Decrease In Capillary Density Research Articles

Intact DNA repair in differentiated cardiomyocytes is essential for maintaining cardiac function in response to pressure overload in mice

Abstract Introduction DNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage-induced aging-related diseases. For example, deficient repair of endogenously generated DNA damage in mice with cardiomyocyte-restricted inactivation of Xpg, is associated with progressive heart failure. Purpose Here we tested the hypothesis that unrepaired DNA damage in differentiated cardiomyocytes increases cardiac vulnerability in response to hemodynamic overload. Methods To increase the burden of spontaneous DNA damage, we generated mice with cardiomyocyte-restricted inactivation of DNA repair endonuclease XPG. At 8 weeks of age, αMHC-Xpgc/- and control (Ctrl) mice were subjected to pressure overload by transverse aortic constriction (TAC). Eight weeks after TAC, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements, followed by molecular and histological analyses. Results Cardiomyocyte-restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction (Table). TAC-induced LV hypertrophy is similar in both groups (Ctrl 38%; αMHC-Xpgc/- 34%). In Ctrl mice, LV hypertrophy was accompanied by minimal LV dilation and modest changes in systolic and diastolic LV function. Conversely, TAC in αMHC-Xpgc/- produced severe LV dysfunction and resulted in overt congestive heart failure, demonstrated by aggravation of LV dilation, and marked increases in LV end-diastolic pressure, left atrial weight and lung fluid weight, which was accompanied by further increases in the expression levels of the hypertrophic marker genes atrial natriuretic peptide and beta-myosin heavy chain (Table). Moreover, lectin staining revealed a decrease in capillary density and TUNEL staining revealed further elevated levels of myocardial apoptosis. In addition, a significant increase of myocardial collagen content was observed. Conclusion Cardiomyocyte-restricted loss of DNA repair protein XPG increases cardiac vulnerability to develop heart failure in response to pressure overload. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only during basal conditions, but also in response to a pathological stimulus.

Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain.

Age-related cerebromicrovascular changes, including blood-brain barrier (BBB) disruption and microvascular rarefaction, play a significant role in the development of vascular cognitive impairment (VCI) and neurodegenerative diseases. Utilizing the unique model of heterochronic parabiosis, which involves surgically joining young and old animals, we investigated the influence of systemic factors on these vascular changes. Our study employed heterochronic parabiosis to explore the effects of young and aged systemic environments on cerebromicrovascular aging in mice. We evaluated microvascular density and BBB integrity in parabiotic pairs equipped with chronic cranial windows, using intravital two-photon imaging techniques. Our results indicate that short-term exposure to young systemic factors leads to both functional and structural rejuvenation of cerebral microcirculation. Notably, we observed a marked decrease in capillary density and an increase in BBB permeability to fluorescent tracers in the cortices of aged mice undergoing isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis), compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, aged heterochronic parabionts (A-(Y)) exposed to young blood exhibited a significant increase in cortical capillary density and restoration of BBB integrity. In contrast, young mice exposed to old blood from aged parabionts (Y-(A)) rapidly developed cerebromicrovascular aging traits, evidenced by reduced capillary density and increased BBB permeability. These findings underscore the profound impact of systemic factors in regulating cerebromicrovascular aging. The rejuvenation observed in the endothelium, following exposure to young blood, suggests the existence of anti-geronic elements that counteract microvascular aging. Conversely, pro-geronic factors in aged blood appear to accelerate cerebromicrovascular aging. Further research is needed to assess whether the rejuvenating effects of young blood factors could extend to other age-related cerebromicrovascular pathologies, such as microvascular amyloid deposition and increased microvascular fragility.

Intact DNA Repair in Differentiated Cardiomyocytes Is Essential for Maintaining Cardiac Function in Response to Pressure Overload in Mice

Introduction: DNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage-induced aging-related diseases. For example, deficient repair of endogenously generated DNA damage in mice with cardiomyocyte-restricted inactivation of Xpg, is associated with progressive heart failure (de Boer et al. Aging Cell 2023). Here we tested the hypothesis that unrepaired DNA damage in differentiated cardiomyocytes increases cardiac vulnerability in response to hemodynamic overload. Methods: At 8 weeks of age, αMHC-Xpgc/- and control (Ctrl) mice were subjected to pressure overload by mild transverse aortic constriction (TAC). Eight weeks after TAC, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements, followed by histological and molecular analyses. Results: Cardiomyocyte-restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction. TAC-induced LV hypertrophy was similar in both groups (Ctrl 38%; αMHC-Xpgc/- 34%). In Ctrl mice, LV hypertrophy was accompanied by minimal LV dilation and only modest changes in systolic and diastolic LV function. Conversely, TAC in αMHC-Xpgc/- produced severe LV dilation and dysfunction and resulted in overt backward failure, demonstrated by marked increases in LV end-diastolic pressure, left atrial weight and lung fluid weight. These changes were accompanied by further increases in the expression levels of the hypertrophic marker genes atrial natriuretic peptide and beta-myosin heavy chain. Moreover, lectin staining revealed a decrease in capillary density and TUNEL staining revealed further elevated levels of myocardial apoptosis in αMHC-Xpgc/--TAC mice as compared to Ctrl-TAC mice. In addition, a significant increase of myocardial collagen content was observed in αMHC-Xpgc/--TAC but not in Ctrl-TAC mice. Conclusion: Cardiomyocyte-restricted loss of DNA repair protein Xpg increases cardiac vulnerability to develop heart failure in response to pressure-overload. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only under basal conditions, but also during increased cardiac loading conditions. Supported by the Dutch Heart Foundation [Grants 2017B018-ARENA-PRIME; 2021B008-RECONNEXT]. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Radiation effects on retinal layers revealed by OCT, OCT-A, and perimetry as a function of dose and time from treatment

Optical coherence tomography (OCT) has become a key method for diagnosing and staging radiation retinopathy, based mainly on the presence of fluid in the central macula. A robust retinal layer segmentation method is required for identification of the specific layers involved in radiation-induced pathology in individual eyes over time, in order to determine damage driven by radiation injury to the microvessels and to the inner retinal neurons. Here, we utilized OCT, OCT-angiography, visual field testing, and patient-specific dosimetry models to analyze abnormal retinal layer thickening and thinning relative to microvessel density, visual function, radiation dose, and time from radiotherapy in a cross-sectional cohort of uveal melanoma patients treated with 125I-plaque brachytherapy. Within the first 24 months of radiotherapy, we show differential thickening and thinning of the two inner retinal layers, suggestive of microvessel leakage and neurodegeneration, mostly favoring thickening. Four out of 13 eyes showed decreased inner retinal capillary density associated with a corresponding normal inner retinal thickness, indicating early microvascular pathology. Two eyes showed the opposite: significant inner retinal layer thinning and normal capillary density, indicating early neuronal damage preceding a decrease in capillary density. At later time points, inner retinal thinning becomes the dominant pathology and correlates significantly with decreased vascularity, vision loss, and dose to the optic nerve. Stable multiple retinal layer segmentation provided by 3D graph-based methods aids in assessing the microvascular and neuronal response to radiation, information needed to target therapeutics for radiation retinopathy and vision loss.

Влияние исходных структурных нарушений и послеоперационного изменения перфузии на функциональное восстановление сетчатки после хирургического лечения сквозных макулярных разрывов

Purpose. To evaluate effect of preoperative local structural retinal changes and capillary perfusion in idiopathic full-thickness macular holes (FTMH) on the recovery of functional activity of the retina after surgical treatment. Materials and methods. We used optical coherence tomography (OCT) and OCT-angiography (OCT-A), microperimetry, multifocal electroretinography. In 25 eyes with FTMH the density of capillaries in the superficial and deep capillary plexus (SCP and DCP), retinal sensitivity (RS), amplitude and implicit time of P1 were studied at 13 points located at different distances from the fixation point were evaluated. Data were analyzed in the projection of the hole, intraretinal cystic changes (ICC), neuroepithelial detachment (NED) and intact retina before surgical treatment, 7 days, and 3 months after. Results. In the area of hole, ICC, and NED, in comparison with intact areas of the retina, a significant decrease in RS, an increase in implicit time and a decrease in amplitude of P1, and a decrease in capillary density in the SCP and DCP were revealed. Functional restoration of the retina with an increase in its perfusion was noted 3 months after the surgery. The correlation was found between postoperative changes in RS and changes in capillary density in the SCP in the projection of NED (R=0.32, p=0.001) and ICC (R=0.19, p=0.001), as well as in the DCP in the projection of NED and ICC (R=0.31, p=0.001). The change in the amplitude P1 in the postoperative period significantly correlated with the change in perfusion in the SCP in the projection of the NED (R=0.38, p=0.001) and the hole area (R=0.31, p=0.001), as well as in the DCP in the projection of the ICC (R=0.31, p=0.01) and in the area of NED (R=0.28, p=0.001). Conclusion. Thus, when using a multimodal topographically oriented approach, a relationship was found in the postoperative period of changes in functional parameters at various points in the macular area with changes in local perfusion at the level of both SCP and DCP, while the relationship is most significant in the projection of NED along the tear edge and in the areas of ICC. Key words: full-thickness macular hole (FTMH), microperimetry, multifocal electroretinography, multimodal imaging, optical coherence tomography, optical coherence tomography-angiography

Diagnostic Value of Capillary Density at Periungual Capillaroscopy in the Diagnosis of Connective Tissue Disease

Our study aims to demonstrate the contribution of quantitative analysis of capillaroscopic study in the early diagnosis of connective tissue diseases. One hundred and fifteen patients were evaluated by capillaroscopy. Raynaud's phenomenon is the most frequently encountered acro-syndrome leading to the request for capillaroscopic examination. capillaroscopy reveals minor dystrophy in 83.5% of patients and major dystrophy in 60% of them. On a quantitative level, 77 patients present, among the four examined fingers, at least one finger with a capillary density <25 capillaries/3mm. For the diagnosis of connective tissue disease, this threshold is statistically significant with an odds ratio of 4.21 (95% CI = 1.47-11.99; p = 0.008). For this same diagnosis, its positive predictive value is 38%, its negative predictive value is 86%. A low capillary density, as a diagnostic test for connective tissue disease, has a sensitivity of 85% and a specificity of 41%. There is no significant difference between the decrease in capillary density for the diagnosis of connective tissue disease for each examined finger in terms of positive predictive value, negative predictive value, sensitivity, and specificity

Hypoxia-Inducible Factor-1α (HIF-1α) as a Biomarker for Changes in Microcirculation in Individuals with Systemic Sclerosis.

Systemic sclerosis is an autoimmune disease characterized by tissue fibrosis and microangiopathy. Vascular changes such as a decrease in capillary density diminish blood flow and impair tissue oxygenation. Reliable ways to monitor disease activity and predict disease progression are desired in the process of patient selection for clinical trials and to optimize individual patient outcomes. Hypoxia-inducible factor-1 (HIF-1) is a dimeric protein complex that plays an integral role in the body's response to hypoxia. Our study aimed to investigate the potential abnormalities of HIF-1α plasma concentration and its possible association with disease activity and vascular abnormalities in patients with systemic sclerosis. Blood plasma levels of HIF-1α were measured in patients with systemic sclerosis (n = 50) and in healthy individuals (n = 30) using commercially available ELISA test kits. The results showed a marked increase in HIF-1α levels in patients with systemic sclerosis (3.042ng/ml [2.295-7.749]) compared to the control group (1.969ng/ml [1.531-2.903] p < 0.01). Patients with diffuse cutaneous SSc (2.803ng/ml, IQR 2.221-8.799) and limited cutaneous SSc (3.231ng/ml, IQR 2.566-5.502) exhibited elevated serum HIF-1α levels compared to the control group (p < 0.01). We found a notable increase in HIF-1α plasma concentration in patients with an "active" pattern (6.625ng/ml, IQR 2.488-11.480) compared to those with either an "early" pattern (2.739, IQR 2.165-3.282, p < 0.05) or a "late" pattern (2.983ng/ml, IQR 2.229-3.386, p < 0.05). Patients with no history of digital ulcers had significantly higher levels of HIF-1α (4.367ng/ml, IQR 2.488-9.462) compared to patients with either active digital ulcers (2.832ng/ml, IQR 2.630-3.094, p < 0.05) or healed digital ulcers (2.668ng/ml, IQR 2.074-2.983, p < 0.05). Our results indicate that HIF-1α may serve as a biomarker in assessing microcirculatory changes in individuals with systemic sclerosis.

A pilot study of diabetic retinopathy in a porcine model of maturity onset diabetes of the young type 3 (MODY3)

Diabetic retinopathy (DR) is a leading cause of blindness in the working population. Because novel therapeutic intervention require testing, there is an urgent need for reliable animal models that faithfully replicate DR. Pig eyes have many similarities to human eyes anatomically and physiologically. Thus, attempts have been made to establish porcine models of DR by surgical, pharmaceutical or genetical induction of insulin deficiency, and dietary intervention. A previous study reported a transgenic pig model of maturity onset diabetes of the young type 3 (MODY3) developed signs of severe DR such as hemorrhage and proliferative tissue at the surface of the retina. However, the course of development of DR has not been studied in detail in this model. The purpose of this study was to investigate the early phase of DR in a MODY3. MODY3 and wild-type (WT) pigs underwent fundus photography and fluorescein angiogram (FA) before they developed cataracts. Animals were euthanized at age 1, 4, 7, and 10 months. Whole-mount retina and 10-μm thick paraffinized sections were stained with isolectin B4, and vessel density was determined by MATLAB software. At 4 and 7 months, retinal arterioles were immediately cannulated, and vasomotor action was measured by incubation with bradykinin and sodium nitroprusside. In the MODY3 pigs, fasting blood sugar levels gradually increased up to 500 mg/dL. Vascular tortuosity and yellowish spindle-shaped lesions were confirmed in MODY3 pigs at the age of 7 months; however, no microaneurysms were detected on FA. Compared with age-matched WT pigs, MODY3 pigs showed a significant decrease in blood vessel density in the intermediate and deep vascular plexus at 4 and 7 months of age and a slight decrease in capillary density in the superficial vascular plexus at 7 months of age. In MODY3 pigs, electron microscopy revealed thickening of the capillary basement membrane and leukostasis in the major blood vessels at 10 months of age. Bradykinin-induced dilation of retinal arterioles was diminished in MODY3 pigs as early as 7 months of age. Within 1 year after birth, MODY3 pigs show all typical early vascular lesions of diabetes except for microaneurysm formation. This pilot study suggests that the MODY3 pigs may serve as a suitable DR model to test effects of newly developed compounds on DR.

Evaluation of serum vascular endothelial growth factor level and findings of nailfold capillaroscopy by dermatoscope in the differential diagnosis of palmoplantar psoriasis and palmoplantar eczema.

This study aimed to evaluate VEGF level, capillaroscopic findings, and these features for differential diagnosis of palmoplantar psoriasis and eczema patients. This comparative cross-sectional study included 40 patients clinical and histopathologically diagnosed with eczema or psoriasis (20 psoriasis and 20 eczema) and 30 patients of similar age and gender without inflammatory disease in the control group. Serum samples of patients were collected and analyzed for VEGF by enzyme-linked immunosorbent assay (ELISA) and at the same time, we applied capillaroscopy with computerized dermatoscopy qualitatively and semiquantitatively. In the qualitative evaluation, a decrease in capillary density and a significant increase of the avascular area was in palmoplantar plaque psoriasis (PPP) and palmoplantar eczema (PPE) patients compared to the control group. In the semiquantitative evaluation, the mean score decreased capillary density was significantly higher in PPE than in the PPP and control groups (p<0.001). Minor morphological change (tortuous, crossed and enlarged capillary) scores were significantly higher in patients with PPE compared to PPP and control groups (p=0.011). Major morphological change (mega, meandering, branching, bushy, bizarre, and disorganized polymorphic capillary) score was significantly higher in patients with PPP than PPE and the control group (p<0.001). Major morphological change and m-PPPASI scores were correlated in PPP patients (p<0.05). Disorganized capillaries in PPP patients were significantly higher than in the PPE and control groups (p<0.001). There was no significant correlation between serum VEGF value and clinical severity and capillaroscopy findings of the patients. Significant morphological changes were detected between PPP, PPE, and control groups in the qualitative and semi-quantitative evaluation of capillaroscopic findings. In the differential diagnosis of PPP and PPE, major morphological change, especially the presence of disorganized polymorphic capillaries, was considered an important finding in the capillaroscopic evaluation. These capillaroscopic findings may be helpful to discriminate eczema and psoriasis. However, there was no significant relationship between serum VEGF level and the patients' capillaroscopic findings and clinical severity.

Investigation of the evolution of tumor-induced microvascular network under the inhibitory effect of anti-angiogenic factor, angiostatin: A mathematical study.

Anti-angiogenesis as a treatment strategy for normalizing the microvascular network of tumors is of great interest among researchers, especially in combination with chemotherapy or radiotherapy. According to the vital role that angiogenesis plays in tumor growth and in exposing the tumor to therapeutic agents, this work develops a mathematical framework to study the influence of angiostatin, a plasminogen fragment that shows the anti-angiogenic function, in the evolutionary behavior of tumor-induced angiogenesis. Angiostatin-induced microvascular network reformation is investigated in a two-dimensional space by considering two parent vessels around a circular tumor by a modified discrete angiogenesis model in different tumor sizes. The effects of imposing modifications on the existing model, i.e., the matrix-degrading enzyme effect, proliferation and death of endothelial cells, matrix density function, and a more realistic chemotactic function, are investigated in this study. Results show a decrease in microvascular density in response to the angiostatin. A functional relationship exists between angiostatin's ability to normalize the capillary network and tumor size or progression stage, such that capillary density decreases by 55%, 41%, 24%, and 13% in tumors with a non-dimensional radius of 0.4, 0.3, 0.2, and 0.1, respectively, after angiostatin administration.

223 Evaluation of nailfold capillaries in dermatomyositis using a dermatoscope

Nailfold capillary (NC) abnormalities are increasingly utilized in the evaluation of rheumatic conditions. Their presence can distinguish primary Raynaud’s phenomenon from secondary etiologies and are used in the diagnostic criteria of scleroderma. Dermoscopy is a convenient method of evaluating NC changes with similar efficacy to capillaroscopy. We imaged all ten nailfolds of subjects with dermatomyositis (DM) using a dermatoscope with a smartphone adapter. Fingernails were cleaned with an alcohol swab prior to evaluation. Images were assessed for loop dilation (LD), abnormal morphology (AM), capillary bed disorganization (CBD), capillary hemorrhage (CH), capillary dropout (CD), decreased capillary density (DCD), and subpapillary plexus visibility (SP). Cutaneous Dermatomyositis Area and Severity activity (CDASI-A) scores and systemic activity (lung, muscle, or joint involvement) were collected. Analysis used Student’s t-test and chi-square test. Subjects with hypertension, hyperlipidemia, diabetes, glaucoma, or other primary rheumatic disease were excluded. 44 subjects, 17 with amyopathic DM (ADM), were included. Mean (standard error) CDASI activity and damage scores were 13 (1.05) and 4 (0.39), respectively. 89% of subjects demonstrated capillary abnormalities. LD (77%), followed by CBD (73%), were the two most common findings. NC changes were most often found on 4th and 5th fingers. Thumbs demonstrated the fewest abnormalities. Mean CDASI-A was higher in patients with AM (CDASI 16 vs 10, p=0.003), CD (15 vs 10, p=0.016), DCD (17 vs 10, p<0.001), and trended towards significance for LD and CBD. There was a trend towards a higher percentage of CH in patients with ADM compared to those with muscle disease (no difference in CDASI-A). Subjects with skin limited disease (n=23) vs active systemic disease demonstrated more AM (74% vs 38%, p=0.02; no difference in CDASI-A). Given its prevalence, NC changes are useful in the evaluation of DM. AM, CD, and DCD may be markers of cutaneous disease activity.

Correlation of nailfold capillaroscopy findings with history of digital ulcer on same finger: Results of SCLEROCAP study.

This study is part of Sclerocap, a multicenter study aiming at validating prospectively the prognostic value of Maricq's and Cutolo's capillaroscopic classifications during a three-year longitudinal follow-up. A history of past or present digital ulcer was recorded at inclusion and nailfold capillaroscopy was performed. Elementary findings as well as Cutolo and Maricq's classifications were assessed. 387 patients were included in Sclerocap (327 females, 60 males) and 3096 fingers were examined by capillaroscopy at inclusion: 316 fingers (10%) belonging to 113 patients had a history of DU. Late Cutolo's stage was statistically correlated with a history of DU, both by univariate: OR 2.08 [1.09-3.96] and multivariate analysis: OR 1.97 [1.06-3.63]. Among the elemental abnormalities, only edema and decreased capillary density were correlated with a history of DU by multivariate analysis: respectively OR 1.92 [1.17-3.16] and 0.65 [0.49-0.85]. This cross-sectional study in a large cohort of patients with systemic sclerosis shows a correlation between a history of digital ulcer and edema, a decrease in capillary density and the late stage in Cutolo's classification. The extent of capillary abnormalities on one finger is associated with a history of local digital ulcer. Capillaroscopy might be used to predict the risk of DU but these results need first to be confirmed by prospective studies.

Genesis of Antibiotic Resistance (AR) LXXXVIII: Turbulence Modeling(TM) of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2)‐NCT01663701: “Hypnotic Trance Ameliorate Turbulence to Laminar Flow (Homeostasis)”: A Neuropsychiatric Basis

An effort is made to substantiate that vascular abnormalities (fluid dynamic/mechanical properties) could be restored to homeostasis by an appropriate hypnotic trance. Clinical Background:Sepsis: Clinical data/Record(observation): decreased capillary density ref Fig 4 c., PMID: 34055944, hypovolemia, endothelial dysfunction, increased WBC accumulation, thrombi deposition, altered CCP, NFP gradient, shunting, degradation of endothelial glycocalyx, vascular hyper permeability (PMID: 23566729; PMID: 20179590; PMID: 24067428), as an indicator of sepsis progress to septic shock. Neuropsychiatry diagnostic index: HAND (HIV associate neurodegenerative disorder), PTSD, psychosis, depression, mania, ANI, MND, HIV associated dementia (HAD), possible multifocal leukoencephalopathy (CMV origin, Toxoplasmaencephalitis, diffused myelin pallor, opportunistic infections, and neurosyphilis (Jarisch Herxheimer reaction). Geometry: Part I: RBC, Platelets, WBC: p47‐56; Part II: blood velocity, and function, Table 2.1; 2,2; 2.3; p63; ISBN 9780128024089; Governing Equations: Part A: CD, https://www.grc.nasa.gov/www/k‐12/airplane/shaped.html;; Part B: Keulegan – Carpenter Number equation: □=Vm/ƒoscD; Clinical Data: Hemodynamics Hypnotic Trance:Before hypnotic induction: 120.65 mmHg / 79.84 mmHg (Derived →PP= 41 mmHg Normal;Derived →MAP=93mmHg); After hypnotic induction: 115.92 mmHg /76.16 mmHg; (Derived →PP= 40 mmHg Normal;Derived →MAP= 89 mmHG)).Heart rate before hypnotic induction: 86.16 / beats per minute (Derived →CO= 86.16/ beats per minute x 70ml/min=6029.8 ml/min); After hypnotic induction, to 78.89 beats per minute (Derived →CO=78.89/ beats per minute x 70 ml/min=5522.3ml/min). (Kurnia S, et.al., (2021). Blood Pressure Control and Heart Rate: Effectiveness Brief Hypnotic Induction Methods on Adults. 10.2991/assehr.k.210423.004). Spirometry (Homeostasis): VT: 500 ml; IRV: 3100 ml; ERV: 1200 ml; VC: 4800 ml; RV: 1200 ml; A respiratory rate of 12 breaths/ minute, the minute ventilation = 12 x 500 = 6000 ml. alveoli alveolar ventilation (volume of air/min that actually reaches the alveoli) = 12 x 350 = 4200ml. Clinical correlation:The basis for correlating the sepsis, neurological(physiological/psychiatric) and hypnotic trance is that the hypnotic trance subject recovers to homeostasis provided abreaction not encountered by the subject as much as the sepsis, neurological ‐ physiological/psychiatric patients with appropriate Dx, and Tx. Taken together, it is suggested that a decrease in capillary density observed in sepsis and en route to septic shock is a transient phenomenon implicit of a reversible loss of hemodynamic function, for patients Txwith SSSP‐ERP‐EGDT similar to that of SSSP‐2 NCT0166370. Such patient cohort could possibly be reverted to sustain homeostasis in a patient‐specific hypnotic suggestion(s), re‐alert concluding with a reassuring‐post hypnotic trans conversation (devoid of abreaction).

Sex features of cutaneous microvasculature in healthy working-age people

Aim. To study sex characteristics of cutaneous microvascular structure and function in a cohort of healthy working-age people without cardiovascular diseases.Material and methods. The study included 35 healthy men (42±4 years) and 34 women (41 ±5 years). The cardiovascular system was assessed in all patients. The microcirculatory bed of the skin was investigated by the following non-invasive methods: 1) computerized video capillaroscopy; 2) laser Doppler flowmetry; 3) photoplethysmography.Results. According to computerized video capillaroscopy in men, compared with women, there was a smaller number of both functioning capillaries (78 vs 86 capillaries/mm2, respectively (p&lt;0,05)) and their total number (100 vs 120 capillaries/mm2, respectively (p&lt;0,001)). Against the background of a decrease in capillary density in men, there was a higher skin interstitial hydration — 113 vs 96 gm (p&lt;0,005) in men than in women. At the level of precapillary arterioles, where humoral tone regulation prevails. Laser Doppler flowmetry revealed lower pulse amplitude in men than in women — 0,87 vs 1,02 pf, respectively (p&lt;0,05), which indicates a lower arterial blood inflow to exchange microvessels. Against this background, the constrictor response of precapillary arterioles to a sympathetic nervous system stimulation in men is higher than in women — 45% vs 40%, respectively (p&lt;0,05). At the level of large arterioles, where neural tone regulation prevails, photoplethysmography revealed lower augmentation index standardized at a heart rate in men (-4,6 vs 1,7%, respectively, p&lt;0,05), which indicates lower rigidity of muscular vessels in men.Conclusion. In working-age healthy people, sex differences are noted at all cutaneous microvascular levels, which must be taken into account when planning studies.

Lycopene ameliorates insulin resistance and increases muscle capillary density in aging via activation of SIRT1

Lycopene (Ly) is a kind of hydrocarbon, which belongs to the family of tetraterpene carotene and exists in red fruits and vegetables. The decrease of capillary density and blood flow with age is a significant reason for the increase of mortality and morbidity. Herein, our study aims to explore the effects of Ly (a bioactive food compound) on vascular aging in vitro and in vivo and its potential mechanisms. The cytological results showed that Ly could promote the proliferation of human umbilical vein endothelial cell (HUVECs) and enhance the ability of HUVECs to form capillary-like structures. Furthermore, the expression of SIRT1 in aged HUVECs was up-regulated. In vivo, aging rats showed signs of insulin resistance and blood vessel damage. Additionally, the capillary density and blood flow were reduced during the vascular aging process in both D‐gal‐induced and naturally aging muscle. However, when Ly was given, these conditions could be reversed. Simultaneously, the contents of ATP, lactic acid and pyruvic acid were determined, and it was found that Ly could promote angiogenesis by increasing the utilization rate of glucose and promoting energy metabolism. Finally, in the insulin resistance cell model, we knocked down the SIRT1 and administrated with Ly, and found that it couldn't restore insulin transdution. In conclusion, all the data in this study demonstrate that Ly could reactivate SIRT1 and improve insulin resistance, which was a reversible cause of vascular aging.

Effective Picosecond Nd:YAG laser on seborrheic dermatitis and its mechanism.

The Picosecond Nd:YAG laser has advantages in skin rejuvenation, which has little damage to surrounding tissues due to the ultra-short pulse width. We perform clinical application of Picosecond Nd:YAG laser's tender skin mode, which could improve the seborrheic dermatitis. Sixty-three subjects with facial seborrheic dermatitis are randomized to be control and observation groups. Records regarding skin subjective improvement, skin barrier function-related data, skin microbial status, and dermoscopy detection of the two patient groups before and after treatments are investigated. Improvements of erythema and scales in observation group are significant compared with controls (p<0.05). In terms of skin barrier function, there are significant changes regarding transepidermal water loss and epidermal seborrhea content in observation group after the laser treatments. Skin microbial state, pityrosporum furfur, and Demodex significantly decrement in observation group. Microscopical findings of infiltration mode advise that scales and capillary congestion and dilatation are significantly improved in observation group. Compared with controls, epidermal gloss increases, pore fineness improves, and capillary density decreases in the observation group. Picosecond Nd:YAG laser could efficiently decrease erythema area and seborrheic dermatitis scales and reduce pruritus incidence. The sebaceous gland secretion of seborrhea and multiplying of epidermal parasitic microbiological are inhibited after laser treatment. Less epidermal seborrhea content and inflammation are induced by parasitic microbiology, which is helpful for skin barrier function and microvascular remodeling.

Assessment of nail findings in children with atopic dermatitis.

Cutaneous findings are well known in atopic dermatitis (AD), but nail changes have not received as much attention. To determine the clinical and disease-related capillaroscopic findings of nail findings in paediatric patients with AD. In total, 100 participants aged 2-16 years were sourced from the dermatology outpatient clinic: 50 of these had been diagnosed with AD according to the Hanifin-Rajka criteria, and the others were 50 healthy controls (HCs) without AD. The AD severity score (SCORing Atopic Dermatitis; SCORAD) was calculated for all patients with AD. A digital epiluminescence device was used for nailfold capillaroscopy. The nail findings detected in patients with AD were pitting, punctate leuconychia, trachyonychia, onycholysis and onychomadesis. Pitting was significantly (P < 0.01) more frequent in the patient group (26%) than in the HC group (6%). Similarly, the patient group had significantly higher rates for capillary density decrease (P < 0.01), capillary array irregularity (P < 0.001), capillary dilatation increase (P < 0.001), tortuosity (P = 0.04), ramification increase (P = 0.02), bush-like appearance (P = 0.02) and avascular areas (P < 0.01). Significant correlations were determined between pitting and trachyonychia (P < 0.05, r = 0.21), capillary density decrease (P < 0.05, r = 0.25), avascular areas (P < 0.001; r = 0.29) and SCORAD (P < 0.05, r = 0.35). The nailfold capillaroscopic images of children with AD were similar to those of scleroderma spectrum disorder. Thus, we believe it would be beneficial to support detailed clinical examination of patients with a capillaroscopic examination.

Associations Between Capillary Diameter, Capillary Density, and Microaneurysms in Diabetic Retinopathy: A High-Resolution Confocal Microscopy Study.

PurposeTo use high-resolution histology to define the associations between microaneurysms, capillary diameter and capillary density alterations in diabetic retinopathy (DR).MethodsQuantitative comparisons of microaneurysm number, capillary density and capillary diameter were performed between eight human donor eyes with nonproliferative DR and six age- and eccentricity-matched normal donor eyes after retinal vascular perfusion labelling. The parafovea, 3-mm, 6-mm, and 9-mm retinal eccentricities were analyzed and associations between microvascular alterations defined.ResultsMean capillary density was reduced in all retina regions in the DR group (P = 0.013). Microaneurysms occurred in all retina regions in the DR group, but the association between decreased capillary density and microaneurysm number was only significant in the 3-mm (P = 0.040) and 6-mm (P = 0.007) eccentricities. The mean capillary diameter of the DR group (8.9 ± 0.53 µm) was greater than the control group (7.60 ± 0.40 µm; P = 0.033). There was no association between capillary diameter increase and capillary density decrease (P = 0.257) and capillary diameter increase and microaneurysm number (P = 0.147) in the DR group. Within the parafovea of the DR group, capillary density was significantly reduced, and capillary diameter was significantly increased in the deep capillary plexus compared with the superficial and intermediate plexuses (all P < 0.05).ConclusionsIn DR, capillary density reduction occurs across multiple retina eccentricities with a predilection for the deep capillary plexus. The association between microaneurysm number and capillary density is specific to retina eccentricity. Capillary diameter increase may be an early biomarker of DR. These findings may refine the application of optical coherence tomography angiography techniques for the management of DR.

Exercise and insulin-like growth factor1 supplementation improve angiogenesis and angiogenic cytokines in a rat model of diabetes-induced neuropathy.

What is the central question of this study? Do changes in levels of angiogenesis-related mediators [vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1) and nuclear factor-κB (NF-κB)] in the sciatic nerve mediate diabetic neuropathy in the streptozotocin-induced type1 diabetic male rat? Can exercise and insulin-like growth factor1 (IGF-I) treatment improve the diabetes-related decrease in angiogenesis in sciatic nerve in these animals? What is the main finding and its importance? Levels of VEGF-A, TSP-1 and NF-κB change in the sciatic nerve of diabetic rats and might mediate diabetic neuropathy. Treatment with IGF-I and exercise could increase angiogenesis in the diabetic rats by increasing VEGF-A and decreasing TSP-1 and NF-κB expression in the sciatic nerve. Diabetic neuropathy is a severe complication of diabetes that affects 40-50% of diabetic people in the world. The aim of this study was to characterize alterations in angiogenesis and related molecular mediators in the sciatic nerve in diabetic conditions alone or in diabetes in combination withexercise and/or administration of insulin-like growth factor1 (IGF-I). Forty male Wistar rats were assigned into one of five groups, namely control, diabetes, diabetes+exercise, diabetes+IGF-I and diabetes+exercise+IGF-I. Type1 diabetes was induced by i.p. injection of streptozotocin (60mgkg-1 ). After 30 days of treatment with exercise or IGF-I alone or in combination, diabetic neuropathy was evaluated with a hotplate, glycated haemoglobin was measured, angiogenesis was determined by immunostaining for PECAM-1/CD31, and expressions of vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1) and nuclear factor-κB (NF-κB) were determined by enzyme-linked immunosorbent assay.After 4weeks, the diabetes group showed a significant decrease in capillary density and VEGF-A levels, but a significant increasein glycated haemoglobin in blood, TSP-1 and NF-κB levels in the sciatic nerve compared with the control group, and these effects were ameliorated by exercise and IGF-I. However, simultaneous treatment of diabetic rats with IGF-I and exercise did not have any synergistic effects. These findings indicate that diabetes-induced neuropathy may be associated, in part, with decreasedangiogenesis mediated by overproduction of TSP-1 and NF-κB, in addition to reduced production of VEGF-A. The findings also showed that exercise and IGF-I can reduce neuropathy, followed by increased angiogenesis, by changes in TSP-1, NF-κB and VEGF-A production levels.

4260Loss of Pnn in cardiomyocytes results in impairment of intercalated discs and arrhythmogenic cardiomyopathy in mice

Abstract Background Pnn, a multiple functional protein that localizes within nucleus and in the cytoplasmic region of desmosome. Although recent studies have characterized the physiological role of nuclear Pnn in regulating pre-mRNA alternative splicing and gene transcription, the function of Pnn in desmosome, particularly in cardiomyocytes, remains unidentified. Purpose and methods In the present study, we applied an inducible cardiomyocyte-specific Pnn depletion mouse model (Myh6-CreERT2, Pnnflox/flox) to observe the impact of loss of Pnn on cardiac structure and function in adult mice. Results Six weeks after tamoxifen injection to induce cardiac Pnn depletion, the electrocardiographic abnormalities and decrease of left ventricular ejection fraction (LVEF) were observed. Histopathological examination showed that the proliferation of cardiac fibroblasts and expression of α-smooth muscle actin were increased with Pnn depletion, while the cell-cell connection among cardiomyocytes were impaired. In addition, cellular hypertrophy and decrease of capillary density were also found. Results from Immunofluorescent staining further showed that the distribution pattern of desmosomal proteins and adherent junctional proteins, including desmoglein, desmocollin, plakoglobin, plakophllin, desmoplakin and β-catenin were altered in the cardiomyocytes with Pnn depletion. Both desmosomal and adherent junctional proteins were translocated form cell-cell junction to cytoplasm, indicating the disruption of intercalated discs in Pnn-depleted cardiomyocytes. Microarray data also indicated that loss of cardiac Pnn regulated the mRNA expression of genes responsible for extracellular matrix-receptor interaction, ribosome, and integrin. In addition, expression levels of oxidative stress-associated proteins were significantly regulated by Pnn depletion. Impairment of intercalated disc Conclusion Results from present study indicated that Pnn plays an essential role in the maintenance of intercalated disc integrity of cardiomyocytes, while cardiomyocyte-specific loss of Pnn leads to arrhythmogenic cardiomyopathy in mice. Acknowledgement/Funding Ministry of Science and Technology Taiwan, MOST-106-2320-B-182A-010-MY3