In vivo effects of anti-idiotype on Plasmodium chabaudi infection in mice.

A polyclonal anti-idiotype was raised in rabbits following immunization with a murine monoclonal antibody which recognized a 250,000 MW antigen of Plasmodium chabaudi-infected erythrocytes. The monoclonal antibody, NIMP M23 (clone 3,) has been shown to protect mice against homologous parasite challenge. Following purification, the anti-idiotype was shown to bind only the immunizing idiotype and to recognize antigen-binding site-associated anti-idiotype. Mice primed with anti-idiotype and challenged with live parasites had an altered course of infection, with significant reduction in their peak parasitaemia levels. Anti-idiotype priming did not induce an antigen-reactive antibody response in vivo but a population of T cells capable of proliferating in vitro to P. chaubaudi-infected red cells was stimulated. These data are discussed in the context of possible idiotypic interaction in murine malaria.     

Intravenous Phenylephrine Preconditioning of Cardiac Grafts From Non–Heart-Beating Donors

Background. Hypoxia and warm ischemia produce severe injury to cardiac grafts harvested from non–heart-beating donors. To potentially improve recovery of such grafts, we studied the effects of intravenous phenylephrine preconditioning.Methods. Thirty-seven blood-perfused rabbit hearts were studied. Three groups of non–heart-beating donors underwent intravenous treatment with phenylephrine at 12.5 (n = 8), 25 (n = 7), or 50 μg/kg (n = 7) before initiation of apnea. Non–heart-beating controls (n = 8) received saline vehicle. Hypoxic cardiac arrest occurred after 6 to 12 minutes of apnea, followed by 20 minutes of warm in vivo ischemia. A 45-minute period of ex vivo reperfusion ensued. Nonischemic controls (n = 7) were perfused without antecedent hypoxia or ischemia.Results. Phenylephrine 25 μg/kg significantly delayed the onset of hypoxic cardiac arrest compared with saline controls (9.6 ± 0.5 versus 7.7 ± 0.4 minutes; p = 0.00001), yet improved recovery of left ventricular developed pressure compared with saline controls (57.1 ± 5.3 versus 41.0 ± 3.4 mm Hg; p = 0.04). Phenylephrine 25 μg/kg also yielded a trend toward less myocardial edema than saline vehicle (p = 0.09).Conclusions. Functional recovery of nonbeating cardiac grafts is improved by preconditioning. We provide evidence that the myocardium can be preconditioned with phenylephrine against hypoxic cardiac arrest.(Ann Thorac Surg 1997;63:1664–8)     

A case of mosaic trisomy 2 diagnosed at amniocentesis in an abnormal fetus and confirmed in multiple fetal tissues

Pseudomosaicism for trisomy 2 is a relatively common finding at amniocentesis. However, genuine trisomy 2 mosaicism is extremely rare. As a result, very few cases have been described and little information is available with which to counsel the parents of an affected fetus. We describe a case of mosaic trisomy 2 diagnosed at amniocentesis in a fetus with multiple anomalies on ultrasound scan. Following termination of pregnancy, the fetus was found to have mild dysmorphic features, together with an absent gall bladder, cystic left kidney, a 13th left rib and mild unilateral talipes. The presence of trisomy 2 cells was confirmed by both standard cytogenetic analysis and fluorescent in-situ hybridisation techniques in multiple fetal tissues, as well as in the cord and placenta.     

Correlates of cognitive dysfunction in an ambulatory elderly population

Mini-Mental State Examination (MMSE) scores were studied in an ambulatory elderly population to identify correlates with self-reported signs, symptoms, diseases, drugs and laboratory values. A total of 1,264 subjects were studied including 844 women and 420 men. In this study, 5.0% of men and 5.3% of women scored less than 24 on the MMSE. A linear-regression model revealed eleven factors of significance in predicting scores on the MMSE. The most important predictors were age (p less than 0.0001), self-reported memory loss (p less than 0.0001), complaints of swollen feet or ankles (p less than 0.0010), the total number of diseases reported (0.0006) and the serum lactate dehydrogenase concentration (p less than 0.0098). Results suggest that cognitive function in the elderly is not related to the general level of health or consistently affected by specific disease states.     

The solubilization of model Alzheimer tangles: reversing the beta-sheet conformation induced by aluminum with silicates.

Neurofibrillary tangles are one of two lesions found in the brain of Alzheimer disease victims. With synthetic peptide fragments of human neurofilament NF-M17 (Glu-Glu-Lys-Gly-Lys-Ser-Pro- Val-Pro-Lys-Ser-Pro-Val-Glu-Glu-Lys-Gly, phosphorylated and unphosphorylated), CD studies were done to examine the effect of sodium orthosilicate on the conformational state produced by Al3+ on fragments of neuronal proteins. Previous studies had shown a conformational transition from alpha-helix and random to beta-pleated sheet upon addition of Al3+ to both phosphorylated and unphosphorylated peptides. If sufficient quantities of Al3+ are added, the peptide precipitates from solution. The ability to reverse or slow the progression of aggregation was examined. Al3+ binding was reversed with 1-2 molar equivalents of sodium orthosilicate (with respect to Al3+), altering the conformation from beta-sheet to random coil and resulting in a CD spectrum similar to that of the initial peptide. The tight binding of the SiO4(4-) with the Al3+ provides the mechanism for this transition. These results provide additional information toward understanding the role of aluminum in the Alzheimer diseased brain and suggest the investigation of the possible use of silicates as a therapeutic agent.     

The case of the disappearing generalist: does it need to be solved?

The proportion of generalist physicians in the United States has declined steadily over 50 years, bringing it to the lowest percentage of trained primary care physicians of any developed country; the trend toward subspecialization is accelerating. Many analysts believe this imbalance between generalists and subspecialists to be a major cause of America's high health care costs, heavy dependence on biotechnology, and consumer dissatisfaction. Others argue that sub-specialists can provide excellent primary care services, and the decrease in the number of generalists is not a problem. Three contrasting views on the implications of this trend state that today's generalists are an important and scarce resource that must be bolstered; that subspecialists can replace generalists as providers of primary care; and that the free market will determine the best manpower mix. A final view, on the marketplace option, posits that generalism will not recover until it creates a vital, and unique, role in handling the primary care challenges of the twenty-first century. These competing viewpoints are used to clarify assumptions underlying our major policy options in the arena of health manpower.     

Multiplex PCR analysis of in vivo-arising deletion mutations in the hprt gene of human T-lymphocytes

A multiplex polymerase chain reaction (PCR) procedure was adapted for the rapid and efficient evaluation of deletions of the hypoxanthine guanine phosphoribosyltransferase (hprt) gene in human T-lymphocytes. The hprt clonal assay was used to isolate in vivo-arising hprt-deficient T-cells from six healthy males. Mutant frequencies ranged from 9-27 × 10^?6. Simple crude cellular extracts from 223 mutants were analyzed for hprt gene deletion. Sixteen (7.2%) were found to be due to total gene deletion and 22 (9.9%) were due to partial gene deletion. The relatively high frequency of total gene deletions was caused by replicate isolates of a single mutational event as shown by single-strand conformation polymorphism (SSCP) analysis of rearranged T-cell receptor (TCR)-γ genes. Eighteen of the 22 partial hprt gene deletion mutants were determined to be of independent origin based on a unique hprt mutation or SSCP-TCR-γ pattern. One-half (9/18) of the partial deletion mutants involved all or part of exon 4 alone, suggesting that this region of the hprt gene is prone to deletion. The small deletions effecting exon 1 (1 mutant), exon 2 (2 mutants), and exon 4 (6 mutants) would not have been detected by conventional Southern blot analysis and may represent a new, previously unrecognized class of mutations. The ready isolation of such intragenic deletions will allow the characterization of breakpoint junctions and may provide insights into the important processes of DNA breakage and rejoining. © 1994 Wiley-Liss, Inc.     

Biopterin in Parkinson''s disease.

Tetrahydrobiopterin is an essential co-factor in the natural synthesis of dopamine. Oral tetrahydrobiopterin was given in small doses to four patients with early Parkinson's disease but had no discernible effect.     

Quantitative SPECT leads to improved performance in discrimination tasks related to prodromal Alzheimer's disease.

We investigated the impact of the quantitation and reconstruction protocol on clinical tasks. The performance of standard clinical reconstruction procedures in discrimination tasks related to the diagnosis of prodromal Alzheimer's disease (AD) was compared with the performance of a quantitative approach incorporating improved corrections for scatter, attenuation, intrinsic spatial resolution, and distance-dependent spatial resolution. METHODS: Seventeen normal controls (normal group), 56 subjects who did not have dementia, who did have memory problems, but who did not develop AD within 5 y of follow-up (questionable group), and 27 subjects who did not have dementia, who did have memory problems, and who did develop AD over the follow-up period (converter group) were considered in this study. (99m)Tc-hexamethylpropyleneamine oxime SPECT and MRI studies were performed for each subject at baseline. The standard quantitation protocol (STD), routinely used in our clinic, consisted of Compton window scatter correction followed by filtered backprojection with attenuation correction using a uniform attenuation map. In the improved quantitative approach (QUAN), projections were corrected for scatter by use of a general spectral method and reconstructed by use of ordered-subset(s) expectation maximization, incorporating corrections for collimator response and attenuation using both a uniform attenuation map (QUANunif) and a nonuniform attenuation map (QUANnonunif). Mean SPECT activity concentration and MRI volume were estimated for 7 structures: rostral anterior cingulate gyrus, caudal anterior cingulate gyrus, posterior cingulate gyrus, hippocampus, basal forebrain, amygdala, and the banks of the superior temporal sulcus. Data were analyzed by pairwise discriminant analysis, and performance in binary group discrimination was measured by correlated receiver-operating-characteristic analysis. RESULTS: The use of QUANnonunif yielded a small but systematic improvement in discrimination accuracy for normal versus converter groups (accuracy or area under the receiver-operating-characteristic curve [Az], 0.965), normal versus questionable groups (Az, 0.973), and questionable versus converter groups (Az, 0.881) compared with the results obtained with QUANunif (Az, 0.955, 0.962, and 0.866, respectively). Discrimination performance was significantly lower (P < 0.05) with STD than with QUAN in all 3 tasks (Az with STD, 0.906, 0.878, and 0.768, respectively). MRI volume estimation led to a lower overall performance in all 3 tasks than did QUANnonunif (Az with MRI, 0.947, 0.917, and 0.872, respectively). CONCLUSION: Improved quantitative image reconstruction with accurate compensation for scatter, attenuation, and variable collimator response led to significantly better performance in discrimination tasks related to the diagnosis of prodromal AD than did standard clinical reconstruction procedures. The use of a nonuniform brain attenuation map yields a small improvement in discrimination accuracy.