Organ transplantation and glucocorticoid-induced osteoporosis.
Explore the source record for details and available documents.
Glucocorticoids↗
Biomedical subjects
M Nobile
Publications and source records attributed to M Nobile.
Osmosensitivity of an inwardly rectifying chloride current revealed by whole-cell and perforated-patch recordings in cultured rat cortical astrocytes.
The osmosensitivity of the inwardly rectifying Cl(-) current (I(Clh)), expressed by primary cultured rat neocortical astrocytes long-term treated with dibutyryl cyclic AMP, was investigated in the whole-cell and perforated-patch modes. In whole-cell experiments, whereas hypotonic extracellular solution (Delta=100 mOsmol) did not cause any change in I(Clh), hypertonicity produced a slowly developing, approximately 40% reversible decrease in current magnitude. By contrast, in perforated-patch experiments, exposure to a less hypertonic saline (Delta=50 mOsmol) depressed the current to approximately 50%, and hypotonicity induced a approximately 50% slow increase in I(Clh). These differences in osmosensitivity between the two experimental modes suggest that the osmoregulation of I(Clh) may be mediated by complex intracellular mechanism(s), which appear(s) to be partly compromised by the dialysis of the astrocytic cytoplasm.
Animals↗
Skewed maturation of memory HIV-specific CD8 T lymphocytes.
Understanding the lineage differentiation of memory T cells is a central question in immunology. We investigated this issue by analysing the expression of the chemokine receptor CCR7, which defines distinct subsets of naive and memory T lymphocytes with different homing and effector capacities and antiviral immune responses to HIV and cytomegalovirus. Ex vivo analysis of the expression of CD45RA and CCR7 antigens, together with in vitro analysis of the cell-division capacity of different memory CD8+ T-cell populations, identified four subsets of HIV- and CMV-specific CD8+ T lymphocytes, and indicated the following lineage differentiation pattern: CD45RA+ CCR7+ --> CD45RA- CCR7+ --> CD45RA- CCR7- --> CD45RA+ CCR7-. Here we demonstrate through analysis of cell division (predominantly restricted to the CCR7+ CD8+ T-cell subsets) that the differentiation of antigen-specific CD8+ T cells is a two-step process characterized initially by a phase of proliferation largely restricted to the CCR7+ CD8+ cell subsets, followed by a phase of functional maturation encompassing the CCR7- CD8+ cell subsets. The distribution of these populations in HIV- and CMV-specific CD8+ T cells showed that the HIV-specific cell pool was predominantly (70%) composed of pre-terminally differentiated CD45RA- CCR7- cells, whereas the CMV-specific cell pool consisted mainly (50%) of the terminally differentiated CD45RA+ CCR7- cells. These results demonstrate a skewed maturation of HIV-specific memory CD8+ T cells during HIV infection.
Adult↗
Recombinant wheat antifungal PR4 proteins expressed in Escherichia coli.
PR proteins are soluble and host-coded molecules with antifungal activity induced by a variety of agents. Wheat contains several PR proteins and among them are those of the class 4 coded wheatwin1 and wheatwin2; the two native proteins have been isolated from wheat kernel and the coding cDNA clones have been recently characterized. Herein, we report the expression of recombinant wheatwin1 and wheatwin2 in Escherichia coli-insoluble fractions; a new protocol for the purification in high yields and correct processing of the two proteins was developed. The recombinant proteins have molecular weights identical to that of the native proteins, indicating that the removal of the N-terminal methionine and cyclization of glutamine to pyroglutamate was complete. Both recombinant proteins inhibited in vitro the growth of Fusarium culmorum exhibiting antifungal properties similar to those of the native proteins.
Antifungal Agents↗
Isolation and amino acid sequence of two new PR-4 proteins from wheat.
We have purified and characterized two new pathogenesis-related (PR) proteins from wheat belonging to the PR-4 family. We named the proteins wheatwin3 and wheatwin4 in analogy with the previously characterized wheatwin1 and wheatwin2. Their isoelectric points were 7.1 and 8.4, respectively. We determined the complete amino acid sequence of both proteins by a rapid approach based on the knowledge of the primary structures of the homologous wheatwin1 and wheatwin2. Wheatwin3 differs from wheatwin1 in one substitution at position 88, while wheatwin4 differs from wheatwin2 in one substitution at position 78. The secondary structure and solvent accessibility of these residues were determined on the three-dimensional model of wheatwinl. Residue 88 was very accessible and was located in a flexible region. Preliminary results indicate that, like wheatwin1 and wheatwin2, wheatwin3 and wheatwin4 have antifungal activity.
Alkylation↗
Vertebral morphometry by X-ray absorptiometry before and after liver transplant: a cross-sectional study.
OBJECTIVES: To evaluate bone density and fracture prevalence in patients with end-stage liver diseases (ESLD) awaiting liver transplant and in orthotopic liver-transplant (OLTx) recipients by using dual energy X-ray absorptiometry. DESIGN: In a cross-sectional study 27 patients (16 males and 11 females, mean age 49.9 +/- 1.7 years) with ESLD, and 36 subjects (26 males and 10 females, mean age 50.5 +/- 1.6 years) who had undergone OLTx 1-70 months before, were recruited. METHODS: All patients underwent biochemical assessment of mineral metabolism. Bone density measurement of the spine and femur and morphometric X-ray absorptiometry (MXA) of the vertebrae were also obtained. RESULTS: Bone density was decreased in both groups as compared to the expected normal values. Spinal density did not differ between the two groups, while femoral bone mass was lower in OLTx than in ESLD patients (T-scores of: femoral neck -1.91 +/- 0.16 vs -1.12 +/- 0.22, P < 0.01; total femur -1.62 +/- 0.16 vs -0.94 +/- 0.23, P < 0.02). Bone alkaline phosphatase was the only independent predictor of femoral density (R2 = -0.21, P < 0.05). Symptomatic fractures were reported by 25% of OLTx and 15% of ESLD patients. MXA vertebral fractures were present in 28% of OLTx and 7.5% of ESLD (P < 0.05) patients. Most of these fractures had been asymptomatic. Total methylprednisolone intake was higher in patients with MXA vertebral fractures than in non-fractured patients (P < 0.05). CONCLUSIONS: Fragility fractures, especially of the spine, occur more frequently after liver transplantation, with corticosteroid treatment being the most important risk factor. Morphometric X-ray absorptiometry represents a useful technique for identifying vertebral fractures even in liver transplanted patients.
Absorptiometry, Photon↗
Alendronate prevents further bone loss in renal transplant recipients.
The aim of this study was to investigate the effects of alendronate, calcitriol, and calcium in bone loss after kidney transplantation. We enrolled 40 patients (27 men and 13 women, aged 44.2 +/- 11.6 years) who had received renal allograft at least 6 months before (time since transplant, 61.2 +/- 44.6 months). At baseline, parathyroid hormone (PTH) was elevated in 53% of the patients and the Z scores for bone alkaline phosphatase (b-ALP) and urinary type I collagen cross-linked N-telopeptide (u-NTX) were higher than expected (p < 0.001). T scores for the lumbar spine (-2.4 +/- 1.0), total femur (-2.0 +/- 0.7), and femoral neck (-2.2 +/- 0.6) were reduced (p < 0.001). After the first observation, patients were advised to adhere to a diet containing 980 mg of calcium daily and their clinical, biochemical, and densitometric parameters were reassessed 1 year later. During this period, bone density decreased at the spine (-2.6 +/- 5.7%;p < 0.01), total femur (-1.4 +/- 4.2%; p < 0.05), and femoral neck (-2.0 +/- 3.0%; p < 0.001). Then, the patients were randomized into two groups: (1) group A-10 mg/day of alendronate, 0.50 microg/day of calcitriol, and 500 mg/day of calcium carbonate; and (2) group B-0.50 microg/day of calcitriol and 500 mg/day of calcium carbonate. A further metabolic and densitometric reevaluation was performed after the 12-month treatment period. At the randomization time, group A and group B patients did not differ as to the main demographic and clinical variables. After treatment, bone turnover markers showed a nonsignificant fall in group B patients, while both b-ALP and u-NTX decreased significantly in alendronate-treated patients. Bone density of the spine (+5.0 +/- 4.4%), femoral neck (+4.5 +/- 4.9%), and total femur (+3.9 +/- 2.8%) increased significantly only in the alendronate-treated patients. However, no trend toward further bone loss was noticed in calcitriol and calcium only treated subjects. No drug-related major adverse effect was recorded in the two groups. We conclude that renal transplanted patients continue to loose bone even in the long-term after the graft. Alendronate normalizes bone turnover and increases bone density. The association of calcitriol to this therapy seems to be advantageous for better controlling the complex abnormalities of skeletal metabolism encountered in these subjects.
Adult↗
Cautionary note: complex (dys) function of the serotonin transporter.
Explore the source record for details and available documents.
Antimanic Agents↗
Single-channel analysis of a ClC-2-like chloride conductance in cultured rat cortical astrocytes.
The single-channel behavior of the hyperpolarization-activated, ClC-2-like inwardly rectifying Cl- current (IClh), induced by long-term dibutyryl-cyclic-AMP-treated cultured cortical rat astrocytes, was analyzed with the patch-clamp technique. In outside-out patches in symmetrical 144 mM Cl-solutions, openings of hyperpolarization-activated small-conductance Cl channels revealed burst activity of two equidistant conductance levels of 3 and 6 pS. The unitary openings displayed slow activation kinetics. The probabilities of the closed and conducting states were consistent with a double-barrelled structure of the channel protein. These results suggest that the astrocytic ClC-2-like Cl- current Iclh is mediated by a small-conductance Cl channel, which has the same structural motif as the Cl- channel prototype CIC-0.
Animals↗
Lumbar osteoarthritis, bone mineral density, and quantitative ultrasound.
Low bone mass is a major risk factor for osteoporotic fractures. Thus, bone density evaluation, performed by Dual Energy X-ray Absorptiometry (DXA) is important for diagnosis and monitoring treatment of osteoporosis. The accuracy of DXA, particularly at the lumbar spine, can be affected by several factors such as degenerative diseases. To evaluate the effects of vertebral osteophytosis on densitometric measurements, we examined 198 women, aged 32-81 years, who had undergone lateral X-ray of the lumbar spine. We classified patients according to different grades of osteophytosis, and evaluated bone density at the lumbar spine and the proximal femur by DXA. We also performed quantitative ultrasound at the heel (QUS). Patients with severe osteophytosis were significantly older (p < 0.0005), and values were adjusted for this parameter. We observed a significant increase in lumbar bone density with worsening osteophytosis (p < 0.02). On the contrary, no significant differences were found at the femur and QUS. According to bone density at the femoral neck, we subdivided patients into two groups: osteoporotic (group A) and non-osteoporotic (group B). Both groups showed increasingly high bone density at the spine with worsening osteophytosis (A: p < 0.01; B: p < 0.02). No differences were found in all the other evaluations. In conclusion, lumbar spine measurement is dramatically influenced by osteophytosis, particularly in the elderly. Consequently, other strategies should be performed such as evaluation of the hip and also measurement of the heel by ultrasound, which could be an interesting approach in these cases.
Absorptiometry, Photon↗
Idiopathic hypercalciuria: O2(-)NO relationship and altered bone metabolism.
The pathogenesis of idiopathic hypercalciuria (IH) has not been elucidated yet, but a correlation between IH and altered bone metabolism has been proposed. Since nitric oxide (NO) regulates osteoclasts' bone resorption, a possible role for NO can be suggested. In this study we evaluated iNOS gene expression by reverse transcription of mRNA from monocytes, followed by polymerase chain reaction in patients with IH subdivided into fasting (FH) and absorptive (AH) hypercalciuria. Since superoxide (O2-), which metabolizes NO, is overproduced by osteoclasts during bone resorption, peroxynitrite plasma level was evaluated as index of O2-. Vertebral BMD in IH as a whole group was lower vs controls (C) (Z score=-1.78+/-0.2 vs 0.51+/-0.25, p<0.001), but only FH patients showed a reduced bone density (2.13+/-0.18 vs 0.51+/-0.25, p<0.0001). PTH and calcitriol were not different. FH showed an increase in b-ALP vs AH and C (41.1+/-2.6 vs 30.1+/-3.9 vs 26.6+/-3.6 U/l p<0.02), and higher uHP, either on NCD (17.7+/-1.6 vs 11.4+/-1.3 mg/g uCr, p<0.04) or after LCD (26.7+/-2.5 vs 16.7+/-1.9, p<0.01). Cells from FH patients, but not from both AH patients and C, expressed iNOS. Peroxynitrite plasma level was elevated in FH (0.30+/-0.07) pmol/l while not detectable in AH and C. This study confirms an altered bone metabolism only in FH which shows an abnormal NO system. The increased iNOS gene expression in FH, in fact, points toward an altered NO system's activity downstream the generation of NO. A possible interaction of NO with O2-, which breaks down NO, and the role of this interaction in the pathophysiology of IH is discussed.
Adult↗
Long-term persistence of low bone density in orthotopic liver transplantation.
We determined bone density and metabolism in 46 patients (35 males, 11 females) who had undergone liver transplantation 1-48 months previously. Twenty-one patients were then followed for the next 24 months. At each visit, blood and urine samples for bone and liver metabolism parameters, as well as spinal and femoral dual-energy X-ray absorptiometry (DXA) scans, were obtained. Basal spinal and femoral density was low (p < 0.001). Patients with pre-transplant cholestatic diseases had lower spinal density than all the other subjects (p <0.05) and the cumulative methylprednisolone intake was an independent negative predictor of total hip density (p < 0.02). At baseline, urinary hydroxyproline and N-telopeptide were at the upper normal level and decreased only after 24 months of follow-up (p < 0.05). During the first year of follow-up, femoral density decreased (p < 0.05) and a partial recovery was observed for both spine and femur after 24 months. After 12 months, femoral bone density was negatively associated with serum cyclosporin A levels (p < 0.005) and cumulative methylprednisolone intake (p < 0.05), while the percent decrease in spinal density after the first 12 months was negatively predicted by mean daily methylprednisolone intake (p < 0.05). In patients with pre-transplant cholestatic diseases, femoral and spinal density increased after the first (p < 0.05) and second year (p < 0.05), respectively. In patients with previous post-necrotic cirrhosis, femoral density decreased after 12 months (p<0.05) and was still lower than baseline after 24 months (p < 0.05). However, at the end of the study the cumulative percentage of femoral neck osteoporosis was 43%. In conclusion, an elevated prevalence of spinal and femoral osteoporosis is present even many years after liver transplantation, with immunosuppressive treatment and pre-transplant liver disease being the most important pathogenetic factors.
Adult↗
pH modulation of an inward rectifier chloride current in cultured rat cortical astrocytes.
The effects of changes in extra- and intracellular pH in the pathophysiological range (6.0-8.0) on astroglial plasma membrane ionic currents were investigated with the whole-cell patch-clamp technique. In cultured rat neocortical type-1 astrocytes differentiated by a long-term treatment with dibutyryl cyclic-AMP, exposure to an extracellular pH of 6.4 induced, as compared with the control extracellular pH at 7.3, a sustained and reversible increase in the holding current at -60mV. The rise in current was accompanied by a decrease in the apparent input resistance. Ion substitution experiments indicated that extracellular pH 6.4 upregulated the resting Cl(-) conductance, whereas an opposite effect could be observed at extracellular pH 8.0. Recordings of isolated Cl(-) currents showed that this modulation occurred on the previously identified hyperpolarization-activated, inwardly rectifying Cl(-) current, I(Clh). Extracellular acidification to pH 6.4 shifted the voltage dependence of I(Clh) activation by approximately 20mV towards more positive potentials, whereas a approximately 20mV opposite shift was observed upon exposure to extracellular pH 8.0. These effects were paralleled by an increase (extracellular pH 6.4) or decrease (extracellular pH 8.0) in the maximal conductance. Decreasing (6.0) or increasing (8.0) the intracellular pH shifted the steady-state activation of I(Clh) towards more negative or positive potentials, respectively, leaving unchanged the current sensitivity to extracellular pH modifications. The modulation of the inward rectifier Cl(-) current expressed by differentiated cultured neocortical astrocytes indicates that extra- and intracellular changes in pH occurring in a pathophysiological range may contribute to regulating Cl(-) accumulation in astroglial cells.
Animals↗
An open trial of paroxetine in the treatment of children and adolescents diagnosed with dysthymia.
This open-label study examined the potential efficacy of paroxetine in the treatment of children and adolescents diagnosed with dysthymia over a period of 3 months. Seven subjects were evaluated by the Hamilton Depression Rating Scale (HAM-D), by the Clinical Global Impression Severity of Illness Scale (CGI-S), and the Clinical Global Impression Improvement Scale (CGI-I). Seventy-one percent of patients had a satisfactory response, suggesting the efficacy of paroxetine in children with dysthymia.
Adolescent↗
Some ado about a polymorphism.
Explore the source record for details and available documents.
Adolescent↗
Large-conductance calcium-activated anion channel characteristics in neuroblastoma cells.
Large-conductance anion channel characteristics were investigated in neuroblastoma cells (N2A) by using different configurations of the patch-clamp technique. In excised patches, the channel was induced by depolarising potentials in 90% of experiments, had a conductance of 340 pS in symmetrical 135 mmol/l NaCl and exhibited the typical bell-shape activity. Neither the channel induction nor the channel activity was affected by rising the Ca2+ concentration on the cytopasmic side of membranes. In cell-attached configuration the maximal channel activity was shifted towards more positive potentials in comparison to that of excised patches and an increase in intracellular Ca2+, obtained by extracellular application of the Ca2+-ionophore A23187 in the presence of 0.2 micromol/l Ca2+, induced single-channel currents in 80% of patches compared to 31% of cell-attached experiments showing channel activity in normal conditions. In turn, application of 2 micromol/l Ca2+ induced channel activity in 100% of patches. The reversal potential of the channel in cell-attached patches was around -10 mV as the resting potential of cells eliciting channel activity. For cells where channel activity was not detected in cell-attached mode, the resting potential was around -45 mV. Channel activity could be restored in most whole-cell recordings in the presence of 2 micromol/l or more intracellular Ca2+ concentrations. The Ca2+-induction and the relation between channel activity and cell resting potential seem to suggest a role of the large-conductance anion channel in resting potential modulation during some basic functions of the neuroblastoma cell proliferation.
Animals↗
[Cerebral metastatis. Diagnostic and therapeutic features].
Brain metastases represent the most frequent intracranial neoplasms in adults: between 15 and 25% of patients with systemic tumors will face brain metastases along the clinical course of disease. Lung cancers, breast cancers and melanomas are the commonest causes of brain metastases (about 75%), while the primary site remains unknown inasmuch as 15% of cases. Headache, focal neurological deficits, epilepsy and intracranial hypertension are the most frequent initial symptoms and signs. Computerized Tomography and Magnetic Resonance represent the methods of choice for diagnosis. Supportive care is based on corticosteroids and antiepileptic drugs. Anticancer therapy planning must be based on prognostic factors: performance status, tumor activity and age. Surgical removal followed by external adjuvant radiotherapy is considered the best treatment in patients with single brain metastases and systemic disease under control or absent. Stereotactic radiosurgery is preferable in cases of unoperable metastatic lesions of the brain or progressive systemic disease. The usefulness of whole brain radiotherapy following surgery or radiosurgery is debated. In patients with multiple brain metastases, apart from radiotherapy, surgical excision of the symptomatic lesions, when feasible, seems advantageous. Chemotherapy is a valid option only in cases of metastases from chemosensitive neoplasms (small-cell lung tumors or breast tumors).
Brain Neoplasms↗
Dopamine receptor D4 gene is not associated with major psychoses.
We previously reported an association between dopamine receptor D4 (DRD4) gene exon 1 variants and delusional disorder. The aim of this investigation was to study the DRD4 gene exon 1 and 3 variants in schizophrenia, delusional, bipolar, and unipolar disorders. We studied 651 inpatients affected by schizophrenia (n = 229), delusional (n = 86), bipolar (n = 210), and unipolar (n = 126) disorders (DSM III-R) and 471 healthy controls; these were typed for DRD4 variants at the first and third exon using polymerase chain reaction techniques. DRD4 variants were not associated with schizophrenic and delusional subjects even when possible confounders like gender and onset were considered. A marginal association between DRD4 exon 3 variants with unipolar (excess of DRD4*2/4, p = 0.004) and bipolar (excess of DRD4*2/4, p = 0.001) disorders was observed, both associations drop to insignificance when corrected for multiple testing. Our results exclude that coding variants of the DRD4 exon 1 and 3 may play a major role in conferring susceptibility to major psychoses; moreover, we could not replicate the association of DRD4 exon 1 variant with delusional disorder.
Adult↗