Development of Graves' hyperthyroidism during the early phase of pregnancy in a patient with pre-existing and long-standing Hashimoto's hypothyroidism.
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Adult↗
Biomedical subjects
M Gola
Publications and source records attributed to M Gola.
Development of acromegaly in a patient with anorexia nervosa: pathogenetic and diagnostic implications.
Anorexia nervosa (AN) is a psychosomatic disorder characterized by an alteration in body image, resulting in eating abnormalities that lead to malnutrition associated with secondary endocrinological disturbances. AN is associated with high levels of GH and low levels of IGF-I, suggestive of a nutritionally acquired lack of GH action or GH resistance and of an unbalanced hypothalamic GH neuroregulation with GHRH prevalence on SS tone. In this clinical report, we describe the development of acromegaly in a patient affected by AN and we discuss pathogenetic and diagnostic implications.
Acromegaly↗
Resistance to somatostatin analogs in acromegaly: an evolving concept?
The aim of acromegaly treatment is to control the disease by suppressing GH hyperactivity and reducing the size or impeding the growth of the pituitary GH secreting mass. Over recent years, many studies have emphasized the role of SS analogs in the treatment of acromegaly. In fact, SS analogs have been demonstrated to be an effective tool not only in the control of GH hypersecretion but also more recently in the control of tumor growth, in a relevant number of acromegalic patients both as primary or adjunctive treatment. In this context, the therapeutic failure of medical treatment with SS analogs needs to be accurately defined particularly when they are used as primary treatment but also when they are given to patients previously operated upon, since other effective therapeutic options are nowadays available. Current definition of resistance to SS analogs is based on their efficacy to control GH and IGF-I. However, due to the emerging significance of the shrinkage effect of SS analogs on pituitary adenomas as well as to the apparent dissociation between this effect and the biochemical effects of treatment with these analogs, an evolution in the concept of SS resistance is likely to be occurring. In this review, we will discuss the biological basis of the discordance between biochemical and volumetric effects of SS analogs, and we will address the intriguing clinical and therapeutic aspects related to a possible redefinition of the resistance to SS analogs.
Acromegaly↗
Growth hormone deficiency in the adult.
Growth hormone deficiency (GHD) in adults may be of either adult or childhood onset and may occur as isolated GHD or as multiple hormone deficiencies. Adult-onset GHD (AoGHD) usually results from damage to the pituitary gland or hypothalamus. GH is frequently undetectable in normal subjects and thus GHD cannot be distinguished from the normal state using a single random GH measurement. In general, a stimulation test is required to recognize GHD. Insulin tolerance test (ITT) has been considered the gold standard by the most important scientific societies, although alternative tests, in particular GHRH plus arginine have been proposed as valuable alternative to ITT. The clinical syndrome associated with AoGHD is characterized by a wide array of symptoms and important chronic complications, such as cardiovascular complications, which may be responsible for an increased mortality. The rationale for GH replacement in adults GHD patients is justified by the beneficial effects on some clinical end-points, such as quality of life (QoL) and cardiovascular risk factors, whereas the effects on mortality risk are still controversial. Over the recent years, guidelines on the use of rhGH as a substitution treatment in adult hypopituitarism have been issued by international (Growth hormone research society-GRS, Endocrine Society) and relevant national (National Institute of Clinical Excellence-UK, NICE) institutions. The aim of the paper is to review and discuss these guidelines.
Adult↗
Cardiovascular risk in aging and obesity: is there a role for GH.
GH has significant impact in adults. In fact, patients with the GH deficiency (GHD) syndrome are now recognized as having an increased cardiovascular risk. The effects of human aging on GH secretion have been evaluated by a number of researchers. Studies of 24 h secretion of GH have shown variable reductions in most 24-h GH secretory parameters in middle-aged and in older men and women, resulting in a decrease in plasma levels of its anabolic mediator IGF-I. Obesity is also associated with several endocrine and metabolic abnormalities. These include decreased serum GH concentrations, reduced GH half-life, frequency of GH secretory episodes and daily GH production rate. The mechanism of the low GH in obesity is not completely understood nor is it clear whether its relationship with visceral adiposity is causal. The aim of this article will be to review the available clinical data concerning the potential involvement of "subclinical" or perhaps better "functional" GHD, which is observed in aging and obesity, in the increase in cardiovascular risk which characterizes these two conditions.
Age Factors↗
Diagnostic and therapeutic consensus on acromegaly.
In February 1999 and May 2000, two workshops were held in Cortina, Italy and Montecarlo, respectively, to develop a consensus defining the diagnosis and treatment of acromegaly. The workshops were sponsored by the Italian Society of Endocrinology, the Pituitary Society and European Neuroendocrine Association. Partecipants from all over the world included endocrinologists, neurosurgeons and radiotherapists skilled in the management of acromegaly. This review paper summarizes the main points of the two consensus statements published following these two workshops.
Acromegaly↗
GH deficiency in the adult and bone.
GH acts on various tissues and organs, like liver, kidney, bone and muscle. There are no conclusive data on adult onset GH deficiency (GHD) effects on bone remodeling. In fact reduced, increased or unchanged values of serum markers of bone formation and resorption have been described. However, a direct link between GHD and reduced bone mass in hypopituitarism is supported by reports that GH replacement therapy can improve bone mineral density (BMD) in these patients. Recently, many studies have shown an increased prevalence of osteoporosis in adult-onset GHD patients, and the fracture rate in these subjects seems to be twice that in the non-GH-deficient population. Long-term studies in these years have described a BMD increase in GHD patients during treatment with GH alone or in combination with biphosphonates. To understand if these BMD changes may result in a reduction of fracture risk, it is necessary to carry out a longitudinal follow-up of large cohorts of GHD adults on GH replacement therapy.
Adult↗
Diagnosis and treatment of acromegaly and its complications: consensus guidelines.
In February 1999, May 2000 and April 2002, three workshops were held in Cortina, Montecarlo and Versailles, respectively, to develop a consensus defining the diagnosis and treatment of acromegaly and its complications. The workshops were sponsored by the Pituitary Society and European Neuroendocrine Association. Invited international participants included endocrinologists, neurosurgeons and radiotherapists skilled in the management of acromegaly. This review paper summarizes the main points of the three consensus statements published following these three workshops.
Acromegaly↗
Negative regulation of CFTR activity by extracellular ATP involves P2Y2 receptors in CFTR-expressing CHO cells.
Extracellular nucleotides exert autocrine/ paracrine effects on ion transport by activating P2 receptors. We studied the effects of extracellular ATP and UTP on the cystic fibrosis transmembrane conductance regulator (CFTR) channel stably expressed in Chinese Hamster Ovary cells (CHO-BQI cells). CFTR activity was measured using the (125I) iodide efflux technique and whole-cell patch-clamp recording in response to either forskolin or xanthine derivatives. Using RT-PCR and intracellular calcium concentration ([Ca2+]i) measurement, we showed that CHO-BQI cells express P2Y2 but not P2Y4 receptors. While ATP and UTP induced similar increases in [Ca2+]i, pre-addition by one of these two agonists desensitized the response for the other, suggesting that ATP- and UTP-induced [Ca2+]i increases were mediated by a common receptor, which was identified as the P2Y2 subtype. CFTR activity was reduced by ATP and UTP but not by ADP or adenosine applications. This inhibitory effect of ATP on CFTR activity was not due to a change in cAMP level. Furthermore, CFTR activation by forskolin or IBMX failed to promote [Ca2+]i increase, suggesting that CFTR activation did not generate an ATP release large enough to stimulate P2Y2 receptors. Taken together, our results show that endogenous P2Y2 receptor activation downregulates CFTR activity in a cAMP-independent manner in CHO cells.
Adenosine Triphosphate↗
Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation.
Kaliotoxin (KTX), a blocker of voltage-gated potassium channels (Kv), is highly selective for Kv1.1 and Kv1.3. First, Kv1.3 is expressed by T lymphocytes. Blockers of Kv1.3 inhibit T lymphocyte activation. Second, Kv1.1 is found in paranodal regions of axons in the central nervous system. Kv blockers improve the impaired neuronal conduction of demyelinated axons in vitro and potentiate the synaptic transmission. Therefore, we investigated the therapeutic properties of KTX via its immunosuppressive and symptomatic neurological effects, using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The T line cells used to induce adoptive EAE were myelin basic protein (MBP)-specific, constitutively contained mRNA for Kv1.3. and expressed Kv1.3. These channels were shown to be blocked by KTX. Activation is a crucial step for MBP T cells to become encephalitogenic. The addition of KTX during Ag-T cell activation led to a great reduction in the MBP T cell proliferative response, in the production of IL-2 and TNF, and in Ca(2+) influx. Furthermore, the addition of KTX during T cell activation in vitro led a decreased encephalitogenicity of MBP T cells. Moreover, KTX injected into Lewis rats impaired T cell function such as the delayed-type hypersensitivity. Lastly, the administration of this blocker of neuronal and lymphocyte channels to Lewis rats improved the symptoms of EAE. We conclude that KTX is a potent immunosuppressive agent with beneficial effects on the neurological symptoms of EAE.
Adoptive Transfer↗
Clinical review 136: Primary lymphoma of the pituitary: an emerging clinical entity.
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Adult↗
The soma and neurites of primary afferent neurons in the guinea-pig intestine respond differentially to deformation.
1. Intrinsic primary afferent neurons in the small intestine are exposed to distortion of their processes and of their cell bodies. Recordings of mechanosensitivity have previously been made from these neurons using intracellular microelectrodes, but this form of recording has not permitted detection of generator potentials from the processes, or of responses to cell body distortion. 2. We have developed a technique to record from enteric neurons in situ using patch electrodes. The mechanical stability of the patch recordings has allowed recording in cell-attached and whole cell configuration during imposed movement of the neurons. 3. Pressing with a fine probe initiated generator potentials (14 +/- 9 mV) from circumscribed regions of the neuron processes within the same myenteric ganglion, at distances from 100 to 500 microm from the cell body that was patched. Generator potentials persisted when synaptic transmission was blocked with high Mg2+, low Ca2+ solution. 4. Soma distortion, by pressing down with the whole cell recording electrode, inhibited action potential firing. Consistent with this, moderate intra-electrode pressure (10 mbar; 1 kPa) increased the opening probability of large-conductance (BK) potassium channels, recorded in cell-attached mode, but suction was not effective. In outside-out patches, suction, but not pressure, increased channel opening probability. Mechanosensitive BK channels have not been identified on other neurons. 5. The BK channels had conductances of 195 +/- 25 pS. Open probability was increased by depolarization, with a half-maximum activation at a patch potential of 20 mV and a slope factor of 10 mV. Channel activity was blocked by charybdotoxin (20 nM). 6. Stretch that increased membrane area under the electrode by 15 % was sufficient to double open probability. Similar changes in membrane area occur when the intestine changes diameter and wall tension under physiological conditions. Thus, the intestinal intrinsic primary afferent neurons are detectors of neurite distortion and of compression of the soma, these stimuli having opposite effects on neuron excitability.
Action Potentials↗
Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. Clues to design analogs with enhanced selectivity.
BgK is a peptide from the sea anemone Bunodosoma granulifera, which blocks Kv1.1, Kv1.2, and Kv1.3 potassium channels. Using 25 analogs substituted at a single position by an alanine residue, we performed the complete mapping of the BgK binding sites for the three Kv1 channels. These binding sites included three common residues (Ser-23, Lys-25, and Tyr-26) and a variable set of additional residues depending on the particular channel. Shortening the side chain of Lys-25 by taking out the four methylene groups dramatically decreased the BgK affinity to all Kv1 channels tested. However, the analog K25Orn displayed increased potency on Kv1.2, which makes this peptide a selective blocker for Kv1.2 (K(D) 50- and 300-fold lower than for Kv1.1 and Kv1.3, respectively). BgK analogs with enhanced selectivity could also be made by substituting residues that are differentially involved in the binding to some of the three Kv1 channels. For example, the analog F6A was found to be >500-fold more potent for Kv1.1 than for Kv1.2 and Kv1.3. These results provide new information about the mechanisms by which a channel blocker distinguishes individual channels among closely related isoforms and give clues for designing analogs with enhanced selectivity.
Amino Acid Substitution↗
Development of substituted Benzo[c]quinolizinium compounds as novel activators of the cystic fibrosis chloride channel.
Chloride channels play an important role in the physiology and pathophysiology of epithelia, but their pharmacology is still poorly developed. We have chemically synthesized a series of substituted benzo[c]quinolizinium (MPB) compounds. Among them, 6-hydroxy-7-chlorobenzo[c]quinolizinium (MPB-27) and 6-hydroxy-10-chlorobenzo[c]quinolizinium (MPB-07), which we show to be potent and selective activators of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. We examined the effect of MPB compounds on the activity of CFTR channels in a variety of established epithelial and nonepithelial cell systems. Using the iodide efflux technique, we show that MPB compounds activate CFTR chloride channels in Chinese hamster ovary (CHO) cells stably expressing CFTR but not in CHO cells lacking CFTR. Single and whole cell patch clamp recordings from CHO cells confirm that CFTR is the only channel activated by the drugs. Ussing chamber experiments reveal that the apical addition of MPB to human nasal epithelial cells produces a large increase of the short circuit current. This current can be totally inhibited by glibenclamide. Whole cell experiments performed on native respiratory cells isolated from wild type and CF null mice also show that MPB compounds specifically activate CFTR channels. The activation of CFTR by MPB compounds was glibenclamide-sensitive and 4, 4'-diisothiocyanostilbene-2,2'-disulfonic acid-insensitive. In the human tracheal gland cell line MM39, MPB drugs activate CFTR channels and stimulate the secretion of the antibacterial secretory leukoproteinase inhibitor. In submandibular acinar cells, MPB compounds slightly stimulate CFTR-mediated submandibular mucin secretion without changing intracellular cAMP and ATP levels. Similarly, in CHO cells MPB compounds have no effect on the intracellular levels of cAMP and ATP or on the activity of various protein phosphatases (PP1, PP2A, PP2C, or alkaline phosphatase). Our results provide evidence that substituted benzo[c]quinolizinium compounds are a novel family of activators of CFTR and of CFTR-mediated protein secretion and therefore represent a new tool to study CFTR-mediated chloride and secretory functions in epithelial tissues.
Animals↗
Specific distribution of sodium channels in axons of rat embryo spinal motoneurones.
1. The distribution of Na+ channels and development of excitability were investigated in vitro in purified spinal motoneurones obtained from rat embryos at E14, using electrophysiological, immunocytochemical and autoradiographical methods. 2. One hour after plating the motoneurones (DIV0), only somas were present. They expressed a robust delayed rectifier K+ current (IDR) and a fast-inactivating A-type K+ current (IA). The rapid neuritic outgrowth was paralleled by the emergence of a fast-activating TTX-sensitive sodium current (INa), and by an increase in both K+ currents. 3. The change in the three currents was measured daily, up to DIV8. The large increase in INa observed after DIV2 was accompanied by the onset of excitability. Spontaneous activity was observed as from DIV6. 4. The occurrence of axonal differentiation was confirmed by the fact that (i) only one neurite per motoneurone generated antidromic action potentials; and (ii) 125I-alpha-scorpion toxin binding, a specific marker of Na+ channels, labelled only one neurite and the greatest density was observed in the initial segment. Na+ channels therefore selectively targeted the axon and were absent from the dendrites and somas. 5. The specific distribution of Na+ channels was detectable as soon as the neurites began to grow. When the neuritic outgrowth was blocked by nocodazole, no INa developed. 6. It was concluded that, in spinal embryonic motoneurone in cell culture, Na+ channels, the expression of which starts with neuritic differentiation, are selectively addressed to the axonal process, whereas K+ channels are present in the soma prior to the neuritic outgrowth.
Animals↗
Cystic fibrosis transmembrane conductance regulator (CFTR) confers glibenclamide sensitivity to outwardly rectifying chloride channel (ORCC) in Hi-5 insect cells.
Increasing evidence is now accumulating for the involvement of the cystic fibrosis transmembrane conductance regulator (CFTR) in the control of the outwardly rectifying chloride channel (ORCC). We have examined the sensitivity of ORCC to the sulfonylurea drug glibenclamide in Hi-5 (Trichoplusia ni) insect cells infected with recombinant baculovirus expressing either wild-type CFTR, DeltaF508-CFTR or E. coli beta galactosidase cDNA and in control cells either infected with virus alone or uninfected. Iodide efflux and single channel patch-clamp experiments confirmed that forskolin and 1-methyl-3-isobutyl xanthine (IBMX) or 7-methyl-1,3 dipropyl xanthine (DPMX) activate CFTR channels (unitary conductance: 9.1 +/- 1.6 pS) only in cells expressing CFTR. In contrast, we identified 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS)-sensitive ORCC in excised membrane patches in any of the cells studied, with similar conductance (22 +/- 2.5 pS at -80 mV; 55 +/- 4.1 pS at +80 mV) and properties. In the presence of 500 microm SITS, channel open probability (Po) of ORCC was reversibly reduced to 0.05 +/- 0.01 in CFTR-cells, to 0.07 +/- 0.02 in non-CFTR expressing cells and to 0.05 +/- 0.02 in DeltaF508-cells. In Hi-5 cells that did not express CFTR, glibenclamide failed to inhibit ORCC activity even at high concentrations (100 microm), whereas 500 microm SITS reversibly inhibited ORCC. In contrast in cells expressing CFTR or DeltaF508, glibenclamide dose dependently (IC50 = 17 microm, Hill coefficient 1.2) and reversibly inhibited ORCC. Cytoplasmic application of 100 microm glibenclamide reversibly reduced Po from 0.88 +/- 0.03 to 0.09 +/- 0.02 (wash: Po = 0.85 +/- 0.1) in CFTR cells and from 0.89 +/- 0.05 to 0.08 +/- 0.05 (wash: Po = 0.87 +/- 0.1) in DeltaF508 cells. In non-CFTR expressing cells, glibenclamide (100 microm) was without effect on Po (control: Po = 0. 89 +/- 0.09, glib.: Po = 0.86 +/- 0.02; wash: Po = 0.87 +/- 0.05). These data strongly suggest that the expression of CFTR confers glibenclamide sensitivity to the ORCC in Hi-5 cells.
1-Methyl-3-isobutylxanthine↗
Patch testing with additional series of allergens.
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Adult↗
Epidemiological survey of contact dermatitis in Italy (1984-1993) by GIRDCA (Gruppo Italiano Ricerca Dermatiti da Contatto e Ambientali).
BACKGROUND: The Gruppo Italiano Ricerca Dermatiti da Contatto e Ambientali (GIRDCA) resolved to obtain the most relevant data regarding contact dermatitis (CD) in Italy by means of a multicenter epidemiological study, involving research units (RU) throughout the country. The survey was performed with the collaboration of Generale Per l'Informatica, Rome (GEPIN) over the periods 1984 to 1988 and 1989 to 1993. The analytical study (of a transverse kind) was aimed at supplying prevalence measures. MATERIALS AND METHODS: The number of subjects taking part in the survey was 42,839. All patients underwent patch testing with the GIRDCA standard series and were included in the survey only if the final diagnosis was either CD or eczematous dermatitis caused by contact. The main anamnestic, clinical data, and allergological test results of all patients were codified into a chart, and subsequently transcribed into a data bank. The data were then processed cumulatively and were statistically analysed by a chi-square for trend test. RESULTS: The four most frequent diagnoses (which, when considered together, make up 39,496 cases, or about 92% of all cases) proved to be nonoccupational allergic contact dermatitis (ACD), nonoccupational irritant contact dermatitis (ICD), occupational ACD, and occupational ICD. The haptens most frequently causing positive reactions in the total number of cases over the first 5 years were, in order of frequency: nickel sulphate, potassium dichromate, cobalt chloride, fragrance mix, balsam of Peru, and, in the second 5-year period, nickel sulphate, cobalt chloride, potassium dichromate, fragrance mix, and thimerosal. Occupational CD (ACD and ICD) was present in 11,694 cases overall, corresponding to approximately 27% of the total number of cases examined, and approximately 29% of all CD (including forms of nonoccupational CD). Regarding distribution by sex, a substantial equivalence of males and females for ACD, and a prevalence of females with ICD can be observed. Five occupations were reputed to be responsible for over 60% of total cases of occupational CD (housewives, bricklayers, workers in the metallurgic and mechanical industries, hairdressers, and healthcare personnel). Regarding the pathogenesis, a clearly dominant percentage of ACD may be observed among bricklayers and hairdressers, and of ICD among housewives. The haptens most frequently noted over the entire decade as the cause of positive reaction in occupational ACD were, in order of frequency, potassium dichromate, nickel sulphate, cobalt chloride, p-phenylenediamine and thiuram mix. Nonoccupational CD (ACD and ICD) was present in 27,802 cases overall, corresponding to about 65% of all cases under examination and over 70% of all CD (also including forms of occupational CD). In regard to distribution by sex, a clear dominance of females, as opposed to males, can be noted for ACD and also (although to a lesser extent) for ICD. The main products and materials (ie, components and relative substances) that are pinpointed as being responsible for nonoccupational ACD, were, in order of frequency, clothing accessories, cosmetics, topical pharmaceuticals, and clothing. The haptens most frequently recognized as the cause of positive reactions were, in order of frequency, nickel sulphate, fragrance mix, cobalt chloride, balsam of Peru, potassium dichromate, ethylenediamine, and diaminodiphenylmethane.
Dermatitis, Allergic Contact↗