Neuronal units linked to microvascular modules in cerebral cortex: response elements for imaging the brain

How neuronal activity changes cerebral blood flow is of biological and practical importance. The rodent whisker-barrel system has special merits as a model for studies of changes in local cerebral blood flow (LCBF). Stimulus-evoked changes in neural firing and 'intrinsic signals' recorded through a cranial window were used to define regions of interest for repeated flow measurements. Whisker-activated changes in flow were measured with intravascular markers at the pia. LCBF changes were always prompt and localized over the appropriate barrel. Stimulus-related changes in parenchymal flow monitored continuously with H2 electrodes recorded short latency flow changes initiated in middle cortical layers. Activation that increased flow to particular barrels often led to reduced flow to adjacent cortex. Dye was injected into single penetrating arterioles from the pia of the fixed brain and injected into arterioles in slices of cortex where barrels were evident without stains. Arteriolar and venular domains at the surface were not directly related to underlying barrels. Capillary tufts in layer IV were mainly coincident with barrels. The matching between a capillary plexus (a vascular module) and a barrel (a functional neuronal unit) is a spatial organization of neurons and blood vessels that optimizes local interactions between the two. The paths of communication probably include: neurons to neurons, neurons to glia, neurons to vessels, glia to vessels, vessels to vessels and vessels to brain. Matching a functional grouping of neurons with a vascular module is an elegant means of reducing the risk of embarrassment for energy-expensive neuronal activity (ion pumping) while minimizing energy spent for delivery of the energy (cardiac output). For imaging studies this organization sets biological limits to spatial, temporal and magnitude resolution. Reduced flow to nearby inactive cortex enhances local differences.     

A novel role for murine IL-4 in vivo: induction of MUC5AC gene expression and mucin hypersecretion

Mucus hypersecretion and plugging of lower respiratory tract airways contributes to the morbidity and mortality associated with asthma. Interleukin (IL)-4 plays a putative role in some forms of asthma. Thus, transgenic mice that overexpress murine IL-4 selectively within the lung were used to study the effect of IL-4 on mucus glycoprotein gene expression and mucin release. Histologic examination of lung sections from IL-4 mice revealed that nonciliated epithelial cells from conducting airways were hypertrophic, due at least in part to the accumulation of mucus glycoprotein. The cytoplasm of these cells stained positively for glycoproteins using mucicarmine, alcian blue (AB), and periodic acid-Schiff (PAS). Ciliated cells were also enlarged but did not show any mucin-specific staining. Inclusion granules typically found in nonciliated (Clara) cells of control mice were absent in the IL-4 transgenic mice. Northern blot analysis of total RNA from lung tissue revealed that the expression of the MUC5AC, but not MUC2, mucin gene was distinctly upgraded in IL-4 transgenic mice compared to transgene-negative controls. In addition, a 5- to 10-fold increase in AB- and PAS-positive material was found in lavage fluid from IL-4 overexpressing mice compared to transgene-negative controls. Thus, the overexpression of IL-4 locally within the lung enhances mucus glycoprotein synthesis by altering gene expression, results in the accumulation of mucus glycoprotein in nonciliated epithelial cells, and induces the release of mucus into the airway lumen. We therefore hypothesize that the overproduction of mucus seen in some patients with asthma may be a direct result of the action of IL-4 within the inflamed lung.     

Parents'' sung performances for infants

We have cloned an unique gene encoding the heavy chain of a type II myosin in the fission yeast, Schizosaccharomyces pombe. The myo2+ gene encodes a protein of 1526 amino acids with a predicted molecular weight of 177 kDa and containing consensus binding motifs for both essential and regulatory light chains. The S. pombe myo2+ head domain is 45% identical to myosin IIs from Saccharomyces cerevisiae and Homo sapiens and 40% identical to Drosophila melanogaster Structurally, myo2+ most closely resembles budding yeast MYO1, the tails of both myosin IIs containing a number of proline residues that are predicted to substantially disrupt the ability of these myosins to form coiled coils. The myo2+ gene is located on chromosome III, 8.3 map units from ade6+. Deletion of approximately 70% of the coding sequence of myo2+ is lethal but myo2delta spores can acquire a suppressor mutation that allows them to form viable microcolonies consisting of filaments of branched cells with aberrant septa. Overexpression of myo2+ results in the inhibition of cytokinesis; cells become elongated and multinucleate and fail to assemble a functional cytokinetic actin ring and are either aseptate or form aberrant septa. These results suggest that a contractile actin-myosin based cytokinetic mechanism appeared early in the evolution of eukaryotic cells and further emphasise the utility of fission yeast as a model organism in which to study the molecular and cellular basis of cytokinesis.     

Resolution of abnormal MR signal intensity in patients with stress fractures of the femoral neck

OBJECTIVE: The purpose of this study was to describe the natural evolution of abnormal MR signal intensity after the diagnosis of a stress fracture of the femoral neck and to ascertain the time to resolution of that abnormal signal intensity. SUBJECTS AND METHODS: Ten patients who had been previously diagnosed with stress fractures of the femoral neck after positive MR scans of the hip were examined with MR imaging at regular intervals. In each patient T1-weighted and short inversion time inversion recovery (STIR) sequences were obtained until the abnormally bright, diffuse MR signal intensity (representing edema) disappeared from the STIR images. Time to resolution was correlated with each patient's age and presence or absence of a fatigue line on MR imaging. Statistical analysis was done using Fisher's exact test. RESULTS: Edema resolved in seven patients within 3 months of initial diagnosis, in two patients within 6 months, and in the remaining patient within 12 months. We found no statistically significant correlation between time to resolution and patient age or the presence of a fatigue line on MR imaging. Residual sclerosis occurred in five patients, all of whom had a fatigue line. Two of these patients developed bright T1 signal (fatty marrow conversion) around the area of sclerosis. In the remaining three patients, STIR images revealed a brightened fatigue line, which we presumed was caused by granulation tissue. CONCLUSION: In this study, 90% of patients showed resolution of abnormal MR signal intensity on STIR imaging within 6 months of the initial diagnosis of stress fracture of the femoral neck. Such data may prove helpful in examining patients with recurrent symptoms who undergo repeated MR scanning. When an abnormally bright, diffuse MR signal intensity on STIR imaging is seen more than 6 months after an original injury, such abnormal signal intensity is likely to represent new injury.     

In vitro antineoplastic activity of a novel lanthionine-containing peptide

It has been a long-term goal to discover peptides that can kill tumor cells while sparing normal tissues. Lan-7 is a novel, chemically stable peptide structurally related to somatostatin that contains a lanthionine bridge between the two cysteines in the peptide; TT-232 is a less stable analogue containing a disulfide bridge. The antitumor activity of Lan-7 was examined, relative to that of TT-232 and the clinically used analogue octreotide, against a panel of malignant human tumor cell lines and normal human hematopoietic precursors. Lan-7 was cytotoxic to all four tumor cell lines, with IC50 values ranging over a 2-fold range from 16 to 36 microM. The potency of Lan-7 was comparable to that of TT-232, and both of these agents were two to three times more potent than octreotide. At concentrations that were highly cytotoxic to tumor cells, Lan-7 produced no significant toxicity to normal human hematopoietic precursors. Lan-7 induced apoptosis in human ovarian carcinoma 2008 cells over the same concentration range at which it produced cytotoxicity, but it did so without activating G1, S, or G2 checkpoints, given that it produced no perturbation of cell cycle phase distribution. Cells engineered to overexpress P-glycoprotein were not more resistant to Lan-7 than isogeneic cells not expressing the mdr1 gene. These results make Lan-7 of interest as a potential cancer chemotherapeutic agent.     

Magnetic resonance imaging of articular cartilage in the knee. An evaluation with use of fast-spin-echo imaging

The purpose of this study was to demonstrate that specialized magnetic resonance imaging provides an accurate assessment of lesions of the articular cartilage of the knee. Arthroscopy was used as the comparative standard. Eighty-eight patients who had an average age of thirty-eight years were evaluated with magnetic resonance imaging and subsequent arthroscopy because of a suspected meniscal or ligamentous injury. The magnetic resonance imaging was performed with a specialized sequence in the sagittal, coronal, and axial planes. Seven articular surfaces (the patellar facets, the trochlea, the femoral condyles, and the tibial plateaus) were graded prospectively on the magnetic resonance images by two independent readers with use of the 5-point classification system of Outerbridge, which was also used at arthroscopy. Six hundred and sixteen articular surfaces were assessed, and 248 lesions were identified at arthroscopy. Eighty-two surfaces had chondral softening; seventy-five, mild ulceration; fifty-three, deep ulceration, fibrillation, or a flap without exposure of subchondral bone; and thirty-eight, full-thickness wear. To simplify the statistical analysis, grades 0 and 1 were regarded as disease-negative status and grades 2, 3, and 4 were regarded as disease-positive status. When the grades that had been assigned by reader 1 were used for the analysis, magnetic resonance imaging had a sensitivity of 87 per cent (144 of 166), a specificity of 94 per cent (424 of 450), an accuracy of 92 per cent (568 of 616), a positive predictive value of 85 per cent (144 of 170), and a negative predictive value of 95 per cent (424 of 446) for the detection of a chondral lesion. Interobserver variability was minimum, as indicated by a weighted kappa statistic of 0.93 (almost perfect agreement). With use of this readily available modified magnetic resonance imaging sequence, it is possible to assess all articular surfaces of the knee accurately and thereby identify lesions that are amenable to arthroscopic treatment.     

Surgical management of aberrant sentinel lymph node drainage in cutaneous melanoma

BACKGROUND: Sentinel lymph node (SLN) mapping by lymphoscintigraphy has changed the surgical management of regional lymph node metastases for melanoma. SLNs lying outside of traditional nodal basins are now being identified. Our hypothesis is that when preoperative lymphoscintigraphy identifies aberrant SLNs, these nodes should be excised and, if histologically positive, lymphadenectomy of the aberrant nodal basin should be performed. METHODS: Patients with melanomas 1 mm or larger Breslow thickness and clinical stage N0M0 underwent lymphoscintigraphy and excision with SLN biopsy. Preoperative lymphoscintigraphy, intraoperative gamma probe, and intraoperative injection of isosulfan blue were performed to identify the SLN. Aberrant SLNs were defined as epitrochlear, supraclavicular, or popliteal nodes for extremity lesions and intramuscular nodes for truncal and head and neck lesions. RESULTS: Thirty-two patients were entered into the protocol. Seven (22%) were found to have aberrant nodes. Five of 19 patients with extremity melanoma had an aberrant SLN; 2 of 13 patients with truncal and head and neck melanoma had an aberrant SLN. CONCLUSIONS: This study demonstrates that (1) aberrant SLNs are encountered with similar frequency for extremity and truncal lesions, (2) biopsy should be performed on aberrant SLNs with intraoperative lymph node mapping with the gamma probe and blue dye, and (3) lymphadenectomy of the aberrant region should be considered if the aberrant SLN is positive.     

Variation in incidence of indinavir-associated nephrolithiasis among HIV-positive patients

BACKGROUND: Nephrolithiasis may be an important consequence of indinavir therapy; however little has been published on the variation in incidence between different populations of patients or the possible mechanisms of calculus formation. OBJECTIVE: To examine variation in the incidence of indinavir-associated nephrolithiasis (IAN) in HIV-positive patients in relation to hemophilia and hepatitis C virus (HCV) infection. METHODS: Clinical data were abstracted retrospectively from the medical records of all adult patients treated with indinavir from September 1995 to September 1997. Occurrence of first IAN, defined as flank pain and hematuria after initiation of therapy, was analyzed in relation to hemophilia status and HCV infection. RESULTS: There were 17 episodes of IAN (22%) among 79 patients treated with indinavir. Of 10 patients with hemophilia, 50% developed IAN as compared with 17% of patients without hemophilia (P = 0.03). Median days to first IAN was 22 (range 7-110 days) for hemophiliacs and 156 (range 5-611 days) for those without hemophilia. Data for HCV status were available for 74 out of 79 patients: 10 out of 27 (37%) patients with HCV developed IAN compared with six out of 42 (14%) without HCV (P = 0.02). CONCLUSION: Overall incidence of IAN was higher than that previously reported and was significantly greater in hemophiliacs than in non-hemophiliacs. HCV may be a contributing factor.