Enlightening brain energy metabolism.

Brain tissue metabolism is distributed across several cell types and subcellular compartments, which activate at different times and with different temporal patterns. The introduction of genetically-encoded fluorescent indicators that are imaged using time-lapse microscopy has opened the possibility of studying brain metabolism at cellular and sub-cellular levels. There are indicators for sugars, monocarboxylates, Krebs cycle intermediates, amino acids, cofactors, and energy nucleotides, which inform about relative levels, concentrations and fluxes. This review offers a brief survey of the metabolic indicators that have been validated in brain cells, with some illustrative examples from the literature. Whereas only a small fraction of the metabolome is currently accessible to fluorescent probes, there are grounds to be optimistic about coming developments and the application of these tools to the study of brain disease.

Slowly progressive behavioral frontotemporal dementia with C9orf72 mutation. Case report and review of the literature.

We present a 86-year-old woman without relevant medical history and two brothers who died by dementia, who started at 55 years with depression and personality changes with ongoing worsening (>30 years) and functional decline. Screening dementia blood test and brain magnetic resonance imaging did not show results that pointed to a secondary cause. The patient met the diagnostic criteria for possible behavioral frontotemporal dementia with a slow progression (bvFTD-SP), suggesting a benign variant. A genetic study confirmed a C9ORF72 hexanucleotide expansion, making this the sixth case mentioned in the literature. We review and discuss the other cases described previously.

TARDBP mutation associated with semantic variant primary progressive aphasia, case report and review of the literature.

Semantic variant primary progressive aphasia (svPPA) is a clinical syndrome included in the frontotemporal dementia (FTD) spectrum. Unlike other forms of FTD, it is sporadic in the majority of cases and not commonly associated with motor neuron disease (MND). We describe a case of svPPA associated with MND in the same family, due to a mutation of the transactive response DNA binding protein (TARDBP) gene, and review the literature.

Cerebral amyloid angiopathy-related inflammation: clinical features and treatment response in a case series.

INTRODUCTION: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an entity characterised by an inflammatory response to ß-amyloid deposition in the walls of cerebral microvessels. METHODS: We conducted a retrospective review of a series of patients with a diagnosis of CAA-ri according to histopathological study findings or clinical-radiological diagnostic criteria. RESULTS: The study included 7 patients (5 men) with a mean age of 79 years. Disease onset was acute or subacute in 6 patients. The most frequent symptoms were cognitive impairment (n = 6), behavioural alterations (n = 5), epileptic seizures (n = 5), focal neurological signs (n = 4), and headache (n = 2). Cerebrospinal fluid was abnormal in 3 patients (lymphocytic pleocytosis and high protein levels). The most frequent MRI findings were microbleeds (n = 7), subcortical white matter hyperintensities on T2-FLAIR sequences (n = 7), and leptomeningeal enhancement (n = 6). Lesions were bilateral in 3 patients and most frequently involved the parieto-occipital region (n = 5). Amyloid PET studies were performed in 2 patients, one of whom showed pathological findings. Two patients underwent brain biopsy, which confirmed diagnosis. All patients received immunosuppressive therapy. An initially favourable clinical-radiological response was observed in all cases, with 2 patients presenting radiological recurrence after treatment withdrawal, with a subsequent improvement after treatment was resumed. CONCLUSIONS: Early diagnosis of CAA-ri is essential: early treatment has been shown to improve prognosis and reduce the risk of recurrence. Although a histopathological study is needed to confirm diagnosis, clinical-radiological criteria enable diagnosis without biopsy.

Visualizing physiological parameters in cells and tissues using genetically encoded indicators for metabolites.

The study of metabolism is undergoing a renaissance. Since the year 2002, over 50 genetically-encoded fluorescent indicators (GEFIs) have been introduced, capable of monitoring metabolites with high spatial/temporal resolution using fluorescence microscopy. Indicators are fusion proteins that change their fluorescence upon binding a specific metabolite. There are indicators for sugars, monocarboxylates, Krebs cycle intermediates, amino acids, cofactors, and energy nucleotides. They permit monitoring relative levels, concentrations, and fluxes in living systems. At a minimum they report relative levels and, in some cases, absolute concentrations may be obtained by performing ad hoc calibration protocols. Proper data collection, processing, and interpretation are critical to take full advantage of these new tools. This review offers a survey of the metabolic indicators that have been validated in mammalian systems. Minimally invasive, these indicators have been instrumental for the purposes of confirmation, rebuttal and discovery. We envision that this powerful technology will foster metabolic physiology.

Hantavirus ecology in rodent populations in three protected areas of Argentina.

In this study, we identified hantavirus genotypes and their reservoirs and evaluated the spatial and temporal distribution of the virus in rodent population in three protected areas of Argentina over 3 years (2007-2010). A total of 837 rodents were captured with an effort of 22 117 trap-nights. We detected the genotype Lechiguanas in Oligoryzomys nigripes and O. flavescens and Pergamino in Akodon azarae. There was no correlation between seroprevalence and trap success of the host. The proportion of seropositive males was significantly higher than the proportion of seropositive females. The total length of seropositives was higher than that of seronegatives in each host species. Seropositive individuals were observed in warm months and not in cold months, which suggests an infection cycle. This investigation confirms that protected areas of central east Argentina are places with a variety of sylvan rodents species associated with different hantavirus genotypes where reservoirs are numerically dominant. Although there was more than one known reservoir of hantavirus, only one species had antibodies in each area. This can be explained because the transmission of the virus does need not only the presence of a rodent species but also a threshold density. Longevity of even a small proportion of the host population in cold months may provide a trans-seasonal mechanism for virus persistence. The seroprevalence detected was higher than the one found before in rodent populations of Argentina, and this explains the appearance of human cases in two of these three areas.

Cerebral amyloid angiopathy-related inflammation: clinical features and treatment response in a case series. / Inflamación relacionada con angiopatía amiloide: características clínicas y respuesta al tratamiento en una serie de casos.

INTRODUCTION: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an entity characterised by an inflammatory response to ß-amyloid deposition in the walls of cerebral microvessels. METHODS: We conducted a retrospective review of a series of patients with a diagnosis of CAA-ri according to histopathological study findings or clinical-radiological diagnostic criteria. RESULTS: The study included 7 patients (5 men) with a mean age of 79 years. Disease onset was acute or subacute in 6 patients. The most frequent symptoms were cognitive impairment (n = 6), behavioural alterations (n = 5), epileptic seizures (n = 5), focal neurological signs (n = 4), and headache (n = 2). Cerebrospinal fluid was abnormal in 3 patients (lymphocytic pleocytosis and high protein levels). The most frequent MRI findings were microbleeds (n = 7), subcortical white matter hyperintensities on T2-FLAIR sequences (n = 7), and leptomeningeal enhancement (n = 6). Lesions were bilateral in 3 patients and most frequently involved the parieto-occipital region (n = 5). Amyloid PET studies were performed in 2 patients, one of whom showed pathological findings. Two patients underwent brain biopsy, which confirmed diagnosis. All patients received immunosuppressive therapy. An initially favourable clinical-radiological response was observed in all cases, with 2 patients presenting radiological recurrence after treatment withdrawal, with a subsequent improvement after treatment was resumed. CONCLUSIONS: Early diagnosis of CAA-ri is essential: early treatment has been shown to improve prognosis and reduce the risk of recurrence. Although a histopathological study is needed to confirm diagnosis, clinical-radiological criteria enable diagnosis without biopsy.

[Trajan's decision: a neurological point of view]. / La decisión de Trajano: un punto de vista neurológico.

The emperor of Rome, Marco Ulpio Trajano, ruled the Roman Empire from 98 to 117 AD, being the first emperor of non-Italian origin and the man who took the Empire to its maximum geographical extent. Trajan's death is surrounded by mystery, given Adriano's controversial adoption as his successor just before his death, as well as rumors of poisoning by his wife, Plotina. In addition, despite the limited literary sources available, episodes of «paralysis¼, «stroke¼, «dropsy¼, diarrhea and nonspecific episodes of «illness¼ have been documented, related to the worsening of his health the months before his death. His special love of wine and life habits related to the personality of the emperor, could be associated with his delicate state of health during the last year of his government, although it is not possible to rule out other pathological processes with neurological involvement associated with the last years of life of the optimus princeps, which could interfere with his last decisions as ruler. In this article, the historical sources available are reviewed in order to analyze, from the neurological point of view, the last moments of the emperor with which Rome reached its maximum military splendor.

TITLE: La decisión de Trajano: un punto de vista neurológico.El emperador de Roma Marco Ulpio Trajano gobernó el Imperio romano desde el año 98 hasta el 117 d.C., y fue el primer emperador de origen no itálico y el hombre que llevó al Imperio a su máxima extensión geográfica. La muerte de Trajano está rodeada de misterio, dada la polémica adopción de Adriano como su sucesor justo antes del momento de su fallecimiento, así como los rumores de envenenamiento por parte de su mujer, Plotina. Además, a pesar de las escasas fuentes literarias disponibles, se han documentado episodios de «parálisis¼, «apoplejía¼, «hidropesía¼, diarrea y episodios inespecíficos de «enfermedad¼ relacionados con el empeoramiento de su salud los meses antes de su muerte. Su especial afición al vino y los hábitos de vida relacionados con la personalidad del emperador pudieron estar asociados con su delicado estado de salud durante el último año de su gobierno, si bien no es posible descartar otros procesos patológicos con afectación neurológica asociados a los últimos años de vida del optimus princeps, los cuales pudieron interferir con sus últimas decisiones como gobernante. En este artículo se revisan las fuentes históricas disponibles con el objeto de analizar, desde el punto de vista neurológico, los últimos momentos del emperador con el que Roma alcanzó su máximo esplendor militar.

[Oral nutritional supplementation in hematologic patients]. / Suplementación oral nutricional en pacientes hematológicos.

RATIONALE: Hematological patients often present anorexia which along with other secondary effects from the chemotherapy and/or radiotherapy treatments compromise their nutritional status. Oral supplementation can aid to fulfill the energy and protein requirements of these patients. Nevertheless, the use of commercial nutritional supplements normally available, is limited by its poor intake. OBJECTIVE: To evaluate the degree of fulfillment of the prescribed supplements and fulfillment of energy requirements, as well as the development of nutritional status in hematological patients hospitalized for treatment with chemotherapy and/or radiotherapy. METHODS: Prospective, randomized and open study of inpatients at the hematological ward. Patients were randomized sequentially and they were assigned into 3 different nutritional interventions providing: Group 1 (G1), a flavored supplement; Group 2 (G2): a non flavored (neutral) supplement and Group 3 (G3): "kitchen" foods as supplements. Need and amount of nutritional supplements were provided according to the oral intake previously analyzed. Nutritional assessment (at admission and discharge) was based in the Subjective Global Assessment test (SGA), Risk Nutritional Index (RNI) and percentage of lost weight. Both fulfillment of supplement intake and achievement of energetic requirements were analyzed. RESULTS: 125 patients of 51.3 +/- 16.8 years; 45% men and 55% women. DIAGNOSIS: 54% lymphoma, 33% leukemia, 8% myeloma and others 4%. Length of stay (LOS): 7.0 +/- 3.6 d. The nutritional assessment done by SGA showed significant negative changes in G2 and G3 (G1: 30% developed malnutrition and 28% improved their nutritional status, p = NS; G2: 50% developed malnutrition against 7% whom improved their nutritional status, p = 0.002; y G3: 37% developed malnutrition against 21% whom improved their nutritional status, p = 0.02). According to RNI, patients evolved negatively from their nutritional state but no significant differences were found within groups (G1, from 81% of malnutrition to 90%; G2, from 77% to 91%, and G3 from 71% to 85%). Globally, during hospitalization patients lost weight significantly (2.3 +/- 2.2 kg, p < 0.001), but within groups weight loss differences were not significant (G1, 1.16 kg; G2, 1.75 kg, y G3, 1.17 kg). All three groups required intake of supplements (G1, 47%; G2, 30%, and G3, 47%). The percentage of fulfillment of oral intake was similar in both commercial supplemented groups (G1, 47% and G2, 58%) although it was significantly greater in those receiving kitchen supplements (G3, 100%, p < 0.001). The fulfillment of energy requirements at admission and discharge did not showed significant changes (G1, from 53% to 46%; G2, from 67% to 52% and G3 from 49% to 55%). CONCLUSION: Our results suggest that hematological patients admitted to hospital for treatment with chemotherapy and/or radiotherapy loose weight during their hospitalization and present intakes below their energy requirements so they need supplementation. Kitchen supplements are better accepted than commercial ones although that does not result in an increased total energy intake. The group which received commercial flavored supplements was the only one which did not showed negative significant changes in the nutritional status evaluated by SGA.

[Severe and acute hyponatremia in a schizophrenic patient with potomania]. / Hiponatremia aguda grave en un paciente esquizofrénico potomano.

Acute and severe hyponatremia causes a metabolic encephalothy. It is physiopathologically based on the cerebral edema, and its fatal symptoms include seizures and coma. We present a case of an extreme hyponatremia of multifactorial etiology in a schizophrenic patient with potomania. Potomania does not usually cause hyponatremia, unless it coexists with other trigger factors. This patient had a syndrome of inappropriate antidiuretic hormone (SIADH), and a deep hypokaliemia, due to vomiting and a treatment with indapamida, which perpetuates the deficit of extracellular sodium. In the patient's treatment, aripiprazole was the only recently introduced drug with which cases of inappropriate vasopressin secretion have been reported. Management of a severe hyponatremia must be considered a vital emergency, independent of the cause, and 3% hypertonic saline must be administered. The increase of the sodium level must not be higher than 25 mmol/L in the first 24-48 hours, to avoid a secondary brain injury.

[Foodborne disease outbreak in El Huecú community, province of Neuquén]. / Brote de enfermedad alimentaria en la localidad de El Huecú, provincia de Neuquén.

In the summer of 2006, an epidemic outbreak of acute gastrointestinal illness related to food consumption occurred in a small town in the province of Neuquén, Argentina. During a popular feast, approximately 800 local residents attended lunch held in the facilities of the Municipal Gymnasium. About three hours later, nearly 150 attendees sought medical assistance at the local hospital due to acute gastroenteritis. A case-control epidemiological investigation was conducted using representative non-probability sampling. The epidemiological investigation showed a common-source foodborne disease outbreak with a case-control ratio of 1:1.8. The main symptoms were abdominal cramps (88%), vomiting (73.5%) and diarrhea (60%). The cake was identified as the source of infection (OR 9.79; IC 95%, 2.66-36.00; p = 0.0001), and unsatisfactory hygienic conditions in food production, conservation and handling steps were identified. Coagulase positive, enterotoxigenic Staphylococcus aureus, subspecies aureus was detected in a piece of cake, with a count of 2.4 x 10(6) CFU/g, and in samples from the hands and nostrils of three people involved in food preparation and service. The strains isolated from both the cake and one of the food handlers carried the sea gene, and presented the same Smal-PFGE pattern. The foodborne disease outbreak was considered to be due to contamination in the preparation process of the cake consumed at the feast, which was related to inadequate hygienic conditions, lack of refrigeration and cold chain disruption.

[Past and present of monitoring the functional immune response developed against Epstein-Barr and Adenovirus in hematopoietic stem cell transplantation]. / Pasado y presente de la monitorización de la respuesta funcional inmunológica desarrollada frente a Epstein-Barr y Adenovirus en el trasplante de progenitores hematopoyéticos.

Epstein-Barr (EBV) and Adenovirus (AdV) viral infections represent a significant cause of morbi-mortality in allogeneic hematopoietic stem cell transplantation recipients due to the use of immunomyelosuppressive treatments and the prolonged period of immunodeficiency that they generate. To date, the post-transplant protective role of EBV and AdV specific CD8+ T lymphocytes (CTLs) has been demonstrated. However, other factors are increasingly important in regulating the reconstitution and activity of CTLs specific to these viruses such as different cell subpopulations (CD4 + T lymphocytes, regulatory T lymphocytes, dendritic cells, Natural Killer cells, etc.), molecular mechanisms of immunoregulation and the drugs administered to the patient as prophylaxis for a possible graft-versus-host disease. The aim of this review is to analyze the importance of monitoring the functional EBV and AdV-specific cellular response in the management of post-transplant recipients.

Is cutting stress responsible for the limited durability of heart valve bioprostheses?

The limited durability of the valve bioprostheses made from calf pericardium is partially due to the calcification of this biomaterial and to mechanical fatigue of the tissue. The object of this study is to determine the harmful effect on the pericardial membrane of cutting caused by the suture thread by showing the different elastic behaviors of the biomaterials employed. This cutting stress is established during the process of molding the valve leaflet, creating a vulnerable point from the very moment of construction, which is an important factor in the limited duration of the bioprosthesis.

Improvement of the tissue integration of a new modified polytetrafluoroethylene prosthesis: Mycro Mesh.

We studied the behaviour of the different tissue interfaces formed on a new type of prosthesis used for the repair of abdominal wall defects, Mycro Mesh (W. L. Gore and Ass., Flagstaff, AZ, USA), which consists of perforated layers of polytetrafluoroethylene (PTFE). In 20 New Zealand white rabbits, a full-thickness (except skin) 7 cm x 5 cm defect was created in the anterior abdominal wall. The defects were repaired with a prosthetic implant (Mycro Mesh) that was placed in direct contact with abdominal viscera and subcutaneous tissue. At 14, 30, 60 and 90 d post-implantation, samples were obtained from the tissue interfaces formed between the prosthesis and subcutaneous tissue, visceral peritoneum and receptor tissue, respectively. Samples were studied by optical microscopy and scanning electron microscopy. The immunohistological study was made with RAM-11, a monoclonal antibody specific for rabbit macrophages. Tensile strength was measured with an Instron tensiometer using 2 cm wide strips obtained parallel to the shorter axis of the implant. Strips included the prosthesis and two anchor zones on the receptor tissue. Macroscopically, the prosthesis induced little adhesion formation on the visceral peritoneum interface. Microscopically, an organized neoperitoneum and abundant tissue formed on the subcutaneous interface. In the prosthesis perforations, bridges of tissue linked the peritoneal and subcutaneous sides. The macrophage response decreased significantly in intensity between day 14 and day 90 (Student-Newman-Keuls test, P = 0.01). Tensile strength increased significantly (Wilcoxon test, P < 0.05) at every study period. To conclude: the Mycro Mesh prosthesis proved suitable for implantation in sites where it comes in contact with abdominal viscera and it provided good support for the formation of an organized neoperitoneum; the perforations in the prosthetic material improved implant integration; the macrophage response was not altered by the biomaterial and the tensile strength of the prosthesis increased as scar tissue formation and tissular integration of the prosthesis progressed.

Experimental assay of a Dual Mesh polytetrafluoroethylene prosthesis (non-porous on one side) in the repair of abdominal wall defects.

The porosity of the prosthetic biomaterials used to repair defects in the abdominal wall seems to influence the tissue repair process insofar as tissue integration of the prosthetic material and the formation of adhesions with abdominal viscera are concerned. We studied the behaviour of a new type of polytetrafluoroethylene prosthesis used for the repair of abdominal wall defects. Dual Mesh (DM), which has two different faces; one face has a porosity between 30 and 60 microns, while the other is non-porous. In 20 New Zealand White rabbits, a full-thickness (except skin) 7 cm x 5 cm defect was created in the anterior abdominal wall that was repaired with DM. At 14, 30, 60 and 90 days, samples were obtained and studied by light and scanning electron microscopy. An immunohistochemical study was made with antibody anti-rabbit macrophages (RAM-11). Tensile strength was measured with an Instron tensiometer using 2-cm-wide strips obtained parallel to the shorter axis of the implant. DM induced little tissue adhesion to the material on the visceral peritoneum interface and was surrounded by organized repair tissue. The biomaterial was integrated in the repair tissue on the subcutaneous interface, but not on the peritoneal interface. The macrophage response decreased between days 14 and 90 (P < 0.001). Tensile strength increased significantly (P < 0.05) at every study period. We conclude that the DM prosthesis has little tendency to formation of visceral adhesions, the DM prosthesis was well tolerated by the receptor organism and the tensile strength of the prosthesis/receptor tissue interface increased with time.

Tissue response to polypropylene meshes used in the repair of abdominal wall defects.

The degree of integration of biomaterials used in the repair of abdominal wall defects seems to depend upon the structure of the prosthesis. Several polypropylene (PP) prostheses are currently available which differ in the number of PP filaments, the type of weave and the porosity. The aim of this study was to evaluate the integration, adhesion formation and resistance to traction of three types of PP prostheses (Marlex, Trelex and Prolene) used in the partial or total repair of abdominal wall defects. Abdominal wall defects (7 x 5 cm) were created in 54 New Zealand rabbits involving all the tissue layers (total substitutions (TS); n = 27) or all layers excluding the parietal peritoneum (partial substitutions (PS); n = 27). The defects were repaired with PP monofilament prostheses of different weave (1 mm porosity) (Marlex, n = 18; Trelex, n = 18) or bifilament (2 mm porosity) (Prolene; n = 18). They were placed in contact on one side with subcutaneous tissue and on the other with abdominal viscera or parietal peritoneum. Animals were killed at 30, 60 and 90 days and samples of prosthesis and scar tissue processed for light and scanning microscopy. The adhesion formation with viscera was evaluated. Resistance to traction was measured with a tensiometer using strips including the prosthesis and anchorage tissue. Adhesions were detected in all the TS and in four PS. Microscopic analysis revealed total integration of the TS samples by fibrous and disorganized tissue. Prostheses used for PS were integrated by white adipose tissue with the exception of the areas around the mesh nodes and anchorage zones. The foreign body reaction could be seen as a moderate accumulation of white blood cells. Tensiometric analysis showed an increase in resistance to traction with time (P < 0.001) in each type of prosthesis, but no differences were detected (P > 0.001) between them. We concluded that: (a) the formation of adhesions was almost inhibited when the parietal peritoneum was left intact; (b) in both TS and PS, polypropylene prostheses integrated completely although the composition of the scar tissue was seem to differ; and (c) resistance to traction was similar in both TS and PS.

Resistance and elasticity of the suture threads employed in cardiac bioprostheses.

The mechanoelastic features of five types of sutures were studied. The breaking stress for each was determined by means of tensile tests in which a constant strain rate was applied, and a tensile test with graduated stress and relaxation defined the elastic limit, i.e. the point beyond which deformation becomes irreversible. The study of the stress-strain curve during this elastic period enabled us to obtain the mathematical function that governs these reversible deformations, which shows excellence of fit (R2 > 0.98). The prime derivative at each point of the resulting functions is the elastic modulus, the best parameter for comparing the elasticities of the suture threads. Since breaking stress alone does not suitably define the mechanical quality of a suture, we propose the use of other parameters during the elastic period, such as percentage of elongation at a point 10 times lower than the elastic limit (safety coefficient of 10), and tensile stress and elastic modulus at the said point, which are more reliable in the assessment of the resistance and elasticity of these threads.