Edward H. Adelstein

The chronically reserpinized rat as a possible model for cystic fibrosis. I. Submaxillary gland morphology and ultrastructure.

Extract: Submaxillary glands of rats treated with reserpine for 7 days showed striking morphologic changes when studied by light and electron microscopy. Grossly, the glands from treated animals were smaller and firmer than those from untreated controls. There was a marked accumulation of periodic acid-Schiff (PAS)-positive material in acinar cells and in the lumen of intralobular ducts, which appeared to be obstructed and distended by the precipitated material. In the acinar cells, this material occurred in discrete globules that coalesced at times, filling the acinar cytoplasm almost entirely and pushing the nuclei towards the periphery of the cell. The duct cells showed increased numbers of dark, discrete granules which did not stain with PAS, but colored with toluidine blue. In electron micrographs, the PAS-positive material that accumulated in acinar cells had a fibrillar appearance and there was a decrease in perinuclear rough endoplasmic reticulum in affected secretory cells. The increased mucopolysaccharide material is probably secretory material, as stimulation of the gland results in its partial disappearance. The observed changes were progressive and first became evident after 3 days of treatment with the drug. By the 7th day, the changes described were full blown and generalized. A similar obstructive exocrinopathy has been described in the submaxillary gland of patients with cystic fibrosis. These findings suggest that the chronically reserpinized rat may be a potentially useful model in evaluating the pathogenesis of cystic fibrosis.Speculation: Reserpine treatment for several days results in morphologic changes in the submaxillary glands of rats which are similar to the obstructive exocrinopathy reported in cystic fibrosis. These and other observations suggest that the reserpinized rat may be a useful model for the study of disorders of the mucus-producing glands.

Structural analysis of monosulfated side-chain oligosaccharides isolated from human tracheobronchial mucous glycoproteins.

To determine the location of some sulfate esters on respiratory mucins, an unambiguous sequencing strategy was developed for a crude, monosulfated oligosaccharide fraction derived from tracheobronchial mucous glycoproteins, isolated from sputum from a patient with cystic fibrosis, and which possessed Ricinus communis-I lectin affinity. Employing fractionation by Bio-Gel P-2 chromatography and high-voltage paper electrophoresis of the pool, eighteen branched and four straight-chained monosulfated oligosaccharides, each possessing at least one neutral D-galactose residue at a nonreducing terminus, were purified. Desulfated analogs of each sulfated oligosaccharide were then produced. Elucidation of their structures and sulfate ester locations was accomplished through a parallel comparative sequencing approach for the sulfated oligosaccharide and its desulfated analog. The method was based on their carbohydrate composition and parallel analysis by sequential exoglycosidase degradations, endoglycosidase digestion, permethylation analyses, and specific lectin affinities. Key to this approach was the inability for specific exoglycosidases and lectins to cleave or bind to, respectively, carbohydrates of their specificity which occupied nonreducing termini and possessed a sulfate ester. Herein we report the structures of twenty-two novel sulfated oligosaccharides. Oligosaccharides ranged from trisaccharides to heptasaccharides, were branched and unbranched, and each possessed a single sulfate ester on either C-6 of a terminal or an internal D-galactose residue or on C-6 of an internal residue of 2-acetamido-2-deoxy-D-glucose (N-acetyl-D-glucosamine).

The effects of taxol, methylprednisolone, and 4-aminopyridine in compressive spinal cord injury: a qualitative experimental study.

BACKGROUND Taxol is a diterpene alkaloid that stimulates tubulin production in cells. It may be effective in preserving the cytoskeleton of spinal cord axons after injury. METHODS Thirty-nine rats were submitted to spinal cord compression. The animals were divided into three groups that received taxol (18.75 mg/m2), methylprednisolone (30 mg/kg), or 4-aminopyridine (1 mg/kg). Taxol was administered as one dose immediately after injury and two additional doses on days 14 and 21. Methylprednisolone was given as a single injection immediately postinjury. Four-aminopyridine was administered on days 25, 26, and 27. A group of nine injured animals served as a control without any treatment. Evoked potentials were recorded before, during, and 4 weeks postinjury. Behavioral tests were measured to evaluate recovery of motor function. RESULTS The taxol and methylprednisolone-treated animals demonstrated a significant improvement in comparison with the control group. No functional improvement was found at 1 mg/kg treatment of 4-aminopyridine in rats. CONCLUSIONS We conclude that taxol and methylprednisolone given shortly after the compression injury improve functional outcome after an incomplete spinal cord injury.

Lymphocyte-tumor cell interaction in patients with head and neck cancer.

Peripheral lymphocytes from 12 patients with squamous cell carcinoma of the head and neck were incubated with autologous tumor explants. Four of the 12 patients demonstrated lymphocyte induced tumor cytotoxicity. These lymphocytes adhered to the tumor cells and deposited a radioactive label from their surface onto tumor cells. The deposition of this label was associated with tumor death.

Interval breast cancers are not biologically distinct—Just more difficult to diagnose

BACKGROUND Breast cancer diagnosed within 1 year of a negative annual screening examination is called interval breast cancer (IBC) and is considered to be a more virulent subtype of disease. METHODS We reviewed clinical data on 24 women who were diagnosed as having IBC while participating in the Breast Cancer Detection Demonstration Project at Ellis Fischel Cancer Hospital and the Womens Cancer Control Program screening project in Columbia, Missouri, between 1974 and 1992. We reinterpreted mammograms from the visit prior to the diagnosis of IBC for possible misdiagnosis, changes suggestive of malignancy, and Wolfes patterns. Archival paraffin blocks from 19 patients were used to determine qualitative expression of tumor markers. RESULTS Observed 5-, 8-, and 10-year survival rates were identical to published data for patients with non-IBC. Seventy-four percent of the mammograms evidenced dysplastic Wolfes patterns (P2 and DY), and one patient was found retrospectively to have shown evidence of cancer which was missed. Compared to breast cancers in general, fewer IBC tumors expressed tumor markers associated with poor prognosis. CONCLUSIONS Survival rates and tumor marker expressions in this retrospective cohort suggest that IBC tumors are not more biologically aggressive than noninterval tumors. They are more difficult to diagnose both by physical examination and mammography.

Origin of muscle action potentials evoked by transcranial magnetic stimulation in cats

We studied the effects of transcranial magnetic stimulation on ipsilateral and contralateral forelimb extensor muscles in anesthetized cats. A magnetic stimulator, operating at 100% intensity, was used through a circular coil, which was placed tangentially over the midline scalp. Bilateral activation of extensor muscles was readily obtained in all animals. The onset latencies were 7.3 +/- 1.1 and 7.07 +/- 0.8 msec for the contralateral and ipsilateral muscles, respectively. The amplitude of muscle response was unstable in magnitude, nevertheless, it did not show any significant difference between the two sides. The latency of response for ipsilateral and contralateral muscles was similar, which suggests simultaneous activation of motor pathways servicing forelimb muscles. Lesioning or ablation of the motor cortex and decerebration at mid-colliculi level did not abolish the evoked responses elicited at high intensity magnetic stimulation. Stereotactic electrical stimulation of the vestibular nuclei complex was performed, and satisfactory ipsilateral motor responses were obtained. Subsequently, a stereotactic radiofrequency lesion was made at the vestibular nuclei complex, with morphological confirmation. After this lesion, the motor evoked potentials (MEPs) were significantly diminished in amplitude. This finding strongly suggests that the generator of the MEPs resides in the brainstem, mainly at the vestibular nuclei complex.

Alkaline Phosphatase, Sucrase, and Insulin-like Growth Factor Receptors are Present in Atrophied Small Bowel 14 Years after Jejunoileal Bypass

The authors obtained atrophied and hypertrophied small intestinal tissue from a patient undergoing jejunoileal (JI) bypass reversal. Tissue from both segments was examined for insulin, insulin-like growth factor-I (IGF-I) and IGF-II receptors, and alkaline phosphatase and sucrase. We were interested in the potential of the atrophied segment to respond to luminal stimulation once the food train was re-established. Within the atrophic segment, flow cytometric evaluation of the receptors revealed (expressed as percent positive staining cells): Insulin, 17.1%; IGF-I, 33.6%; and IGF-II, 60.8%, while the immunoreactive sucrase was 87.7% and alkaline phosphatase was 88.6%. Actual sucrase activity (expressed as glucose generated) in this segment was 17.9ng/min/μg protein and alkaline phosphatase was 28.0 U/L/μg protein as assessed by conventional methods. Receptor evaluation in the hypertrophic segment demonstrated 9.7% positive staining cells for insulin, 26.6% for IGF-I and 70.2% for IGF-II. Immunoreactive sucrase was 91.2% and alkaline phosphatase was 91.4%. Enzyme activity for sucrase was 10.4ng/min/μg protein and for alkaline phosphatase was 59.4U/L/μg protein. This data suggests that even in atrophied bowel insulin and IGF receptors as well as sucrase and alkaline phosphatase enzymes are present and may assist in the rapid recovery of the atrophied portion following reversal of the JI bypass.