Alterations in inflammatory markers and clinical outcome after spontaneous intracerebral hemorrhage - Preliminary results.

OBJECTIVE: After an intracerebral hemorrhage, there is an immunological reaction, the specific mechanism of which is not fully understood, that seems to contribute to secondary brain injury. In this study, we investigated alterations of inflammatory markers in the blood and clinical outcome after an intracerebral hemorrhage. METHODS: Between July 2013 and February 2016, we performed a prospective study for which we recruited patients who had suffered an intracerebral hemorrhage. Using various scoring scales we evaluated the neurological state upon admission and discharge, and at one and three months following the ICH. During the hospital stay, various inflammatory markers were examined in blood samples. RESULTS: Out of 132 screened patients, 27 were included (48.2% male, mean age 68 years). We found significantly elevated serum concentrations of interleukin-6 (p=0.006) at the time of admission and throughout days three and five. There were also elevated c-reactive protein and granulocyte-colony stimulating factor concentrations found. The concentrations of these immune parameters showed significant monotonic relationships. The ROC analyses showed a better discrimination for mortality with regard to the percentage of T helper cells than with regard to the ICH volume alone. CONCLUSION: Our results may be regarded as preliminary evidence of the occurrence of inflammation after intracerebral hemorrhage. If there is a relationship between inflammation and clinical outcome remains speculative.

Cytotoxic effects of statins and thiazolidinediones on meningioma cells.

Statins are inhibitors of the cholesterol synthesis pathway with pleiotropic effects, while thiazolidinediones (TDZ) are peroxisomal proliferator activator receptor γ (PPAR-γ) agonists with potent proapoptotic activity. For both groups of substances a cytotoxic effect against several human tumors is presumed. Direct comparison of several statins and TDZ has not been performed on meningioma cells until now. We compared the antiproliferative/cytotoxic effect of five statins, two TDZ, and their combinations on various human meningioma cell lines and nontumorous cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, cell cycle analysis, and caspase-3 assay. Simvastatin (SMV) and its combination with the TDZ pioglitazone (PGZ) turned out to be the most effective treatment. After 96 h the 50% inhibition concentration (IC(50)) of SMV in MTT assays for two more sensitive meningioma cell lines (one benign and one malignant) was below 0.9 µM, while the IC(50) was 2.8 µM or higher for two other meningioma lines. Fluorescence-activated cell sorting (FACS) analysis suggested that MTT results mostly represented cytotoxic rather than antiproliferative effects. Strong caspase-3 induction suggested participation of intrinsic apoptosis in meningioma cell death. In contrast, SMV showed no substantial effects on fibroblasts and astrocytes. Addition of 40 µM PGZ significantly decreased the fraction of clonogenic cells in soft-agar assays, as compared with 2.8 µM SMV alone. Taken together, SMV showed a significant cytotoxic effect against human meningioma cells, which was moderately enhanced by PGZ.

The role of statins in neurosurgery.

Statins are drugs used to control cholesterol disorders and prevent cardiovascular diseases. Their denominated pleiotropic effects have demonstrated a broad action spectrum that might profit some neurological and neurosurgical diseases. These effects are correlated to dose and kind of statin. We accomplished a systematic review in PubMed and MEDLINE about studies of statins and main neurosurgical diseases. If statins are administered after subarachnoid hemorrhage, a significant lower incidence of vasospasm as well as delayed ischemic deficits and decreased mortality could be found; the results of a large multicenter trial are expected. In other complex diseases as intracerebral hemorrhage or traumatic brain injury, the evidence for positive effects of a treatment with statin increased. Additionally, promising experimental results indicate that high statin doses are able to promote cell death in tumor cells, especially in gliomas. Moreover, experimental and observational studies suggest the ability of statins to modulate the immune system, by that they can reduce incidence and severity of sepsis. The origin of these multiple effects from neuroprotection to tumoral apoptosis is not totally explained so far. Recent data in literature are discussed in this review. More trials in humans are urgently required to finally determine if statins could contribute to the current management of neurosurgical diseases.

Treatment of Spinal Myoclonus Due to Degenerative Compression Myelopathy with Cervical Spinal Cord Stimulation: A Report of 2 Cases.

BACKGROUND: Spinal myoclonus (SM) is a rare hyperkinetic movement disorder that is either idiopathic or secondary to spinal cord lesions. The treatment is either symptomatic only or addresses the underlying etiology. We describe 2 patients with SM with compression myelopathy who were treated with spinal cord stimulation (SCS). CASE DESCRIPTION: The first patient was a 39-year-old man with cervicobrachial pain owing to compression myelopathy at level C5-6 underwent fusion. A year later, he developed neurologic deficits including left-limb dominant tetraparesis and involuntary movements of the right leg. Despite ventral fusion at C5-7 due to progressive myelopathy, the involuntary movements extended to both left extremities. A paddle electrode was placed at level C5-6. SM disappeared immediately under stimulation, and the effect continued even after 24 months. The second patient, a 57-year-old man, underwent fusion at level C5-6 in 1998. Since then, he experienced a persistent tremor in his left hand. After 20 years, he developed cervicobrachial pain of the right upper limb with paresis. Compression myelopathy at segment C6-7 was treated with fusion plating. Six months later, pain returned in both upper limbs, and the tremor extended discretely to his right side. A paddle electrode for SCS was placed at level C7-Th1. SM disappeared immediately under stimulation, and the effect persisted after 10 months. Both patients reported sustained pain reduction. CONCLUSIONS: SCS might offer a more selective medicament-free therapy option for SM. The activation of intraspinal networks and replacement of supraspinal descending influences are mechanisms of SCS in this disorder.

Simultaneous Administration of Statins and Pioglitazone Limits Tumor Growth in a Rat Model of Malignant Glioma.

BACKGROUND/AIM: Statins are cholesterol reducers with considerable dose-dependent effect against glioma cells. The apoptotic effect could be increased by combining statins or by adding pioglitazone (PGZ). The last one is an anti-diabetic drug, an agonist of the peroxisome proliferator-activated receptor-gamma (PPARG). We used an animal model to test the effect of such combination in vivo and we investigated the changes on immunological processes. MATERIALS AND METHODS: Thirty-three rats (F344/DuCrl) were anesthetized and glioblastoma (F98) cells were implanted stereotactically. Animals were randomized into four groups: i) control (N=9); ii) intraperitoneal injection of PGZ 10 mg/kg/day (N=8); iii) oral administration of atorvastatin (ATVS) 40 mg/kg and lovastatin (LVS) 50 mg/kg (N=8); iv) oral administration of ATVS 40 mg/kg, LVS 50 mg/kg and PGZ 5 mg/kg (N=8). Treatment was started at 3rd postoperative day and continued for 14 days. The animals were followed-up for 30 days after start of therapy. Survival time, tumor volume, proliferation rate, counts of peripheral and tumor infiltrating leukocytes were compared. RESULTS: No difference of survival time or incidence of neurological deficits was observed. The combination of statins with PGZ led to a significant reduction in tumor volume by approximately 40% (p<0.05), statins combination was less effective and PGZ alone did not affect tumor volume. The groups treated with statins displayed significantly lower counts of peripheral CD3+, CD4+ and CD8+ T-cells and lower tumor associated CD68-positive cells (p<0.01, in respect to controls or PGZ alone). The proliferation rate was not statistically different. No relevant toxic effects were observed. DISCUSSION: Statins and PGZ are well-tolerated in rats and produced a significant tumor reduction, while an impact on neurological deficits or survival improvement could not be demonstrated. The reduction of infiltrating macrophages by using statins and PGZ should be further studied.

Survival in granular cell astrocytomas.

BACKGROUND: Granular cell astrocytomas (GCAs) are rarely encountered aggressive glial neoplasms. Treatment options comprise surgery, radiotherapy, and chemotherapy. Due to the small number of cases, a standard therapeutic regimen for GCA does not exist. MATERIAL AND METHODS: We report on the case of a 64-year-old woman with GCA subjected to tumor biopsy followed by radiochemotherapy with temozolomide. We provide clinical, histopathologic, and magnetic resonance imaging findings as well as a complete follow-up. To assess the relation of age, gender, time of publication, and different treatment options with survival we performed log-rank tests and calculated Cox regression models and hazard ratios in data from all available reports on GCA. RESULTS: A significant difference in survival rates in favor of adjuvant therapy (radiotherapy or radiochemotherapy) at 12 months was found. Age > 70 years at the time of diagnosis had a significantly unfavorable impact on survival at 12 months. Although not statistically significant, a tendency toward higher probability of survival at 12 months was found in cases reported after 2002. In surgically treated patients, we could not find a significant impact of extent of resection on survival. A significant impact of gender on survival was not found. CONCLUSION: Adjuvant therapy is significantly related to a higher probability of survival at 12 months and may therefore be recommended for patients with a GCA. Further analysis of these rare neoplasms is warranted.

Resveratrol decreases B-cell lymphoma-2 expression and viability in GH3 pituitary adenoma cells of the rat.

OBJECTIVE: Resveratrol is a phytoestrogen with various antiproliferative and proapoptotic effects. This in vitro study aimed to analyze the effect of resveratrol on the viability and expression of modulators of apoptosis in GH3 pituitary adenoma cells of the rat. METHODS: GH3 cells were incubated with resveratrol concentrations from 20 to 100 µM for 48-72 hours. Cell viability was quantified using a hemocytometer. We assessed the ability of resveratrol to kill GH3 cells by an enzyme-linked immunosorbent assay (ELISA) of nucleosome liberation and by DNA degradation (unidimensional gel electrophoresis). Relative messenger RNA (mRNA) expression of survivin, B-cell lymphoma-2 protein (BCL-2) and BCL-2-associated X protein (BAX) normalized to ß2 microglobulin was measured using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: GH3 cell survival significantly decreased with increasing concentrations of resveratrol. In GH3 cells treated with 100 µM resveratrol, ELISA demonstrated a significant rise of nucleosome liberation, which typically occurs during apoptosis. In parallel, gel electrophoresis showed degradation of DNA into random fragments, pointing to a necrotic mode of cell death in most GH3 cells. In GH3 cells treated with 100 µM resveratrol, qRT-PCR detected a significant decrease of BCL-2 mRNA expression and a decrease of survivin mRNA expression, whereas a change of BAX mRNA expression could not be found. The BAX/BCL-2 ratio was significantly increased in GH3 cells after resveratrol treatment. CONCLUSIONS: Resveratrol reduces GH3 cell viability in a dose-dependent manner by inducing nonapoptotic cell death and apoptosis. Apoptosis in GH3 cells is probably mediated by resveratrol-dependent downregulation of apoptosis inhibitors, namely BCL-2 and possibly survivin. Further investigation of the potential effects of resveratrol on pituitary adenoma cells is warranted.

Cytotoxic effect of different statins and thiazolidinediones on malignant glioma cells.

PURPOSE: Glioblastoma multiforme is still a tumor with very poor prognosis. Statins are actually used for the treatment of dyslipidemias and thiazolidinediones for improving insulin sensitivity in diabetes. Statins are inhibitors of the cholesterol pathway, while thiazolidinediones are peroxisomal proliferator activator receptor γ (PPAR) agonists. For both, a potent pro-apoptotic activity has been suggested. METHODS: We compared the antiglioma effect of simvastatin, atorvastatin, lovastatin, pravastatin, rosuvastatin, rosiglitazone, pioglitazone and their combinations at several concentrations on human glioblastoma cell lines U87, U 138, LN 405 and rat RG II. The cytotoxic effect was assessed using a cell proliferation assay after 48 and 144 h. Caspase 3 activity and the addition of isoprenoids and PPAR-y inhibitor GW9662 were assessed. Experiments were as well conducted under hypoxia for 24 h. RESULTS: We demonstrated a significant cytotoxic effect with a combination of statins plus pioglitazone. The effect was observed after 48 h and dramatically increased after 144 h. The combination of 2 types of statins (synthetic and natural) allowed a fivefold dose reduction. Statin effect was reversed with isoprenoids and partially with PPAR-γ antagonists, while thiazolidinediones effect was slightly affected by PPAR-γ antagonists. A marked increase in caspase 3 activity was achieved by combining atorvastatin with lovastatin. Cytotoxicity of the combination of statins and thiazolidinediones did not decrease under hypoxia. CONCLUSION: The assessed combination of statins with thiazolidinediones shows a synergistic cytotoxic effect against glioblastoma cells in vitro, which could represent a feasible therapeutic schema.

Experience with a new design of endoretractor for gasless laparoscopic cholecystectomy.

BACKGROUND: Cholecystectomy has replaced open surgery and is regarded as the standard procedure today. The pneumoperitoneum needed to create working space can induce cardiovascular changes. Gasless laparoscopic surgery is effective; we evaluate a new retractor design. METHODS: Patients older than 15 years with elective cholecystectomy and American Society of Anesthesiology I-II were consequently assigned to conventional or gasless surgery. We evaluated surgical time, hemodynamic stability, hours of hospital stay, and days of recuperation. RESULTS: We analyzed 22 cholecystectomies, 10 by the gasless technique and 12 by gas laparoscopy. We did not observe significant differences in surgical time, length of hospital stay, or days of recuperation. However, surgical exposition time was longer in the retractor group than was expected by chance (P<0.05). Hemodynamic stability was similar between the groups. CONCLUSIONS: Similar surgical and recuperation times and length of hospital stay were observed. Our design is comparable with conventional laparoscopic surgery despite longer surgical exposition time.

[Surgical site infection in non-traumatic surgery]. / Infección del sitio operatorio en cirugía abdominal no traumática.

BACKGROUND: Risk factors of surgical site infection (SSI) have been widely studied, such as abdominal surgery, surgical time >2 h, contaminated or dirty surgery, three or more diagnoses at discharge, and ASA classification >II. METHODS: A prospective risk factor study was carried out for SSI in patients who underwent non-traumatic abdominal surgery, comparing an institutional (Secretary of Health) and a private third-level hospital during the period from October 2001 to May 2002. RESULTS: We studied 527 patients with 21 cases (3.98%) of SSI and four deaths due to this cause, 0.75% of the total population and 19% of patients with SSI. The mean age was 47.5 +/- 19.1 years, and there were 195 (37%) males and 332 (63%) females. The incidence of SSI in the private hospital was 2.1% and in the institutional hospital 5%, without statistical significance (p = 0.09). Within the infected group we found 14 superficial infections, 5 deep infections, and 2 infections in the organ or surgical field. Variables included in the models of logistic regression were smoke, blood transfusion, trichotomy, and wound type. CONCLUSIONS: Observed infection incidence was within the expected range. In our study there were no differences between facilities, and SSI incidence is similar to what has previously been reported.

Infección del sitio operatorio en cirugía abdominal no traumática / Surgical site infection in non-traumatic surgery

BACKGROUND: Risk factors of surgical site infection (SSI) have been widely studied, such as abdominal surgery, surgical time >2 h, contaminated or dirty surgery, three or more diagnoses at discharge, and ASA classification >II. METHODS: A prospective risk factor study was carried out for SSI in patients who underwent non-traumatic abdominal surgery, comparing an institutional (Secretary of Health) and a private third-level hospital during the period from October 2001 to May 2002. RESULTS: We studied 527 patients with 21 cases (3.98%) of SSI and four deaths due to this cause, 0.75% of the total population and 19% of patients with SSI. The mean age was 47.5 +/- 19.1 years, and there were 195 (37%) males and 332 (63%) females. The incidence of SSI in the private hospital was 2.1% and in the institutional hospital 5%, without statistical significance (p = 0.09). Within the infected group we found 14 superficial infections, 5 deep infections, and 2 infections in the organ or surgical field. Variables included in the models of logistic regression were smoke, blood transfusion, trichotomy, and wound type. CONCLUSIONS: Observed infection incidence was within the expected range. In our study there were no differences between facilities, and SSI incidence is similar to what has previously been reported.