Precise and accurate measurement of proton T1 in human brain in vivo: Validation and preliminary clinical application

Precise and accurate inversion-recovery (PAIR) magnetic resonance (MR) measurements of T1 were obtained in eight brain regions and cerebrospinal fluid of 26 healthy volunteers. Accuracy of the technique was assessed by measuring T1 in small fluid volumes with the PAIR technique and with two independent spectroscopic techniques. The mean difference between T1 measured with PAIR and with the two spectroscopic techniques was 3.1% ± 1.3. The precision (reproducibility) of measurements with the PAIR technique was excellent. The coefficient of variation (CV) across 16 measurements in a head phantom was 2.0%, compared with a CV of 2.7% across 45 separate measurements in a single subject. The within-subject CV was 1.8% ± 0.6 in white matter and 1.4% ± 1.0 in basal ganglia. The between-subject CV in 26 healthy volunteers was 3.6% ± 0.6 in white matter and 4.1% ± 1.9 in basal ganglia. Comparison between a patient with an active recurrent brain tumor and an agematched patient with an inactive brain tumor showed that T1 was significantly elevated throughout the brain of the active-tumor patient, especially in white matter tracts, even though no tumor or edema was detected in the white matter on standard MR images. Comparisons between five brain tumor patients and four healthy volunteers of similar age showed that T1 was significantly and substantially elevated throughout the white matter tracts and in the caudate nucleus, putamen, and thalamus. These results are consistent with the hypothesis that white matter tracts are selectively vulnerable to edema and that T1 increases in white matter are a sensitive indicator of patient status or tumor aggressiveness.     

Pulsed-field gel electrophoretic analysis of leptospiral DNA.

The genomic structures of spirochete species are not well characterized, and genetic studies on these organisms have been hampered by lack of a genetic exchange mechanism in these bacteria. In view of these observations, pulsed-field gel electrophoresis was used to examine the genomes of Leptospira species. Live cells, prepared in agarose plugs, were lysed in situ, and the DNA was analyzed under different electrophoretic conditions. Pulsed-field gel electrophoresis of DNA digested with infrequently cutting restriction enzymes showed that the genome of Leptospira interrogans serovar canicola is approximately 3.1 Mb, while that of the saprophytic L. biflexa serovar patoc I is 3.5 Mb. DNA forms of approximately 2,000 and 350 kb which were present in samples from L. interrogans serovars were not readily detected in nonpathogenic serovars. Three distinct populations, designated type alpha, beta, and gamma, of L. interrogans DNA molecules were further analyzed with two-dimensional gel electrophoresis. Evidence suggested that two of these DNA forms, type alpha and gamma, were linear structures. Pulsed-field gel electrophoresis has proven to be a valuable tool with which to size bacterial genomes and to take the first steps toward characterization of a form of leptospiral DNA which behaves as a linear molecule and which may be related to the virulence of L. interrogans.     

Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies

This article describes how genetic components of disease susceptibility can be evaluated in case-control studies, where cases and controls are sampled independently from the population at large. Subjects are assumed unrelated, in contrast to studies of familial aggregation and linkage. The logistic model can be used to test collapsibility over phenotypes or genotypes, and to estimate interactions between environmental and genetic factors. Such interactions provide an example of a context where non-hierarchical models make sense biologically. Also, if the exposure and genetic categories occur independently and the disease is rare, then analyses based only on cases are valid, and offer better precision for estimating gene-environment interactions than those based on the full data.     

Corticotropin-Releasing Factor Reduces Lipopolysaccharide-Induced Pulmonary Vascular Leak

Previous studies have suggested that corticotropin-releasing factor (CRF) has immunoregulatory effects in addition to its neuroendocrine role. We examined the ability of CRF to inhibit lipopolysaccharide (LPS)-induced pulmonary vascular leak in vivo. Female BALB/C mice were treated with either normal saline (NS) or CRF prior to injection with LPS. Pulmonary vascular leak was inhibited by CRF as assessed by measurement of lung wet-to-dry ratios. The stress-induced increase in serum corticosterone levels in mice injected with LPS alone was not further increased by treatment with CRF. This indicates that the effect of CRF was not mediated centrally by stimulation of endogenous steroid release. Histologic examination of the lungs revealed that leukocyte infiltration was significantly depressed in CRF-treated mice thus confirming the protective effect of CRF. In addition, a modest prolongation of survival was demonstrated in CRF-treated mice following challenge with LPS (p=.08). These data indicate the potential utility of CRF as a modulator of pulmonary vascular leak.     

Prevention of vascular injuries in revision total hip replacement.

Iliac-vessel injury from total hip arthroplasty is associated with hemorrhagic complications and an increased death rate. The authors identified seven patients who had severe medial displacement of the acetabular prosthesis and associated vascular injury to the iliac vessels after total hip replacement. One patient had two hip replacements. Preoperative findings included a pelvic mass (three hips), pelvic pain (eight), radiologic evidence of cement in the pelvis (three) and the acetabular prosthesis in the pelvis (eight), computed tomographic evidence of cement in the pelvis and proximity of the prosthesis to the iliac vessels (four), and arteriography showing displacement or compression of the iliac vessels (seven). Operative management in all cases involved medial exposure, mobilization and repair of the iliac vessels before revision of the hip prosthesis. Postoperative complications were deep vein thrombosis (three), in spite of prophylaxis, and occlusion of a vein interposition graft (one) requiring placement of a femoral crossover graft. There were no deaths, amputations or hemorrhagic complications. The authors advocate preoperative identification of patients who have iliac-vessel involvement by their total hip prosthesis and initial medial extraperitoneal exposure and repair of these vessels before removal of the displaced acetabular prosthesis.     

Binding potency of paroxetine analogues for the 5-hydroxytryptamine uptake complex.

The in-vitro inhibition constants (Ki) of 14 structural analogues of the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor paroxetine were determined to assess the structure-affinity relationship of these derivatives. A goal of these studies was to determine those positions on paroxetine which could be derivatized without significantly decreasing the affinity of the drug for the binding site, so that radiolabels such as [18F]fluoroalkyl groups might be appended for future in-vivo imaging studies of the 5-HT uptake system. Using the methyl moiety as a steric probe for these studies, it was found that the rank order of potency of various methyl-substituted paroxetine analogues for inhibiting the binding of [3H]paroxetine to the 5-HT re-uptake site was: 4'-approximately equal to 3'-approximately equal to 2'- > 2'-approximately equal to 1- > 5'- > 6'-methyl. The in-vitro equipotent molar ratios (EPMR, Ki(analogue)/Ki(paroxetine)) of the analogues were determined, and the EPMRs of the 4'-, 3'-, and 2'-methyl derivatives were 1.9, 2.2 and 2.2, respectively. The 4'- and 2'-fluoromethyl and -fluoroethyl analogues were synthesized, and the EPMRs of the 4'- and 2'-fluoromethyl derivatives were determined to be 2.0 and 3.5, and those of the 4'- and 2'-fluoroethyl analogues were 5.2 and 6.2, respectively. The 2'-fluoromethyl analogue was unstable in aqueous solutions, and it is not a promising ligand for in-vivo studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered corticomotor representation in patients with Parkinson's disease.

In 6 patients with Parkinson's disease (PD) and 6 age-matched controls, transcranial magnetic stimulation was applied at 56 regions over the motor cortex and premotor cortex of each hemisphere, with the first dorsal interosseous (FDI) muscle of both hands activated at 15% maximum voluntary contraction during stimulation. For each site, motor evoked potential (MEP) landmarks were recovered, including MEP amplitude, MEP onset latency, and silent period duration. Scaled MEP amplitudes were used to construct individual cortical maps of the FDI muscles. The maps revealed an anterior displacement of the muscle representation in PD patients. This anterior shift over motor cortical areas may reflect increased contributions of corticocortical connections between motor cortex and premotor cortical areas, possibly enhanced by the visual feedback aspect of the task. These alterations may reflect adaptations to the impairments in striatocortical circuits in PD.     

Anosognosia in mild cognitive impairment: Relationship to activation of cortical midline structures involved in self-appraisal.

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer's disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants' activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD.