January 1997 - 7 Year Old Girl with Seizures

A seven year old girl presented with six month history of seizures. An MRI scan showed a cortical lesion in the left temporal lobe which was resected. Neuropathology examination demonstrated meningioangiomatosis, an unusual hamartomatous condition sometimes associated with neurofibromatosis 2. Approximately 50 cases of meningioangiomatosis have been reported in the literature. These are reviewed and compared to the current case.     

Prevalence of<Emphasis Type="Italic"> Enterocytozoon bieneusi</Emphasis> in post-weaned dairy calves in the eastern United States

Fecal specimens were obtained from 3- to 8-month-old post-weaned dairy calves on farms in Vermont, New York, Pennsylvania, Maryland, Virginia, North Carolina, and Florida. After removal of fecal debris by sieving and density gradient centrifugation, 59 of 452 calves (13%) from 11 farms in six states were found positive for Enterocytozoon bieneusi by PCR and DNA sequence analysis. Based on gene sequence data this genotype of E. bieneusi found in post-weaned calves was 100% identical to that found in pre-weaned calves in North America and differed by only two positions in 1,069 base pairs from specimens analyzed from humans. However, compared with previous reports, the prevalence of E. bieneusi was significantly higher in post-weaned than in pre-weaned calves from many of the same farms.     

Oxygen and lactic acid transport in skeletal muscle

A mathematical model of oxygen and lactic acid transport in skeletal muscle is used to test the effects of reactive hyperemia on oxygen and lactic acid concentrations following a period of ischemia. The model is based on the Krogh cylinder as the geometrical representation of the functional unit of transport, i.e., a capillary and the tissue it supplies. Included in the mathematical development of the model are the convective and diffusive transport of the chemical species, the nonlinear aspects of oxygen and lactic acid kinetics, and the reversible reaction of oxygen with hemoglobin in capillary blood and myoglobin in the tissue. The steady-state solution to the model is obtained first as the baseline for the study. Ischemia is then simulated by the cessation of capillary blood flow. This is followed by a reactive hyperemic response that is a function of the occlusion duration. The general effect of reactive hyperemia is to shorten the time intervals for initial return of tissue oxygen levels and the washout of accumulated lactic acid and to maintain tissue oxygen levels above steady-state values.     

Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2

Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. USH is clinically and genetically heterogeneous with at least 11 chromosomal loci assigned to the three USH types (USH1A-G, USH2A-C, USH3A). Although the different USH types exhibit almost the same phenotype in human, the identified USH genes encode for proteins which belong to very different protein classes and families. We and others recently reported that the scaffold protein harmonin (USH1C-gene product) integrates all identified USH1 molecules in a USH1-protein network. Here, we investigated the relationship between the USH2 molecules and this USH1-protein network. We show a molecular interaction between the scaffold protein harmonin (USH1C) and the USH2A protein, VLGR1 (USH2C) and the candidate for USH2B, NBC3. We pinpoint these interactions to interactions between the PDZ1 domain of harmonin and the PDZ-binding motifs at the C-termini of the USH2 proteins and NBC3. We demonstrate that USH2A, VLGR1 and NBC3 are co-expressed with the USH1-protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. Our data indicate that the USH2 proteins and NBC3 are further partners in the supramolecular USH-protein network in the retina and inner ear which shed new light on the function of USH2 proteins and the entire USH-protein network. These findings provide first evidence for a molecular linkage between the pathophysiology in USH1 and USH2. The organization of USH molecules in a mutual 'interactome' related to the disease can explain the common phenotype in USH.     

Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau

Neurofibrillary pathology was produced in the brains of adult rats after localized gene transfer of human tau carrying the P301L mutation, which is associated with frontotemporal dementia with parkinsonism. Within 1 month of in situ transfection of the basal forebrain region of normal rats, tau-immunoreactive and argyrophilic neuronal lesions formed. The fibrillar lesions had features of neurofibrillary tangles and tau immunoreactivity at light and electron microscopic levels. In addition to neurofibrillary tangles, other tau pathology, including pretangles and neuropil threads, was abundant and widespread. Tau gene transfer to the hippocampal region of amyloid-depositing transgenic mice produced pretangles and threads, as well as intensely tau-immunoreactive neurites in amyloid plaques. The ability to produce neurofibrillary pathology in adult rodents makes this a useful method to study tau-related neurodegeneration.     

Cooperation between the Cdk inhibitors p27KIP1 and p57KIP2 in the control of tissue growth and development

Cell cycle exit is required for terminal differentiation of many cell types. The retinoblastoma protein Rb has been implicated both in cell cycle exit and differentiation in several tissues. Rb is negatively regulated by cyclin-dependent kinases (Cdks). The main effectors that down-regulate Cdk activity to activate Rb are not known in the lens or other tissues. In this study, using multiple mutant mice, we show that the Cdk inhibitors p27^KIP1 and p57^KIP2 function redundantly to control cell cycle exit and differentiation of lens fiber cells and placental trophoblasts. These studies demonstrate that p27^KIP1 and p57^KIP2 are critical terminal effectors of signal transduction pathways that control cell differentiation.     

Inhibition of interleukin-17 prevents the development of arthritis in vaccinated mice challenged with Borrelia burgdorferi

We showed that Borrelia burgdorferi-vaccinated interferon gamma-deficient (IFN-gamma(0)) mice challenged with the Lyme spirochete developed a prominent chronic severe destructive osteoarthropathy. The immune response underlying the development of the severe destructive arthritis involves interleukin-17 (IL-17). Treatment of vaccinated IFN-gamma(0) mice challenged with B. burgdorferi with anti-IL-17 antibody delayed the onset of swelling of the hind paws but, more importantly, inhibited the development of arthritis. Histopathologic examination confirmed that treatment with anti-IL-17 antibody prevented the destructive arthropathy seen in vaccinated and challenged IFN-gamma(0) mice. Similar preventive results were obtained when vaccinated and challenged IFN-gamma(0) mice were treated with anti-IL-17 receptor antibody or sequentially with anti-IL-17 antibody followed by anti-IL-17 receptor antibody. By contrast, treatment of vaccinated and challenged IFN-gamma(0) mice with recombinant IL-17 (rIL-17) did not alter the development and progression of arthritis found in vaccinated and challenged IFN-gamma(0) mice without treatment with rIL-17. Therapeutic intervention may be a realistic approach to prevent arthritis, especially if IL-17 is involved in the perpetuation of chronic or intermittent arthritis.     

Distress and DNA repair in human lymphocytes

This research assessed differences in DNA repair in lymphocytes from high-and low-distressed individuals. A median split on Minnesota Multiphasic Personality Inventory (MMPI) Scale 2 divided 28 newly admitted nonpsychotic psychiatric inpatients into high- and low-distress subgroups. The high-distress subgroup had significantly poorer DNA repair in lymphocytes exposed to X-irradiation than low-distress subjects. We also found that lymphocytes obtained from this psychiatric sample had significantly poorer DNA repair than lymphocytes from nonpsychiatric control subjects when compared 5 hr after X-irradiation. A high level of distress therefore appears to be associated with significant dysfunctional differences at the molecular level which may have important implications for health. These data provide evidence for a direct pathway through which distress could influence the incidence of cancer.This research was funded in part by General Molecular Applications, Inc., the Bremer Foundation, the Samuel J. Roessler Fund, and Comprehensive Cancer Center Core Grant CA-16068-09.     

Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency

X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a severe inherited neurodegenerative disease, associated with the accumulation of very long-chain fatty acids (VLCFA). The recent unexpected observation that the accumulation of VLCFA in tissues of the Abcd1-deficient mouse model for X-ALD is not due to a deficiency in VLCFA degradation, led to the hypothesis that mitochondrial abnormalities might contribute to X-ALD pathology. Here, we report that in spite of substantial accumulation of VLCFA in whole muscle homogenates, normal VLCFA levels were detected in mitochondria obtained by organellar fractionation. Polarographic analyses of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between X-ALD and control mice. Moreover, analysis by electron microscopy, revealed normal size, structure and localization of mitochondria in muscle of both groups. Similar to the results obtained in skeletal muscle, the mitochondrial enzyme activities in brain homogenates of Abcd1-deficient and wild-type animals also did not differ. Finally, studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of X-ALD patients and controls revealed no abnormalities. Thus, we conclude that the accumulation of VLCFA per se does not cause mitochondrial abnormalities and vice versa-mitochondrial abnormalities are not responsible for the accumulation of VLCFA in X-ALD mice.     

Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis.

We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.