Metabolic management of microenvironment acidity in glioblastoma.

Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.

Ultrastructure of the Mitochondria-Associated Membranes in Human Tumor Specimens.

Conventional transmission electron microscopy is an essential tool to understand the structure-function relationships and play a vital role in biological research. Mitochondria-associated membranes are linked with cancer processes in a fundamental manner. A conventional transmission electron microscopy method for preparing specimens in clinical and research settings for the study-analysis of the mitochondria-associated membranes in human tumors is presented. The sample processing includes chemical fixation by immersion, dehydration, embedding, polymerization, sectioning, and staining.

On the Origin of ATP Synthesis in Cancer.

ATP is required for mammalian cells to remain viable and to perform genetically programmed functions. Maintenance of the ΔG'ATP hydrolysis of -56 kJ/mole is the endpoint of both genetic and metabolic processes required for life. Various anomalies in mitochondrial structure and function prevent maximal ATP synthesis through OxPhos in cancer cells. Little ATP synthesis would occur through glycolysis in cancer cells that express the dimeric form of pyruvate kinase M2. Mitochondrial substrate level phosphorylation (mSLP) in the glutamine-driven glutaminolysis pathway, substantiated by the succinate-CoA ligase reaction in the TCA cycle, can partially compensate for reduced ATP synthesis through both OxPhos and glycolysis. A protracted insufficiency of OxPhos coupled with elevated glycolysis and an auxiliary, fully operational mSLP, would cause a cell to enter its default state of unbridled proliferation with consequent dedifferentiation and apoptotic resistance, i.e., cancer. The simultaneous restriction of glucose and glutamine offers a therapeutic strategy for managing cancer.

Changes in the severity of gastric mucosal inflammation associated with Helicobacter pylori in humans coinfected with intestinal helminths.

BACKGROUND: Though a few studies in animal models suggest that intestinal helminths (IH) favorably affect evolution of gastritis associated with Helicobacter pylori (H. pylori) the studies supporting this concept in humans are only a few and are based on serological data. METHODS: To evaluate the possible influence of IH on the human gastric mucosa, three groups of Venezuelan adults with gastropathy (endoscopically diagnosed) were studied: H. pylori-/IH- (n = 17), H. pylori+/IH- (n = 18), and H. pylori+/IH+ (n = 11). Histological analysis (hematoxylin-eosin) and immunohistochemical staining (peroxidase) for cytokines interleukin-1beta (IL-1ß), tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin 4 (IL-4) were undertaken in gastric antral biopsies. RESULTS: Expression of the four cytokines was detected in all individuals in varying degrees, but proinflammatory cytokines were expressed in a higher degree in the H. pylori+/IH- group, mainly IL-1ß (Th1-dominant immune response), associated with a higher degree of both histological inflammation and gastric cancer risk index (GCRI), as compared to the H. pylori-/IH- group. In contrast, an increased expression of IL-4 and a reduced expression of proinflammatory cytokines (Th2-dominant response), plus the tendency to a lower degree of mononuclear infiltration, mucosal atrophy in gastric corpus, and GCRI, were evidenced in the coinfected group. CONCLUSIONS: The findings of the present study is perhaps the first histological evidence of a possible modulatory effect of IH on the gastric mucosal inflammatory response due to H. pylori infection in humans.

Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma.

Glioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effective therapy for decades. Although glucose and glutamine are the major fuels that drive GBM growth and invasion, few studies have targeted these fuels for therapeutic management. The glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with a calorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while the KD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentable ketone bodies. The diet/drug therapeutic strategy killed tumour cells while reversing disease symptoms, and improving overall mouse survival. The therapeutic strategy also reduces edema, hemorrhage, and inflammation. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower dosage to achieve therapeutic effect. The findings support the importance of glucose and glutamine in driving GBM growth and provide a therapeutic strategy for non-toxic metabolic management.

Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?

No major advances have been made in improving overall survival for glioblastoma (GBM) in almost 100 years. The current standard of care (SOC) for GBM involves immediate surgical resection followed by radiotherapy with concomitant temozolomide chemotherapy. Corticosteroid (dexamethasone) is often prescribed to GBM patients to reduce tumor edema and inflammation. The SOC disrupts the glutamate-glutamine cycle thus increasing availability of glucose and glutamine in the tumor microenvironment. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive GBM growth through substrate level phosphorylation in the cytoplasm and the mitochondria, respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability while elevating ketone bodies that are neuroprotective and non-fermentable. Information is presented from preclinical and case report studies showing how KMT could target tumor cells without causing neurochemical damage thus improving progression free and overall survival for patients with GBM.

Ultrastructural characterization of the Mitochondria-associated membranes abnormalities in human astrocytomas: Functional and therapeutics implications.

Mitochondria-associated membranes (MAMs) are currently considered an intracellular organelle "hot spot" for the intracellular signaling. MAMs are thought to function in cellular energy homeostasis, apoptosis, and calcium signaling. MAM ultrastructure in surgical specimens from human astrocytic neoplasms was studied. Abnormalities in respect to density, length, and width were found. Poorly differentiated glioma like-stem cells deficient in MAM and well-differentiated glioma cells abundant in MAM were observed. This finding could be the structural basis of functional role of MAM linked to some metabolic abnormalities in astrocytic tumors associated to mitochondrial dysfunction and the Warburg effect and their therapeutics implications.

Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy.

The Big Potassium (BK) ion channel is commonly known by a variety of names (Maxi-K, KCNMA1, slo, stretch-activated potassium channel, KCa1.1). Each name reflects a different physical property displayed by this single ion channel. This transmembrane channel is found on nearly every cell type of the body and has its own distinctive roles for that tissue type. The BKα channel contains the pore that releases potassium ions from intracellular stores. This ion channel is found on the cell membrane, endoplasmic reticulum, Golgi and mitochondria. Complex splicing pathways produce different isoforms. The BKα channels can be phosphorylated, palmitoylated and myristylated. BK is composed of a homo-tetramer that interacts with ß and γ chains. These accessory proteins provide a further modulating effect on the functions of BKα channels. BK channels play important roles in cell division and migration. In this review, we will focus on the biology of the BK channel, especially its role, and its immune response towards cancer. Recent proteomic studies have linked BK channels with various proteins. Some of these interactions offer further insight into the role that BK channels have with cancers, especially with brain tumors. This review shows that BK channels have a complex interplay with intracellular components of cancer cells and still have plenty of secrets to be discovered.

Mitochondrial network in glioma's invadopodia displays an activated state both in situ and in vitro: potential functional implications.

Gliomas are typically characterized by their infiltrative nature, and the prognosis can be linked to the invasive nature of the tumoral cells. Glioblastoma multiforme are very invasive cancers and this contributes to their lethality. The invadopodia are considered essential for their motility. Human glioma cell invadopodia were examined with transmission electron and immunofluorescent microscopy. By electron microscopy, in situ gliomas (fibrillary astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, pilocytic astrocytoma) show mitochondria with a dense matrix condensed configuration, indicating an active state. The mitochondria were frequently in close contact with an extended smooth endoplasmic reticulum displaying an endoplasmic reticulum subfraction associated with mitochondria. Mitochondria were seen within the filopodia that were penetrating into the extracellular matrix. The activated mitochondria and smooth endoplasmic reticulum were also detected within the invadopdia, which was associated microblood vessels. Fluorescent microscopy confirmed that D54 and U251 glioma cells growing in vitro also contained filopodia with mitochondria. The U251 glioma cells' filopodia that penetrated through 1.2-µm pores of transwell chambers also contained mitocondria, suggesting that the mitochondria are actively involved in the invasion process. Migration and invasion of tumor cells requires an increase in cellular motility and involves formation of lamellipodia, protrusions of the plasma membrane, and individual filopodia [ 1 ]. Gliomas are typically characterized by their infiltrative nature, resulting in a poorly demarcated interface between tumor and normal brain tissue. Their poor prognosis can be linked to the invasive nature of these cells. The motility of these tumor cells is correlated with the presence of invadopodia [ 2 ], and, consequently, more insight is necessary into their structural and molecular aspects. Evidence of robust invadopodia activity in glioblastoma multiforme cells has been reported [ 3 , 4 ]. Because of the significant impact of invadopodia in oncological events such as cell invasion and matrix degradation, more insight into structural and molecular aspects is needed [ 2 ]. The dynamic assembly of invadopodia is still not well understood [ 2 ], and little is known of the alterations in mitochondrial structure and function that contribute to cell mobility [ 5 ]. This paper describes two prominent structural features of the mitochondrial network present within the glioma´s invadopodia that we have recently observed. We believe these two features (activated mitochondria and smooth ER, along with mitochondria contained within the filopodia) might provide researchers with possible targets for future therapies that can control glioma invasiveness.

Comparison of three methods based on endoscopic gastric biopsies for diagnosis of Helicobacter pylori active infection in a clinical setting.

CONTEXT: The correct diagnosis and effective treatment of Helicobacter pylori gastric infection are essential in controlling this infection. OBJECTIVE: To compare the diagnostic value of three tests based in endoscopic gastric biopsies histopathological evaluation with hematoxylin-eosin (H-E) staining, urease rapid test and microbiological culture for detecting Helicobacter pylori active infection, in order to make recommendations for daily clinical practice. METHODS: Gastric biopsies from 115 adult patients (85 female/30 male) were obtained by upper gastrointestinal endoscopy and studied by histopathological evaluation with H-E (antrum-corpus), urease test in 2 hours (antrum) and microbiological culture (antrum). RESULTS: Helicobacter pylori active infection was diagnosed in 67% of patients. Helicobacter pylori active infection was detected by histopathological evaluation with H-E, urease test and microbiological culture in 87%, 79% and 70% of the positive cases, respectively. There were significant differences when histopathological evaluation with H-E and urease test rapid test when compared with microbiological test (P<0.01). There was no significant difference between histopathological evaluation with H-E and urease test (P = 0.7). The kappa index of agreement for histopathological evaluation with H-E/urease test was 0.56, histopathological evaluation with H-E/microbiological culture 0.6, and urease test/microbiological culture 0.64. CONCLUSIONS: In a hospital setting like the one studied, histopathological evaluation with H-E and urease test are the most recommended tests for diagnosis of Helicobacter pylori active infection based in endoscopic biopsies. If pathological information of gastric lesions will be required, histopathological evaluation with H-E is essential. Urease test is mandatory if a prompt diagnosis is necessary. Microbiological culture can be used in cases of persistent or complicated infection, which may require studies on Helicobacter virulence or antimicrobial susceptibility. Selected cases might demand a combination of several tests. The three tests exhibit a good concordance level for Helicobacter pylori active infection diagnosis.

Comparison of three methods based on endoscopic gastric biopsies for diagnosis of Helicobacter pylori active infection in a clinical setting / Comparação de três métodos baseados em biopsias gástricas endoscópicas para o diagnóstico da infecção ativa pelo Helicobacter pylori em um ambiente clínico

CONTEXT: The correct diagnosis and effective treatment of Helicobacter pylori gastric infection are essential in controlling this infection. OBJECTIVE: To compare the diagnostic value of three tests based in endoscopic gastric biopsies histopathological evaluation with hematoxylin-eosin (H-E) staining, urease rapid test and microbiological culture for detecting Helicobacter pylori active infection, in order to make recommendations for daily clinical practice. METHODS: Gastric biopsies from 115 adult patients (85 female/30 male) were obtained by upper gastrointestinal endoscopy and studied by histopathological evaluation with H-E (antrum-corpus), urease test in 2 hours (antrum) and microbiological culture (antrum). RESULTS: Helicobacter pylori active infection was diagnosed in 67 percent of patients. Helicobacter pylori active infection was detected by histopathological evaluation with H-E, urease test and microbiological culture in 87 percent, 79 percent and 70 percent of the positive cases, respectively. There were significant differences when histopathological evaluation with H-E and urease test rapid test when compared with microbiological test (P<0.01). There was no significant difference between histopathological evaluation with H-E and urease test (P = 0.7). The kappa index of agreement for histopathological evaluation with H-E/urease test was 0.56, histopathological evaluation with H-E/microbiological culture 0.6, and urease test/microbiological culture 0.64. CONCLUSIONS: In a hospital setting like the one studied, histopathological evaluation with H-E and urease test are the most recommended tests for diagnosis of Helicobacter pylori active infection based in endoscopic biopsies. If pathological information of gastric lesions will be required, histopathological evaluation with H-E is essential. Urease test is mandatory if a prompt diagnosis is necessary. Microbiological culture can be used in cases of persistent or complicated infection, which may require studies on Helicobacter virulence or antimicrobial susceptibility. Selected cases might demand a combination of several tests. The three tests exhibit a good concordance level for Helicobacter pylori active infection diagnosis.

CONTEXTO: O diagnóstico correto e o tratamento eficaz da infecção pelo Helicobacter pylori são essenciais no controle desta infecção. OBJETIVO: Comparar o valor de três testes de diagnóstico baseado em biopsias gástricas endoscópicas: avaliação histopatológica com hematoxilina-eosina (H-E), teste da urease e cultura microbiológica para a detecção da infecção ativa pelo H. pylori, com a finalidade de recomendações para a clínica diária prática. MÉTODOS: Biopsias gástricas de 115 pacientes (85 mulheres e 30 homens) foram obtidas por endoscopia digestiva alta e estudadas por avaliação histopatológica com H-E (antro-corpo), teste de urease em 2 horas (antro) e cultura microbiológica (antro). RESULTADOS: Infecção ativa pelo H. pylori foi diagnosticada em 67 por cento dos pacientes e detectada pela avaliação histopatológica com H-E, pelo teste de urease e pela cultura microbiológica em 87 por cento, 79 por cento e 70 por cento dos casos positivos, respectivamente. Houve diferenças significativas quando a avaliação histopatológica com H-E e o teste rápido de urease quando comparadas com a cultura microbiológica (P<0,01). Não houve diferença significativa entre a avaliação histopatológica com H-E e o teste de urease (P = 0,7). O índice kappa para avaliação histopatológica com H-E/teste de urease foi de 0,56, avaliação histopatológica com H-E/cultura microbiológica 0,6, e teste de urease/cultura microbiológica 0,64. CONCLUSÕES: Em condições similares ao estudado, avaliação histopatológica com H-E e teste de urease são os testes mais recomendados para o diagnóstico de infecção ativa pelo H. pylori com base em biopsias endoscópicas. A avaliação histopatológica com H-E é essencial quando exigido o estudo de lesões gástricas. O teste de urease é obrigatório no caso de diagnóstico precoce rápido. A cultura microbiológica pode ser usada em casos de infecção persistente ou complicada, que podem exigir estudos sobre a virulência ou susceptibilidade do Helicobacter aos antimicrobianos. Os casos selecionados podem exigir a combinação de vários testes. Os três testes apresentam bom nível de concordância para o diagnóstico da infecção ativa pelo H. pylori.

[Histopathological study of the presence of Helicobacter pylori-type bacteria in surgical specimens from patients with chronic cholecystitis]. / Estudio histopatológico de la presencia de bacterias tipo Helicobacter pylori en especímenes quirúrgicos con colecistitis crónica.

INTRODUCTION: Helicobacter species have recently been found to be associated with some diseases of the biliary tree but this relationship remains unclear and further studies are required. The aim of this study was to determine the presence of H. pylori-type bacteria in patients with a diagnosis of chronic cholecystitis through histopathological study of surgical gallbladder specimens. MATERIALS AND METHODS: Surgical gallbladder specimens from patients with a diagnosis of chronic cholecystitis were examined histopathologically. The macroscopic characteristics of the specimens were identified. Histopathological slices were stained with hematoxylin-eosin and Giemsa. RESULTS: Of the 68 patients who underwent cholecystectomy, 56 (81%) were women and 12 (19%) were men. The mean age was 39.56+11.94 years. H. pylori-type bacteria were found in 6%. CONCLUSIONS: The results of this study do not allow us to conclude that the presence of H. pylori-type bacteria is a major factor in the etiology and/or pathogenesis of chronic cholecystitis. In patients with chronic cholecystitis undergoing cholecystectomy included in the present study, the etiology of the disease may be more closely linked with the presence of gallstones.

Electron microscopy morphology of the mitochondrial network in gliomas and their vascular microenvironment.

Gliomas still represent a serious and discouraging brain tumor; despite of the diversity of therapeutic modalities, the prognosis for patients is still poor. Understanding the structural and functional characteristics of the vascular microenvironment in gliomas is essential for the design of future therapeutic strategies. This review describes and analyzes the electron microscopy morphology of the mitochondrial network in human gliomas and their vascular microenvironment. Heterogenous mitochondrial network alterations in glioma cells and in microvascular environment are implicated directly and indirectly in the processes linked to hypoxia-tolerant and hypoxia-sensitive cells phenotype, effects of the hypoxia-inducible factor-1α, increased expression of several glycolytic protein isoforms as well as fatty acid synthase, and survivin. The prevalent existence of partial and total cristolysis observed suggests that oxidative phosphorylation is severely compromised. A mixed therapy emerged as the most appropriate.

Correlación clínico-patológica en casos fatales de dengue en Maracaibo, Venezuela / Clinical and pathological correlation in fatal dengue cases found in Maracaibo, Venezuela

INTRODUCCIÓN: dada la importancia del dengue en América, es elemental conocer la causa de muerte de los infectados y evaluar los escasos estudios de necropsias. OBJETIVO: describir y analizar los hallazgos anatomopatológicos relevantes en casos fatales de dengue en un área endémica venezolana. MÉTODOS: se estudiaron 8 casos mortales con criterios clínico-epidemiológicos de dengue o comprobados mediante pruebas serológicas (o ambos), sometidos a necropsia clínica completa. Los tejidos se procesaron con técnicas histopatológicas habituales. RESULTADOS: todos los casos evidenciaron enfermedad pulmonar severa (daño alveolar difuso, edema pulmonar no cardiogénico, tromboembolismo, bronconeumonía, neumonitis, hemorragia intraalveolar); 6 mostraron derrame en cavidad pleural o abdominal, o en ambas. Necrosis hepática focal se presentó en 2 casos. La causa de muerte se relacionó con insuficiencia respiratoria en 6 casos secundaria a enfermedad pulmonar, 2 con choque hipovolémico y 1 desarrolló insuficiencia hepática. CONCLUSIONES: los casos mortales por dengue estudiados evidenciaron compromiso pulmonar severo relacionado con la muerte, a diferencia de lo reportado en otros estudios de necropsias en América. También desarrollaron afectación multiorgánica, que en la mayoría de los casos condujo a la muerte no vinculada directamente a choque hipovolémico. Estos hallazgos de necropsias permitirían proyectar estrategias terapéuticas en pro de evitar la mortalidad.

INTRODUCTION: given the importance of dengue in America, it is indispensable to know the cause of death of the infected people and to evaluate the few necropsy studies available. OBJECTIVE: to describe and to analyze the relevant clinical and pathological findings in fatal dengue cases of dengue in a Venezuelan endemic area. METHODS: eight fatal cases, according to clinical and epidemiological dengue criteria and/or confirmed by complete serological tests were studied after complete clinical necropsy. The tissues were processed by standard histopathological techniques. RESULTS: all these cases showed severe lung disease (diffuse alveolar damage, non cardiogenic pulmonary edema, thromboembolism, bronchopneumonia, pneumonitis, intralveolar hemorrhage). Six presented with pleural or abdominal effusion. Focal hepatic necrosis was found in two cases. The cause of death was related to respiratory failure in six cases secondary to lung disease; two with hypovolemic shock, and one developed liver failure. CONCLUSIONS: the studied dengue cases showed fatal severe pulmonary compromise leading to death, unlike those reported in other studies of autopsies in The Americas. They also developed multiple organ failure, which in most cases led to death not directly associated to hypovolemic shock. These findings in autopsies will allow designing therapeutic strategies to avoid mortality.

[Clinical and pathological correlation in fatal dengue cases found in Maracaibo, Venezuela]. / Correlación clínico-patológica en casos fatales de dengue en Maracaibo, Venezuela.

INTRODUCTION: Given the importance of dengue in America, it is indispensable to know the cause of death of the infected people and to evaluate the few necropsy studies available. OBJECTIVE: To describe and to analyze the relevant clinical and pathological findings in fatal dengue cases of dengue in a Venezuelan endemic area. METHODS: Eight fatal cases, according to clinical and epidemiological dengue criteria and/or confirmed by complete serological tests were studied after complete clinical necropsy. The tissues were processed by standard histopathological techniques. RESULTS: All these cases showed severe lung disease (diffuse alveolar damage, non cardiogenic pulmonary edema, thromboembolism, bronchopneumonia, pneumonitis, intralveolar hemorrhage). Six presented with pleural or abdominal effusion. Focal hepatic necrosis was found in two cases. The cause of death was related to respiratory failure in six (6) cases secondary to lung disease; two with hypovolemic shock, and one developed liver failure. CONCLUSION: the studied dengue cases showed fatal severe pulmonary compromise leading to death, unlike those reported in other studies of autopsies in The Americas. They also developed multiple organ failure, which in most cases led to death not directly associated to hypovolemic shock. These findings in autopsies will allow designing therapeutic strategies to avoid mortality.

Ultrastructural cutaneous microvascular pathology of young adults aged up to 50 years with chronic kidney disease and vascular cognitive impairment.

BACKGROUND: Studies suggest a link between chronic kidney disease and cognitive impairment. Skin biopsy is hire in the study of leucoaraiosis since permit establish the responsible vascular pathology of subcortical white matter changes because the pathological hallmark is systemic. The aim was to study the ultrastructural changes of cutaneous small vessel of patients aged up to 50 years with chronic kidney disease (CKD) and vascular cognitive impairment (VCI). METHODS: Clinical, laboratorial, cerebral imaging, neuropsycological evaluation for executive functions (Clox test), and skin biopsy to 4 patients aged up to 50 years with CKD and VCI were done. Skin biopsy was prepared for conventional transmission electron microscopy study. RESULTS: Clinical diagnosis included hypertension, diabetes, and CKD in all cases. All cases developed VCI in a relatively short period. Small vessels study revealed small vessel disease type-degenerative microangiopathy. The principal findings were increase of wall-lumen ratio, thickened basal membrane, and collagen fibers proliferation. CONCLUSIONS: Cutaneous degenerative microangiopathy is matched with cerebral microvascular pathology and could be important for the development of cognitive impairment in young adults with CKD. The characterization of microvascular pathology in skin biopsies, in this type of patients, could contribute to the knowledge of some pathophysiological and therapeutical topics and possibly be useful in clinical setting. Added patients are needed to establish a complete characterization of microangiopathy.

Ultrastructural characterization of macrophage-like mononuclear leukocytes in human astrocytic tumors.

The aim of this study was to describe the ultrastructural features of macrophage-like mononuclear leukocytes associated with human astrocytic tumors. Tumoral biopsies of 10 patients with a pathological diagnosis of astrocytic tumor by means of transmission electron microscopy were examined. The macrophage-like mononuclear leukocyte shows ultrastructural characteristics related with the physiologic phenotype of the alternatively activated macrophage (M2), localized principally around of tumoral vasculature and tumor milieu; classically activated macrophages (M1) in surrounding necrosis areas were observed. The presence of these two ultrastructural kinds of macrophage-like mononuclear leukocytes into different areas of the tumor denotes that cellular response of TAMs is dependent of microenvironment stimuli in different parts of a tumor. The process of transvascular emigration of monocyte/macrophage-like mononuclear leukocytes into tumor is presented. The preponderance of alternatively activated macrophage-like mononuclear leukocytes suggests disequilibrium between pro-tumoral leukocytes and anti-tumoral leukocytes. Therefore, macrophage polarization toward anti-tumoral macrophage-like mononuclear leukocytes would be a potential target for therapeutic manipulation in human astrocytic tumors.

Electron microscopy morphology of the mitochondrial network in human cancer.

Mitochondria have been implicated in the process of carcinogenesis, which includes alterations of cellular metabolism and cell death pathways. The aim of this review is to describe and analyze the electron microscopy morphology of the mitochondrial network in human cancer. The structural mitochondrial alterations in human tumors are heterogeneous and not specific for any neoplasm. These findings could be representing an altered structural and functional mitochondrial network. The mitochondria in cancer cells, independently of histogenesis, predominantly are seen with lucent-swelling matrix associated with disarrangement and distortion of cristae and partial or total cristolysis and with condensed configuration in minor scale. Mitochondrial changes are associated with mitochondrial-DNA mutations, tumoral microenvironment conditions and mitochondrial fusion-fission disequilibrium. Functionally, the structural alterations suppose the presence of hypoxia-tolerant and hypoxia-sensitive cancer cells. Possibly, hypoxia-tolerant cells are related with mitochondrial condensed appearance and are competent to produce adequate amount of ATP by mitochondrial respiration. Hypoxia-sensitive cells are linked with lucent-swelling and cristolysis mitochondria profile and have an inefficient or null oxidative phosphorylation, which consequently use the glycolytic pathway to generate energy. Additionally, mitochondrial fragmentation is associated with apoptosis; however, alterations in the mitochondrial network are linked with the reduction in sensitivity to apoptosis induces and/or pro-apoptotic conditions. Pharmacological approaches designed to act on both glycolysis and oxidative phosphorylation can be considered as a new approach to selectively kill cancer cells.

Importance and repercussions of renal and cardiovascular pathology on stroke in young adults: an anatomopathologic study of 52 clinical necropsies.

INTRODUCTION: Stroke in young adults has seldom been studied in a necropsy series. The objective of the present clinical necropsy-based investigation was to analyze stroke and its relationship with cardiovascular and renal pathology in young adults. MATERIALS AND METHODS: The protocols of 52 clinical necropsies with diagnoses of stroke in patients aged 18 - 49 years, performed between the years 1990-2006, were reviewed. RESULTS: Hemorrhagic stroke was diagnosed in 36 patients (69.3%), whereas the remaining 16 (30.7%) had ischemic stroke. Hypertensive cardiopathy was evident in 88.4% of the cases. Chronic renal pathology, directly or indirectly related to hypertension, was observed in 55.7% of the patients. Ischemic stroke as a result of occlusive atherosclerotic disease was seen in 50% of cases. Cardiogenic emboli were found in 25% of the cadavers. Hemorrhagic stroke was associated with hypertension in 43% of the cases, with ruptured vascular malformations in 29%, and coagulopathies in 17% of the cases. Hypertensive cardiopathy was present in patients with either ischemic or hemorrhagic stroke (81.2% and 91.6%, respectively). The most frequently observed renal ailments were chronic pyelonephritis (23%) and nephrosclerosis (21.1%). These were associated with ischemic stroke in 43.7%, and 12.5% of the cases, respectively, and with 13.8% and 25% of the hemorrhagic stroke cases. DISCUSSION: Hypertensive cardiopathy, occlusive atherosclerotic disease, chronic pyelonephritis and nephrosclerosis are among the pathophysiologycal mechanisms that apparently and eventually interact to induce a significant number of cases of stroke in young adults. A chronic systemic inflammatory state appears to be an important related condition because it possibly constitutes an accelerant of the pathophysiologycal process.

Ultrastructural mitochondrial pathology in human astrocytic tumors: potentials implications pro-therapeutics strategies.

This study was realized to illustrate and analyze the ultrastructural mitochondrial pathology in human astrocytic tumors. Tumoral biopsies of 10 patients with pathological diagnosis of astrocytic tumors by means of transmission electron microscopy were examined. Mitochondria exhibits heterogeneous morphology in all the cases. Mitochondrial swelling with partial or total cristolysis was the most constant alteration observed. Mitochondrial fusion-fission phenomena have been demonstrated. These findings suggest that the majority of astrocytoma cells are incompetent to produce adequate amount of energy by means of oxidative phosphorylation. Ultrastructural mitochondrial pathology indicates that possibly both glycolytic inhibition and inhibition or down-regulation of mitochondrial respiration would be a potential tool for future therapeutic strategies in cases of human astrocytic tumors.