Biomedical subjects
Publications and source records attributed to J Martinez.
In addition to excreting lignin-degrading peroxidases, the white rot fungus Phanerochaete flavido-alba also excretes a laccase. This protein was purified to homogeneity and found to have a molecular weight of 94,000 and an isoelectric point lower than 3.55. Its UV-visible spectrum is typical of copper-containing proteins.
With the renaissance of interest in how best to care for patients with terminal illness comes the need to recognize palliative care and hospice programs as the completion of comprehensive cancer care, not as its antithesis. In practical terms, admission to a hospice program is appropriate when efforts to control the biologic disease have ceased to be helpful and the primary medical focus is on symptom control and quality of life. In this article, the authors explore the goals of palliative care, review the transition to a hospice program, and assess the Medicare Hospice Benefit. Furthermore, they reflect on the importance of and barriers to the appropriate adoption of palliative care programs as well as palliative care education in oncology.
Neurotensin (NT) has been shown to be involved in neuroendocrine regulation, and the presence of both the peptide and its receptors has been demonstrated in the hypothalamus. In the present study, we show that hypothalamic neurons in primary cultures express the neurotensin receptor (NTR) and we examined a possible regulation of this receptor by glucocorticoids and activators of adenylate cyclase. In the hypothalamic cultures, 125I-NT bound to a single class of binding sites, presenting a selectivity similar to that observed for the high-affinity NTR previously described in the adult rat brain. Radioautographic studies demonstrated that these 125I-NT binding sites were present on 3% of the neurons. A 48-h treatment with forskolin (fsk) decreased 125I-NT binding by 30%. No effect of dexamethasone (dex) alone was found on that parameter. However, a combined treatment with both agents led to a 40% decrease in 125I-NT binding, corresponding to a reduced number of binding sites, and to a 68% decrease in the amount of NTR mRNA. In parallel, the dex plus forsk treatment increased NT release in the incubation medium. Moreover, the decreases in 125I-NT binding and NTR mRNA induced by this treatment were abolished in the presence of an anti-NT antibody or SR 48692, a non-peptidic antagonist of NTR, suggesting that the down-regulation of NTR observed after dex plus fsk treatment was mediated by the release of endogenous NT. Agonist-induced down-regulation of the NTR in this system was confirmed by the application of an exogenous NT analogue, JMV 449. The present findings indicate that, in hypothalamic cultures, dex and fsk indirectly down-regulate NTR expression via the release of endogenous NT.
The synthesis of analogs of the C-terminal tridecapeptide of gastrin is described. These pseudopeptide analogs were obtained either by replacing the C-terminal phenylalanine amide with 2-phenylethylalcohol or with 2-phenylethylamine, or by replacing the peptide bond between Trp and Leu, or between Leu and Asp with an aminomethylene (CH2NH). The ability of these compounds to stimulate gastric acid secretion in anesthetized rats and to inhibit binding of labeled CCK-8 to isolated cells from rabbit fundic mucosa was tested. [desPhe13, Leu11]-HG-12-I-beta-phenylethylester 33, [desPhe13, Leu11]-HG-12-II-beta-phenylethylester 38, [desPhe13, Leu11]-HG-12-I-beta-phenylethylamide 32, and [desPhe13, Leu11]-HG-12-II-beta-phenylethylamide 37 acted as gastrin receptor antagonists, while [Trp10-psi(CH2NH)-Leu11]-HG-13-I 31 and [Trp10-psi(CH2NH)-Leu11]-HG-13-II 36 acted as agonists. Unexpectedly, [Leu11-psi(CH2NH)-Asp12]-HG-13-I 30 and [Leu11-psi (CH2NH)-Asp12]-HG-13-II 35 were almost devoid of affinity for the gastrin receptor.
In the present study we compared various CCK(B) receptor antagonists and tried to detect a difference in biological activity between the C-terminal octapeptides of cholecystokinin (CCK-8) and [Leu11]gastrin-(5-17) in isolated rabbit gastric glands. Binding experiments showed that different CCK(B)/gastrin receptor agonists bound with high affinity and that antagonists inhibited this binding in accordance with a CCK(B)/gastrin pharmacological profile. [Leu11]gastrin-(5-17), CCK-8 and cionin were found to induce [14C]aminopyrine accumulation to 25% above the basal level. Under the same experimental conditions, histamine induced a response twice as great as the response obtained with [Leu11]gastrin-(5-17) or CCK-8. [Leu11]gastrin-(5-17) (10(-7) M), CCK-8 (10(-8) M) and cionin (10(-8) M) appeared to be full agonists. CCK(B)/gastrin receptor antagonists including L-365,260 (3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin++ +-3-yl)-N-(3-methylphenyl) urea), L-364,718 (3S-(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin++ +-3-yl)-1H-indole-2-carboximide) (a selective CCK(A) receptor antagonist), PD-135,158 (4([2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2. 2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl] amino-4-oxo-[1S-1alpha.2beta[S*(S*)]4alpha]]-butano nate N-methyl-D-glucamine) (bicyclo system 1S-endo), YM-022 ((R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-++ +benzodiazepin-3-yl]-3-(3-methylphenyl)urea) and JMV-180 (Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-O-CH2-CH2-C6H5) exhibited the same profile for inhibition of [Leu11]gastrin-(5-17) or CCK-8-induced [14C]aminopyrine accumulation in rabbit gastric glands. These results suggested that [Leu11]gastrin-(5-17) and CCK-8 induced [14C]aminopyrine accumulation by the same mechanism. [Leu11]gastrin-(5-17)- or CCK-8-induced [14C]aminopyrine accumulation was inhibited by about 40% by the histamine H2 receptor blocker cimetidine. These results are consistent with there being cooperativity between [Leu11]gastrin-(5-17) (or CCK-8) and histamine in the acid secretory pathway. Similarly, the CCK(B)/gastrin receptor antagonists were tested against histamine-induced [14C]aminopyrine accumulation and surprisingly, only compound L-365,260 appeared active and even more potent than cimetidine.
The psychological and physiological effects of acute low-potency benzodiazepine administration on lactate-induced panic were examined in 10 patients with panic disorder (PD). The patients, who had panicked during a standard sodium-lactate infusion, underwent a repeat infusion modified by pretreatment with intravenous diazepam (5 mg). Acute Panic Inventory (API) scores preceding the second lactate infusion, which were associated with diazepam pretreatment, were significantly reduced in compared with those measured before the first lactate infusion. However, the second visit "fear of doom" item of the API was significantly reduced relative to the same time point of the first visit 35 min before lactate infusion, when diazepam had not yet been administered. Thus, the reduction of prelactate anxiety preceding the second infusion appeared to reflect both pharmacological and nonpharmacological contributions. The diazepam pretreatment condition was associated with a significantly increased infusion duration and a significant attenuation of rate of API symptom increase in response to lactate. Despite significant attenuation of lactate infusion effects associated with the diazepam pretreatment condition, 7 of 10 patients experienced a second panic attack. This pilot study suggests that diazepam pretreatment is associated with a marked reduction of symptomatic response during a second lactate infusion, although the magnitude of attenuation observed was insufficient to block lactate-induced panic in a majority of lactate-vulnerable PD patients.
We have shown that gastrin and cholecystokinin octapeptide (CCK-8) are differently coupled to G protein (GTP-binding protein) through type B cholecystokinin receptors in guinea-pig brain membranes and Jurkat cells. Indeed, the gastrin-13 binding affinity is strongly reduced by stable guanyl nucleotides, whereas CCK-8 binding is only slightly affected. In order to determine the structural requirements regulating such coupling, we have synthesized several gastrin and cholecystokinin fragments (sulphated or unsulphated) elongated at the N-terminus of the common C-terminal tetrapeptide. We investigated their interaction with CCKB receptors in guinea pig brain membranes and Jurkat cells and their involvement in the G protein coupling. Their apparent binding affinities to CCKB receptors were measured by inhibition of [125I]Bolton Hunter-CCK-8 (3-[125I]iodo-4-hydroxyphenyl)propionyl-CCK-8) binding in the presence or absence of GTP gamma S (guanosine 5'-O-(3-thio)triphosphate) or aluminum tetrafluoride (AlF4-). Activation of the G proteins by GTP gamma S or AlF4- led to a decrease in binding affinity for the gastrin related peptides, the common CCK-gastrin C-terminal forms, the cholecystokinin hexapeptide and the unsulphated cholecystokinin heptapeptide. Sulphated CCK-7, CCK-8, and cionin apparent binding affinities were not affected. These finding indicated that the sulphated tyrosine in position 7 in CCK (as counted from the C-terminus), provides the cholecystokinin selectivity for the CCKB receptor compared to gastrin. The results are discussed with the aim to better clarify the physiological relevance of gastrin and cholecystokinin toward CCKB receptors and their related intracellular events.
Previous familial cases of recurrent heterotaxia have suggested an autosomal recessive or exceptionally X-linked or dominant inheritance. Here, we report six families including 18 affected members, consistent with autosomal dominant inheritance. Among these, four families have more than one case of heterotaxia. The other two families have one member with heterotaxia and at least one other affected member with an "isolated" heart malformation, which could be considered as a mild form of heterotaxia. In five families, the disorder is transmitted through two or three generations. In one family, the patients are of the same generation but are linked to each other by obligate carriers. We suggest a rule to classify these families with heart malformations, according to the etiologic factor involved (rule of precocity). This rule might be useful to other disruptions of morphogenetic processes.
It has been reported that substitution of the Met31 residue in Boc-CCK4 (Boc-Trp30-Met31-Asp32-Phe33-NH2, CCK33 numbering) by trans-3-propyl-L-proline yields a highly potent and selective CCK-B agonist. To further explore the structural requirements of the Met31 side chain in the receptor-bound conformation of CCK4, we have synthesized several Ac-CCK4 analogs containing substitution of Met31 by 3- and 4-(alkylthio)-substituted proline derivatives. To this end we have developed novel synthetic routes to enantiomerically pure N-Boc-4-cis- and -trans-(methylthio)prolines and racemic N-Boc-3-cis and -trans-[(4-methylbenzyl)thio]prolines. The protected mercaptoprolines were incorporated into Ac-CCK4 analogs using SPPS and were alkylated using various electrophiles following cleavage from the solid support. Binding assays reveal that 3-(alkylthio)prolines analogs have higher affinities at the CCK-B receptor than the corresponding 4-(alkylthio)proline analogs, and that trans-3-(alkylthio)proline analogs had higher affinities than corresponding cis-3-(alkylthio)proline analogs. Within both the cis- and trans-3-(alkylthio)proline series, the order of potency was found to be Me < Et < n-Pr. The trans-3-(n-propylthio)-L-proline analog demonstrates a higher affinity than that reported for Boc-CCK4[trans-3-propyl-L-Pro31]. Comparison of the low-energy structures calculated for several high-affinity Ac-CCK4 analogs reveal a common geometry which we propose to be the CCK-B receptor-bound conformation. This model shows grouping of the hydrophobic side chains of Trp, Met, and Phe at one side of the molecule and the hydrophilic side chain of Asp and the C-terminal carboxamide at the other side.
The sequence of a cholecystokinin (CCK) related peptide was modified to obtain analogues, which interact selectively either with CCK-B, or with delta-opioid receptors. Two kinds of peptides were designed, namely, the cyclic peptides of the H-Tyr-cyclo (D-Pen-Gly-Trp-L/D-3-transmercaptoproline)-Asp-Phe-NH2 sequence (compounds 1a and 1b, respectively), and the linear peptides of the H-Tyr-D-Val-Gly-Trp-L/D-3-trans-methylmercaptoproline-Asp-Phe- NH2 sequence (compounds 2a and 2b, respectively). The only difference between the chemical structures of the linear analogues compared to the cyclic ones is that one covalent bond has been eliminated and a sulfur atom is replaced by a methyl group. Molecular modeling showed that, among low-energy conformers of cyclic compounds 1, there are three-dimensional structures compatible to the model for delta-receptor-bound conformer, suggested earlier [G. V. Nikiforovich, V.J. Hruby, O. Prakash, and C.A. Gehrig (1991) Biopolymers, vol. 31, pp. 941-955]. Results of binding assays fully supported the rationale for the design of compounds 1 and 2. The cyclic analogue 1a has Ki values of 4.5 and > 5000 nM at delta- and mu-opioid receptors, respectively; and IC50 values of 1.6 and > 10,000 nM for CCK-A and CCK-B receptors, respectively. The results of this study demonstrate a possibility to redirect a peptide sequence that interacts with one type of receptors (CCK-B receptors) toward interaction with another type (delta-opioid receptors) belonging to a different physiological system. This redirection could be performed by changing the conformational properties of the peptide with very minimal changes in its chemical structure.
Acute disseminated encephalomyelitis (ADEM) is a white matter inflammatory disease which usually follows a viral infection or pharmaceutical intervention. We describe a case of presumed ADEM in a heart/lung transplant patient, the etiology of which cannot be elucidated. The fascinating aspect is the mode of clinical presentation and the rapid resolution of radiologic abnormalities. Histologic examination of the brain is provided in an attempt to elucidate the radiographic abnormalities.
The aim of this study was to quantify the incidence of childhood accidents and to describe the morbidity profile of accidents in the autonomous region of Andalusia, Spain, for a three-month period (January to March) in 1990. For that purpose, a population survey based on a stratified multiphase sample design was carried out. We collected information about the most serious accident each child had suffered during the study period according to the opinion of the person interviewed (the mother in most of the cases). The cumulative incidence of childhood accidents in Andalusia for a three-month period was 19.4%, higher in urban areas than in rural ones, and lower as the age of the age group increased. As had occurred in previous studies, a higher number of accidents was observed among the male population, however, this result was not statistically significant. During the same period of time, the incidence of traffic accidents for population 0 to 14 years was 0.8%. Accidents among younger children (0 to 4 years of age) occurred mainly at home, while for children of a higher age (5 to 9 and 10 to 14) they took place, in a larger number of cases, either outdoors or at school. When the accident happened, those from the first group were mainly in the presence of their parents or other adults; in the other two groups, there were more friends or schoolmates present. Fractures and injuries, of minor severity, mainly on the head and the extremities and with no sequelae, were the most frequent types of accident.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: The success of coronary revascularization for ischemic cardiomyopathy (left ventricular ejection fraction of 0.25 or less) has been unpredictable. We and others have demonstrated that the hospital operative mortality rate for these operations has been surprisingly low, particularly if evidence of ischemia is present. We subsequently liberalized our selection criteria based on our hypothesis that coronary artery bypass grafting is safe in this subset of patients regardless of the status of their distal coronary vasculature. METHODS: To examine this hypothesis, we studied retrospectively our patients undergoing coronary artery bypass grafting from 1983 to 1993. Ninety-six patients with ejection fractions of 0.25 or lower underwent this operation, with 88 hospital survivors (mortality 8%). All of the patients had clinical symptoms of heart failure. The male to female ratio was 4.6:1. The average age was 63.1 +/- 0.9 years (mean +/- standard error of the mean). Patients were excluded if they had valvular heart disease other than mild to moderate mitral regurgitation, required resection of a ventricular aneurysm, or required an emergency operation for acute coronary occlusion. Possible predictors of death were examined retrospectively. The catheterization films were reviewed retrospectively by a cardiovascular surgeon who was blinded to patient outcome and was never involved in the clinical management of any of the patients. Vessel quality was described as good, fair, or poor. RESULTS: Increased age and poor vessel quality were the only significant predictors of poor outcome. Sex, presence or absence of angina, preoperative angina, preoperative ejection fraction, preoperative arrhythmia disorder, aortic cross-clamp time, and the number of bypass grafts had no significant effect on outcome in the perioperative period. CONCLUSION: These results demonstrate that poor vessel quality and older age are predictors of poor outcome in patients with low ejection fractions undergoing myocardial revascularization. We conclude that poor distal coronary vasculature is a contraindication to coronary artery bypass grafting in patients with an ejection fraction of 0.25 or less, even if angina is present.
BACKGROUND: Topical preparations are sometimes applied before phototherapy without consideration of their potential to block UVB. OBJECTIVE: Our purpose was to examine the ability of topical preparations to block UVB. METHODS: Volunteers pretreated with mineral oil, a clear liquid emollient, 5% crude coal tar, 6% salicylic acid ointment, emollient creams, and petrolatum underwent minimal erythema dose testing. Transmission of UVB through a clear film coated with the preparations was measured. RESULTS: Tars and salicylic acid blocked UVB. Thick application of petrolatum and emollient creams can reduce transmission of UVB. Mineral oil and a clear liquid emollient did not significantly affect transmission or erythemogenicity of UVB. CONCLUSION: Clear liquid emollient and mineral oil can be used before phototherapy. If not removed before phototherapy, preparations containing tar or salicylic acid, or thickly applied petrolatum or emollients, can block UVB and presumably reduce its efficacy in the treatment of psoriasis.
The in vivo effects of JMV-320 (a highly selective CCKB receptor ligand) and of CCK-4 on exploratory activity and memory in rats were compared. JMV-320 and CCK-4 did not modulate exploratory activity in an open field test but decreased it in an elevated plus-maze. CCK-4 (50 micrograms/kg) impaired passive avoidance response 3 h after training and JMV-320 (1 and 10 micrograms/kg) decreased active avoidance response 24 h after training. The behavioral effects of JMV-320 resemble the effects of CCK-4 and suggest that in vivo JMV-320 acts as a CCKB receptor agonist.
In this paper the authors examine the interrelationship of both the noradrenergic (NA) system and the hypothalamic-pituitary-adrenal (HPA) axis and its implications for panic disorder (PD). Seventeen PD patients and 16 healthy volunteers were challenged orally 12 weeks apart with the alpha 2-agonist clonidine (13 healthy volunteers and 12 patients repeated the challenge). Between challenges, PD patients were treated with fluoxetine, with 10 of 12 improving at least moderately. Both during the acute phase of the illness and during the phase of pharmacological improvement, patients demonstrated a greater percentage of reductions of plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and plasma cortisol during clonidine challenge. We used correlational matrices to examine the relationship between the NA system, as reflected by plasma MHPG, and the HPA axis, as reflected by plasma cortisol measures. Healthy volunteers exhibited multiple significant "couplings" between either baseline or maximal decrease (delta max) of plasma MHPG, with either baseline or delta max plasma cortisol measures both within the first and second challenges and between the first and second challenges. In contrast, PD patients demonstrated "uncoupling" of the NA system and the HPA axis, with no significant correlations observed between either baseline and/or maximal decrease (delta max) measures of MHPG with the same cortisol measures for either the first or second challenge. The same uncoupling was observed for NA/HPA correlations between the first and second challenges. These data suggest that the hyperresponsivity to clonidine in PD patients persists during fluoxetine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
We studied the formation of capillary tubes by endothelial cells which were sandwiched between two fibrin gels under serum-free conditions. After formation of the overlying fibrin gel, the endothelial cell monolayer rearranged into an extensive net of capillary tubes. Tube formation was apparent at 5 h and was fully developed by 24 h. The capillary tubes were vacuolated, and both intracellular and intercellular lumina were present. Maximal tube formation was observed with fibrin II (which lacks both fibrinopeptide A and B), minimal tube formation with fibrin I (which lacks only fibrinopeptide A), and complete absence of tube formation with fibrin 325 (which lacks the NH2-terminal beta 15-42 sequence, in addition to fibrinopeptides A and B). The inability of fibrin 325 to stimulate capillary tube formation supports the idea that beta 15-42 plays an important role in this process, and its importance was confirmed by the finding that exogenous soluble beta 15-42 inhibited fibrin II-induced capillary tube formation. This effect was specific for fibrin, since beta 15-42 did not inhibit tube formation by endothelial cells sandwiched between collagen gels. The interaction of the apical surface of the endothelial cell with the overlying fibrin II gel, as opposed to the underlying fibrin gel upon which the cells were seeded, was necessary for capillary tube formation. These studies suggest that the beta 15-42 sequence of fibrin interacts with a component of the apical cell surface and that this interaction plays a fundamental role in the induction of endothelial capillary tube formation.
BACKGROUND: Recent evidence suggests that late reperfusion of an occluded infarct-related artery after an acute myocardial infarction may reduce the frequency of subsequent arrhythmic events. Late mechanical reperfusion by percutaneous transluminal coronary angioplasty (PTCA) under these circumstances has a high success rate. The present study was performed to test the hypothesis that the late mechanical restoration of anterograde flow in an occluded infarct artery after an acute myocardial infarction causes a resolution of late potentials. METHODS: Twenty subjects (10 men, one woman; aged 32-77 years) suffering a first acute myocardial infarction, with signal-averaged electrocardiographic (ECG) recordings and a severely occluded infarct-related artery, were prospectively identified. RESULTS: Eighteen patients underwent successful PTCA of the occluded artery 6-32 days after a first acute myocardial infarction. Late potentials were observed in 14 patients 5-22 days after the infarction. A follow-up signal-averaged ECG was performed 1-8 days later. In the subgroup of 12 patients with successful reperfusion and an abnormal signal-averaged ECG before PTCA, seven (58.3%) showed resolution of the late potentials at follow-up; in these patients the filtered QRS duration showed a significant reduction (112.1 +/- 14.2 to 96.7 +/- 12.7 ms, P = 0.02), the root-mean-square voltage increased (9.8 +/- 6.5 to 33.1 +/- 15.5 microV, P = 0.017), and the duration of low-amplitude signals < 40 microV decreased after angioplasty (46.3 +/- 11.0 to 28.5 +/- 6.5 ms, P < 0.022). In contrast, two patients with late potentials before PTCA and unsuccessful reperfusion had no significant changes in signal-averaged ECG. CONCLUSIONS: In some patients with an acute myocardial infarction, late mechanical reperfusion of the culprit vessel may reduce the incidence of abnormalities on the signal-averaged ECG. Whether this will improve long-term survival has yet to be confirmed in a large trial.