Treatment of thrombotic microangiopathies with plasma exchange

Thrombotic microangiopathy (TMA) is a syndrome characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, fever and renal dysfunction. This retrospective analysis sought to determine the clinical characteristics and outcome of patients with TMA treated with plasma exchange at the Department of Dialysis, University Hospital Zagreb. From 1982 to July 2005, 17 patients (10 male and 7 female, age ranging from 18 to 74 years) have been diagnosed with TMA. The most common presenting symptom was purpura in 76.5%, followed by neurologic disturbance in 70.5%, renal function abnormality in 41.1%, and fever in 29.4% of patients. Patients were treated with a daily plasma exchange, which was continued until the normalization of platelet count with minimal hemolysis. Plasma exchange treatment was first tapered and later discontinued with careful monitoring of laboratory parameters. Of the 17 patients, 13 achieved complete remission after 5-32 sessions, two had partial response, and two had no response and died of progressive disease. Four patients developed chronic relapsing TMA, and three of them progressed to end-stage renal disease. Survival at 1 year in our series exceeds 88%, but decreased with duration of follow-up. Overall, with the median follow up of 5 years, 6 patients died from consequences of TMA (35.3%); three with chronic TMA, and 2 in the acute phase of progressive disease. A 74-year old male who developed TMA after prostate cancer died from disseminated malignant disease. Our results demonstrate a high incidence of renal function abnormalities in patients with TMA at presentation, but also during long term follow-up. Development of end-stage renal disease was associated with poor prognosis. Further studies, long term follow-up and establishment of international registries are needed to clarify many dilemmas associated with the diagnosis, treatment and outcomes of patients with TMA.     

Effects of APACHE II score on mechanical ventilation; prediction and outcome

AIM: To evaluate the influence of Acute Physiology and Chronic Health Evaluation (APACHE II) score on the choice of mechanical ventilation method and treatment outcome. METHODS: A prospective, randomized trial was carried out at the multidisciplinary Intensive Care Unit over 22 months. Research sample consisted of 129 patients who required mechanical ventilation, divided in two groups: APACHE II < or = 20 and APACHE II > 20. Both groups were than randomized for either noninvasive or invasive mechanical ventilation. Comparison was made based on patient characteristics, objective parameters and influence of APACHE II score on treatment success and failure. RESULTS: APACHE II scoring was shown to have statistical significance on outcome assessment. Statistical significance was in favour of patients with APACHE II score < or = 20 vs > 20 (ventilator associated pneumonia 0 vs. 10, tracheotomy 0 vs. 16, Intensive Care Unit mortality 0 vs 12). Furthermore, in the group with APACHE II score > 20, after randomization, there was a statistical significance in favour of noninvasive mechanical ventilation in need for tracheotomy 2 (4%) vs. 14 (28%) (p < 0.001). CONCLUSION: Using good patient selection and applying strict protocols, in the group of patients with APACHE II < or = 20 all patients had successful mechanical ventilation, while in the group of patients with APACHE II > 20, noninvasive mechanical ventilation can be applied.     

Effects of adult-onset streptozotocin-induced diabetes on the rat brain antioxidant status and the activities of acetylcholinesterase, (Na+,K+)- and Mg2+-ATPase: modulation by L-cysteine

Uncontrolled diabetes is known to affect the nervous system. The aim of this study was to investigate the effect of the antioxidant L-cysteine (Cys) on the changes caused by adult-onset streptozotocin (STZ)-induced diabetes on the rat brain total antioxidant status (TAS) and the activities of acetylcholinesterase (AChE), (Na⁺,K⁺)-ATPase and Mg²⁺-ATPase. Thirty-eight male Wistar rats were divided into six groups: C_A (8-week-control), C_B (8-week-control + 1-week-saline-treated), C + Cys (8-week-control + 1-week-Cys-treated), D_A (8-week-diabetic), D_B (8-week-diabetic + 1-week-saline-treated) and D + Cys (8-week-diabetic + 1-week-Cys-treated). All diabetic rats were once treated with an intraperitoneal (i.p.) STZ injection (50 mg/kg body weight) at the beginning of the experiment, while all Cys-treated groups received i.p. injections of Cys 7 mg/kg body weight (daily, for 1-week, during the 9th-week). Whole rat brain parameters were measured spectrophotometrically. In vitro incubation with 0.83 mM of Cys or 10 mM of STZ for 3 h was performed on brain homogenate samples from groups C_B and D_B, in order to study the enzymes’ activities. Diabetic rats exhibited a statistically significant reduction in brain TAS (−28%, D_A vs C_A;−30%, D_B vs C_B) that was reversed after 1-week-Cys-administration into basal levels. Diabetes caused a significant increase in AChE activity (+27%, D_A vs C_A; +15%, D_B vs C_B), that was further enhanced by Cys-administration (+57%, D + Cys vs C_B). The C + Cys group exhibited no significant difference compared to the C_B group in TAS (+2%), but showed a significantly increased AChE activity (+66%, C + Cys vs C_B). Diabetic rats exhibited a significant reduction in the activity of Na⁺,K⁺-ATPase (−36%, D_A vs C_A;−48%, D_B vs C_B) that was not reversed after 1-week Cys administration. However, in vitro incubation with Cys partially reversed the diabetes-induced Na⁺,K⁺-ATPase inhibition. Mg²⁺-ATPase activity was not affected by STZ-induced diabetes, while Cys caused a significant inhibition of the enzyme, both in vivo (−14%, C + Cys vs C_B;−17%, D + Cys vs C_B) and in vitro (−16%, D_B + in vitro Cys vs C_B). In vitro incubation with STZ had no effect on the studied enzymes. The present data revealed a protective role for Cys towards the oxidative effect of diabetes on the adult rat brain. Moreover, an increase in whole brain AChE activity due to diabetes was recorded (not repeatedly established in the literature, since contradictory findings exist), that was further increased by Cys. The inhibition of Na⁺,K⁺-ATPase reflects a possible mechanism through which untreated diabetes could affect neuronal excitability, metabolic energy production and certain systems of neurotransmission. As concerns the use of Cys as a neuroprotective agent against diabetes, our in vitro findings could be indicative of a possible protective role of Cys under different in vivo experimental conditions.     

Corrélations anatomo-topographiques de l''artère ophtalmique examinée sur 4 plans horizontaux

Sans résumé(Traduction : S. Deplus)     

Neurologic sequelae of bone changes in multiple myeloma and its therapy

Multiple myeloma (MM) is a plasma cell malignancy characterized by infiltration of bone marrow, bone destruction, infiltration of soft tissues with plasma cells, and suppression of normal hematopoiesis. The production of monoclonal immunoglobulins with or without light chains is a major feature of the disease. Full spectrum of plasma cell dyscrasias include monoclonal gammapathy of undetermined significance, smouldering myeloma, indolent multiple myeloma, and fully developed, symptomatic multiple myeloma. The usual presenting features of MM include bone pain, weakness, fatigue, fever and infection. Neurologic symptoms are less common but one must not forget that MM may present with a neurologic disease. Careful neurologic history and examination are mandatory in patients with MM. Neurologic symptoms may be a direct manifestation of MM or may be due to the immune effect of monoclonal proteins directed against different neural structures. Finally, metabolic consequences (uremia, hypercalcemia, hyperviscosity) of MM may produce a broad spectrum of different neurologic symptoms including headache, blurring of vision, drowsiness, precoma, coma, vertigo, ataxia, hemiparesis and epileptiform seizures. The most common location of bone changes in MM is the thoracic spine, where it causes osteolytic changes with consequent compressive fractures. The most disastrous sequel is paraplegia. Multiple vertebral involvement with the evidence of osteolytic changes in other bones is usual, but solitary vertebral myeloma may occur. Myeloma usually involves the bone of the vertebral body and then spreads into the extradural space. However, patients with solitary extradural myeloma have been reported. Skull myeloma is frequently asymptomatic. It may grow externally or, rarely, there is intracranial expansion. Involvement of the cranial nerves is not rare, with II, V, VI, VII and VIII cranial nerves being most often affected. Isolated intracerebral plasmacytomas are extremely rare. Diagnostic approach includes plain X-rays of the skeleton, which was found to be the method of choice for demonstration of osteolytic changes, whereas magnetic resonance with gadolinium enhancement most reliably displays the degree of vertebral involvement and demonstrates any associated soft tissue mass. Current treatment of osteolytic changes in multiple myeloma include chemotherapy, radiotherapy in combination with dexamethasone, monthly infusions of bisphosphonates, surgical decompression, and kyphoplasty. Therapeutic approach is dictated by the presenting symptoms. In case of pain as the predominant symptom, treatment with chemotherapy and radiotherapy may be appropriate. Compressive symptoms are relieved with dexamethasone followed by radiotherapy and chemotherapy. Surgical decompression is used in patients with vertebral collapse and vertebral instability. Kyphoplasty is a new method used in the treatment of osteolytic changes of vertebral bodies. A viscous cement is injected into the cavity by a balloon-like inflatable bone tampon. It has been successfully employed to improve the quality of life, to reduce pain, and to increase overall functioning in patients with vertebral compression fractures by restoring most of the original height of the vertebral body. Bisphosphonates reduce pain associated with osteolytic changes in multiple myeloma, but also significantly reduce skeletal events (pathologic fracture, spinal cord compression, surgery or irradiation of bone) via unknown mechanism. It seems that bisphosphonates, by inhibiting bone resorption, alter the microenvironment in which the MM cells grow.     

Hodgkin s disease with nephrotic syndrome as a complication of ulcerative colitis: case report

We describe a case of a 32-year-old patient with ulcerative colitis complicated by Hodgkin s disease who presented with nephrotic syndrome. The patient had suffered from relapsing ulcerative colitis for 6 years before he developed Hodgkin s lymphoma. He was treated for Hodgkin s disease with 9 cycles of combined chemotherapy (COPP/ABV) and achieved the stabile remission of lymphoma, nephrotic syndrome, and ulcerative colitis. To the best of our knowledge, this is the first report on ulcerative colitis associated with Hodgkin s disease and nephrotic syndrome.     

Overexpression of G1-S cyclins and cyclin-dependent kinases during multistage human pancreatic duct cell carcinogenesis.

PURPOSE: Molecular analysis of pancreatic intraepithelial neoplasia lesions and ductal adenocarcinoma suggested a multistage paradigm for pancreatic duct cell carcinogenesis. This study investigated the molecular basis for the neoplastic duct cells in this pancreatic intraepithelial neoplasia-carcinoma sequence to acquire progressive enhancement of their proliferative potential. EXPERIMENTAL DESIGN: Using tissue microarray blocks containing 15 to 40 pancreatic intraepithelial neoplasia lesions and ductal adenocarcinoma of pancreas, we studied by immunohistochemistry the expression profiles of cyclins and cyclin dependent kinases (CDKs) that regulate the G1-S cell cycle checkpoints. The role of cyclins D3 and D1 in three pancreatic cancer cell lines was investigated using specific short interfering RNA technique. RESULTS: Cyclin D3 overexpression was noted the earliest in pancreatic intraepithelial neoplasia-1A and was prevalent in 90% to 100% of high-grade pancreatic intraepithelial neoplasias and ductal cancer. Cyclin A overexpression was also noted early and reached 50% to 100% of high-grade pancreatic intraepithelial neoplasias and cancer, but the percentage of abnormal duct cells showing overexpression of cyclin A was significantly lower than cyclin D3. Cyclin E overexpression occurred in 20% to 25% of high-grade pancreatic intraepithelial neoplasias and in 75% of ductal carcinoma. Cyclin D1 demonstrated the lowest frequency of overexpression that occurred late. CDK2 and CDK4 overexpression was also noted in early pancreatic intraepithelial neoplasias and progressively increased to reach 60% to 75% in carcinoma. The down-regulation of cyclin D3 mRNA and protein levels using specific short interfering RNA resulted in growth inhibition of pancreatic cancer cell lines. CONCLUSION: The results provide additional insight into the mechanism of G1-S cell cycle checkpoints deregulation during stepwise pancreatic duct cell carcinogenesis, and suggest a p16-independent role for cyclin D3 in deregulating the G1 cell cycle checkpoints during early stages of pancreatic duct cell carcinogenesis.     

Low dissemination rates,non-transparency of trial premature cessation and late registration in child mental health: observational study of registered interventional trials

The aim of this observational study was to explore trial premature cessation, non-publication and trial registration time in child mental health. Data were extracted for “closed” trials in Clinicaltrials.gov registry and European Union Clinical Trial Register (EUCTR) and corresponding publications of completed trials indexed in three data bases (PubMed, Scopus and Google Scholar). We restricted the extraction to the ‘Behaviours and Mental Disorders’ category and participants’ age of 0–17 years. Outcome measures were trial completion, results reporting within a year after the trial completion, publishing an article in a peer-reviewed journal within an average time to publish (729 days), and registration time. The number of EUCTR trials was relatively small (n?=?35) and with many inconsistencies. Out of 827 “closed” trials extracted from ClinicalTrials.gov, 69% were completed, 24.2% of prematurely ceased trials did not report reasons for early termination, 12.2% of the completed trials had results reported within a year, and 29.3% had an article published within 24 months after completion. Middle-sized (100–499 participants) and behavioural trials had higher chances of being successfully completed. Middle-sized and industry-funded trials were associated with results reporting. Chances for publishing an article were lower for industry-funded trials. Industry funding and drug interventions were related to timely registration. Large sample and non-industry funding were related to retrospective registration, which was recorded more often in recent years than before (we observed trials registered from 2002 until 2017). This study found low dissemination rates in the field of child mental health, with worrying under-reporting of premature termination causes. These findings indicate that more children are being subjected to unnecessary risk that comes with trial participation.