Interleukin-6, soluble interleukin-6 receptor/interleukin-6 complex and insulin resistance in obese children and adolescents.

BACKGROUND/AIM: To study the characteristics of interleukin 6 (IL6), soluble form of interleukin 6 receptor (sILR)/IL6 complex in obese children and adolescents and its relationship with insulin resistance (IR). SUBJECTS AND METHODS: 66 obese children and adolescents [34 boys, mean age 10.3 ± 2.9 years, z-score of body mass index (BMI) 4.76 ± 1.36] and 24 non-obese healthy sex- and age-matched controls. Fasting levels of glucose, insulin, IL6, sIL6, sgp130 were measured. IR was assessed by homeostasis model assessment of IR (HOMA-IR). RESULTS: Obese subjects showed increased levels of insulin and IL-6 and higher HOMA-IR compared to controls (117.67 ± 50.9 vs. 62.42 ± 29.4 pmol/L, 2.73 ± 0.98 vs. 1.07 ± 0.41 pg/ml and 4.03 ± 2.16 vs. 1.83 ± 1.05 for insulin, IL-6 and HOMA-IR, respectively, p < 0.01 in all cases). sIL-6R levels were significantly lower in obese subjects (34.7 ± 14.2 vs. 55.6 ± 15.2 ng/ml in controls, p = 0.005), whereas sgp130 levels were not significantly different. In obese subjects, IL-6 directly correlated with z-score BMI (r = 0.481, p = 0.009) and with waist-to-height ratio (r = 0.494, p = 0.007), while sIL6-R was inversely related to HOMA-IR (r = -0.522, p = 0.002). Insulin resistant subjects showed higher levels of IL6 and lower levels of sIL6R (3.31 ± 0.72 vs. 2.25 ± 0.64 pg/ml, p = 0.020 and 25.3 ± 9.3 vs. 42.5 ± 10.4 ng/ml, p = 0.013, respectively). CONCLUSIONS: In obese children and adolescents, IR is associated with elevated levels of IL-6 and diminished values of sIL-6R.

Feasibility and effectiveness of primary umbilical hernia repair with biologic graft: preliminary study.

BACKGROUND: In this prospective non-randomized observational cohort study we evaluated: the feasibility and effectiveness of primary umbilical hernia repair with open tension-free and sutureless technique using a porcine small intestinal submucosa (Surgisis) prosthesis, the quality of the treatment in terms of reduction of postoperative discomfort and the complications at early and long-term follow-up. METHODS: Thirty-six consecutive patients, mean age 45.25 +/- 12.19 years, affected by primary umbilical uncomplicated hernia with a defect size < or = 3 cm, were treated in a day-surgery setting. A tailored flat Surgisis graft was used to ensure an overlap of at least 2 cm; in all patients the mesh was fixed by fibrin glue. Collected data included: visual analogic scale (VAS) pain scores at 24 hours, 72 hours, and 7, 15, and 30 days and number of analgesic medications after operation, complications rate, the quality of life measured by Short Form 36 health survey questionnaire (SF-36) before the operation and at long term follow-up. RESULTS: The mean follow-up time was 5.6 +/- 1.4 years. Postoperative pain was low: the mean visual analogic scale (VAS) scores were 2.8 at 24 h, 1.8 at 72 h, and 0.9, 0.3, and 0.04 at 7, 15, and 30 days, respectively. 77.8% of the patients (28/36) did not use any analgesic drugs. Seroma was reported in 13.8% of the patients (5/36); there were no hematomas, infection, chronic pain and no major complications or mortality (< or = 30 days). Recurrence rate was 2.8% (1/36). Patient satisfaction showed a significant improvement in all SF-36 domain scores (P < 0.001). CONCLUSIONS: The biologic mesh seems to be a safe and reliable device for repairing primary umbilical hernia with high patient comfort, even if not yet an alternative to synthetic mesh.

A case of extraovarian primary peritoneal carcinoma in an oophorectomized-hysterectomized patient: a diagnostic dilemma.

Extra Ovarian Primary Peritoneal Carcinoma (EOPPC) is a rare type of adenocarcinoma of the pelvic and abdominal peritoneum. The objective examination and the histological aspect of the neoplasia virtually overlaps with that of ovarian carcinoma. The reported case is that of a 72 year-old patient who had undergone a total hysterectomy with bilateral annessiectomy surgery 20 years earlier subsequently to a diagnosis for uterine leiomyomatosis. The patient came to our attention presenting recurring abdominal pain, constipation, weight loss, severe asthenia and fever. Her blood test results showed hypochromic microcytic anemia and a remarkable increase CA125 marker levels. Instrumental diagnostics with Ultrasound (US) and CT scans indicated the presence of a single peritoneal mass (10-12 cm diameter) close to the great epiploon. The patient was operated through a midline abdominal incision and the mass was removed with the great omentum. No primary tumor was found anywhere else in the abdomen and in the pelvis. The operation lasted approximately 50 minutes. The post-operative course was normal and the patient was discharged four days later. The histological exam of the neoplasia, supported by immunohistochemical analysis, showed a significant positivity for CA 125, vimentin and cytocheratin, presence of psammoma bodies, and cytoarchitectural pattern resembling that of a serous ovarian carcinoma even in absence of primitiveness, leading to a final diagnosis of EOPPC. The patient later underwent six cycles of chemotherapy with paclitaxel (135 mg/m²/24 hr) in association with cisplatin (75mg/m²). At the fourth year follow-up no sign of relapse was observed.

COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells following binding with the cell surface ACE2 receptors, thereby leading to coronavirus disease 2019 (COVID-19). SARS-CoV-2 causes viral pneumonia with additional extrapulmonary manifestations and major complications, including acute myocardial injury, arrhythmia, and shock mainly in elderly patients. Furthermore, patients with existing cardiovascular comorbidities, such as hypertension and coronary heart disease, have a worse clinical outcome following contraction of the viral illness. A striking feature of COVID-19 pandemics is the high incidence of fatalities in advanced aged patients: this might be due to the prevalence of frailty and cardiovascular disease increase with age due to endothelial dysfunction and loss of endogenous cardioprotective mechanisms. Although experimental evidence on this topic is still at its infancy, the aim of this position paper is to hypothesize and discuss more suggestive cellular and molecular mechanisms whereby SARS-CoV-2 may lead to detrimental consequences to the cardiovascular system. We will focus on aging, cytokine storm, NLRP3/inflammasome, hypoxemia, and air pollution, which is an emerging cardiovascular risk factor associated with rapid urbanization and globalization. We will finally discuss the impact of clinically available CV drugs on the clinical course of COVID-19 patients. Understanding the role played by SARS-CoV2 on the CV system is indeed mandatory to get further insights into COVID-19 pathogenesis and to design a therapeutic strategy of cardio-protection for frail patients.

Conjugated polymers optically regulate the fate of endothelial colony-forming cells.

The control of stem and progenitor cell fate is emerging as a compelling urgency for regenerative medicine. Here, we propose a innovative strategy to gain optical control of endothelial colony-forming cell fate, which represents the only known truly endothelial precursor showing robust in vitro proliferation and overwhelming vessel formation in vivo. We combine conjugated polymers, used as photo-actuators, with the advantages offered by optical stimulation over current electromechanical and chemical stimulation approaches. Light modulation provides unprecedented spatial and temporal resolution, permitting at the same time lower invasiveness and higher selectivity. We demonstrate that polymer-mediated optical excitation induces a robust enhancement of proliferation and lumen formation in vitro. We identify the underlying biophysical pathway as due to light-induced activation of TRPV1 channel. Altogether, our results represent an effective way to induce angiogenesis in vitro, which represents the proof of principle to improve the outcome of autologous cell-based therapy in vivo.

ePTFE soft tissue patch reconstruction of hemidiaphragmatic agenesis with late clinical presentation.

In this paper we describe a case of a 71-year-old man affected by left hemidiaphragm agenesis who presented an extensive enterothorax after an asymptomatic history for many years. The patient had late development of severe constipation and occasional episodes of bowel obstruction and vomiting. The surgical correction of this congenital anomaly consisted of restoring the continuity of the diaphragmatic barrier with a 2-mm-thick expanded polytetrafluoroethylene soft tissue patch(Gore-Tex) after the herniated viscera have been replaced into the abdominal cavity. At 26 months' follow-up no recurrence has been observed. We would suggest that this is the first known elderly patient surgically treated and the eighth case reported in the literature. The use of a single-layer ePTFE mesh allows a good anatomical and functional repair. An overview of the literature is also reported.

Latrunculin A depolarizes starfish oocytes.

Depolymerization of the actin cytoskeleton may liberate Ca2+ from InsP3-sensitive stores in some cell types, including starfish oocytes, while inhibiting Ca2+ influx in others. However, no information is available on the modulation of membrane potential (V(m)) by actin. The present study was aimed to ascertain whether the widely employed actin depolymerizing drug, latrunculin A (Lat A), affects V(m) in mature oocytes of the starfish Astropecten aranciacus. Lat A induced a membrane depolarization which was mimicked by cytochalasin D, another popular actin disruptor, and prevented by jasplakinolide, a stabilizer of the actin network. Lat A-elicited depolarization consisted in a positive shift in V(m) which reached the threshold of activation of voltage-gated Ca2+ channels (VGCC), thus triggering an action potential. Lat A-promoted depolarization lacked the action potential in Ca2+-free sea water, while it was abolished upon removal of external Na+. Moreover, membrane depolarization was prevented by pre-injection of BAPTA and heparin, but not ryanodine. These data indicate that Lat A induces a membrane depolarization by releasing Ca2+ from InsP3Rs. The Ca2+ signal in turn activates a Ca2+-dependent Na+ entry, which causes the positive shift in V(m) and stimulates the VGCC.

Fine structural detection of calcium ions by photoconversion.

We propose a tool for a rapid high-resolution detection of calcium ions which can be used in parallel with other techniques. We have applied a new approach by  photo-oxidation of diaminobenzidine in presence of the emission of an excited fluorochrome specific for calcium detection. This method combines the selectivity of available fluorophores to the high spatial resolution offered by transmission electron microscopy to detect even fluorescing molecules even when present in low amounts in membrane-bounded organelles. We show in this paper that Mag-Fura 2 photoconversion via diaminobenzidine oxidation is an efficient way for localizing Ca2+ ions at EM level, is easily carried out and reproducible, and can be obtained on a good amount of cells, since the exposition in our conditions is not limited to the direct irradiation of the sample via an objective but obtained with a germicide lamp. The end product is sufficiently electron dense to be detected clearly when present in sufficient amount within a membrane boundary.

Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms.

A quarter of patients with essential thrombocythemia or primary myelofibrosis carry a driver mutation of CALR, the calreticulin gene. A 52-bp deletion (type 1) and a 5-bp insertion (type 2 mutation) are the most frequent variants. These indels might differentially impair the calcium binding activity of mutant calreticulin. We studied the relationship between mutation subtype and biological/clinical features of the disease. Thirty-two different types of CALR variants were identified in 311 patients. Based on their predicted effect on calreticulin C-terminal, mutations were classified as: (i) type 1-like (65%); (ii) type 2-like (32%); and (iii) other types (3%). Corresponding CALR mutants had significantly different estimated isoelectric points. Patients with type 1 mutation, but not those with type 2, showed abnormal cytosolic calcium signals in cultured megakaryocytes. Type 1-like mutations were mainly associated with a myelofibrosis phenotype and a significantly higher risk of myelofibrotic transformation in essential thrombocythemia. Type 2-like CALR mutations were preferentially associated with an essential thrombocythemia phenotype, low risk of thrombosis despite very-high platelet counts and indolent clinical course. Thus, mutation subtype contributes to determining clinical phenotype and outcomes in CALR-mutant myeloproliferative neoplasms. CALR variants that markedly impair the calcium binding activity of mutant calreticulin are mainly associated with a myelofibrosis phenotype.

Somatostatin in the prevention of recurrent bleeding after endoscopic haemostasis of peptic ulcer haemorrhage: a preliminary report.

OBJECTIVE: Although endoscopic injection therapy provides excellent initial haemostasis in actively bleeding ulcers, the incidence of recurrent haemorrhage is not negligible. The aim of this study was to compare somatostatin, omeprazole and ranitidine in preventing further haemorrhage after endoscopic injection haemostasis. METHODS: Seventy-three patients with major stigmata of ulcer haemorrhage at endoscopy were treated with epinephrine injection and randomly assigned to receive either omeprazole (n = 24) or ranitidine (n = 24) or somatostatin (n = 25). The three groups were similar in all background variables including mean age, clinical and endoscopic features, severity of bleeding and timing of the haemostatic procedure. All patients underwent a second endoscopic look at 48 h. Failures of treatment or retreatment underwent emergency surgery. RESULTS: There were no statistically significant differences between the groups in terms of initial haemostasis, need for emergency surgery, transfusion requirements, length of hospital stay or mortality. Early recurrent haemorrhage was 5/22 (22.7%) in the ranitidine group, 5/23 (21.7%) in the omeprazole group and 2/23 (8.7%) in the somatostatin group. No major side-effect was noted with drug therapy. CONCLUSIONS: The preliminary results suggest that somatostatin might be more effective than ranitidine and omeprazole in the prevention of recurrent haemorrhage following endoscopic injection therapy of bleeding peptic ulcers.

Effect of corticosteroid treatment on hemopoiesis in vivo and in vitro in a patient with Felty's syndrome.

We have studied the CFU-GM and BFU-E in vitro growth in a neutropenic and anemic patient with Felty's syndrome, either before or one and three months after steroid therapy when neutrophils and erythrocytes returned to normal. Both CFU-GM growth and CSA production were found to be low before therapy, and prednisone was shown to raise them to normal levels. The in vitro growth of BFU-E and the production of BPA by T lymphocytes of the patient were significantly lower than normal when studied before therapy. However, the T lymphocytes incubated in vitro with hydrocortisone regained their ability to stimulate the BFU-E growth. After prednisone therapy both BFU-E growth and BPA production by T lymphocytes returned to normal. Possible pathogenetic mechanisms of impaired granulo- and erythropoiesis in Felty's syndrome are discussed. The in vitro study with hydrocortisone can help to identify steroid-sensitive patients.

In vitro growth of erythroid progenitor cells (BFU-E) and production of burst-promoting activity (BPA) by T lymphocytes in patients with myelodysplastic syndromes.

The in vitro growth of circulating erythroid progenitors (BFU-E) populations and the production of burst-promoting activity (BPA) by T lymphocytes have been studied in 17 patients with myelodysplastic syndromes. Based on the in vitro growth patterns of BFU-E, four groups of patients have been identified: i) normal BFU-E growth; ii) low spontaneous BFU-E growth, but normal response to LCM; iii) impaired BFU-E response to LCM; iv) no BFU-E growth. The pattern of BFU-E growth seems to be related to the clinical stage of the disease rather than to the FAB subgroup to which the patients belong. The ability of T lymphocytes to stimulate BFU-E growth was significantly reduced in all patients. The possible mechanisms inducing the impaired production of BPA by T lymphocytes are discussed. The in vitro evaluation of circulating erythroid precursors can supply useful prognostic information and possibly indications concerning the responsiveness of erythropoietic stem cells to recombinant human erythropoietin in vivo.

Alterations of erythropoiesis in chronic uremic patients treated with intermittent hemodialysis.

The in vitro growth of the blood burst-forming cells (BFU-E) of 9 chronic uremic patients, treated with intermittent hemodialysis three times a week has been studied at the time of maximum and minimum level of retained nitrogen catabolites. The effect of uremic sera on the vitro growth of normal BFU-E was also studied. The in vitro growth of blood BFU-E was shown to be greatly reduced in all uremic patients and dialysis did not modify their growth. The sera of uremic patients significantly inhibited the in vitro growth of normal blood BFU-E when it was taken at the time of maximum retention of nitrogen catabolites. However, inhibition of normal BFU-E growth was not seen when uremic sera were taken at the time of minimum retention of nitrogen catabolites. These data seem to indicate a long lasting suppression of BFU-E in chronic uremia due to serum inhibitor/s.

T lymphocyte subsets in chronic uremic patients treated with maintenance hemodialysis.

Blood T lymphocyte subsets have been studied using monoclonal antibodies in 10 chronic uremic patients treated with maintenance hemodialysis. Both total T lymphocytes identified by the antibody OKT3, and the helper-inducer T lymphocyte subset identified by the antibody OKT4 were found to be significantly lower than normal. The cytotoxic-suppressor T cell subset was only moderately, even if significantly reduced, so that the T4/T8 ratio in uremic patients was significantly lower than normal. These data provide an additional contribution to the interpretation of immunological and hematological deficiencies observed in chronic uremia.

Defective in vitro growth of BFU-E of elderly subjects revealed by hydrocortisone.

The effect of aging on hematopoiesis and bone marrow exhaustion have long been debated. Unexplained anemia and impaired in vitro proliferation of erythroid precursors is frequently observed in the elderly. As hydrocortisone is known to increase the BFU-E in vitro growth, we have studied the response of BFU-E to hydrocortisone in a group of nonanemic elderly subjects. The BFU-E growth in methylcellulose from blood mononuclear cells (MNC), stimulated by lymphocyte-conditioned medium (LCM), either with or without hydrocortisone, of 10 subjects aged 76-91 years was compared with the BFU-E growth from MNC of a group of ten young subjects. While LCM induced a significant increase of BFU-E growth, both in young and old subjects, hydrocortisone induced a significant increase of BFU-E growth only in young subjects. This study shows that in the elderly, there is a latent defect of erythropoiesis, possibly consisting of a defective ability to modulate the receptors for erythropoietin on BFU-E, and that hydrocortisone offers a useful tool to identify it.

Autoimmune thrombocytopenic purpura and dermatomyositis associated with chronic hepatitis C. A therapeutic dilemma.

We recently observed a patient with chronic C hepatitis who developed first autoimmune thrombocytopenic purpura and subsequently dermatomyositis. While the association could be coincidental, it is possible that hepatitis C virus could have induced autoantibodies or circulating immune complexes which contributed to both. Although concerns are sometimes raised about the use of corticosteroids and immunosuppressive therapy to control symptoms in hepatitis C virus infected patients with rheumatic or autoimmune diseases, corticosteroid and immunosuppressive therapies are considered appropriate in cases of chronic C hepatitis with rapidly progressive autoimmune diseases. Our case illustrates the paradox that, despite the continuing presence of a viremic form of chronic C hepatitis, clinical symptoms improved with combined immunosuppressive therapy, without deterioration of the hepatitis. Our results could be the consequence of the association of immunosuppressive therapy intensive enough to control the autoimmune thrombocytopenic purpura and dermatomyositis with alpha-interferon whose antiviral capacity may have been able to prevent re-exacerbation of the hepatitis.

Two cases of autoimmune thrombocytopenic purpura associated with antiphospholipid antibodies.

We report 2 cases of autoimmune thrombocytopenic purpura associated with antiphospholipid antibodies. In the first case the titer of antiphospholipid antibodies was neither related to disease activity nor influenced by immunosuppressive therapy. In the second, cerebral infarction occurred in spite of severe thrombocytopenia. Our results provide additional evidence that antiphospholipid antibodies are not involved in the pathogenesis of autoimmune thrombocytopenic purpura. Nevertheless, the frequency and clinical significance of this association would suggest that patients with autoimmune thrombocytopenic purpura should be tested for antiphospholipid antibodies, particularly before pregnancy or surgical procedures.

Autoimmune hemolytic anemia in chronic hepatitis C virus infection: an unusual extrahepatic autoimmune manifestation.

We report a case of Coombs positive autoimmune hemolytic anemia occurring in a patient with chronic hepatitis C, never treated with interferon-alpha. Prednisone treatment induced the complete remission of both clinical and hematological findings after 2 months. The indirect Coombs test turned negative, while the direct Coombs test remained weakly positive. Autoimmune hemolytic anemia during chronic hepatitis C has been reported to develop only after or simultaneously with interferon-alpha therapy. After discarding other possible causes such as drugs, infectious, neoplastic, lymphoproliferative diseases, and essential mixed cryoglobulinemia, we made the hypothesis of a correlation between autoimmune hemolytic anemia and hepatitis C virus infection.

The relationship between splenic marginal zone B-cell lymphoma and chronic liver disease associated with hepatitis C virus infection.

An etiologically important role has been suggested for hepatitis C virus infection in the development of low-grade B-cell non-Hodgkin's lymphoma, such as splenic marginal zone B-cell lymphoma. We present a study of 3 patients with splenic marginal zone B-cell lymphoma and chronic hepatitis C, and describe clinical, histologic, and immunohistochemical features and the response to therapy in these cases. All 3 patients underwent splenectomy, polychemotherapy and alpha-interferon therapy. The first patient achieved complete remission; the second died of hepatic failure and anasarca 3 months after admission; as this writing, the third remains in complete remission 4.5 years after diagnosis. In the second patient, a long latency period of chronic hepatitis C virus infection was observed. Our data indicate that when early detection of the disease is possible, splenic marginal zone B-cell lymphoma has a relatively favorable prognosis. Our results could furthermore suggest an etiologic role for hepatitis C virus infection in the development of splenic B-cell lymphoma through multistep cooperating events. A fuller understanding of the virus-related mechanisms of lymphoproliferation could contribute significantly to the development of new therapeutic strategies.

Acquired factor VIII inhibitor associated with prostatic cancer: successful treatment with steroid and immunosuppressive therapy.

Factor VIII inhibitors are antibodies of the IgG class that block functional epitopes or antigenic sites of factor VIII. They occur in about 5-20% of hemophilia A patients after infusions of factor VIII concentrate. Antibodies to factor VIII can also arise spontaneously in association with various autoimmune and chronic inflammatory diseases, hematologic malignancies, solid tumors, certain drugs, dermatologic conditions, and in puerperium. In the majority of cases, the clinical course is characterized by severe hemorrhages. Strategies to treat such inhibitors are controversial. We present the case of a patient with prostatic cancer who developed acquired factor VIII inhibitor. His severe bleeding complications were treated successfully with cyclophosphamide in combination with methylprednisolone. Within a few months, moreover, the immunosuppressive therapy brought about complete disappearance of the inhibitor and normalization of coagulation parameters. Our case illustrates that, although the clinical course in patients with acquired factor VIII inhibitor is not predictable, and the inhibitor may disappear spontaneously, combined therapy with cyclophosphamide and methylprednisolone should be considered for patients with severe hemorrhages.