Biomedical subjects
Publications and source records attributed to C Dominguez.
In this report we discuss the design, synthesis, and validation of a novel series of cyclic urea inhibitors of the blood coagulation protein Factor Xa. This work culminates in compound 11, a monoamidine inhibitor of fXa employing a new S4 ligand that reduces the cationic character of these analogs. Compound 11 represents a lead for a series of more potent and selective inhibitors.
BACKGROUND: Latex IgE-mediated hypersensitivity has been recognized as an international health problem. However, there is poor information on the efficiency of the diagnostic methods available. OBJECTIVE: The purpose of this study was to specify the efficiency of several diagnostic methods for latex allergy. METHODS: We designed a prospective study involving 50 adult patients with latex allergy, as diagnosed by a suggestive clinical history and a positive skin-prick test (SPT) to a latex extract. One control group of 50 subjects paired for age, sex, total IgE levels and latex exposure, and another control group of 30 subjects with pollen allergy were used. A low-ammoniated natural-latex and several glove-latex extracts were elaborated. SPTs with these extracts, as well as with four different commercial-latex extracts were performed. Latex-specific serum IgE was determined by the CAP and the AlaSTAT methods. RESULTS: Diagnostic sensitivity was 98% for the natural-latex extract SPT, from 90% to 98% for the commercial-latex extract SPT, and from 64% to 96% for the glove-latex extract SPT. Diagnostic specificity of SPT was 100%, and no severe adverse reactions were observed during skin testing. With respect to the latex-specific serum IgE determinations, sensitivity was 86% for the CAP system and 84% for the AlaSTAT assay, and specificity was dependent on the population considered. CONCLUSION: SPT with natural latex extracts has shown a diagnostic efficiency close to 100%, significantly higher than that of latex-specific serum IgE determination.
During the week of October 15-24, 1995 a team of 65 medical, anaesthesiology, surgical, nursing and paramedical personnel travelled to Guatemala City, Guatemala to perform cardiac surgery on children with complex congenital and acquired valvular heart disease. During this mission 42 patients had their lesions surgically repaired. Cardiopulmonary bypass was required in 36 cases. There were no anaesthetic or surgical deaths. All six patients who did not require cardiopulmonary bypass were extubated in the operating room. Of the patients who required cardiopulmonary bypass, 23 were extubated in the operating room (64%). There was no intraoperative anaesthetic morbidity nor postoperative respiratory complications. No patients was reintubated after planned extubation. Cardiac surgery in paediatric age patients can safely be performed in developing countries if close attention is paid to proper patient selection and one maintains the standards of care practised in developed countries.
OBJECTIVE: To assess the subjective cure rates in a group of women who had undergone delayed/secondary anal sphincteroplasty and in a subgroup of women to compare the integrity of the anal sphincteric complex as evaluated by physical examination and vaginal probe anal sonography with subjective cure rates of fecal incontinence. STUDY DESIGN: The charts of all patients who underwent delayed anal sphincteroplasty from 1991 to 1995 were reviewed for demographics and perioperative information. Available patients underwent interview, physical examination and vaginal probe anal sonography. Paired t-test, Wilcoxon rank sum and Fisher's exact test were used to evaluate the data. RESULTS: The mean age of the 16 patients prior to sphincteroplasty was 35 years (SD +/- 12) and mean parity 2 (SD +/- 1.8). In 94%, fecal incontinence was attributed to obstetric trauma and in one was secondary to rape. Anal sphincteroplasty was accomplished using the overlapping technique in seven (44%) and utilizing the end-to-end technique in the remainder; all patients also underwent posterior colpoperineorrhaphy. Information on postoperative symptomatology was available from 10 patients (63%). Subjectively 4 were cured (40%), 4 were improved (40%), and 2 were unimproved (20%). Of these 10 women, seven agreed to undergo postoperative physical examinations; 5 (71%) had intact external sphincters, and 2 (29%) did not. On vaginal probe anal sonography, the external and internal sphincters were intact in six (86%) and five (71%), respectively. There was no correlation between patients' symptoms and the integrity of the sphincter as noted on physical or sonographic evaluation (P > .05). Physical examination accurately identified sphincteric anatomy in six of seven (86%) when compared to sonographic examination. CONCLUSION: Subjective success (cured or improved) of anal sphincteroplasty in this series was 80%). We found no correlation between symptomatic relief and anal sphincter integrity as evaluated by physical and sonographic examination.
Chemical microsensors based on ion-selective field effect transistor (ISFET) transducers with ion-selective and enzymatic membranes have been fabricated. In this case, photolithographically patterned membranes based on acrylated urethanes have been developed and applied onto the gate area of ISFET chips. Aliphatic urethane diacrylate has been used for K+ and NH+4 membranes, while a photocurable hydrogel formulation based on other type of acrylated urethane has been optimized for urea-FET sensors. Resulting potassium and ammonium sensors show similar performances to those found when PVC membranes are employed. An integrated packaging process for ISFET-based sensors has been developed giving the possibility of carrying out most of the encapsulation on wafer level. For this purpose, a photocurable polyurethane encapsulant formulation has been optimized to be microstructured by photolithography. Finally, a preliminary study of biocompatibility of photosensitive formulations containing urethane oligomers has been performed in order to examine future applications in biomedical and clinical analysis.
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The risk of spontaneous abortion (SAB) in the semiconductor industry was examined in a historical cohort study of pregnancies at 14 companies. We identified female employees who had worked for at least 6 months and whose ages ranged from 18 to 44 years during the 1986-1989 study period. Using company records, we included all fabrication-room (fab) employees and an approximately equal number of nonfabrication (nonfab) employees, for a total sample of 7,269. Telephone interviews with 6,088 women (84%) identified 904 eligible pregnancies and 113 SABs. Exposure classification was based on questionnaire and industrial hygiene assessments of tasks the women performed during the first trimester of pregnancy. Using logistic regression to control for age, smoking, ethnicity, education, income, year of pregnancy, and stress, we found a higher risk of SAB in fab employees than in nonfab employees (15.0% of fab pregnancies ended in SAB vs. 10.4% of nonfab pregnancies, adjusted relative risk [RR] = 1.43, 95% CI = 0.95-2.09). Analysis of fab work groups showed that the highest relative risk was in masking employees (17.5% SAB rate, adjusted RR = 1.78, 95% CI = 1.17-2.62 in comparison with nonfab employees). Within masking, the highest risk was found in etching-related process employees (22.2% SAB rate, adjusted RR = 2.08, 95% CI = 1.27-3.19 in comparison to nonfab employees.
We evaluated the clinical characteristics found in 21 children who showed allergic reactions upon incidental inhalation of fish odors or fumes, from 197 diagnosed with IgE-mediated fish hypersensitivity. Allergic reactions to fish via ingestion began in most patients (86%) within the first 24 months of life. The vast majority (19/21) of patients showed cutaneous symptoms, either alone or, less frequently, associated with other clinical manifestations. Hake and flounder were the species of fish most frequently implicated in eliciting clinical manifestations upon ingestion. After diagnosis, all these patients were placed on a strict fish-avoidance diet. During this period of avoidance, patients reported allergic reactions (mean age 7 years) after incidental exposure to airborne fish odors or fumes. Clinical manifestations through inhalation were respiratory (mainly wheezing) in 12 patients and cutaneous (mainly urticaria) in nine patients. Nineteen of 21 patients reported three or more episodes upon exposure to fish aerosols; in most cases, these episodes occurred at home when other people were eating fish. In conclusion, incidental inhalation of fish odors or fumes could play an important role in accidental and unknown encounters with fish in children on fish-avoidance diets for fish IgE-mediated hypersensitivity. Such exposures could elicit clinical symptoms and could have some effect in delaying the development of tolerance.
A series of polyamines based on the high affinity sigma receptor ligand N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) were developed and evaluated for their binding characteristics at sigma-1 and sigma-2 receptor subtypes. The data indicated that a considerable degree of structural variation is possible while still retaining nanomolar affinity at sigma receptors. As the structure of the polyamines was varied, their binding at sigma-1 and sigma-2 subtypes showed quite different and in some cases opposite trends, supporting the belief that these are pharmacologically distinct entities. Polyamines containing two nitrogen atoms showed optimal binding at both sigma-1 and sigma-2 receptor subtypes. Although additional nitrogen atoms resulted in decreased affinity at sigma-1 and sigma-2 subtypes, an increase in selectivity for sigma-2 subtypes was evident; the parent 3 showed greater selectivity for sigma-1 subtypes. Internitrogen spacings had a large effect on binding affinity and subtype selectivity. For example, the difference between N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)-N,N'- dimethylethylenediamine (8) [K(i) = 29.9 nM at sigma-1 receptor and 18.3 nM at sigma-2 receptor] to N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)- N,N'-dimethylethylenediamine (10) [K(i) = 1.49 nM at sigma-1 receptor and 12.1 nM at sigma-2 receptor] illustrates the importance of internitrogen spacing. Triamines 11 and 13 [Ki(sigma-2)/K(i)(sigma-1) = 0.19 and 0.10, respectively] containing the N-N-N-Ar spacings 3-3-2 and 4-4-2, proved to be the most sigma-2 subtype selective of the 15 polyamines examined in this study. The N-N-N spacings appear to be an important factor in their sigma-2 subtype selectivity. These compounds will serve as templates in the design of still further sigma-2 subtype selective ligands. The pyrrolidine ring (present in most of the polyamines tested in this series) proved to be an important recognition site for sigma receptor binding activity. Furthermore, alkyl substitution also appears to be important since the stripped down polyamines N-[2-(3,4-dichlorophenyl)ethyl]ethylenediamine (15) and N1-[2-(3,4-dichlorophenyl)ethyl]diethylenetriamine (16) exhibited relatively low binding affinity.
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Histological changes in the contralateral testis in 8 prepubertal children whose ages ranged from 3 to 7.5 years with a history of testicular torsion and subsequent atrophy were studied. The following histological parameters were evaluated: fertility tubular index (FTI), Sertoli cell index (SCI) and minimum tubular diameter (MTD). According to our findings and following Nistal and Paniagua's classification (1984) for tubular alterations, we found 5 cases (62.5%) who present the following alterations. Type 1 (case 2): FTI was decreased above 50% corresponding to slight germinal hypoplasia with normal MTD and SCI. Type 2 (cases 3 and 5): testis with remarkable germinal hypoplasia; FTI was between 30 and 50% while MTD was below normal values. Type 3 (case 8): testis with diffuse tubular hypoplasia; FTI was below 30%, whereas MTD showed 33% decrease regarding normal values. Type 4 (case 6): testes with hyperplasia of Sertoli cells; SCI was increased one third with regard to that corresponding to his age; FTI showed severe hypoplasia of germ cells. No relationship between alterations in either the age of the patients or the time elapsed since the torsion was observed. Because of all these facts and the young age of our patients, we believe that the alterations found in the contralateral testis were due to congenital dysgenesia.
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As a continuation of our earlier study (J. Med. Chem. 1992, 35, 4334-4343) we conformationally restricted the sigma-receptor ligand 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylamine (1) by incorporating it into a series of homologous piperazines 3-9 and homopiperazines 10 and 11, diazabicyclononanes and decanes, bridgehead bicyclooctanes and nonanes as well as other miscellaneous compounds. sigma-Receptor binding affinities were obtained using [3H](+)-pentazocine in guinea pig brain membrane sigma 1 sites. The studies suggest that the nitrogen lone pair orientation found in the piperazines affords the strongest binding interaction. Other nitrogen lone pair orientations or compounds representing unlikely staggered conformations of 1 [ as in 4-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[3.2.2]nonane (16)] show very weak sigma interaction. Comparison of the binding data of different N-substituted homologues of 1 with those of the 1-[2-(3,4-dichlorophenyl)ethyl]-4-alkylpiperazines suggests that the two nitrogen atoms of 1 are working in opposition to one another in terms of their sensitivity to steric bulk. The high binding affinity of the 1,4-diazabicyclo[4.3.0]nonanes 12 suggests that these may approximate the methyl and pyrrolidine ring conformations found in 1 when it is bound to the sigma receptor. Compound 12 exhibited a 4-fold enantioselectivity favoring (+)-12. The synthesis of 6,7-dichloro-2-[[2-(1-pyrrolidinyl)ethyl]amino]tetralin (19) and its desmethyl derivative 20 permitted constraint of the 3,4-dichlorophenyl and N-methyl moieties of 1 into a gauche orientation. The binding data suggests that this conformation in 1 favors strong binding interaction at sigma-receptors. sigma-Receptor Ki's ranged from 0.55 nM for 1-[2-(3,4-dichlorophenyl)ethyl]-4-n-butylpiperazine (7) to 654 nM for 16. Overall comparison of the results indicate that 1 is subject to considerable conformational freedom and suggests that the sigma receptor is not subject to rigid stereochemical restraints with 1. These results add to our earlier study where we restrained 1 using simple monocyclic heterocycles.
A series of imidazo[1,5-a][1,4]benzodiazepine esters have been synthesized with varying ester side chains and 8-position substituents. The affinities of these compounds were evaluated at both "diazepam-insensitive" (DI) and diazepam-sensitive (DS) subtypes of the benzodiazepine receptor (BZR). A profound steric effect of the 3-position ester side chain moiety was observed on ligand affinity at DI. In contrast, ester size had a less robust effect on ligand affinity at DS. The tert-butyl ester compound 8 displayed the highest affinity (Ki = 1.7 nM) for DI within a series of 8-chloro esters. Furthermore, halogens at the 8-position resulted in an enhancement of both ligand affinity and selectivity at DI among the series of tert-butyl esters examined. The 8-nitro derivative 23 and 8-isothiocyanato congener 25 had high affinities for both DI and DS but exhibited little subtype selectivity (10.8 and 2.7 nM at DI versus 14 and 3.7 nM at DS, respectively). The 8-azido tert-butyl ester 29 exhibited a significantly higher affinity (Ki = 0.43 nM) and selectivity (DI/DS ratio of 0.2) than the corresponding ethyl ester, the prototypic DI ligand 1 (Ro 15-4513). Among the compounds synthesized, 29 is the highest affinity ligand for DI described to date while its 8-bromo analog 18 is the most selective ligand (DI/DS ratio of 0.17) for this novel BZR subtype.
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We reviewed the microorganisms isolated from gynecologic surgery wounds showing signs of infection, from January to December 1990. A total of 88 samples of abdominal wall exudates from as many patients who had undergone abdominal hysterectomy were studied. In 54 women (61.3%), cultures were positive and, in 26 specimens (48.1%), mixed aerobic-anaerobic flora were isolated. In 28 cases (51.9%), a single microorganism was isolated, the most frequent being Staphylococcus aureus, followed by Mycoplasma hominis and Escherichia coli. Mycoplasma hominis was unexpectedly frequent, appearing in five women with wall abscess and fever.
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OBJECTIVE: We investigated the prevalence of renal calcifications in children with autosomal recessive polycystic kidney disease and studied the metabolic changes that could cause this complication. SUBJECTS AND METHODS: Nine patients with known autosomal recessive polycystic kidney disease were examined with sonography and CT and screened for biochemical evidence of metabolic causes of nephrocalcinosis. RESULTS: CT showed bilateral renal calcifications in seven of the nine patients. The two patients without renal calcifications were less than 1 year old. Four patients had only a few calcifications and three patients had many. The severity of the renal calcifications correlated with the degree of kidney failure. All patients with kidney failure were found to have urine acidification defects. Hypocitraturia was present in all patients. CONCLUSION: Our results show that renal calcifications are common in older children with autosomal recessive polycystic kidney disease. Hypocitraturia and the urine acidification defect resulting from kidney failure are the leading factors in the pathogenesis of the calcifications.