Biomedical subjects
Publications and source records attributed to P Kaminsky.
We report the effects of enzyme replacement therapy in a patient with Gaucher's disease associated with a monoclonal gammopathy. Alglucerase induces a linear decline in immunoglobulin and beta 2-microglobulin levels. This observation suggests that this treatment decreases the chronic antigenic stimulation commonly found in Gaucher's disease.
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Gaucher disease, a condition transmitted by autosomal recessive inheritance, results from a genetic defect in beta-glucosidase, an enzyme which degrades sphingolipids. Deficiency in beta-glucosidase leads to accumulation of its substrate, glycosylceramide, in macrophages and, in the more severe cases, in neurons. Clinically, splenomegaly, hepatomegaly, bone destruction, cytopenia, and in some cases, central neurological lesions develop. Three phenotypes have been described according to the absence (type 1) or presence of neurological involvement (type 2: severe, type 3: intermediate severity). The disease occurs in patients of all ethnic origins but type 1 is particularly well known in Ashkenese Jews and type 3 is found in the Swedish province of Norrbottnie. About forty mutations of the beta-glucosidase gene have been identified. Four account for 80% of the known mutations (1226G, 1448C, 84GG, IVS2+1). Residual enzyme activity of mutant beta-glucosidase explains some of the phenotypic variations. The phenotype resulting from the 1226G mutation has sufficient enzyme activity for degradation of gangliosides in the brain, explaining the absence of neurological involvement in patients with this allele. Treatment is based on enzyme supplemention: blood parameters return to normal and the volume of the spleen and liver are greatly reduced after 6 months. In infants with very severe disease, bone marrow graft may be used.
The social work department of a large New York City teaching hospital has conducted practice research studies over the past five years to better improve the early identification of high risk elderly patients. A recent prospective study is presented of the relationship between functional capacity and discharge status/length of stay, the results of which directly led to a change in the inpatient delivery system. A sample of 250 randomly selected patients, 65 years or older, selected upon admission, were tested using the Katz ADL, the IADL and the Short Portable Mental Status Questionnaire (PMSQ) to distinguish those patients likely to remain hospitalized beyond medical necessity. Results of a logistic regression indicate that low functional capacity patients (IADL: Wald = 5.6; P < .02) were likely to remain beyond medical necessity. The model predicted group membership correctly 90.6% of the time. These findings have led the medical center to develop an acute care geriatric unit in cooperation with an affiliated nursing home.
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Gaucher's disease is an autosomal recessive inherited disorder, characterized by genetic deficiency of lysosomial glucocerebrosidase. Its substrate (glycosylceramide) subsequently accumulates in cells of monocyte/macrophage origin, resulting in enlargement of the spleen and liver, skeletal lesions, and, in the most severe phenotypes, in neurological disorders. Thirty-six mutations have been at present documented in the gene encoding for the glucocerebrosidase, but four of them (N370S, L444P, 84GG and IVS2+1) are really frequent, particularly in ashkenaze population. Gaucher's disease is diagnosed by the presence of Gaucher cells, especially in bone marrow aspirate, and by assessing the glucocerebrosidase activity. The prognosis has been considerably improved by enzyme replacement therapy.
Parathyroid hormone related protein (PTHrP) is the aetiological factor for the syndrome of humoral hypercalcemia of malignancy. The PTHrP gene encodes three isoforms of respectively 139, 141 and 173 amino acids with N-terminal homology to parathormone (PTH). PTHrP, which has a wide tissue distribution, appears to be a polyhormone with different physiologic functions that depend on the particular fragment secreted. PTHrP may act in an autocrine, a paracrine or an endocrine fashion. There is evidence for a role in the growth and development of both embryonic and mature tissues, in cellular differentiation, in smooth muscle relaxation, lactation and calcium and magnesium transport. The best known PTHrP functions are those mediated by the N-terminal domain fixation on the classical PTH/PTHrP receptor. Nevertheless, several other functions are mediated by different fragments of PTHrP such as midregion fragments or carboxy-terminal forms. Each of these functional forms of PTHrP has one or several physiological function(s) which is (are) mediated by his own specific receptors and signal transduction pathways, some of which may be tissue specific.
Endemic areas of lead poisoning have recently been rediscovered raising an important public health problem, particularly for pregnant women and their offspring. Theoretically, pregnant women can no longer be exposed to occupational sources with the application of public health regulations but other sources including water contamination, wall paint, industrial wastes and automobile exhaust fumes cannot be ignored. The placental barrier is permeable to free serum lead and levels in cord blood reaches 5 to 10% of the maternal blood level. In addition, lead may be released from maternal bone reserves during pregnancy and thus become a major source of intoxication for the fetus. Lead content in fetal organs increases with gestational age and may affect the nervous system and calcium dependent organs. Moderate lead levels of 100 micrograms/L can inhibit fetal haeme and erythropoiesis. Besides the classical signs of lead poisoning, pregnant women risk spontaneous abortion and increased blood pressure. Manifestations in the fetus and newborn include prematurity, fetal hypotrophy and malformations. Other manifestations are not seen until several years after birth and include retarded mental development and muscular and behaviour disorders. Diagnosis is based on screening tests which should be used in cases of suspected accidental or environmental intoxication. Tests should include assay of zinc protoporphyrins and aminolevulinic acid dehydrase. A search for the source of the contamination should be undertaken when blood levels above 250 micrograms/L are observed. Treatment with metal chelators is not recommendable (except in extreme life-threatening cases) during pregnancy due to their teratogenic effect. Prevention is the only adequate treatment.
Patterns of intact parathyroid hormone (iPTH) elimination and subsequent recovery of parathyroid function were studied in seven patients undergoing surgical removal of solitary hyperfunctioning parathyroid adenoma. Using a sensitive two-site immunoradiometric assay, iPTH levels were measured pre, peri-, and postoperatively. Blood samples were taken at very early and at late stages, including 3, 6, 9, and 15 minutes and 48, 72, and 96 h after adenomectomy. A biexponential formula was calculated to fit the decreasing values of iPTH in all patients. The PTH half-life in the early phase was 1.4 +/- 1.1 minutes (95% confidence limits). The PTH half-life in the second phase was 64.45 +/- 32.19 minutes (95% confidence limits). A third phase is represented by a slow, linear increase in plasma iPTH values as a result of the recovery of healthy suppressed parathyroid glands. The extrapolation to baseline of the later phase shows that the recovery of normal parathyroid function begins as soon as 240 minutes after adenomectomy and is independent of the decrease in PTH of adenomatous origin. All individual results were consistent with this model. Five patients had iPTH values below 5 pg/ml, one had 15 pg/ml, and the last had 27 pg/ml 5 h after parathyroid adenomectomy. The recovery of the hormonal activity of the remaining glands occurred rapidly. By the postoperative hour 24 the mean serum iPTH concentration was 12.28 +/- 8.07 pg/ml. The intraoperative serum iPTH concentration offers a model to assess both recovery of hormonal secretion from functionally suppressed parathyroid glands and disappearance of parathyroid hormone.
Lead may be an industrial and an environmental hazard which becomes of greater importance every year. Classical symptoms of plumbism are rare, whenever minor clinical signs increase in frequency. Erythrocyte zinc protoporphyrin and delta-aminolaevulinic acid dehydratase are reliable indicators of the importance of the lead poisoning in individuals. The concentration of lead in blood is also a suitable biological indicator as is EDTA mobilization test. The treatment is based on the use of chelating agents such as calcium EDTA or DMSA, but the only solution is reduction or removal of the sources of lead exposure.
The purpose of this study was to investigate the energetic metabolism in obese Zucker rats, using phosphorus nuclear magnetic resonance spectroscopy at rest and during a 2-Hz muscle stimulation and subsequent recovery. Animals were anesthetized with ketamine (150 mg/kg ip). Fed obese rats and 2-day-fasted obese rats were compared with their normally fed and 2-day-fasted lean litter mates. No differences were found between the two groups for ATP, total creatine, phosphocreatine (PCr), and intracellular pH. Starvation in lean rats resulted in a significant fall in inorganic phosphate (Pi), increased resting ADP level, and decreased PCr and ADP recovery after stimulation. The obese rats exhibited a decreased PCr/Pi and increased ADP at rest and a decreased PCr resynthesis and ADP metabolization rate after stimulation. Muscle stimulation in fasted obese rats induced higher PCr depletion and more pronounced acidosis. These results suggest an in vivo mitochondrial metabolism dysfunction in fasted lean as well as in fed and fasted obese rats.
A diagnosis of sarcoidosis was evoked in a 61-year-old man on clinical and histologic bases. Nevertheless, a bile duct carcinoma was disclosed in association with the discovery of generalized sarcoid-like granulomas. This is only the third time that such an association has been described. HLA-B8, DR3, and DRw52 antigens were found, suggesting that altered immunologic mechanisms could play a role in the pathogenesis of this sarcoid-like reaction.
Two cases of splenic arteriovenous fistula (SAVF) are reported and the literature pertaining to this disease is discussed. SAVF is a rare but curable cause of portal hypertension. Until recently, diagnosis was based and angiographic findings. However, it can now be reached with duplex-Doppler sonography, CT or MRI. Duplex-Doppler sonography highlights an enlarged splenic vein with a turbulent flow. CT scan detects the arterial aneurysms and shows the early opacification of the enlarged splenic vein. MRI depicts all the morphological abnormalities and flow-void due to time-of-flight losses may indicate the location of the fistula. Intra-arterial obliteration of the fistula is a good alternative to surgical procedure for treating SAVF in avoiding the potentially serious threat of gastrointestinal hemorrhage.
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This paper gives an overview of the hypotheses concerning the mechanisms of inorganic lead toxicity on cells and tissues, with emphasis on the effect of low-concentration lead. Inhibition of heme synthesis is responsible not only for lead-induced anaemia, but also for accumulation of delta-aminolaevulinic acid (ALA) and for lowering the concentration of cytochromes contained in the mitochondrial respiratory chain. Auto-oxidation of ALA is thought to result in the formation of free radicals. On the other hand, lead replaces ionic calcium in its role as second cell messenger. This mechanism would explain the abnormalities observed in synaptic transmission, arteriolar vasoreactivity and functioning of such cells as osteoclasts and osteoblasts. Nuclear toxicity, with abnormal expression of DNA genes and inhibition of certain enzymes such as membrane Na+/K+ ATPase, are also considered. The mechanisms of tissue toxicity are discussed.
The thenar muscles and gastrocnemius of a patient with myotonic dystrophy were investigated, at rest, by phosphorus nuclear magnetic resonance spectroscopy. A decrease in phosphocreatine level and an increase in inorganic phosphate and phosphodiester levels were found in the gastrocnemius, which was clinically spared, whilst the thenar muscles, which were wasted and affected by myotonia, exhibited only an increased inorganic phosphate level and an elevated pH. These findings were comparable with those found in other muscular disorders, such as Duchenne's and Becker's dystrophies, as well as in limb girdle dystrophy. They suggested that the abnormalities observed were unrelated to myotonia or wasting, and the possibility of a secondary mitochondrial disorder in myotonic dystrophy, is to be considered.
Many potentially severe hemostatic disorders have been reported in thyroid diseases. Hyperthyroidism has been associated with thrombocytopenia, coagulation factor abnormalities, and decreased fibrinolytic and plasminogen activities. In hypothyroidism, potentially severe hemorrhagic disorders have been reported, including platelet function abnormalities and coagulation factor alterations such as acquired von Willebrand disease.
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