Cancer cell(s) cycle sequencing reveals universal mechanisms of apoptosis.

In this paper, cell cycle in higher eukaryotes and their molecular networks signals both in G1/S and G2/M transitions are replicated in silico. Biochemical kinetics, converted into a set of differential equations, and system control theory are employed to design multi-nested digital layers to simulate protein-to-protein activation and inhibition for cell cycle dynamics in the presence of damaged genomes. Sequencing and controlling the digital process of four micro-scale species networks (p53/Mdm2/DNA damage, p21mRNA/cyclin-CDK complex, CDK/CDC25/weel/SKP2/APC/CKI and apoptosis target genes system) not only allows the comprehension of the mechanisms of these molecule interactions but paves the way for unraveling the participants and their by-products, until now quite unclear, which have the task of carrying out (or not) cell death. Whatever the running simulations (e.g., different species signals, mutant cells and different DNA damage levels), the results of the proposed cell digital multi-layers give reason to believe in the existence of a universal apoptotic mechanism. As a consequence, we identified and selected cell check points, sizers, timers and specific target genes dynamic both for influencing mitotic process and avoiding cancer proliferation as much as for leading the cancer cell(s) to collapse into a steady stable apoptosis phase.

Temporal mediobasal tumors: a proposal for classification according to surgical anatomy.

OBJECTIVE: Development of a classification for temporal mediobasal tumors based on anatomical and neuroradiological aspects to help evaluate surgical accessibility and risk. METHODS: Preoperative magnetic resonance imaging, surgical approaches and outcomes of 235 patients with a temporal mediobasal tumor were analyzed retrospectively. Surgical landmarks were defined in accordance with operative anatomy. Previous classifications of these tumors were reviewed and a new classification system was developed. RESULTS: The new classification system recognises four types of temporal mediobasal tumor based on anatomical landmarks, location, and size. Type A comprises lesions confined to the uncus, hippocampus, parahippocampus, and/or amygdala. Type B comprises lesions in the area immediately lateral to the structures where type A tumors are located but sparing lateral gyri. Type C tumors are larger lesions, which occupy the area of type A and type B simultaneously. Type D tumors originate from the temporal mediobasal region and invade into the adjacent structures of the temporal stem, insular cortex, claustrum, putamen, or pallidum. The area occupied by a tumor in the axial plane was divided into anterior (a) and posterior (p) subregions. Progressive grading from A to D and from "a" to "p" was based on the view that larger and more posteriorly growing tumors were more difficult to remove. Lesions located in the anterior subregion (n = 173) were easier to remove by the transsylvian route (39%) or after partial anterior lobectomy (32%). For the posterior lesions (n = 62), a subtemporal approach was more appropriate (75%). CONCLUSIONS: Based on a series of 235 temporal mediobasal tumors, a classification system was designed to aid in decision making about operability, surgical risk, and approach.

Surgery for temporal mediobasal tumors: experience based on a series of 235 patients.

OBJECTIVE: To describe the clinical characteristics, diagnosis, various approaches, and outcomes in a retrospective review of a large series of temporomediobasal (TMB) tumors. METHODS: Charts from 235 patients with TMB tumors were identified from the glioma and epilepsy surgery database and from the electronic operations log. Preoperative magnetic resonance imaging scans were available for all patients and postoperative follow-up was available for 155 of these patients (mean follow-up period, 59 mo; range, 2-172 mo). Preoperative symptoms, approaches, technical problems, and surgical complications are described. RESULTS: Two hundred and thirty-five patients with intra-axial TMB tumors (mean age, 35 yr) were collected during an 11-year period. The largest tumor groups were astrocytomas (38.0%), gangliogliomas (29.8%), dysembryoplastic neuroepithelial tumor (11.1%), and glioblastomas (11.1%). The most frequent tumor location was the mesial Type A tumor (45.1%), with this type also showing the highest proportion of benign (World Health Organization Grades I and II) histological features (91.3%). Of all tumors, 76.2% were benign. Larger tumor size was associated with higher frequency of malignant histopathological findings. The leading symptom was epilepsy in 91% of patients, followed by drug-resistant epilepsy in 71.5%. Significant preoperative neurological deficits, such as hemiparesis or aphasia, were seen in 3.8% of the patients; another 12% had visual field deficits. Thirty-eight patients with low-grade tumors had undergone surgery previously. Several surgical approaches were chosen: transsylvian in 28%, anterior two-thirds temporal lobe resection in 23%, temporal pole resection in 15.3%, subtemporal in 19%, and transcortical in 6%. The most frequent neurological complications were transient: dysphasia (4.2%), hemiparesis (5%), and oculomotor disturbance (2.5%). Permanent nonvisual neurological complications occurred in fewer than 2% of the patients and significant new hemianopic defects were found in another 5.4% of the patients. The most severe complication was one intraoperative internal carotid artery lesion. One patient died. CONCLUSION: Small tumor size, magnetic resonance imaging, and microsurgery have made resection of mostly benign TMB tumors possible in a large number of patients. This series supports the conclusion that these tumors can be operated on with a relative degree of safety for the patient, provided that the anatomy of the mesial temporal lobe and the variety of approaches are well known to the surgeon. However, because of the complex anatomic structures in the vicinity, transient neurological deterioration is not infrequent and certain neurological disturbances (e.g., quadrantanopia) even seem to be unavoidable, whereas permanent significant deficits are rare.

Surgery for temporal mediobasal tumors: experience based on a series of 235 patients.

OBJECTIVE: To describe the clinical characteristics, diagnosis, various approaches, and outcomes in a retrospective review of a large series of temporomediobasal (TMB) tumors. METHODS: Charts from 235 patients with TMB tumors were identified from the glioma and epilepsy surgery database and from the electronic operations log. Preoperative magnetic resonance imaging scans were available for all patients and postoperative follow-up was available for 155 of these patients (mean follow-up period, 59 mo; range, 2-172 mo). Preoperative symptoms, approaches, technical problems, and surgical complications are described. RESULTS: Two hundred and thirty-five patients with intra-axial TMB tumors (mean age, 35 yr) were collected during an 11-year period. The largest tumor groups were astrocytomas (38.0%), gangliogliomas (29.8%), dysembryoplastic neuroepithelial tumor (11.1%), and glioblastomas (11.1%). The most frequent tumor location was the mesial Type A tumor (45.1%), with this type also showing the highest proportion of benign (World Health Organization Grades I and II) histological features (91.3%). Of all tumors, 76.2% were benign. Larger tumor size was associated with higher frequency of malignant histopathological findings. The leading symptom was epilepsy in 91% of patients, followed by drug-resistant epilepsy in 71.5%. Significant preoperative neurological deficits, such as hemiparesis or aphasia, were seen in 3.8% of the patients; another 12% had visual field deficits. Thirty-eight patients with low-grade tumors had undergone surgery previously. Several surgical approaches were chosen: transsylvian in 28%, anterior two-thirds temporal lobe resection in 23%, temporal pole resection in 15.3%, subtemporal in 19%, and transcortical in 6%. The most frequent neurological complications were transient: dysphasia (4.2%), hemiparesis (5%), and oculomotor disturbance (2.5%). Permanent nonvisual neurological complications occurred in fewer than 2% of the patients and significant new hemianopic defects were found in another 5.4% of the patients. The most severe complication was one intraoperative internal carotid artery lesion. One patient died. CONCLUSION: Small tumor size, magnetic resonance imaging, and microsurgery have made resection of mostly benign TMB tumors possible in a large number of patients. This series supports the conclusion that these tumors can be operated on with a relative degree of safety for the patient, provided that the anatomy of the mesial temporal lobe and the variety of approaches are well known to the surgeon. However, because of the complex anatomic structures in the vicinity, transient neurological deterioration is not infrequent and certain neurological disturbances (e.g., quadrantanopia) even seem to be unavoidable, whereas permanent significant deficits are rare.

Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system.

OBJECT: Important central nervous system (CNS) manifestations in patients with hereditary hemorrhagic telangiectasia (HHT) include arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Hereditary hemorrhagic telangiectasia is caused by germline mutations of two genes: ENG (HHT Type 1) and ACVRL1 (HHT Type 2). The ENG gene variations have been associated with the formation of intracranial aneurysms. The authors studied whether sequence variations in ACVRL1 or ENG are associated with the development of clinically sporadic arteriovenous dysplasias and aneurysms of the CNS. METHODS: The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis. One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers. The authors identified a statistically significant association between the IVS3 -35A/T polymorphism in intron 3 of the ACVRL1 gene and the development of AVMs and DAVFs (p = 0.004; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.19-2.51; after adjustments for age and sex), but not aneurysms (crude OR 0.82; 95% CI 0.55-1.18). CONCLUSIONS: The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.

The regional oxygen saturation of pituitary adenomas is lower than that of the pituitary gland: microspectrophotometric study with potential clinical implications.

OBJECTIVE: To study the regional oxygen saturation (rSO(2)) of pituitary adenomas, in comparison with that of the pituitary gland. METHODS: Microspectrophotometric (MSP) measurements of rSO(2) in adenomas and pituitary tissue were performed for a series of patients undergoing first-time transsphenoidal pituitary adenoma surgery, in a standardized anesthesia setting. The areas of measured tissue were sampled for histopathological and immunohistochemical (CD34 and CD45) assessments. The results of MSP measurements were compared with the results of the histopathological and immunohistochemical assessments. RESULTS: Thirty-six MSP measurements and tissue samples were obtained among 22 patients with pituitary macroadenomas, including 14 from adenoma tissue, 17 from the anterior pituitary lobe, and 5 from the posterior pituitary lobe. The rSO(2) of adenoma tissue (mean +/- standard deviation, 43.3 +/- 23.2%) was statistically significantly (P = 0.001) lower than the values for the anterior pituitary lobe (mean +/- standard deviation, 71.8 +/- 18.3%) and posterior pituitary lobe (mean +/- standard deviation, 74.9 +/- 4.8%). The difference between the rSO(2) values for the anterior pituitary lobe and posterior pituitary lobe was not significant. There were no statistically significant differences in microvessel density (as assessed with CD34 staining) or lymphocyte density (as assessed with CD45 staining) among the three tissue types. CONCLUSION: As assessed with MSP measurements, the rSO(2) of adenoma tissue was significantly lower than that of the pituitary gland, indicating differences in their blood supply and/or metabolism in pituitary macroadenomas. Further studies are needed to determine whether MSP measurements can reliably facilitate intraoperative delineation of adenoma and pituitary tissue, in the effort to achieve complete tumor removal with minimal injury to pituitary tissue.

Cellular pathology of amygdala neurons in human temporal lobe epilepsy.

The amygdala complex substantially contributes to the generation and propagation of focal seizures in patients suffering from temporal lobe epilepsy (TLE). A cellular substrate for increased excitability in the human amygdala, however, remains to be identified. Here, we analyzed the three-dimensional morphology of 264 neurons from different subregions of the amygdaloid complex obtained from 17 "en bloc" resected surgical specimens using intracellular Lucifer Yellow (LY) injection and confocal laser scanning microscopy. Autopsy samples from unaffected individuals ( n=3, 20 neurons) served as controls. We have identified spine-laden, spine-sparse and aspinous cells in the lateral, basal, accessory basal and granular nuclei. Semiquantitative analysis points to significant changes in neuronal soma size, number of dendrites and spine densities in specimens from epilepsy patients compared to controls. Neuronal somata in the epilepsy group were smaller compared to controls ( P<0.01), neurons had fewer first-order dendrites ( P<0.01), whereas the maximum density of spines per dendritic segment in these cells was increased in TLE patients ( P<0.01). There were also dendritic alterations such as focal constrictions or spine bifurcations. These changes were consistent between amygdaloid subregions. The dendritic morphology of amygdaloid neurons in TLE patients points to substantial changes in synaptic connectivity and would be compatible with altered neuronal circuitries operating in the epileptic human amygdala. Although the morphological alterations differ from those described in hippocampal subregions of a similar cohort of TLE patients, they appear to reflect a characteristic pathological substrate associated with seizure activity/propagation within the amygdaloid complex.

Degenerative lumbar spondylolisthesis-induced radicular compression: nonfusion-related decompression in selected patients without hypermobility on flexion-extension radiographs.

OBJECT: The authors conducted a study to determine the results of decompressive surgery without fusion in selected patients who presented with radicular compression syndromes caused by degenerative lumbar spondylolisthesis and in whom there was no evidence of hypermobility on flexion-extension radiographs. METHODS: The medical records and radiographs obtained in 49 patients were reviewed retrospectively. Clinical status was quantified by summing self-assessed Prolo Scale scores. All 49 patients (55% female, mean age 68.7 years) presented with leg pain accompanied by lumbalgia in 85.7% of the cases. Preoperatively the median sum of Prolo Scale scores was 4. The mean preoperative degree of forward vertebral displacement was 13.5% and was located at L-4 in 67% of the cases. Osseous decompression alone was performed in 53%, and an additional discectomy at the level of displacement was undertaken in the remaining patients because of herniated discs. Major complications (deep wound infection) occurred in 2%. During a mean follow-up period of 3.73 years, 10.2% of the patients underwent instrumentation-assisted lumbar fusion when decompression alone failed to resolve symptoms. At last follow up the median overall Prolo Scale score was 8. Excellent and good results were demonstrated in 73.5% of the patients. Prolonged back pain (r = 0.381) as well as the preoperative degree of displacement (r = 0.81) and disc space height (r = 0.424) influenced outcome (p < or = 0.05); additional discectomy for simultaneous disc herniation at the displaced level did not influence outcome (p > 0.05). CONCLUSIONS: These results appear to support a less invasive approach in this subgroup of elderly patients with degenerative lumbar spondylolisthesis-induced radicular compression syndromes and without radiographically documented hypermobility. Additional discectomy for simultaneous disc herniation of the spondylolisthetic level did not adversely influence the outcome. Complication rates are minimized and fusion can eventually be performed should decompression alone fail. A prospective controlled study is required to confirm these results.

Multiple subpial transections: outcome and complications in 20 patients who did not undergo resection.

OBJECT: The authors describe patient characteristics, surgical methods, complications, and outcome over time in a cohort of patients who underwent multiple subpial transection (MST) without concomitant cortical resection. METHODS: Twenty consecutive patients in whom drug-resistant epilepsy had been diagnosed a mean of 16 +/- 9 years earlier (mean +/- standard deviation [SD]) were treated with MST without cortical resection. The mean follow-up period was 49.3 +/- 18.3 months (mean +/- SD, median 58 months). At 12 months of follow up, two of the 20 patients were Engel Class I, one was Class II, six were Class III, and 11 were Class IV. At latest follow up, one patient was Engel Class I, one was Class II, seven were Class III, and 11 were Class IV. According to an alternative five-tiered classification system, two outcomes were excellent, seven were good, one was fair, nine were poor, and one was worse. Outcome was found to be better in patients with no lesions observed on magnetic resonance (MR) imaging, and worse in those with large MST areas. Outcome had a tendency to change (this occurred in 13 of 20 cases). Five patients (25%) improved and seven (35%) deteriorated in Engel outcome class, and in one (5%) both developments occurred over time. Most outcome class changes occurred before the end of the 2nd year (nine), and four were observed in the 5th year. There where seven transient neurological deficits and four surgical complications. There was no permanent significant morbidity, and there were no deaths. CONCLUSIONS: Forty-five percent of patients achieved a worthwhile improvement after pure MST, if Engel outcome Class III is deemed a worthwhile improvement. The alternative five-tiered classification resulted in 50% with worthwhile improvement (excellent, good, or fair outcome), 45% with poor, and 5% with worse outcome. Lesions that are detectable on MR imaging, and large MST areas are predictive of worse results. Significant intraoperative problems may arise, but this happens infrequently. There is a notable rate of transient morbidity but the rate of permanent morbidity is not significant.

Quimioluminiscencia: una interesante alternativapara la detección analítica en sistemas de flujo / Unfamiliar though exciting analytical detection in flowing streams: chemiluminescence

El estudio del tipo de interacción involucrada en la formación de dispersiones sólidas de tolbutamida con distintas proporciones de acetamida y propianamida, ha requerido del diseño y validación de un método analítico por cromatografía líquida de alta eficacia (CLAE) que permita cuantificar la proporción de los transportadores en mezclas físicas y en dispersión sólida. El método resultó ser lineal, preciso y exacto en el intervalo de concentración de 100-1,56 µg/mL para tolbutamida y 50-0,781 µg/mL para acetamida y propianamida (AU)

Spectrophotometric and second-derivative spectrophotometric determination of mercury in organomercurials by means of benzyl 2-pyridyl ketone 2-quinolylhydrazone.

Mercury(II) reacts with benzyl 2-pyridylketone 2-quinolylhydrazone (BPKQH) in the pH range 9.0-10.4, to form a stable 1:2 (metal:ligand) complex which has a sharp absorption maximum at 475 nm and molar absorptivity 5.01 x 10(4) 1.mole(-1).cm(-1). It is proposed for use in spectrophotometric determination of mercury at microg/ml levels and analysis for organomercurials. The sensitivity of the method can be increased significantly by employing derivative spectrophotometry, making mercury determination at ng ml levels feasible.