The Family in Medical Decisionmaking

Should the authority to make treatment decisions be extended to the competent patient's family? Neither arguments from fairness nor communitarian concerns justify such an infringement on patient autonomy.     

Developmental Expression of Neuron-Specific Enolase Immunoreactivity and Cytochrome Oxidase Activity in Neocortical Transplants

The present study has examined certain metabolic markers in fetal neocortical tissue transplanted to the cortex, hippocampus, striatum, or ventricle. Particularly, the immunocytochemical expression of neuron-specific enolase (NSE) was studied in a series of host rats ranging between 10 days and 15 months postoperative. NSE is a major glycolytic pathway enzyme found in all neurons. The antibody to NSE is a very reliable marker for neuronal functional metabolic activity and developmental status and its onset has been shown to coincide with synaptic connections. In some grafts oxidative metabolic status was investigated using cytochrome oxidase (CO) histochemistry. In addition, the normal development of NSE expression in rat neocortex was also examined. In normal development, NSE was weakly expressed in fetal brain, but by 1-2 weeks postnatal the enzyme was strongly expressed in all neurons. Typical cortical laminar patterns were evident at 30 days with neurons in layer V and scattered interneurons the most strongly stained. In cortex-cortex transplants NSE expression was very weak; at 1-3 weeks postoperative, it was practically nonexistent; and at all later times only a minority of neurons had normal expression when compared to that in normal development even though by Nissl staining standards in adjacent sections they appeared "normal." Labeling indices ranged between 30 and 49%. Intraventricular grafts had consistently low NSE expression with labeling indices ranging between 18 and 46%. However, when the neocortical tissue was placed in other regions, neuronal NSE appeared only slightly below normal. CO histochemistry corroborated the NSE activity with regards to graft placement. Several possibilities that may account for reduced NSE profile in transplanted neurons include incomplete migration patterns, reduced synaptic connectivity, and potential ischemia causing lowered protein synthesis during reestablishment of vascular connections. If neuronal glycolysis is weakened, it is possible that neurotransmitter production or axonal transport are reduced. Since most energy capacity in brain is dependent on the glycolytic sequence for oxidative metabolism, reduced glycolytic capacity, as depicted by NSE expression, may suggest the presence of transplanted neurons that have adapted to their new environment with a relatively immature profile.     

Acetylcholinesterase Staining in Human Auditory and Language Cortices: Regional Variation of Structural Features

Cholinergic innervation of the cerebral neocortex arises fromthe basal forebrain and projects to all cortical regions. Acetylcholinesterase(AChE), the enzyme responsible for deactivating acetylcholine,is found within both cholinergic axons arising from the basalforebrain and a subgroup of pyramidal cells in layers III andV of the cerebral cortex. This pattern of staining varies withcortical location and may contribute uniquely to cortical microcircuitrywithin functionally distinct regions. To explore this issuefurther, we examined the pattern of AChE staining within auditory,auditory association, and putative language regions of whole,postmortem human brains. The density and distribution of acetylcholine-containing axonsand pyramidal cells vary systematically as a function of auditoryprocessing level. Within primary auditory regions AChE-containingaxons are dense and pyramidal cells are largely absent. Adjacentcortical regions show a decrease in the density of AChE-containingaxons and an increase in AChE-containing pyramidal cells. Theposterior auditory and language regions contain a relativelyhigh density of AChE-containing pyramidal cells and AChE-containingaxons. Although right and left posterior temporal regions arefunctionally asymmetrical, there is no apparent asymmetry inthe general pattern of AChE staining between homologous regionsof the two hemispheres. Thus, the pattern of AChE staining covarieswith processing level in the hierarchy of auditory corticalregions, but does not vary between the functionally distinctright and left posterior regions. An asymmetry in the size of layer III AChE-rich pyramidal cellswas present within a number of cortical regions. Large AChE-richpyramidal cells of layer III were consistently greater in sizein the left hemisphere as compared to the right. Asymmetry inlayer III pyramidal cell size was not restricted to language-associatedregions, and could potentially have a variety of etiologiesincluding structural, connectional, and activational differencesbetween the left and right hemisphere.     

MR monitoring of MR-guided radiofrequency thermal ablation of normal liver in an animal model

The purpose of this study was to determine the suitability of MRI to accurately detect radiofrequency (RF) thermoablative lesions created under MR guidance. In vivo RF lesions were created in the livers of six New Zealand White rabbits using a 2-mm-diameter titanium alloy RF electrode with a 20-mm exposed tip and a 50-W RF generator. This was performed using a 0.2T clinical C-arm MR imager for guidance and monitoring. Each animal was sacrificed and gross evaluation was performed. Histologic correlation was performed on the first two animals. The MR-compatible RF electrode was easily identified on rapid gradient-echo images used to guide electrode placement. A single lesion was created in each rabbit liver. Lesions ranged from approximately 10 to 17 mm in diameter (mean, 13.5 mm). T2-weighted and short T1 inversion recovery (STIR) images demonstrated lesions ranging in diameter from 12 to 18 mm (mean, 14.6 mm). Lesion dimensions determined from images closely correlated with those determined at gross examination with the discrepancy never exceeding 2 mm, for an r² value of .87. MRI performed at the time of MR-guided RF ablation accurately demonstrated created lesions. This modality may provide a new option for the treatment of local and regional neoplastic disease.     

Localization of tissue plasminogen activator mRNA in adult rat brain

The distribution of tissue plasminogen activator (tPA) messenger RNA in rat brain was studied using in situ hybridization with ³⁵S UTP-labeled RNA probes derived from a fulllength tPA cDNA. Sense strand controls produced low, even backgrounds, with small elevations in the hippocampus. Full-length antisense probes produced strong signals over cerebral ventricular ependyma (including ependyma of the subcommissural organ), meninges, blood vessels, and Purkinje cell layer of the cerebellum, as well as strong signals over scattered cells throughout the brain. Some of these scattered labeled cells were large with lightly stained nuclei, while others were small with darkly stained nuclei. The large labeled cells, which were probably neurons, constituted 8% and 8% of cells in the brain stem and neocortex, respectively, and 100% of Purkinje cells. The small cells, which were present in all areas of the brain, constituted 3–11 % of cells in individual brain areas.     

Molecular characterization of a consistent 4.5-megabase deletion at 4q28 in prostate cancer cells

Spectral karyotyping of prostate cell lines LNCaP, DU145, PC3, and 22RV demonstrated structural chromosome rearrangements involving the distal long arm of chromosome 4. In all but 22RV, these are nonreciprocal translocations between chromosomes 4 and 10. In 22RV, an apparently reciprocal t(2q;4q) is seen. Fluorescence in situ hybridization analysis of the chromosome 4 translocation breakpoints demonstrated that deletions were associated with all of the translocations, resulting in a net loss of chromosome material. Overlapping deletions in 4q28 approximately 34 were seen in LNCap, DU145, and 22RV, which defined an approximately 4.5-megabase pair common region of deletion. The deletion in PC3 was more proximal on 4q, involving the 4q21 approximately q26 region. A meta analysis of high-resolution definition of losses of chromosome material from published studies demonstrates that loss of 4q material may occur in at least 50% of primary tumors. This analysis defines a series of genes in the critical 4q region, which is potentially associated with prostate tumor development.     

The inhibitory Fcgamma receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells

Deletion of the gene encoding the Fc immunoglobulin G receptor IIB (FcgammaRIIB) results in a fulminant, lupus-like disease in C57BL/6 but not BALB/c mice. Here we have investigated this strain-specific, epistatic loss of tolerance using gene-targeted immunoglobulin variable heavy-chain (V(H)) alleles 3H9 or 56R, which encode DNA-specific heavy chains, expressed on the C57BL/6 or BALB/c background. The combination of C57BL/6 and V(H) 56R (B6.56R) resulted in a loss of tolerance; hybridoma and single-cell analysis indicated an FcgammaRIIB-independent difference in immunoglobulin light-chain usage, consistent with an alteration in receptor editing. FcgammaRIIB deficiency resulted in an increase in immunoglobulin G (IgG) antibodies to DNA in the serum, an increased frequency of anti-DNA-reactive IgG(+) B cells with a plasma cell phenotype and immune complex deposition in the glomeruli and renal disease in B6.56R mice. Thus, FcgammaRIIB provides a distal peripheral checkpoint to limit the accumulation of autoreactive plasma cells, thereby maintaining tolerance.     

The Validity of the Neale and Kendler Model-Fitting Approach in Examining the Etiology of Comorbidity

Given that knowledge regarding the etiology of comorbidity between disorders can have a significant impact on research regarding the classification, treatment, and etiology of the disorders, the ability to reject incorrect hypotheses regarding the causes of comorbidity is very important. A simulation study was conducted to assess the validity of the Neale and Kendler (1995) model-fitting approach in examining the etiology of comorbidity between two disorders. First, data were simulated under the assumptions of the 13 alternative comorbidity models described by Neale and Kendler. Second, model-fitting analyses testing the comorbidity models were conducted on the simulated datasets. Thirteen sets of data with varying model parameters were simulated to test Neale and Kendler's assertion that their model-fitting approach is appropriate across a range of potential prevalences and degrees of familiality. The validity of the model-fitting approach in examining unselected twin data and a combination of selected family data and unselected family data was explored. The model-fitting approach successfully discriminated several classes of comorbidity models, although discrimination between models within classes of related models was less accurate. Results suggest that the model-fitting approach can be a useful tool in examining the etiology of the comorbidity between disorders if the caveats of the present study's results are considered carefully. As predicted by Neale and Kendler, variations in the disorder prevalences and familial correlations did not affect the validity of their model-fitting approach, but affected the power to discriminate the correct model. As suggested by Neale and Kendler, the model-fitting approach can be applied to both unselected and selected data and to both twin and family data.     

Which treatment for whom for ADHD? Moderators of treatment response in the MTA

Using receiver operating characteristics, the authors examined outcome predictors (variables associated with outcome regardless of treatment) and moderators (variables identifying subgroups with differential treatment effectiveness) in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD; MTA). Treatment response was determined using parent- and teacher-reported ADHD and oppositional defiant symptoms, with levels near or within the normal range indicating excellent response. Among 9 baseline child and family characteristics, none predicted but 3 moderated treatment response. In medication management and combined treatments, parental depressive symptoms and severity of child ADHD were associated with decreased rates of excellent response; when these 2 characteristics were present, below-average child IQ was an additional moderator. No predictors or moderators emerged for behavioral and community comparison treatments. The authors discuss conceptual and clinical implications of research on treatment moderators.     

The effect of hydrolytic enzymes on the acetylcholine sensitivity of the skeletal muscle cell membrane

Isometric tension developed by rat soleus and extensor digitorum longus (EDL) muscles in response to acetylcholine (Ach) applied in vitro was recorded. Tension of contractures elicited in response to Ach increased after muscles had been incubated with phospholipase C, pepsin, or soluble fractions prepared from muscle homogenate.Using intracellular microelectrodes, resting membrane potential (RMP) and depolarisation in response to Ach added to the bathing medium were recorded in endplate-free regions of the muscle fibres. No significant change in RMP was observed in muscles incubated with soluble muscle fraction or phospholipase C, but depolarisation in response to Ach or carbachol was significantly increased. The time course for the increase in depolarisation and the contracture response to Ach was similar.When all available receptors were blocked with -bungarotoxin prior to incubation so that no response to Ach could be elicited, with subsequent incubation in muscle soluble fraction or phospholipase C, both contractures and depolarisation in response to Ach returned. These results support the hypothesis that receptors, not previously available to interact with Ach or -bungarotoxin were revealed following incubation.