Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease

Antibodies to the lysosomal hydrolases, cathepsins B and D and β-hexosaminidase A, revealed alterations of the endosomal-lysosomal system in neurons of the Alzheimer disease brain, which preceded evident degenerative changes and became marked as atrophy, neurofibrillary pathology, or chromatolysis developed. At the earliest stages of cell atrophy, hydrolase-positive lysosomas accumulated at the basal pole and then massively throughout the perikarya and proximal dendrites of affected pyramidal neurons in Alzheimer prefrontal cortex and hippocampus, far exceeding the changes of normal aging. Secondary lysosomes as well as tertiary residual bodies (lysosomes/lipofuscin) increased implying stimulated, autophagocytosis and lysosomal system activation. Less affected brain regions, such as the thalamus, displayed similar though less extensive alterations. Certain thalamic neurons exhibited a distinctive lysosome-related abnormality characterized by the presence of cell surface blebs of varying size and number filled with intense hydrolase immunoreactivity. At more advanced stages of degeneration in still intact neurons, hydrolase-positive lipofuscin, particularly in the form of abnormal large aggregates, nearly filled the cytoplasm. Similar lipofuscin aggregates were oberved in abundance in the extracellular space following cell lysis and were usually associated with deposits of the β-amyloid protein. Degenerating neurons and their processes were the major source of these aggregates within senile plaques which contained high concentrations of acid hydrolases. We have shown in previous studies that these lysosomal hydrolases in plaques are enzymatically-active. The persistence of lysosomal structures in the brain parenchyma after neurons hyve degenerated is a striking and potentially diagnostic feature of Alzheimer disease which has not been observed, to our knowledge, in other degenerative diseases. The lysosomal response in degerating Alzheimer neurons represents a probable link between an early activation of the lysosomal system in at-risk, normal-appearing neurons and the end-stage contribution of lysosomes to senile plaque formation of emphasizes a slowly progressive disturbance of the lysosomal system throughout the development of Alzheimer disease.     

A question of rhythm: recent advances in growth hormone research.

Research by Dr. Gloria Shaffer Tannenbaum at the McGill University-Montreal Children's Hospital Research Institute has led to the development of a new test to differentiate children who are deficient in growth hormone from those who are short but growing normally. This clinical application is the fruit of Tannenbaum's discovery that growth hormone secretion occurs in a rhythmic pattern regulated by intricate interactions between two neurohormones: growth hormone-releasing hormone (GHRH) and somatotropin release-inhibiting factor (SRIF). In the test an analogue of SRIF is used to allow stores of growth hormone to build up. A subsequent challenge with GHRH is then used to identify children with a genuine deficiency. Tannenbaum's research also indicates that there are sexual differences in the pattern of growth hormone release and that growth hormone regulates its own secretion by means of a negative feedback system.     

Superiority of the University of Wisconsin solution over simple crystalloid for extended heart preservation. A study of left ventricular pressure-volume relationship.

To compare the effects of the University of Wisconsin solution with those of an extracellular crystalloid solution, Krebs-Ringer bicarbonate, as cardiac preservation media, we studied 35 adult dogs in an isolated heart preparation. Four groups of seven hearts were preserved in University of Wisconsin solution for 6 or 12 hours or in Krebs-Ringer bicarbonate solution for 6 or 12 hours. An additional group of seven hearts with no ischemia was used for a control group. In the four preservation groups, hearts were arrested by electrolyte solution (Normosol with potassium chloride, 20 mEq/L, added, 4 degrees C), flushed with 200 ml of the preservation solution, and then stored in the same solution at 1 degree to 2 degrees C. The hearts were mounted on an isolated heart preparation equipped with a computer-controlled servo-pump system that used a mock arterial system to modulate the aortic input impedance presented to the left ventricle. Left ventricular pressure-volume loops were measured on-line for 2 hours of reperfusion with autologous warm oxygenated blood. Elastance was derived from the end-systolic pressure-volume relationship, and diastolic compliance was derived from the end-diastolic pressure-volume relationship. The total left ventricular performance was assessed by the preload recruitable stroke work area, the slope, and its x-intercept, all of which derived from the stroke work (pressure-volume area)-end-diastolic volume relationship. Extended global ischemia had more deleterious effects on the end-diastolic than the end-systolic pressure-volume relationship. In confirmation with other studies, elastance did not accurately reflect the level of ventricular contractile dysfunction because of the significant amount of diastolic dysfunction. The preservation of myocardial systolic and diastolic functions, as demonstrated by the preload recruitable stroke work area and diastolic compliance, was better in the University of Wisconsin solution groups than in the Krebs-Ringer bicarbonate solution groups after 6 and 12 hours of preservation. In addition, 6 hours of preservation with University of Wisconsin solution maintained normal systolic and diastolic functions as compared with those of the control group. Preservation with University of Wisconsin solution prevented any myocardial edema formation; by contrast, this was significantly increased after 12 hours in Krebs-Ringer bicarbonate solution. Groups preserved with University of Wisconsin solution had less reperfusion injury as evidenced by the release of coronary sinus creatine kinase during reperfusion; they also had improved oxygen use during reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

“Lytic” lesions in autologous bone grafts: demonstration of medullary air pockets on post mortem computed tomography

Donor bone grafts are an important aspect of orthopaedic surgery. The use of plain film as a pathological screening tool before donor bone dispatch has revealed “lytic” lesions in proximal humeri. Donor demographics did not support the diagnosis of myeloma and subsequent computed tomography (CT) scans of these bones identified the lesions as air, not pathology. In total, 27 long bones were scanned and 100% (27/27 cases) exhibited air within the trabecular bone. Three distinct patterns were found: ovoid, linear/branching, and broad channel. A longitudinal course of CT scans was performed to identify at which stage air appeared within the bone. Pre-retrieval, preprocessing, and postprocessing scans revealed that air originated between the retrieval and preprocessing stages of donor bone preparation. There may be multiple aetiology of this phenomenon, including bone retrieval and natural decomposition.     

Reconstructive options after temporal bone resection for squamous cell carcinoma.

Squamous cell carcinoma (SCC) of the temporal bone is a rare, aggressive and highly malignant tumour that requires specialised, multidisciplinary surgery for its treatment. Reconstruction of the defect is as crucial as the tumour ablation in terms of mortality and postoperative morbidity. METHODS: The experience of the East Anglian Skull Base Surgery Service from 1982 to 2004 in managing 42 consecutive patients (22 females; age range 37-80 years) undergoing extended and lateral temporal bone resection for SCC is presented. RESULTS: The overall 5-year survival was 31.0% (median follow up: 97 months) when both curative and palliative procedures were included. On multivariate analysis, the favourable prognostic factors were male sex, well-differentiated tumours and stage N(0) neck. The reconstructions in 38 patients were analysed. The majority (24/38) had free tissue transfer reconstructions and most of these were radial forearm free flaps. Later in the series, other free flap types such as anterolateral thigh flaps and lateral arm flaps were employed. Pedicled myocutaneous flaps and local flaps were also used. CONCLUSIONS: This paper analyses the outcomes of the various reconstructions and discusses the evolution of their care in our unit. The information obtained from the review of our data is extrapolated to offer guidance on the choice of reconstructive option in these patients.     

Estimation methods for Maximum Residue Limits for pesticides

Maximum Residue Limits (MRLs) are standards that represent the maximum residue concentration expected to be found if a pesticide is applied according to good agricultural practice (GAP). MRLs are established only where the residues in food resulting from particular use patterns of the pesticide pass the public health risk assessment. Foodstuffs are monitored for MRL compliance and MRL exceedance can have economic and trade consequences. There is a trade-off when deciding on values for MRLs. The aim is to establish MRLs at levels that are high enough to prevent chance exceedance but not so high that misuse will not be detected. Small data sets typically available for estimating MRLs present problems for establishing consistent values. A review of MRL estimation methods is presented together with an assessment of the various methods.