose transport into ischemic brain. Specifically, the present study investigates glucose transporter-1 (GLUT1) function and expression at the BBB in a focal brain ischemia model of mice pre-exposed to nicotine. Nicotine was administrated subcutaneously by osmotic pump at the dose of 4.5 mg/kg/day for 1, 7, or 14 days to reflect the plasma levels seen in smokers. Ischemic-reperfusion (IR) injury was induced by 1 h transient middle cerebral artery occlusion (tMCAO) and 24 h reperfusion. Glucose transport was estimated using an in situ brain perfusion technique with radiolabeled glucose and brain vascular GLUT1 expression was detected with immunofluorescence. The nicotine pre-exposure (1, 7 & 14 day) resulted in significant reduction in D-glucose influx rate (K in ) across the BBB, with a 49% reduction in 14 day nicotine-infused animals. We observed a 41% increase in carrier-mediated glucose transport across the BBB in saline-infused tMCAO animals compared to saline-infused sham animals. Interestingly, in the tMCAO group of animals pre-exposed to nicotine for 14 days had significantly attenuated increased glucose transport by 80% and 38% compared to saline-infused tMCAO and sham animals respectively. Furthermore, immunofluorescence studies of GLUT1 protein expression in the brain microvascular endothelium confirmed that GLUT1 was also induced in saline-infused tMCAO animals and this protein expression induction was reduced significantly (P < 0.01) with 14 day nicotine pre-exposure in tMCAO animals. Nicotine pre-exposure reduced the IR-enhanced GLUT1 transporter function and expression at the BBB in a focal brain ischemia mouse model. These studies suggest that nicotine exposure prior to stroke could create an enhanced glucose deprived state at the neurovascular unit (NVU) and could provide an additional vulnerability to enhanced stroke injury.


Hospitalization in pregnancy due to human respiratory syncytial virus associated disease.
Despite pregnancy being a state of physiologic immune alteration, it has not previously been described as a risk factor for hospitalization due to human respiratory syncytial virus (RSV). This retrospective case series describes two cases of hospitalization due to RSV associated illness in pregnancy. It remains to be determined if the current RSV surge is more dangerous to pregnant patients than those in seasons past. These cases support the importance of maintaining RSV on the differential for respiratory illness in pregnancy.


Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection.
Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.


NMR structures of phospholipase A2 reveal conformational changes during interfacial activation.
It has long been proposed that the higher activity of phospholipase A2 (PLA2) for substrates presented as multimolecular aggregates compared to dispersed molecules (interfacial activation) arises due to a conformational change in the enzyme. X-ray studies have, however, failed to identify any such change. Here we report the solution structures of porcine pancreatic PLA2 both free and as a ternary complex with micelles and a competitive inhibitor. Important differences between these structures indicate that conformational changes may play an important role in the mechanism of interfacial activation in PLA2s.


The effects of diverse proteins on the solubilization of various hydrophobic probes by protein.detergent complexes.
The solubilization behavior of various protein.detergent complexes with respect to a particular water-insoluble organic substance ("hydrophobic probe") dimethylaminoazobenzene, was reported in earlier studies. The present report describes further the solubilization of other hydrophobic probes (e.g. Sudan II, naphthalene, anthracene and azobenzene) in various protein.sodium dodecyl sulfate complexes, in order to enlarge the scope of our understanding of these phenomena, which undoubtedly play a part in the transport of different water-insoluble organic substances in the living organisms. Solubilization by the various protein.SDS complexes is found to be specific for each probe. The amount of a particular probe solubilized is nearly always equal to the amounts which are solubilized by pure SDS micelles equivalent in amount to the SDS bound. Serious exceptions are found with two heme proteins (e.g. myoglobin and hemoglobin) and a few others. The hemeprotein.SDS complexes also exhibit regions of flat plateaus in the solubilization curves, whereas the binding equilibria show progressively larger amounts of SDS bound. The solubilization of probes by cationic detergent (cetylpyridinium chloride and cetyltrimethylammonium bromde).protein complexes indicate that the solubilization phenomena are related to the environment of the binding sites (the cationic detergents are known to bind at different sites on the protein than the anionic detergents, i.e. SDS in the present case). With anionic detergents the effective chain length of the pseudo-micellar protein.detergent clusters is sufficient to cause an increase in solubilizing effectiveness of about 1.5 between the complexes and pure micelles. When small probes such as naphthalene are used such ratios are found. With larger probes the effectiveness ratio is reduced to 1.0 or even less as a result of steric interference with the formation of the protein.detergent.probe clusters. The solubilization energy exhibited by each protein.detergent complex is largely determined by the individual protein, and by the charge on the detergent.


Enhanced mutability at the tk locus in the radiosensitive double-strand break repair mutant xrs5.
The thymidine kinase locus (tk) has been utilised as the target locus to measure the induced mutation frequency following X-irradiation in the X-ray-sensitive xrs5 mutant and its parent CHO K1 line of Chinese hamster cells. Mutations to tk- cells were measured by plating cells in selective medium containing trifluorothymidine after a post-irradiation expression time of 4 days. Our results show that the mutation frequency was 3-4 times higher in the xrs5 mutant than in the CHO K1 cell line. This enhanced mutation frequency in xrs5 is though to result from the deficiency in DNA double-strand break repair in this cell line which also results in the enhanced cell killing and higher frequencies of chromosomal aberrations in response to X-irradiation. The findings of the present study suggest that DNA double-strand break is a critical lesion leading to mutations in irradiated cells.


Synthesis and Toxicity of Halogenated Bisphenol Monosubstituted-Ethers: Establishing a Library for Potential Environmental Transformation Products of Emerging Contaminant.
As an important branch of halogenated bisphenol compounds, the halogenated bisphenol monosubstituted-ether compounds have received a lot of attention in environmental health science because of their toxicity and variability. In this study, a synthetic method for bisphenol monosubstituted-ether byproduct libraries was developed. By using the versatile and efficient method, tetrachlorobisphenol A, tetrabromobisphenol A, and tetrabromobisphenol S monosubstituted alkyl-ether compounds were accessed in 39-82 % yield. Subsequently, the cytotoxicity of 27 compounds were screened using three different cell lines (HepG2, mouse primary astrocytes and Chang liver cells). Compound 2,6-dibromo-4-[3,5-dibromo-4-(2-hydroxyethoxy)benzene-1-sulfonyl]phenol was more toxic than other compounds in various cells, and the sensitivity of this compound to the normal hepatocytes and cancer cells was inconsistent. The compounds 2,6-dichloro-4-(2-{3,5-dichloro-4-[(prop-2-en-1-yl)oxy]phenyl}propan-2-yl)phenol and 2,6-dibromo-4-(2-{3,5-dibromo-4-[(prop-2-en-1-yl)oxy]phenyl}propan-2-yl)phenol were the most toxic to HepG2 cells, and most of the other compounds inhibited cell proliferation. Moreover, typical compounds were also reproductive and developmental toxic to zebrafish embryos at different concentrations. The synthetic byproduct libraries could be used as pure standard compounds and applied in research on environmental behavior and the transformation of halogenated flame retardants.


Exercise Self-Efficacy as a Mediator between Goal-Setting and Physical Activity: Developing the Workplace as a Setting for Promoting Physical Activity.
Physical activity (PA) is ranked as a leading health indicator and the workplace is a key setting to promote PA. The purpose of this study was to examine how goal-setting and exercise self-efficacy (SE) during a health promotion program influenced PA level among Japanese workers. Using a cross-sectional study design, we surveyed 281 employees. The short version of the International Physical Activity Questionnaire was used to assess PA level. Exercise SE was assessed using a partially modified version of Oka's exercise SE scale. Personal goals were assessed as the total numbers of "yes" responses to five items regarding "details of personal goals to perform PA". A mediational model was used to examine whether exercise SE mediates between the number of personal goals and PA level. The mean age of the participants was 46.3 years, 76.2% were men, and the most common occupational category was software engineer (30.6%). The average PA level per week exceeded the recommended level in 127 participants (45.2%). One hundred and eighty-four participants (65.5%) set some form of concrete personal goal to perform PA. The relationship between the number of personal goals and PA level was mediated by exercise SE. Our study showed that exercise SE mediates goal-setting and increases PA. The results suggest that the components of PA promotion programs should be tailored to enhance participants' confidence in performing PA.


The utility of syndecan-1 circulating levels as a biomarker in patients with previous or active COVID-19: a systematic review and meta-analysis.
With the emergence of coronavirus disease of 2019 (COVID-19), several blood biomarkers have been identified, including the endothelial biomarker syndecan-1, a surface proteoglycan. In the current systematic review and meta-analysis, we aimed to assess the diagnostic and prognostic role of syndecan-1 in COVID-19. PubMed, Embase, Scopus, and Web of Science, as international databases, were searched for relevant studies measuring blood syndecan-1 levels in COVID-19 patients, COVID-19 convalescents, and healthy control subjects, in patients with different COVID-19 severities and/or in COVID-19 patients with poor outcomes. Random-effect meta-analysis was performed using STATA to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for the comparison between COVID-19 patients and healthy control subjects or COVID-19 convalescents and controls. After screening by title/abstract and full text, 17 studies were included in the final review. Meta-analysis of syndecan-1 levels in COVID-19 compared with healthy control subjects revealed that patients with COVID-19 had significantly higher syndecan-1 levels (SMD 1.53, 95% CI 0.66 to 2.41, P < 0.01). In contrast, COVID-19 convalescent patients did not show significant difference with non-convalescents (SMD 0.08, 95% CI -0.63 to 0.78, P = 0.83). Regarding disease severity, two studies reported that more severe forms of the disease were associated with increased syndecan-1 levels. Moreover, patients who died from COVID-19 had higher syndecan-1 levels compared with survivors (SMD 1.22, 95% CI 0.10 to 2.33, P = 0.03). Circulating syndecan-1 level can be used as a biomarker of endothelial dysfunction in COVID-19, as it was increased in COVID-19 patients and was higher in more severe instances of the disease. Further larger studies are needed to confirm these findings and further enlighten the role of syndecan-1 in clinical settings.


Sorption and desorption of organophosphate esters with different hydrophobicity by soils.
Organophosphate esters (OPEs) are ubiquitous contaminants with potentially hazardous effects on both the environment and human health. Knowledge about the soil sorption-desorption process of organic chemicals is important in order to understand their fate, mobility, and bioavailability, enabling an estimation to be made of possible risks to the environment and biota. The aim of this study was to use the batch equilibrium technique to evaluate the sorption-desorption behavior of seven OPEs (TCEP, TCPP, TBEP, TDCP, TBP, TPhP, and EHDP) in soils with distinctive characteristics (two unamended soils and a soil amended with sewage sludge). The equilibrium concentrations of the OPEs were determined by high performance liquid chromatography coupled to a triple quadrupole mass spectrometer (HPLC-MS/MS). All the compounds were sorbed by the soils, and soil organic carbon (OC) played an important role in this process. The sorption of the most soluble OPEs (TCEP, TCPP, and TBEP) depended on soil OC content, although desorption was ≥ 58.1%. The less water-soluble OPEs (TDCP, TBP, TPhP, and EHDP) recorded total sorption (100% for TPhP and EHDP) or very high sorption (≥ 34.9%) by all the soils and were not desorbed, which could be explained by their highly hydrophobic nature, as indicated by the logarithmic octanol/water partition coefficient (Kow) values higher than 3.8, resulting in a high affinity for soil OC. The results of the sorption-desorption of the OPEs by soils with different characteristics highlighted the influence of these compounds' physicochemical properties and the content and nature of soil OC in this process.


Regional treatment options for patients with ocular melanoma metastatic to the liver.
Ocular melanoma is the most common primary ocular malignancy and has a significant predilection for metastasis to the liver. More than 40% of patients have hepatic metastases present at initial diagnosis, and the liver becomes involved in up to 95% of individuals who develop metastatic disease. The median survival of patients after diagnosis of liver metastasis ranges from 2 to 7 months. Metastatic disease localized to the liver has proven to be resistant to most available chemotherapy and immunotherapy regimens. Recognition of the grave prognosis associated with liver metastasis from ocular melanoma has led to the evaluation of new regional treatment modalities primarily designed to control tumor progression in the liver, including hepatic arterial chemotherapy, hepatic artery chemoembolization, regional immunotherapy, isolated hepatic perfusion, and percutaneous hepatic perfusion. This article reviews the efficacy, outcomes, and morbidities of the multiple locoregional therapies available today.


Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis.
To eliminate cervical cancer as a public health problem, the World Health Organization had recommended routine vaccination of adolescent girls with two doses of the human papillomavirus (HPV) vaccine before sexual initiation. However, many countries have yet to implement HPV vaccination because of financial or logistical barriers to delivering two doses outside the infant immunisation programme. Using three independent HPV transmission models, we estimated the long-term health benefits and cost-effectiveness of one-dose versus two-dose HPV vaccination, in 188 countries, under scenarios in which one dose of the vaccine gives either a shorter duration of full protection (20 or 30 years) or lifelong protection but lower vaccine efficacy (e.g. 80%) compared to two doses. We simulated routine vaccination with the 9-valent HPV vaccine in 10-year-old girls at 80% coverage for the years 2021-2120, with a 1-year catch-up campaign up to age 14 at 80% coverage in the first year of the programme. Over the years 2021-2120, one-dose vaccination at 80% coverage was projected to avert 115.2 million (range of medians: 85.1-130.4) and 146.8 million (114.1-161.6) cervical cancers assuming one dose of the vaccine confers 20 and 30 years of protection, respectively. Should one dose of the vaccine provide lifelong protection at 80% vaccine efficacy, 147.8 million (140.6-169.7) cervical cancer cases could be prevented. If protection wanes after 20 years, 65 to 889 additional girls would need to be vaccinated with the second dose to prevent one cervical cancer, depending on the epidemiological profiles of the country. Across all income groups, the threshold cost for the second dose was low: from 1.59 (0.14-3.82) USD in low-income countries to 44.83 (3.75-85.64) USD in high-income countries, assuming one dose confers 30-year protection. Results were consistent across the three independent models and suggest that one-dose vaccination has similar health benefits to a two-dose programme while simplifying vaccine delivery, reducing costs, and alleviating vaccine supply constraints. The second dose may become cost-effective if there is a shorter duration of protection from one dose, cheaper vaccine and vaccination delivery strategies, and high burden of cervical cancer.


Transcriptional and post-transcriptional regulation of transmembrane protein 132A.
Transmembrane protein 132A (TMEM132A) was first isolated from rat brain using PCR-selected cDNA subtraction, and it was found to be predominantly expressed in the brain. However, the transcriptional regulation of the TMEM132A gene has not been fully characterized. In this study, we characterized the promoter activity of the 880-bp region upstream of the mouse TMEM132A, identifying several putative sites recognized by transcription factors, which are highly conserved between the mouse and human TMEM132A genes. Using four different mouse cell lines (Neuro2a, NSC-34, NIH3T3, and Raw264.7), we first evaluated the intrinsic levels of TMEM132A mRNA and protein expression. Interestingly, TMEM132A mRNA was expressed in all four cell lines, whereas the protein was negligible in Raw264.7 cells even by transfection of TMEM132A gene. Then, we analyzed the TMEM132A promoter activity using serial deleted constructs, finding it was nearly same pattern in all four cell lines. A mutational analysis of the TMEM132A promoter identified a critical region for its activation just upstream of the transcriptional start site. Finally, we investigated the levels of TMEM132A mRNA and protein after exposure to five different neurotoxic stimuli, including thapsigargin, tunicamycin, serum starvation, homocysteine, and hydrogen peroxide. Treatment with thapsigargin, a calcium modulating agent, markedly attenuated the levels of TMEM132A mRNA and protein in NSC-34 cells. These results give new insight into the mechanisms involved in regulating TMEM132A expression, and suggest that several transcriptional and post-transcriptional pathways regulate TMEM132A expression under developmental and pathophysiological conditions.


Changes in hepatic protein expression in spontaneously hypertensive rats suggest early stages of non-alcoholic fatty liver disease.
Hypertension is a systemic disorder affecting numerous physiological processes throughout the body. As non-alcoholic fatty liver disorder (NAFLD) is a common comorbidity of hypertension in humans, we hypothesized that molecular hepatic physiology would be altered in a model of genetic hypertension. Despite the broad use of the spontaneously hypertensive rat (SHR) model, little is known regarding how hypertension influences hepatic function under basal conditions. In order to determine whether hypertension induces changes in the hepatic protein expression suggestive of early stages of NAFLD, we compared the whole tissue proteome of livers from SHR and Wistar Kyoto (WKY) 16 week old rats using 2DGE and MALDI-TOF MS. Fifteen proteins were identified that display different levels of expression between the SHR and WKY livers: 50% of proteins have mitochondrial or anti-oxidant functions while 20% are involved in lipid metabolism. Quininoid dihydropterin reductase, sulfite oxidase, and glutathione-S-transferase mu 1 were all identified as either undergoing a difference in post-translation modification or a difference in protein abundance in SHR compared to WKY livers. As oxidative stress is a well described component of both NAFLD and hypertension in SHR, the identification of novel changes in protein expression provides possible mechanisms connecting these two pathologies in humans.


Conversion of L-tryptophan to serotonin and melatonin in human melanoma cells.
We showed in human melanoma cells tryptophan hydroxylase (TPH) and hydroxyindole methyltransferase genes expression with the sequential enzymatic activities of TPH, serotonin (Ser) N-acetyltransferase and hydroxyindole methyltransferase. The presence of the products Ser, 5OH-tryptophan, N-acetylserotonin, melatonin (Mel), 5-methoxytryptamine and 5-methoxytryptophol was documented by liquid chromatography-mass spectrometry. Thus, human melanoma cells can synthesize and metabolize Ser and Mel.


P53 status as a predictive biomarker for patients receiving neoadjuvant radiation-based treatment: a meta-analysis in rectal cancer.
Numerous studies have yielded inconsistent results regarding the relationship between p53 status and the response to neoadjuvant radiation-based therapy in patients with rectal cancer. We conducted a meta-analysis to clarify the relationship between p53 status and response to radiation-based therapy in rectal cancer. A total of 30 previously published eligible studies including 1,830 cases were identified and included in this meta-analysis. Wild-type form of p53 status (low expression of p53 protein and/or wild-type p53 gene) was associated with pathologic response in rectal cancer patients who received neoadjuvant radiation-based therapy (good response: risk ratio [RR] =1.30; 95% confidence intervals [CI] =1.14-1.49; p<0.001; complete response RR=1.65; 95% CI=1.19-2.30; p=0.003; poor response RR=0.85; 95% CI=0.75-0.96; p=0.007). In further stratified analyses, this association remained for sub-groups of good and poor response in neoadjuvant radiotherapy (RT) setting, good and complete response in chemoradiotherapy (CRT) setting. And the association between response and the presence of p53 gene mutations was stronger than that between response and protein positivity. The results of the present meta-analysis indicate that P53 status is a predictive factor for response in rectal cancer patient undergoing neoadjuvant radiation-based therapy.


Correlation Between Timed Barium Esophagogram and Esophageal Transit Scintigraphy Results in Achalasia.
Timed barium esophagogram (TBE) and esophageal transit scintigraphy (ETS) have been adopted as useful ways to evaluate achalasia patients. TBE has merit as a simple, non-invasive, and convenient method. The study sought to compare the results of these two tests and verify their usefulness in evaluating treatment response. In addition, we assessed whether TBE could effectively replace ETS through correlation analysis. The medical records of 50 achalasia patients treated between September 2011 and June 2014 were reviewed retrospectively. The height and width of the barium column at 1, 2, and 5 min were measured by TBE. Half-life (T 1/2, min) and R 30 (percentage of remaining radioactivity 30 s after radioisotope ingestion) were measured by ETS. Both tests were performed before and after treatment, and the tests were carried out 1 and 2 days after procedures. And we analyzed the correlation between the parameters from the two tests. The parameters of TBE and ETS were improved after treatment (p < 0.05). Before treatment, the height and width results at 5 min from TBE positively correlated with the T 1/2 parameter from ETS (correlation coefficients of 0.59 and 0.75, respectively). After treatment, the correlation coefficients between the 5-min height and width of the barium column by TBE and T 1/2 by ETS were 0.55 and 0.46, respectively. Both TBE and ETS are useful modalities in assessing esophageal emptying and response to achalasia treatment. TBE and ETS results have a statistically significant correlation both pre- and post-treatment. We suggest that TBE could effectively replace ETS for the assessment of achalasia.


Thermal Characterization of Phantoms Used for Quality Assurance of Deep Hyperthermia Systems.
Tissue mimicking phantoms are frequently used in hyperthermia applications for device and protocol optimization. Unfortunately, a commonly experienced limitation is that their precise thermal properties are not available. Therefore, in this study, the thermal properties of three currently used QA phantoms for deep hyperthermia are measured with an "off-shelf" commercial thermal property analyzer. We have measured averaged values of thermal conductivity (k = 0.59 ± 0.07 Wm-1K-1), volumetric heat capacity (C = 3.85 ± 0.45 MJm-3K-1) and thermal diffusivity (D = 0.16 ± 0.02 mm2s-1). These values are comparable with reported values of internal organs, such as liver, kidney and muscle. In addition, a sensitivity study of the performance of the commercial sensor is conducted. To ensure correct thermal measurements, the sample under test should entirely cover the length of the sensor, and a minimum of 4 mm of material parallel to the sensor in all directions should be guaranteed.


Outdoor ozone and building-related symptoms in the BASE study.
Reactions between ozone and indoor contaminants may influence human health and indoor air quality. The U.S. EPA Building Assessment Survey and Evaluation (BASE) study data were analyzed for associations between ambient ozone concentrations and building-related symptom (BRS) prevalence. Multiple logistic regression (MLR) models, adjusted for personal, workplace, and environmental variables, revealed positive relationships (P < 0.05) between ambient ozone concentrations and upper respiratory (UR), dry eyes, neurological and headache BRS (odds ratios ranged from 1.03 to 1.04 per 10 mug/m(3) increase in ambient ozone concentrations). Other BRS had marginally significant relationships with ambient ozone (P < 0.10). A linear dose-response in UR symptoms was observed with increasing ambient ozone (P = 0.03); most other symptoms showed similar but not statistically significant trends. Ambient ozone correlated with indoor concentrations of some aldehydes, a pattern suggesting the occurrence of indoor ozone chemistry. Coupled with the MLR ambient ozone-BRS analysis, this correlation is consistent with the hypothesis that ozone-initiated indoor reactions play an important role in indoor air quality and building occupant health. Replication with increased statistical power and with longitudinal data is needed. If the observed associations are confirmed as causal, ventilation system ozone removal technologies could reduce UR BRS prevalence when higher ambient ozone levels are present. This paper provides strong statistical evidence that supports (but does not prove) the hypothesis that ozone entrained into buildings from the outdoor air is involved in increasing the frequency that occupants experience and a range of upper and lower respiratory, mucosal and neurological symptoms by as much as a factor of 2 when ambient ozone levels increase from those found in low-ozone regions to those typical of high-ozone regions. Although replication is needed, the implication is that reducing the amount of ozone entrained into building ventilation systems, either by ambient pollution reduction or engineered gas-phase filtration, may substantially reduce the prevalence of these symptoms experienced by occupants.


Cognitive Expectancies for Hypnotic Use among Older Adult Veterans with Chronic Insomnia.
To examine relationships between cognitive expectancies about sleep and hypnotics and use of medications commonly used for insomnia (hypnotics). We analyzed baseline data from older veterans who met diagnostic criteria for insomnia and were enrolled in a trial comparing CBTI delivered by a supervised, sleep educator to an attention control condition (N = 159; 97% male, mean age 72 years). We classified individuals as hypnotic users (N = 23) vs. non-users (N = 135) based upon medication diaries. Associations between hypnotic status and Dysfunctional Beliefs and Attitudes about Sleep-16 (DBAS) total score (0-10, higher = worse) and two DBAS medication item scores (Item 1: "…better off taking a sleeping pill rather than having a poor night's sleep;" Item 2: "Medication… probably the only solution to sleeplessness"; 0-10, higher = worse) were examined in logistic regression models. Higher scores on the DBAS medication items (both odds ratios = 1.3; p-values < .001) were significantly associated with hypnotic use. DBAS-16 total score was not associated with hypnotic use. Cognitive expectancy (dysfunctional beliefs) about hypnotics was associated with hypnotic use in older adults with chronic insomnia disorder. Strategies that specifically target dysfunctional beliefs about hypnotics are needed and may impact hypnotic use in older adults.


Use of metformin and aspirin is associated with delayed cancer incidence.
While the chemoprevention effect of aspirin is well-established, the effects of metformin in cancer prevention is still controversial. This study is to investigate the use of aspirin, metformin, or the combination of both is associated with delayed cancer incidence. This dataset is based on the electronic medical record of public hospitals in Hong Kong. Patients were classified into 1. aspirin user, 2. metformin user, 3. both aspirin and metformin user and 4. control group with neither aspirin nor metformin used. Aspirin and/or metformin must have been taken for over 6 months in the treatment group and cancer incidences was counted at least 6 months after exposure to such medications. The primary outcome of this study was overall incidence of cancer during the follow-up period. The secondary outcomes were cancer incidences of specific sites, including colon/rectum, liver, oesophagus, pancreas, stomach, lung, breast, kidney, bladder and prostate. Cox proportional hazards regression models were fitted to estimate hazard ratios of cancer risks. Inverse probability of treatment weighting was used to control for the medication effects. A total of 120,971 aspirin users, 11,365 metformin users, and 6630 aspirin plus metformin users, were identified. Compare to the control groups, those who used aspirin alone demonstrated a significant reduction in overall cancer risk (HR 0.80, 95% CI 0.73-0.87). Similarly, those who used metformin alone also showed an overall reduction in cancer risk (HR 0.79, 95% CI 0.71-0.88). Patients who received both aspirin and metformin showed the most significant reduction in overall cancer risk (HR 0.53, 95% CI 0.45-0.63). Metformin showed a significant reduction in cancer risk of lung, oesophagus and bladder. There is a similar decrease in overall cancer rate with the use of aspirin or metformin alone. A more significant reduction in overall cancer risk was found with the use of both agents.


Erratum: The Significance of Rectus Femoris for the Favorable Functional Outcome After Total Femur Replacement: Erratum.
[This corrects the article DOI: 10.1097/GOX.0000000000000610.].


Facilitating factors and barriers to the implementation of intensive home-based behavioural intervention for young children with autism.
Although international interest in intensive home-based early behavioural intervention for children with autism is increasing, there is little or no published research on the experiences of families conducting these programmes. One hundred and forty-one UK parents conducting Lovaas-style interventions with their young child with autism were asked to identify factors that acted as facilitative factors and barriers to the implementation of these programmes. Parents responded to written questions contained within a questionnaire survey, and their responses were subjected to a content analysis procedure. Several of the facilitative factors and barriers were found to be similar. For example, a supportive therapy team was the most frequently cited facilitative factor, and problems recruiting and maintaining a suitable team was the most frequently reported barrier. Other factors seemed to be more independent constructs. For example, an important barrier was the lack of time and personal energy, but plenty of time and energy was not cited as a facilitative factor. The practical implications of these results for families and for services supporting families engaged in intensive early behavioural intervention are discussed. In addition, more general implications for the designers of behavioural intervention programmes are identified.


Oligosaccharide, sucrose, and allulose effects on the pasting and retrogradation behaviors of wheat starch.
The pasting and retrogradation behaviors of starch are altered by the presence of sugars and are important in dictating the storage stability and texture of starch-containing foods. The use of oligosaccharides (OS) and allulose in reduced-sugar formulations is being explored. The objectives of this study were to determine the impacts of different types and concentrations (0% to 60% w/w) of OS (fructo-OS, gluco-OS, isomalto-OS, gluco-dextrin, and xylo-OS) and allulose on the pasting and retrogradation attributes of wheat starch compared to starch in water (control) or sucrose solutions using DSC and rheometry. Physicochemical properties of the additives and their effects on amylose leaching were also considered. Significant differences in starch pasting, retrogradation, and amylose leaching were found between the control and additive solutions, influenced by additive type and concentration. Allulose increased starch paste viscosity and promoted retrogradation over time (60% conc. PV = 7628 cP; ΔHret, 14 = 3.18 J/g) compared to the control (PV = 1473 cP; ΔHret, 14 = 2.66 J/g) and all OS (PV = 14 to 1834 cP; ΔHret,14 = 0.34 to 3.08 J/g). In the allulose, sucrose, and xylo-OS solutions, compared to the other OS types, the gelatinization and pasting temperatures of starch were lower, more amylose leaching occurred, and pasting viscosities were higher. Increasing OS concentrations elevated gelatinization and pasting temperatures. In most 60% OS solutions these temperatures exceeded 95 °C thereby preventing starch gelatinization and pasting in the rheological analysis, and in conditions relevant for inhibiting starch gelatinization in low moisture-sweetened products. Fructose-analog additives (allulose and fructo-OS) promoted starch retrogradation more than the other additives, while xylo-OS was the only additive that limited retrogradation across all OS concentrations. The correlations and quantitative findings from this study will assist product developers in selecting health-promoting sugar replacer ingredients that impart desirable texture and shelf-life properties in starch-containing foods.


A FLASH of insight into cellular chemistry: genetically encoded labels for protein visualization in vivo.
Genetically encoded fluorescent labels, such as green fluorescent protein, make it possible to visualize a protein's natural distribution and environment in living cells. A new approach to protein labeling in living cells has been devised in which a small, membrane-permeable ligand binds with high affinity and specificity to a short peptide motif that can be incorporated into the protein of interest; the ligand becomes brightly fluorescent after binding to the peptide.


Elastin in asthma.
Extracellular matrix is generally increased in asthma, causing thickening of the airways which may either increase or decrease airway responsiveness, depending on the mechanical requirements of the deposited matrix. However, in vitro studies have shown that the altered extracellular matrix produced by asthmatic airway smooth muscle cells is able to induce increased proliferation of non-asthmatic smooth muscle cells, which is a process believed to contribute to airway hyper-responsiveness in asthma. Elastin is an extracellular matrix protein that is altered in asthmatic airways, but there has been no systematic investigation of the functional effect of these changes. This review reveals divergent reports of the state of elastin in the airway wall in asthma. In some layers of the airway it has been described as increased, decreased and/or fragmented, or unchanged. There is also considerable evidence for an imbalance of matrix metalloproteinases, which degrade elastin, and their respective inhibitors the tissue inhibitors of metalloproteinases, which collectively help to explain observations of both increased elastin and elastin fragments. A loss of lung elastic recoil in asthma suggests a mechanical role for disordered elastin in the aetiology of the disease, but extensive studies of elastin in other tissues show that elastin fragments elicit cellular effects such as increased proliferation and inflammation. This review summarises the current understanding of the role of elastin in the asthmatic airway.


Expression of Nestin and Glial Fibrillary Acidic Protein in the Marginal Ischemic Zone of the Brain in SHR Rats.
We studied spatial organization and structural characteristics of striatal glial cells in spontaneously hypertensive rats (SHR) in 48 h after 30-min focal ischemia. Immunocytochemical analysis of nestin and glial fibrillar acidic protein (GFAP) revealed 3 types of activated astrocytes: expressing only nestin, only GFAP, or both markers. There were no nestin-immunopositive astrocytes in the striatum of sham-operated rats. In cells expressing nestin and GFAP, localization of these markers did not completely coincide, which can be explained by different functions of these proteins or formation of heterodimers of nestin with other intermediate filament proteins.


[RECUR - Establishment of An Automated Digital Registry for Patients with Recurrent Stones in the Upper Urinary Tract].
Kidney stones, like cardiovascular diseases and diabetes mellitus, affect a large number of people. Patients suffer from acute pain, repeated hospitalizations and associated secondary diseases, such as arterial hypertension and renal insufficiency. This results in considerable costs for the society and its health care system. The recurrence rate is as high as 50%. The registry for RECurrent URolithiasis (RECUR) aims to fill existing evidence gaps. The prospective and longitudinal RECUR registry is funded by the German Ministry of Education and Science (BMBF). It is based on the digital infrastructure of the German Medical Informatics Initiative (MII). RECUR aims to include patients that have suffered from more than one stone occurrence and treated at any one of the ten participating university hospitals of the MIRACUM consortium. The intention is to obtain new information on risk factors and to evaluate different diagnosis and treatment algorithms. Along with the data form the patient's Electronic Health Records (EHR), the RECUR project will also collect Patient Reported Outcomes data from patients with recurrent kidney stones. These data will be collected at participating sites using digital questionnaires via a smartphone app. These data will be merged with medical data from the hospital information systems and saved in the MII research data repositories. The RECUR registry has a model character due to its fully federated, digital approach. This allows the recruitment of many patients, the collection of a wide range of data and their processing with low administrative and personnel costs.


Rapid repair of human disease-specific single-nucleotide variants by One-SHOT genome editing.
Many human diseases ranging from cancer to hereditary disorders are caused by single-nucleotide mutations in critical genes. Repairing these mutations would significantly improve the quality of life for patients with hereditary diseases. However, current procedures for repairing deleterious single-nucleotide mutations are not straightforward, requiring multiple steps and taking several months to complete. In the current study, we aimed to repair pathogenic allele-specific single-nucleotide mutations using a single round of genome editing. Using high-fidelity, site-specific nuclease AsCas12a/Cpf1, we attempted to repair pathogenic single-nucleotide variants (SNVs) in disease-specific induced pluripotent stem cells. As a result, we achieved repair of the Met918Thr SNV in human oncogene RET with the inclusion of a single-nucleotide marker, followed by absolute markerless, scarless repair of the RET SNV with no detected off-target effects. The markerless method was then confirmed in human type VII collagen-encoding gene COL7A1. Thus, using this One-SHOT method, we successfully reduced the number of genetic manipulations required for genome repair from two consecutive events to one, resulting in allele-specific repair that can be completed within 3 weeks, with or without a single-nucleotide marker. Our findings suggest that One-SHOT can be used to repair other types of mutations, with potential beyond human medicine.


Efficiency analysis of primary healthcare facilities in Afghanistan.
Afghanistan's health system is unique in that primary healthcare is delivered by non-governmental organizations funded by multilateral or bilateral donors, not the government. Given the wide range of implementers providing the basic package of health services, there may be performance differences in service delivery. This study assessed the relative technical efficiency of different levels of primary healthcare services and explored its determinants. Data envelopment analysis was used to assess the relative technical efficiency of three levels of primary healthcare facilities (comprehensive, basic, and sub-health centers). The inputs included personnel and capital expenditure, while the outputs were measured by the number of facility visits. Data on inputs and outputs were obtained from national health information databases for 1263 healthcare facilities in 31 provinces. Bivariate analysis was conducted to assess the correlation of various elements with efficiency scores. Regression models were used to identify potential factors associated with efficiency scores at the health facility level. The average efficiency score of health facilities was 0.74 when pooling all 1,263 health facilities, with 102 health facilities (8.1%) having efficiency scores of 1 (100% efficient). The lowest quintile of health facilities had an average efficiency score of 0.36, while the highest quintile had a score of 0.96. On average, efficiency scores of comprehensive health centers were higher than basic and sub-health centers by 0.11 and .07, respectively. In addition, the difference between efficiency scores of facilities in the highest and lowest quintiles was highest in facilities that offer fewer services. Thus, they have the largest room for improvement. Our findings show that public health facilities in Afghanistan that provide more comprehensive primary health services use their resources more efficiently and that smaller facilities have more room for improvement. A more integrated delivery model would help improve the efficiency of providing primary healthcare in Afghanistan.


Intermediate filaments of normal and neoplastic tissues of the female genital tract with emphasis on problems of differential tumor diagnosis.
Cytokeratins of normal epithelia and of some neoplasms of the female genital tract were studied by immunofluorescence microscopy of frozen sections and by two-dimensional gel electrophoresis of cytoskeletal proteins from microdissected tissues. All normal epithelia were stained with the monoclonal cytokeratin antibody KG 8.13 whereas certain monoclonal antibodies stained only simple epithelia. As revealed by gel electrophoresis the normal epithelia of the ovarian surface, oviduct, endometrium and endocervix contained cytokeratin polypeptides Nos. 7, 8, 18 and 19. In contrast, stratified exocervical epithelium showed a much more complex pattern (polypeptides No. 1, 2, 4, 5, 6, 11, 13, 14, 15, 16, 17 and 19). A similar pattern was found in the vagina. All epithelial neoplasms studied, regardless of the degree of histologic differentiation, were stained with antibody KG 8.13 as well as with conventionally obtained guinea pig antibodies to bovine muzzle prekeratins. The ovarian, endometrial and endocervical epithelial tumors maintained the pattern of their cells of origin, i.e. they expressed only cytokeratins Nos. 7, 8, 18 and 19. In one type of endocervical adenocarcinoma an additional cytokeratin polypeptide (No. 17) was detected. In contrast, the epithelial tumors of the lower genital tract showed a more complex pattern which also showed some differences with respect to that described for the corresponding normal tissue. Thus, in non-keratinizing squamous cell cervical carcinomas, cytokeratins Nos. 5, 6, 7, 8, 13, 14, 15, 16, 17, 18 and 19 were present, whereas the keratinizing cervical cancers showed polypeptides Nos. 5, 6, 13, 14, 16, 17 and 19.(ABSTRACT TRUNCATED AT 250 WORDS)


What Were the Nursing Practices of Mental Health Nurses in Mental Institutions 1800 to 1960: A Scoping Review.
This scoping literature review describes the practices of nurses working in mental asylums between 1800 and 1960 prior to the introduction of psychotropic drugs. Studies published in English from 1976 to 2021 from CINAHL, PubMed, ProQuest, PsyINFO, MEDLINE and Google were searched in August 2021. Twenty-three papers were retrieved with three distinct periods identified that shaped nursing practice. These were custodial care, moral and somatic treatment. Shifts in nursing practice were shaped by the desire of psychiatry to be recognised as a medical speciality, the feminisation of nursing and the formal development of nurse training in general hospitals.


Trauma education in a state of emergency: a curriculum-based analysis.
Trauma is the leading cause of death from ages 1-44-y in the United States and the fifth leading cause of death overall, but there are few studies quantifying trauma education in medical school. This study reviews curriculum hours devoted to trauma education at a northeastern medical school. We reviewed the preclinical curriculum at a northeastern medical school affiliated with three adult and two pediatric level I trauma centers verified by the American College of Surgeons. We reviewed curricular hours and we categorized them according to the leading ten causes of death in the United States. We also compared the number of educational hours devoted to trauma to other leading causes of death. The total amount of time devoted to trauma education in the first 2 y of medical school was 6.5 h. No lectures were given on the fundamentals of trauma management, traumatic brain injury, or chest or abdominal trauma. The most covered topic was heart disease (128 h), followed by chronic lower respiratory disease (80 h). Curricular time for heart disease, chronic lower respiratory disease, cancer, diabetes, renal disease, and influenza and pneumonia far exceeded that devoted to trauma, after adjusting for the mortality burden of these diseases (P < 0.05 for all). Our study demonstrates that trauma education at a northeastern medical school is nearly absent. With the large burden of trauma and rise in mass casualty incidence, the preclinical curriculum might not be sufficient to expose students to the fundamentals of trauma management. A broader multi-institutional study may shed more insight on these curricular deficiencies in trauma education and detect if these deficiencies are widespread nationally.


In vivo depression of reserve albumin binding capacity by cadmium: a preliminary evaluation.
The effect of cadmium upon the depression of reserve albumin binding capacity (%RABC) was investigated in male, New Zealand white rabbits at daily dosages of 0.65 mg and 0.90 mg Cd/kg body weight. Correlations of % RABC to the duration of exposure were strongest at the higher dosage. After 30-35 days exposure, the decline in % RABC was partially reversed. Levels of total protein in urine increased sharply within a few days after the % RABC had been reduced by cadmium to their lowest values.


Incidence of potential drug interactions in medication prescriptions for children and adolescents in the University Hospital Olomouc, Czech Republic.
Drug interactions are important potential causes of adverse drug reactions. However, studies of their occurrence in children are almost entirely lacking. This study evaluates the incidence of potential drug interactions (PDIs) in medication prescriptions for children. The study was performed at the University Hospital in Olomouc. PDIs in each patient's prescriptions were identified. Multivariate analysis was performed in order to assess the risk factors confounding the potential interactions. Univariate analysis was used to assess which diagnostic groups and medication groups significantly increase or lower the odds of a potential drug-drug interaction. A total of 6,078 patients meeting the inclusion criteria entered the study. They received 19,522 prescriptions. PDIs were identified in 3.83 % of patients (moderate-to-severe cases in 0.47 %). Patient age (p = 0.008), the average number of prescriptions per visit (p < 0.0001), and the number of visits per year (p < 0.0001) were found to increase the risk of drug interaction. The presence of epilepsy, leukemia, or rheumatoid arthritis and related disease diagnoses were discovered to increase the risk of PDIs significantly. The risk of PDIs in children is low, but it increases significantly with age and the number of drugs prescribed, particularly antiepileptics and immunosuppressants. The finding of a potential interaction in 0.47 % of all children in whom any medication was prescribed should not be underestimated since it means a significant risk for one child out of every 200, and it is also substantially higher in the chronically ill. Pediatricians should be aware of relevant interactions and should prevent them by therapeutic drug monitoring or appropriate clinical and laboratory monitoring.


Amyloid deposit corresponds to technetium-99m-pyrophosphate accumulation in abdominal fat of patients with transthyretin cardiac amyloidosis.
Radionuclide imaging using bone-avid tracers plays a critical role in diagnosing transthyretin cardiac amyloidosis (ATTR-CA), but technetium-99m-pyrophosphate (PYP) rarely allows the detection of extracardiac amyloid infiltration. We retrospectively investigated the frequency of PYP uptake in the subcutaneous abdominal fat of patients with ATTR-CA and its relevance to the results of fine-needle aspiration biopsy (FNAB) of this tissue. Chest-centered images of PYP scintigraphy were obtained 2 h after the intravenous injection of the tracer (20 mCi), and the frequency of PYP uptake in the subcutaneous abdominal fat was evaluated. Amyloid deposits of fat smears taken by subcutaneous abdominal fat FNAB were assessed by Congo red staining. Twenty-four patients with ATTR-CA were included. Ten (41.7%) patients showed some PYP uptake in the subcutaneous abdominal fat (positive PYP group), and 14 patients did not (negative PYP group). Amyloid deposits were detected by subcutaneous abdominal fat FNAB in 7/10 patients (70.0%) of the positive PYP group versus 0/14 patients (0%) of the negative PYP group, and the difference was significant. In patients with ATTR-CA, abnormal PYP uptake in the subcutaneous abdominal fat could reflect the regional amyloid deposition confirmed by FNAB of this tissue.


Carotid Intima-Media Thickness is Inversely Related to Bone Density in Female but not in Male Patients with Acute Stroke.
Atherosclerosis and osteoporosis are two major public health problems. It is still uncertain whether an abnormal carotid ultrasonography, either increased intima-media thickness (IMT) or plaque thickness, is associated with osteoporosis in acute ischemic stroke patients. To investigate the possible relationships between osteoporosis and carotid atherosclerosis, we evaluated the correlation between carotid IMT/plaque thickness and bone mineral density (BMD) in acute ischemic stroke patients. Patients having their first ischemic stroke within seven days were screened for the study. The IMT was scanned approximately 10 mm proximal to the beginning of the dilatation of the carotid bulb. The plaques were measured in both common and internal carotid arteries. The BMD was measured at total hip and lumbar spine in the anterior-posterior projection, using dual-energy x-ray absorptiometry. A total of 155 patients were enrolled in the study and the mean age was 68.3 ± 10.34 years. Multiple linear regression analysis reveals that age (P < .001), smoking (P = .016), and osteoporosis (P = .001) were significantly associated with increased carotid IMT/plaque thickness. Old age, current smoking, and osteoporosis were significantly related to increased IMT/plaque thickness in acute ischemic stroke patients. In women, IMT/plaque thickness was significantly related to age (P = .01) and osteoporosis (P = .025). In men, though there was no significant relationship, a trend toward old age and having osteoporosis was observed in increased IMT/plaque thickness (P = .051, P = .086). This study showed that carotid IMT/plaque thickness was inversely related to the BMD in female but not in male patients with acute ischemic stroke.


Cloning of cDNA and chromosomal location of genes encoding the three types of subunits of the wheat tetrameric inhibitor of insect alpha-amylase.
We have characterized three cDNA clones corresponding to proteins CM1, CM3 and CM16, which represent the three types of subunits of the wheat tetrameric inhibitor of insect alpha-amylases. The deduced amino acid sequences of the mature polypeptides are homologous to those of the dimeric and monomeric alpha-amylase inhibitors and of the trypsin inhibitors. The mature polypeptides are preceded by typical signal peptides. Southern blot analysis of appropriate aneuploids, using the cloned cDNAs as probes, has revealed the location of genes for subunits of the CM3 and of the CM16 type within a few kb of each other in chromosomes 4A, 4B and 4D, and those for the CM 1 type of subunit in chromosomes 7A, 7B and 7D. Known subunits of the tetrameric inhibitor corresponding to genes from the B and D genomes have been previously characterized. No proteins of this class have been found to be encoded by the A genome in hexaploid wheat (genomes AA, BB, DD) or in diploid wheats (AA) and no anti alpha-amylase activity has been detected in the latter, so that the A-genome genes must be either silent (pseudogenes) or expressed at a much lower level.


Efficient genetic manipulation of 1321N1 astrocytoma cells using lentiviral gene transfer.
1321N1 astrocytoma cells are frequently used to analyze stimulus-induced intracellular signaling. These experiments require genetic manipulation of the cells and several chemical and physical methods have been employed in the past. Recently, microporation has been suggested as the best method to transfect 1321N1 astrocytoma cells. Here, we demonstrate that lentiviral gene transfer into 1321N1 cells is highly efficient, cheap and non-toxic. In addition, lentiviral gene transfer efficiently facilitates stable expression of small hairpin RNAs. Finally, lentiviral gene transfer can be used to implant promoter/luciferase reporter genes into the chromatin of the cells, allowing promoter studies using templates that are embedded into the nucleosomal structure of the chromatin.


Cost-effectiveness of semi-annual surveillance for hepatocellular carcinoma in cirrhotic patients of the Italian Liver Cancer population.
It was recently shown that semi-annual surveillance for hepatocellular carcinoma (HCC) in cirrhotic patients provides a prognostic advantage over the annual program; however, its cost-effectiveness (CE) in the general cirrhotic population still needs to be defined. A Markov model was built to compare CE of these two strategies, considering literature results and treatment modalities of 918 cirrhotic patients from the Italian Liver Cancer (ITA.LI.CA) database. Results from the Markov model suggest that, compared to annual surveillance, semi-annual surveillance leads to a gain in quality-adjusted life expectancy, in an unselected cirrhotic population, of 1.35 quality-adjusted life-months (QALMs) over 10 years since surveillance start in compensated patients, and of 0.73 QALMs in decompensated patients. Semi-annual surveillance was more cost-effective in compensated than in decompensated cirrhosis, with an incremental CE ratio (ICER) of 1997 and 3814€/QALM, respectively. In compensated cirrhosis, semi-annual surveillance was more cost-effective than the annual program when the annual HCC incidence was ≥3.2% and the relative survival gain after cancer diagnosis was ≥20% with respect to the annual program. In decompensated cirrhosis, semi-annual surveillance was cost-effective in patients amenable to liver transplantation. In both groups, CE of semi-annual surveillance improved with the increase of annual incidence and the survival benefit obtainable with HCC treatment. Both surveillance strategies for HCC in cirrhotic patients can be recommended, according to the individual risk profile for HCC occurrence and the expected survival gain obtainable after tumor diagnosis and therapy.


Panniculitis associated with cutaneous T-cell lymphoma and cytophagocytic histiocytosis.
A 36-year-old woman had a 6-year history of recurrent panniculitis with development of an angiocentric and angiodestructive cutaneous T-cell lymphoma (CTCL) of the helper cell phenotype. She subsequently developed a rapidly progressive fatal syndrome characterized by cytophagocytic histiocytosis and hyperlipidaemia. Cytophagocytic histiocytosis has previously been reported in association with panniculitis, malignancy and infection, but not with CTCL and the precise relationship between panniculitis, CTCL, cytophagocytic histiocytosis and hyperlipidemia is unclear.


Hepatitis C virus present in the sera of infected patients interferes with the autophagic process of monocytes impairing their in-vitro differentiation into dendritic cells.
Autophagy has a pivotal role in the in-vitro monocyte differentiation into macrophages and dendritic cells (DCs), the most powerful antigen presenting cells (APC) with the unique capacity to initiate an adaptive immune response. Autophagy is also a mechanism by which these cells of innate immunity may degrade intracellular pathogens and mediate the antigen processing and presentation, essential to clear an infection. For these reasons, pathogens have learned how to manipulate autophagy for their own survival. In this study we found that hepatitis C virus (HCV), derived from sera of infected patients, blocked the autophagic process in differentiating monocytes, seen as LC3 II and p62 expression levels. The suppression of autophagy correlated with a reduction of cathepsins D, B and proteolytic activity, and resulted in impairment of monocyte differentiation into DCs, as indicated by the reduction of CD1a acquirement. These data suggest that the block of autophagy might be one of the underlying mechanisms of the HCV-mediated immune subversion that frequently leads to viral persistence and chronic hepatitis.


A Comparative Study of Orbital Blow Out Fracture Repair, Using Autogenous Bone Graft and Alloplastic Materials.
Maxillofacial trauma, a common injury in urban population following road traffic accident or act of interpersonal violence of which orbital floor fractures is common. It impairs the integrity of the extraocular muscles and may be accompanied by enophthalmos, orbital deformity and diplopia. Orbital reconstruction is essential to improve anatomical and visual deformity. Repair of orbital floor is done by autologous bone graft or synthetic implants. Compare outcome of orbital floor reconstruction in blow out orbital fracture using autogenous bone graft from iliac crest, outer table of mandible, alloplastic implant- silastic block and titanium mesh. 30 patients having orbital fractures were considered in study population. All the patients were treated by ORIF and repair of floor by subcilliary incision. Out of 30 patients, repair of orbital floor was done by autologous bone graft from iliac crest in 7 patients (Group A), bone graft from outer table of mandible in 5 patients (Group B), implant using silastic block in 8 patients (Group C) and titanium mesh in 10 patients (Group D). Factors analyzed were age, sex, cause of fracture and treatment outcome in terms of correction of pre operative diplopia and enophthalmos, rate of development of post operative infection, wound dehiscence and implant exposure. All patents were reviewed at 4 weeks and 12 weeks following operation. 71.42% of patients in Group A had early correction of diplopia and enophthalmos. This was 100% in rest of the groups. All patients had complete correction when assessed at 12 weeks post operatively. Post operative complication rate was 20% and 12.5% in Group B and C respectively. There were no complications in the rest of the groups within the follow up period. No statistically significant difference as to the chance of occurrence of complication could be found amongst the groups. Autologous bone graft has no immunological reaction but donor site morbidity. Silastic block may case immunological reaction, infection, poor drainage of orbital floor. But titanium mesh for orbital floor repair has excellent outcome and superior to other modality of treatment.


[New approach to the diagnosis of meningococcal infection: latex-erythrocyte agglutination].
A principal possibility and advantages of the diagnosis of meningococcal infection by means of agglutination of sensibilized latex particles with erythrocytes have been demonstrated. Polysterene carboxylated latex has been sensibilized by rabbit JgG to meningococcus of serogroup A. Dynamics of absorption of meningococcal polysaccharide on erythrocytes in vivo has been studied in mice.


Constraints on an induced defense: the role of leaf area.
Folivory results in both leaf damage and the loss of photosynthetic capacity. Leaf damage activates the production of induced defenses, but diminished photosynthetic capacity resulting from lost leaf area may impair a plant's ability to respond defensively. Because damage-induced nicotine production in Nicotiana sylvestris (Solanaceae) is an energy-demanding, active process, we predicted that the loss of leaf area would constrain this plant's ability to produce an induced nicotine pool. We examined our prediction in an experiment which combined leaf puncture and removal protocols, quantified induced nicotine pools on a whole-plant basis, and accounted for losses in the nicotine pool due to removed leaves and lost growth potential. In contrast to our prediction, leaf removal did little to diminish the growth-corrected estimates of the induced nicotine pool in plants with sufficient damage "cue"; only when plants had lost 88% or more of their leaf area did the induced nicotine pool decline significantly. These results demonstrate that the induced defense is relatively insensitive to current photosynthetic capacity. In contrast to the size of the induced nicotine pool, the concentration of nicotine in the remaining shoot tissues continued to rise as puncture damage increased over all defoliation levels tested. The mechanisms responsible for inducible nicotine production may have evolved as a means of providing shoot tissues with protection that is proportional to the amount of damage incurred while keeping production costs constant for the remaining plant parts.


Pediatric Postoperative Pain Management in Korea: Parental Attitudes Toward Pain and Analgesics, Self-Efficacy, and Pain Management.
This study aimed to explore parental attitudes toward children's pain and analgesic drugs and parental self-efficacy and use of pain relief strategies in children's postoperative pain management in Korea, and to identify the relationships among these variables. A cross sectional descriptive study was conducted. Participants were 124 parents of hospitalized children (aged 4-9 years) undergoing tonsillectomy in Korea. A considerable proportion of parents held misconceptions about how children express pain. For example, 87.9% of parents perceived that children always tell their parents when they are in pain. Moreover, parents reported significant attitudinal barriers to analgesic use with 60.5% of parents believed that side effects are something to worry about when giving children pain medication. Parental attitudes to use analgesics were significantly different by children's gender, family income, and length of hospital stay. Emotional support methods such as touch, parental presence, and comfort/reassurance were the frequently used, whereas cognitive-behavioral approaches such as distraction were less frequently used nonpharmacological pain relief strategies. A parent's self-efficacy in managing children's pain significantly correlated with the appropriate use of analgesics and parental use of pain relief strategies. Promoting parental self-efficacy in postoperative pain management is important. Educational interventions focused on behavioral changes of parents, including practical guidance for pharmacological and nonpharmacological pain relief strategies, are needed. Providing parents with proper, effective education about children's postoperative pain management should not only provide accurate information but should also enhance parents' self-efficacy in assessing and managing children's pain.


Pulse arrival time is not an adequate surrogate for pulse transit time in terms of tracking diastolic pressure.
We compared pulse arrival time (PAT) and pulse transit time (PTT) in terms of their ability to track diastolic pressure (DP). We performed the comparison using high fidelity, invasive arterial waveforms recorded from six dogs during multiple interventions. On average, DP ranged from 40 to 106 mmHg and therefore varied widely. PAT and PTT were able to predict DP with average root-mean-squared-errors of 9.8 ± 5.8 mmHg and 5.7 ± 2.0 mmHg (p = 0.02). Thus, even though PAT is simpler to measure, we can only recommend using PTT for tracking DP.


Erectile dysfunction in men with diabetes mellitus.
During a fourteen-month period, 497 men were evaluated for a primary complaint of erectile dysfunction. The initial evaluation consisted of a history taken in a conventional manner and supplemented by a patient-completed sexual function questionnaire, a physical examination, and serum testosterone, serum prolactin, and nocturnal penile tumescence studies. When appropriate, additional evaluations, including penile vascular studies, two-hour oral glucose tolerance tests, and psychiatric consultation were obtained. Abnormal glucose metabolism was present in 161 men (32%). Five men (1%) had insulin-dependent diabetes mellitus (IDDM), 80 men (16%) had noninsulin-dependent diabetes mellitus (NIDDM), 55 men (11.1%) had newly diagnosed noninsulin-dependent diabetes mellitus, and 21 men (4.2%) had impaired glucose tolerance tests. One hundred forty-seven of these men (91.3%) had organic pattern impotence, and 14 (8.7%) had psychogenic pattern impotence.


Surface potential and the interaction of weakly acidic uncouplers of oxidative phosphorylation with liposomes and mitochondria.
The pH dependence of the binding of weakly acidic uncouplers of oxidative phosphorylation to rat-liver mitochondria and liposomes is mainly determined by the pKa of the uncoupler molecule. The absorption and fluorescene excitation spectra of the anionic form of weakly acidic uncouplers of oxidative phosphorylation are red-shifted upon interaction with liposomal or mitochondrial membranes. The affinity for the liposomes, as deduced from the red shift, is independent of the degree of saturation of the fatty acid chains of different lecithins. The intensity of the spectra at one pH value is strongly dependent upon the surface charge of the liposomes. With positively charged liposomes the results obtained can be almost quantitatively explained with the Gouy-Chapman theory, but with negatively charged ones deviations are observed. At a particular pH, the divalent ion Ca-2+ stongly influences the intensity of the spectra in the presence of negatively charged liposomes, but has no effect with neutral liposomes. With mitochondrial membranes an effect of Ca-2+ similar to that with negatively charged liposomes is observed. Depletion of the phospholipids of the mitochondria and subsequent restoration of the mitochrondrial membrane with lecithin, strongly diminishes this effect, but restoration with negatively charged phospholipids does not influence it. From these observations it is concluded that the anionic form of the uncoupler molecule when bound to mitochondria is located within the partly negatively charged phospholiped moiety of the membrane, with its anionic group pointing to the aqueous solution.


The use of biomarkers in surveillance, medical screening, and intervention.
Building on mechanistic information, much of molecular epidemiologic research has focused on validating biomarkers, that is, assessing their ability to accurately indicate exposure, effect, disease, or susceptibility. To be of use in surveillance, medical screening, or interventions, biomarkers must already be validated so that they can be used as outcomes or indicators that can serve a particular function. In surveillance, biomarkers can be used as indicators of hazard, exposure, disease, and population risk. However, to obtain rates for these measures, the population at risk will need to be assessed. In medical screening, biomarkers can serve as early indicators of disease in asymptomatic people. This allows for the identification of those who should receive diagnostic confirmation and early treatment. In intervention (which includes risk assessment and communication, risk management, and various prevention efforts), biomarkers can be used to assess the effectiveness of a prevention or control strategy as well as help determine whether the appropriate individuals are assigned to the correct intervention category. Biomarkers can be used to provide group and individual risk assessments that can be the basis for marshalling resources. Critical for using biomarkers in surveillance, medical screening, and intervention is the justification that the biomarkers can provide information not otherwise accessible by a less expensive and easier-to-obtain source of information, such as medical records, surveys, or vital statistics. The ability to use validated biomarkers in surveillance, medical screening, and intervention will depend on the extent to which a strategy for evidence-based procedures for biomarker knowledge transfer can be developed and implemented. This will require the interaction of researchers and decision-makers to collaborate on public health and medical issues.


Molecular aspects of the congenital and acquired Long QT Syndrome: clinical implications.
The Long QT Syndrome (LQTS) is a complex and multi-factorial disorder that predisposes to life-threatening ventricular arrhythmias. Both hereditary and acquired subforms have been identified over the years. Recently, it has become clear that the interaction of multiple acquired and genetic aetiologic factors (e.g. disease modifiers) play an important role in differentiating genotype into a continuous spectrum of clinical or subclinical phenotypes. The genotype-phenotype correlation thereby remains very unpredictable in asymptomatic patients, raising important concerns for clinical practice and also for drug development. Therefore, this review aims at providing a comprehensive overview on LQTS highlighting the molecular mechanisms of arrhythmogenesis involved in both the hereditary and the acquired subtypes of the disorder. From this perspective this manuscript then focuses on how the genotype translates into phenotype. A logical overview is provided with the multitude of hereditary and acquired factors that are involved and of the complexity of the interactions that ultimately result in the heterogeneous expressivity and the unpredictability of the phenotype. Based on recent basic and clinical data this review further aims at providing an update on the clinical properties and management of LQT patients including diagnostic work-up and therapy.


Noise in the nervous system.
Noise--random disturbances of signals--poses a fundamental problem for information processing and affects all aspects of nervous-system function. However, the nature, amount and impact of noise in the nervous system have only recently been addressed in a quantitative manner. Experimental and computational methods have shown that multiple noise sources contribute to cellular and behavioural trial-to-trial variability. We review the sources of noise in the nervous system, from the molecular to the behavioural level, and show how noise contributes to trial-to-trial variability. We highlight how noise affects neuronal networks and the principles the nervous system applies to counter detrimental effects of noise, and briefly discuss noise's potential benefits.


The iron metallome in eukaryotic organisms.
This chapter is focused on the iron metallome in eukaryotes at the cellular and subcellular level, including properties, utilization in metalloproteins, trafficking, storage, and regulation of these processes. Studies in the model eukaryote Saccharomyces cerevisiae and mammalian cells will be highlighted. The discussion of iron properties will center on the speciation and localization of intracellular iron as well as the cellular and molecular mechanisms for coping with both low iron bioavailability and iron toxicity. The section on iron metalloproteins will emphasize heme, iron-sulfur cluster, and non-heme iron centers, particularly their cellular roles and mechanisms of assembly. The section on iron uptake, trafficking, and storage will compare methods used by yeast and mammalian cells to import iron, how this iron is brought into various organelles, and types of iron storage proteins. Regulation of these processes will be compared between yeast and mammalian cells at the transcriptional, post-transcriptional, and post-translational levels.


Occupational therapy gender imbalance; revisiting a lingering issue.
Recently, it has been suggested that gender disparity in Occupational Therapy has to do with segregated gendered job norms that position female dominated professions as a 'step down' for many males. Interestingly, this suggestion was not underpinned by experiences of males in the profession. Thirteen male Occupational Therapists with a variety of backgrounds were invited to this Round Table research, focussing on the broader issue of the existing gender imbalance in Occupational Therapy. Two themes emerged: 'The core values of the profession', and 'Broadening the scope of the profession'; none of them suggesting that male/female imbalance was necessarily the most pressing issue. A gender-unrelated approach to everyday problem-solving was put forward to achieve increased diversity in Occupational Therapists' backgrounds, better reflecting the people they serve. By broadening the scope and the way the profession is presented, and encouraging innovative and more entrepreneurially driven approaches, diversity in the workforce could be further facilitated. These findings are discussed within the context of 'The mutual constitution of cultures and selves' model. Diversity in the Occupational therapy workforce could be further facilitated with a shift in focus away from the male/female perspective to an intersectional approach.