Systemic lupus erythematosus and diffuse alveolar hemorrhage, etiology and novel treatment strategies.

Diffuse alveolar hemorrhage is a severe respiratory complication of systemic lupus erythematosus. The illness develops over hours to a few days and is the systemic lupus erythematosus-associated syndrome with highest mortality. Although no specific symptoms have been identified, a number of features are associated with diffuse alveolar hemorrhage, with a drop in blood hemoglobin the most prominent. Dyspnea, blood-stained sputum, diffuse infiltrates identified by chest imaging, elevated single breath-diffusing capacity for monoxide, thrombocytopenia and C3 hypocomplementemia are other commonly reported signs of diffuse alveolar hemorrhage. The etiology is not completely understood but many patients develop diffuse alveolar hemorrhage concomitant with lupus nephritis, suggesting immune complex-driven pathology. Biopsy studies have identified both cases with capillaritis and a bland non-inflammatory phenotype. An animal model of diffuse alveolar hemorrhage has indicated requirement of B lymphocytes and complement receptor-mediated apoptotic body phagocytosis by monocytes as part of the pathogenesis. This review will discuss considerations when diagnosing the condition and available therapies. Infections and other causes of hemorrhage have to be excluded as these require different treatment strategies. Methylprednisolone and cyclophosphamide remain the most commonly used therapies. Plasmapheresis and rituximab are other beneficial treatment options. A few studies have also considered intrapulmonary Factor VII therapy, extracorporeal membrane oxygenation and mesenchymal stem cell therapy. There is an unmet need of better definition of diffuse alveolar hemorrhages etiology and pathology for development of improved treatment strategies.

Role of Eosinophil Granulocytes in Allergic Airway Inflammation Endotypes.

Eosinophil granulocytes are intriguing members of the innate immunity system that have been considered important defenders during parasitic diseases as well as culprits during allergy-associated inflammatory diseases. Novel studies have, however, found new homoeostasis-maintaining roles for the cell. Recent clinical trials blocking different Th2 cytokines have uncovered that asthma is heterogeneous entity and forms different characteristic endotypes. Although eosinophils are present in allergic asthma with early onset, the cells may not be essential for the pathology. The cells are, however, likely disease causing in asthma with a late onset, which is often associated with chronic rhinosinusitis. Assessment of eosinophilia, fraction exhaled nitric oxide (FeNO) and periostin are markers that have emerged useful in assessing and monitoring asthma severity and endotype. Current scientific knowledge suggests that eosinophils are recruited by the inflammatory environment, activated by the innate interleukin (IL)-33 and prevented from apoptosis by both lymphocytes and innate immune cells such as type two innate immune cells. Eosinophils contain four specific granule proteins that exhibit an array of toxic and immune-modulatory activates. The granule proteins can be released by different mechanisms. Additionally, eosinophils contain a number of inflammatory cytokines and lipid mediators as well as radical oxygen species that might contribute to the disease both by the recruitment of other cells and the direct damage to supporting cells, leading to exacerbations and tissue fibrosis. This review aimed to outline current knowledge how eosinophils are recruited, activated and mediate damage to tissues and therapies used to control the cells.

Convalescent plasma treatment in severely immunosuppressed patients hospitalized with COVID-19: an observational study of 28 cases.

BACKGROUND: Immunosuppressed patients are particularly vulnerable to severe infection from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), risking prolonged viremia and symptom duration. In this study we describe clinical and virological treatment outcomes in a heterogeneous group of patients with severe immunosuppression due to various causes suffering from COVID-19 infection, who were all treated with convalescent plasma (CCP) along with standard treatment. METHODS: We performed an observational, retrospective case series between May 2020 to March 2021 at three sites in Skåne, Sweden, with a population of nearly 1.4 million people. All patients hospitalized for COVID-19 who received CCP with the indication severe immunosuppression as defined by the treating physician were included in the study (n = 28). RESULTS: In total, 28 severely immunocompromised patients, half of which previously had been treated with rituximab, who had received in-hospital convalescent plasma treatment of COVID-19 were identified. One week after CCP treatment, 13 of 28 (46%) patients had improved clinically defined as a decrease of at least one point at the WHO-scale. Three patients had increased score points of whom two had died. For 12 patients, the WHO-scale was unchanged. CONCLUSION: As one of only few studies on CCP treatment of COVID-19 in hospitalized patients with severe immunosuppression, this study adds descriptive data. The study design prohibits conclusions on safety and efficacy, and the results should be interpreted with caution. Prospective, randomized trials are needed to investigate this further.

Eosinophil cationic protein (ECP).

ECP (eosinophil cationic protein) was first purified from human myleoid cells in 1971 and identified as an eosinophil granule protein in 1975. ECP is a heterogeneous protein with molecular weights of the variants from 16-24 kDa. ECP is extremely basic with a pI of pH 10.8. The gene for ECP is found on chromosome 14 adjacent to other proteins of the ribonuclease family, with which ECP shares some sequence homologies. ECP has a variety of biological activities interacting with other immune cells and plasma proteins such as coagulation factors and proteins of the complement system. The cytotoxic activity, however, is the most conspicuous. The different isoforms of ECP seem to have different biological properties with respect to cytotoxicity and the effects on fibroblasts. ECP can be measured in biological fluids, by means of sensitive immunoassays, as an indication of eosinophil turnover and activity in vivo.

Monocytes, but not macrophages, produce the eosinophil cationic protein.

The eosinophil cationic protein (ECP) is a cytotoxic protein with ribonuclease activity, produced and stored in bone marrow eosinophil myelocytes. Mature circulating eosinophils contain about 10 pg ECP per cell. The aim of this study was to investigate the possibility that monocytes produce and store ECP. By results from flow cytometry and specific protein measurement it is shown that human monocytes contain ECP (monocytes about 10 fg ECP per cell). RT-PCR analysis indicated the presence of mRNA coding for ECP in blood monocytes but not in alveolar macrophages. Furthermore, mRNA coding for ECP and low amounts of the protein were found in three myeloid cell lines representing different stages of monocytic differentiation. Differentiation of U-937 cells to macrophages induced lowered transcription of the ECP gene and reduced protein production. Immunohistochemical staining of lung tissue indicated that lung macrophages do not contain ECP. It is concluded that ECP is produced to a low extent by human monocytes and that the production is shut down during macrophage differentiation. This might indicate an alternative transcriptional regulation of the ECP gene in the monocytic lineage compared to the eosinophil lineage.

Questionnaire versus direct technical measurements in assessing postures and movements of the head, upper back, arms and hands.

OBJECTIVES: This study compares questionnaire-assessed exposure data on work postures and movements with direct technical measurements. METHODS: Inclinometers and goniometers were used to make full workday measurements of 41 office workers and 41 cleaners, stratified for such factors as musculoskeletal complaints. The subjects answered a questionnaire on work postures of the head, back, and upper arms and repeated movements of the arms and hands (3-point scales). The questionnaire had been developed on the basis of a previously validated one. For assessing worktasks and their durations, the subjects kept a 2-week worktask diary. Job exposure was individually calculated by time-weighting the task exposure measurements according to the diary. RESULTS: The agreement between the self-assessed and measured postures and movements was low (kappa = 0.06 for the mean within the occupational groups and kappa = 0.27 for the whole group). Cleaners had a higher measured workload than office workers giving the same questionnaire response. Moreover, the subjects with neck-shoulder complaints rated their exposure to movements as higher than those without complaints but with the same measured mechanical exposure. In addition, these subjects also showed a general tendency to rate their postural exposure as higher. The women rated their exposure higher than the men did. CONCLUSIONS: The questionnaire-assessed exposure data had low validity. For the various response categories the measured exposure depended on occupation. Furthermore, there was a differential misclassification due to musculoskeletal complaints and gender. Thus it seems difficult to construct valid questionnaires on mechanical exposure for establishing generic exposure-response relations in epidemiologic studies, especially cross-sectional ones. Direct technical measurements may be preferable.

Myocarditis and abortion associated with intrauterine infection of sows with porcine circovirus 2.

Porcine circovirus 2 (PCV2) is a recently identified agent that has been associated with postweaning multisystemic wasting syndrome (PMWS) in swine populations. In this report, the potential spectrum of disease associated with PCV2 is expanded by evidence of vertical transmission and associated reproductive failure. PCV2 was isolated from a litter of aborted piglets from a farm experiencing late-term abortions and stillbirths. Severe, diffuse myocarditis was present in 1 piglet associated with extensive immunohistochemical staining for PCV2 antigen. Variable amounts of PCV2 antigen were also present in liver, lung, and kidney of multiple fetuses. The presence of other agents that have been associated with fetal lesions and abortion in swine, including porcine parvovirus, porcine reproductive respiratory syndrome virus, encephalomyocarditis virus, and enterovirus, could not be established.

The functional heterogeneity of eosinophil cationic protein is determined by a gene polymorphism and post-translational modifications.

BACKGROUND: The eosinophil is a cytotoxic cell and takes part in parasite killing and tissue-destructive processes by secretion of proteins such as eosinophil cationic protein (ECP). A polymorphism was demonstrated in the ECP gene, giving rise to a substitution of arginine at position 97 with threonine. This polymorphism is related to disease development. OBJECTIVE: To investigate the functional and molecular heterogeneity of native ECP and the functional consequences of the replacement of arginine with a threonine. METHODS: ECP was purified from healthy blood donors by gel filtration, ion-exchange chromatography and reversed-phase chromatography. Recombinant ECPs i.e. rECP 97(arg) and rECP 97(thr) were produced by the pFASTBAC baculovirus expression system. The cytotoxic activity was determined against an erythroleukaemia or a small cell lung cancer cell line. RESULTS: Native ECP was purified to apparent homogeneity and showed a considerable molecular heterogeneity and a corresponding functional heterogeneity with respect to cytotoxic activity. After reduction, the native cytotoxic ECP showed three bands on sodium dodecylsulphate polyacrylamide gel electrophoresis : one major band at 18-20 kDa and two minor bands at about 10 and 5 kDa, respectively. The 5 kDa contained two masses differing with 56.2 Da, which corresponds to the difference in molecular masses of arginine and threonine. rECP 97(arg) was cytotoxic in contrast to rECP97(thr). Deglycosylation with N-glycosidase F did not affect the cytotoxic activity of native ECP to any measurable extent nor the activity of rECP 97(arg), whereas rECP 97(thr) achieved cytotoxic activity. The RNase activities of the recombinant and native ECPs were similar. CONCLUSION: We conclude that ECP is present in several molecular forms with varying biological activities. Some of this functional heterogeneity is based on the genetic polymorphism of the ECP gene and some on post-translational modifications. In subjects carrying the ECP 97(thr) variant, the cytotoxic activity may be disguised by N-linked glycosylation of the active site.

Induration penis plastica. Experience of treatment with procarbazine Natulan.

Eighteen patients with plastic induration of the penis were treated with procarbazine, a cytotoxic agent. Ten patients experienced a good to excellent result; 7 patients no improvement and in one patient treatment had to be prematurely withdrawn because of gastro-intestinal side-effects. No other serious side-effects occurred in the present investigation. Patients with impaired erection, previous gastric surgery and alcoholics are deemed less suitable for this form of therapy. It can be recommended to other patients in otherwise good condition and is especially suitable when diffuse fibrosis is present or when cavernosography indicates deep infiltration of the disease into the intercavernous septum. Selection can be made from those patients who show no tendency to spontaneous remission or those unsuitable for or unresponsive to other therapeutic measures.

Early and late complications of ileal condiut urinary diversion.

The early and late complications of cutaneous uretero-ileostomy in 61 patients are reported. Only complications attributable to the urinary diversion procedure are detailed. The early complications included intestinal obstruction in 4 cases, enterocutaneous fistula in 4, urinary fistula in 6 and wound disruption in 3 cases The surgical mortality was 6.6%. The predominant late complications were uretero-ileal obstruction with progressive hydronephrosis in 14 patients, 8 of whom underwent re-operation. Stomal problems arose in 6 patients and stone in the urinary tract in 5 patients. Full preoperative irradiation and isolated anastomosis between the ureters and the ileal segment increased the frequency of these late complications. Some measures are discussed which may reduce this fairly high complication rate.

Induratio penis plastica Peyronie's disease. Clinical features and etiology.

The clinical and laboratory findings in 106 patients with Peyronie's disease as well as histopathological examinations of biopsies from the plaques were studied. The clinical symptoms and signs were in general similar to those found in previous studies, but bone marrow smears showed an increased number of plasma cells and lymphocytes in 18 of 24 examined. Biopsy of the plaque in cases of long-term symptomatology disclosed a fibrosis poor in cellular components. In patients with a short history of the disease and a tender induration, an inflammatory component of the specimens with perivascular accumulation of lymphocytes and balooning of endothelial cells in the small vessels was seen. Characteristic cells with "cross-banded" nuclei, described earlier only in Dupuytren's contracture and experimental fibrosis, was observed for the first time in Peyronie's disease. Based on these findings a combined traumatic-immunological etiology is suggested.

Treatment of urinary incontinence by the Scott-Bradley-Timm artificial sphincter. A report of eight cases.

Eight patients were treated with an implantable artificial urinary sphincter. Five patients had neurogenic bladders, two had postprostatectomy incontinence and one severe recurring stress incontinence. The main problem was mechanical failure of the device in four patients. The present results (follow up two to ten months) may be classified as satisfactory in six and unsatisfactory in two patients.