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Biomedical subjects

U Saxena

Publications and source records attributed to U Saxena.

At least 37 records · Page 2Linked to original sources
PubMed1993

Apolipoprotein E modulates low density lipoprotein retention by lipoprotein lipase anchored to the subendothelial matrix.

Lipoprotein lipase (lipase), a key enzyme in lipoprotein triglyceride metabolism, has been shown to markedly increase low density lipoprotein (LDL) retention by subendothelial matrix. In the present study we assessed the role that lipoprotein and matrix components play in retention of LDL by lipase anchored to the subendothelial matrix. Lipase addition to subendothelial matrix increased LDL retention by 66-fold. Scatchard analysis of LDL binding to lipase-containing matrix yielded an association constant of 12 nM. Exogenous addition of the matrix components, heparan sulfate and dermatan sulfate (i.e. chondroitin sulfate B), reduced LDL retention by greater than 90%. These glycosaminoglycans (GAGs) also reduced lipolytic activity associated with the matrix, suggesting that lipase was released from its binding sites on the matrix. In contrast, other matrix components (collagen, fibronectin, vitronectin, and chondroitin sulfate A) neither affected LDL release nor matrix lipolytic activity. Thus, heparan sulfate and dermatan sulfate function to anchor lipase to the subendothelial cell matrix. The effects of apolipoprotein E (apoE) and apoA-I were also examined. Preincubation of the subendothelial matrix with apoE, followed by washing, did not affect subsequent lipase binding to the matrix nor its ability to retain LDL. However, the direct addition of apoE alone or in combination with phospholipid liposomes decreased lipase-mediated LDL retention in a concentration-dependent fashion. Addition of apoA-I had no effect. Thus, in these studies apoE functions to displace LDL bound to lipase, but not lipase anchored to the matrix. To further examine the physiologic implications of this process, we assessed the ability of human apoE-rich and apoE-poor high density lipoproteins (HDL) to displace LDL from matrix-anchored lipase. ApoE-rich HDL reduced LDL retention dramatically (86% at 2.5 micrograms/ml). In contrast, apoE-poor HDL, at the highest concentration evaluated (400 micrograms/ml), decreased LDL retention by only 32%. Overall, these data suggest apoE and specifically apoE-containing HDL reduce the lipase-mediated retention of LDL by subendothelial matrix. This observation, in part could explain the protective effects of apoE and apoE-containing HDL against atherosclerosis.

Animals↗
PubMed1993

Treatment of paucibacillary leprosy.

BACKGROUND: When multidrug therapy was introduced a decade ago to shorten the duration of treatment, paucibacillary leprosy was advocated 6 months of treatment. The diagnosis is based mainly on clinical and histopathologic examination, negative slit-skin smear examination, and positive lepromin test. METHODS: The case records of 508 paucibacillary leprosy patients attending our urban leprosy center have been analyzed with reference to regularity of therapy, response to multidrug regimen, follow-up, and relapse. RESULTS: The incidence of paucibacillary leprosy was found to be 37%. Defaulter rate was 45%. Nine percent of the cases attended the center with deformities emphasizing the need for corrective surgery and early case detection to prevent them. CONCLUSIONS: The main problem that we faced was the optimum duration of treatment, which is as yet an unsettled question. The opinions of other workers have been given, and a slight modification in current WHO regimen has been suggested without significantly affecting the cost of therapy.

Drug Therapy, Combination↗
PubMed1993

Post-kala-azar dermal leishmaniasis: a clinical and therapeutic study.

BACKGROUND: Post-kala-azar dermal leishmaniasis is a condition peculiarly confined to the Indian subcontinent. METHODS: The clinical features and investigations in 18 patients of post-kala-azar dermal leishmaniasis were studied. RESULTS: There was a polymorphic picture from hypopigmented macules to nodules and plaques. Mucous membranes were affected in five, the lips and glans penis being the most frequent sites. Histopathologically, a rich dermal infiltrate was seen in indurated lesions and in macules; it was confined to perivascular foci in the upper dermis. Leishman-Donovan bodies were seen in 16. CONCLUSIONS: The lesions cleared in 4 to 5 months after treatment with sodium antimony gluconate intramuscularly 20 mg/kg/day up to a maximum of 1 g/day. The drug was well tolerated.

Adolescent↗
PubMed1992

Lipoprotein lipase-mediated lipolysis of very low density lipoproteins increases monocyte adhesion to aortic endothelial cells.

Lipoprotein lipase (LPL) bound to vascular endothelial cells hydrolyses triglycerides in plasma lipoproteins. To explore the role of LPL in atherogenesis, the effect of LPL-mediated lipolysis of very low density lipoproteins (VLDL) on monocyte adhesion to endothelial cells was examined. Adhesion of U937 monocytes to porcine aortic endothelial cells that were incubated with VLDL and purified bovine milk LPL was markedly higher than endothelial cells that were incubated with VLDL alone. The increase in monocyte adhesion obtained with VLDL was dependent on the concentration of the lipoprotein, monocyte dose and time of incubation. The increase in adhesion correlated with generation of free fatty acids from the hydrolysis of triglycerides in VLDL by LPL. Furthermore, direct addition of oleic acid to endothelial cells also increased adhesion of monocytes. We postulate that LPL-derived lipolytic products increase monocyte adhesion to vascular endothelium and thereby promote atherogenesis.

Animals↗
PubMed1992

CT in complete congenital eventration of diaphragm with aplasia of lung.

Complete eventration of the diaphragm and pulmonary aplasia, though rare anomalies, should be considered in new-borns with respiratory distress. Such anomalous conditions occurring either alone or in combination elude diagnosis and pose problems for management. CT is a very effective, non invasive means of diagnosis which in the past depended largely on invasive procedures such as bronchography, angiography and thoracotomy.

Diaphragmatic Eventration↗
PubMed1992

Lipoprotein lipase increases low density lipoprotein retention by subendothelial cell matrix.

Lipoprotein lipase (LPL), the rate-limiting enzyme for hydrolysis of plasma lipoprotein triglycerides, is a normal constituent of the arterial wall. We explored whether LPL affects (a) lipoprotein transport across bovine aortic endothelial cells or (b) lipoprotein binding to subendothelial cell matrix (retention). When bovine milk LPL was added to endothelial cell monolayers before addition of 125I-labeled LDL, LDL transport across the monolayers was unchanged; but, at all concentrations of LDL tested (1-100 micrograms), LDL retention by the monolayers increased more than fourfold. 125I-labeled LDL binding to extracellular matrix increased when LPL was added directly to the matrix or was added to the basolateral side of the endothelial cell monolayers. Increased LDL binding required the presence of LPL and was not associated with LDL aggregation. LPL also increased VLDL, but not HDL, retention. Monoclonal anti-LPL IgG decreased both VLDL and LDL retention in the presence of LPL. Lipoprotein transport across the monolayers increased during hydrolysis of VLDL triglyceride (TG). In the presence of LPL and VLDL, VLDL transport across the monolayers increased 18% and LDL transport increased 37%. High molar concentrations of oleic acid to bovine serum albumin (3:1) in the medium increased VLDL transport approximately 30%. LDL transport increased 42% when oleic acid was added to the media. Therefore, LPL primarily increased retention of LDL and VLDL. A less remarkable increase in lipoprotein transport was found during hydrolysis of TG-containing lipoproteins. We hypothesize that LPL-mediated VLDL and LDL retention within the arterial wall potentiates conversion of these lipoproteins to more atherogenic forms.

Biological Transport↗
PubMed1992

Multidrug therapy in multibacillary leprosy; experience in an urban leprosy center.

The article records the experience of treating multibacillary (BB, BL and LL) leprosy with multidrug therapy (MDT) in an urban leprosy center. The problem of leprosy is to be properly assessed throughout the Indian subcontinent because most of the epidemiological data from the areas labeled low-endemic have to be updated. The regularity of therapy must be ensured and monitored constantly, but in spite of our efforts to do so some factors were beyond our control, such as providing a means of livelihood for the migrants from other places. In addition, the intake of drugs also has to be periodically checked from the history and discoloration of skin and, most importantly, confirmed by performing random spot tests for dapsone in the urine. The main problems discussed are the difficulty in demonstrating acid-fast bacilli in slit-skin smears from the macular form of borderline leprosy (also called dimorphous macular) and, secondly, whether the duration of multibacillary therapy was adequate since only approximately 50% of our patients achieved smear negativity after taking MDT for the stipulated period of 24 months. Experiences from other centers have suggested that the duration of MDT should be prolonged in multibacillary patients to achieve smear-negative status. Yet another group notes that smear negativity is gradually achieved during the period of surveillance following stoppage of MDT after 24 months. These questions await more information from good centers with controlled field studies.

Dapsone↗
PubMed1991

Identification and characterization of the endothelial cell surface lipoprotein lipase receptor.

The hydrolysis of triglycerides in plasma lipoproteins is mediated by lipoprotein lipase (LPL) that is bound to vascular endothelial cells. The specific endothelial cell surface protein(s) with which LPL associates has not been characterized. To identify this LPL binding protein(s), radioiodinated cell surface proteins from cultured bovine aortic endothelial cells were chromatographed using bovine LPL-Sepharose. A single radioiodinated protein of apparent molecular mass 220 kDa was specifically retained by the gel and eluted with 0.4 M NaCl. A LPL-binding protein of similar size was obtained after metabolic labeling of the cellular proteoglycans with 35SO4, indicating that the 220-kDa protein is a proteoglycan. After heparitinase or nitrous acid treatments the molecular mass of the LPL-binding protein decreased to approximately 50 kDa, suggesting that it contains heparin sulfate chains. A 220-kDa protein from the basal cell surface was also identified using LPL-Sepharose chromatography. 125I-LPL was cross-linked to the endothelial cell surface using ethylene glycobis (succinimidylsuccinate). A single ligand-receptor complex, approximately 350 kDa, was obtained. Heparin and unlabeled LPL decreased the cross-linking of radioiodinated LPL to the cell surface receptor. To examine whether the receptor mediates the internalization of cross-linked 125I-LPL, cells containing 125I-LPL complexed to the surface were incubated at either 37 or at 4 degrees C. The amount of 125I-LPL internalized by the cells was 74% greater at 37 degrees C than at 4 degrees C. This suggested that LPL cross-linked to the receptor was internalized in a temperature-dependent manner. Thus, a 220-kDa heparan sulfate proteoglycan functions as an endothelial cell surface receptor for LPL.

Animals↗
PubMed1991

Transport of lipoprotein lipase across endothelial cells.

Lipoprotein lipase (LPL), synthesized in muscle and fat, hydrolyzes plasma triglycerides primarily while bound to luminal endothelial cell surfaces. To obtain information about the movement of LPL from the basal to the luminal endothelial cell surface, we studied the transport of purified bovine milk LPL across bovine aortic endothelial cell monolayers. 125I-labeled LPL (125I-LPL) added to the basal surface of the monolayers was detected on the apical side of the cells in two compartments: (i) in the medium of the upper chamber, and (ii) bound to the apical cell surface. The amount of 125I-LPL on the cell surface, but not in the medium, reached saturation with time and LPL dose. Catalytically active LPL was transported to the apical surface but very little LPL activity appeared in the medium. Heparinase treatment of the basal cell surface and addition of dextran sulfate (0.15 microM) to the lower chamber decreased the amount of 125I-LPL appearing on the apical surface. Similarly, the presence of increasing molar ratios of oleic acid/bovine serum albumin at the basal surface decreased the transport of active LPL across the monolayer. Thus, a saturable transport system, which requires heparan sulfate proteoglycans and is inhibited by high concentrations of free fatty acids on the basal side of the cells, appears to exist for passage of enzymatically active LPL across endothelial cells. We postulate that regulation of LPL transport to the endothelial luminal surface modulates the physiologically active pool of LPL in vivo.

Animals↗
PubMed1991

Comparative efficacy of drug regimens in skin tuberculosis.

Three antituberculous drug regimens have been employed to study the therapeutic response in 90 patients with any one of the commonly encountered paucibacillary forms of skin tuberculosis, namely lupus vulgaris, tuberculosis verrucosa cutis and scrofuloderma. The first two regimens contained rifampicin, isoniazid and either pyrazinamide or thiacetazone, and the third regimen had rifampicin and isoniazid only. The disease was clinically defined as localized when confined to one area and widespread when the lesions were disseminated. The observations revealed that the response of lupus vulgaris and tuberculosis verrucosa cutis was alike in all the three regimens, with the localized lesions subsiding completely after 4 months of therapy and the more extensive forms taking 5 months. Patients with scrofuloderma responded similarly to both the triple drug regimens. The discharge, sinuses and ulcers cleared in 6 months but the lymph nodes took longer to regress, up to 7 months in localized and 9 months in more widespread scrofuloderma. To obtain the same results with rifampicin and isoniazid, all patients with widespread scrofuloderma and one-third of those with localized forms had to be treated for 10 and 9 months, respectively. No serious drug side-effects, apart from giddiness with rifampicin and acneiform eruptions with thiacetazone, were encountered. No instances of relapse were noted in the 50% of patients who were followed-up for 3 1/2 years after therapy. Single-drug therapy with isoniazid for lupus vulgaris, as given in the past, is to be discouraged as it may promote the emergence of drug-resistant bacilli in those with an undetected focus of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Persistent reaction in paucibacillary leprosy: case reports.

Three patients of histopathologically confirmed borderline-tuberculoid leprosy showing no acid-fast bacilli and with lesions confined to the face, 2 on the cheek and 1 on the forehead, were given multidrug therapy as recommended by the WHO for paucibacillary cases. Within 3 months the lesions showed signs of upgrading (or reversal) reaction which was substantiated by histopathology. In 1 patient the facial nerve was affected leading to facial palsy. The lymphocyte transformation test did not show a significant rise. All 3 patients were given oral prednisolone for periods varying between 5 and 7 months, but the response was poor except in 1 patient in whom the facial palsy responded favourably. Injections of sodium antimony gluconate tried in 1 patient after stoppage of steroids did not control the reaction. After 18 months of regular follow-up during therapy, the cutaneous reaction in the patient with facial nerve involvement subsided leaving significant atrophy. However, in the other 2 patients the skin lesion persisted with clinical and histopathological evidence of upgrading reaction. The reasons for the unnatural persistence of reaction in these patients is not clear.

Adolescent↗
PubMed1991

Post-kala-azar dermal leishmaniasis: a case report strikingly resembling lepromatous leprosy.

An adult man with post-kala-azar dermal leishmaniasis who had lessons distributed in a manner strikingly similar to lepromatous leprosy is described. He was mistakenly treated with multidrug therapy as recommended by the WHO Expert Committee on leprosy. All investigations including slit-skin smears, histopathology, culture for Leishmania donovani and an indirect fluorescent antibody test to confirm post-kala-azar dermal leishmaniasis proved futile. The diagnosis was ultimately based on the previous history of kala-azar, the absence of other disorders which were ruled out by relevant laboratory tests and the good therapeutic response to sodium antimony gluconate. The epidemiological significance of this case and the salient points to distinguish this condition from leprosy are discussed.

Animals↗
PubMed1991

Multibacillary leprosy presenting as a solitary skin lesion; report of three cases and its significance in control programs.

Three patients with solitary skin lesions showing the cardinal signs of leprosy were seen and clinically classified among the paucibacillary cases. Initially, they were treated with two drugs (rifampin and dapsone) as recommended by the WHO Expert Committee. On the first visit of their follow-up, they were seen to be histopathologically either in the borderline (BB) or borderline lepromatous (BL) group, and acid-fast bacilli were demonstrated in the sections. Later they were put on three drugs (rifampin, dapsone and clofazimine) as given for multibacillary cases, and therapeutically they also behaved like bacilliferous leprosy. Such cases are rare and the reasons for the occurrence are not clear. Further studies on the subtle relationship between the local host factors and the virulence of the organisms grown from these lesions may offer an explanation. In light of these cases and previous reports of even lepromatous leprosy presenting as a single skin lesion, field workers--including both medical and paramedical workers--should carefully perform and interpret slit-skin smears from clinically diagnosed paucibacillary cases so that such unusual presentations of the disease are treated appropriately and not missed.

Adolescent↗
PubMed1990

Metabolism of endothelial cell-bound lipoprotein lipase. Evidence for heparan sulfate proteoglycan-mediated internalization and recycling.

Lipoprotein lipase (LPL) hydrolyzes triglyceride in plasma lipoprotein primarily while bound to vascular endothelial cells. LPL metabolism by cultured endothelial cells was studied. Purified radioiodinated bovine LPL bound to porcine aortic endothelial cells at 4 degrees C with an association constant of 0.18 x 10(7) m-1. Analysis of the time course of LPL dissociation from endothelial cells at 4 degrees C yielded a dissociation rate constant of 3.9 x 10(-6)s-1. After 1 h at 37 degrees C, 28% of the LPL initially bound to the cell surface was no longer releasable by heparin or trypsin treatments, suggesting that LPL was internalized by the cells. Addition of heparin to the medium or pretreatment of the cells with heparinase markedly reduced the amount of LPL internalized, establishing a requirement for cell surface heparan sulfate proteoglycans in the process. When cells containing internalized LPL were incubated at 37 degrees C, a time-dependent increase in the amount of LPL in the medium and a corresponding decrease in LPL associated with the cells was found. This suggested that internalized LPL was released back into the medium. The catalytic activity, molecular size, and heparin-binding characteristics of the released LPL was similar to native LPL. Addition of either heparin, heparinase, or excess unlabeled LPL to prevent the rebinding of released 125I-LPL to the cell surface increased the amount of 125I-LPL present in the medium, suggesting that there is a process of recycling of 125I-LPL bound to the cell surface. Studies examining the effect of pH on dissociation of LPL from its binding site showed less dissociation of cell surface bound LPL at pH 5.5 compared with pH 7.4 and 8.5. These results suggest that even at acidic pH as in endocytotic vesicles, LPL remains bound to proteoglycans and this may facilitate the recycling of internalized LPL molecules.

Animals↗
PubMed1990

Interaction of lipoprotein lipase with glycosaminoglycans and apolipoprotein C-II: effects of free-fatty-acids.

Lipoprotein lipase (LPL) bound to endothelial cells is released from the cell surface by triacylglycerol-rich lipoproteins and oleic acid (Saxena, U., Witte, L.D. and Goldberg, I.J. (1989) J. Biol. Chem. 264, 4349-4355). Studies were conducted to compare the ability of different fatty acids to release 125I-labelled bovine milk LPL bound to endothelial cells and to define the mechanism for this effect. Using fatty acid/bovine serum albumin (BSA) solutions (molar ratio, 6:1), the release of LPL from endothelial cell surfaces using monounsaturated (18:1), polyunsaturated (18:2) and saturated (16:0) fatty acids was 78%, 60% and 28%, respectively. Release of LPL from heparin-agarose followed a similar pattern, suggesting that the fatty acids specifically affected LPL-heparin interaction. Short-chain fatty acids (C6, C8 and C10), medium-chain fatty acids (C12 and C14) and elaidic acid, a transisomer of oleic acid, released less 125I-LPL than oleic acid from heparin-agarose. To determine whether oleic acid release of 125I-LPL from heparin-agarose was due to binding of the fatty acid to heparin or LPL, oleic acid was incubated with either LPL or heparin-agarose prior to performing the affinity chromatography. Only the prior incubation with LPL affected the binding to heparin-agarose. This demonstrates that dissociation of LPL from heparin required interaction of fatty acid with LPL. At high molar ratios of fatty acid:BSA (greater than 3:1), apo C-II is known to be ineffective as an activator of LPL. To determine whether this effect is due to decreased association of apo C-II with LPL, 125I-apo C-II (0.5-10 nmol) was allowed to bind to LPL-Sepharose. A 6:1 molar ratio of oleic acid:BSA produced up to 69% decrease in the amount of 125I-apo C-II bound to the gel. This dissociation of apo C-II from LPL by oleic acid was also demonstrated using gel-filtration chromatography. Thus, the amount and type of fatty acids may be important in regulating LPL activity in vivo by affecting both LPL interaction with glycosaminoglycans and with apo C-II.

Animals↗