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Biomedical subjects

P Schlesinger

Publications and source records attributed to P Schlesinger.

At least 19 recordsLinked to original sources
PubMed1989

Extracellular protons acidify osteoclasts, reduce cytosolic calcium, and promote expression of cell-matrix attachment structures.

Because metabolic acids stimulate bone resorption in vitro and in vivo, we focused on the cellular events produced by acidosis that might be associated with stimulation of bone remodeling. To this end, we exposed isolated chicken osteoclasts to a metabolic (butyric) acid and observed a fall in both intracellular pH and cytosolic calcium [( Ca2+]i). These phenomena were recapitulated when bone resorptive cells, alkalinized by HCO3 loading, were transferred to a bicarbonate-free environment. The acid-induced decline in osteoclast [Ca2+]i was blocked by either NaCN or Na3VO4, in a Na+-independent fashion, despite the failure of each inhibitor to alter stimulated intracellular acidification. Moreover, K+-induced membrane depolarization also reduced cytosolic calcium in a manner additive to the effect of protons. These findings suggest that osteoclasts adherent to bone lack functional voltage-operated Ca2+ channels, and they reduced [Ca2+]i in response to protons via a membrane residing Ca-ATPase. Most importantly, acidosis enhances formation of podosomes, the contact areas of the osteoclast clear zone, indicating increased adhesion to substrate, an early step in bone resorption. Thus, extracellular acidification of osteoclasts leads to decrements in intracellular pH and calcium, and appears to promote cell-matrix attachment.

Animals↗
PubMed1989

Cytoplasmic pH is regulated in isolated avian osteoclasts by a Cl-/HCO3- exchanger.

Osteoclast resorb bone in an acid compartment formed by the bone-attachment site. The low pH of the resorption compartment provides a lysosome-like milieu suitable for acid proteases to degrade collagen. Solubilization of the hydroxyapatite that makes up bone mineral consumes about 2 moles of protons per moles of calcium dissolved, requiring a massive proton flux to maintain a low pH in the resorption compartment. In order to determine how the osteoclast maintains a physiological cytoplasmic pH while secreting massive amounts of acid, we studied the intracellular pH of osteoclasts using esterified fluorescein derivatives while controlling the electrolyte composition of the medium. The principal finding is that osteoclasts have a high capacity for chloride/bicarbonate exchange which enables them to maintain normal intracellular pH in the face of a large loading of base equivalents. Thus, the overall process of proton secretion during bone resorption is similar to the polarized acid elimination by renal epithelia, involving a proton pump on one surface of the cell, and a Cl-/HCO3- exchange to maintain cytoplasmic pH.

Acid-Base Equilibrium↗
PubMed1987

Foreign body ingestion: review and suggested guidelines for management.

Eighty percent of ingested foreign bodies which reach to stomach will pass uneventfully through the gastrointestinal tract. The remainder may cause obstruction, perforation or hemorrhage. The risk of complications is increased with long sharp metal objects and animal bones, and may be higher in patients with adhesions due to prior abdominal surgery. Pre-existing intestinal disease such as Crohn's or intestinal stenosis may predispose to complications. The use of overtubes has made endoscopic removal of sharp objects safer. In patients at increased risk for complications, we recommended early endoscopic retrieval of ingested foreign objects.

Child↗
PubMed1985

Endometrial and menstrual response to subcutaneous oestradiol and testosterone implants and continuous oral progestogen therapy in post-menopausal women.

A regimen of subcutaneous implants of oestradiol and testosterone in combination with continuous oral norethisterone (0.35mg to 5mg daily) was used to treat 71 non-hysterectomised post-menopausal women for up to 30 mth in an attempt to avoid the withdrawal periods associated with conventional cyclical therapy, while at the same time protecting the endometrium from oestrogenic overstimulation. Amenorrhoea, defined as no vaginal bleeding for at least 3 mth, occurred immediately in 5.4-55.6% of women, the percentage depending on the daily dose of the progestogen. In those women who bled, the dose of norethisterone was adjusted at 3-mth intervals. Despite this protocol, only 51.0% of the patients were amenorrhoeic after 6 mth, and 63.2% after 1 yr. Although eight women did develop amenorrhoea for 12-27 mth, there was a high drop-out rate by the others, mainly because of unacceptable irregular bleeding. Irrespective of the bleeding pattern, endometrial biopsies 6 mth after treatment revealed endometrial atrophy. It is concluded that this form of therapy is inferior to oral continuous combined hormone replacement where amenorrhoea can almost invariably be achieved.

Administration, Oral↗
PubMed1985

Amenorrhea and endometrial atrophy with continuous oral estrogen and progestogen therapy in postmenopausal women.

An oral regimen of continuous conjugated equine estrogens (Premarin 0.625 or 1.25 mg daily) and low-dose progestogen (Norethisterone 0.35 to 2.1 mg daily) have been used to treat 95 nonhysterectomized postmenopausal women for up to 2.5 years. This method of hormone replacements was undertaken in an attempt to avoid the withdrawal bleeding and progestogenic side effects associated with conventional cyclical therapy with estrogen and progestogen, while simultaneously protecting the endometrium from estrogenic over-stimulation. With the lower dose of estrogen, amenorrhea was achieved immediately in 30 of 46 patients (65%), and after adjustments to the dose of the progestogen in all ten patients observed for at least one year (maximum 2.5 years). With the higher dose of estrogen, irregular spotting during the first three months resulted in the cessation of treatment by six of the 49 patients (12%), but 23 (47%) women had no bleeding during that time; by 15 months, all 13 patients who had remained in treatment had become amenorrheic (maximum 2.25 years). Endometrial biopsy specimens after six months of combined treatment in 56% of patients revealed atrophic histology regardless of the dose of the estrogen.

Administration, Oral↗
PubMed1979

Urinary dihydroxanthopterin in the diagnosis of malignant hyperphenylalaninemia and phenylketonuria.

Assessment of urinary dihydroxanthopterin is proposed as a simple method of recognition of patients with malignant hyperphenylalaninemia (MHPA). High levels of urinary dihydroxanthopterin are found in untreated patients with phenylketonuria (PKU) or with dihydropteridine reductase (DHPR) deficiency. After dietary control of the serum phenylalanine level in PKU, the urinary dihydroxanthopterin falls to near normal levels. In DHPR deficiency urinary dihydroxanthopterin levels are high even when serum phenylalanine levels are in the range achieved on dietary treatment. Low levels would be expected in patients with defects in tetrahydrobiopterin synthesis even before dietary treatment. Confirmation of the diagnosis of different forms of MHPA then requires more detailed studies, but dietary treatment of other PKU patients can proceed with confidence.

Biopterins↗
PubMed1979

Circulating levels of pregnancy specific beta 1 glycoprotein in late pregnancy: nyctohemeral and day-to-day variation, and variation during labour.

Circulating levels of pregnancy-specific beta 1 glycoprotein have been determined in a number of physiological situations in late pregnancy. The apparent variation in five subjects studied over a 24-hour period was not in excess of that due to the assay. Excess variation was apparent in 2 of 11 subjects studied daily for up to 8 days, and in 6 of 16 patients studied serially during labour.

Circadian Rhythm↗
PubMed1979

Malignant hyperphenylalaninemia--clinical features, biochemical findings, and experience with administration of biopterins.

Four cases of malignant hyperphenylalaninemia (MHPA) are described. Pretreatment serum phenylalanine levels were 1.5, 3.0, 2.4, and 0.9 mmoles/l. Dihydropteridine reductase (DHPR) deficiency was proven in one patient by assays on cultured fibroblastic cells and was presumed in her sibling and in another deceased patient whose parents' fibroblastic cells show approximately 50% of normal enzyme activity. DHPR and phenylalanine hydroxylase deficiency were excluded by assays on liver obtained at autopsy in the 4th patient. Parenteral administration of tetrahydrobiopterin (BH4) corrected the hyperphenylalaninemia and increased the levels of catecholamines and 5-hydroxy-indoles in the one patient studied in life, but BH4 did not reach the cerebrospinal fluid. A 3-wk course of BH4 therapy had no clinical effect. Oral biopterin was absorbed and excreted in the urine, but did not alter the serum phenylalanine level. The frequency of MHPA in Australia was estimated as 7 in 258 patients with phenylketonuria.

Biopterins↗