Genetic prion disease with codon 196 PRNP mutation: clinical and pathological findings

Ten percent to 15% of all human transmissible spongiform encephalopathy are characterized by a mutation in prion protein gene (PRNP). They are distinct with respect to clinical signs, disease onset, disease duration, and diagnostic findings. During our surveillance activities in Germany, we identified 7 patients with the rare mutation E196K in PRNP gene, thereof 4 patients belonging to 2 families. The clinical syndromes were characterized by nonspecific and psychiatric symptoms at disease onset and progressed to predominant motor signs. These patients showed a late median disease onset of 71 years and short disease duration of 6.5 months. In absence of family history, they mimicked sporadic Creutzfeldt-Jakob disease (CJD). In clinical tests they were 100% positive for 14-3-3 protein detection in cerebrospinal fluid and less sensitive for magnetic resonance imaging (MRI) and electroencephalogram (EEG) abnormalities. As a secondary magnetic resonance imaging (MRI) abnormality, we have seen conspicuous common involvement of the subcortical white matter in 57%. Four patients underwent autopsy—pathological lesions revealed striking similarity to sporadic Creutzfeldt-Jakob disease but also involvement of the white matter.     

Feasibility of an ovarian cancer quality-of-life psychoeducational intervention

Background. Diagnosis of ovarian cancer often portends a poor prognosis with significant quality-of-life (QOL) concerns. Method. We report on a pilot study that tested the feasibility of a structured, ovarian cancer psychoeducational intervention (OCPI). Patients (N=33) were randomly assigned to either the control or OCPI study arms in which those in the intervention arm received 4 sequential, structured, in-person educational sessions. Data were collected at the time of accrual and at 1 and 3 months postaccrual. Results. This study demonstrated the feasibility of a structured psychoeducational program in an outpatient clinical setting. Conclusion. Study findings underscore the importance of developing interventions that address the 4 QOL domains impacted by ovarian cancer and support initiating a comprehensive psychoeducational intervention earlier in the course of illness.     

Basolateral amygdaloid multi-unit neuronal correlates of discriminative avoidance learning in rabbits

Basolateral (BL) amygdaloid multi-unit activity was recorded as male albino rabbits learned to avoid a foot-shock unconditioned stimulus (US) by stepping in an activity wheel to an acoustic (pure tone) warning stimulus (CS+). A second tone (CS−) of different auditory frequency than the CS+ was presented in an irregular order on half of the conditioning trials but was never followed by the US. BL amygdaloid neurons developed, in the first session of conditioning, enhanced CS-elicited discharges relative to discharges recorded during pretraining with tones and noncontingent US presentations (excitatory plasticity), and greater discharges to the CS+ than to the CS− (discriminative plasticity). The discriminative plasticity attained maximal magnitude as the rabbits reached the asymptote of behavioral discrimination, and persisted during post-asymptotic training. Peak excitatory plasticity occurred in the session of the first significant behavioral discrimination and decline during the asymptotic and post-asymptotic stages of training. Similar patterns of excitatory and discriminative plasticity in structures directly interconnected with the BL nucleus (anterior cingulate cortex; medial dorsal thalamic nucleus) and effects of lesions suggest that the neurons in these areas participate in a circuit involved in mediation of avoidance learning.     

Quality of care for patients diagnosed with diabetes at screening

OBJECTIVE: Screening for diabetes has the potential to be an effective intervention, especially if patients have intensive treatment of their newly diagnosed diabetes and comorbid hypertension. We wished to determine the process and quality of diabetes care for patients diagnosed with diabetes by systematic screening. RESEARCH DESIGN AND METHODS: A total of 1,253 users of the Durham Veterans Affairs Medical Center aged 45-64 years who did not report having diabetes were screened for diabetes with an HbA(1c) test. All subjects with an HbA(1c) level > or =6.0% were invited for follow-up blood pressure and fasting plasma glucose (FPG) measurements. A case of unrecognized diabetes was defined as HbA(1c) > or =7.0% or FPG > or =126 mg/dl. For each of the 56 patients for whom we made a new diagnosis of diabetes, we notified the patient's primary care provider of this diagnosis. One year after diagnosis, we reviewed these patients' medical records for traditional diabetes performance measures as well as blood pressure. Follow-up blood pressure was also ascertained from medical record review for all subjects with HbA(1c) > or =6.0% who did not have diabetes. We compared blood pressure changes between patients with and without diabetes. RESULTS: Among patients diagnosed with diabetes at screening, 34 of 53 (64%) had evidence of diet or medical treatment for their diabetes, 42 of 53 (79%) had HbA(1c) measured within the year after diagnosis, 32 of 53 (60%) had cholesterol measured, 25 of 53 (47%) received foot examinations, 29 of 53 (55%) had eye examinations performed by an eye specialist, and 16 of 53 (30%) had any measure of urine protein. The mean blood pressure decline over the year after diagnosis for patients with diabetes was 2.3 mmHg; this decline was similar to that found for 183 patients in the study without diabetes (change in blood pressure, -3.6 mmHg). At baseline, 48% of patients with diabetes had blood pressure <140/90, compared with 40% of patients without diabetes; 1 year later, the same 48% of patients with diabetes had blood pressure <140/90, compared with 56% of patients without diabetes (P = 0.31 for comparing the change in percent in control between groups). CONCLUSIONS: Patients with diabetes diagnosed at screening achieve less tight blood pressure control than similar patients without diabetes. Primary care providers do not appear to manage diabetes diagnosed at screening as intensively as long-standing diabetes and do not improve the management of hypertension given the new diagnosis of diabetes.     

Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man

Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P < 0.05) with decreased plaque macrophages (P < 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P < 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P < 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population-based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.     

An Integrative Review of American Nurses'' Perceived Cultural Self-Efficacy

PURPOSE: To review use of the Cultural Self-Efficacy Scale (CSES) and to summarize the cumulative findings. METHODS: A combination of literature searches and questionnaires to those who have requested the scale indicated 26 known uses. Fifteen reported sufficient data for statistical analysis. FINDINGS: Of the 26 known uses of the CSES, 8 were published in peer-reviewed journals, 5 in dissertations, 8 in theses, and 3 as data sets only. Two additional theses were not retrievable for the study. On a 5-point Likert-type scale, nurses reported the highest degree of self-efficacy with African American (3.1) and Hispanic (3.1) patients and the lowest with Asian American patients (2.4). Six of the reports include Cronbach's alpha coefficients, ranging from .86 to .98. In the final sample of 15 studies, nurses did not report feeling confident caring for patients from other cultures. CONCLUSIONS: Although the CSES has been used in many settings with over 3,000 nurses, inconsistencies in the data preclude specific conclusions. Further research is needed using consistent reporting practices and sufficient predictor variables to draw further conclusions regarding the scale's psychometric properties.     

Inactivation of a Defined Active Site in the Mouse 20S Proteasome Complex Enhances Major Histocompatibility Complex Class I Antigen Presentation of a Murine Cytomegalovirus Protein

Proteasomes generate peptides bound by major histocompatibility complex (MHC) class I molecules. Avoiding proteasome inhibitors, which in most cases do not distinguish between individual active sites within the cell, we used a molecular genetic approach that allowed for the first time the in vivo analysis of defined proteasomal active sites with regard to their significance for antigen processing. Functional elimination of the δ/low molecular weight protein (LMP) 2 sites by substitution with a mutated inactive LMP2 T1A subunit results in reduced cell surface expression of the MHC class I H-2L^d and H-2D^d molecules. Surface levels of H-2L^d and H-2D^d molecules were restored by external loading with peptides. However, as a result of the active site mutation, MHC class I presentation of a 9-mer peptide derived from a protein of murine cytomegalovirus was enhanced about three- to fivefold. Our experiments provide evidence that the δ/LMP2 active site elimination limits the processing and presentation of several peptides, but may be, nonetheless, beneficial for the generation and presentation of others.     

The determination of osteopetrotic phenotypes by selective inactivation of red cell carbonic anhydrase isoenzymes

Red cell carbonic anhydrase isoenzyme activities (HCA-I and HCA-II) were quantitated in blood hemolysates of two female siblings affected with autosomal recessive osteopetrosis in addition to family members who were both obligate and potential heterozygotes as well as normal controls. Selective inactivation of red cell hemolysates with 20 mmol/l bromopyruvic acid (pH 7.5) for 50 min at 25 degrees C lead to a near quantitative removal of HCA-I activity without significant loss of HCA-II activity. Comparison of untreated hemolysate HCA activity with residual activity in bromopyruvate treated samples allowed determination of HCA-II/HCA-I activity ratios. Estimation of activity ratios was also attempted by use of the inhibitor I- which is known to discriminate between the two isoenzymes. Hemolysate HCA activity of the two affected individuals (homozygotes) was completely abolished by the procedure, consistent with an absence of the bromopyruvate resistant HCA-II isoenzyme in the red cells of these individuals. HCA-I activities were found to be elevated significantly above normal. Both parents (obligate heterozygotes) were found to have normal HCA-I activities and HCA-II activities 60-80% of normal. Computed HCA-II/HCA-I activity ratios fell into these ranges: 0 for homozygotes, 0.82-0.87 for obligate heterozygotes and 1.08-1.16 for normal controls. KI values for I- inhibition of hemolysate HCA activity gave 0.25-0.30 mmol/l, 0.9-1.5 mmol/l and 2.0 mmol/l for the three categories. These relations should prove useful in the screening of osteopetrotic phenotypes.     

Early Parkinson's disease: Longitudinal changes in brain activity during sequence learning

Impairment of sequence learning is common in Parkinson's disease (PD), but the time course of this cognitive abnormality is not known. We assessed longitudinal changes in sequence learning performance and associated task-related cerebral blood flow in 13 early stage PD patients who underwent H₂¹⁵O PET at baseline and again 2 years later. Ten healthy volunteer subjects served as controls. A trend toward decline in learning performance (p = 0.08) was evident over the 2 years of follow-up. During this interval, significant declines in learning-related activation were detected in parietal and temporo-occipital association areas and in the right dorsolateral prefrontal cortex. Learning-related activation in these regions was normal at baseline, but declined to subnormal levels (p < 0.01) at 2 years. Significant hippocampal activation (p < 0.005) was present in the subjects with high learning performance over time. The findings are consistent with a decline in learning-related neural activity in cortical areas with prominent Lewy body formation.