Comorbidities in Male Patients With Lichen Sclerosus: A Case-Control Study.

OBJECTIVE: Lichen sclerosus (LS) is a chronic inflammatory skin disease. In male patients, it usually involves the glans penis and foreskin and can cause phimosis or meatal stenosis. The aim of this cross-sectional case-control study was to identify clinically important comorbidities in male patients with LS. MATERIALS AND METHODS: By searching Turku University Hospital electronic health records, the authors identified 630 male patients diagnosed with LS between 2004 and 2020. To investigate possible comorbidities, the authors compared this patient group to a 10-fold larger control group. RESULTS: The incidence of LS increased during the study period, from 5 to 27.5 per 100,000 men. Patients were most often diagnosed at 21 to 25 years of age. Patients with LS exhibited markedly increased risks of penile carcinoma (odds ratio [OR], 81.0; 95% CI = 10.82-3516.7; p < .001) and carcinoma in situ of the penis (OR = 60.5; 95% CI = 7.32-2738.9; p < .001). Patients also more commonly exhibited lichen planus (OR = 16.8; 95% CI = 8.97-32.39; p < .001), psoriasis (OR = 3.3; 95% CI = 1.80-5.70; p = .004), angina pectoris (OR = 1.8; 95% CI = 1.10-2.81; p = .013), obesity (OR = 2.6; 95% CI = 1.72-3.77; p < .001), type 2 diabetes (OR = 2.3; 95% CI = 1.74-3.09; p < .001), and hypertension (OR = 1.9; 95% CI = 1.53-2.37; p < .001). The most commonly performed urological procedures were operation for phimosis, uroflowmetry, and ultrasound measurement of residual urine. CONCLUSIONS: Genital malignancies, other dermatological conditions, and diseases related to metabolic syndrome should be considered when treating patients with LS.

In Silico and In Vitro Analysis of IL36RN Alterations Reveals Critical Residues for the Function of the Interleukin-36 Receptor Complex.

Generalized pustular psoriasis is a potentially life-threatening skin disease, associated with IL36RN disease alleles. IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), a protein that downregulates the activity of IL-36 cytokines by blocking their receptor (IL-36R). Although generalized pustular psoriasis can be treated with IL-36R inhibitors, the structural underpinnings of the IL-36Ra/IL-36R interaction remain poorly understood. In this study, we sought to address this question by systematically investigating the effects of IL36RN sequence changes. We experimentally characterized the effects of 30 IL36RN variants on protein stability. In parallel, we used a machinelearning tool (Rhapsody) to analyze the IL-36Ra three-dimensional structure and predict the impact of all possible amino acid substitutions. This integrated approach identified 21 amino acids that are essential for IL-36Ra stability. We next investigated the effects of IL36RN changes on IL-36Ra/IL-36R binding and IL-36R signaling. Combining invitro assays and machine learning with a second program (mCSM), we identified 13 amino acids that are critical for IL-36Ra/IL36R engagement. Finally, we experimentally validated three representative predictions, further confirming the reliability of Rhapsody and mCSM. These findings shed light on the structural determinants of IL-36Ra activity, with potential to facilitate the design of new IL-36 inhibitors and aid the interpretation of IL36RN variants in diagnostic settings.

Comorbidity of Urogynecological and Gastrointestinal Disorders in Female Patients With Lichen Sclerosus.

OBJECTIVE: Lichen sclerosus (LS) is a chronic inflammatory disease with a significant impact on quality of life. The aim of this cross-sectional case-control study was to characterize concomitant urogynecological and gastrointestinal disorders in female patients with LS. METHODS: A medical records search between 2004 and 2012 yielded 455 women and girls (mean age 64 years) with LS. The study cohort was compared with a 10-fold age- and sex-matched control cohort. Gynecological cancers and their precursors; gynecological, urinary, and gastrointestinal disorders; and pain syndromes were evaluated. RESULTS: The well-known association between LS and increased risk of vulvar cancer and its precursors was also found in our study (relative risk [RR] = 100.0; p < .001 and high-grade squamous intraepithelial lesions RR = 110.0; p < .001, respectively), but we also found an increased risk for cervical cancer (RR = 6.0; p = .005) and endometrial cancer (RR = 2.9; p < .001). Gynecological pain syndromes such as dyspareunia (RR = 20.0; p < .001) and interstitial cystitis (RR = 5.0; p < .001) and urinary incontinence (RR = 4.8; p < .001) were also increased. Among gastrointestinal disorders, we found increased risk for celiac disease (RR = 6.8; p < .001), diverticular intestine diseases (RR = 1.9; p < .001), functional intestinal disorders (RR = 2.3; p = .003), and anal and rectal fissures (RR = 2.4; p = .046). CONCLUSIONS: We found that female patients with LS have an increased risk for gynecological cancers as well as for several urogynecological and gastrointestinal disorders. Increased awareness is required to identify and treat these concomitant disorders.

Correlation between Oswestry disability index and 12-item self-administered version of World Health Organization Disability Assessment Schedule (WHODAS 2.0) in patients with chronic low back pain.

The objective of the study was to investigate the correlation between the 12-item WHO Disability Assessment Schedule (WHODAS 2.0) and the Oswestry disability index (ODI). Prospective cross-sectional study of 1379 patients (age 48 years) with chronic low back pain. The Spearman's rank correlation test was employed. Of all the possible 143 correlations, 46 (32%) were strong and nine (6%) were very strong. The strongest correlations ≥0.6 were seen for 'personal care' (ODI) vs. 'washing whole body' (WHODAS 2.0), 'personal care' (ODI) vs. 'getting dressed' (WHODAS 2.0), 'walking' (ODI) vs. 'walking long distances' (WHODAS 2.0) and 'social life' (ODI) vs. the WHODAS 2.0 total score. In conclusion, while items defining physical functioning were mostly strongly correlated, items defining social or psychological functioning were less associated. Both scales could be used together providing valuable information regarding the functioning of people with chronic low back pain.

Risk of symptomatic venous thromboembolism after abdominal aortic aneurysm repair in long-term follow-up of 1021 consecutive patients.

OBJECTIVE: Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism (PE), is an infrequent but consequential and potentially preventable complication after major surgical procedures. The aim of the study was to describe the long-term occurrence of symptomatic VTE in patients undergoing abdominal aortic aneurysm (AAA) repair and to ascertain patient-specific risk factors as well as to compare the rate with that of a reference population. METHODS: The study included all patients who had undergone endovascular or open AAA repair, both elective and urgent/acute cases, at the Tampere University Hospital (Finland) between February 2001 and December 2016; 59% of patients had undergone endovascular and 41% open repair, and 23% of all cases had required urgent or emergency treatment. Information about later treatment episodes for symptomatic VTE and survival data were obtained from national registries. The reference population was obtained from national registries with a random sample of inhabitants matched for age, sex, and location of residence with a 4:1 ratio and was analyzed similarly. RESULTS: Altogether, 1021 patients and 4065 controls were included (88% male; median age, 74 years in both groups). The high-risk period for VTE lasted for approximately 3 months, and during that time, its occurrence was highest in patients with coronary disease (2.5%), after open repair (2.4%), and in an urgent or emergency setting (2.6%), whereas the rate was low after endovascular aneurysm repair (1.0%). The cumulative incidence of VTE at 3 months, 1 year, 3 years, and 5 years was 1.1%, 1.6%, 2.7%, and 4.5% in patients and 0.1%, 0.3%, 1.0%, and 1.8% in the reference population, respectively (P < .001 each). Most VTE events were PE in the patient group. The 5-year mortality rates were 37.9% in patients and 23.8% in controls (P < .001). CONCLUSIONS: The incidence of symptomatic VTE, particularly PE, after AAA repair is significant, in both short-term and long-term follow-up. Open surgery, acute setting, and concomitant coronary disease appear to increase the risk.

Early postoperative statin administration does not affect the rate of atrial fibrillation after cardiac surgery.

OBJECTIVES: Postoperative atrial fibrillation is the most frequent complication after cardiac surgery, and the use of statins in preventing them is being extensively studied. The aim of this study was to investigate whether a pause in the administration of statins affects the occurrence of atrial fibrillation after cardiac surgery in a prospective randomized and controlled setting. METHODS: A total of 301 patients without chronic atrial fibrillation with prior statin medication scheduled for elective or urgent cardiac surgery involving the coronary arteries and/or heart valves were prospectively recruited and randomized for statin re-initiation on either the first (immediate statin group) or the fifth (late statin group) postoperative day, using the original medication and dosage. The immediate statin group comprised 146 patients and the late statin group 155 patients. Except for a somewhat higher rate of males (85% vs 73%, P = 0.016) in the immediate statin group, the baseline characteristics and the distribution of procedures performed within the groups were comparable. The occurrence of postoperative atrial fibrillation and the clinical course of the patients were compared between the groups. RESULTS: The incidence of atrial fibrillation was 46% and the median delay after surgery before the onset of atrial fibrillation was 3 days in both groups (P = NS). No differences were observed in the frequency of the arrhythmia in any subgroup analyses or in other major complications or clinical parameters. No adverse effects related to early statin administration were detected. CONCLUSIONS: Early re-initiation of statins does not appear to affect the occurrence of postoperative atrial fibrillation. CLINICAL TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT)-2016-001655-44.

Incidence, presentation and risk factors of late postoperative pericardial effusions requiring invasive treatment after cardiac surgery.

OBJECTIVES: Occurrence and risk factors of late postoperative pericardial effusions requiring invasive treatment, i.e. pretamponade and tamponade, following cardiac surgery are incompletely described in current literature. The purpose of this study was to define the incidence and presentation of late pretamponade and tamponade as well as to outline significant predisposing factors. METHODS: A cohort of 1356 consecutive cardiac surgery patients treated in a tertiary academic centre between January 2013 and December 2014 was followed up for 6 months after surgery. Pericardial effusion was considered late when presenting after the 7th postoperative day. The incidence, timing and risk factors, as well as symptoms and clinical findings associated with late pretamponade and tamponade in patients surviving at least 7 days was analysed. RESULTS: Of 1308 patients included in the analysis, 81 (6.2%) underwent invasive treatment for late postoperative pericardial effusion, 27 (2.1%) for pretamponade and 54 (4.1%) for tamponade, respectively, with a median delay of 11 (range 8-87) days after the primary operation. Haemodynamic instability was present in 34.6%, signs of cardiac chamber compression in 54.3% and subjective symptoms, mostly dyspnoea, in 56.8% of patients, respectively. Treated patients were younger, had lower EuroSCORE-II rating, less coronary disease, better cardiac function, higher preoperative haemoglobin values and had mostly undergone elective surgery involving cardiac valves. In multivariable analysis, independent risk factors were single valve surgery and high preoperative haemoglobin level, whereas age 60-69 years was associated with lower risk. CONCLUSIONS: Younger, generally healthier patients undergoing valve surgery are at greatest risk for developing late tamponade or pretamponade.

Activin inhibition limits early innate immune response in rat kidney allografts-a pilot study.

Activins are members of the transforming growth factor-beta (TGF-ß) superfamily of cytokines. They play critical roles in the onset of acute and chronic inflammatory responses. The aim of this study was to investigate how activin inhibition affects acute kidney injury and inflammation after transplantation. The study was carried out in kidney transplantation and renal ischemia-reperfusion models in the rat. Soluble activin type 2 receptor (sActRIIB-Fc) was used to inhibit activin signaling. Transplantation groups were as follows: (i) cyclosporine A (CsA) (ii) CsA + sActRIIB-Fc, (iii) CsA+ inactive protein control Fc-G1. IRI groups were as follows: (i) no treatment, (ii) sActRIIB-Fc. Serum activin B concentration was significantly elevated after transplantation and IRI, whereas activin A was produced locally in renal allografts. Activin inhibition efficiently limited neutrophil, macrophage, and dendritic cell infiltration to the allografts measured 72 h after transplantation. In addition, sActRIIB-Fc treatment modulated serum cytokine response after transplantation and reduced the early accumulation of fibroblasts in the graft interstitium. In conclusion activin inhibition reduces the innate immune response early after renal transplantation in the rat. It also limits the accumulation of fibroblasts in the graft suggesting that activins may be involved in the fibrogenic signaling already early after kidney transplantation.

Intensive perioperative simvastatin treatment protects from chronic kidney allograft injury.

BACKGROUND/AIMS: Ischemia-reperfusion injury (IRI) and innate immune response augment adaptive immunity and may also trigger repair processes that lead to uncontrolled fibrosis and atherosclerosis as seen in chronic allograft injury. Simvastatin has been shown to protect from renal IRI in several experimental studies. The aim of this study was to examine the effect of donor simvastatin pretreatment and early initiation of recipient simvastatin treatment on chronic kidney allograft injury. METHODS: A rat renal transplantation model was used. Simvastatin was administered perorally for donor (5 mg/kg) and/or for recipient (2 mg/kg) 2 hours before transplantation and/or as daily treatment starting on the first postoperative day (2 mg/kg/day). The study included 5 groups: (1) no simvastatin, (2) donor pretreatment, (3) daily recipient treatment, (4) donor pretreatment + daily recipient treatment and (5) donor pretreatment + recipient pretreatment + daily recipient treatment. The grafts were recovered at day 90 for histopathological and immunohistochemical analysis. Kidney function was followed weekly with serum creatinine, and 24-hour urine protein was measured 60 and 90 days after transplantation. RESULTS: We found that donor and recipient simvastatin pretreatment combined with daily recipient treatment reduced graft inflammation and chronic allograft injury. Treatment using only statins started after transplantation reduced inflammation to some extent, but did not affect chronic kidney allograft injury. Pretreatment using only donor statins impaired graft function and increased proteinuria. CONCLUSION: Our data suggest that perioperative recipient statin treatment reduces inflammation and may protect the graft in the long term.

Sirolimus inhibits lymphangiogenesis in rat renal allografts, a novel mechanism to prevent chronic kidney allograft injury.

Lymphangiogenesis occurs in renal allografts and it may be involved in the maintenance of the alloreactive immune response and thus participate in the development of chronic kidney allograft injury. Sirolimus (SRL) has been shown to inhibit lymphangiogenesis. The aim of this study was to describe lymphangiogenesis and its regulation during the development of chronic kidney allograft injury and to investigate the effect of SRL on allograft lymphangiogenesis and chronic kidney allograft injury. A rat renal transplantation model was used. Allografts treated with cyclosporine A or with SRL were analyzed in various time points. Syngenic transplantations were used as controls. Kidney function was followed with serum creatinine. Histology was analyzed by Chronic Allograft Damage Index (CADI). Immunohistochemistry was used to detect lymphatic vessels, VEGF-C and VEGFR-3. In cyclosporine-treated allografts VEGF-C/VEGFR-3 pathway was strongly upregulated leading to extensive lymphangiogenesis 60 days after transplantation. Lymphangiogenesis correlated positively with the CADI score. Sirolimus efficiently inhibited lymphangiogenesis, improved graft function and attenuated the development of chronic kidney allograft injury when compared with cyclosporine. In conclusion, lymphangiogenesis is associated with chronic kidney allograft injury and SRL is a potent inhibitor of lymphangiogenesis in renal allografts. Inhibition of lymphatic proliferation could mediate the nephroprotective properties of SRL.

Vascular endothelial growth factor in chronic rat allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) is a complex process of alloimmune responses and chronic inflammation leading to fibrosis and vasculopathy. We examined the biological role of proinflammatory vascular endothelial growth factor (VEGF) in a rat renal transplantation model of CAN. METHODS: Syngraft and allograft recipients were treated with a suboptimal dose of cyclosporine A which allows acute rejection and CAN to develop. Intragraft VEGF, VEGFR-1 and VEGFR-2 expressions were determined at 5, 14, 30 and 60 days. Protein tyrosine kinase inhibitor PTK787 was used to inhibit VEGFR activity. RESULTS: In nontransplanted kidneys and syngrafts, mild VEGF expression was observed in the glomeruli and tubuli. VEGFR-1 was detected in vascular structures and VEGFR-2 in glomeruli as well. In allografts, total intragraft VEGF expression and interstitial inflammatory cell VEGF expression were induced and correlated with the chronic allograft damage index (CADI) score. Total intragraft and interstitial inflammatory cell VEGFR-1 expression was induced and interstitial cell VEGFR-1 expression correlated with the CADI score. Blocking VEGF receptor signaling with PTK787 significantly reduced fibrosis and the CADI score, but did not affect early inflammation or VEGF, VEGFR-1, VEGFR-2 expressions compared to vehicle treated group. CONCLUSIONS: Interstitial inflammatory cell VEGF and VEGFR-1 expressions are induced during the development of CAN. Increased VEGF activity may enhance the alloimmune induced inflammatory responses leading to fibrosis and CAN.

[Ruptured aortic arch aneurysm with hemorrhagic cardiac tamponade; report of a case].

The ruptured aortic arch aneurysm with cardiac tamponade is rare and has severely high mortality. We report a case of ruptured aortic arch aneurysm with cardiac tamponade. A 66-year-old man who had syncope attack was transferred to city hospital. Brain computed tomography (CT) showed no significant lesion and he admitted to our hospital for suspecting of aortic dissection. Chest CT showed ruptured aortic arch aneurysm and pericardial effusion. Emergent operation was done on the same day. It was found that the hematoma beneath the tunica adventitia existed at the distal arch and extended to the ascending aorta. Cardiac tamponade was caused by rupture of subadventitial hematoma in pericardial space. Aortic arch replacement was performed using selective cerebral perfusion under deep hypothermia. Postoperatively, he had no cerebral complication and was discharged uneventfully.

[Blue toe syndrome after coronary artery bypass grafting].

We report three cases of blue toe syndrome (BTS) after coronary artery bypass grafting (CABG). All patients were cyanotic and exhibited painful toes two to four weeks after CABG. They were treated with antiplatelet and anticoagulant agents, and one patient underwent replacement of the abdominal aorta. Thus, BTS may occur after CABG with coronary angiography, extra-corporeal circulation or intraaortic balloon pumping. For the treatment of BTS, surgery remains the most effective option.

[An autopsy case of neurogenic pulmonary edema due to suicide by hanging].

A 43-year-old man died of pulmonary edema after hanging himself. His cardiac function and renal function were normal. No aspiration, trauma, or overhydration was present, and high doses of catecholamine had not been administered. Autopsy findings revealed hypoxic brain damage, cerebral edema and pyknosis of nerve cells in the medulla oblongata. These findings resulted in a diagnosis of neurogenic pulmonary edema. To our knowledge, there have been no previous reports of neurogenic pulmonary edema due to airway obstruction.

[Multiple pulmonary nodules due to ticlopidine-induced pneumonitis].

A 54-year-old man had been treated with Ticlopidine for antithrombotic therapy after a myocardial infarction. Six months after the start of Ticlopidine, pruritic skin rash developed. After 8 months, chest X-ray films revealed multiple nodules, and the patient was admitted to our hospital. Laboratory data indicated liver dysfunction and sputum eosinophilia. Transbronchial biopsy specimens disclosed intraluminal organization and alveolar septal thickening with lymphocyte infiltration. After cessation of Ticlopidine, the cutaneous lesions quickly improved, and multiple nodules completely resolved within 4 months. These findings resulted in a diagnosis of Ticlopidine-induced pneumonitis. The radiographic pattern of multiple pulmonary nodules was very rare. Sputum eosinophilia may be helpful in the diagnosis of drug-induced pneumonitis. To our knowledge, there have been no previous reports of Ticlopidine-induced pneumonitis in Japan.

L-asparaginase induced complete remission in Epstein-Barr virus positive, multidrug resistant, cutaneous T-cell lymphoma.

A 30-year-old man was admitted to our hospital with subcutaneous tumors and a high fever. Based on biomicroscopic findings of the tumor, the patient was diagnosed as having diffuse, medium, well-differentiated malignant lymphoma. Immunochemical analysis showed that CD3, CD4, CD25, and TCR beta were positive, and in situ hybridization revealed Epstein-Barr virus-encoded small RNAs in the nuclei of the lymphoma cells. Despite the patient's resistance to multidrug therapy, complete remission was achieved using L-asparaginase. This case is unique because of its peculiar clinical course and a possible association with the Epstein-Barr virus. L-asparaginase may be an important treatment in other patients who exhibit some of these characteristics.

Secondary monocytic leukemia with rearrangement of the MLL gene occurring during the course of adult T-cell leukemia.

In June 1994, a 39 year-old male with adult T-cell leukemia was admitted to our hospital and received combination chemotherapy including epipodophyllotoxin for approximately 1 year. The monocyte count increased gradually beginning in April 1995, accelerating to 100 x 10(9)/l in January 1996, when he was diagnosed with acute monocytic leukemia. Inv(11)(q21;q23) x 2 was recognized at that time by chromosome analysis, and rearrangement of the MLL gene was shown by Southern blot analysis. From the clinical course and subsequent examinations, the case was regarded as epipodophyllotoxin-related secondary leukemia. Recently, epipodophyllotoxin has frequently been used as a treatment agent for adult T-cell leukemia. It is valuable to note that secondary leukemia may follow even such an aggressive leukemia as adult T-cell leukemia.

Actions of cyclic esters, S-esters, and amides of phenyl- and phenylthiophosphonic acids on mammalian and insect GABA-gated chloride channels.

Cyclic esters, S-esters, and amides of phenyl(thio)phosphonic acid were synthesized to probe the interaction between noncompetitive antagonists of ionotropic gamma-aminobutyric acid (GABA) receptors and their binding site. Some of these compounds competitively inhibited the specific binding of [3H]EBOB, a noncompetitive GABA antagonist, to rat-brain and housefly-head membranes. The trans isomer of the ester bearing a tert-butyl group at the 5-position and a bromine atom at the p-position (5t) was most potent in rat receptors with an IC50 value of 40 nM, while the trans isomer of the S-ester bearing the same substituents (10t) was most potent in housefly receptors with an IC50 value of 55 nM. In both cases, the corresponding amide analogue (12t) was less potent. The potencies of 5t and 12t tended to decrease in the presence of GABA, particularly in housefly receptors, while that of 10t remained unchanged. The rank order of activity in inhibiting [3H]EBOB binding to housefly-head membranes in the presence of GABA (10t > 5t > 12t) was in accord with that of insecticidal activity. S-Ester 10t depressed 10 microM and 300 microM GABA-induced 36Cl- influx into mouse cerebral synaptoneurosomes, whereas ester 5t depressed 10 microM GABA-induced 36Cl- influx but not 300 microM GABA-induced flux. Amide 12t was inactive at both GABA concentrations. These findings indicate that six-membered cyclic phenylthiophosphonic acid derivatives act as noncompetitive antagonists of GABA receptors and suggest that 10t is able to bind to the receptor in the open, desensitized, and closed states, whereas the affinity of 5t and 12t is lower in the open and desensitized states than in the closed state. The derivatives have similar structures except for the heteroatoms at the 1- and 3-positions, so that the heteroatoms may play a unique role when antagonists bring the open state of the GABA-gated channel to the desensitized or closed state.

[A case of tuberculous abscess in the chest wall close to the thickening pleural lesion following tuberculous pleuritis].

A 33-year-old woman with a history of right tuberculous pleuritis was successfully treated in December 1992 by administration of anti-tuberculous drugs, she demonstrated residual localized pleural thickening on chest computed tomography (CT) and gradually developed a subcutaneous mass in the right chest which became apparent in March 1993. In September, chest CT revealed a periocostal abscess in the right anterior chest wall close to the localized pleural thickening. The patient was diagnosed with tuberculous abscess in the right chest wall on confirmation of acid-fast bacilli in a needle aspiration material of the abscess, and was referred to our hospital. Anti-tuberculous chemotherapy was continued but the chest abscess grew, so on January 28, 1994 she underwent a resection of the abscess, the third costal cartilage and bone, and the parietal pleural lesion connected to the abscess. Histopathological examination showed that the abscess and parietal pleural lesion were compatible with tuberculosis, i.e. both lesions consisted of caseous necrosis and epitheloid cell granuloma, but acid-fast bacilli were not demonstrated in both lesions. After one year of postoperative anti-tuberculous chemotherapy, she was followed without any therapy for 3 years and there has been no recurrence to date. When a localized thickening pleural lesion remains after tuberculous pleuritis, complication of tuberculous abscess in the chest wall should be considered.