Insulin increases ceramide synthesis in skeletal muscle.

AIMS: The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle. METHODS: Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG) were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis. RESULTS: In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals. CONCLUSIONS: This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects.

Bone ingrowth into porous silicon nitride.

Achieving solid skeletal attachment is a requirement for the clinical success of orthopedic implants. Porous or roughened surfaces and coatings have been developed and used with mixed success to achieve attachment due to bone ingrowth. Silicon nitride is a high performance ceramic whose strength, imaging properties, and biocompatibility make it a candidate material for orthopedic implants. A porous form of silicon nitride, cancellous-structured ceramic (CSC), has been developed. CSC is a nonresorbable, partially radiolucent porous structure that can be bonded to orthopedic implants made of silicon nitride to facilitate skeletal attachment. The purpose of this study was to quantify the extent and rate of bone ingrowth into CSC in a large animal model. Cylindrical implants were placed bilaterally using staged surgeries in the medial femoral condyle of six sheep. Condyles were retrieved after 3 and 6 months in situ and prepared for examination of bone growth under SEM. Bone grew into CSC to extents and at rates similar to those reported for other titanium porous surfaces in studies involving large animals and postmortem retrievals in humans. Bone ingrowth was observed at depths of penetration greater than 3 mm in some implants after only 12 weeks in situ. Bone ingrowth into CSC is a viable method for achieving skeletal attachment.

A measure of food seeking in individuals with Prader-Willi syndrome.

BACKGROUND: Individuals with Prader-Willi syndrome (PWS), a chromosome 15 genetic disorder, often have a significant preoccupation with food and problem behaviour related to food seeking is often prevalent. METHODS: In the present study, we compared how individuals with PWS responded on a survey regarding the acceptability of food in various locations that varied according to degree of appropriateness for human consumption (e.g. food on a plate, food in a garbage can). For a subgroup of participants, we observed how they actually responded when placed in a room with food items placed in the same locations depicted in the survey. In the first part of the study, three groups (25 typically developing individuals, 7 individuals with intellectual disability (ID), and 19 individuals with PWS) responded to a visual survey to determine the degree of acceptability of food items in various locations (e.g. on a table near a hairbrush, on the floor behind a toy box, in a trash can). In the second part of the study, these food items (popcorn, jelly beans) were placed in the 12 locations described above. Nine individuals diagnosed with PWS (deletion type) and three individuals with ID were given some break time in the room for 15 min. The amount of food consumed, the time spent food seeking, and time spent interacting with materials were measured. RESULTS: Results of the survey indicated that the PWS group differed significantly with regard to how they responded on the survey from the typically developing group, but did not differ significantly from the ID group. Results of the food seeking observations indicated that only three individuals with PWS ate a significant number of items. The three individuals did not differ from the rest of the group according to IQ or compulsivity score; however, they had significantly lower body mass index (BMI) scores and were younger than the other participants. CONCLUSIONS: The findings from the survey indicate that individuals with PWS are able to discriminate the appropriateness of eating items in more or less contaminated areas; however, the amount of time spent seeking food and the amount of food covertly consumed appeared to depend more directly on age and BMI.

Forgetting our facts: the role of inhibitory processes in the loss of propositional knowledge.

Seven experiments are reported that show that retrieving facts from long-term memory is accomplished, in part, by inhibitory processes that suppress interfering facts. When asked to repeatedly retrieve a recently learned proposition (e.g., recalling The actor is looking at the tulip, given cues such as Actor looking t__), subjects experienced a recall deficit for related facts (e.g., The actor is looking at the violin) on a recall test administered 15 min later. Importantly, this retrieval-induced forgetting was shown to generalize to other facts in which the inhibited concepts took part (e.g., The teacher is lifting the violin), replicating a finding observed by M. C. Anderson and B. A. Spellman (1995) with categorical stimuli. These findings suggest a critical role for suppression in models of propositional retrieval and implicate the mere retrieval of what we know as a source of forgetting of factual knowledge.

A functional magnetic resonance imaging study of auditory mismatch in schizophrenia.

OBJECTIVE: Previous research has noted functional and structural temporal lobe abnormalities in schizophrenia that relate to symptoms such as auditory hallucinations and thought disorder. The goal of the study was to determine whether the functional abnormalities are present in schizophrenia at early stages of auditory processing. METHOD: Functional magnetic resonance imaging activity was examined during the presentation of the mismatch stimuli, which are deviant tones embedded in a series of standard tones. The mismatch stimuli are used to elicit the mismatch negativity, an early auditory event-related potential. Ten patients with schizophrenia and 10 comparison subjects were presented the mismatch stimuli condition and a control condition in which only one tone was presented repeatedly. RESULTS: The superior temporal gyrus showed the most prevalent and consistent activation. The superior temporal gyrus showed less activation in the schizophrenic subjects than in the comparison subjects only during the mismatch stimuli condition. CONCLUSIONS: This result is consistent with those of mismatch negativity event-related potential studies and suggests that early auditory processing is abnormal in chronic schizophrenia.

Suppressing unwanted memories by executive control.

Freud proposed that unwanted memories can be forgotten by pushing them into the unconscious, a process called repression. The existence of repression has remained controversial for more than a century, in part because of its strong coupling with trauma, and the ethical and practical difficulties of studying such processes in controlled experiments. However, behavioural and neurobiological research on memory and attention shows that people have executive control processes directed at minimizing perceptual distraction, overcoming interference during short and long-term memory tasks and stopping strong habitual responses to stimuli. Here we show that these mechanisms can be recruited to prevent unwanted declarative memories from entering awareness, and that this cognitive act has enduring consequences for the rejected memories. When people encounter cues that remind them of an unwanted memory and they consistently try to prevent awareness of it, the later recall of the rejected memory becomes more difficult. The forgetting increases with the number of times the memory is avoided, resists incentives for accurate recall and is caused by processes that suppress the memory itself. These results show that executive control processes not uniquely tied to trauma may provide a viable model for repression.

The created environment for physical assessment by case managers.

Goals of gerontological nursing include maximizing health and confronting functional impairments. The health of older adults is often fragile because of age-related change, complicated by chronic illnesses. Identification of changes in health status permits responsive care and consultation but requires proficiency in physical assessment. In 1995, research was conducted in Alberta, Canada, on registered nurse case managers' reported use of assessment skills. Nineteen continuing-care facilities in 1 of 17 provincial health regions participated (N = 189). After expert review and pilot testing, questionnaires were distributed to two independent groups: nurse administrators/staff development coordinators and case managers (response rate = 73%). Qualitative data were subjected to descriptive, interpretive, and pattern coding. Reported are factors constraining or facilitating physical assessment in continuing care. Neuman's concept of the created environment provided a factor-organizing framework. A holistic view of environment and data source triangulation increased confidence in the comprehensiveness and credibility of results.

Continuing care nurses' perceptions of need for physical assessment skills.

The purpose of this descriptive research was to identify the perceived learning needs of registered nurse case managers for physical assessment skills, their facility with computers, and barriers and supports to the enhancement and application of physical assessment by these caregivers in the work-place. Nineteen continuing care facilities in one Alberta Health Region participated. Using data source triangulation, two independent groups, case managers (n = 150) and nurse administrators or staff development officers (n = 39) responded to a questionnaire developed by the researchers. The case managers reported that skill in physical assessment was very important in their work, but current skill was inadequate to meet resident care needs. Both groups ranked the thorax and lungs, cardiovascular/peripheral vascular systems, and abdomen as the top three body systems or regions in terms of the case managers' learning needs. This research identified that for these case managers, upgrading skills in physical assessment was a continuing education priority and suggested computer-assisted instruction as a potential delivery method.

Location of death in Canada. A comparison of 20th-century hospital and nonhospital locations of death and corresponding population trends.

This report compares 20th-century Canadian hospital and nonhospital location-of-death trends and corresponding population mortality trends. One of the chief findings is a hospitalization-of-death trend, with deaths in hospital peaking in 1994 at 80.5% of all deaths. The rise in hospitalization was more pronounced in the years prior to the development of a national health care program (1966). Another key finding is a gradual reduction since 1994 in hospital deaths, with this reduction occurring across all sociodemographic variables. This suggests nonhospital care options are needed to support what may be an ongoing shift away from hospitalized death and dying.

Canopy Wetness and Humidity Prediction Using Satellite and Synoptic-Scale Meteorological Observations.

A method for predicting canopy wetness and humidity from remotely-acquired meteorological and radiation data is described. This method employs a surface energy balance model to scale from the above-canopy macroclimate to in-canopy microclimate conditions. Above-canopy temperature, vapor pressure, and wind speed inputs were obtained from objective analyses of hourly measurements from the synoptic weather network, while downwelling long- and shortwave radiation forcings were estimated from standard satellite observations. Precipitation (irrigation + rainfall) was the only input acquired in-field. Model predictions compared well with measurements of nighttime dew accumulation and relative humidity made in irrigated potato crops grown in central Wisconsin. Maximum dew amount measured in full canopies over four nights was reproduced to within 0.05 to 0.1 mm. The practical utility of this method to disease management was assessed by processing modeled and measured canopy microclimate data from two weather stations over three growing seasons through the BLITECAST disease forecasting system. Given the uncertainties inherent in the measurement of humidity, the model reasonably reproduced disease severity values generated from in-situ measurements in all but one case, where the canopy had suffered partial defoliation. Because the model simulates the microclimate within a healthy, uniform canopy, it may in many cases produce more reliable regional forecasts for plant disease than would a single set of in-situ measurements.

The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy.

OBJECTIVES: 1. To determine the prevalence of endometrial hyperplasia in postmenopausal women taking standard proprietary regimens of sequential oestrogen/progestogen; 2. to determine the effects of nine months treatment with an oral continuous combined regimen of 2 mg 17beta-oestradiol and 1 mg norethisterone acetate (Kliofem [Kliogest outside the UK]; Novo Nordisk, Denmark) on endometrial histology in postmenopausal women. DESIGN: An open, prospective study in postmenopausal women. SETTING: Fifty-four menopause clinics in the UK. PARTICIPANTS: 2028 postmenopausal women: 1312 (Group A) taking sequential oestrogen-progestogen hormone replacement therapy (HRT), and 716 (Group B) not taking HRT, were recruited. In Group A, 388 women took preparations containing 10 days of progestogen, 921 had 12 days, and 3 had 13 days per cycle. METHODS: Endometrial aspiration biopsies were taken towards the end of a three-month run-in period (Group A) or at study entry (Group B), before administration of the continuous combined HRT regimen. Biopsies were repeated at the end of the nine month treatment period. MAIN OUTCOME MEASURE: Endometrial histology. RESULTS: Initial endometrial biopsy data were available for 1106 women in Group A, who by the time of endometrial investigation had been taking HRT for a median duration of 2.56 years (5th to 95th centiles: 0.77 to 8.49 years). Data were available for 661 untreated women, who had no bleeding and had not taken HRT within the last year (Group B). Complex hyperplasia was found in 59 women (5.3%), and atypical hyperplasia in a further eight (0.7%) in Group A. In Group B there were no cases with complex hyperplasia, but one woman showed atypical hyperplasia (0.2%). At the end of the nine months of continuous combined therapy there was no case of hyperplasia among 1196 biopsies (upper 95% confidence limit of risk 0.31%) in women completing the study. Within this Group all of the women with complex hyperplasia arising during previous sequential HRT and who completed the study (n = 38) reverted to normal endometrial patterns. There was no case of endometrial carcinoma during the study. CONCLUSIONS: Despite taking standard regimens of sequential HRT containing at least 10 days of progestogen, there was a 5.3% prevalence of complex endometrial hyperplasia, and a 0.7% prevalence of atypical hyperplasia. However, continuous combined HRT (Kliofem) containing daily progestogen is not associated with an increased risk of hyperplasia and will convert the endometrium to normal in those with complex hyperplasia arising during previous sequential HRT.

Retrieval-induced forgetting: evidence for a recall-specific mechanism.

Previous work has shown that recalling information from long-term memory can impair the long-term retention of related representations--a phenomenon known as retrieval-induced forgetting (Anderson, Bjork, & Bjork, 1994). We report an experiment in which the question of whether retrieval is necessary to induce this form of impairment was examined. All the subjects studied six members from each of eight taxonomic categories (e.g., fruit orange). In the competitive practice condition, the subjects practiced recalling three of the six members, using category-stem cues (e.g., fruit or__). In the noncompetitive practice condition, the subjects were reexposed to these same members for the same number of repetitions but were asked to recall the category name by using the exemplar and a stem as cues (e.g., fr__orange). Despite significant and comparable facilitation of practiced items in both conditions, only the competitive practice subjects were impaired in their ability to recall the nonpracticed members on a delayed cued-recall test. These findings argue that retrieval-induced forgetting is not caused by increased competition arising from the strengthening of practiced items, but by inhibitory processes specific to the situation of recall.

Pathology and pathophysiology of uterine smooth-muscle tumors.

Smooth-muscle tumors of uterine origin encompass a broad family of neoplasms. The leiomyoma, by far the most common of all the neoplasms, generally is hormone sensitive, with rates of growth semiquantitatively related to estrogen and progesterone receptor levels. Several forms of degenerative change can occur in the leiomyoma. The most common is hyaline degeneration, which is important in that it should not be mistaken for the coagulative tumor cell necrosis seen in leiomyosarcoma. Red degeneration (necrobiosis) is a form of degeneration that occurs characteristically but not exclusively in pregnancy, and the process is often the cause of pain and fever. Several forms of treatment have been used medically in the treatment of leiomyoma. Gonadotropin-releasing hormone analogs or agonists or selective arterial embolization with polyvinylformaldehyde particles may lead to substantial degeneration or infarction of the leiomyoma, respectively. Several variants of leiomyoma, the cellular and symplastic leiomyomas, are important to recognize, as they can be misinterpreted as sarcoma. In addition, there are two unusual growth patterns of leiomyoma that are important to recognize. Both the benign metastasizing leiomyoma and disseminated peritoneal leiomyomatosis are found outside the uterus, and neither is malignant. Recent studies offer insights into their origin and hormonal influences. From a diagnostic and therapeutic point of view, the leiomyosarcoma, while rare, is clinically of great import. Coagulative necrosis, cytologic atypia, and mitotic counts are all important in diagnosing the condition.

Organicity in obsessive-compulsive disorder.

Though pharmacological and/or behavioral interventions have proven highly effective, 20 to 30% of the obsessive-compulsive disorder (OCD) population is treatment refractory. This study describes the OCD clinical profile that is correlated to organicity. Two groups of OCD patients were presented: an organic group and a control nonorganic group. The 9 organic patients exhibit an indifference to their illness, a lack of motivation, are nonanxious even during exposure exercises, are nondepressed, have rigid and concrete thinking, are treatment refractory, and have some type of organic impairment. The 10 nonorganic patients are also treatment refractory but do not exhibit the clinical profile correlated to the organic OCD patients. Furthermore, MRI results indicate that no organic impairment exists in this control group. All of these patients were tried on medication and behavior therapy to no avail. Reasons for lack of response in organic OCD patients, based on cerebral anatomical changes, are discussed.

Similarity and inhibition in long-term memory: evidence for a two-factor theory.

Recalling a past experience often requires the suppression of related memories that compete with the retrieval target, causing memory impairment known as retrieval-induced forgetting. Two experiments examined how retrieval-induced forgetting varies with the similarity of the competitor and the target item (target-competitor similarity) and with the similarity between the competitors themselves (competitor-competitor similarity). According to the pattern-suppression model (M. C. Anderson & B. A. Spellman, 1995), high target-competitor similarity should reduce impairment, whereas high competitor-competitor similarity should increase it. Both predictions were supported: Encoding target-competitor similarities not only eliminated retrieval-induced forgetting but also reversed it, whereas encoding competitor-competitor similarities increased impairment. The differing effects of target-competitor and competitor-competitor similarity may resolve conflicting results concerning the effects of similarity on inhibition.

White matter abnormalities in mobility-impaired older persons.

OBJECTIVE: To investigate the relationship between white matter abnormalities and impairment of gait and balance in older persons. METHODS: Quantitative MRI was used to evaluate the brain tissue compartments of 28 older individuals separated into normal and impaired groups on the basis of mobility performance testing using the Short Physical Performance Battery. In addition, individuals were tested on six indices of gait and balance. For imaging data, segmentation of intracranial volume into four tissue classes was performed using template-driven segmentation, in which signal-intensity-based statistical tissue classification is refined using a digital brain atlas as anatomic template. RESULTS: Both decreased white matter volume, which was age-related, and increased white matter signal abnormalities, which were not age-related, were observed in the mobility-impaired group compared with the control subjects. The average volume of white matter signal abnormalities for impaired individuals was nearly double that of control subjects. CONCLUSIONS: This cross-sectional study suggests that decreased white matter volume is age-related, whereas increased white matter signal abnormalities are most likely to occur as a result of disease. Both of these changes are independently associated with impaired mobility in older persons and therefore likely to be additive factors of motor disability.

Quantitative follow-up of patients with multiple sclerosis using MRI: reproducibility.

The reproducibility of an automated method for estimating the volume of white matter abnormalities on brain magnetic resonance (MR) images of multiple sclerosis (MS) patients was evaluated. Twenty MS patients underwent MR imaging twice within 30 minutes. Measurement variability is introduced mainly by MRI acquisition and image registration procedures, which demonstrate significantly worse reproducibility than the image segmentation. The correction of partial volume artifacts is essential for sensitive measurements of overall lesion burden. The average lesion volume difference (bias) between two MR exams of the same MS patient (N = 20) was 0.05 cm3, with a 95% confidence interval between -0.17 and +0.28 cm3, suggesting that the proposed measurement system is suitable for clinical follow-up trials, even in relatively small patient cohorts. The limits of agreement for lesion volume were between -1.3 and +1.5 cm3, implying that in individual patients changes in lesion load need to be at least this large to be detected reliably. This automated method for estimating lesion burden is a reliable tool for the evaluation of MS progression and exacerbation in patient cohorts and potentially also in individual patients.

A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish.

Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5. 22 x 10(-4); SIBPAL Pempirical value <3 x 10(-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3.29, P = 2.57 x 10(-3); SIBPAL Pempirical value <1 x 10(-3)) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.

The core metal-recognition domain of MerR.

MerR, the metalloregulatory protein of the mercury-resistance operon (mer) has unusually high affinity and specificity for ionic mercury, Hg(II). Prior genetic and biochemical evidence suggested that the protein has a structure consisting of an N-terminal DNA binding domain, a C-terminal Hg(II)-binding domain, and an intervening region involved with communication between these two domains. We have characterized a series of MerR deletion mutants and found that as little as 30% of the protein (residues 80-128) forms a stable dimer and retains high affinity for Hg(II). Biophysical measures indicate that this minimal Hg(II)-binding domain assumes the structural characteristics of the wild-type full-length protein both in the Hg(II) center itself and in an immediately adjacent helical protein domain. Our observations are consistent with the core Hg(II)-binding domain of the MerR dimer being constituted by a pair of antiparallel helices (possibly in a coiled-coil conformation) comprised of residues cysteine 82 through cysteine 117 from each monomer followed by a flexible loop through residue cysteine 126. These antiparallel helices would have a potential Hg(II)-binding site at each end. However, just as in the full-length protein, only one of these potential binding sites in the deleted proteins actually binds Hg(II).