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Immunocytochemical localization of the main intrinsic polypeptide (MIP) in ultrathin frozen sections of rat lens.
The in situ distribution of the 26-kdalton Main Intrinsic Polypeptide (MIP or MP 26), a putative gap junction protein in ocular lens fibers, was defined at the electron microscope level using indirect immunoferritin labeling of ultrathin frozen sections of rat lens. MIP was found distributed throughout the plasma membrane of the lens fiber cell, with no apparent distinction between junctional and nonjunctional membrane. MIP was not detectable in the basal or lateral plasma membrane of the lens epithelial cell, including the interepithelial cell gap junctions; nor was MIP detectable in the plasma membrane or gap junctions of the hepatocyte. Previous reports have indicated that the protein composition of the lens fiber cell junction differs from that of the hepatocyte gap junction. The evidence presented here suggests that the composition of the fiber cell junction and plasma membrane is also immunocytochemically distinct from that of its progenitor, the lens epithelial cell
Search algorithms as a framework for the optimization of drug combinations
Combination therapies are often needed for effective clinical outcomes in the
management of complex diseases, but presently they are generally based on
empirical clinical experience. Here we suggest a novel application of search
algorithms, originally developed for digital communication, modified to
optimize combinations of therapeutic interventions. In biological experiments
measuring the restoration of the decline with age in heart function and
exercise capacity in Drosophila melanogaster, we found that search algorithms
correctly identified optimal combinations of four drugs with only one third of
the tests performed in a fully factorial search. In experiments identifying
combinations of three doses of up to six drugs for selective killing of human
cancer cells, search algorithms resulted in a highly significant enrichment of
selective combinations compared with random searches. In simulations using a
network model of cell death, we found that the search algorithms identified the
optimal combinations of 6-9 interventions in 80-90% of tests, compared with
15-30% for an equivalent random search. These findings suggest that modified
search algorithms from information theory have the potential to enhance the
discovery of novel therapeutic drug combinations. This report also helps to
frame a biomedical problem that will benefit from an interdisciplinary effort
and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio
Presenting patient data in the electronic care record: the role of timelines
OBJECTIVE: To establish the current level of awareness and investigate the use of timelines within clinical computing systems as an organized display of the electronic patient record (EPR). DESIGN: Multicentre survey conducted using questionnaires and interview. SETTING: Seven UK hospitals and several general practice surgeries. PARTICIPANTS: A total of 120 healthcare professionals completed a questionnaire which directed structured interviews. Participants fell into two cohorts according to whether or not they had used clinical timelines, which gave 60 timeline users and 60 prospective timeline users. MAIN OUTCOME MEASURES: To investigate the awareness of timelines, and the potential benefits of timelines within clinical computing systems. RESULTS: Fifty-eight percent of participants had not heard of the specific term timelines despite 75% of users utilizing a form of timeline on a daily basis. The potential benefits of future timelines were clinical audit (95%CI 77.6-91.6), increased time efficiency (95%CI 77.7-91.6%), reduced clinical error (95%CI 71.0-86.7) and improved patient safety (95%CI 70.0-85.9). One continuous timeline view between primary and secondary care was considered to be of great potential benefit in allowing communication via a unified patient record. CONCLUSIONS: The concept of timelines has enjoyed proven success in healthcare in the USA and in other sectors worldwide. Clinicians are supportive of timelines in healthcare. Formal input from clinicians should be sought when designing and implementing computer systems in healthcare. Timelines in healthcare support clinicians cognitive processes by improving the amount of data available and improving the way in which data are presented
Acceptability, Accuracy and Safety of Disposable Transnasal Capsule Endoscopy for Barrett’s Esophagus Screening
BACKGROUND & AIMS: Screening for Barrett's esophagus (BE) with conventional esophagogastroduodenoscopy (C-EGD) is expensive. We assessed the performance of a clinic-based, single use transnasal capsule endoscope (EG Scan II) for the detection of BE, compared to C-EGD as the reference standard. METHODS: We performed a prospective multicenter cohort study of patients with and without BE recruited from 3 referral centers (1 in the United States and 2 in the United Kingdom). Of 200 consenting participants, 178 (89%) completed both procedures (11% failed EG Scan due to the inability to intubate the nasopharynx). The mean age of participants was 57.9 years and 67% were male. The prevalence of BE was 53%. All subjects underwent the 2 procedures on the same day, performed by blinded endoscopists. Patients completed preference and validated tolerability (10-point visual analogue scale [VAS]) questionnaires within 14 days of the procedures. RESULTS: A higher proportion of patients preferred the EG Scan (54.2%) vs the C-EGD (16.7%) (P<.001) and the EG Scan had a higher VAS score (7.2) vs the C-EGD (6.4) (P=.0004). No serious adverse events occurred. The EG Scan identified any length BE with a sensitivity value of 0.90 (95% CI, 0.83-0.96) and a specificity value of 0.91 (95% CI, 0.82-0.96). The EG Scan identified long segment BE with a sensitivity value of 0.95 and short segment BE with a sensitivity values of 0.87. CONCLUSION: In a prospective study, we found the EG Scan to be safe and to detect BE with higher than 90% sensitivity and specificity. A higher proportion of patients preferred the EG Scan to C-EGD. This device might be used as a clinic-based tool to screen populations at risk for BE. ISRCTN registry identifier: 70595405; ClinicalTrials.gov no: NCT02066233
A primary care database study of asthma among patients with and without opioid use disorders
Substance misuse is associated with poor asthma outcome and death. People with opioid use disorder (OUD) may be at particular risk, however, there have been no case-control studies of asthma care and outcomes in this patient group. A primary care database study of patients with asthma aged 16–65 years was conducted using a matched case-control methodology. The dataset comprised 275,151 adults with asthma, of whom 459 had a clinical code indicating a lifetime history of OUD. Cases with a history of OUD were matched to controls 1:3 by age, gender, smoking status and deprivation index decile. Attendance at annual review (30%) and for immunisation (25%) was poor amongst the overall matched study population (N = 1832). Compared to matched controls, cases were less likely to have attended for asthma review during the previous 12 months (OR = 0.60, 95% CI 0.45–0.80) but had similar immunisation rates. Higher rates of ICS (OR = 1.50, 1.13–1.98) and oral prednisolone use (OR = 1.71, 1.25–2.40) were seen amongst those with a history of OUD and 7.2% had a concurrent diagnosis of COPD (OR = 1.86, 1.12–2.40). We found that people with asthma and a history of OUD have worse outcomes on several commonly measured metrics of asthma care. Further research is required to identify reasons for these findings, the most effective strategies to help this vulnerable group access basic asthma care, and to better understand long-term respiratory outcomes
Meta-Review of Metanalytic Studies with Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Major Depression
BACKGROUND: Major Depression (MD) and treatment-resistant depression (TRD) are worldwide leading causes of disability and therapeutic strategies for these impairing and prevalent conditions include pharmacological augmentation strategies and brain stimulation techniques. In this perspective, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique with a favorable profile of tolerability which, despite being recently approved by the Food and Drug Administration (FDA) for the treatment of patients with medication-refractory unipolar depression, still raises some doubts about most effective parameters of stimulation.METHODS: A literature search was performed using PubMed for the years 2001 through February 2011 in order to review meta-analytic studies assessing efficacy and safety issues for rTMS in depressive disorders. Fifteen meta-analyses were identified and critically discussed in order to provide an updated and comprehensive overview of the topic with specific emphasis on potentially optimal parameters of stimulation.RESULTS: First meta-analyses on the efficacy of rTMS for the treatment of MD and TRD have shown mixed results. On the other hand, more recent meta-analytic studies seem to support the antidepressant efficacy of the technique to a greater extent, also in light of longer periods of stimulation (e.g. > 2 weeks).CONCLUSION: rTMS seems to be an effective and safe brain stimulation technique for the treatment of medication refractory depression. Nevertheless, further studies are needed to better define specific stimulation-related issues, such as duration of treatment as well as durability of effects and predictors of response
Induction of p38- and gC1qR-dependent IL-8 expression in pulmonary fibroblasts by soluble hepatitis C core protein
BACKGROUND: Recent studies suggest that HCV infection is associated with progressive declines in pulmonary function in patients with underlying pulmonary diseases such as asthma and chronic obstructive pulmonary disease. Few molecular studies have addressed the inflammatory aspects of HCV-associated pulmonary disease. Because IL-8 plays a fundamental role in reactive airway diseases, we examined IL-8 signaling in normal human lung fibroblasts (NHLF) in response to the HCV nucleocapsid core protein, a viral antigen shown to modulate intracellular signaling pathways involved in cell proliferation, apoptosis and inflammation. METHODS: NHLF were treated with HCV core protein and assayed for IL-8 expression, phosphorylation of the p38 MAPK pathway, and for the effect of p38 inhibition. RESULTS: Our studies demonstrate that soluble HCV core protein induces significant increases in both IL-8 mRNA and protein expression in a dose- and time-dependent manner. Treatment with HCV core led to phosphorylation of p38 MAPK, and expression of IL-8 was dependent upon p38 activation. Using TNFα as a co-stimulant, we observed additive increases in IL-8 expression. HCV core-mediated expression of IL-8 was inhibited by blocking gC1qR, a known receptor for soluble HCV core linked to MAPK signaling. CONCLUSION: These studies suggest that HCV core protein can lead to enhanced p38- and gC1qR-dependent IL-8 expression. Such a pro-inflammatory role may contribute to the progressive deterioration in pulmonary function recently recognized in individuals chronically infected with HCV
The Murid Herpesvirus-4 gH/gL Binds to Glycosaminoglycans
The first contact a virus makes with cells is an important determinant of its tropism. Murid Herpesvirus-4 (MuHV-4) is highly dependent on glycosaminoglycans (GAGs) for cell binding. Its first contact is therefore likely to involve a GAG-binding virion glycoprotein. We have previously identified two such proteins, gp70 and gp150. Gp70 binds strongly to GAGs. However, deleting it makes little difference to MuHV-4 cell binding or GAG-dependence. Deleting gp150, by contrast, frees MuHV-4 from GAG dependence. This implies that GAGs normally displace gp150 to allow GAG-independent cell binding. But the gp150 GAG interaction is weak, and so would seem unlikely to make an effective first contact. Since neither gp70 nor gp150 matches the expected profile of a first contact glycoprotein, our understanding of MuHV-4 GAG interactions must be incomplete. Here we relate the seemingly disconnected gp70 and gp150 GAG interactions by showing that the MuHV-4 gH/gL also binds to GAGs. gH/gL-blocking and gp70-blocking antibodies individually had little effect on cell binding, but together were strongly inhibitory. Thus, there was redundancy in GAG binding between gp70 and gH/gL. Gp150-deficient MuHV-4 largely resisted blocks to gp70 and gH/gL binding, consistent with its GAG independence. The failure of wild-type MuHV-4 to do the same argues that gp150 is normally engaged only down-stream of gp70 or gH/gL. MuHV-4 GAG dependence is consequently two-fold: gp70 or gH/gL binding provides virions with a vital first foothold, and gp150 is then engaged to reveal GAG-independent binding
A self-rating scale for patient-perceived side effects of inhaled corticosteroids
BACKGROUND: Patient-reported side effect questionnaires offer a simple method for the systematic measurement of drug-related side effects. In order to measure patients' inhaled corticosteroids (ICS) related side effect perceptions the 14-day retrospective Inhaled Corticosteroid Questionnaire (ICQ) was developed. In this research we aim to assess the construct validity and reliability of the ICQ and test its responsiveness to dose changes in adult asthma patients. METHODS: In a cross-sectional study, current inhaler users with asthma completed the ICQ (27 with non ICS inhaler; 61 BDP equivalent daily ICS low dose ≤400 μg; 62 mid dose 401–800 μg; and 105 with high dose >800 μg). We generated 3 construct validity hypotheses: 1) a hierarchical dose-response pattern for scoring of the individual items on the ICQ, and statistically significant differences in the scores of each of the 15 ICQ domains by ICS dose group 2) an association between ICS dose and ICQ scoring after adjusting for appropriate confounders in multiple regression; 3) greater convergence between local side effect domains than between systemic and local domains of the scale. Test-retest reliability was assessed on a randomly selected subgroup of patients (n = 73) who also completed the ICQ a second time after 7 days. In a separate longitudinal study, 61 patients with asthma completed the ICQ at baseline and after changing their daily ICS dose, at 2- and 6- months, in order to test the ICQ's responsiveness. RESULTS: All three construct validity hypotheses were well supported: 1) a statistically significant difference existed in scores for 14 domains, the high ICS dose group scoring highest; 2) ICS dose independently predicted ICQ scoring after adjusting for confounders; 3) greater convergence existed between local ICQ domains than between local and systemic domains. The ICQ had good reproducibility: test-retest intraclass correlation coefficients were ≥0.69 for all but the 'Facial Oedema' domain. In the longitudinal study, ICQ scores for 'Voice Problems' changed significantly at 2- and 6-months from baseline and other ICQ domains displayed trends in scoring change accordant with dose modulation at 6-months. CONCLUSION: The ICQ has good dose-related discriminative properties, is valid, reliable, and shows potential responsiveness to ICS dose change
Predicting participation of people with impaired vision in epidemiological studies
The characteristics of the target group and the design of an epidemiologic study, in particular the recruiting methods, can influence participation. People with vision impairment have unique characteristics because those invited are often elderly and totally or partially dependent on help to complete daily activities such as travelling to study sites. Therefore, participation of people with impaired vision in studies is less predictable than predicting participation for the general population.This study was supported by FCT (COMPETE/QREN) grant reference PTDC/DPT-EPI/0412/2012 in the context of the Prevalence and Costs of Visual Impairment in Portugal: a hospital based study (PCVIP-study). PLR is funded by FCT (COMPETE/QREN) grant reference SFRH/BD/119420/2016
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