IgG4-related disease. Clinical manifestation differential diagnosis and recent International Diagnostic Criteria for IgG4-related disease.

Immunoglobulin G4- related disease (IgG4-RD) is a rare systemic fibro-inflammatory disorder. Autoimmune pancreatitis is the most frequent manifestation of IgG4-RD. However, IgG4-RD can affect any organ such as salivary glands, orbits, retroperitoneum, prostate and many others. Recent research enabled a clear clinical and histopathological description of IgG4-RD and in 2019 four Clinical phenotypes of IgG4-related disease were described. Diagnosis is based on morphological examination with typical findings of lymphoplasmocellular inflammation, storiform fibrosis and obliterative phlebitis in IgG4-RD biopsies and the tissue invading plasma cells largely produce IgG4. Elevated serum IgG4 levels are found in many but not all patients. New diagnostic criteria for IgG4-RD have been published recently in 2019 and 2021. This review summarizes current knowledge on pathophysiology, clinical manifestations, diagnosis and differential diagnosis of IgG4-RD from the point of view 2022 and in next article brings overview of the IgG4-RD therapy.

Langerhans cell histiocytosis (LCH). Overview of symptoms of LCH, which may lead the patients to any of these medical specialists.

Langerhans cell histiocytosis (LCH) is a rare condition with incidence in adults 1-2/1 million, wherein Langerhans cells proliferate abnormally, adversely impacting organs including most frequently bones, skin, lungs, pituitary gland, lymph nodes, gums and other organs. The LCH course varies widely among patients from a self-limiting condition, to one that progresses. But LCH only very rarely culminates in death. To aim of this text is to review all possible symptoms and manifestations of this disease.

Therapy of immunoglonuline IgG4 related disease (IgG4-RD).

Immunoglobulin IgG4 related disease (IgG4-RD) is a heterogeneous disorder with multi-organ involvement recognised as a separate entity at the beginning of this century only. Evolving therapy is reviewed in this paper. Glucocorticoids are first choice drug but long administration of glucocorticoids is connected with many adverse effects. In case of combination glucocorticoids and immunosuppressive agents lower doses of glucocorticoids are needed, the response rate is higher and therapy is better tolerated. Rituximab is drug, that is possible use as monotherapy or in combination with glucocorticoids and immunosuppressive drugs. Only one study compared two immunosuporessive drugs, mycophenolate mofetil and cyclophosphamide. The response rated was similar but remissions were longer after glucocorticoids with cyclophosphamide then glucocorticoids with mycofenolat mofetil. No other comparative study of combination of various imunossupressive drugs with glucocorticoids was published. Rituximab has high number (90 %) of response rate in monotherapy, but can be used in combination with glucocorticoids and immunosuppressives. Rituximab is now preferred and recommended for maintenance therapy administered in 6-month interval. In case of advanced disease, we prefer therefore combination of rituximab, cyclofosphamide and dexamethasone for initial therapy followed by maintenance with rituximab in 6 months interval. There are two new drugs under investigation abatacept and dupilimab with promising results. Although we have very intensive therapies for good results of therapy early diagnosis before irreversible fibrotic changes in IgG4-RD involved organs is still needed.

Multicentric Castlemans disease. Symptoms, diagnostics and therapy.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric (UCD) or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor. In this paper, we briefly report about symptoms of iMCD and about the International, evidencebased consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease and International evidence based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Plectin-mediated cytoskeletal crosstalk controls cell tension and cohesion in epithelial sheets.

The coordinated interplay of cytoskeletal networks critically determines tissue biomechanics and structural integrity. Here, we show that plectin, a major intermediate filament-based cytolinker protein, orchestrates cortical cytoskeletal networks in epithelial sheets to support intercellular junctions. By combining CRISPR/Cas9-based gene editing and pharmacological inhibition, we demonstrate that in an F-actin-dependent context, plectin is essential for the formation of the circumferential keratin rim, organization of radial keratin spokes, and desmosomal patterning. In the absence of plectin-mediated cytoskeletal cross-linking, the aberrant keratin-desmosome (DSM)-network feeds back to the actin cytoskeleton, which results in elevated actomyosin contractility. Also, by complementing a predictive mechanical model with Förster resonance energy transfer-based tension sensors, we provide evidence that in the absence of cytoskeletal cross-linking, major intercellular junctions (adherens junctions and DSMs) are under intrinsically generated tensile stress. Defective cytoarchitecture and tensional disequilibrium result in reduced intercellular cohesion, associated with general destabilization of plectin-deficient sheets upon mechanical stress.

Factors Determining Postoperative Ileus After Surgery for Colon Cancer: Comparison of Right- and Left-Sided Resections.

INTRODUCTION: The passage of flatus and stool, as well as tolerating a solid diet, represents a crucial moment in recovery after colonic resections. The present study compares functional recovery after left and right colectomies for colon cancer. MATERIALS AND METHODS: This is a retrospective analysis. Consecutive patients with elective left and right colon resections were examined. Primary analysis compared time to first bowel motion and development of postoperative ileus. Secondary analyses tried to define risk factors for prolonged restoration of bowel function in right- and left-sided resection groups. RESULTS: In total, 147 patients were included. While laparoscopic approach was preferred for both sides (87% vs. 87%; p=0.496), left colectomies took longer (183 vs. 153 min; p=0.012), the lymph node harvest was smaller (16 vs. 20; p=0.005), and there was an increased need for perioperative fluids (4451 vs. 4039ml; p=0.006). Epidural use, postoperative potassium level, and glycemia were similar. Also, no significant differences were observed for complications and length of stay. First flatus was observed at postoperative day 1, 9 (left), and 2.5 (right), respectively (p=0.002). There was no significant difference in passage of first stool and intake of first solid food. Twenty-seven patients (35%) needed a postoperative nasogastric tube after right colectomy compared to 11 patients (16%) after left colectomy (p=0.012). Right-sided colectomies required the tube for longer (6.1 vs. 3.4; p=0.005). CONCLUSIONS: Postoperative ileus was more frequent after right-sided colectomies despite shorter operative time. The reason for this finding is currently unknown and deserves further attention. For the time being, we can just be more cautious with early feeding after right colectomy.

Social factors influence the course and prognosis of malignat diseases.

BACKGROUND: A statement of the dia-gnosis of malignant disease fundamentally changes the identity of a man. A healthy person changes to a patient. A lot of studies analyzed the influence of marital status on the disease development. PURPOSE: We present an analysis of interpersonal relationships in connection with oncological diseases. The majority of the authors consider living in a couple as a positive prognostic factor. On the other hand, malignant disease at a younger age increases the risk of divorce or breakup.

Transformation of IgM-MGUS into Waldenström´s macroglobulinemia in two of six patients treated for Schnitzler´s syndrome.

Transformation of IgM-MGUS into Waldenström´s macroglobulinemia in two of six patients treated for Schnitzler´s syndrome Schnitzler´s syndrome is a very rare, adult-onset, apparently acquired autoinflammatory disease. Chronic urticarial rash and symptoms of systemic inflammation including fever, arthralgia and bone pain with the presence of monoclonal immunoglobulin M (IgM), rarely IgG, are among hallmarks of the disease. We performed a retrospective study of 6 patients (5 men, 1 woman) diagnosed with Schnitzler´s syndrome fulfilling the Strasbourg criteria who had been treated at our centre in the University Hospital Brno from 2007 to 2021. Median age at diagnosis was 54 (45-67) years, median follow up was 8 (3-14) years. All 6 patients had IgM κ monoclonal gammopathy, increased CRP and/or erythrocyte sedimentation rate and arthralgia or bone pain, 4 patients suffered from fever, three had leucocytosis 10 × 109/L and lymphadenopathy was found in one patient. 18FDG-PET/CT scan with low-dose total body CT became a part of the initial baseline assessment in 5 patients with suspected Schnitzler´s syndrome, while Na18F-PET/CT was used in one patient to confirm the presence of osteosclerotic leasions as a criterion of the disease. All patients had osteosclerotic or hyperostotic bone lesions detected by low-dose CT examination, with increased 18FDG uptake in illiac and femoral bone marrow. The patient with Na18F-PET/CT scan revealed intensive abnormal tracer uptake with Na18F-PET/CT being more sensitive for detection of osteosclerotic lesions in Schnitzler´s syndrome than 18FDG-PET/CT. All patients were treated with daily subcutaneous anakinra without any adverse events, with excellent clinical results. We observed complete disappearance of urticaria and other symptoms persisting during years of anakinra administration. IgM-MGUS transformed into Waldenström´s macroglobulinemia in two of six patients, but only one patient developed symptoms requiring RBD (Rituximab, Bendamustin, and Dexamethasone) treatment, which induced almost complete remission of the disease. Successful RBD therapy enabled to prolong intervals of maintenance anakinra from 24 to 48 hours with almost complete control of urticarial rash and other symptoms. We suggest close monitoring of patients with Schnitzler´s syndrome to early capture potential transformation into Waldenström´s macroglobulinemia with succesful treatment of both conditions.

Hereditary hemorrhagic telangiectasia (OslerWeberRendu syndrome) - Part II. Pharmacological therapy and international guidelines for the therapy 2020.

Hereditary hemorrhagic telangiectasia also known as Osler-Weber-Rendu syndrome, is an disorder that causes abnormal blood vessel formation with bleeding. Inhibition of angiogenesis amelioretes bleeding complication. Anti-angiogenic agents such as bevacizumab, aflibercept, thalidomid, lenadomid and other new anti-angiogenic thyrosinkinase inhibitors, as well as sirolimus and takrolimus have emerged as a promising systemic or local therapy in reducing bleeding complications but are not curative. Other pharmacological agents include iron supplementation, antifibrinolytics and hormonal treatment. This review concentrates on new anti-agioproliferative drugs with effect in HHT- discusses the new biology of HHT, management issues that face the practising hematologist, and considerations of future directions in HHT treatment.

Unicentric Castlemans disease. Symptoms, diagnostics and therapy.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms - multicentric Castleman disease. The first-ever diagnostic and treatment guidelines were recently developed for UCD and published 2020. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic because of compression of vital neighbouring structures may be rendered amenable to resection by medical therapy (rituximab, steroids), radiotherapy, or embolization. In this article, we report about the symptoms of this disease and about the diagnostics recommendation published in the International, evidence-based consensus diagnostic criteria for HHV-8-negative/ idiopathic multicentric Castleman disease and about the therapeutic recommendation published in International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease published in the year 2020.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) Part I. Pathophysiology, clinical symptoms and recommend screening for vascular malformations.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that causes abnormal blood vessel formation. Patients with HHT may have telangiectasias and later may develop arteriovenous malformations in various organs. Pacients suffer from many complications caused by the malformations and therefore by patients with HHT must by performed screening of this arteriovenous malformations. Optimal treatment of this malformations is best delivered throught a multidisciplinary approach. Farmacological treatment is described in next paper.

[Anal fissure]. / Anální fisura.

Anal fissure is one of the very frequent and painful proctologic diseases. Linear ulcer is situated in the anal canal and extending from the dentate line to the margin of the anus. Fissure can cause pain and bleeding. Diagnosis is made from the history and local inspection. Acute anal fissure should be treated conservatively - increased fibre and fluid intake, warm baths, local anaesthetic ointment, alternatively with nitrates and if all else fails by botulinum toxin. Treatment of chronic fissure will start conservatively but operative options are necessary in many cases.

Transanal Tube as a Means of Prevention of Anastomotic Leakage after Rectal Cancer Surgery.

BACKGROUND: Anastomotic leaks after low anterior resection for rectal cancer remain the most feared complication. The aim of our study was to investigate whether the use of a transanal tube could reduce the leakage rate after this surgical procedure. METHODS: This is a retrospective analysis of a single-institution experience. The study includes 66 patients who underwent low anterior resection for rectal cancer without stoma creation between January 2008 and June 2013. Patients were divided into two groups, i.e. those with a transanal drainage tube (TT; n = 9) and those without tube (NTT; n = 57), and evaluated for clinically evident anastomotic leakage and postoperative complications. RESULTS: The postoperative anastomotic leakage appeared in 5 patients (9%) in the NTT group while no single case was observed within the TT group. Despite the disadvantageous background in the TT group (a transanal stent was used in the most high-risk patients), these patients had no postoperative complications. In the NTT group, 23% had some kind of postoperative complications, and 5% died. The difference between the two groups is not significant. CONCLUSIONS: Our study showed that the use of a transanal tube in low anterior resection for rectal cancer could potentially be a simple and effective method of reducing anastomotic leakage. In order to prove our observations, larger prospective randomized studies should be performed.

Sensitivity of NOS-dependent vascular relaxation pathway to mineralocorticoid receptor blockade in caveolin-1-deficient mice.

Endothelial caveolin-1 (cav-1) is an anchoring protein in plasma membrane caveolae where it binds endothelial nitric oxide synthase (eNOS) and limits its activation, particularly in animals fed a high salt (HS) diet. Cav-1 also interacts with steroid receptors such as the mineralocorticoid receptor (MR). To test the hypothesis that vascular reactivity is influenced by an interplay between MR and cav-1 during HS diet, we examined the effects of MR blockade on NOS-mediated vascular relaxation in normal and cav-1-deficient mice. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) were fed for 14 days a HS (4% NaCl) diet with and without the MR antagonist eplerenone (Epl; 100 mg x kg(-1) x day(-1)). After systolic blood pressure (BP) was measured, the thoracic aorta was isolated for measurement of vascular reactivity, and the aorta and heart were used for measurement of eNOS and MR expression. BP was not different between WT + Epl and WT, but was higher in cav-1(-/-) + Epl than in cav-1(-/-) mice. Phenylephrine (Phe)-induced vascular contraction was less in cav-1(-/-) than WT, and significantly enhanced in cav-1(-/-) + Epl than in cav-1(-/-), but not in WT + Epl compared with WT. Endothelium removal and NOS blockade by N(omega)-nitro-l-arginine methyl ester (l-NAME) enhanced Phe contraction in cav-1(-/-), but not cav-1(-/-) + Epl. ACh-induced aortic relaxation was reduced in cav-1(-/-) + Epl versus cav-1(-/-), but not in WT + Epl compared with WT. Endothelium removal, l-NAME, and the guanylate cyclase inhibitor ODQ abolished the large ACh-induced relaxation in cav-1(-/-) and the remaining relaxation in the cav-1(-/-) + Epl but had similar inhibitory effect in WT and WT + Epl. Real-time RT-PCR indicated decreased eNOS mRNA expression in the aorta and heart, and Western blots revealed decreased total eNOS in the heart of cav-1(-/-) + Epl compared with cav-1(-/-). Vascular and cardiac MR expression was less in cav-1(-/-) than WT, but not in cav-1(-/-) + Epl compared with cav-1(-/-). Plasma aldosterone (Aldo) was not different between WT and cav-1(-/-) mice nontreated or treated with Epl. Thus in cav-1 deficiency states and HS diet MR blockade is associated with increased BP, enhanced vasoconstriction, and decreased NOS-mediated vascular relaxation and eNOS expression. The data suggest that, in the absence of cav-1, MR activation plays a beneficial role in regulating eNOS expression/activity and, consequently, the vascular function during HS diet.

Vascular and cellular calcium in normal and hypertensive pregnancy.

Normal pregnancy is associated with significant hemodynamic changes in the cardiovascular system in order to meet the metabolic demands of mother and fetus. These changes include increased cardiac output, decreased vascular resistance, and vascular remodeling in the uterine and systemic circulation. Preeclampsia (PE) is a major complication of pregnancy characterized by proteinuria and hypertension. Several risk factors have been implicated in the pathogenesis of PE including genetic and dietary factors. Ca2+ is an essential dietary element and an important regulator of many cellular processes including vascular function. The importance of adequate dietary Ca2+ intake during pregnancy is supported by many studies. Pregnancy-associated changes in Ca2+ metabolism and plasma Ca2+ have been observed. During pregnancy, changes in intracellular free Ca2+ concentration ([Ca2+](i)) have been described in red blood cells, platelets and immune cells. Also, during pregnancy, an increase in [Ca2+](i) in endothelial cells (EC) stimulates the production of vasodilator substances such as nitric oxide and prostacyclin. Normal pregnancy is also associated with decreased vascular smooth muscle (VSM) [Ca2+](i) and possibly the Ca2+-sensitization pathways of VSM contraction including protein kinase C, Rho-kinase, and mitogen-activated protein kinase. Ca2+-dependent matrix metalloproteinases could also promote extracellular matrix degradation and vascular remodeling during pregnancy. Disruption in the balance between dietary, plasma and vascular cell Ca2+ may be responsible for some of the manifestation of PE including procoagulation, decreased vasodilation, and increased vasoconstriction and vascular resistance. The potential benefits of Ca2+ supplements during pregnancy, and the use of modulators of vascular Ca2+ to reduce the manifestations of PE in susceptible women remain an important area for experimental and clinical research.