Global Energy Metabolism Deficit in Alzheimer Disease Brain.

BACKGROUND: The understanding of Alzheimer's disease (AD) has been dominated by the amyloid hypothesis. However, therapies targeting beta-amyloid have largely failed, generating interest in other potential pathogenic factors including energy metabolism. OBJECTIVES: To interrogate canonical energy metabolism pathways from human prefrontal cortical tissue samples obtained from necropsy comparing AD and control. DESIGN, SETTING, AND PARTICIPANTS: Postmortem pre-frontal cortical tissue from 10 subjects histologically diagnosed with AD and 10 control (CTRL) subjects was subjected to untargeted metabolomics to interrogate energy metabolism pathways. The samples were matched by age, sex, and post-mortem interval. Metabolite Measurements: Untargeted metabolomics analyses were via Metabolon®. RESULTS: Glucose-derived energy metabolites in the glycolytic and pentose phosphate pathway and the ketone body ß-hydroxybutyrate were uniformly decreased in AD brain vs. CTRL brain. CONCLUSION: This pilot study aimed to identify energy metabolism abnormalities using untargeted brain metabolomics in two independent subject cohorts. Our study revealed a pattern of global energy deficit in AD brain, supporting a growing body of evidence of deficient energy metabolism in AD.

Bronchoalveolar lavage in children with cystic fibrosis: how many lobes should be sampled?

BACKGROUND: The European Respiratory Society guidance on bronchoalveolar lavage (BAL) in children was published in 2000. It recommended taking one BAL specimen from the most affected lobe or from the right middle lobe in diffuse disease. In 2007, the European Respiratory Society modified the recommendations for children with cystic fibrosis (CF), suggesting two BAL specimens (right middle lobe and the lingula or the most affected lobe). OBJECTIVE: To determine if BAL samples from one or two lobes give the full picture of lower airway infection in children with CF. DESIGN, SETTING AND PATIENTS: A retrospective review of all paediatric patients with CF who underwent flexible bronchoscopy between May 2007 and May 2009 was undertaken. MAIN OUTCOME MEASURES: As BAL specimens from all six lobes were collected, the BAL results were reviewed to identify if positive cultures would have been missed if only one lobe (right middle or most affected) or two lobes (right middle plus the lingula or most affected) had been sampled. RESULTS: The results of 39 bronchoscopic procedures in 31 children were reviewed. The BAL samples were taken from 6 lobes in all 39 procedures. Had only one lobe been used, 26 positive cultures (14 organisms) would have been missed in 11 patients. Had two lobes been used, 12 positive cultures (8 organisms) would have been missed in 7 patients. CONCLUSION: A single-lobe BAL is insufficient in assessing patients with CF for lower airway infection. Even when BAL specimens are taken from two lobes, a number of infections may be missed.

T regulatory cells distinguish two types of primary hypophysitis.

Numerous cases of primary hypophysitis have been described over the past 25 years with, however, little insight into the cause(s) of this disease. In order to guide treatment, a better understanding of the pathogenesis is needed. We studied the pathogenesis of primary hypophysitis by analysing systematically the immune response at the pituitary tissue level of consecutive cases of 'lymphocytic' hypophysitis who underwent pituitary biopsy. In order to investigate further the pathogenesis of their diseases we characterized two cases at clinical, cellular and molecular levels. We show here, for the first time, that lymphocytic hypophysitis probably encompasses at least two separate entities. One entity, in agreement with the classical description of lymphocytic hypophysitis, demonstrates an autoimmune process with T helper 17 cell dominance and lack of T regulatory cells. The other entity represents a process in which T regulatory cells seem to control the immune response, which may not be self- but foreign-targeted. Our data suggest that it may be necessary to biopsy suspected primary hypophysitis and to analyse pituitary tissue with immune markers to guide treatment. Based on our results, hypophysitis driven by an immune homeostatic process should not be treated with immunosuppression, while autoimmune-defined hypophysitis may benefit from it. We show here for the first time two different pathogenic processes classified under one disease type and how to distinguish them. Because of our findings, changes in current diagnostic and therapeutic approaches may need to be considered.

Unilateral limb enlargement in a dog with a malignant peripheral nerve sheath tumor.

A 3- to 4-month-old female Golden Retriever dog presented with right hind limb enlargement. Physical examination of the limb and radiographic findings initially included soft tissue swelling with elongation, bowing, and cortical irregularity of the femur and tibia. During a period of approximately 7 months, pathology in the limb progressed to include tarsal laxity, muscle atrophy, avulsion of the gastrocnemius muscle, and luxation of the patella. During surgical intervention to shorten the limb and repair the patellar luxation, a large soft tissue cyst was identified along the caudal aspect of the femur and stifle. The limb was later amputated, and a final diagnosis of malignant peripheral nerve sheath (PNS) tumor of the sciatic nerve and surrounding soft tissues was made. The unilateral limb enlargement in this dog appears to have been because of the development and progression of a malignant PNS tumor. The presentation and associated pathologic changes in the limb are unusual for canine PNS tumor but have similarities with neurofibromatosis in the limbs of humans.

Anterior cingulate metabolism correlates with stroop errors in paranoid schizophrenia patients.

UNLABELLED: Using [O-15]-H(2)O PET Carter et al. (1997) reported that medicated patients with schizophrenia performing computerized single trial Stroop (1935) showed a reduction in the anterior cingulate activation response to the more attention demanding, incongruent Stroop condition. In that study, both patients and controls also showed a direct correlation between anterior cingulate activation and errors committed during incongruent trials of the task. In this study we follow up with an examination of paranoid schizophrenia outpatients and controls with very high resolution positron emission tomography (PET) and the longer half-life tracer [F-18]-fluorinated deoxyglucose (FDG) (Valk et al. 1990). All subjects (10 controls and 9 paranoid schizophrenia patients) were studied with FDG-PET while performing a computerized trial-by-trial version of the Stroop task during the uptake phase of the tracer (Carter et al. 1992). RESULTS: As in previous studies using the single trial Stroop, patients were able to perform the task but made more color-naming errors during incongruent trials than controls. The patients in the present study showed a trend towards increased metabolic activity in the right anterior cingulate cortex. In the patient group, but not in controls, the anterior cingulate glucose metabolic rate correlated positively with the total incongruent trial errors. CONCLUSION: These results are consistent with the hypothesis that the anterior cingulate plays a performance-monitoring role during human cognition. This study does not rule out a reduction in error sensitivity in this region of the brain in schizophrenia, as other studies have suggested, however the data show that in unmedicated patients with the paranoid subtype this function is preserved to some extent.

A double-blind randomized trial of two dose regimens of misoprostol for cervical ripening and labor induction.

OBJECTIVES: The objective of this study was to compare the efficacy and safety of two dosing regimens of misoprostol for cervical ripening and labor induction. METHODS: Patients who fulfilled the study criteria were randomized to received misoprostol 25 microg or 50 microg intravaginally every 3 h for a total of eight doses for cervical ripening or until labor was established. Endpoints for successful cervical ripening was achievement of Bishop score of nine or greater, and for labor induction reaching the active phase of labor in the first 24 h. The rates of success, duration of first and second stages of labor, type of delivery, significant side effects, and neonatal outcome were measured and compared between the two study groups. Two hundred and fifty-one patients were randomized in two groups--126 received 50 microg and 125 received 25 microg misoprostol. Demographics of the two study groups were similar. RESULTS: Patients in the 50 microg group had a shorter first stage (848 min vs. 1,122 min, P < 0.007), shorter induction-to-vaginal delivery interval (933 min vs. 1,194 min, P < 0.013), decreased incidence of oxytocin augmentation (53.9% vs. 68%, P < 0.015), and decreased total units of oxytocin (2,763 mU vs. 5,236 mU, P < 0.023), but there was a higher hyperstimulation rate (19% vs. 7.2%, P < 0.005). CONCLUSIONS: Successful induction rate, delivery types, and fetal outcome were similar in both groups. Although the rate of vaginal delivery and neonatal outcome were similar in both groups, the 50 microg regimen had shorter first and second stages of labor, and a higher hyperstimulation rate that was easily manageable, allowing for flexibility in using the higher dose in low-risk pregnancies.

Intraarterial thrombolysis in a pig model: a preliminary note.

PURPOSE: To develop a pig model of arterial thrombosis suitable for assessing different methods of thrombolysis and to use this model to compare the efficacy of intraarterial thrombolysis performed by continuous proximal urokinase infusion versus mechanical clot disruption combined with intrathrombic urokinase injection. METHODS: In a control group of five pigs, a thrombus was made in a short segment of femoral artery and observed for 2 hours to assess its stability. In a treatment group of six pigs, intraarterial thrombolysis was performed immediately after thrombus formation. Thrombolysis was accomplished by continuously infusing urokinase into the proximal leading edge of the thrombus in three pigs and by mechanical clot disruption combined with intrathrombic urokinase injection in the remaining three pigs. RESULTS: There was no spontaneous reestablishment of flow in the control group during the 2-hour observation period. In the first treatment group, no flow was observed after a 1-hour treatment period when urokinase was infused continuously into the proximal edge of the thrombus. In the second treatment group, with mechanical clot disruption and intrathrombic urokinase injection, some degree of flow was observed in all three pigs. Reestablishment of flow was more sustained and of a greater degree with the addition of systemic heparinization. CONCLUSION: This animal model could provide a useful way to evaluate and compare different methods of thrombolysis. Our results suggest that mechanical clot disruption combined with intrathrombic urokinase injection is more effective in achieving reestablishment of flow than is continuous infusion of urokinase into the proximal edge of the thrombus.

Temporal lobe metabolic differences in medication-free outpatients with schizophrenia via the PET-600.

Regional cerebral glucose metabolic rates (rCMRglc) were compared in 18 unmedicated outpatients with schizophrenia and 11 normal controls using high resolution positron emission tomography (PET) and the tracer [F-18]-2-fluoro-2D-deoxyglucose (FDG). From previous work we expected to see abnormal hippocampal rCMRglc in the patients, but no striatal abnormalities. Trial-by-trial Stroop cognitive task, which has been shown to activate the anterior cingulate, was performed within a day of the PET study. As our patients performed abnormally on the Stroop we tested for a correlation between the anterior cingulate rCMRglc and Stroop performance. We found no whole slice cortical average glucose metabolic abnormalities. As, predicted we found abnormally decreased left hippocampal rCMRglc in the patients. No striatal or cingulate rCMRglc abnormalities were noted in patients, but they demonstrated a highly positive correlation between anterior and cingulate rCMRglc and Stroop facilitation. Patients with higher Stroop interference had more prominent hippocampal metabolic decreases. These localized temporal lobe abnormalities could account for some of the patient's positive symptoms and are consistent with recent findings in the literature.

Imaging findings of the developing temporal bone in fetal specimens.

PURPOSE: To trace the development of the normal fetal temporal bone by means of plain radiography, MR, and CT. METHODS: Eighteen formalin-fixed fetal specimens, 13.5 to 24.4 weeks' gestational age, were examined with a mammographic plain film technique, CT, and MR imaging at 1.5 T. Temporal bone development and ossification were assessed. RESULTS: The membranous labyrinth grows with amazing rapidity and attains adult size by the middle of the gestation period. The cochlea, vestibule, and semicircular canals are very prominent and easily recognized on MR images. The otic capsule develops from a cartilage model. Ossification of the otic capsule proceeds rapidly between 18 and 24 weeks from multiple ossification centers that replace the cartilaginous framework. The mastoid, internal auditory canal, vestibular aqueduct, and external auditory canal continue to grow after birth. CONCLUSION: The study of fetal developmental anatomy may lead to a better understanding of congenital disorders of the ear. Faster MR scanning techniques may provide a method for in utero evaluation of the fetal temporal bone.

Pulmonary artery sarcoma in a pregnant woman: report of a case.

BACKGROUND: We report the case of a 23-year-old pregnant woman with hemoptysis, cor pulmonale, and pulmonary artery sarcoma. The physiologic changes of pregnancy may have unmasked the pulmonary lesion. CASE: A 23-year-old woman presented at 28 weeks' gestation with acute onset of hemoptysis and dyspnea. A hilar mass was noted and a pulmonary embolus was diagnosed. Biopsy of the hilar mass was nondiagnostic. Emergency cesarean delivery was performed because of rapid clinical deterioration and an acute loss of fetal heart tones. Both mother and infant died. Autopsy of the mother demonstrated a large pulmonary artery sarcoma with metastases to both lungs and terminal bacterial bronchopneumonia. CONCLUSION: Hemodynamic changes of pregnancy may have unmasked the pulmonary lesion in this case. Pulmonary artery sarcoma is an extremely rare tumor.

Alzheimer's disease. Beta-amyloid precursor protein expression in the nucleus basalis of Meynert.

The nucleus basalis of Meynert (nbM) was examined using immunocytochemistry for beta-amyloid precursor protein (beta APP) expression in Alzheimer's disease (AD). In mild AD cases, light labeling of the cell body and proximal processes was observed, and small intracellular structures were labeled rarely. In the more severe cases, intense cytoplasmic beta APP labeling was seen, often along with small beta APP-positive structures. Double-labeling experiments demonstrated that in the more severe cases these small structures were also decorated by a neurofibrillary tangle (NFT) antiserum. Other neurons in the severe cases showed incorporation of beta APP into large inclusions, which were also labeled with the NFT antiserum. However, some large inclusions in the severe cases were labeled by the NFT antiserum but contained no beta APP. Extraneuronal NFTs did not show beta APP labeling and did not react with an antibody to the beta-amyloid peptide. These results suggest that increased expression of beta APP coincides with intracellular NFT formation in the nbM, but that the formation of extraneuronal NFTs results in a loss of beta APP immunoreactivity.

Alzheimer's disease: beta-amyloid precursor protein expression in plaques varies among cytoarchitectonic areas of the medial temporal lobe.

The anatomic distributions of beta-amyloid peptide (beta AP) and beta-amyloid precursor protein (beta APP) in the medial temporal lobe were examined with immunocytochemistry in Alzheimer's disease. beta AP-containing plaques were found most frequently in the cortical and basal regions of the amygdala, and in the hippocampal CA1, subiculum, and dentate molecular layer. beta APP expression in plaques was found in a similar distribution, with some, but not all beta AP plaques also showing beta APP. In the cortical and basal amygdala, some cases showed beta APP in the centers of plaques, whereas in the hippocampus, all cases displayed beta APP mainly in plaque neurites. The lateral regions of the amygdala contained mainly diffuse beta AP plaques which had little beta APP. These findings suggest that although beta APP expression and beta AP deposition generally colocalize, processing of beta APP may vary among closely interconnected anatomic regions.

An osmotic gradient in ischemic brain edema.

We studied how the osmotic pressure gradient between blood and the brain is related to the development of ischemic brain edema. Focal cerebral ischemia was produced by left MCA occlusion in rats. Brain osmolality was determined with a vapor pressure osmometer, water content of the brain tissue was measured by wet and dry weight, and the tissue sodium and potassium contents were assayed by flame photometry. Permeability of BBB was tested by EB. These measurements were made from the cortical core of MCA territory at various intervals from 1 hr to 14 days after occlusion. Brain osmolality increased from 311 +/- 2 mOsm/kg (M +/- SE) to 329 +/- 2 mOsm/kg (n = 7, p less than 0.01) by 6 hrs after occlusion. Serum osmolality did not significantly change. The osmotic gradient between blood and the brain was about 26 mOsm/kg. Brain osmolality then decreased to 310 +/- 2 mOsm/kg by 12 hr after occlusion and remained about the same level for up to 14 days. Water content progressively increased within 1 day, then gradually decreased by 14 days. Sodium plus potassium content of the brain tissue did not increase and EB extravasation was not seen within 6 hr of occlusion. These findings indicate that an osmotic pressure gradient contributes to the formation of edema only during the early stage of cerebral ischemia. Brain osmolality is not related to tissue electrolyte change and BBB disruption to protein.

Ischemic brain edema and the osmotic gradient between blood and brain.

The relationship of the osmotic pressure gradient between blood and brain, and the development of ischemic brain edema was studied. Focal cerebral ischemia was produced by left middle cerebral artery occlusion in rats. Brain osmolality was determined with a vapor pressure osmometer, brain water content by wet-dry weight, and tissue sodium and potassium contents by flame photometry. Permeability of the BBB was tested by Evans blue. Measurements were made from the ischemic cortex within 14 days of occlusion. Brain osmolality increased from 311 +/- 2 to 329 +/- 2 mOsm/kg by 6 h after occlusion. Serum osmolality did not change significantly. The osmotic gradient between blood and brain peaked at approximately 26 mOsm/kg. Brain osmolality then decreased to 310 +/- 2 mOsm/kg by 12 h after occlusion and remained at about that same level. Water content increased progressively within 1 day of occlusion, then gradually decreased by 14 days. Brain tissue sodium plus potassium content did not increase within 6 h of occlusion, and Evans blue extravasation was not seen within that time. These findings indicate that an osmotic pressure gradient contributes to the formation of edema only during the early stage of cerebral ischemia. Furthermore, the increase in brain osmolality is not related to tissue electrolyte change or BBB disruption to protein.