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Blood flow in the calf was measured during postexercise hyperemia in normal subjects and in PAD patients by means of a foot ergometer that gives direct reading of the work performed. In normals, first and peak flow increased with the rise of work load up to 100 KGM. The duration of hyperemia increased with a work load of 30 to 200 KGM. In PAD patients, first flow did not coincide with peak flow. Peak flow was lower and delayed, and the duration of hyperemia was more prolonged than in normal subjects. In patients with intermittent claudication, first flow, peak flow, and work load were higher than in patients with rest pain or impending gangrene. Exercise hyperemia appears as a useful test for screening normal limbs from those with arterial obstruction. Since in PAD patients exercise is interrupted when muscular pain appears, it is evident that the earlier the arrest of work and the appearance of pain, the greater is the involvement in the arterial tree of the leg. Therefore the exercise hyperemia test can be used also as a means of evaluating the different stages of PAD. [ABSTRACT FROM AUTHOR]

To test the hypothesis of a myofascial component in intermittent claudication, 56 male patients were studied. Calf blood flow, at rest and during postischemic and postexercise hyperemia, presence of trigger areas, and exercise tolerance were evaluated and compared. The results can be summarized as follows: The exercise tolerance is reduced when trigger areas are present in the calf muscles, and the more severe the trigger areas, the lower is the exercise tolerance. Trigger areas are more severe when the hyperemic flow is more reduced. The peak flow of reactive hyperemia is also correlated to work load. Pain in intermittent claudication is a complex phenomenon. According to the aforesaid results, the severity of limb ischemia and the presence of trigger areas in the calf appear to be the major factors. Besides the two reasons already known, a third is suggested to explain calf claudication: the elective location of trigger points in the gastrocnemius muscle. [ABSTRACT FROM AUTHOR]

Reactive and exercise hyperemia were compared in healthy men and in patients with PAD. In both patients and normals the calf blood flow of reactive hyperemia was recorded after a 5-minute ischemia. Exercise hyperemia was measured in normals after variable work loads (30 and 50 kg) and immediately after the occurrence of pain in patients with PAD. In healthy limbs the first and peak flows of exercise and reactive hyperemia are similar. The recovery time For basal flow is prolonged alter exercise. However, reactive and exercise hyperemia differ significantly when arterial obstruction due to arteriosclerosis obliterans is present. First flow and peak flow are higher and recovery time more prolonged alter exercise. It is also likely that the control mechanisms of the two hyperemic reactions arc different. Muscular exercise, when protracted until pain occurs, can produce a metabolic and circulatory adjustment other than that of ischemia. There is experimental evidence to support this hypothesis. [ABSTRACT FROM AUTHOR]

The best-fit method was applied to data of calf basal resting and reactive hyperemia blood flow, recorded at 4-hr, intervals during a day in 15 patients with intermittent claudication. The mathematical-statistical analysis suggests existence of a circadian rhythm of calf blood flow, which has early evening peaks and a nocturnal trough with a nadir occurring after midnight and before 4 a.m. This rhythm displays marked similarities to those of all other circulatory values. It is hard to decide whether or not the mechanism of rhythm has an independent endogenous origin. It is known that many of the circulatory variables are interrelated and that some are clearly related to other circadian rhythms. Perhaps the rhythmic reduction of limb blood flow, which begins during the night, is the mechanism underlying the nocturnal pain of subjects with limb ischemia by peripheral arterial disease. [ABSTRACT FROM AUTHOR]

In this technical report we describe the thermographic setting protocol suitable for the FLIR T650SC thermal imager (FLIR Systems, Inc., Wilsonville, OR), an instrument that detects electromagnetic radiation in the infrared field which is physiologically emitted from the human body. FLIR T650SC thermal imager processes infrared radiations graphically and analyzes them through a specific software. In biomedicine, infrared thermography is a promising technique amongst other conventional methods used for detecting skin temperature differences considered as a possible sign of disturbances in the human body. Currently, automatic screening of temperature from a safe distance is an instrument utilized in the front line of the SARS CoV2 emergency. The processing method of the thermogram considers an initial setting of constant parameters that cannot be subsequently modified such as temperature range, focusing and image composition. After the acquisition variable values important in the processing and analysis of the thermogram, such as detection of environment temperature, reflected temperature, emissivity, relative humidity and contrast palette, are set in the software. The analysis is performed using the FLIR Tools software. In the biomedical field standardized acquisition of thermograms facilitates the identification of trigger points and areas of hyper- and hypothermia distributed on the skin surface and muscle bundles. The protocol made it possible to create images with the same acquisition method for all patients. The thermal imaging camera is a valid screening tool because its execution is rapid, it is non-invasive, well-tolerated, and at a low cost for patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Politi et al.)

Many complex behaviors in biological systems emerge from large populations of interacting molecules or cells, generating functions that go beyond the capabilities of the individual parts. Such collective phenomena are of great interest to bioengineers due to their robustness and scalability. However, engineering emergent collective functions is difficult because they arise as a consequence of complex multi-level feedback, which often spans many length-scales. Here, we present a perspective on how some of these challenges could be overcome by using multi-agent modeling as a design framework within synthetic biology. Using case studies covering the construction of synthetic ecologies to biological computation and synthetic cellularity, we show how multi-agent modeling can capture the core features of complex multi-scale systems and provide novel insights into the underlying mechanisms which guide emergent functionalities across scales. The ability to unravel design rules underpinning these behaviors offers a means to take synthetic biology beyond single molecules or cells and toward the creation of systems with functions that can only emerge from collectives at multiple scales., (Copyright © 2020 Gorochowski, Hauert, Kreft, Marucci, Stillman, Tang, Bandiera, Bartoli, Dixon, Fedorec, Fellermann, Fletcher, Foster, Giuggioli, Matyjaszkiewicz, McCormick, Montes Olivas, Naylor, Rubio Denniss and Ward.)

Synthetic genetic circuits allow us to modify the behavior of living cells. However, changes in environmental conditions and unforeseen interactions with the host cell can cause deviations from a desired function, resulting in the need for time-consuming reassembly to fix these issues. Here, we use a regulatory motif that controls transcription and translation to create genetic devices whose response functions can be dynamically tuned. This allows us, after construction, to shift the on and off states of a sensor by 4.5- and 28-fold, respectively, and modify genetic NOT and NOR logic gates to allow their transitions between states to be varied over a >6-fold range. In all cases, tuning leads to trade-offs in the fold-change and the ability to distinguish cellular states. This work lays the foundation for adaptive genetic circuits that can be tuned after their physical assembly to maintain functionality across diverse environments and design contexts.

Visualization of complex genetic systems can help efficiently communicate important design features and clearly illustrate overall structures. To aid in the creation of such diagrams, standards such as the Synthetic Biology Open Language Visual (SBOLv) have been established to ensure that specific symbols and shapes convey the same meaning for genetic parts across the field. Here, we describe several ways that the computational tool DNAplotlib can be used to automate the generation of SBOLv standard-compliant diagrams covering simple genetic designs to large libraries of genetic constructs.

Context: Myofibroblastic proliferations of the urinary bladder, which share some similarities with nodular fasciitis, were first reported in 1980. Since then, they have had several designations, the most frequently used being inflammatory myofibroblastic tumor. Based on both histopathologic and prognostic grounds, some authors prefer the term pseudosarcomatous myofibroblastic proliferation, at least for some of the proliferations. These same scientists also assimilate the so-called postoperative spindle cell nodules with the pseudosarcomatous myofibroblastic proliferations. Little is known about these low-grade myofibroblastic proliferations., Objectives: To review the literature about low-grade myofibroblastic proliferations occurring in the urinary bladder., Data Sources: Textbooks and literature review. We obtained most of the clinicopathologic peculiarities from a patient population composed of the most-relevant, previously reported cases., Conclusions: The low-grade myofibroblastic proliferations of the urinary bladder are rare lesions affecting males more often than they do females. The most-common signs and symptoms are hematuria and dysuria. Histopathologically, they are spindle cell proliferations in a loose myxoid stroma, even though compact proliferations or hypocellular fibrous patterns can be found. Immunohistochemistry is quite nonspecific, except for ALK-1 positivity (20%-89%). Fluorescence in situ hybridization has demonstrated clonal genetic aberrations involving the ALK gene in 50% to 60% of cases. After surgery, only 6% of patients experience local recurrence, without metastases or deaths from the disease. Malignant transformation has been reported exceptionally. These myofibroblastic proliferations are probably part of a continuum with, at one end, benign pseudosarcomatous proliferations and, at the opposite end, more-aggressive lesions. Because of the frequently indolent clinical course, aggressive treatment would be unjustified.

Background: Idiopathic retroperitoneal fibrosis (IRF) is a rare fibro-inflammatory disorder characterized by a periaortic tissue which often encases the ureters causing acute renal failure. IRF histology shows fibrosis and a chronic inflammatory infiltrate with frequent tissue eosinophilia. We assessed a panel of molecules promoting eosinophilia and fibrosis in IRF patients and performed an immunogenetic study., Methods: Serum levels of eotaxin/CCL11, regulated and normal T-cell expressed and secreted (RANTES), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-5, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) were measured using a multiplex assay in 24 newly diagnosed, untreated IRF patients and 14 healthy controls. Retroperitoneal biopsies (available in 8/24 patients) were histologically evaluated to assess eosinophil infiltration, whereas mast cells (MCs) were identified by immunohistochemical analysis for human tryptase. Immunohistochemistry for eotaxin/CCL11 and its receptor CCR3 was also performed. Six single nucleotide polymorphisms (SNPs) within the CCL11 gene (rs6505403, rs1860184, rs4795896, rs17735961, rs16969415 and rs17809012) were investigated in 142 IRF patients and 214 healthy controls., Results: Serum levels of eotaxin/CCL11 were higher in IRF patients than in controls (P = 0.009). Eotaxin/CCL11 drives tissue infiltration of eosinophils and MCs, which can promote fibrosis. Eosinophilic infiltration was prominent (>5 cells/hpf) in five (62.5%) cases, and abundant tryptase-positive MCs were found in all cases; notably, MCs were in a degranulating state. Immunohistochemistry showed that CCL11 was highly produced by infiltrating mononuclear cells and that its receptor CCR3 was expressed by infiltrating eosinophils, MCs, lymphocytes and fibroblasts. None of the tested CCL11 SNPs showed disease association, but the TTCCAT haplotype was significantly associated with IRF (P = 0.0005)., Conclusions: These findings suggest that the eotaxin/CCL11-CCR3 axis is active in IRF and may contribute to its pathogenesis; the TTCCAT haplotype within the CCL11 gene is significantly associated with IRF.

Introduction: Atrial fibrillation (AF) in mitral regurgitation (MR) is a complex disease where multiple factors may induce left-atrial structural remodeling (SR). We explored the differential SR of the left-atrial posterior wall (LAPW) of patients affected by MR with or without persistent AF, and the expression of key proteins involved in its pathogenesis., Methods and Results: Light microscopy of LAPW samples from 27 patients with MR and persistent AF (group 1), 33 with MR in sinus rhythm (group 2), and 15 autopsy controls (group 3) was used to measure myocyte diameter, percentage of myocytolytic myocytes, interstitial fibrosis, and capillary density; RT-PCR and Western blotting were used to assess the mRNA and protein levels of SOD-1, SOD-2, HO-1, calpain, MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF; immunofluorescence was used to locate these proteins. Myocyte diameter was similar in groups 1 and 2, but larger than controls. Compared to group 2, group 1 had more myocytolytic myocytes (20.8 ± 5.6% vs 14.7 ± 4.5%; P < 0.0001), increased interstitial fibrosis (10.4 ± 5.1% vs 7.5 ± 4.2%; P < 0.05), and decreased capillary density (923 ± 107 No/mm(2) vs 1,040 ± 100 No/mm(2); P < 0.0001). All of the proteins were more expressed in groups 1 and 2 than in controls. The protein and mRNA levels of SOD-1, SOD-2, MMP-2, and MMP-9 were higher in group 1 than in group 2., Conclusions: The LAPW of MR patients with or without AF shows considerable SR. The former has more severe histopathological changes and higher levels of proteins involved in SR, thereby reaching a threshold beyond which the sinus impulse cannot normally activate atrial myocardium., (© 2011 Wiley Periodicals, Inc.)

The epithelioid variant of malignant peripheral nerve sheath tumours (MPNSTs) is a very rare malignancy. We describe the case of a 30-year-old man complaining of acute pain in his right elbow, mild distal paraesthesias, and some motor deficiencies. He was discovered as having a small fusiform swelling of the median nerve. In view of its very small size, shape, and nonspecific MRI signal, it had initially suggested a benign lesion. The diagnosis of epithelioid MPNST was made only at the histopathological examination. This malignant neoplasm recurred locally fourteen months after surgery. In addition to describe the above very rare case, we have reviewed the literature on epithelioid MPNSTs clearly involving deep major nerve trunks. This case serves as a warning that, even in major nerve trunks, tiny lesions may in reality be early intraneural MPNSTs which, due to their deep location, must be treated adequately with wide margin surgery since the resection margin status represents one of the major parameters influencing the local control of disease and its clinical outcome.

Blood, plasma and serum viscosity and blood filtration were investigated in 43 unselected mixed cryoglobulinemia patients. A hyperviscosity syndrome was present in only one patient, and rapidly improved after plasma exchange and cyclophosphamide therapy. A clear-cut increase in blood viscosity was infrequently observed in mixed cryoglobulinemia, although significant differences were present in the plasma and serum viscosity of patients and controls. In contrast, blood filtration was severely impaired in a high percentage of cases (51 and 72% of the values recorded at 37 degrees and 25 degrees C, respectively), and was on the average significantly higher in patients than in controls. Indirect evidence suggests that blood viscosity is at least in part related to cryoglobulins. In 19 patients studied before and after cryoglobulin removal, serum viscosity significantly decreased when the serum was deprived of cryoglobulins. In addition, the cryocrit correlated with all the hemorheological parameters with the exception of blood filtration. The hemorheological findings were compared with multisystemic features of the disease, i.e. liver, renal, lung, neurologic, vascular and funduscopic alterations. The potential clinical relevance of the hemorheological parameters was stressed by the close correlation between blood filtration parameters and serum creatinine. Furthermore, by discriminant analysis, viscosity and blood filtration changes were the serological parameters most significantly associated with the presence of renal, liver and neurological involvement. Thus, hemorheological parameters are frequently abnormal in mixed cryoglobulinemia patients, and seem to play a significant clinical role; they should therefore be included in the work-up of these patients.

The blocking of trigger points in the calf by the local injection of an anesthetic agent was performed in 15 patients with intermittent claudication. Reactive and exercise hyperemia, work load and duration of exercise were recorded before and after infiltration of the trigger points. Reactive hyperemia does not change, but the exercise tolerance of the leg significantly improves after local blocking of the trigger areas and the exercise hyperemia increases because of the higher work load. The pain pattern of intermittent claudication can be activated by the summation of abnormal input from muscles, due to contraction in the presence of anoxia, with activity from trigger points. Local infiltration of trigger areas blocks theirir activity. The vicious cycle of pain is interrupted and the exercise tolerance of the leg is increased, without improving blood circulation.

Calf basal resting and reactive hypercemia blood flow were measured at 4-h intervals during a day in fifteen healthy subjects and in fifteen patients with intermittent claudication by means of a venous occlusion plethysmograph. Mathematical-statistical analysis of the data failed to demonstrate circadian periodicity of calf blood flow in healthy subjects, but proved the existence of a 24-h rhythm of calf basal resting and reactive hyperemia blood flow in patients with intermittent claudication. This different behavior of calf blood flow can be understood if one considers that in healthy subjects the voluntary muscles in the extremities have a blood supply which can be instantaneously adjusted over a large area. In patients with peripheral arterial disease, on the other hand, the vascular responses in voluntary muscles of the limbs to various endogenous or exogenous stimuli are impaired and reduced. The circadian rhythm observed in patients with intermittent claudication has early evening peaks and a nocturnal trough with a nadir occurring after midnight and before 0400. This rhythm displays marked similarities with those of all other circulatory values. As to the mechanism of rhythm, it is hard to decide whether or not it has an independent endogenous origin. It is known that many of the circulatory variables are interrelated and that some are clearly related to other circadian rhythms. Perhaps the rhythmic reduction of limb blood flow which occurs during the night is the mechanism underlying the nocturnal pain of subjects with limb ischemia by peripheral arterial disease.