PubMed Health⌕ Search

Biomedical subjects

F de Miguel

Publications and source records attributed to F de Miguel.

At least 19 recordsLinked to original sources
PubMed2006

[Pittsburgh experience with botulinum toxin A injection].

We report one institution's six-year experience using botulinum toxin A (BONT-A) in the bladder and urethra in 110 patients for a variety of lower urinary tract dysfunction. 110 patients (age 19-82) were injected with BONT-A into the bladder (n=42) or urethra (n=68), 35 M, 75 F. Voiding dysfunction included: neurogenic detrusor overactivity and/or detrusor sphincter dyssynergia, overactive bladder (OAB), benign prostatic hyperplasia (BPH), bladder neck obstruction (BNO) and interstitial cystitis (IC). Currently, 27 patients have undergone further injections (up to 6) at intervals > 6 months. All the patients with bladder BONT-A injection had preoperative evidence of involuntary detrusor contractions during urodynamic testing. Analysis of the 110 patients indicates that 67.3% reported a decrease or absence of incontinence. Diaries indicate a decrease in both day and night voiding symptoms. Efficacy occurred within 7 days and lasted for at least 6 months. Condition specific QOL symptom scores also demonstrated improvement. There have been no long-term complications. Two MS women with mild baseline stress urinary incontinence reported increased leakage with stress after BONT-A external sphincter injection. One MS woman who had a bladder injection had an increased residual urine from 78 to 155 ml. She did not have to perform intermittent catheterization. BONT-A injection is a safe and promising treatment modality for a variety of lower urinary tract dysfunctions for both skeletal and smooth muscle dysfunction. In our series, BONT-A is equally effective in women as it is in men. Bladder injections with BONT-A are effective for not only neurogenic detrusor overactivity but also overactive bladder. BONT-A can even be considered for IC.

Adult↗
PubMed2005

Injection of skeletal muscle-derived cells into the penis improves erectile function.

We investigated the effect of intrapenile injection of muscle-derived cells (MDC) on the erectile function in rats with bilateral cavernous nerve injury. Rat MDC were harvested and transduced with a retrovirus expressing the lacZ gene. Hanks' balanced salt solution (HBSS) (20 microl) or MDC (1 x 10(6) cells/side) were injected in each corpora cavernosa immediately before bilateral cavernous nerve transection. Intracavernous pressures (ICP) were measured 2 or 4 weeks after surgery with electrical stimulation of the pelvic nerves. Mean maximal ICP of sham group was significantly lower than that of control group both at 2 and 4 weeks after surgery. When MDC were injected into the penis, ICP improved over the sham-injected group at both 2 and 4 weeks after surgery. Percent area of PGP 9.5 staining was significantly greater in MDC-injected penis than in sham-injected at 2 and 4 weeks. Penile MDC injection can facilitate recovery of injured penile innervation and improve erectile function.

Animals↗
PubMed2001

The C-terminal region of PTHrP, in addition to the nuclear localization signal, is essential for the intracrine stimulation of proliferation in vascular smooth muscle cells.

PTHrP is secreted by most cell types. In addition to a paracrine/autocrine role, PTHrP has "intracrine" actions, entering the nuclear compartment under the direction of a classic bipartite nuclear localization signal. In vascular smooth muscle cells, nuclear entry stimulates mitogenesis. In the current study, we sought to more precisely define the regions of PTHrP required for the activation of mitogenesis in vascular smooth muscle cells. PTHrP deletion mutants missing large regions [i.e. the signal peptide, N terminus (1--36), mid region (38--86), nuclear localization signal, C terminus (108--139), or combinations of the above] were expressed in A-10 vascular smooth muscle cells. The consequences on nuclear localization and proliferation were examined. Deletion of the nuclear localization signal prevented nuclear entry and slowed proliferation. Deletion of the highly conserved N terminus or mid region had no impact on nuclear localization or on proliferation. Deletion of the C terminus had no deleterious effect on nuclear localization but dramatically reduced proliferation. Thus, the nuclear localization signal is both necessary and sufficient for nuclear localization of PTHrP. In contrast, activation of proliferation in vascular smooth muscle cells requires both an intact nuclear localization signal and an intact C terminus. Whereas the nuclear localization signal is required for nuclear entry, the C terminus may serve a trans-activating function to stimulate mitogenesis once inside the nucleus of vascular smooth muscle cells.

Amino Acid Sequence↗
PubMed2000

Parathyroid hormone-related protein, parathyroid hormone, and vitamin D in hypercalcemia of malignancy.

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. In the majority of cancer patients, hypercalcemia appears to be a consequence of the tumor production of parathyroid hormone (PTH)-related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy, in contrast to those with primary hyperparathyroidism, have an uncoupled bone turnover, and they usually have low circulating levels of 1.25(OH)2D3. We performed a case-control study to assess the relationship of plasma PTHrP, PTH and 1.25(OH)2D3 with hypercalcemia in cancer patients with a variety of tumors. Sixty of these patients had hypercalcemia, and 45 were normocalcemic. We measured PTHrP and PTH by immunoradiometric assay (Nichols), and 1.25(OH)2D3 by radioreceptor assay (Nichols), in plasma in both groups of cancer patients. Using a logistic regression analysis, we found that the higher PTHrP in plasma, the higher association with hypercalcemia occurred in these patients. In addition, the decreased plasma levels of PTH and 1.25(OH)2D3 in the majority of cancer patients were found to be significantly associated with hypercalcemia. Our results indicate that the combined determination of PTH, PTHrP and 1.25(OH)2D3 in plasma represents a more comprehensive approach to the investigation of hypercalcemia in cancer patients. Our data also support the role of PTHrP as a humoral factor responsible for hypercalcemia in these patients.

Adult↗
PubMed2000

Suspected sexual abuse: an unusual presentation form of congenital myotonic dystrophy.

UNLABELLED: In children, anal abnormalities due to various causes may be confused with sexual abuse. We present the case of a child in whom the suspicion of abuse due to anal dilatation led to the previously unknown diagnosis of myotonic dystrophy. Myopathic involvement of the perianal musculature is a known feature of congenital myotonic dystrophy that usually appears in late childhood or adolescence. CONCLUSION: We stress the importance of considering an underlying myopathic condition in the differential diagnosis of anal laxity. Further studies, such as anal ultrasonography, may help when the diagnosis of abuse is not clear.

Child↗
PubMed2000

Relationship of plasma bone cytokines with hypercalcemia in cancer patients.

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. This syndrome appears to be a consequence of the tumor production of humoral factors, mainly parathyroid hormone related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy have features suggesting that factors other than PTHrP might play a role in this syndrome. We performed a case-control study in cancer patients with and without hypercalcemia. A total of 105 patients with a variety of tumors, 60 of them with hypercalcemia (corrected serum calcium over 2.6 mmol/l), and 45 without hypercalcemia. In a previous study, we demonstrated that plasma PTHrP was highly associated with hypercalcemia in these patients. In the present study, we measured the plasma levels of various bone cytokines: interleukin-1beta (IL-1beta), interleukin-6 (IL-6), transforming growth factor (TGF) alpha, and tumor necrosis factor (TNF) alpha, in these cancer patients. We also determined C-terminal type I procollagen (PICP) and C-terminal telopeptide of type I collagen (ICTP), bone formation and bone resorption markers, respectively, in serum in these patients. We found that these osteolytic cytokines do not increase in plasma by the presence of hypercalcemia. In fact, using a logistic regression analysis, a significant (P<0.02) association was found between the low plasma levels of IL-1beta and TGFalpha and hypercalcemia, independent of plasma PTHrP and the presence of bone metastasis, in these patients. No significant association between the plasma levels of IL-6 or TNFalpha and hypercalcemia was found in these cancer patients. Serum ICTP correlated (r=0.35; P=0.008) with hypercalcemia in these patients, but none of the cytokines studied in plasma correlated with either ICTP or PICP in these hypercalcemic patients. Our data indicate that the circulating levels of several bone cytokines are not enhanced by PTHrP in hypercalcemic cancer patients. The mechanism responsible for the association between the low plasma levels of some of these cytokines and hypercalcemia in these patients remains obscure. However, this finding does not rule out the possible local bone effects of these cytokines, contributing to hypercalcemia in cancer patients.

Adult↗
PubMed2000

Characterization of parathyroid hormone/parathyroid hormone-related protein receptor and signaling in hypercalcemic Walker 256 tumor cells.

Parathyroid hormone (PTH)-related protein (PTHrP) is the main factor responsible for humoral hypercalcemia of malignancy. Both PTH and PTHrP bind to the common type I PTH/PTHrP receptor (PTHR), thereby activating phospholipase C and adenylate cyclase through various G proteins, in bone and renal cells. However, various normal and transformed cell types, including hypercalcemic Walker 256 (W256) tumor cells, do not produce cAMP after PTHrP stimulation. We characterized the PTHrP receptor and the signaling mechanism upon its activation in the latter cells. Scatchard analysis of PTHrP-binding data in W256 tumor cells revealed the presence of high affinity binding sites with an apparent K(d) of 17 nM, and a density of 90 000 sites/cell. In addition, W256 tumor cells immunostained with an anti-PTHR antibody, recognizing its extracellular domain. Furthermore, reverse transcription followed by PCR, using primers amplifying two different regions in the PTHR cDNA corresponding to the N- and C-terminal domains, yielded products from W256 tumor cell RNA which were identical to the corresponding products obtained from rat kidney RNA. Consistent with our previous findings on cAMP production, 1 microM PTHrP(1-34), in contrast to 10 microg/ml cholera toxin or 1 microM isoproterenol, failed to affect protein kinase A activity in W256 tumor cells. However, in these cells we found a functional PTHR coupling to G(alpha)(q/11), whose presence was demonstrated in these tumor cell membranes by Western blot analysis. Our findings indicate that W256 tumor cells express the PTHR, which seems to be coupled to G(alpha)(q/11). Taken together with previous data, these results support the hypothesis that a switch from the cAMP pathway to the phospholipase C-intracellular calcium pathway, associated with PTHR activation, occurs in malignant cells.

Adrenergic beta-Agonists↗
PubMed1999

Parathyroid hormone-related protein (107-139) decreases alkaline phosphatase in osteoblastic osteosarcoma cells UMR 106 by a protein kinase C-dependent pathway.

The C-terminal (107-111) region of parathyroid hormone-related protein (PTHrP) appears to inhibit osteoclastic bone resorption, and to affect osteoblastic growth and differentiation. We tested the effect of human PTHrP (107-139) on alkaline phosphatase (ALP) activity in osteoblastic osteosarcoma UMR 106 cells. We found that this C-terminal PTHrP peptide, between 10 nM and 10 fM, inhibited ALP activity in these cells during the log phase of growth. Human PTHrP (1-34) amide and human PTHrP (1-141) were as potent as PTHrP (107-139) in growing UMR 106 cells. This inhibitory effect of 10 nM PTHrP (107-139) on ALP activity was also observed in serum-depleted cells, and in the presence of 10 nM dexamethasone, which increased ALP activity by 40% in these cells. In addition, this effect of PTHrP (107-139) was blunted by 25 nM bisindolylmaleimide I, a protein kinase C inhibitor. These results support a role for the C-terminal region of PTHrP as a modulator of bone formation.

Alkaline Phosphatase↗
PubMed1999

Effects of transforming growth factor beta1 on cell growth and parathyroid hormone-related protein in Walker 256 tumor cells.

Hypercalcemic strains of the rat Walker 256 (W256) tumor synthesize parathyroid hormone-related protein (PTHrP) and at least one of them produces an ill-defined transforming growth factor activity. We tested the production of transforming growth factor (TGF) beta by a hypercalcemic W256 tumor strain, and assessed its effects on tumor cell growth and PTHrP expression. We found that addition of TGF beta1 for 7 days inhibited cell growth ([3H]thymidine incorporation and cell number) dose dependently, between 0.04-20 pM. The antiproliferative effect of TGF beta1 on W256 tumor cell growth was likely mediated by binding to high affinity receptors (Kd = 14 pM) in these cells. At different tumor cell growth stages, acidified cell-conditioned medium contained immunoreactive TGF beta1. However, the nonacidified tumor cell-conditioned medium was found to contain neither immunoreactive nor bioactive TGF beta. Moreover, exposure of W256 tumor cells to a neutralizing anti-TGF beta1 antibody failed to affect tumor cell proliferation. Thus, W256 tumor cells appear to secrete TGF beta in an inactive form. Using reverse transcription followed by PCR, we found that addition of 20 pM TGF beta1 increased its own mRNA expression, apparently by stimulating gene transcription, within 6-12 h in W256 tumor cells. In addition, 20 pM TGF beta1 stimulated PTHrP mRNA in these cells at 24 h; an effect which was mediated, at least in part, by increasing PTHrP mRNA stability. Immunoreactive PTHrP decreased in the W256 tumor cell-conditioned medium after treatment with 20 pM TGF beta1 for 24-48 h. These results support the validity of this W256 tumor strain for in vivo studies to clarify the relative role of TGF beta and PTHrP in the pathogenesis of humoral hypercalcemia of malignancy.

Animals↗
PubMed1999

Parathyroid hormone-related peptide stimulates DNA synthesis and insulin secretion in pancreatic islets.

Parathyroid hormone (PTH)-related protein (PTHrP) is present in the pancreatic islet. Recent data in transgenic mice suggest that PTHrP might modulate islet mass and insulin secretion. In the present study, we assessed the effect of the N-terminal PTH-like region of PTHrP on DNA synthesis in isolated rat islets. PTHrP (1-34), between 1 pM and 10 nM, for 48 h stimulated []thymidine incorporation into rat islets. This effect was maximally induced, about 2.5-fold over control, by 10 pM of this peptide, decreasing thereafter. In contrast, PTHrP (38-64) amide or PTHrP (107-139) were ineffective in increasing DNA synthesis in islets. Using reverse transcription followed by PCR, we confirmed that rat islets express PTHrP and the type I PTH/PTHrP receptor. Addition of a neutralizing anti-PTHrP antibody to the incubation medium of proliferating islets decreased islet DNA synthesis by 30%. The effect of a submaximal dose (30 pM) of PTHrP (1-34) on DNA synthesis in rat islets was abolished by 25 nM bisindolylmaleimide I, a protein kinase C (PKC) inhibitor, but not by 25 microM adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, a protein kinase A inhibitor. Moreover, 100 nM phorbol-12-myristate-13-acetate for 48 h also increased DNA synthesis 2-fold over controls in islets. PTHrP (1-34), at 100 nM, in contrast to 50 microM forskolin or 10 mM NaF, failed to affect adenylate cyclase activity in islet membranes. PTHrP, at 30 pM, was also found to increase 2-fold insulin released into the islet-conditioned medium within 24-48 h. Our results suggest that PTHrP is a modulator of pancreatic islet growth and/or function by a PKC-mediated mechanism.

Adenylyl Cyclases↗
PubMed1998

Comparison of two immunoradiometric assays for parathyroid hormone-related protein in the evaluation of cancer patients with and without hypercalcemia.

Hypercalcemia is a common paraneoplastic syndrome due to the secretion by tumors of parathyroid hormone-related protein (PTHrP) and/or other osteolytic factors. In the present study, we have measured plasma PTHrP using two immunoradiometric assays for PTHrP, assay N (Nichols) and assay I (INCSTAR), recognizing the 1-86 domain of PTHrP, for the evaluation of malignancy-associated hypercalcemia. The study included 25 tumor patients with hypercalcemia (HCa) [corrected serum calcium (SCa) > or = 2.70 mmol/L], 20 normocalcemic patients with cancer (NCa), and ten healthy control subjects. Plasma PTHrP was either undetectable or within the respective normal range in the majority of NCa patients and in the control subjects, with both assays. Plasma PTHrP was increased in 13 and 15 of HCa cases with assay N and assay I, respectively. PTHrP was elevated in plasma in 5/6 (assay N) and 3/6 (assay I) HCa patients with squamous tumors. However, plasma PTHrP was high in only 2/9 (assay N) and 1/9 (assay I) HCa cases with hematological tumors. Less than 40% of HCa patients with bone metastases, and >75% of those without bone involvement, had elevated plasma PTHrP with both assays. Detectable plasma PTHrP and SCa were significantly correlated using assay N (p = 0.025) and assay I (p = 0.01), in the HCa group. A highly significant correlation (p <0.001) was found between detectable plasma PTHrP with both assays, and a high agreement between them based on simple kappa statistics (p < 0.001), in the latter group. Our results indicate that each assay may be similarly useful in detecting PTHrP hyperproduction in cancer patients.

Adult↗
PubMed1993

Characterization of calcium transport in the luminal and the basolateral membrane from kidney cortex of hypercalcemic rats bearing the Walker 256 carcinosarcoma.

The Walker 256 (W256) carcinosarcoma did not significantly modify calcium uptake by brush border membrane (BBM) vesicles in the kidney of the host rat, compared with that in membranes isolated from control animals. However, it showed a tendency to increase at near equilibrium in W256 tumor-host rats, associated with a decreased BBM protein content. ATP-dependent calcium influx by basolateral membrane (BLM) vesicles from W256 tumor-bearing rats was also increased compared with that in control BLM. This stimulation was due to a decreased Km for calcium. Passive calcium permeability or the Na+/Ca2+ exchanger were unchanged in BLM from W256 tumor-host rats compared with control BLM. Pre-stimulation of control rat cortical tubules with either 10(-7) M parathyroid hormone-related protein (PTHrP) (1-34) or 10(-4) M N6,2'-O-dibutiryl cyclic AMP before BLM isolation, did not modify the ATP-dependent calcium uptake by BLM vesicles compared with control membranes. However, our results do not rule out that the stimulated ATP-dependent calcium influx in BLM from W256 tumor-host rats could be mediated by the interaction among PTHrP and other humoral factors. Our findings suggest a possible mechanism for the increased renal calcium reabsorption in this animal model for humoral hypercalcemia of malignancy.

Adenosine Triphosphate↗
PubMed1992

Isolation of a 18,000-Da molecular weight form of parathyroid hormone-related protein from the rat Walker carcinosarcoma 256.

The hypercalcaemic Walker carcinosarcoma 256 is a rat model for humoral hypercalcaemia of malignancy (HHM). Tumour products such as parathyroid hormone-related proteins (PTHRP) and various growth factors appear to be responsible for this syndrome. Recently, PTHRP immunoreactivity has been detected in the conditioned medium of Walker tumour cells. The present report describes the isolation of a 18,000-Da molecular weight form of PTHRP from Walker tumour homogenates, by using a relatively simple immunoaffinity purification method. Our results suggest that this PTHRP form is similar to that purified from other HHM-related tumours.

Animals↗
PubMed1991

Co-purification of calcium transport-stimulating and DNA synthesis-stimulating agents with parathormone-like activity isolated from the hypercalcaemic strain of the Walker 256 tumour.

One of the strains of the Walker 256 carcinosarcoma induces in the rat a humoral hypercalcaemia of malignancy (HHM) syndrome which is similar to that reported in human patients. We have isolated from this tumour a chromatographic fraction which displays an adenylate cyclase stimulating activity in dog kidney cortical membranes, similar to that of a parathormone (PTH) related protein isolated from various HHM related tumours. In addition, this fraction stimulated initial calcium (Ca) uptake in confluent Madin-Darby canine kidney (MDCK) cell monolayers in a dose-dependent manner. Maximal stimulation of Ca uptake was associated with an enhanced Ca efflux from MDCK cells preloaded with the cation, and with an increased DNA synthesis in these cells. These activities might be involved in development of increased tubular calcium reabsorption in Walker 256 tumour-bearing rats.

Adenylyl Cyclases↗
PubMed1990

Evidence of 1,25-dihydroxyvitamin D synthesis by the rat Walker carcinosarcoma 256.

We tested the existence of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the Walker carcinosarcoma 256 implanted in rats. This tumour has been shown to induce hypercalcaemia in the host animal. We found this enzyme activity in tumour homogenates, which was in the same range as that in the kidney of tumour-bearing rats. Our results suggest that 1,25-dihydroxyvitamin D synthesized by the Walker tumour might be involved in the mechanism responsible for the hypercalcaemia in the host rat.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗