Skill learning and repetition priming in Alzheimer's disease.

While perceptual-motor learning occurs normally in Alzheimer's disease (AD) patients, their ability to acquire the skill of reading transformed text has not been well delineated. AD patients and matched controls were timed as they read two blocks of words presented in mirror image. Control subjects displayed both skill learning and repetition priming, whereas AD patients displayed only repetition priming. Skill learning in AD patients was associated with their ability to complete verbal analogies. They displayed the expected impairment in recognition for the words from the mirror reading task. The failure of AD patients to acquire the mirror reading skill can be understood through a task analysis and may reflect an underlying deficit in abstract reasoning that precludes the development of appropriate pattern analyzing strategies needed to transform rotated text.     

Activation of muscle fibers in individual motor units revealed by 2-deoxyglucose-6-phosphate

Motor units of the cat tibialis posterior muscle were selectively activated by prolonged electrical stimulation of functionally isolated motor axons in situ. During the activation, the glucose analog 2-deoxyglucose (DG) was administered systemically. Single muscle fibers were subsequently examined for accumulation of the metabolite 2-deoxyglucose-6-phosphate (DG6P) by an analytical assay and for depletion of glycogen by a PAS glycogen-specific staining reaction (periodic acid Schiff; PAS). In general, levels of DG6P were 20 times greater in unstained (PAS-negative) fibers compared with stained (PAS-positive) fibers. However, some glycogen-depleted fibers, particularly in putative ischemic fascicles of the muscle, did not have elevated DG6P, suggesting that depletion of glycogen is not always a reliable indicator of fiber activation. Furthermore, the PAS-staining reaction was not necessarily indicative of quantitative glycogen levels in single fibers. Thus, this report shows that DG6P accumulation enhances the identification of motor-unit fibers selectively activated via their common motor-nerve axon. Evidence is also presented for differential glucose uptake in muscle fibers of different phenotype, thereby indicating that the DG6P measurement in muscle has broad applicability to the investigation of cellular glucose utilization.     

Stimulation or inhibition of the respiratory burst in cultured macrophages in a mycobacterium model: initial stimulation is followed by inhibition after phagocytosis.

Microorganisms cause varying degrees of stimulation of superoxide (O2-) production (respiratory burst [RB]) in macrophages but in some cases apparently inhibit the RB induced in the same monolayers by a conventional stimulator. We have explored these differences. A mycobacterium model, the slowly multiplying mouse pathogen Mycobacterium microti, induced a modest RB in resident macrophage monolayers, compared with the substantial RB induced by opsonized zymosan (Zy). However, if the 1-h M. microti pulse immediately preceded the Zy assay (instead of being concurrent), the RB was consistently less than that elicited by the Zy alone. Cytochalasin (an inhibitor of phagocytosis) enhanced Zy-induced RB, supporting the view that the burst is cell surface mediated, but this agent apparently eliminated the inhibition of the Zy-induced RB caused by prior M. microti exposure, suggesting that this inhibition may have an intracellular origin. The inhibition described extended not only to another mycobacterium (Mycobacterium bovis BCG) but also to a previous application of Zy itself. The general implications for macrophage functions of these observations on timing and sites of initiation are briefly discussed.     

Proliferative activity of colonic mucosa at different distances from primary adenocarcinoma as determined by the presence of statin: A nonproliferation-specific nuclear protein

The field change is one hypothesis concerning the development of colorectal carcinoma. Removal of a carcinoma without its entire surrounding altered mucosa may result in the development of a recurrence. S44, a monoclonal antibody directed against statin, a nuclear protein expressed in nonproliferating cells in either a quiescent or senescent state, was used to determine the rate of cell growth in colorectal mucosa at different distances from carcinomas. The specimens of 18 patients undergoing resection of a colorectal carcinoma were immediately opened after operation, and strips of mucosa were taken at distances of 1 cm, 5 cm, and 10 cm from the carcinoma. For each location, 10 longitudinally oriented crypts were evaluated for statin-positive cells identified by the presence of a dark brown peroxidase-conjugated antibody reaction product. The average percentage of statin-positive cells per crypt was significantly lower at a 1-cm distance from the carcinoma compared with the mucosa located 5 and 10 cm from the carcinoma (20.89±4.33 at 1 cm, 32.41±5.27 at 5 cm, and 34.23±6.45 at 10 cm). None of the calculated parameters showed any significant difference between the 5-cm and 10-cm locations. The fact that the proliferation rate of the mucosal cells returns to the normal level at 5 cm from the margin of the carcinoma suggests that cells located within this distance still retain proliferative potential even though they are morphologically indistinguishable from their normal counterparts. We conclude that failure to remove this transitional, potentially proliferative mucosa may result in subsequent development of anastomotic or perianastomotic recurrences.This study was conducted with support from the Sir Mortimer B. Davis-Jewish General Hospital Foundation and the American Physician Fellowship and with grants to Eugenia Wang from the Medical Research Council of Canada and from the National Institute on Aging of the National Institutes of Health of the U.S.A.     

The acute inflammatory response to lipopolysaccharide in CNS parenchyma differs from that in other body tissues.

Acute inflammation is important for defence against infection, wound repair and the mediation of auto-immune tissue destruction. Myelomonocytic recruitment in acute inflammation is a stereotyped and non-specific response to tissue insult which begins within 2 h. In this study, lipopolysaccharide was injected into the murine CNS and other body sites of mice to compare the inflammatory responses. Doses of lipopolysaccharide which induced typical myelomonocytic recruitment in skin and the choroid plexus had no effect in CNS parenchyma, apart from the morphological activation of local resident microglia. The CNS parenchymal response proceeded independently of that in the choroid plexus-cerebral ventricles and had three distinct and unique phases. Initially there was minimal neutrophil exudation and a two-day delay before any increase in macrophage-microglial cell number. Next, there was a rapid increase in macrophage-microglial cell numbers during the third day, mainly due to recruitment of blood monocytes. During this phase, leukocyte recruitment was restricted to monocytes which rapidly adopted the arborized microglial phenotype. Monocytes migrated through an intact blood-brain barrier independent of changes in solute permeability. Finally, there was a florid myelomonocytic reaction predominantly in the white matter, one week after intracerebral injection of 2 micrograms lipopolysaccharide. At this time, the leukocyte reaction disrupted the blood-brain barrier, mononuclear phagocytes expressed macrophage morphology and abundant major histocompatibility complex Class II antigen, and T lymphocytes were present. Myelomonocytic entry into the CNS was partially inhibited by prior blockade of the type 3 complement receptor, known to mediate leukocyte adhesion to endothelium elsewhere. The processes which lead to rapid myelomonocytic recruitment in other tissues are absent in CNS parenchyma. Understanding the molecular mechanisms responsible could have considerable significance both for CNS pathophysiology as well as possible anti-inflammatory therapeutic application elsewhere in the body.     

Second-messenger pathways involved in the regulation of survival in germinal-centre B cells and in Burkitt lymphoma lines.

Spontaneous apoptosis in germinal-centre (GC) B cells can be prevented by treatment with anti-immunoglobulin (Ig). By contrast, susceptible group-I Burkitt lymphoma (BL) cells can be driven to apoptosis by anti-Ig. The second-messenger pathways involved in the regulation of apoptosis in GC B lymphocytes and in BL cell lines were studied using pharmacological agonists or inhibitors of intracellular calcium ([Ca2+]i) and protein kinase C (PKC). Anti-Ig was found to mobilize Ca2+ in group-I cells. Pre-incubation with the Ca2+ chelator EGTA partially reduced apoptosis induced by anti-Ig or by Ca2+ ionophore in group-I BL cells. Activation of PKC with phorbol ester reduced such Ca(2+)-driven programmed cell death (PCD) to control levels of apoptosis. Apoptosis in group-I BL cell lines could also be triggered by the kinase inhibitors staurosporine and Ro-31-8220 at concentrations selective for PKC activity. Expression of the bcl-2 protein in BL group-I cells following gene transfer affords protection from apoptosis induced by ionomycin or anti-Ig. In the present study, bcl-2 was additionally found to protect from apoptosis driven by staurosporine. The high levels of spontaneous apoptosis exhibited by normal GC B cells were reduced, but not abrogated, by co-culture with phorbol ester. These results indicate that, in group-I BL cells, imbalance in the phosphoinositide pathway of signalling, in favour of [Ca2+]i and away from PKC, results in apoptosis: constitutive phosphorylation of key proteins by PKC may therefore suppress apoptosis in BL as well as in GC B cells.     

The optimal technique for electrical cardioversion of atrial fibrillation

The optimal approach to electrical cardioversion of atrial fibrillation includes appropriate patient selection, anticoagulation, careful selection and monitoring of antiarrhythmic therapy, and proper electrical cardioversion technique. The optimal technique requires the use of metal electrodes, with one electrode of at least 8 cm in diameter placed in the anterior position, and the second of 12–13 cm diameter placed posteriorly just below the left scapulae, with generous amounts of the appropriate gel (such as Hewlett-Packard Redux Paste) as the electrode-skin interface and firm pressure to the paddle electrode with the patient in expiration. Thus the anterior-posterior chest diameter is decreased and less air between the electrodes is assured. The initial shock strength should be 200 J. The shock is synchronized with the electrocardiographic QRS complex. This report reviews the justification for these recommendations.     

Effects of the PPAR-gamma agonist rosiglitazone on renal haemodynamics and the renin-angiotensin system in diabetes.

BACKGROUND: Thiazolidinediones (TZD) have been reported to improve early stages of diabetic nephropathy independent of glycaemic control. Since blockade of the renin-angiotensin system (RAS) is known to reduce the risk of nephropathy, we hypothesised that the renal effect of TZDs might be related to a favourable effect on the intrarenal RAS. We aimed to determine if the TZD rosiglitazone could reduce RAS activation. METHODS: We studied adult type 2 diabetic patients and placed them on rosiglitazone for three months. We have previously used the renal haemodynamic response to angiotensin-converting enzyme (ACE) inhibition to demonstrate the state of RAS activation, and thus measured renal plasma flow (RPF) and glomerular filtration rate (GFR) before and after administration of captopril at 0 month and at three months. Plasma renin activity (PRA), active renin, aldosterone and natriuretic peptides were analysed. RESULTS: The RPF response to ACE inhibition was not altered. There was no change in GFR, PRA, active renin and aldosterone levels. Two patients developed oedema one had an elevated baseline active renin and another had an elevated baseline aldosterone level. CONCLUSION: The favourable effects of TZDs on diabetic nephropathy is likely not related to an influence on the RAS.