Bilingualism is a long-term cognitively challenging experience that modulates metabolite concentrations in the healthy brain.

Cognitively demanding experiences, including complex skill acquisition and processing, have been shown to induce brain adaptations, at least at the macroscopic level, e.g. on brain volume and/or functional connectivity. However, the neurobiological bases of these adaptations, including at the cellular level, are unclear and understudied. Here we use bilingualism as a case study to investigate the metabolic correlates of experience-based brain adaptations. We employ Magnetic Resonance Spectroscopy to measure metabolite concentrations in the basal ganglia, a region critical to language control which is reshaped by bilingualism. Our results show increased myo-Inositol and decreased N-acetyl aspartate concentrations in bilinguals compared to monolinguals. Both metabolites are linked to synaptic pruning, a process underlying experience-based brain restructuring. Interestingly, both concentrations correlate with relative amount of bilingual engagement. This suggests that degree of long-term cognitive experiences matters at the level of metabolic concentrations, which might accompany, if not drive, macroscopic brain adaptations.

Protective role of olesoxime against wild-type α-synuclein-induced toxicity in human neuronally differentiated SHSY-5Y cells.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α-Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the SNCA gene or copy number variations are associated with some forms of familial PD. Here, the objective of the study was to evaluate whether olesoxime, a promising neuroprotective drug can prevent ASYN-mediated neurotoxicity. EXPERIMENTAL APPROACH: We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild-type ASYN in neuronally differentiated human neuroblastoma (SHSY-5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane-bound ASYN oligomers and cell death combining both apoptotic and non-apoptotic pathways. KEY RESULTS: Olesoxime fully protected differentiated SHSY-5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase-9 activation suggesting that olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, olesoxime displayed neurotrophic effects on neuronally differentiated SHSY-5Y cells, independent of ASYN expression, by promoting their differentiation. CONCLUSIONS AND IMPLICATIONS: Because ASYN is a common underlying factor in many cases of PD, olesoxime could be a promising therapy to slow neurodegeneration in PD.

Bone mass, areal, and volumetric bone density are equally accurate, sensitive, and specific surrogates of the breaking strength of the vertebral body: an in vitro study.

The validity of the bone mineral density (BMD) measurement depends on its accuracy as a predictor of the breaking strength of bone. As the breaking strength is proportional to the square of the apparent density, a small error in the calculation of BMD may result in a larger error in the predicted bone strength. The aims of this study were (i) to determine whether inaccuracies in the measurement of the dimensions, projected area, and volume of the vertebral body (used to derive the areal and volumetric BMD) result in errors in the predicted breaking strength and (ii) to compare the accuracy, sensitivity, and specificity of bone mineral content (BMC), areal BMD, volumetric BMD, and volumetric bone mineral apparent density (BMAD) as surrogates of bone strength. We measured the BMC (by densitometry), dimensions and volume (using calipers, densitometry, the Carter et al. and Peel and Eastell methods), and breaking strength (using the Instron 1114 apparatus, Newtons, N) of 22 vertebral body specimens. All methods resulted in errors in height, width, and depth between -11.3 +/- 1.0 and 30.4 +/- 1.8% relative to the "gold" standard caliper method. The vertebral body volume (of 38.0 +/- 1.2 cm3) measured by submersion was used as the gold standard to derive the volumetric BMD gold standard (of 0.162 +/- 0.01 g/cm3). All methods, except the Peel and Eastell method, resulted in errors ranging between -10.7 +/- 1.5 and 56.9 +/- 3.4% in vertebral body volume and -35.6 +/- 1.5 to 12.6 +/- 1.8% in volumetric BMD (all p < 0.0005). The same absolute value for volumetric BMD predicted a breaking strength that differed according to the method used to derive BMD. For example, a volumetric BMD of 0.162 g/cm3 predicted a breaking strength of 6208 N (submersion method), 5473 N (caliper method), 6095 N (Peel and Eastell method), 7697 N (DXA method), and 9470 N (Carter et al. method). The mean volumetric BMD derived by each method differed (0.181, 0.165, 0.133, and 0.104 g/cm3, respectively). However, all were accurate; each predicted a similar breaking strength (6177, 6217, 6209, and 6221 N respectively). Likewise, breaking strengths predicted by the mean BMC, areal BMD by calipers, and areal BMD by dual-energy X-ray absorptiometry (DXA) were 6267, 6214, and 6244 N, respectively. The methods were equally sensitive; a 1 standard deviation (SD) decrease in volumetric BMD resulted in a similar decrease in the breaking strength of 1818 (caliper), 2080 (Peel and Eastell), 2001 (DXA), and 1625 N (BMAD by Carter et al). A 1 SD decrease in BMC, areal BMD (using calipers) and areal BMD (using DXA) predicted a decrease in the breaking strength of 2019, 1738, and 1825 N, respectively. All methods were equally specific; the variance in bone strength explained by bone mass did not differ for volumetric BMD (38-61% depending on the method), BMC (58%), or areal BMD (48%). In conclusion, despite errors in the measurement of the dimensions of the vertebral body, bone mass, areal, and volumetric bone density are equally accurate, sensitive, and specific surrogates of the breaking strength of bone in vitro.

The benefit of hormone replacement therapy on bone mass is greater at the vertebral body than posterior processes or proximal femur.

The aim of this study was to determine whether the higher vertebral bone mass in women receiving hormone replacement therapy (HRT) is confined to the trabecular rich vertebral body rather than the predominantly cortical posterior processes, and to determine whether the protective effect of HRT at the proximal femur, a predominantly cortical site, is less than at the spine. Bone mass (g) of the third lumbar vertebra (total, vertebral body and posterior processes, measured by lateral scanning), and bone mineral density (g/cm2) of the femoral neck, Ward's triangle, and trochanter were measured using dual X-ray absorptiometry in a cross-sectional study of 71 women receiving HRT for 5.7 +/- 0.4 years (mean +/- SEM), ranging from 1 to 21 years, 69 age-matched controls, and 42 premenopausal controls aged 20 to 40 years. Relative to untreated postmenopausal controls, total bone mass of the third lumbar vertebra (body plus posterior processes) by postero-anterior (PA) scanning was 0.4 +/- 0.1 SD or 9.6 +/- 3.0% higher in HRT treated women (p < 0.01). By lateral scanning, total bone mass was higher than age-matched controls (z score 0.4 +/- 0.1 SD or 11.2 +/- 3.4%, p < 0.01). This difference was confined to the vertebral body (z score 0.6 +/- 0.1 SD, p < 0.001), which was 17.1 +/- 3.3% higher than in age-matched controls (p < 0.001). Bone mass of the posterior processes was no higher [z score 0.1 +/- 0.1, not significant (NS)]. The deficit at the vertebral body in HRT-treated women, relative to premenopausal controls, was half the deficit at the vertebral body in untreated postmenopausal women (t score -0.7 +/- 0.1 vs. -1.4 +/- 0.1 SD, respectively; p < 0.001) but no less at the posterior processes (t score -1.6 +/- 0.2 vs. -1.9 +/- 0.2 SD, respectively; NS). Similarly, the deficit in the vertebral body in the HRT treated group was half the deficit at their posterior processes (t score -0.7 +/- 0.1 SD vs. -1.6 +/- 0.2, respectively; p < 0.001). In HRT-treated women, bone mass diminished significantly with age at the posterior processes (r = -0.31, p < 0.01), but not at the vertebral body (r = -0.21, p = 0.07). Bone mass diminished significantly with age at the vertebral body and posterior processes in untreated women (r = -0.55, p < 0.001; r = -0.45, p < 0.001, respectively). Bone density (g/cm2) diminished at all femoral sites with advancing age in HRT-treated women. A protective effect was seen at the femoral neck and Ward's triangle, but not trochanter (z score 0.2 +/- 0.1, p = 0.06; 0.3 +/- 0.1, p < 0.05; 0.0 +/- 0.1, NS, respectively). In conclusion, the protective effect of HRT against bone loss at the vertebral body, the site of fracture in osteoporosis, may be underestimated by PA scanning. The greater benefit at the vertebral body, and more modest effect at the proximal femur, suggests that HRT may be a more effective means of reducing the risk of spine than hip fractures.

The mechanism underlying the hypocholesterolemic effect of chronic fish oil feeding in rats is not due to increased excretion of dietary cholesterol.

The role of the excretion of dietary cholesterol in the hypocholesterolaemic effect of chronic fish oil feeding in rats was investigated. The hepatic uptake and processing of [3H]cholesterol carried in chylomicrons derived from fish oil was studied in vivo in rats fed a low fat diet or a diet supplemented with fish oil for 21 days. In addition, the effects of the fish oil diet on cholesterol esterification, cholesteryl ester hydrolysis, bile acid synthesis and biliary lipid secretion were determined. In rats fed the fish oil as compared to the low fat diet, the uptake of [3H]cholesterol from the blood and its secretion into bile as bile acids was significantly slower, and this was entirely due to a decrease in the bile acid fraction. Biliary bile acid mass secretion was unchanged by fish oil feeding, while biliary cholesterol and phospholipid secretion was increased. No significant differences were observed either in the expression of mRNA for cholesterol 7alpha hydroxylase or the secretion of bile acids into bile after 20 h biliary drainage between the fish oil and low fat diet groups, suggesting that bile acid synthesis is not affected. These results indicate that the access of chylomicron cholesterol to the hepatic substrate pool for bile acid formation is decreased in the fish oil fed rats, and this, together with its slower uptake from the blood, accounts for the retardation of its excretion via the bile. Thus, the hypocholesterolemic effect of dietary fish oil in rats is not due to more rapid metabolism of cholesterol originating from the diet.

An integrated residency in internal and preventive medicine.

The importance of preventive and population-based principles in clinical practice is widely acknowledged. The challenge of imparting these principles in either undergraduate or postgraduate medical education has, however, not been fully met. The necessary skills are provided comprehensively by preventive medicine residency programs, but at the expense of clinical training. Sequential residencies in primary care and preventive medicine, the currently available means of obtaining thorough preparation in both clinical and population-based principles, represent an inefficient, generally unappealing, and non-integrated approach. In response to these concerns, and in an effort to make preventive medicine training appeal to a wider audience, the authors developed and implemented a residency program fully integrating internal and preventive medicine. The program meets, and generally exceeds, the requirements of both specialty boards over a four-year period. The program provides extensive training in clinical, preventive, and public health skills, along with case management and cost-effective care, conferring the MPH degree and leading to dual board eligibility. The model is ideally wed to the demands of the modern health care environment in the United States, is extremely attractive to applicants, and may warrant replication both to train academic and administrative leaders and to raise the standards of preventive and public health practice in primary care.

Task-achievement, obsessive-compulsive, type A traits, and job satisfaction of professionals in public practice accounting.

This paper contains a description of the results of a two-year study of task-achievement, obsessive-compulsive, Type A traits, and job satisfaction within randomly selected groups of 499 public practice accountants in Ontario, Canada. The results supported the notion that this profession attracts and conditions personalities with task-oriented, order-driven, Type A characteristics. With the exception of those who were advanced partners, the majority of public practice accountants were only moderately job-satisfied and were reportedly not committed to staying in their present jobs until retirement.

Gastroduodenal dyspepsia: a personal view integrating clinical, endoscopic, histological and management criteria. The spiro syndrome.

I am presenting my view on how to approach the difficult subject of dyspepsia, based on my personal experience and the writings and teachings of Howard M. Spiro. Symptoms arising from the esophagus, and called esophageal dyspepsia, are separated from symptoms arising from the stomach, designated as gastroduodenal dyspepsia. The holistic approach to patients with dyspepsia, and designated Spiro syndrome, is the main purpose of this report. I am introducing a newly defined classification, and criteria, using an interchangeable, standardized nomenclature, to be used by the clinician, endoscopist, and pathologist for diagnosing and managing the causes of gastroduodenal dyspepsia. There are five clinical/endoscopic/histological categories to be considered as possible causes of gastroduodenal dyspepsia. Often these entities are found to be asymptomatic, or a combination may cause symptoms: (1) idiopathic dyspepsia--normal endoscopy and histology; (2) congestive gastropathy/duodenopathy; (3) gastritis/duodenitis; (4) peptic ulcer crater, and (5) gastric cancer. I believe this holistic, unifying approach to diagnosis and management of dyspepsia will enhance the communication between physicians and help standardize the terminology for clinical investigation.

No acid, no polys--no "active" gastritis, no dyspepsia. A proposal.

The current dilemma in characterizing non-ulcer dyspepsia (NUD) is due to the very nature of the term which has forced the dependence for diagnosis primarily on symptomatology and the absence of an ulcer crater as ascertained by radiographs or endoscopy. I propose a new classification which I believe is consistent and well founded, based on the presence of histologic gastritis and acid secretion of the stomach. Four categories are presented: (a) normal histology, (b) "active" gastritis, (c) "inactive" gastritis, and (d) atrophic gastritis with achlorhydria. Acid secretion is present in categories a-c. The classification is dependent on the presence of the "poly" to denote active gastritis, round cells to classify inactive gastritis, and the loss of parietal and chief cells with achlorhydria to define gastric atrophy. I propose that polys and acid, which characterize active gastritis, are necessary for producing dyspepsia and/or gastroduodenal mucosal injury, and provide a rationale for treatment. The accepted causes of active gastritis include acid-peptic disease, Campylobacter pylori, and aspirin/nonsteroidal anti-inflammatory drug (NSAID) medication.

The Yale-Affiliated Gastroenterology Program: 1965-1995. A community-university model of collaboration.

The Yale-Affiliated Gastroenterology Program (YAGP) originated in 1965 from the informal arrangements of two gastroenterologists, one university based and the other in a community hospital. Conceived at a time when there was little central authority, either on a national or on a hospital/medical school level, its links were forged by the personal relationships of its directors. The process of growth remained informal and flexible enough for the directors to meet the special requirements of their own community and hospital. YAGP provided an important model for improving medical care and education in community hospitals since it addressed personnel needs, contributed to the education of physicians, and fostered clinical research in digestive diseases. YAGP evolved its own standards and its own accreditation mechanism, but faltered when the Accreditation Committee on Graduate Medical Education provided national rather than local criteria. Increased controls by hospitals and medical schools led to more formal ties and programs, and YAGP ceased to matter. Still, there may be lessons from what was in its time an innovation, on a local and state level rather than on a national level.

Ulcerative colitis and scleroderma. A coincidental relationship?

Speculation continues that ulcerative colitis is an autoimmune disorder that is frequently associated with other diseases with a similar underlying pathogenic mechanism. In 1965 we reported a patient with ulcerative colitis and scleroderma in support of this hypothesis. Now we supply a follow-up of over 30 years to describe how each disease acted independently, evidence, we believe, that the association was primarily fortuitous.

Purification and cDNA cloning of anthranilate synthase from Ruta graveolens: modes of expression and properties of native and recombinant enzymes.

Ruta graveolens utilizes anthranilate synthase (AS) for the synthesis both of tryptophan in primary metabolism and acridone alkaloids in secondary metabolism. AS has been purified from plants and cell cultures of R. graveolens 670- and 1700-fold, respectively. Glutamine- and ammonia-dependent AS activities were strictly co-purified in all steps. Through cDNA cloning and complementation of Escherichia coli deletion mutants defective for AS, it is shown that young Ruta plants express two genes for functional AS alpha subunits, AS alpha 1 and AS alpha 2. The data indicate that AS alpha from Ruta requires an AS beta subunit with a native molecular weight of 60-65 kDa for the glutamine-dependent reaction. Protein synthesized in vitro from cloned cDNA is processed upon import into isolated chloroplasts, indicating that mature AS alpha subunits are active in plastids in vivo. AS alpha 1 and AS alpha 2 are constitutively expressed in Ruta cell cultures, but AS alpha 1 steady-state mRNA levels are increased 100-fold 6 h subsequent to elicitation whereas AS alpha 2 expression remains constitutive. Increased AS alpha 1 transcription corresponds to elicitor-induced alkaloid accumulation. The data indicate that Ruta regulates anthranilate flux into primary and secondary metabolism through differential regulation of AS genes specific to these pathways.

Isoenzymes of pyruvate kinase in etioplasts and chloroplasts.

Isoenzymes of pyruvate kinase from green leaves of castor bean and etiolated leaves of pea plants have been separated by ion filtration chromatography. One of the isoenzymes is localized in the plastid, whereas the other is in the cytosol. The cytosolic enzyme has a pH optimum from pH 7 to pH 9, and is able to utilize nucleotides other than ADP as the phosphoryl acceptor. The plastid enzyme has a much sharper optimum at pH 8, and is less efficient at using alternative nucleotides. The plastic pyruvate kinase, unlike the cytosolic enzyme, requires the presence of dithiothreitol or 2-mercaptoethanol during isolation and storage to stabilize the activity.

Endoscopic treatment of Dieulafoy's lesion of the duodenum.

Dieulafoy's lesion is an often unrecognized cause of catastrophic upper gastrointestinal hemorrhage, typically seen in otherwise asymptomatic patients. Although the lesion is most often found in the stomach, it has rarely been reported to occur in the jejunum and duodenum. Endoscopic treatment has recently been attempted to arrest the bleeding from these lesions, when found in the stomach, with satisfactory results. We report a patient with a bleeding duodenal Dieulafoy lesion who was successfully treated with endoscopic injection of epinephrine (1:10,000) and electrocoagulation. Endoscopic treatment of Dieulafoy's lesion should be attempted before surgery and, as in other causes of acute nonvariceal hemorrhage, be considered the treatment of choice.