Scanning electron microscope measurement of width and shape of 10nm patterned lines using a JMONSEL-modeled library.

The width and shape of 10nm to 12 nm wide lithographically patterned SiO2 lines were measured in the scanning electron microscope by fitting the measured intensity vs. position to a physics-based model in which the lines' widths and shapes are parameters. The approximately 32 nm pitch sample was patterned at Intel using a state-of-the-art pitch quartering process. Their narrow widths and asymmetrical shapes are representative of near-future generation transistor gates. These pose a challenge: the narrowness because electrons landing near one edge may scatter out of the other, so that the intensity profile at each edge becomes width-dependent, and the asymmetry because the shape requires more parameters to describe and measure. Modeling was performed by JMONSEL (Java Monte Carlo Simulation of Secondary Electrons), which produces a predicted yield vs. position for a given sample shape and composition. The simulator produces a library of predicted profiles for varying sample geometry. Shape parameter values are adjusted until interpolation of the library with those values best matches the measured image. Profiles thereby determined agreed with those determined by transmission electron microscopy and critical dimension small-angle x-ray scattering to better than 1 nm.

Dopamine D2 receptors quantified in vivo in human narcolepsy.

Assays in brain tissues from humans suffering from narcolepsy, and from genetically narcoleptic dogs have suggested that dopamine function may be disturbed in this condition. We have used the specific D2 receptor ligand N-(3-[18F]fluoropropyl)-spiperone and positron tomography to study a group of 6 well-characterized medication-free, HLA-DR2 DRW15 DW6-positive narcoleptic patients and a group of age- and sex-matched control individuals during life. We found no difference in striatal D2 receptor binding between these two groups. These results suggest that narcolepsy is not associated with alterations in D2 receptor density and affinity.

Three clinical syndromes of schizophrenia in untreated subjects: relation to brain glucose activity measured by positron emission tomography (PET).

A number of studies of chronically ill, medicated patients have found that the clinical symptoms of schizophrenia segregate into three syndromes which can be labelled poverty, disorganization, and reality distortion. It has been previously found that each of these syndromes is associated with a specific pattern of perfusion (rCBF) in paralimbic and association cortex and in related subcortical nuclei. We replicated the symptom factors in 20 untreated subjects. Utilizing positron emission tomography with 18-F-fluorodeoxyglucose as a tracer for glucose metabolism, we reconstructed a map of the entire cortical activity from 16 to 20 tomographic slices. Each of the three syndromes was associated with a different pattern of regional glucose metabolism. Findings in common with previous studies were an association of poverty with left cortical metabolic activity in prefrontal and superior parietal areas, reality distortion with left temporal activity, and disorganization with left inferior parietal lobule. This is the first report of an association between regional metabolic activity and clinical syndromes in untreated patients, strengthening previous models of distributed neural networks in this disorder.

Identifying variables associated with inaccurate self-monitoring of blood glucose: proposed guidelines to improve accuracy.

PURPOSE: This study was conducted to evaluate patients' proficiency in self-monitoring of blood glucose (SMBG). METHODS: Diabetes nurse educators in 4 suburban Minneapolis clinic sites surveyed the SMBG training/cure practices of 280 patients with type 1 and type 2 diabetes. Participant SMBG technique was measured by direct observation. Participants performed a finger puncture and used their own meters to measure the first blood sample. A second sample was measured on the HemoCue B Glucose analyzer, and a third sample was used to measure hemoglobin. The series of tests were then repeated. If either of the 2 glucose tests was more than 15% from the HemoCue value, participants were reeducated about the manufacturer's suggested procedure. RESULTS: Of the 280 participants, 19% had blood glucose test results greater than the 15% limit for meter accuracy. After reeducation, 69% of those who had initially failed achieved acceptable results. The most significant problems were lack of periodic meter technique evaluation, difficulty using wipe meters, incorrect use of control solutions, lack of hand washing even when observed, and unclean meters. CONCLUSIONS: As a result of the study, guidelines were subsequently developed to evaluate meter accuracy in an outpatient setting. Further effort is needed to establish standards for evaluating SMBG.

Implications of positron emission tomography research for the investigation of the actions of antipsychotic drugs.

Positron emission tomography studies of regional brain metabolic activity, cerebral blood flow and D2 dopamine receptor binding in schizophrenics and controls are reviewed. Methodological influences on the validity of the data generated by these technologies include problems with measurement as well as clinical and anatomical heterogeneity. Work in these fields to date, however, has produced strong support for the role of D2 dopamine receptor blockade in antipsychotic efficacy. Neuroleptic-induced changes in regional brain metabolism over time have also been observed; however, the relationship between such actions and symptomatic change needs to be further clarified. Future studies on time-course of neuroleptic-associated changes in regional brain metabolism, blood flow and dopamine receptor binding in schizophrenics have the potential to provide greater insight into the relationship of these actions to symptomatic changes and drug-induced side-effects.

A meta-analysis of HLA-antigen prevalences in alcoholics and alcoholic liver disease.

In the search for genetic factors influencing susceptibility to the development of alcoholism and alcoholic liver disease, 28 studies have been published analysing the distribution of human leucocyte antigens (HLA) in alcoholics compared to healthy controls. A number of HLA-phenotypes has been suspected of being associated with both alcoholism and alcoholic liver disease. In the present study a meta-analysis is carried out on the data from these studies, subdivided according to race and degree of liver injury. The conclusion is that none of the HLA-phenotypes so far investigated in Caucasians can be shown to be significantly more common in any of the studied patient categories than in controls, whereas the results of Japanese studies are less clear. The limitations of the data material and the design of the studies are discussed, as well as the strength and limitations of the method of meta-analysis.

[3H]dopamine labeling of D3 dopaminergic sites in human, rat, and calf brain.

The binding of [3H]dopamine to brain regions of calf, rat, and human was investigated. The calf caudate contained the highest density of [3H]dopamine binding sites, with a Bmax value of 185 fmol/mg protein, whereas rat and human striatum contained one-third this number of sites. The KD values for [3H]dopamine in all tissues were 2-3 nM. Dopaminergic catecholamines (dopamine, apomorphine, 6,7-dihydroxy-2-aminotetralin, and N-propylnorapomorphine) inhibited the binding of [3H]dopamine in all three species, at low concentrations, with IC50 values of 1.5 to 6 nM. Neuroleptics, in contrast, inhibited the binding at high concentrations (with IC50 values of 200 to 40,000 nM). The [3H]dopamine binding sites were saturable, heat-labile, and detectable only in dopamine-rich brain regions; these sites differed from D2 dopamine sites (labeled by [3H]butyrophenone neuroleptics), and from D1 dopamine sites (labeled by [3H]thioxanthene neuroleptics) associated with the dopamine-stimulated adenylate cyclase. We have, therefore, called these high-affinity [3H]dopamine binding sites D3 sites. [3H]Apomorphine and [3H]ADTN also appeared to label D3 sites. These ligands however, were less selective than [3H]dopamine, and labeled sites other than D3 as well. Assay conditions were important in determining the parameters of [3H]dopamine binding. The optimum conditions for selective labeling of the D3 dopaminergic sites, using [3H]dopamine, required the presence of EDTA and ascorbate.

Resolution of dopamine and serotonin receptor components of [3H]spiperone binding to rat brain regions.

A procedure was developed to identify receptors for dopamine and serotonin separately and selectively by means of [3H]spiperone and to measure the density of each receptor in different regions of the rat brain. In the striatum, the binding of [3H]spiperone to dopamine receptors was inhibited by sulpiride but not by quinazolinedone R43448 (R43448); in the frontal cortex, however, the binding of [3H]spiperone to serotonin receptors was inhibited by R43448 but not by sulpiride. Thus, the density of dopamine receptors (D2 sites) was measured by [3H]spiperone binding in the presence of 0.1 microM R43448 (to preclude the attachment of the 3H-labeled ligand to serotonin sites), while the density of serotonin receptors (S2 sites) was measured by [3H]spiperone binding in the presence of 10 microM sulpiride (to preclude the attachment of the 3H-labeled ligand to dopamine sites). The density of D2 sites was highest in the striatum, followed by the olfactory tubercle, hypothalamus, substantia nigra, and the lower pons--medulla region. All five regions had similar dissociation constants (Kd values) of 0.05--0.15 nM. The density of S2 sites was highest in the frontal cortex, followed by the posterior cortex, olfactory tubercle, striatum, hypothalamus, and thalamus, and all regions had Kd values in the range 0.6--2.3 nM. Thus, because the Kd values were similar for all regions, and because Scatchard analyses revealed a single set of sites for either D2 or S2 (where detected), the main criteria for resolving the dopamine and serotonin components of [3H]spiperone binding were considered fulfilled.

Structural and functional brain imaging in schizophrenia.

We present an evaluation of the contribution of structural and functional brain imaging to our understanding of schizophrenia. Methodological influences on the validity of the data generated by these new technologies include problems with measurement and clinical and anatomic heterogeneity. These considerations greatly affect the interpretation of the data generated by these technologies. Work in these fields to date, however, has produced strong evidence which suggests that schizophrenia is a disease which involves abnormalities in the structure and function of many brain areas. Structural brain imaging studies of schizophrenia using computed tomography (CT) and magnetic resonance imaging (MRI) are reviewed and their contribution to current theories of the pathogenesis of schizophrenia are discussed. Positron emission tomography (PET) studies of brain metabolic activity and dopamine receptor binding in schizophrenia are summarized and the critical questions raised by these studies are outlined. Future studies in these fields have the potential to yield critical insights into the pathophysiology of schizophrenia; new directions for studies of schizophrenia using these technologies are identified.

Striatal binding of 2-amino-6,7-[3H]dihydroxy-1,2,3,4-tetrahydronaphthalene to two dopaminergic sites distinguished by their low and high affinity for neuroleptics.

In order to develop more selective methods for labeling brain dopamine receptors, this study describes in detail the properties of 2-amino-6,7,-[3H]dihydroxy-1,2,3,4,-tetrahydronaphthalene ([3H] ADTN) binding to dopaminergic sites in rat, calf, and human brain. [3H]ADTN labeled two distinct types of dopaminergic binding sites in the brain striatum of the rat, calf, and human. Very low concentrations of dopamine and dopaminergic catecholamines (with IC50 values of 1 to 10 nM) inhibited the binding of [3H]ADTN to both sites. Neuroleptics, however, inhibited the binding of [3H]ADTN in two distinctly separate concentration ranges, with IC50 values of 0.15 to 40 nM at one site and 100 and 50,000 nM at the other site. The site with high affinity for dopamine and low affinity for neuroleptics had binding properties that corresponded to those of the previously characterized D3 site (List, S., M. Titeler, and P. Seeman (1980) Biochem. Pharmacol. 29: 1621-1622). The [3H]ADTN binding site with high affinity for neuroleptics demonstrated binding characteristics similar to a site labeled by 3H-Neuroleptics (Sokoloff, P., M. P. Martres, and J. C. Schwartz (1980) Naunyn Schmiedebergs Arch. Pharmacol. 315: 89-102). [3H]Apomorphine appeared to label the same two sites as [3H]ADTN, while [3H]dopamine labeled only the D3 site. Scatchard analysis of [3H]ADTN or [3H]apomorphine binding, under conditions for selective labeling of the low affinity neuroleptic site (D3) and the high affinity site for neuroleptics, detected a density of 70 fmol/mg of protein for each. The density of the D3 site in the calf striatum (170 fmol/mg of protein) was much greater than that of the high affinity neuroleptic site (50 fmol/mg). In the rat, the dissociation constant (KD) of [3H]ADTN was 2 nM for both sites. [3H]Apomorphine, however, had a higher affinity for the D3 site (KD=1.6 nM) than for the high affinity neuroleptic site (KD=4.2 nM). The present results may explain previously observed species and laboratory differences between the binding of [3H]ADTN, [3H]apomorphine, and [3H]dopamine.

Impaired pancreatic polypeptide response to a meal in type 1 diabetic patients: vagal neuropathy or islet cell dysfunction?

The pancreatic polypeptide (PP) response to a mixed meal was investigated in seven insulin-dependent diabetics without measurable signs of diabetic autonomic neuropathy, and in seven healthy subjects. Since acute changes in metabolic regulation might influence the meal-induced PP response, the insulin-dependent diabetic patients were studied during normo- and hyperglycemic experimental conditions at blood glucose levels of 5 and 15 mmol/l, respectively. The PP response was identical on the two occasions, the response being significantly smaller than in the healthy subjects. Thus, PP response is independent of short-term changes in metabolic control. Since the response was attenuated in the insulin-dependent diabetic patients, who had no otherwise measurable signs of neuropathy, the PP response to a meal could be a sensitive indicator of dysfunction of the reflex arc controlling PP secretion in insulin-dependent diabetic patients. Alternatively, the reduction in PP secretion in these patients reflects dysfunction of the PP secreting cells of the pancreas. Iv injection of cholecystokinin-8 elicited a small but significant increase in PP concentrations, while iv secretin did not increase PP concentrations at all in healthy subjects. These stimuli are therefore less suitable in the assessment of vagal neuropathy.

Enhancement of the viscosity of mucin by serum albumin.

The interaction of serum albumin with a model epithelial mucin from pig stomach was explored by rotary viscometry. During 30 min of incubation of human serum albumin(20mg/ml) and pig gastric mucin (8mg/ml) in iso-osmotic buffers at 37 degrees C, the solution became markedly viscous. Viscosity enhancement was proportional to albumin concentration (2-40mg/ml), was most pronounced under conditions of low shear rate (less than 45S-1), and was considerably greater than the additive or multiplicative viscosity values calculated from albumin or mucin solutions measured separately. The viscous mucin-albumin complex was destroyed by high shear rates (greater than 90S-1), but slowly re-formed under zero shear conditions. Elevation of pH (7 to 9), ionic strength (0.1 to 1.0), and addition of disodium EDTA (5mM) did not cause marked or specific alterations in the viscosity of the mixture, suggesting that electrostatic interactions probably do not stabilize mucin-albumin complexes. Urea (7M) and heating (35 to 55 degrees C) caused a major increase in the viscosity of mucin and mucin-albumin mixtures, suggesting that rupture of hydrogen bonds, unfolding and partial denaturation of mucin promotes greater intertangling (possibly hydrophobic interactions) between mucin and albumin molecules. The implications of mucin-albumin interaction in diseases associated with mucus obstruction are briefly discussed.

Five- to 7-year-old children with Helicobacter pylori infection are smaller than Helicobacter-negative children: a cross-sectional population-based study of 3,315 children.

OBJECTIVE: To test whether Helicobacter pylori-positive children are smaller and weigh less than H pylori-negative children. DESIGN: Cross-sectional population-based study. PARTICIPANTS: In 3,315 5-to 7-year-old preschool and school children, the putative influence of H pylori infection on growth was investigated. Standing height and weight were analyzed in relation to H pylori infection. The diagnosis of H pylori infection was established by 13C-urea-breath test. RESULTS: The prevalence of H pylori infection in boys was 7.2% (95% confidence interval, 5.9-8.9; n = 1,550) and in girls was 6.1% (95% confidence interval, 4.9-7.3; n = 1,552) H pylori-positive children were smaller than noninfected children (117.6 +/- 5.5 cm vs. 118.9 +/- 5.7 cm; P < 0.01). Although H pylori-positive boys were 2.06 cm smaller than H pylori-negative boys (117.4 +/- 5.6 cm vs. 119.5 +/- 5.7 cm; P < 0.001), the difference in girls was not significant (117.9 +/- 5.3 cm vs. 118.4 +/- 5.7 cm). When standing height was adjusted for age, the found differences were more pronounced. Differences between the infected and noninfected children with regard to body weight were not significant (22.4 +/- 4.0 kg vs. 22.1 +/- 4.0 kg), nor was there a significant difference with regard to body-mass index. However, boys with H pylori infection had a lower weight than noninfected boys (21.6 +/- 3.3 kg vs. 22.6 +/- 4.0 kg; P < 0.01), but in girls, these differences were not observed (22.2 +/- 4.0 vs. 22.8 +/- 4.6 kg, respectively). When weight was adjusted for age, H pylori -positive children also had a lower weight than H pylori -negative children because of the lower weight of boys. CONCLUSIONS: H pylori infection is associated with growth delay, growth retardation, or both in affected children.