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Biomedical subjects

M DeSantis

Publications and source records attributed to M DeSantis.

At least 19 recordsLinked to original sources
PubMed1999

Impact of cytotoxic treatment on long-term fertility in patients with germ-cell cancer.

More than half of the patients with testicular germ-cell cancer show impaired spermatogenesis before undergoing cytotoxic treatment. The known pre-treatment infertility and the reversibility of the fertility problems observed in some after successful anti-cancer treatment have so far prevented an assessment of the true role of cytotoxic therapy in long-term fertility. The introduction of wait-and-see strategies (surveillance) for testicular cancer patients and recent prospective trials comparing patients with and without cytotoxic treatment have provided the means for estimating the extent to which treatment itself affects long-term fertility. Whether or not spermatogenesis is irreversibly impaired by chemotherapy is determined by the cumulative dose of cisplatin: at doses below 400 mg/m2, long-term effects on sperm production as well as on endocrine function are unlikely to occur. Higher doses should be expected to cause long-term losses of exocrine and endocrine gonadal function. In contrast, for adjuvant retroperitoneal radiotherapy in stage I seminoma patients, no data are available comparing long-term gonadal function with patients on surveillance. However, using modern radiation techniques, radiation doses to the para-aortic field (< 30 Gy) and testis shielding providing testis scatter radiation (< 30 cG), radiation-induced impairment of fertility is very unlikely.

Antineoplastic Agents↗
PubMed1998

Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy.

In multiple myeloma (MM), previous studies showed that mutations of the p53 gene are rare events in patients with newly diagnosed disease, but it is not known whether deletions of p53 are of any significance in MM. To address this question, we used interphase fluorescence in situ hybridization (FISH) with a DNA probe specific for the p53 locus at 17p13 and investigated bone marrow plasma cells from 72 patients with MM (59 patients = 81.9% before therapy). By FISH, deletions of p53, which were found to be predominantly monoallelic, were detected in 32.8% and 54.5% of patients with newly diagnosed and relapsed MM, respectively. Karyotypes from six of the patients with a p53 deletion by FISH showed a structural abnormality of 17p in only one of them. Additional FISH studies including a distal-17p probe (specific for the D17S34 locus) provided evidence for an interstitial deletion on 17p resulting in loss of p53 hybridization signals in myeloma cells. Among all 59 patients with newly diagnosed MM, presence of a p53 deletion was associated with stage III (P = .054), but not with other laboratory and clinical parameters. Patients with a p53 deletion had significantly shorter survival time compared with those without a deletion, both from the time of diagnosis (median 13.9 v 38.7 months; P < .0001) and from the time of initiation of induction treatment consisting of conventional dose chemotherapy (median 15.9 months v median not reached at 38 months; P < .0002). On stepwise multivariate regression analysis, presence of a p53 deletion was the most significant independent parameter predicting for shortened survival (P = .002). We conclude that a p53 gene deletion, which can be identified by interphase FISH in almost a third of patients with newly diagnosed MM, is a novel prognostic factor predicting for short survival of MM patients treated with conventional-dose chemotherapy.

Adult↗
PubMed1998

99mTc SESTAMIBI scintigraphic evaluation of skeletal muscle disease in patients with systemic sclerosis: diagnostic reliability and comparison with cardiac function and perfusion.

The diagnosis of skeletal muscle involvement in patients with systemic sclerosis (SSc) is usually based on clinical, laboratory, electromyographic, and bioptic evidence of muscle disorder, whereas SSc cardiac disease is well established by nuclear medicine techniques (radionuclide ventriculography and myocardial scintigraphy). Previous reports have retrospectively hypothesized a possible relationship between cardiac and muscle involvement in scleroderma patients. In order to improve overall diagnostic accuracy in the qualitative/quantitative assessment of skeletal muscle involvement in these patients and to compare these results with those obtained at the cardiac level, diethylenetriaminepentaacetic acid (DTPA)-99mTc radionuclide ventriculography and 99mTc SESTAMIBI myocardial and muscular scintigraphic examinations were performed in 10 SSc patients and in five healthy subjects. Muscular radioactivity, as assessed at thigh and calf levels by means of a segmental score, was significantly decreased in SSc patients in comparison with healthy subjects (global score value 15.6+/-2.2 vs 22.7+/-1.6, p<0.001), as well as right ventricular ejection fraction (RVEF, 34.3%+/-5.3 vs 53.6%+/-4.2, p<0.001) and myocardial segmental perfusion (global score value, 19.6+/-2 vs 25.9+/-1.1, p<0.01). The results show a high frequency of skeletal muscle involvement in patients with SSc. Moreover, scleroderma patients with muscle disorders, as evidenced by scintigraphy, show a comparable occurrence of cardiac involvement, even in the absence of clinical signs of cardiac dysfunction.

Cardiomyopathies↗
PubMed1998

Purification and characterization of a recombinant human cripto-1 protein.

Cripto-1 (CR-1) is a novel protein that contains a modified EGF-like motif and that does not directly bind to any of the known erb B type-1 receptor tyrosine kinase receptors. To more clearly define the biological effects of CR-1 and to more adequately compare the structure-function relationships of CR-1 with other members of the EGF family of growth factors, we have expressed a modified, full-length recombinant human CR-1 protein (rhCR-1) in E. coli and have devised a procedure for the solubilization, refolding and purification of a biologically active form of this protein. We have generated the mature form of hCR-1 from computer assisted predictions of potential signal peptide cleavage sites. Expression of the modified rhCR-1 protein in E. coli was limited to the inclusion bodies. The rhCR-1 protein was found to be expressed at high levels in bacterial cells when fused to a histidine-tag sequence. Refolding of rhCR-1 was found to be difficult because of the large number of cysteine residues in the protein which results in protein aggregation. By chemically modifying the cysteine residues in the rhCR-1 protein with 3-trimethylammoniopropyl methanethiosulfonate, additional positive charges have been introduced into the protein by this disulfiding reagent. This modification facilitates solubilization of the protein when rhCR-1 is denatured. The solubilized, denatured protein was then purified by CM cation exchange and C4 reverse phase HPLC chromatography and refolded in a redox buffer. The refolded, modified rhCR-1 protein was found to be biologically active by its ability to inhibit beta-casein expression, to stimulate the tyrosine phosphorylation of Shc and the activation of MAPK and by its capacity to facilitate branching growth of mouse mammary epithelial cells in type I collagen gels.

Animals↗
PubMed1997

Chemical synthesis, structural modeling, and biological activity of the epidermal growth factor-like domain of human cripto.

Cripto, also known as human teratocarcinoma-derived growth factor 1 (TDGF-1), contains a 40 amino acid region with some similarity to the epidermal growth factor (EGF) domain. However, sequence homology is largely restricted to the classical cysteine/glycine motif with only limited similarities in other regions. Significant differences to human EGF include the absence of all seven residues between the two N-terminal half-cystines and a five-residue shorter loop between the third and fourth half-cystines. We examine the hypothesis that, in spite of these differences, cripto can adopt the characteristic EGF-like 1-3, 2-4, 5-6 disulfide bond pattern. A comparative structural model of the growth factor cripto was constructed on the basis of its similarity to EGF, transforming growth factor alpha (TGF-alpha), and the EGF-like domain of human clotting factor IX. The predicted disulfide bridges and disulfide-bridged loops were analyzed and appear viable in the modeled structure. Moreover, to ascertain the importance of disulfide arrangement for cripto bioactivity, two 47-residue peptides were synthesized and then refolded using either a simple oxidative or a controlled sequential refolding protocol. The cripto peptides were tested for their ability to stimulate MAP-kinase activity, for inhibition of beta-casein induction, and for Shc phosphorylation in MDA-MB 453 human mammary carcinoma cells and HC-11 mouse mammary epithelial cells. Data suggest that cripto does adopt the 1-3, 2-4, 5-6 disulfide pattern and thus forms the classical EGF-like fold in spite of the significant deletions within the folding domain. The predicted structure of cripto shows some of the characteristics of both the ErbB1- and ErbB3/ErbB4-binding growth factors.

Amino Acid Sequence↗
PubMed1997

Encapsulated sensory receptors within intraorbital skeletal muscles of a camel.

BACKGROUND: The occurrence of encapsulated sensory receptors in extrinsic ocular muscles differs among and within orders of mammals. Beyond indications that neuromuscular and neurotendinous spindles are present in extraocular muscles of the family Camilidae, little is known of their distributional characteristics. In fact there appear to be no distribution maps for any animal that show both major types of encapsulated muscle receptor in a full set of intraorbital skeletal muscles. METHOD: Serial histological sections of all skeletal muscles from one orbit of an adult, one-humped camel (Camelus dromedarius) were examined for encapsulated receptors. RESULTS: Encapsulated receptors were apparent in all the intraorbital skeletal muscles. Muscle spindles outnumbered tendon organs in the fleshy part of each muscle. For all muscles, spindles were most abundant in the half of the muscle near the origin; levator palpebrae superioris had a more even distribution of spindles along its length than did extraocular muscles. These longitudinal patterns of distribution for muscle spindles related in a general way to the nerve entry zone. Tendon organs occurred anywhere along a muscle's length, but they tended to be more frequent on either side of the major concentration of muscle spindles. Both types of encapsulated receptors were generally located nearer the perimeter than the center of cross sections through muscles. CONCLUSIONS: Encapsulated receptors of classic appearance are plentiful and have distinctive configurations within intraorbital skeletal muscles of the adult dromedary. When analyzed in conjunction with other studies, the present data give rise to testable explanations for the variability among genera in the number of encapsulated receptors in extraocular muscles.

Animals↗
PubMed1993

Location and completeness of reinnervation by two types of neurons at a single target: the feline muscle spindle.

Muscle spindles from the tenuissimus muscle of the cat were examined microscopically to assess the precision and completeness of reinnervation of intrafusal muscle fibers by efferent and afferent neurons. Positions of motor and sensory nerve terminals were charted relative to the cross-sectional area enclosed by the outer capsule of the spindle. Profiles of nerve endings were measured for normally innervated and reinnervated spindles. The tenuissimus was deprived of innervation by freezing its nerve, sometimes in conjunction with either spinal ganglion removal or ventral rhizotomy. Sensory and motor terminals occupied separate locales along the length of normal muscle spindles. Nerve terminals of efferent and afferent neurons were located in appropriate positions along the length of spindles when axons of both types of neurons regrew together and when either category of axon regenerated alone. Precise reinnervation of muscle spindles occurred in spite of a diminished diameter of intrafusal fibers. Repopulation of the spindle with motor endings was less complete than that by sensory endings, based on the proportion and size of the regenerated terminals. We conclude that under optimal conditions for axonal regrowth, efferent and afferent neurons reinnervate their respective regions along intrafusal muscle fibers but motor lags sensory reinnervation within the spindle. The mechanism by which positional specificity happens during reinnervation of intrafusal fibers requires neither an interaction between terminals of the two types of neurons nor target cells of normal bulk.

Animals↗
PubMed1993

Correlative light and electron microscopic study of boutons on neuronal somas isolated from fixed mammalian brain.

Procedures are described for isolating neuronal somas by ultrasonic disruption of fixed rat brain and for fashioning a device that facilitates studying the same single soma by light microscopy and scanning and transmission electron microscopy. The device enables one to carry and repeatedly locate individual cells as well as hold solutions used to bathe the cells. Sequential electron microscopic examination of individual somas was used to confirm the presence of axosomatic boutons at the surface of isolated neurons.

Animals↗
PubMed1992

Regeneration by skeletomotor axons in neonatal rats is topographically selective at an early stage of reinnervation.

The seven sectors of the rat's serratus anterior (SA) muscle are innervated topographically by motor neurons of spinal cord segments C6 and C7 whose axons travel in the long thoracic (LT) nerve. That pattern is roughly mapped early in development and gains its final precision postnatally. The segmentotopic pattern is reestablished better in neonates than adults after cutting the LT nerve. We examined the process of reinnervation to see whether segmental selectivity is reestablished at the outset or whether it arises by rearrangement of the regenerated axons. Recordings were made from muscle fibers 1 to 70 days following a cryogenic lesion of the LT nerve done within 48 h of birth, as well as from sham-operated and unoperated control rats. Reinnervation of all sectors of SA occurred within a week after freezing the nerve. Reinnervation by C6 and C7 motor neurons was topographically selective though not quite to the degree found in controls. The precision observed during the first week of reinnervation did not improve over the next 9 weeks. Thus, selectivity exists from the start rather than being a more random reinnervation subsequently sharpened by elimination of inappropriate connections. The number of muscle fibers innervated by both C6 plus C7 motor neurons was greater after reinnervation than in controls. There was a significant decrease in the percentage of these dually innervated fibers over the initial few weeks of reinnervation but there was no difference among the reinnervated sectors of SA. Reinnervation of SA under optimal conditions resembles normal development in that there is a degree of topographic selectivity of (re)innervation that is present even at the earliest time periods studied. Unlike normal development the topographic selectivity after neonatal reinnervation does not improve over time, and fibers receiving a dual segmental innervation are not preferentially located in sectors where there is the most overlap in segmental projection.

Animals↗
PubMed1991

Left ventricular aneurysm and intraventricular thrombi. Investigation and surgical correlations.

Formation of a left ventricular aneurysm and intraventricular thrombus represents one of the dreaded sequelae of coronary artery disease and acute myocardial infarction. The present emphasis is to reduce the incidence by reduction of cholesterol and fats, elimination of smoking, improved detection and control of hypertension and diabetes mellitus. Earlier diagnosis is available with stress testing and other noninvasive techniques. Cardiac catheterization allows detection of occlusive lesions. The CASS and other studies increasingly prove that percutaneous angioplasty and coronary artery bypass surgery improve life expectancy and implicitly should reduce the incidence of acute myocardial infarction. In the setting of the latter, thrombolytic agents may reduce the amount of myocardial injury. Despite these measures, formation of left ventricular aneurysms remains a common occurrence. Diagnosis and management are critical issues to the cardiac surgeon.

Cardiac Catheterization↗
PubMed1990

Testicular response to melatonin or suprachiasmatic nuclei ablation in the spotted skunk.

Testes of the Western spotted skunk enlarge and regress seasonally. The pineal hormone, melatonin, may be important in timing this seasonal reproductive activity. Likewise, the suprachiasmatic nuclei (SCN) have been implicated as possible neural regulators of pineal and reproductive events. These experiments were conducted to determine whether ablation of the SCN or constant administration of melatonin alters timing of the seasonal pattern of testicular regression and recrudescence. Male skunks (n = 24) were treated as follows: six received two empty Silastic capsules, six received two melatonin-filled Silastic capsules, six received sham lesions to the SCN, and six received lesions to the SCN (SCNx). All skunks were exposed to a natural photoperiod and had regressed testes at the onset of the experiment. Four of six males from the SCNx group had an average of 94 +/- 11.3% of these nuclei destroyed. Sham SCNx, animals with less than 40% of the SCN ablated, and males with empty capsules did not have fully enlarged testes until October. SCNx and melatonin-treated skunks exhibited a hastening of testicular recrudescence with maximal testis size being reached in June. Skunks with lesions to the SCN maintained enlarged testes for 5 months while all other groups exhibited rapid regression after attaining maximal testis size. Testicular regression occurred from July through October in animals receiving continuous melatonin, while controls exhibited recrudescence during this same period. Our data suggest that the SCN, melatonin, and thus the pineal gland, play a role in regulating the seasonal testicular cycle of the spotted skunk.

Analysis of Variance↗
PubMed1990

Results of emergent versus elective cardiac transplantation procedures.

Twenty-six patients underwent emergent (Group I) and 34 patients elective (Group II) cardiac transplantation (C. Tx.) from June 1985 through June 1989. Age, sex, etiology, presence of diabetes, renal failure and pulmonary artery pressures were comparable for both groups (P greater than 0.5). Twenty-two patients were in New York Heart Association (NYHA) Class IV for Group I and 17 for Group II. Group I included 12 patients on inotropic agents, five on intra-aortic balloon pump (IABP) and one on IABP and cardiopulmonary bypass (CPB). Elective patients were stable at home. Location of the donor heart and mean ischemic times were comparable for both groups. Early mortality (within 30 days) included four patients for Group I and two for Group II. There were four late deaths for Group I patients and six for Group II. Four deaths were due to infection, six to rejection, two to malignancy, two neurological and one each to suicide and multisystem failure. Immunosuppression regimen was similar for both groups. The number and severity of early and late rejection episodes were similar despite blood group crossing in 11 patients for Group I (P less than .01). Incidence of infection was comparable. Favorable lifestyles were comparable, including employment of 12 patients for Group I and 16 for Group II. Cumulative survival for the entire series was 70% at two years. The study indicates that the results of emergent and elective cardiac transplantation procedures are equally gratifying, that mortality is mainly related to rejection and sepsis complications and blood group crossing does not significantly increase the number of rejection episodes.

Bacterial Infections↗
PubMed1989

Lesions to the anterior hypothalamus prevent the melatonin-induced lengthening of delayed implantation.

The anterior hypothalamic area (AHA) has been postulated as a site of action for melatonin. We tested the hypothesis that lesions to the AHA (AHAx) would counteract the inhibitory effect of exogenous melatonin on blastocyst implantation in the spotted skunk by removing a possible site of action. Forty-seven females were treated as follows during delayed implantation. In Exp 1, five received empty Silastic capsules, five received Silastic capsules containing melatonin, six received sham AHAx plus empty capsules, none received AHAx plus empty capsules, and eight received AHAx plus capsules containing melatonin. In Exp 2, four skunks each received two empty capsules, five skunks each received two capsules containing melatonin, and five skunks received AHAx plus capsules containing melatonin. All capsules were inserted sc in the interscapular region 14-35 days after surgery in Exp 1 and 2 weeks before surgery in Exp 2. Surgery was performed between January 22 and February 12, 1988, in Exp 1 and on March 2-3, 1989, in Exp 2. The skunks were subjected to a natural photoperiod, and the duration of preimplantation was measured. In Exp 1, AHAx plus empty capsules significantly (P less than 0.05) shortened the duration of preimplantation (163 +/- 14.7 days) compared to that in sham AHAx or intact controls (193 +/- 26.1 and 188 +/- 10.6 days, respectively). Melatonin significantly (P less than 0.05) prolonged the duration of preimplantation (289 +/- 2.9 days) in intact skunks, but failed to do so in skunks with AHAx, as the preimplantation period was significantly shortened (159 +/- 6.1 days). In Exp 2, AHAx reversed the inhibitory effect of melatonin on the duration of preimplantation (191 +/- 21.5 days), as intact melatonin-treated skunks had a significantly longer preimplantation period (260 +/- 2.5 days) than skunks receiving empty capsules (191 +/- 16.4 days). The inhibitory effect of melatonin was reversible in all intact skunks, as blastocysts implanted 23 days, on the average, after cessation of treatment with melatonin. These data are consistent with the hypothesis that a portion of the AHA and/or adjacent regions play an essential role in timing blastocyst implantation in the spotted skunk. The lesions may have given this result by ablating a neural pathway controlling PRL secretion and may or may not have involved a site of action for melatonin.

Animals↗
PubMed1988

Effects of suprachiasmatic nuclear ablation and melatonin on delayed implantation in the spotted skunk.

The suprachiasmatic nuclei (SCN) have been implicated as neural timers of reproductive events and as possible sites of action for melatonin. We tested the hypothesis that ablation of the SCN (SCNx) would counteract the inhibitory effect of exogenous melatonin in blastocyst implantation in the spotted skunk by removing a possible site of action. Thirty-eight pregnant females with unimplanted blastocysts were treated as follows: 4 served as untreated controls, 6 received empty Silastic capsules, 5 received Silastic capsules containing melatonin, 10 received sham lesions in the SCN, 7 received lesions in the SCN and Silastic capsules containing melatonin, and 6 received lesions in the SCN and empty Silastic capsules. All surgical treatments were completed by February 15. The skunks were subjected to a natural photoperiod, and the duration of preimplantation was measured. The lesions destroyed an average of 87 +/- 10% of the SCN and a small amount of the surrounding hypothalamus. SCNx had no significant effect on duration of preimplantation (200 +/- 25.6 days) when compared to sham SCNx (205 +/- 21.5 days). Melatonin significantly (p less than 0.05) lengthened the duration of preimplantation in both intact (277 +/- 59 days) and SCNx (265 +/- 64.7 days) skunks when compared to all other groups. These data are not consistent with the hypothesis that the SCN are required for melatonin to exert its influence on timing of implantation in the spotted skunk.

Animals↗
PubMed1987

Pyloric exclusion. Suture material of choice.

Pyloric exclusion was first reported in 1977 as a temporary method of providing duodenal decompression in an attempt to protect the duodenum in the early postoperative period during the healing phase, followed by the return of normal gastrointestinal transit. It has been adopted by several trauma centers across the country as part of their armamentarium for managing moderate to severe duodenal injuries. Most series report using a polyglycolic acid (PGA) suture in performing the exclusion, anticipating a 3- to 4-week interval before pyloric patency is re-established. A comparison of polypropylene (PP), polyglycolic acid (PGA), and polydioxanone (PDS) sutures in the dog model suggests, however, that only PDS reliably accomplishes this goal. The low (approximately 5-10%) but finite incidence of fistula formation reported with pyloric exclusion using PGA may be improved by using PDS instead.

Animals↗