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1.
Eur J Nucl Med Mol Imaging ; 48(12): 3762-3775, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33687522

RESUMO

Radiation therapy is an effective treatment modality for a variety of cancers. Despite several advances in delivery techniques, its main drawback remains the deposition of dose in normal tissues which can result in toxicity. Common practices of evaluating toxicity, using questionnaires and grading systems, provide little underlying information beyond subjective scores, and this can limit further optimization of treatment strategies. Nuclear medicine imaging techniques can be utilised to directly measure regional baseline function and function loss from internal/external radiation therapy within normal tissues in an in vivo setting with high spatial resolution. This can be correlated with dose delivered by radiotherapy techniques to establish objective dose-effect relationships, and can also be used in the treatment planning step to spare normal tissues more efficiently. Toxicity in radionuclide therapy typically occurs due to undesired off-target uptake in normal tissues. Molecular imaging using diagnostic analogues of therapeutic radionuclides can be used to test various interventional protective strategies that can potentially reduce this normal tissue uptake without compromising tumour uptake. We provide an overview of the existing literature on these applications of nuclear medicine imaging in diverse normal tissue types utilising various tracers, and discuss its future potential.


Assuntos
Braquiterapia , Neoplasias , Medicina Nuclear , Diagnóstico por Imagem , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Planejamento da Radioterapia Assistida por Computador
2.
Neurobiol Learn Mem ; 133: 100-117, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27344942

RESUMO

In the present study, our aim was to investigate whether the novel highly selective 5-hydroxytryptamine6 (5-HT6) receptor antagonist SLV can ameliorate impairments in cognition and social interaction with potential relevance for both schizophrenia and Alzheimer's disease (AD). SLV sub-chronically - treated Wistar rats reared in isolation showed significantly enhanced prepulse inhibition (PPI) and object recognition performance when compared to vehicle - treated rats. In the isolated rats, also a significant reduction in expression of hippocampal neural cell adhesion molecule polysialylation (NCAM-PSA) was found which was ameliorated following treatment with SLV (30mg/kg). The social engagement deficit in rats exposed in utero (on gestational day 12.5) to valproic acid (VPA) was reversed by treatment with SLV (30mg/kg). SLV (20 and 30mg/kg, p.o.) fully reversed MK-801 - induced deficits in the ORT and also scopolamine - induced deficits in both the Object Recognition Task (ORT) and Object Location Task (OLT) in Wistar rats. In addition, a combination of sub-optimal doses of SLV and donepezil attenuated scopolamine-induced ORT deficits. Furthermore, SLV (10mg/kg, p.o.) reversed spontaneous alternation deficits in the T-maze induced by MK-801 administration in Swiss mice and in aged C57Bl/6J mice. SLV additionally improved T-Maze spatial learning and passive avoidance learning in Sprague-Dawley rats with amyoid-beta (Aß) injections into the hippocampus. In contrast, no benefits were found with SLV or the tested reference compounds (donepezil and RVT-101) on cognitive performance of 12months old Tg2576 mice. Also, in the social recognition task, an absence of cognitive enhancing properties was observed with SLV on "normal forgetting" in Wistar rats. Finally, analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from pyramidal cells revealed a reduction in the presence of 1µM of SLV. In conclusion, SLV was investigated in several rodent animal models and found to be effective at a least effective dose (LED) of 20mg/kg and 10mg/kg (p.o.) in the rat and the mouse, respectively.


Assuntos
Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Inibição Pré-Pulso/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Receptores de Serotonina , Reconhecimento Psicológico/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Percepção Social , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Antagonistas da Serotonina/administração & dosagem
3.
Anal Bioanal Chem ; 406(28): 7103-16, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25192790

RESUMO

Prostanoids, derivatives of arachidonic acid, are involved in inflammation and immune reactions. To understand the role of prostanoids produced by diverse immune cells, a highly sensitive quantitation method for prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), 6-keto prostaglandin F1α (6-keto PGF1α), prostaglandin F2α (PGF2α), and thromboxane B2 (TXB2) by means of nano-liquid chromatography-tandem mass spectrometry has been developed. It was validated according to the guidelines of the Food and Drug Administration (FDA) in terms of linearity, precision, accuracy, recovery, stability, and lower limit of quantitation (LLOQ). The LLOQ were 25 pg/mL in the injected solution (75 fg on column (o.c.)) for PGE2 and PGD2 and 37.5 pg/mL (112.5 fg on column) for 6-keto PGF1α, PGF2α, and TXB2, respectively. It was successfully applied to murine mast cells isolated from paws after zymosan injection and to CD4(+) and CD8(+) T lymphocytes from blood of sensitized versus non-sensitized mice in context of a delayed type hypersensitivity model. About 5,000 (T cells) to 40,000 (mast cells) cells were sufficient for quantitation. In the mast cells, the production of PGE2 increased at a significantly higher extent than the synthesis of the other prostanoids. The T lymphocytes did not show any difference in prostanoid production, no matter whether they were obtained from sensitized mice or non-sensitized mice.


Assuntos
Cromatografia Líquida/métodos , Mastócitos/metabolismo , Prostaglandinas/análise , Linfócitos T/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Células Cultivadas , Masculino , Mastócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/citologia
4.
Neurobiol Learn Mem ; 96(2): 392-402, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21757018

RESUMO

The 5-hydroxytryptamine(6) (5-HT(6)) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT(6) antagonists compound (CMP) X and CMP Y and the reference 5-HT(6) antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer's disease, AD) was used as a positive reference compound. First, effects of the 5-HT(6) antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1mg/kg, administered intraperitoneally, i.p., 30 min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT(6) antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT(6) antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine. Donepezil (1mg/kg, oral administration, p.o.), GSK-742457 (3mg/kg, i.p.), CMP X (3mg/kg, i.p.) and CMP Y (30 mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1mg/kg, i.p.) and CMP Y (10mg/kg, p.o.) with the AChEI donepezil (0.1mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT(6) antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1mg/kg, p.o.), GSK-742457 (10mg/kg, p.o.) and CMP Y (30 mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT. In conclusion, the 5-HT(6) antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT(6) receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.


Assuntos
Comportamento Exploratório/efeitos dos fármacos , Guanidinas/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Sulfonamidas/farmacologia , Animais , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Donepezila , Guanidinas/uso terapêutico , Indanos/farmacologia , Indanos/uso terapêutico , Masculino , Transtornos da Memória/induzido quimicamente , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Ratos Wistar , Escopolamina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Sulfonamidas/uso terapêutico
5.
EJNMMI Res ; 11(1): 95, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34568982

RESUMO

RATIONALE: PSMA-directed therapy for metastatic prostate cancer is gaining adoption as a treatment option. However, accumulation of 177Lu/225Ac-PSMA in the salivary glands remains a problem, with risk of dose-limiting xerostomia and potentially severe effect on the quality of life. Gustatory stimulation is an approach that has commonly been used in radioactive iodine therapy to reduce accumulation in the salivary glands. However, based on theoretical differences in biodistribution, it was hypothesized that this could potentially lead to adverse increased toxicity for PSMA-ligand therapy. The primary objective of this work was to determine if gustatory stimulation by eating an assortment of sweet/fatty/acidic foods during the biodistribution phase of [18F]DCFPyl could result in a clinically relevant (> 30%) change in the uptake of the tracer in the salivary glands. METHODS: 10 patients who already received a whole-body [18F]DCFPyl PET/CT scan for evaluation of prostate cancer, underwent a repeat (intervention) PET/CT scan within a month of the first (control) scan. During the intervention scan, patients chose from an assortment of sweet/fatty/acidic foods, which they then chewed and swallowed for a period of time starting 1 min before tracer administration to 10 min thereafter. Data from both scans were analyzed by placing VOIs on the major salivary glands and segmenting them using relative thresholds. RESULTS: A slight increase in PSMA uptake in the parotid glands was observed on the intervention scan when compared to the baseline scan (+ 7.1% SULmean and + 9.2% SULmax, p < 0.05). No significant difference in PSMA uptake in the submandibular glands was seen. CONCLUSIONS: Eating only slightly increases uptake of [18F]DCFPyl in the parotid glands. We nonetheless recommend refraining from gustatory stimulation during the administration and early biodistribution phase of radionuclide therapy with PSMA-ligands to reduce the risk of avoidable additional toxicity.

6.
EJNMMI Res ; 11(1): 25, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33710423

RESUMO

RATIONALE: Salivary glands are highly perfused and express the prostate-specific membrane antigen (PSMA) receptor as well as the sodium-iodide symporter. As a consequence, treatment with 177Lu/225Ac-PSMA for prostate cancer or 131I for thyroid cancer leads to a high radiation dose in the salivary glands, and patients can be confronted with persistent xerostomia and reduced quality of life. Salivation can be inhibited using an antimuscarinic pharmaceutical, such as glycopyrronium bromide (GPB), which may also reduce perfusion. The primary objective of this work was to determine if inhibition with GPB could provide a considerable (> 30%) reduction in the accumulation of administered 123I or 68Ga-PSMA-11 in salivary glands. METHODS: Ten patients who already received a whole-body 68Ga-PSMA-11 PET/CT scan for (re)staging of prostate cancer underwent a repeat PET/CT scan with tracer administration at 90 min after intravenous injection of 0.2 mg GPB. Four patients in follow-up after thyroid cancer, who had been treated with one round of ablative 131I therapy with curative intent and had no signs of recurrence, received 123I planar scintigraphy at 4 h after tracer administration without GPB and a repeated scan at least one week later, with tracer administration at 30 min after intramuscular injection of 0.4 mg GPB. Tracer uptake in the salivary glands was quantified on PET and scintigraphy, respectively, and values with and without GPB were compared. RESULTS: No significant difference in PSMA uptake in the salivary glands was seen without or with GPB (Mean SULmean parotid glands control 5.57, intervention 5.72, p = 0.50. Mean SULmean submandibular glands control 6.25, intervention 5.89, p = 0.12). Three out of 4 patients showed increased 123I uptake in the salivary glands after GPB (Mean counts per pixel control 8.60, intervention 11.46). CONCLUSION: Muscarinic inhibition of salivation with GPB did not significantly reduce the uptake of PSMA-ligands or radioiodine in salivary glands, and can be dismissed as a potential strategy to reduce toxicity from radionuclide therapies.

7.
Neurobiol Learn Mem ; 93(4): 522-31, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20132903

RESUMO

Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 (doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.


Assuntos
Deficiências da Aprendizagem/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Nootrópicos/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sulfonamidas/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Deficiências da Aprendizagem/induzido quimicamente , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Testes Neuropsicológicos , Nootrópicos/administração & dosagem , Nootrópicos/química , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/química , Distribuição Aleatória , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Percepção Social , Sulfonamidas/administração & dosagem , Sulfonamidas/química
8.
Neth Heart J ; 15(4): 151-5, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17612676

RESUMO

Brugada syndrome is an inherited cardiac disease and is associated with a peculiar pattern on the electrocardiogram and an increased risk of sudden death. Electrical storm is a malignant but rare phenomenon in symptomatic patients with Brugada syndrome. We describe a patient who presented with repetitive ICD discharges during two episodes of recurrent VF. After the initiation of isoproterenol infusion and oral quinidine, the ventricular tachyarrhythmias were successfully suppressed. (Neth Heart J 2007;15:151-4.).

9.
Acta Neuropathol Commun ; 5(1): 42, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28578681

RESUMO

Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the 'symptom-free' intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach. Graphical summary of lysophosphatidic signaling in multiple sclerosis.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Lisofosfolipídeos/metabolismo , Esclerose Múltipla/metabolismo , Adolescente , Adulto , Animais , Biomarcadores/metabolismo , Estudos de Coortes , Estudos Transversais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Fatores Imunológicos/farmacologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Adulto Jovem
10.
Physiol Behav ; 89(5): 692-703, 2006 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-16987534

RESUMO

Impaired attention is evident in several neurological and psychiatric disorders. In the present study, attentional capabilities were measured in the operant five-choice serial reaction time task (5-CSRTT) in male (C57BL/6Jx129Sv)F2 hybrid (B6129F2) mice. Main aims were to validate and standardize the test in these mice: to setup procedures, measure potential beneficial effects of sub-chronic nicotine in degraded versions of the 5-CSRTT (by decreasing stimulus duration, inducing white noise and making the stimuli unpredictable) and study disruptive effects of additional administration of the muscarinic antagonist scopolamine. During the baseline pre-nicotine sessions, the B6129F2 mice attained a very good performance in the test (95% accuracy). As stimulus duration was reduced from 2 s to 1 s, response accuracy of the mice decreased. Mice treated with nicotine (0.16 mg/kg) attained significantly higher response accuracy and had a lower percentage of incorrect responses in comparison with the solvent-treated animals. No further beneficial effects of nicotine were found. Reduced response accuracy was also obtained when stimulus duration was reduced from 1 s to 0.5 s and when a variable intertrial interval was introduced. Noise interpolation between trials did not impair performance. Finally, scopolamine (0.16 mg/kg) disrupted attentional functioning. Although most studies have been performed in rats, these results add to the existing evidence that the 5-CSRTT can also be used to assess attentional performance in mice. This offers the opportunity to test transgenic and knockout mice with similar background as the B6129F2 as animal models of psychiatric and neurological diseases.


Assuntos
Atenção/fisiologia , Comportamento de Escolha/fisiologia , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologia , Aprendizagem Seriada/fisiologia , Análise de Variância , Animais , Atenção/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/genética , Escopolamina/farmacologia , Aprendizagem Seriada/efeitos dos fármacos
11.
Behav Brain Res ; 300: 160-74, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26692368

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is a widely-used rodent model for multiple sclerosis (MS), but a single model can hardly capture all features of MS. We investigated whether behavioral parameters in addition to clinical motor function scores could be used to assess treatment efficacy during score-free intervals in the relapsing-remitting EAE model in SJL/J mice. We studied the effects of the clinical reference compounds FTY720 (fingolimod, 0.5mg/kg/day) and dimethyl fumarate (DMF, 20-30 mg/kg/day) on clinical scores in several rodent EAE models in order to generate efficacy profiles. SJL/J mice with relapsing-remitting EAE were studied using behavioral tests, including rotarod, gait analysis, locomotor activity and grip strength. SJL/J mice were also examined according to Crawley's sociability and preference for social novelty test. Prophylactic treatment with FTY720 prevented clinical scores in three of the four EAE rodent models: Dark Agouti (DA) and Lewis rats and C57BL/6J mice. Neither prophylactic nor late-therapeutic treatment with FTY720 reduced clinical scores or reversed deficits in the rotarod test in SJL/J mice, but we observed effects on motor functions and sociability in the absence of clinical scores. Prophylactic treatment with FTY720 improved the gait of SJL/J mice whereas late-therapeutic treatment improved manifestations of reduced social (re)cognition or preference for social novelty. DMF was tested in three EAE models and did not improve clinical scores at the dose used. These data indicate that improvements in behavioral deficits can occur in absence of clinical scores, which indicate subtle drug effects and may have translational value for human MS.


Assuntos
Fumarato de Dimetilo/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Cloridrato de Fingolimode/farmacologia , Imunossupressores/farmacologia , Atividade Motora/efeitos dos fármacos , Comportamento Social , Animais , Encefalomielite Autoimune Experimental/fisiopatologia , Encefalomielite Autoimune Experimental/psicologia , Feminino , Marcha/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ratos Endogâmicos Lew , Reconhecimento Psicológico/efeitos dos fármacos , Índice de Gravidade de Doença , Tempo
12.
J Pediatr Endocrinol Metab ; 18(6): 535-9, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16042319

RESUMO

Although growth hormone (GH) treatment has improved final height prognosis in children with GH deficiency (GHD), adult heights are still disappointing. Final height could be improved by increasing the duration of puberty and in this way increasing total pubertal height gain. Many studies have been published on the effect of gonadal suppression, mostly by gonadotropin releasing hormone (GnRH) analogues, on final height in children with GHD. Because of the different methodologies used in these studies, results are difficult to compare. Both positive and marginal effects on final height have been reported; however, patient numbers are limited. Children with GHD who start puberty at a relatively young age and who have a poor predicted adult height, can benefit from the addition of GnRH analogues. From previous studies, we might conclude that when there is a positive effect, height benefit is marginal. However, additional prospective, randomized controlled trials are needed to further elucidate whether delaying puberty is indicated in children with GHD to improve final height.


Assuntos
Estatura/fisiologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Hormônio do Crescimento Humano/deficiência , Puberdade/fisiologia , Adolescente , Estatura/efeitos dos fármacos , Criança , Ensaios Clínicos como Assunto , Feminino , Hormônio Liberador de Gonadotropina/efeitos adversos , Humanos , Masculino , Puberdade/efeitos dos fármacos
13.
Am J Clin Nutr ; 61(2): 279-86, 1995 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7840064

RESUMO

Measurement of total-body electrical conductivity (TOBEC) has emerged as a rapid, safe, and reproducible method for estimation of infant total body fat (TBF). Agreement of two anthropometric methods [by Dauncey et al (1977) and Weststrate et al (1989)] with TOBEC-TBF was assessed in 435 healthy infants aged 21-365 d. Dauncey-TBF correlated with TOBEC-TBF by r2 = 0.61 and exceeded TOBEC-TBF by 0.14 +/- 0.25 kg in infants < 4 mo of age. Thereafter, TOBEC-TBF exceeded Dauncey-TBF by 0.20 +/- 0.47 kg. We modified Dauncey's method, which significantly improved the correlation to r2 = 0.75. Weststrate-TBF correlated with TOBEC-TBF by r2 = 0.87, but exceeded TOBEC-TBF by 0.5 kg. Both methods showed poor agreement with TOBEC-TBF. We conclude that both methods, although suitable for comparison of TBF between groups, cannot be used to accurately assess TBF in an individual infant.


Assuntos
Tecido Adiposo , Composição Corporal , Antropometria/métodos , Condutividade Elétrica , Feminino , Humanos , Lactente , Masculino , Fatores Sexuais , Dobras Cutâneas
14.
Am J Clin Nutr ; 61(6): 1195-205, 1995 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7762517

RESUMO

Anthropometry is frequently used for nutritional assessment. Little is known in infants about the validity of anthropometric measurements in relation to whole-body fat (TBF) and fat-free mass (FFM) composition. We compared TBF and FFM estimations by total-body electrical conductivity (TOBEC) with anthropometry in 435 healthy infants ages 21-365 d. TBF was best correlated with weight-for-length and calf circumference (r2 = 0.84, r2 = 0.83). FFM was best correlated with body weight (r2 = 0.93). Upper-arm anthropometry, skinfold thickness, and Quetelet's and Ponderal indexes were poorly correlated with TBF and FFM (r2 < 0.65). New anthropometry-based prediction equations were calculated (r2 = 0.90 for TBF and r2 = 0.95 for FFM). New simple indexes (analogous to Quetelet's index) were calculated for TBF (weight x calf circumference/length; r2 = 0.87) and for FFM (square root of weight x length; r2 = 0.95). Prediction equations and indexes were cross-validated in a second population by a second observer. Interobserver variation was largest for equations with skinfold thicknesses included. We conclude that anthropometry can be used for rough estimations of infant body composition, although indexes different than those used in children and adults are preferred.


Assuntos
Antropometria , Composição Corporal , Tecido Adiposo , Condutividade Elétrica , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estado Nutricional , Valor Preditivo dos Testes , Análise de Regressão
15.
Am J Clin Nutr ; 67(5): 885-96, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9583846

RESUMO

This study is the first to report approximations of energy requirements for male and female breast-fed and formula-fed infants based on individual estimates of total daily energy expenditure (TDEE) and energy deposition derived from total body fat (TBF) and fat-free mass (FFM) gain as determined by total-body electrical conductivity. In 46 healthy, full-term infants the effect of > or = 4 mo of exclusive breast-feeding compared with formula feeding on macronutrient and energy intake, TDEE, energy deposition, and growth were investigated prospectively. Metabolizable energy intake (MEI) was assessed from macronutrient intake by test weighing (MEI-TW) and from the sum of TDEE and energy deposition (MEI-Pred). At 1-2, 2-4, 4-8, and 8-12 mo of age MEI-Pred averaged 431 +/- 38, 393 +/- 33, 372 +/- 33, and 355 +/- 21 kJ x kg(-1) x d(-1) for boys, and 401 +/- 59, 376 +/- 25, 334 +/- 33, and 326 +/- 17 kJ x kg(-1) x d(-1) for girls. No significant difference between breast-fed and formula-fed infants was found with respect to weight, length, head circumference, TBF, FFM, and TDEE at all ages, or for gain in length, weight, TBF, and FFM. MEI-TW was significantly different between feeding groups at 1-4 mo of age (formula-fed being greater than breast-fed, P < 0.005). This feeding effect, however, was not significant for MEI-Pred (MJ/d). MEI-TW differed from MEI-Pred only in breast-fed infants at 1-4 mo (P < 0.05 at 2-4 mo). The data from this study indicate that energy requirements in infants are lower than the recommendations in guidelines currently in use.


Assuntos
Alimentação com Mamadeira , Aleitamento Materno , Metabolismo Energético , Crescimento/fisiologia , Alimentos Infantis , Fatores Etários , Composição Corporal/fisiologia , Estatura/fisiologia , Peso Corporal/fisiologia , Interpretação Estatística de Dados , Ingestão de Energia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estado Nutricional , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores Sexuais
16.
Neuroscience ; 105(1): 169-80, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11483310

RESUMO

Sensory processing disturbances, as measured in the P50/sensory gating paradigm, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In this paradigm, the response to the second of paired-click stimuli is attenuated by an inhibitory effect of the first stimulus. Sensory gating has been observed in most healthy human subjects and normal laboratory rats. Because mesolimbic dopamine has been implicated in other filtering disturbances such as prepulse inhibition of the acoustic startle response and given the fact that amphetamine and apomorphine have been shown to disrupt gating, this study was performed to investigate the role of mesolimbic dopamine in sensory gating. The dopamine D2 receptor agonist quinpirole (10 microg/0.5 microl) was injected bilaterally in nucleus accumbens core and shell and effects on cortical and hippocampal sensory gating were investigated. Also, effects of the dopamine D2 receptor antagonist haloperidol (0.1 mg/kg, subcutaneously) as pretreatment were studied. First, quinpirole significantly reduced both the amplitude to the first click and gating as measured in the cortex and in the hippocampus. There was a tendency for the quinpirole effects on hippocampal gating to be more pronounced in rats injected in the shell. Secondly, haloperidol did not antagonize effects of quinpirole on hippocampal parameters, whereas haloperidol pretreatment fully antagonized quinpirole effects on cortical parameters. In conclusion, gating can be significantly reduced when a dopamine agonist is specifically targeted at mesolimbic dopamine D2 receptors. However, an important consideration is that the dopaminergic effects in the present study on gating are predominantly mediated by the effects on the amplitude to the first click. This has also been suggested for systemic amphetamine injections in rats and schizophrenic patients. This casts doubt on whether dopamine receptor activation affects the putative inhibitory process between the first and the second stimulus.


Assuntos
Percepção Auditiva/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Quimpirol/farmacologia , Estimulação Acústica , Animais , Percepção Auditiva/fisiologia , Córtex Cerebral/fisiopatologia , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Eletroencefalografia/efeitos dos fármacos , Potenciais Evocados Auditivos/efeitos dos fármacos , Potenciais Evocados Auditivos/fisiologia , Haloperidol/farmacologia , Hipocampo/fisiopatologia , Masculino , Inibição Neural/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/fisiopatologia , Ratos , Ratos Wistar , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia
17.
Psychopharmacology (Berl) ; 156(2-3): 352-9, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11549235

RESUMO

RATIONALE: Auditory filtering disturbances, as measured in the sensory gating and prepulse inhibition (PPI) paradigms, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In both paradigms, the response to the second stimulus (S2) is attenuated by an inhibitory effect of the first stimulus (S1). Dopamine (DA) agonists have been found to reduce gating of auditory evoked potentials (AEPs) and PPI in healthy human subjects and in rats. These effects have been linked to DA hyperactivity in the mesolimbic system. A non-invasive approach in studying the role of the DA system in PPI and AEP gating is to compare rat genotypes that are marked by distinct DA systems. OBJECTIVES: Several questions were asked in the present study. Are PPI and AEP gating disturbed in (a) rats that are marked by a relatively high DA reactivity of the mesolimbic system, namely apomorphine-susceptible (APO-SUS) and WAG/Rij rats or in (b) rats that are marked by a relatively high DA activity of the nigrostriatal system, namely apomorphine-unsusceptible (APO-UNSUS) and ACI rats? Moreover, is the particular DA balance (c) between the nigrostriatal and mesolimbic system related to deficits in PPI and AEP gating? METHODS: For this purpose, the above-mentioned four rat genotypes (APO-SUS, APO-UNSUS, ACI and WAG/Rij) that vary in DA balance between both systems, were compared in the AEP gating paradigm. PPI was only measured in the ACI and WAG/Rij rats, since it has already been shown in a previous study that APO-SUS rats show diminished PPI as compared to rats of the APO-UNSUS genotype. RESULTS: AEP gating of the vertex N50 was significantly reduced in WAG/Rij rats as compared to the remaining three rat genotypes (APO-SUS, APO-UNSUS and ACI). No PPI deficits were found in the ACI and WAG/Rij rats, although ACI rats had a significantly higher basal startle amplitude. CONCLUSIONS: The PPI deficit in APO-SUS and not in the other genotypes, suggests that especially a relatively high DA reactivity of the mesolimbic system, together with a relatively low activity of the nigrostriatal system, contributes to this deficit. In contrast, the N50 gating deficit in WAG/Rij rats and not in the other genotypes suggests that a relatively high DA activity of the nigrostriatal system together with a relatively high DA reactivity of the mesolimbic system is necessary for the presence of a N50 gating deficit. On the basis of these results we have concluded that both auditory filtering processes are differently regulated by DA in the nigrostriatal and mesolimbic systems.


Assuntos
Percepção Auditiva/genética , Percepção Auditiva/fisiologia , Dopamina/fisiologia , Estimulação Acústica , Animais , Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Genótipo , Masculino , Ratos , Ratos Endogâmicos , Reflexo de Sobressalto/fisiologia
18.
Psychopharmacology (Berl) ; 142(1): 9-17, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10102777

RESUMO

Schizophrenic patients suffer from deficits in information processing. Patients show both a decrease in P50 gating [assessed in the conditioning-testing (C-T) paradigm] and prepulse inhibition (PPI), two paradigms that assess gating. These two paradigms might have a related underlying neural substrate. Gating, as measured in both the C-T paradigm (the gating of a component of the auditory evoked potential (AEP)], and PPI can easily be measured in animals as well as in humans. This offers the opportunity to model these information processing paradigms in animals in order to investigate the effects of neurotransmitter manipulations in the brain. In order to validate the animal model for disturbances in AEP gating, d-amphetamine (0.5 and 1 mg/kg, i.p.) was administered. Gating of an AEP component was changed due to injection of d-amphetamine (1 mg/kg) in the same way as seen in schizophrenic patients: both the amplitude to the conditioning click and the gating were significantly reduced. Next, the effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine (2.5 and 10 mg/kg, i.p.) was investigated to assess its effects in the two gating paradigms. It was found that ketamine (10 mg/kg) did not affect gating as measured with components of the AEP. However, ketamine (10 mg/kg) disrupted PPI of the startle response to the extent that prepulse facilitation occurred. Firstly, it is concluded that AEP gating was disrupted by d-amphetamine and not by ketamine. Secondly, PPI and the C-T paradigm reflect distinct inhibitory sensory processes, since both paradigms are differentially influenced by ketamine.


Assuntos
Dextroanfetamina/farmacologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Condicionamento Psicológico/efeitos dos fármacos , Dopaminérgicos/farmacologia , Interações Medicamentosas , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/fisiologia , Projetos de Pesquisa
19.
Neurosci Res ; 38(2): 165-73, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11000443

RESUMO

Dopaminergic neurotransmission has been shown to participate in the control of absence epilepsy. This type of epilepsy, a generalized non-convulsive form, is associated with bursts of bilateral synchronous spike wave discharges (SWDs) recorded in the EEG. In a previous study, it was suggested that two features of the apomorphine-susceptible (APO-SUS) rat genotype, a relatively low dopaminergic reactivity of the nigrostriatal system and relatively high dopaminergic reactivity of the mesolimbic system, contribute to the high incidence of SWDs. Indeed, apomorphine-unsusceptible (APO-UNSUS) rats, characterized by opposite dopaminergic features, show considerably less SWDs than APO-SUS rats. The first goal of the present study was to assess the baseline SWD incidence in four rat genotypes (WAG/Rij, ACI, APO-SUS and APO-UNSUS) in order to replicate previous findings. It was expected that both the APO-SUS and WAG/Rij rats would show a considerably higher SWD incidence in comparison to the APO-UNSUS and ACI rats. For this purpose, rats were registered for a 19 hour period. Assuming that haloperidol decreases dopaminergic transmission in the nigrostriatal system via inhibition of the dopamine receptors and enhances dopaminergic transmission in the mesolimbic system via inhibition of the noradrenergic receptors, it was postulated that haloperidol would enhance the difference in dopaminergic reactivity between both systems in favor of the accumbens. Therefore, the second purpose in the present study was to investigate whether haloperidol (2 mg/kg, IP) could further potentiate SWD incidence when injected in the APO-SUS rats, already characterized by a relatively low dopaminergic reactivity of the nigrostriatal system and relatively high dopaminergic reactivity of the mesolimbic system, in comparison to the APO-UNSUS rat genotype. Finally, the third aim was to study if another epileptic rat genotype, the WAG/Rij, would show similar increases in SWD incidence following an injection with haloperidol as expected for the APO-SUS. First, previous findings were replicated: the value of the hourly number of SWDs decreased in the following order: APO-SUS > WAG/Rij > APO-UNSUS and ACI. Secondly, earlier data were extended by the fact that the APO-SUS responded to a systemic injection of haloperidol with an increase in SWD number and duration, in contrast to the APO-UNSUS rats. The hypothesis that the SWD incidence would be mostly affected by haloperidol in the APO-SUS rats, was confirmed by these findings. It is suggested that haloperidol increases the SWD incidence in APO-SUS rats by enhancing the difference between the dopaminergic reactivity in the nigrostriatal and mesolimbic system. Finally, further research is required to provide evidence in favor of the hypothesis that the relative dominance of the dopaminergic mesolimbic system is smaller in WAG/Rij than in APO-SUS.


Assuntos
Dopamina/fisiologia , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Animais , Apomorfina/farmacologia , Corpo Estriado/fisiologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Resistência a Medicamentos/genética , Genótipo , Haloperidol/farmacologia , Injeções , Masculino , Núcleo Accumbens/fisiologia , Veículos Farmacêuticos/farmacologia , Fotoperíodo , Ratos , Ratos Endogâmicos/genética , Tempo de Reação , Substância Negra/fisiologia , Transmissão Sináptica/efeitos dos fármacos
20.
Brain Res Bull ; 54(2): 145-51, 2001 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-11275403

RESUMO

In the P(50) gating or conditioning-testing paradigm in the rat, two identical click stimuli are presented with an inter-click interval of 500 ms. The reaction towards the second click, as measured with evoked potentials, is reduced in respect to that towards the first click; this phenomenon is called sensory gating. In the present experiments, the inter-click interval was varied systematically and auditory evoked potentials were measured. Sensory gating was found to occur only at intervals between 500 and 1000 ms, but not at longer intervals. Fos immunohistochemistry was then performed using two groups of rats exposed to double clicks: the inter-click interval was 500 ms in the experimental group and 2500 ms in the control group. Fos induction was analyzed in selected brain structures. In the auditory pathways, Fos-immunoreactive neurons were found in both groups of rats in the inferior colliculus and medial geniculate body. Fos-immunoreactive cells were also examined in the septum and hippocampus. In the ventral part of the lateral septal nucleus, the labeled neurons were significantly fewer in the experimental animals compared to the control group. Smaller and non-significant quantitative differences of Fos-positive neurons were documented in the medial septum and hippocampal CA1 region. These data point out a selective decrease in the lateral septum of Fos induced by auditory sensory gating, and suggest an involvement of this structure, and possibly of other parts of the septo-hippocampal system, in sensory gating mechanisms. The results might be relevant for theories on sensory gating deficits in schizophrenia.


Assuntos
Estimulação Acústica , Condicionamento Psicológico/fisiologia , Potenciais Evocados Auditivos/fisiologia , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleos Septais/fisiologia , Estimulação Acústica/métodos , Animais , Eletroencefalografia , Feminino , Hipocampo/fisiologia , Ratos , Ratos Wistar
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