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Biomedical subjects

D Kimmel

Publications and source records attributed to D Kimmel.

12 recordsLinked to original sources
PubMed1999

Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype.

Allelic alterations of chromosomes 1 and 19 are frequent events in human diffuse gliomas and have recently proven to be strong predictors of chemotherapeutic response and prolonged survival in oligodendrogliomas (Cairncross et al., 1998; Smith et al., submitted). Using 115 human diffuse gliomas, we localized regions of common allelic loss on chromosomes 1 and 19 and assessed the association of these deletion intervals with glioma histological subtypes. Further, we evaluated the capacity of multiple modalities to detect these alterations, including loss of heterozygosity (LOH), fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH). The correlation coefficients for detection of 1p and 19q alterations, respectively, between modalities were: 0.98 and 0.87 for LOH and FISH, 0.79 and 0.60 for LOH and CGH, and 0.79 and 0.53 for FISH and CGH. Minimal deletion regions were defined on 19q13.3 (D19S412-D19S596) and 1p (D1S468-D1S1612). Loss of the 1p36 region was found in 18% of astrocytomas (10/55) and in 73% (24/33) of oligodendrogliomas (P < 0.0001), and loss of the 19q13.3 region was found in 38% (21/55) of astrocytomas and 73% (24/33) of oligodendrogliomas (P = 0.0017). Loss of both regions was found in 11% (6/55) of astrocytomas and in 64% (21/33) of oligodendrogliomas (P < 0.0001). All gliomas with LOH on either 1p or 19q demonstrated loss of the corresponding FISH probe, 1p36 or 19q13.3, suggesting not only locations of putative tumor suppressor genes, but also a simple assay for assessment of 1p and 19q alterations as diagnostic and prognostic markers.

Astrocytoma↗
PubMed1999

Rib biopsy technique for cortical bone evaluation in rhesus monkeys (Macaca mulatta).

Old World primates are often studied to model human skeletal physiology. An important advantage of monkeys over other animal models (i.e., rodents) is the presence of cortical bone Haversian remodeling. Seventy-five female rhesus monkeys (Macaca mulatta) were subjected to bone biopsy. With monkeys in lateral decubitus position, the tenth rib was surgically exposed and freed from periosteum by use of careful sharp and blunt dissection. The rib section was resected, using bone cutters, and the surgical wound was closed. This procedure was repeated for the contralateral rib at a later time point in 65 monkeys. There was no mortality or appreciable morbidity. The bone specimens were (mean +/- SD) 2.50 +/- 0.25 cm long, with 5.5 +/- 1.0 mm2 total cross-sectional area. They were adequate for histologic, immunohistochemical, and quantitative histomorphometric examinations. Prevalence of pneumothorax was approximately 8.0% for the 140 procedures. This complication was immediately and successfully corrected by insertion of a small thoracic tube, evacuation of pneumothorax, and closure of the incision. This well-tolerated, repeatable procedure yields excellent specimens for performance of cortical bone histologic examination without euthanasia, allowing longitudinal evaluation.

Animals↗
PubMed1998

Zoledronate prevents the development of absolute osteopenia following ovariectomy in adult rhesus monkeys.

This study assessed effects of the bisphosphonate zoledronate (ZLN) on bone density and biochemical markers of bone turnover in ovariectomized (OVX) adult female rhesus monkeys. Forty monkeys were randomly assigned to one control or four OVX groups. The control and one OVX group received saline, and the other three OVX groups received ZLN (0.5, 2.5, or 12.5 microg/kg) by a single weekly subcutaneous injection for 69 weeks. Bone mass of the total body (TB), lumbar spine (LS), distal and central radius (dual-energy X-ray absorptiometry), and skeletal turnover markers were measured at baseline and at 13, 26, 39, 52, and 69 weeks of treatment. Increased skeletal turnover and decreased bone mass (LS and TB) were demonstrable by 13 weeks post-OVX. Maximal bone loss (7-8%) at these sites occurred by 39 weeks after OVX and persisted for the study duration. Long-term ZLN treatment was well tolerated and prevented increased skeletal turnover and bone loss in a dose-dependent fashion. Progressive turnover suppression was not observed with any ZLN dose. In conclusion, after OVX, adult rhesus monkeys develop persistent increased bone turnover and absolute osteopenia of the LS and TB, making them an outstanding model of skeletal behavior in perimenopausal women. These OVX-related skeletal changes are dose-dependently blocked by ZLN.

Absorptiometry, Photon↗
PubMed1998

Gene amplification as a prognostic factor in primary and secondary high-grade malignant gliomas.

The purpose of this study was to examine the incidence of gene amplification in patients with primary (de novo) and secondary high-grade gliomas (gliomas evolving from lower grade malignancies) and to assess its prognostic significance. A total of 186 prospectively collected frozen surgical specimens were analyzed. Extracted DNA was examined by Southern blot using probes corresponding to the EGFR, CDK4, MDM2, n-MYC, CYCD1, PDGFR-alpha, MET, c-MYC oncogenes. Complete clinical data regarding age, sex, tumor size, extent of surgical resection, postoperative therapy and patient survival were collected. We showed that EGFR followed by CDK4 were the most frequent oncogene amplifications. Oncogene amplification events were significantly more frequent in grade 4 than in grade 3 astrocytomas, mixed gliomas or oligodendrogliomas (P<0.001). With respect to EGFR, there was a significant difference in the frequency of amplification between primary and secondary gliomas (P=0.001); however, no difference in the amplification frequency of the other oncogenes was observed. There was no apparent correlation between the occurrence of gene amplification and patient survival, possibly because the genes amplified in human gliomas are part of larger signaling pathways.

Adolescent↗
PubMed1997

Lack of germ-line mutations of CDK4, p16(INK4A), and p15(INK4B) in families with glioma.

Gliomas are tumors of the central nervous system that may be inherited in some patients. The gene(s) responsible for the clustering of gliomas in families have not yet been identified. Molecular studies of sporadic high-grade gliomas have revealed mutations or deletions of the genes encoding the protein kinase inhibitors p16(INK4A) and p15(INK4B) in a large proportion of tumors. Moreover, those tumors without deletions frequently display gene amplification and/or over-expression of mRNA encoding the protein kinase cdk4. We hypothesized that germ-line mutations in the p16(INK4A), p15(INK4B), or CDK4 genes might contribute to some cases of familial gliomas. To address this issue, we analyzed 36 kindreds with a predisposition to glial tumors. Genomic DNA from index members of these families was screened by PCR-single-strand conformational polymorphism analysis. We did not detect any functional mutations in the p16(INK4A), p15(INK4B), or CDK4 genes, although two individuals did have a previously described A140T polymorphism in p16(INK4A). Thus, despite the association between the sporadic forms of high-grade glioma and abnormalities of p16(INK4A), p15(INK4B), or CDK4, we found no evidence that germ-line mutations in the coding region of these three genes predispose to inherited glial tumors.

Adult↗
PubMed1995

Bone structure in postmenopausal hyperparathyroid, osteoporotic, and normal women.

The purpose of this study was to test the hypothesis that patients with mild primary hyperparathyroidism are protected against postmenopausal (PM) loss of cancellous bone architecture. To achieve this, we compared bone structure and turnover in iliac bone biopsies from three groups: 16 women with mild primary hyperparathyroidism (PHPT; 58.2 +/- 2.2 years, 11.5 +/- 1.7 years PM), 17 women with untreated primary osteoporosis (OP; 65.1 +/- 2.0 years, 17.2 +/- 2.3 years PM), and 31 healthy women (N; 59.8 +/- 1.4 years, 13.4 +/- 1.5 years PM). The bone formation rate was significantly higher in PHPT than in either OP or N, and not different between OP and N. Cancellous bone volume, total strut length, and indices of connectivity (node number, node to node strut length, and node to terminus ratio) were significantly lower in OP than in either PHPT or N but were the same or higher in PHPT than in N. Indices of disconnectivity were significantly lower in PHPT than in N, whereas they were the same or higher in OP than N. The data were also analyzed in subgroups matched by years PM with no changes in the results. These findings indicate that osteoporotic patients with normal bone turnover have low bone volume and microarchitectural deterioration, while patients with mild PHPT have normal bone volume and normal or greater trabecular connectivity despite higher bone turnover. These findings suggest that mild PHPT protects against the loss of cancellous bone structure that normally follows menopause.

Bone and Bones↗
PubMed1981

Bone cell kinetics and function during experimental uremia.

Bone cell kinetics and function and chondrocyte kinetics were evaluated in uremic rats and their pair-fed controls using quantitative histology and 3H-thymidine labeling. The principle histologic abnormality in the proximal tibial metaphysis of uremic rats was a relative abundance of proliferating and differentiated bone cells. No mineralization abnormalities were observed. There was increased proliferation of bone cells and an increased rate of differentiation of osteoblasts and osteoclast nuclei in uremic animals. There was no change in chondrocyte kinetics, indicating a dissociation of the normal bone elongation and bone maturation processes. The data on osteoclast number and hard tissue suggest individual osteoclasts in uremic animals have sub-normal resorbing efficiency. It is proposed that the cell kinetic alterations are due to secondary hyperparathyroidism. The cause of osteoclast inefficiency is uncertain, but may be related to (1) deficiency of active products of vitamin D; (2) chronic uremia; and/or (3) chronic secondary hyperparathyroidism.

Animals↗
PubMed1975

A rapid plastic embedding technique for preparation of three-micron thick sections of decalcified hard tissue.

A 24 hour start-to-finish method is described for the preparation of three-micron-thick sections of decalcified hard tissues. Following acetone dehydration, the tissue to be embedded is infiltrated under vacuum with a series of graded clearing solutions which approach the content of the final methyl methacrylate mixture. After overnight in a 35 C oven, the plastic is polymerized by four hours heating at 42 C. Three-micron-thick sections are then easily prepared by using a Jung microtome for high resolution histologic or detailed autoradiographic procedures.

Animals↗