Regulation of dermal circadian pathways by a novel topical formulation.

Skin health is impacted by a wide range of intrinsic and extrinsic factors (J Dermatol Sci, 2017, 85, 152), including those that impact circadian rhythm, such as sleep disruption (Textbook of Aging Skin, 2016), UV (Biomed Aging Pathol, 2013, 3, 161) and blue light (Int J Cosmet Sci, 2019, 41, 558). Disruption of the skin's endogenous circadian balance, even by a consistently late bedtime, has deleterious effects on multiple measurements of skin health, including hydration, skin barrier protection, microbiome counts and skin regeneration, among others (Clin Cosmet Investig Dermatol, 2022, 15, 1051). Skin repair processes occur at night and help to maintain important aspects of skin health (FEBS Lett, 2021, 595, 2413). Interest is increasing in the development of topical products that help restore proper circadian function. This study demonstrates that a proprietary topical formulation regulates new and established gene and protein biomarkers of circadian entrainment and circadian rhythm, demonstrating the product's potential to maintain appropriate dermal diurnal balance.

La santé de la peau est affectée par un large éventail de facteurs intrinsèques et extrinsèques (J Dermatol Sci, 2017, 85, 152), y compris ceux qui ont un impact sur le rythme circadien, tels que les troubles du sommeil (Textbook of Aging Skin, 2016), les UV (Biomed Aging Pathol, 2013, 3, 161) et la lumière bleue (Int J Cosmet Sci, 2019, 41, 558). La perturbation du rythme circadien endogène de la peau, même par un coucher systématiquement tardif, a des effets délétères sur de multiples mesures de la santé de la peau, notamment l'hydratation, la protection de la barrière cutanée, le nombre de microbiomes et la régénération de la peau, entre autres (Clin Cosmet Investig Dermatol, 2022, 15, 1051). Les processus de réparation de la peau se produisent la nuit et aident à maintenir les aspects importants de la santé de la peau (FEBS Lett, 2021, 595, 2413). L'intérêt est accru dans le développement de produits topiques qui aident à restaurer une fonction circadienne correcte. Cette étude démontre qu'une formulation topique exclusive régule les biomarqueurs génétiques et protéiques nouveaux et établis de l'entraînement circadien et du rythme circadien, ce qui montre le potentiel du produit à maintenir un équilibre diurne cutané approprié.

The role of imaging in malignant pleural mesothelioma: an update after the 2018 BTS guidelines.

Malignant pleural mesothelioma (MPM) is a primary malignancy of the pleura and is associated with a poor outcome. The symptoms and signs of malignant mesothelioma present late in the natural history of the disease and are non-specific, making the diagnosis challenging and imaging key. In 2018, the British Thoracic Society (BTS) updated the guideline on diagnosis, staging, and follow-up of patients with MPM. These recommendations are discussed in this review of the current literature on imaging of MPM. It is estimated MPM will continue to cause serious morbidity and mortality in the UK late into the 21st century, and internationally, people continue to be exposed to asbestos. We aim to update the reader on current and future imaging strategies, which could aid early diagnosis of pleural malignancy and provide an update on staging and assessment of tumour response.

Non-invasive methods for estimating mPAP in COPD using cardiovascular magnetic resonance imaging.

PURPOSE: Pulmonary hypertension (PH) is associated with a poor outcome in chronic obstructive pulmonary disease (COPD) and is diagnosed invasively. We aimed to assess the diagnostic accuracy and prognostic value of non-invasive cardiovascular magnetic resonance (CMR) models. METHODS: Patients with COPD and suspected PH, who underwent CMR and right heart catheter (RHC) were identified. Three candidate models were assessed: 1, CMR-RV model, based on right ventricular (RV) mass and interventricular septal angle; 2, CMR PA/RV includes RV mass, septal angle and pulmonary artery (PA) measurements; 3, the Alpha index, based on RV ejection fraction and PA size. RESULTS: Of 102 COPD patients, 87 had PH. The CMR-PA/RV model had the strongest diagnostic accuracy (sensitivity 92%, specificity 80%, positive predictive value 96% and negative predictive value 63%, AUC 0.93, p<0.0001). Splitting RHC-mPAP, CMR-RV and CMR-PA/RV models by 35mmHg gave a significant difference in survival, with log-rank chi-squared 5.03, 5.47 and 7.10. RV mass and PA relative area change were the independent predictors of mortality at multivariate Cox regression (p=0.002 and 0.030). CONCLUSION: CMR provides diagnostic and prognostic information in PH-COPD. The CMR-PA/RV model is useful for diagnosis, the RV mass index and PA relative area change are useful to assess prognosis. KEY POINTS: • Pulmonary hypertension is a marker of poor outcome in COPD. • MRI can predict invasively measured mean pulmonary artery pressure. • Cardiac MRI allows for estimation of survival in COPD. • Cardiac MRI may be useful for follow up or future trials. • MRI is potentially useful to assess pulmonary hypertension in patients with COPD.

CT features of pulmonary arterial hypertension and its major subtypes: a systematic CT evaluation of 292 patients from the ASPIRE Registry.

We evaluated the prevalence and prognostic value of CT-pulmonary angiographic (CTPA) measures in 292 treatment naive patients with pulmonary arterial hypertension (PAH). Pulmonary artery calcification (13%) and thrombus (10%) were exclusively seen in PAH-congenital heart disease. Oesophageal dilation (46%) was most frequent in PAH-systemic sclerosis. Ground glass opacification (GGO) (41%), pericardial effusion (38%), lymphadenopathy (19%) and pleural effusion (11%) were common. On multivariate analysis, inferior vena caval area, the presence of pleural effusion and septal lines predicted outcome. In PAH, CTPA provides diagnostic and prognostic information. In addition, the presence of GGO on a CT performed for unexplained breathlessness should alert the physician to the possibility of PAH.

Collapsing glomerulopathy in collagen vascular-like disease.

OBJECTIVE: Collapsing glomerulopathy (CG) is a podocytopathy that is usually associated with human immunodeficiency virus (HIV) and parvovirus B19 infections. CG has been reported in association with definite collagen vascular diseases, mainly systemic lupus erythematosus (SLE). There are a few case reports in the nephrology literature of patients with CG and marked serological abnormalities who do not have sufficient clinical findings to diagnose definite collagen vascular disease. We wish to expand the spectrum of rheumatologic disease that accompanies CG. We describe four patients with CG and collagen vascular-like disease and compare these with 14 similar cases reported in the medical literature. METHODS: Case reports of four new patients with CG and collagen vascular-like disease are presented. We performed a systematic literature review to find all other cases and construct a profile of patients with CG and collagen vascular-like disease. RESULTS: All patients had a similar mode of presentation with severe nephrotic range proteinuria and renal insufficiency resistant to steroids and usual immunomodulatory therapy. All patients had positive antinuclear antibodies (ANA) as well as other marked serological abnormalities but few if any clinical findings that would allow for a definitive diagnosis of a specific collagen vascular disease. Almost all patients became dialysis dependent. Mycophenolate mofetil (MMF) may possibly be a therapeutic option. CONCLUSION: Rheumatologists may be asked to consult on patients with severe proteinuria and renal insufficiency in the presence of marked serological abnormalities but few clinical symptoms and should be aware of this podocytopathy.

The treatment effect of rivaroxaban on clot characteristics in patients who present acutely with first time deep vein thrombosis.

BACKGROUND: The acute vascular disease deep vein thrombosis (DVT) requires oral anticoagulants to prevent progression. Monitoring therapeutic efficacy of direct oral anticoagulants (DOAC), including rivaroxaban, is problematic as no reliable test is available. Advances in rheometry have led to the development of a functional coagulation biomarker using Gel Point (GP) analysis which assesses clot structure formation. The biomarker measures incipient clot formation time (TGP) and quantifies fibrin clot structure in terms of fractal dimension (df). OBJECTIVE: This study aimed to investigate clot structure formation in first time DVT and the effect of rivaroxaban treatment. METHODS: This prospective observational cohort study measured the GP and standard laboratory markers at three sample points: pre-treatment and at 20 and 60 days following 15 mg BD and 20 mg OD rivaroxaban respectively. RESULTS: Forty DVT patients (mean age 64 years [SD±14.8]; 23 males, 17 female) were recruited. The results show that DVT vs non-DVT patients did not have a significantly different GP profile (df: 1.72±0.06 vs 1.70±0.06 and TGP: 267±68 sec vs 262±73 sec) with both within the defined healthy index. In addition, rivaroxaban therapy increased TGP to 392 s (±135 s) after 20 days, and subsequently increased to 395 s (±194 s) at 60 days but did not significantly increase df (from 1.69±0.05 to 1.71±0.06). CONCLUSIONS: The results indicate in this cohort of DVT patients there was no underlying hypercoagulable effect as determined by gel point analysis. Furthermore, the anticoagulant effect of rivaroxaban prolonged clotting, suggesting a protective effect against clot formation, without significantly reducing clot microstructural properties.

Extending the clinical research network approach to all of healthcare.

The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.

Early thymocyte development is regulated by modulation of E2A protein activity.

The E2A gene encodes the E47 and E12 basic helix-loop-helix (bHLH) transcription factors. T cell development in E2A-deficient mice is partially arrested before lineage commitment. Here we demonstrate that E47 expression becomes uniformly high at the point at which thymocytes begin to commit towards the T cell lineage. E47 protein levels remain high until the double positive developmental stage, at which point they drop to relatively moderate levels, and are further downregulated upon transition to the single positive stage. However, stimuli that mimic pre-T cell receptor (TCR) signaling in committed T cell precursors inhibit E47 DNA-binding activity and induce the bHLH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependent pathway. Consistent with these observations, a deficiency in E2A proteins completely abrogates the developmental block observed in mice with defects in TCR rearrangement. Thus E2A proteins are necessary for both initiating T cell differentiation and inhibiting development in the absence of pre-TCR expression. Mechanistically, these data link pre-TCR mediated signaling and E2A downstream target genes into a common pathway.

Plasma homovanillic acid concentration and the severity of schizophrenic illness.

Concentrations of plasma homovanillic acid before treatment were highly correlated with global severity of illness in schizophrenic patients, both before and after treatment. In contrast, a fixed dose of haloperidol did not affect those concentrations. Thus, in patients with a diagnosis of schizophrenia, plasma homovanillic acid may reflect the severity of illness, but not be influenced by short-term pharmacological perturbations by neuroleptics.

Human pancreatic polypeptide has a marked diurnal rhythm that is affected by ageing and is associated with the gastric TFF2 circadian rhythm.

Normal circadian variations in vasoactive intestinal polypeptide, somatostatin, cholecystokinin and pancreatic polypeptide were measured to determine if these alter with aging and to identify gastrointestinal regulatory hormones that might control the dramatic diurnal variation in the gastric cytoprotective trefoil protein TFF2. Plasma pancreatic polypeptide concentrations showed a marked diurnal rhythm (p < 0.0001). Basal and postprandial pancreatic polypeptide concentrations increased with age (p < 0.01). The timing of the diurnal rhythm was consistent with pancreatic polypeptide inhibiting TFF2 secretion and there was a negative association between pancreatic polypeptide and TFF2 concentrations (p < 0.002). The much higher pancreatic polypeptide concentrations in older people will induce increased satiety that may contribute to 'anorexia of ageing'. These results identify potential therapies for treatment of gastric mucosal morbidity and age-associated loss of appetite.

Vasoactive potential of the b(1) bradykinin receptor in normotension and hypertension.

The B(1) type receptor of bradykinin (Bk B(1)R) is believed to be physiologically inert but highly inducible by inflammatory mediators and tissue damage. To explore the potential participation of the Bk B(1)R in blood pressure (BP) regulation, we studied mice with deleted Bk B(2)R gene with induced experimental hypertension, either salt-dependent (subtotal nephrectomy with 0.5% NaCl as drinking water) or renin/angiotensin-dependent (renovascular 2-kidney-1-clip). Compared with the wild-type controls, the B(2)R gene knockout mice had a higher baseline BP (109.7+/-1.1 versus 101.1+/-1.3 mm Hg, P:=0.002), developed salt-induced hypertension faster (in 19.3+/-2.3 versus 27.7+/-2.4 days, P:=0.024), and had a more severe end point BP (148+/-3.7 versus 133+/-3.1 mm Hg, P:<0.05). On the contrary, renovascular hypertension developed to the same extent (149.7+/-4.3 versus 148+/-3.6 mm Hg) and in the same time frame (14+/-2.2 versus 14+/-2.1 days). A bolus infusion of a selective B(1)R antagonist at baseline produced a significant hypertensive response (by 11.4+/-2 mm Hg) in the knockout mice only. Injection of graded doses of a selective B(1)R agonist produced a dose-dependent hypotensive response in the knockout mice only. Assessment of tissue expression of B(1)R and B(2)R genes by reverse transcription-polymerase chain reaction techniques revealed significantly higher B(1)R mRNA levels in the B(2)R knockout mice at all times (normotensive baseline and hypertensive end points). At the hypertensive end points, there was always an increase in B(1)R gene expression over the baseline values. This increase was significant in cardiac and renal tissues in all hypertensive wild-type mice but only in the clipped kidney of the renovascular knockout mice. The B(2)R gene expression in the wild-type mice remained unaffected by experimental manipulations. These results confirm the known vasodilatory and natriuretic function of the Bk B(2)R; they also indicate that in its absence, the B(1)R can become upregulated and assume some of the hemodynamic properties of the B(2)R. Furthermore, they indicate that experimental manipulations to produce hypertension also induce upregulation of the B(1)R, but not the B(2)R, in cardiac and renal tissues.

Techniques for isolation of brush-border and basolateral membrane vesicles from dog kidney cortex.

Two methods are reported for renal membrane preparation from the dog kidney cortex. One method is a simultaneous preparation of brush-border (BBMV) and basolateral (BLMV) membranes. Using readily available laboratory equipment, differential centrifugation produced a supernatant which was treated with Mg2+. The Mg2+ treatment produced a pellet (crude BLMV) which was added to Percoll and centrifuged to produce purified BLMV. The supernatant after Mg2+ treatment eventually yielded pure BBMV after additional Mg2+ precipitations. The second method used an acidic medium in conjunction with divalent-cation precipitation to prepare BBMV. Whichever method was used, BBMV and BLMV showed appropriate enzyme and transport activities.

Proximal regulatory elements and nuclear activities required for transcription of the human Na+/H+ exchanger (NHE-1) gene.

We herein demonstrate competence of the 5' upstream region -1374 to +16 of the human growth factor-activatable Na+/H+ exchanger (NHE-1) gene to promote transcription of the chloramphenicol acetyltransferase gene in cells of hepatic origin (HepG2), vascular-smooth-muscle origin (VSM A7r5) and fibroblasts (3T3). We also describe the mapping of the regulatory elements required for such transcription. Sequential 5' end-deletions indicated that the 5' boundary of the positive regulatory elements of NHE-1 transcription is localized downstream of nucleotide -252 in both HepG2 and VSM A7r5 cells but downstream of nucleotide -654 in 3T3 cells. Footprinting analysis of the 0.25-kb promoter fragment using rat liver nuclear extracts identified 4 protected regions as follows: A, -31 to -9; B, -108 to -65; C, -124 to -111; and D, -239 to -215. Internal deletion and nucleotide substitutions within regulatory element D revealed its essential role for transcription of the human NHE-1 gene in HepG2 and VSM A7r5 cells. DNA binding and competition assays using rat liver nuclear extracts indicated that regulatory element D is recognized by 5 nuclear activities. Four of these activities (designated as NHE-1D1-4) are competed out completely by oligonucleotides containing the binding sites of transcription factors CREB, AP3, NFY, and other CCAAT box-binding proteins (C/EBP alpha or related proteins). This competition profile might be explained by the presence of homology between regulatory element D and the consensus sequence of C/EBP as well as the other competitor oligonucleotides. The actual relationship between these nuclear activities and the C/EBP family of proteins (or other transcription factors) remains to be determined.

Prostaglandin receptor sensitivity in psychiatric disorders.

The cyclic adenosine monophosphate (cAMP) responses to prostaglandin E1 (PGE1) in platelets and leukocytes from drug-free schizophrenic patients, depressive patients, and normal controls have been compared. Both schizophrenic and depressive patients had a significantly lower platelet cAMP response to PGE1 than controls. The platelet cAMP response to PGE1 did not discriminate among exacerbated, remitted, and poor-prognosis schizophrenic patients, or between exacerbated and remitted depressive patients. The cAMP response to PGE1 was negatively correlated with global symptom severity in actively ill schizophrenic patients, but was not correlated with symptom severity in exacerbated depressive patients. The leukocyte cAMP response to PGE1 did not differ among normal controls, schizophrenic patients, and depressive patients. These data indicate that a diminished platelet cAMP response to PGE1 may be a marker common to both schizophrenia and depression but that this effect does not extend to a cAMP-linked PGE1 receptor on another blood cell type.

Evaluating prolactin response to dopamine agonists in schizophrenia. Methodological problems.

Serum prolactin (PRL) level was assessed after challenges with apomorphine hydrochloride, saline, dopamine hydrochloride, or levodopa-carbidopa (Sinemet) in 19 control and 38 chronic schizophrenic subjects. Baseline PRL level varied inversely with age. High correlations existed between baseline PRL level and any subsequent absolute measure of PRL after administration of a dopamine agonist or placebo. Percent decrease was not a function of baseline concentrations and was therefore the only independent measure of drug response. Baseline PRL level was generally lower during exacerbation than remission in patients studied during two states of illness. Percent PRL level decrease after apomorphine administration was significantly greater in normal subjects than in schizophrenics. Correction of apomorphine responses for corresponding placebo (saline) values abolished differences between groups. Prolactin responses after dopamine or levodopa-carbidopa did not differ; however, placebo correction was not possible.

Models of experimental hypertension in mice.

Experimental models of hypertension in various animals are useful in the research of vasoactive mechanisms. Recombinant DNA technology has produced genetically engineered animals, mostly mice, useful in hypertension research. However, the development of hypertensive models in mice is fraught with technical difficulties. We describe here the successful development in mice of two common types of experimental hypertension: the renovascular two-kidney, one clip and mineralocorticoid deoxycorticosterone-salt models. By adapting technology previously used in rats, we succeeded in developing hypertension (defined as systolic pressures higher than 140 mm Hg) in more than 50% of mice so treated. We also adapted the methodology for indirect tail-cuff blood pressure measurements as well as for direct intra-arterial monitoring of blood pressure in conscious, freely moving mice. Application of these techniques in transgenic or gene knockout mice with altered vasoactive hormones or receptors should allow elucidation of the role of the target gene products in various types of hypertension.

Expression of alpha2-adrenergic receptors in normal and atherosclerotic rabbit aorta.

Alpha2-adrenergic receptors (alpha2-ARs) in vascular smooth muscle cells are known to mediate vasoconstriction; however, it is unknown which of the 3 subtypes of alpha2-AR (alpha2A, alpha2B, or alpha2C) is expressed in vascular tissue. We have used subtype-specific probes in in situ hybridization and RNase protection assays to analyze the expression of alpha2-AR in the thoracic aorta of New Zealand White (NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbits, a model for atherosclerosis. We found that the alpha2A-AR mRNA was in endothelial and smooth muscle cells in both NZW and WHHL aorta. In addition, the shoulders and subendothelial regions of the atherosclerotic lesions in WHHL aorta showed abundant expression of alpha2A-AR mRNA. Antibodies to macrophage (RAM-11) and smooth muscle cell (HHF-35) antigens were used to localize macrophage and smooth muscle cells in aortic sections from WHHL rabbits. The expression of alpha2A-AR mRNA within the lesions of WHHL rabbits correlated with the presence of infiltrating macrophages. We discuss the potential role of alpha2A-ARs in macrophage function and in promoting atherosclerosis.

Role of the alpha2B-adrenergic receptor in the development of salt-induced hypertension.

Salt sensitivity is a common trait in patients with essential hypertension and seems to have both an inherited and an acquired component (eg, is influenced by aging and renal insufficiency). Experimental evidence suggests that salt loading induces hypertension via a neurogenic mechanism mediated by the alpha2-adrenergic receptors (alpha2-AR). To explore the alpha2-AR subtype involved in this mechanism, we studied 2 groups of mice genetically engineered to be deficient in one of the 3 alpha2-AR subtype genes (either alpha2B-AR +/- or alpha2C-AR -/- knockout mice) compared with their wild-type counterparts. The mice (n=10 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for up to 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intra-arterial BP recording. The alpha2B-AR-deficient mice had an attenuated BP response in this protocol (baseline 101.8+/-2.7 versus end point 109.9+/-2.8 mm Hg), whereas the BP of their wild-type counterparts went from a baseline 101.9+/-2.3 to an end point 141.4+/-7.1 mm Hg. The other 2 groups had BP increases of 44. 6+/-5.17 and 46.7+/-7.01 mm Hg, with no difference between the mice deficient in the alpha2C-AR gene subtype versus their wild-type counterparts. Body weight, renal remnant weight, and residual renal function were no different among groups. These data suggest that a full complement of alpha2B-AR genes is necessary to raise BP in response to dietary salt loading, whereas complete absence of the alpha2C-AR subtype does not preclude salt-induced BP elevation. It is unclear whether the mechanism(s) involved in this process are of central origin (inability to increase sympathetic outflow), vascular origin (inability to vasoconstrict), or renal origin (inability to retain excess salt and fluid).