Plasminogen: an enigmatic zymogen.

Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.

Anterior Segment Surgeries Under Topical Fresh Frozen Plasma Treatment in Ligneous Conjunctivitis.

PURPOSE: To evaluate the efficacy of topical fresh frozen plasma (FFP) therapy on clinical symptoms, findings, and prognosis after anterior segment surgeries in patients with ligneous conjunctivitis (LC). METHODS: Retrospective case note review. RESULTS: Eleven eyes of 7 cases whose remission was not achieved after medical treatment such as topical corticosteroids, cyclosporine A, and heparin were included in the study. The median age of admission was 19 (1-49) years, median duration of FFP treatment was 48 (15-79) months, median follow-up period was 62 (16-114) months, and median age at symptom onset was 12 (4-252) months. Diagnosis was made according to clinical presentations, plasminogen activities, and response to treatment. Topical FFP that was prepared in our clinic was used in all cases. Surgeries (membrane excision, eyelid surgery, deep anterior lamellar keratoplasty, and cataract surgery) were performed after at least 1 month of FFP treatment. Prosthetic contact lens was applied to one eye. During the follow-up period, recurrences requiring membrane excision and side effects from topical FFP were not observed. CONCLUSIONS: LC is a rare membranous conjunctivitis that proceeds with remissions and recurrences. When it was shown that the etiology of LC is plasminogen deficiency, FFP became the only treatment option targeting the etiology. In this study, we observed that the topical FFP is an effective treatment method that prevents recurrence and ensures regression of membranes and safer anterior segment surgeries in LC.

[Stiff skin syndrome in a pediatric patient: a therapeutic challenge. Clinical case]. / Síndrome de piel indurada en un paciente pediátrico: un desafío terapéutico. Presentación de un caso.

Stiff skin syndrome is a chronic, rare sclerosing disorder that occurs in childhood, characterized by progressive induration of the skin that can cause thoracic restrictions and respiratory distress, limitations in joint mobility and gait difficulties, with significant deterioration of the quality of life. Because their therapeutic options are scarce and ineffective it is essential to start an early physical therapy to prevent these complications and to continue studying this condition to be able to offer patients more and better treatments. We present the case of a 9-year-old patient with indurated skin syndrome and its therapeutic challenge.

El síndrome de la piel indurada es un trastorno esclerosante crónico, infrecuente, que se presenta en la infancia, caracterizado por la induración progresiva de la piel. Esta afección puede provocar restricciones torácicas y dificultad respiratoria, limitaciones en la movilidad articular y trastornos en la marcha, con importante deterioro de la calidad de vida. Debido a que sus opciones terapéuticas son escasas y poco eficaces, es fundamental que el paciente inicie precozmente una terapia física para prevenir estas complicaciones y que se continúe estudiando esta enfermedad a fin de poder ofrecer a los pacientes más y mejores tratamientos. Se presenta el caso de una paciente de 9 años con síndrome de la piel indurada y su desafío terapéutico.

Morphological Analysis of Retinal Microvasculature to Improve Understanding of Retinal Hemorrhage Mechanics in Infants.

Purpose: In this experimental study, we quantify retinal microvasculature morphological features with depth, region, and age in immature and mature ovine eyes. These data identify morphological vulnerabilities in young eyes to inform the mechanics of retinal hemorrhage in children. Methods: Retinal specimens from the equator and posterior pole of preterm (n = 4) and adult (n = 9) sheep were imaged using confocal microscopy. Vessel segment length, diameter, angular asymmetry, tortuosity, and branch points were quantified using a custom image segmentation code. Significant differences were identified through two-way ANOVAs and correlation analyses. Results: Vessel segment lengths were significantly shorter in immature eyes compared to adults (P < 0.003) and were significantly shorter at increasing depths in the immature retina (P < 0.04). Tortuosity significantly increased with depth, regardless of age (P < 0.05). These data suggest a potential vulnerability of vasculature in the deeper retinal layers, particularly in immature eyes. Preterm retina had significantly more branch points than adult retina in both the posterior pole and equator, and the number increased significantly with depth (P < 0.001). Conclusions: The increased branch points and decreased segment lengths in immature microvasculature suggest that infants will experience greater stress and strain during traumatic loading compared to adults. The increased morphological vulnerability of the immature microvasculature in the deeper layers of the retina suggest that intraretinal hemorrhages have a greater likelihood of occurring from trauma compared to preretinal hemorrhages. The morphological features captured in this study lay the foundation to explore the mechanics of retinal hemorrhage in infants and identify vulnerabilities that explain patterns of retinal hemorrhage in infants.

Association of arterial stiffness with aortic calcification and tortuosity.

Impact of arterial stiffness on aortic morphology has not been well evaluated. We sought to investigate the association of brachial-ankle pulse wave velocity (baPWV) with aortic calcification and tortuosity.A total of 181 patients (65.4 ±â€Š10.4 years, males 59.7%) who underwent computed tomographic angiography and baPWV measurement within 1 month of study entry were retrospectively reviewed. Aortic calcification was quantified by the calcium scoring software system. Aortic tortuosity was defined as the length of the midline in the aorta divided by the length of linear line from the aortic root to the distal end of the thoraco-abdominal aorta. In simple correlation analyses, baPWV was correlated with aortic calcification (r = 0.36, P < .001) and tortuosity (r = 0.16, P = .030). However, these significances disappeared after controlling for confounders in multivariate analyses. Factors showing an independent association with aortic calcification were age (ß = 0.37, P < .001), hypertension (ß = 0.19, P = .003), diabetes mellitus (ß = 0.12, P = .045), smoking (ß = 0.17, P = .016), and estimated glomerular filtration rate (ß = -0.25, P = .002). Factors showing an independent association with aortic tortuosity were age (ß = 0.34, P < .001), body mass index (ß = -0.19, P = .018), and diabetes mellitus (ß = -0.21, P = .003).In conclusion, baPWV reflecting arterial stiffness was not associated with aortic calcification and tortuosity. Traditional cardiovascular risk factors were more influential to aortic geometry. Further studies with a larger sample size are needed to confirm our results.

Tortuosity of the superficial femoral artery and its influence on blood flow patterns and risk of atherosclerosis.

The superficial femoral artery (SFA) is a typical atherosclerosis-prone site. We aimed to explore whether the tortuosity of the SFA associates with the occurrence of atherosclerosis and investigate how vascular tortuosity influences the characteristics of blood flow. Ten patients diagnosed with atherosclerotic disease in their SFAs while free of systemic atherosclerosis risk factors were enrolled together with ten atherosclerosis-free patients. The tortuosity of each SFA was quantitatively evaluated by calculating the averaged curvature (AC), maximum curvature (MC) and fraction of high curvature (FC) based on the geometrical model reconstructed from medical images. Hemodynamic studies were performed using both geometrically simplified and anatomically realistic models of the SFA to systematically address the hemodynamic effects of vascular tortuosity. Morphological analyses revealed that all curvature indices of the SFA were significantly larger in patients with atherosclerosis than in atherosclerosis-free patients (AC [mm-1]: 0.034 ± 0.016 vs. 0.018 ± 0.006; MC [mm-1]: 0.055 ± 0.023 vs. 0.034 ± 0.008; FC [%]: 22.77 ± 10.22 vs. 11.39 ± 6.82; p < 0.001). Simulations of blood flows in the geometrically simplified SFAs showed that increasing vascular curvature caused a progressive increase in the area ratios of low wall shear stress (LWSA) and high oscillatory shear index (HOSA). Hemodynamic studies on the anatomically realistic SFAs further demonstrated that high-curvature SFAs (n = 10) had overall larger LWSA and HOSA compared with low-curvature SFAs (n = 10) (LWSA [%]: 4.13 ± 1.91 vs. 1.79 ± 1.13, p = 0.009; HOSA [%]: 4.95 ± 1.92 vs. 2.37 ± 1.51, p = 0.007). These results suggest that increased vascular tortuosity augments the severity and distribution of atherosclerosis-promoting flow disturbances in the SFA and may be an independent risk factor for atherosclerosis.

Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds.

The role of epidermal proteolysis in overdesquamation was revealed in Netherton syndrome, a rare ichthyosis due to genetic deficiency of the LEKTI inhibitor of serine proteases. Recently, we developed activography, a new histochemical method, to spatially localize and semiquantitatively assess proteolytic activities using activity-based probes. Activography provides specificity and versatility compared to in situ zymography, the only available method to determine enzymatic activities in tissue biopsies. Here, activography was validated in skin biopsies obtained from an array of distinct disorders and compared with in situ zymography. Activography provides a methodological advancement due to its simplicity and specificity and can be readily adapted as a routine diagnostic assay. Interestingly, the levels of epidermal proteolysis correlated with the degree of desquamation independent of skin pathology. Thus, deregulated epidermal proteolysis likely represents a universal mechanism underlying aberrant desquamation.

Hemodynamic investigation of a patient-specific abdominal aortic aneurysm with iliac artery tortuosity.

This paper describes a systematic investigation on the hemodynamic environment in a patient-specific AAA with tortuous common iliac artery(CIA) and external iliac artery (EIA). 3D reconstructions from CT scans and subsequent computational simulation are carried out. It is found out that the Newtonian and non-Newtonian models have very similar flow field and WSS distribution. More importantly, it is revealed that the torturous CIA maintained its helical flow. It is concluded that the assumption of Newtonian blood is adequate in capturing the intra-aneurysmal hemodynamics. Moreover, it is speculated that the physiological spiral flow protects the twisted CIA from the thrombosis formation.

Annular Lesions: Diagnosis and Treatment.

Annular lesions can present in a variety of diseases. Knowledge of the physical appearance and history of presentation of these skin findings can help in the diagnosis. A pruritic, annular, erythematous patch that grows centrifugally should prompt evaluation for tinea corporis. Tinea corporis may be diagnosed through potassium hydroxide examination of scrapings. Recognizing erythema migrans is important in making the diagnosis of Lyme disease so that antibiotics can be initiated promptly. Plaque psoriasis generally presents with sharply demarcated, erythematous silver plaques. Erythema multiforme, which is due to a hypersensitivity reaction, presents with annular, raised lesions with central clearing. Lichen planus characteristically appears as planar, purple, polygonal, pruritic papules and plaques. Nummular eczema presents as a rash composed of coin-shaped papulovesicular erythematous lesions. Treatment is aimed at reducing skin dryness. Pityriasis rosea presents with multiple erythematous lesions with raised, scaly borders, and is generally self-limited. Urticaria results from the release of histamines and appears as well-circumscribed, erythematous lesions with raised borders and blanched centers. Annular lesions occur less commonly in persons with fixed drug eruptions, leprosy, immunoglobulin A vasculitis, secondary syphilis, sarcoidosis, subacute cutaneous lupus erythematosus, and granuloma annulare.

Acquired and congenital forms of heterotopic ossification: new pathogenic insights and therapeutic opportunities.

Heterotopic ossification (HO) involves the formation and accumulation of extraskeletal bone tissue at the expense of local tissues including muscles and connective tissues. There are common forms of HO that are triggered by extensive trauma, burns and other bodily insults, and there are also rare congenital severe forms of HO that occur in children with Fibrodysplasia Ossificans Progressiva or Progressive Osseous Heteroplasia. Given that HO is often preceded by inflammation, current treatments usually involve anti-inflammatory drugs alone or in combination with local irradiation, but are not very effective. Recent studies have provided novel insights into the pathogenesis of acquired and genetic forms of HO and have used the information to conceive and test new and more specific therapies in animal models. In this review, I provide salient examples of these exciting and promising advances that are undoubtedly paving the way toward resolution of this debilitating and at times fatal disease.

Arterial tortuosity syndrome: 40 new families and literature review.

PURPOSE: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10. METHODS: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-ß signaling with immunohistochemistry for pSMAD2 and CTGF. RESULTS: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-ß signaling. CONCLUSION: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

Risk factors associated with actinic prurigo: a case control study

Abstract: Background: Actinic prurigo (AP) is an idiopathic photodermatosis. Although its initial manifestations can appear in 6 to 8-year-old children, cases are diagnosed later, between the second and fourth decades of life, when the injuries are exacerbated. Objective: To identify risk factors associated with clinical manifestations of AP such as skin and mucosal lesions. Methods: Thirty patients with AP and 60 controls were included in the study, the dependent variable was the presence of skin or labial mucosal lesions, the independent variables were age, sex, solar exposure, living with pets or farm animals, exposure to wood smoke, smoking habit, years smoking, and hours spent per day and per week in contact with people who smoke. Results: Of the 30 diagnosed AP patients, 66.7% were female. Patients age ranged from 7 to 71 years and the mean age was 35.77 ± 14.55 years. We found significant differences with the age and cohabitation with farm animals. Those who lived with farm animals presented 14.31 times higher probability of developing AP (95% CI 3-78.06). Study limitations: This is a case-control study; therefore, a causal relationship cannot be proven, and these results cannot be generalized to every population. Conclusions: The identification of factors related to the development of AP increases our knowledge of its physiopathology. Moreover, identifying antigens that possibly trigger the allergic reaction will have preventive and therapeutic applications in populations at risk of AP.

Examining tissue composition, whole-bone morphology and mechanical behavior of GorabPrx1 mice tibiae: A mouse model of premature aging.

Gerodermia osteodysplastica (GO) is a segmental progeroid disorder caused by loss-of-function mutations in the GORAB gene, associated with early onset osteoporosis and bone fragility. A conditional mouse model of GO (GorabPrx1) was generated in which the Gorab gene was deleted in long bones. We examined the biomechanical/functional relevance of the GorabPrx1 mutants as a premature aging model by characterizing bone composition, tissue-level strains, and whole-bone morphology and mechanical properties of the tibia. MicroCT imaging showed that GorabPrx1 tibiae had an increased anterior convex curvature and decreased cortical cross-sectional area, cortical thickness and moments of inertia, compared to littermate control (LC) tibiae. Fourier transform infrared (FTIR) imaging indicated a 34% decrease in mineral/matrix ratio and a 27% increase in acid phosphate content in the posterior metaphyseal cortex of the GorabPrx1 tibiae (p < .05), suggesting delayed mineralization. In vivo strain gauge measurement and finite element analysis showed ∼two times higher tissue-level strains within the GorabPrx1 tibiae relative to LC tibiae when subjected to axial compressive loads of the same magnitude. Three-point bending tests suggested that GorabPrx1 tibiae were weaker and more brittle, as indicated by decreasing whole-bone strength (46%), stiffness (55%), work-to-fracture (61%) and post-yield displacement (47%). Many of these morphological and biomechanical characteristics of the GorabPrx1 tibia recapitulated changes in other animal models of skeletal aging. Future studies are necessary to confirm how our observations might guide the way to a better understanding and treatment of GO.

The prevalence and clinical manifestation of hereditary thrombophilia in Korean patients with unprovoked venous thromboembolisms.

BACKGROUND: Hereditary thrombophilia (HT) is a genetic predisposition to thrombosis. Asian mutation spectrum of HT is different from Western ones. We investigated the incidence and clinical characteristics of HT in Korean patients with unprovoked venous thromboembolism (VTE). METHODS: Among 369 consecutive patients with thromboembolic event who underwent thrombophilia tests, we enrolled 222 patients diagnosed with unprovoked VTE. The presence of HT was confirmed by DNA sequencing of the genes that cause deficits in natural anticoagulants (NAs). Median follow-up duration was 40±38 months. RESULTS: Among the 222 patients with unprovoked VTE, 66 (29.7%) demonstrated decreased NA level, and 33 (14.9%) were finally confirmed to have HT in a genetic molecular test. Antithrombin III deficiency (6.3%) was most frequently detected, followed by protein C deficiency (5.4%), protein S deficiency (1.8%), and dysplasminogenemia (1.4%). The HT group was significantly younger (37 [32-50] vs. 52 [43-65] years; P < 0.001) and had a higher proportion of male (69.7% vs. 47%; P = 0.013), more previous VTE events (57.6% vs. 31.7%; P = 0.004), and a greater family history of VTE (43.8% vs. 1.9%; P < 0.001) than the non-HT group. Age <45 years and a family history of VTE were independent predictors for unprovoked VTE with HT (odds ratio, 9.435 [2.45-36.35]; P = 0.001 and 92.667 [14.95-574.29]; P < 0.001). CONCLUSIONS: About 15% of patients with unprovoked VTE had HT. A positive family history of VTE and age <45 years were independent predictors for unprovoked VTE caused by HT.