Avaliação do processo de reestruturação da assistência farmacêutica no município de Aracaju-SE / Assessment of the restructuring of pharmaceutical services in the city of Aracaju (SE, Brazil)

O objetivo do estudo é avaliar o efeito da reestruturação da Assistência Farmacêutica (AssistFar) no município de Aracaju-SE. Foi realizado um estudo retrospectivo longitudinal, de fevereiro a junho de 2011. Para avaliação da Assistência Farmacêutica foi utilizado um banco de dados documental, gerado pelo "Sistema de Controle de Administração de Materiais" e aplicaram-se os indicadores do Instrumento de Auto-Avaliação para o Planejamento da Assistência Farmacêutica (IAPAF) do ?Planejar é Preciso?, que aborda tópicos de acordo com o ?Ciclo da Assistência Farmacêutica?. A aplicação do instrumento foi realizada em três momentos na prática da AssistFar no município de Aracaju. Para análise de cada indicador levou-se em consideração os níveis de qualidade classificados de 1 a 3, sendo o nível 3 o melhor estágio. A maioria dos resultados evidenciou o fortalecimento da gestão após a criação de procedimentos e a inclusão de estratégias de monitoramento dos indicadores de avaliação no plano municipal de saúde. As etapas de institucionalização dos serviços perante a gestão foram as que apresentaram os melhores resultados. Enquanto que a etapa de prescrição foi considerada a mais crítica do processo. Os dados mostram que a falta de ações de desenvolvimento da AssistFar contribuíram para a presença de resultados insatisfatórios, principalmente nas etapas de prescrição e dispensação, sinalizando a necessidade de elaborar uma estratégia de gestão que vise sua reformulação. Neste cenário, é preciso incorporar às equipes de saúde mais farmacêuticos que atuem em todas as etapas da AssistFar, promovendo uma gestão racional de medicamentos...

The objective of the study was to evaluate the effect of the restructuring of Pharmaceutical Services (AssistFar) in the city of Aracaju (capital of Sergipe, Brazil). We conducted a retrospective, longitudinal survey, from February to June 2011. A document database generated by the "Materials Management Control System" was analyzed, to assess the pharmaceutical services, by applying the indicators of the Self-Assessment Instrument for Pharmaceutical Services Planning (IAPAF) that are defined in the government-proposed" Planning is Necessary" method, which covers topics referring to the various steps in the "Cycle of Pharmaceutical Services". This instrument was applied to three stages in the practice of AssistFar in the city of Aracaju, within the study period. For each indicator, the quality of each step was graded from 1 to 3, level 3 being the best. Most results showed a strengthening of management after the establishment of procedures and inclusion of strategies for monitoring the quality indicators, for the municipal health plan. Steps towards the institutionalization of management services showedthe best results. In contrast, the step of prescription was considered the most critical of the Cycle. The data showed that the lack of AssistFar development actions contributed to the unsatisfactory results, especially in the steps of prescribing and dispensing, signaling the need to develop a management strategy that aims to recast it. In this scenario, it will be necessary to involve the health teams, plus the pharmacists, in the work at all stages of AssistFar, promoting the rational management of medicines...

Changes in protein profile detected in seedlings of Caesalpinia peltophoroides (Fabaceae) after exposure to high concentration of cadmium.

Sibipiruna (Caesalpinia peltophoroides Benth) is a tree of the Brazilian Atlantic Forest. It is a flowering ornamental tree widely planted throughout Brazil and indicated for restoration of degraded areas. We examined protein profile changes in leaves of seedlings of C. peltophoroides grown in nutrient solution under greenhouse conditions, after exposure to cadmium (Cd; 32 mg/L). A two-dimensional gel was used to analyze proteins expressed in response to stress 24 and 72 h after initiation of treatment with Cd. Various protein bands were identified that were related to stress response and/or metabolic adjustments, including proteins involved with resistance to stress, including detoxification, degradation, antioxidant, transport, signal transduction, photosynthesis, electron transport, biosynthesis reactions, and transcription regulation. After 24 h of Cd exposure, the genes of most of these proteins were upregulated. These putative proteins were associated with resistance to stress, including heat shock proteins, heat stress transcriptional factor and other transcriptional factors, aquaporins, glutathione transferase and choline monooxygenase. Most of the putative proteins observed after 72 h of exposure to Cd were downregulated. They were mainly photosynthetic process proteins, such as NAD(P)H-quinone oxidoreductase, photosystem I assembly, and photosystem II CP47 chlorophyll apoprotein. There were also proteins involved with degradation, biosynthesis and antioxidant activity, such as ATP-dependent Clp protease, methylthioribose-1-phosphate and glutathione peroxidase 2. Based on preliminary proteomic analysis, we conclude that proteins related to photosynthetic activity are inhibited, decreasing plant performance under stress conditions and that several proteins related to defense mechanisms are activated, inducing the plant defense response.

Growth hormone and heart failure: oxidative stress and energetic metabolism in rats.

Several evidences point for beneficial effects of growth hormone (GH) in heart failure (HF). Taking into account that HF is related with changes in myocardial oxidative stress and in energy generation from metabolic pathways, it is important to clarify whether GH increase or decrease myocardial oxidative stress and what is its effect on energetic metabolism in HF condition. Thus, this study investigated the effects of two different doses of GH on energetic metabolism and oxidative stress in myocardium of rats with HF. Male Wistar rats (n=25) were submitted to aortic stenosis (AS). The HF was evidenced by tachypnea and echocardiographic criteria around 28 weeks of AS. The rats were then randomly divided into three groups: (HF) with HF, treated with saline (0.9% NaCl); (HF-GH1), treated with 1 mk/kg/day recombinant human growth hormone (rhGH), and (HF-GH2) treated with 2 mg/kg/day rhGH. GH was injected, subcutaneously, daily for 2 weeks. A control group (sham; n=12), with the same age of the others rats was evaluated to confirm data for AS. HF had lower IGF-I (insulin-like growth factor-I) than sham-operated rats, and both GH treatments normalized IGF-I level. HF-GH1 animals had lower lipid hydroperoxide (LH), LH/total antioxidant substances (TAS) and glutathione-reductase than HF. Glutathione peroxidase (GSH-Px), hydroxyacyl coenzyme-A dehydrogenase, lactate dehydrogenase(LDH) were higher in HF-GH1 than in HF. HF-GH2 compared with HF, had increased LH/TAS ratio, as well as decreased oxidized glutathione and LDH activity. Comparing the two GH doses, GSH-Px, superoxide dismutase and LDH were lower in HF-GH2 than in HF-GH1. In conclusion, GH effects were dose-dependent and both tested doses did not aggravate the heart dysfunction. The higher GH dose, 2 mg/kg exerted detrimental effects related to energy metabolism and oxidative stress. The lower dose, 1mg/kg GH exerted beneficial effects enhancing antioxidant defences, reducing oxidative stress and improving energy generation in myocardium of rats with heart failure.

Down-regulation of the cardiac sarcoplasmic reticulum ryanodine channel in severely food-restricted rats.

We have shown that myocardial dysfunction induced by food restriction is related to calcium handling. Although cardiac function is depressed in food-restricted animals, there is limited information about the molecular mechanisms that lead to this abnormality. The present study evaluated the effects of food restriction on calcium cycling, focusing on sarcoplasmic Ca2+-ATPase (SERCA2), phospholamban (PLB), and ryanodine channel (RYR2) mRNA expressions in rat myocardium. Male Wistar-Kyoto rats, 60 days old, were submitted to ad libitum feeding (control rats) or 50% diet restriction for 90 days. The levels of left ventricle SERCA2, PLB, and RYR2 were measured using semi-quantitative RT-PCR. Body and ventricular weights were reduced in 50% food-restricted animals. RYR2 mRNA was significantly decreased in the left ventricle of the food-restricted group (control = 5.92 +/- 0.48 vs food-restricted group = 4.84 +/- 0.33, P < 0.01). The levels of SERCA2 and PLB mRNA were similar between groups (control = 8.38 +/- 0.44 vs food-restricted group = 7.96 +/- 0.45, and control = 1.52 +/- 0.06 vs food-restricted group = 1.53 +/- 0.10, respectively). Down-regulation of RYR2 mRNA expressions suggests that chronic food restriction promotes abnormalities in sarcoplasmic reticulum Ca2+ release.

Down-regulation of the cardiac sarcoplasmic reticulum ryanodine channel in severely food-restricted rats

We have shown that myocardial dysfunction induced by food restriction is related to calcium handling. Although cardiac function is depressed in food-restricted animals, there is limited information about the molecular mechanisms that lead to this abnormality. The present study evaluated the effects of food restriction on calcium cycling, focusing on sarcoplasmic Ca2+-ATPase (SERCA2), phospholamban (PLB), and ryanodine channel (RYR2) mRNA expressions in rat myocardium. Male Wistar-Kyoto rats, 60 days old, were submitted to ad libitum feeding (control rats) or 50 percent diet restriction for 90 days. The levels of left ventricle SERCA2, PLB, and RYR2 were measured using semi-quantitative RT-PCR. Body and ventricular weights were reduced in 50 percent food-restricted animals. RYR2 mRNA was significantly decreased in the left ventricle of the food-restricted group (control = 5.92 ± 0.48 vs food-restricted group = 4.84 ± 0.33, P < 0.01). The levels of SERCA2 and PLB mRNA were similar between groups (control = 8.38 ± 0.44 vs food-restricted group = 7.96 ± 0.45, and control = 1.52 ± 0.06 vs food-restricted group = 1.53 ± 0.10, respectively). Down-regulation of RYR2 mRNA expressions suggests that chronic food restriction promotes abnormalities in sarcoplasmic reticulum Ca2+ release.

Additional markers to refine the World Health Organization algorithm for diagnosis of pneumonia.

INTRODUCTION: WHO guidelines for primary care of children with tachypnea indicate that all should receive antibiotics for presumed pneumonia. These guidelines have led to excessive antibiotic use. OBJECTIVE: To examine the value of history of previous respiratory distress, chest indrawing and fever, and response to bronchodilator(BD) to refine these guidelines. DESIGN: Prospective study. SETTING: Urban tertiary care hospital. SUBJECTS: Children, between the ages of 6 and 59 months, presenting with cough and tachypnea. METHODS: 182 children were enrolled. Each child had a chest X-ray that was read by two blinded, independent radiologists. Discordance between the two radiologists led to excluding 17 patients. The remaining 165 children were examined for fever and/or chest indrawing, and if they had a history of previous respiratory distress, challenge with a BD. The association of persistent tachypnea after BD and presence of pulmonary infiltrates was recorded. RESULTS: The median age was 22 months (mean 25.1 +- 14.5 mo) and 75.8% were aged greater than 1 year. There were 58.8% males. Previous respiratory distress occurred in 65.0% and 79.2% of children aged less than 1 year and 1 year, respectively. Pneumonia was radiologically diagnosed in 26/165 (15.8%). 2/40 (5 %) of children without a history of previous respiratory distress had pneumonia diagnosed. Of 125 children with history of previous respiratory distress, pneumonia was identified in 24 (19.2 %). Persistence of tachypnea after BD was associated with pulmonary infiltrate in 14/24 (58.3%), whereas, tachypnea persisted in 32/101 (31.7%) children without pulmonary infiltrates (P = 0.02). The negative predictive value of resolution of tachypnea was 87.3% (95% CI 77.5 93.4). BD non-response was most useful in children without fever and/or with chest indrawing to indicate pneumonia as the cause of the tachypnea. CONCLUSION: This study indicates that by adding the simple procedures of a history of previous respiratory distress, recording of fever and chest indrawing, and observing the response to bronchodilators, pneumonia can be reliably identified in children presenting with tachypnea and cough. It is probable that this approach to management of children with cough and tachypnea could reduce unnecessary use of antibiotics.

Low triiodothyronine (T3) or reverse triiodothyronine (rT3) syndrome modifies gene expression in rats with congestive heart failure.

Heart failure (HF) is frequently associated with euthyroid "sick" syndrome (low T3 and elevated rT3). We investigated if altered thyroid hormone in HF could affect expression of the TH receptor (TRalpha1), and alpha and beta myosin heavy chains (alpha-MHC, beta-MHC). HF was provoked in rats by aortic stenosis. We showed that rT3 generated from liver and kidney deiodination significantly increased and T3 decreased in HF; there was significantly higher TRalpha1 expression, no alpha-MHC expression, but beta-MHC expression. Changes in TRalpha could be compensating for low T3 from HF.

Clinical and laboratory evaluation of hyperlipemic and hypothyroid patients.

OBJECTIVE: To determine the frequency of hypothyroidism in a sample of hyperlipemic patients and evaluate clinical and laboratory factors indicative of thyropathy among them. METHODS: Fifty-one hyperlipemic patients, grouped according to an earlier or recent diagnosis of their thyroid function into euthyroid and hypothyroid, were evaluated with clinical and laboratory examinations of blood levels of free T4 and TSH (by radioimmunoassay). Patients were on average 46.8 +/- 11.7 years old, predominantly of the female sex (62.5 %); 31 % had a previous diagnosis of hypothyroidism and were under treatment with thyroxin. RESULTS: Fourteen three percent of patients analyzed had hypothyroidism, which had not been detected before. Differentiating attributes of the groups analyzed were: a predominance of females among the hypothyroid patients and a higher HDL serum concentration among those recently diagnosed. CONCLUSION: In the present study, new cases of hypothyroidism in hyperlipemic patients were a frequent occurrence, yet few clinical and laboratory data except tests evaluating free T4 and TSH in the blood indicated which patients had thyroid dysfunction.

In situ expression of collagen and proteoglycan genes during development of fibrocartilage in bovine deep flexor tendon.

A region of fibrocartilage develops in bovine deep flexor tendon where the tissue wraps around bone and is subjected to compressive and shear forces in addition to tension. There is no fibrocartilage at this location in fetal tendon or in adjacent adult tendon that is subjected to tensional load only. We investigated the development of fibrocartilage in tendon using in situ hybridization to localize cells that express collagen and proteoglycan genes typical of either tendon or cartilage. The signal for type I collagen and decorin was high in cells throughout fetal and newborn tendon, as is expected in a growing tissue composed predominantly of type I collagen. No signal for aggrecan was seen in either fetal or newborn tendon. No hybridization with any of the probes for collagen or proteoglycan was detected in cells in the tensional region of adult tendon, indicating that the cells in this tissue are normally quiescent. However, the cells in the fibrocartilage of adult tendon displayed a high level of expression for types I and II collagen, decorin, biglycan, and aggrecan. This suggests that the fibrocartilage in adult tendon is a dynamic tissue. Expression of type IIA collagen is considered a marker of prechondrocytes. Type IIA collagen gene expression was present throughout both the tensional and compressed regions of fetal and newborn tendon but was absent in cartilage and adult tendon. This suggests that cells located throughout fetal tendon may have the capacity to develop as chondrocytes. Fibrocartilage signal was detected for type I collagen in 75% of the cells and for type II collagen in 50% of the cells at one location in adult tendon, suggesting that some cells in this tissue could have expressed mRNA for both type I and type II collagen.

Effect of zinc administration on thyrotropin releasing hormone-stimulated prolactinemia in healthy men.

Previous in vitro studies have demonstrated zinc (Zn++) inhibition of basal and of potassium (K+) or thyrotropin-releasing hormone (TRH)-stimulated prolactin (PRL) secretion, in a selective, reversible, and dose-dependent manner. Thus, Zn++ may regulate physiologically pituitary PRL secretion. Furthermore, studies with patients with uremia, cirrhosis or prolactinoma, have shown the coexistence of hypozincemia and hyperprolactinemia and zinc supplementation did not correct hyperprolactinemia in these patients. In normal individuals Zn++ administration produced controversial results on PRL secretion. Here, we investigated whether zinc administration affects TRH-stimulated PRL in healthy men. We found that Zn++ administration does not change the TRH-stimulated PRL. Therefore, in normal conditions, Zn++ does not inhibit TRH-stimulated prolactinemia. In addition, we found that acute increases of blood PRL and TRH do not alter blood Zn++ levels.

Centromeric protein B null mice are viable with no apparent abnormalities.

The centromere protein B (CENP-B) is a centromeric DNA/binding protein. It recognizes a 17-bp sequence motif called the CENP-B box, which is found in the centromeric region of most chromosomes. It binds DNA through its amino terminus and dimerizes through its carboxy terminus. CENP-B protein has been proposed to perform a vital role in organizing chromatin structures at centromeres. However, other evidence does not agree with this view. For example, CENP-B is found at inactive centromeres on stable dicentric chromosomes, and also mitotically stable chromosomes lacking alpha-satellite DNA have been reported. To address the biological function of CENP-B, we generated mouse null mutants of CENP-B by homologous recombination. Mice lacking CENP-B were viable and fertile, indicating that mice without CENP-B undergo normal somatic and germline development. Thus, both mitosis and meiosis are able to proceed normally in the absence of CENP-B.

Extracapsular cataract extraction and intraocular lens implantation in leprosy patients: visual outcome and complications.

In Belo Horizonte, Brazil, 70 eyes of 53 leprosy patients had extracapsular cataract extraction and intraocular lens implantation done during a period of four years. The authors analyzed the outcome regarding restoration of vision and complications after this procedure. The visual acuity improved in 92.9% of the eyes and in 65.7% the acuity had improved by four lines or more on the Snellen chart. The post-operative complications could not be associated only to leprosy infiltration; in any case, they were not too serious and could be controlled.

Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs.

Wolf-Hirschhorn syndrome (WHS) is a multiple anomaly condition characterized by mental and developmental defects, resulting from the absence of the distal segment of one chromosome 4 short arm (4p16.3). Owing to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. The 2.2 Mbp genomic segment previously defined as the critical region by the analyses of patients with terminal or interstitial deletions is extremely gene dense and an intensive investigation of the developmental role of all the genes contained within it would be daunting and expensive. Further refinement in the definition of the critical region would be valuable but depends on available patient material and accurate clinical evaluation. In this study, we have utilized fluorescence in situ hybridization to further characterize a WHS patient previously demonstrated to have an interstitial deletion and demonstrate that the distal breakpoint occurs between the loci FGFR3 and D4S168. This reduces the critical region for this syndrome to less than 750 kbp. This has the effect of eliminating several genes previously proposed as contributing to this syndrome and allows further research to focus on a more restricted region of the genome and a limited set of genes for their role in the WHS syndrome.

Genomic organization of the human fibroblast growth factor receptor 3 (FGFR3) gene and comparative sequence analysis with the mouse Fgfr3 gene.

Fibroblast growth factor receptor 3 (FGFR3) is a developmentally regulated transmembrane protein. Three other FGFRs (1, 2, and 4) in conjunction with FGFR3 are part of the receptor tyrosine kinase super-family. Mutations in three of these genes (FGFR1, 2, and 3) have been determined to be the cause of human growth and developmental disorders. We have characterized a 22-kb DNA fragment containing the human FGFR3 gene and determined 11 kb of its nucleotide sequence. The gene consists of 19 exons and 18 introns spanning 16.5 kb, and the boundaries between exons and introns follow the GT/AG rule. The translation initiation and termination sites are located in exon 2 and exon 19 respectively. The sequence of the 5'-flanking region (1.5 kb) lacks the typical TATA or CAAT boxes. However, several putative binding sites for transcription factors SP1, AP2, Krox 24, IgHC.4, and Zeste are present. The 0.77-kb region from position -889 (5'-flanking region) to -119 (intron 1) contains a CpG island. A comparative sequence analysis of the human and mouse FGFR3 genes indicates that the overall genomic structure and organization of the human gene are nearly identical to those of its mouse counterpart. Furthermore, there is a striking similarity in the promoter regions of both genes, and several of the putative transcription factor-binding sites are conserved across species, suggesting a definitive role of these factors in the transcriptional regulation of these genes.

Heritable genetic alterations in a xeroderma pigmentosum group G/Cockayne syndrome pedigree.

A search for genetic alterations within the XPG gene has been conducted on skin and blood cells cultured from a newly characterized xeroderma pigmentosum (XP) patient (XP20BE). This patient is the ninth known case that falls into the extremely rare XP complementation group G. Four genetic markers within the XPG gene (including two polymorphisms) demonstrated the Mendelian distribution of this gene from the parents to the patient and to an unaffected sibling. The patient (XP20BE) inherited a G to T transversion from his father in exon 1 of the XPG gene that resulted in the conversion of a glutamic acid at codon 11 to a termination codon. The patient also inherited an XP-G allele from his mother that produces an unstable or poorly expressed message. The cause of the latter defect is still uncertain. In addition to these alterations, XP20BE cDNA contained an mRNA species with a large splicing defect that encompassed a deletion from exon 1 to exon 14. This splicing defect, however, appears to be a naturally occurring low-frequency event that results from abnormal splicing that occurs between certain conserved non-consensus splicing signals within the human XPG gene.

Molecular cloning and structural analysis of the functional mouse genomic XPG gene.

The mouse XPG gene is a homolog of the human DNA excision repair gene known to be defective in the hereditary sun-sensitive disorder xeroderma pigmentosum (group-G). Defects in mouse XPG have been shown to directly affect the sensitivity of cultured cells to chemotherapy agents and may play a role in tumor cell drug resistance in vivo. A full-length cosmid clone of mouse XPG was isolated by complementation of the UV sensitivity and repair defect in CHO-UV135 cells. Exon mapping determined that the gene consisted of 15 exons within 32 kb of genomic DNA. Sequencing of intron-exon boundaries revealed that mouse XPG possesses a rare class of intron previously identified in only four other eukaryotic genes; it utilizes AT and AC dinucleotides instead of the expected GT and AG within the splice junctions. Promoter analysis determined that mouse XPG is expressed constitutively and probably initiates transcription from multiple start sites, yet, unlike the yeast homolog RAD2, we found no evidence that it is UVC inducible in cultured cells. Amino acid comparison with human XPG identified a highly conserved acidic region of homology not previously described.

Genomic organization of the mouse fibroblast growth factor receptor 3 (Fgfr3) gene.

The fibroblast growth factor receptor 3 (Fgfr3) protein is a tyrosine kinase receptor involved in the signal transduction of various fibroblast growth factors. Recent studies suggest its important role in normal development. In humans, mutation in Fgfr3 is responsible for growth disorders such as achondroplasia, hypoachondroplasia, and thanatophoric dysplasia. Here, we report the complete genomic organization of the mouse Fgfr3 gene. The murine gene spans approximately 15 kb and consists of 19 exons and 18 introns. One major and one minor transcription initiation site were identified. Position +1 is located 614 nucleotides upstream from the ATG initiation codon. The translation initiation and termination sites are located in exons 2 and 19, respectively. Five Sp1 sites, two AP2 sites, one Zeste site, and one Krox 24 site were observed in the 5'-flanking region. The Fgfr3 promoter appears to be contained within a CpG island and, as is common in genes having multiple Sp1-binding sites, lacks a TATA box.

Endocrine interaction between zinc and prolactin. An interpretative review.

Zinc plays a very important role in animal and human metabolism. Nowadays, it is one of the most extensively studied trace element, since its sphere of action has been demonstrated to be very broad. From the biochemical standpoint, it controls more than 300 different enzymes, many of them involved with intermediary metabolism, DNA and RNA synthesis, gene expression, and immunocompetence. It also plays a significant role in hormonal homeostasis, since it can interact with almost all hormones. Zn2+ is closely related to the thyroid and steroid hormones, insulin, parathormone, and pituitary hormones, particularly prolactin (PRL). Zn2+ can inhibit PRL secretion within a range of physiologically and pharmacologically relevant concentrations. This property has raised the possibility of clinical applications of zinc. In this article, we review the literature on the subject in an attempt to provide a comprehensible general view.

Defective lens fiber differentiation and pancreatic tumorigenesis caused by ectopic expression of the cellular retinoic acid-binding protein I.

All-trans retinoic acid, a metabolite of retinol, is a possible morphogen in vertebrate development. Two classes of cellular proteins, which specifically bind all-trans retinoic acid, are thought to mediate its action: the nuclear retinoic acid receptors (RAR alpha, beta, gamma), and the cytoplasmic binding proteins known as cellular retinoic acid-binding proteins I and II (CRABP I and II). The function of the retinoic acid receptors is to regulate gene transcription by binding to DNA in conjunction with the nuclear retinoid X receptors (RXR alpha, beta, gamma), which in turn have 9-cis retinoic acid as a ligand. Several lines of evidence suggest that the role of the cellular retinoic acid-binding proteins is to control the concentration of free retinoic acid reaching the nucleus in a given cell. Here, we have addressed the role of the cellular retinoic acid-binding protein I in development by ectopically expressing it in the mouse lens, under the control of the alpha A-crystallin promoter. We show that this ectopic expression interferes with the development of the lens and with the differentiation of the secondary lens fiber cells, causing cataract formation. These results suggest that correct regulation of intracellular retinoic acid concentration is required for normal eye development. In addition, the generated transgenic mice also present expression of the transgene in the pancreas and develop pancreatic carcinomas, suggesting that overexpression of the cellular retinoic acid-binding protein is the cause of the tumors. These results taken together provide evidence for a role of the cellular retinoic acid-binding protein in development and cell differentiation. The relevance of these findings to the possible role of the cellular retinoic acid-binding proteins in the transduction of the retinoic acid signal is discussed.

Spatial and temporal pattern of expression of the cellular retinoic acid-binding protein and the cellular retinol-binding protein during mouse embryogenesis.

Retinol (vitamin A) and retinoic acid are potent teratogens and also represent good candidates for normal morphogens during development. Their actions may be mediated by the cellular retinoic acid-binding protein (CRABP) and the cellular retinol-binding protein (CRBP). As a step towards understanding the possible function for CRABP and CRBP in morphogenesis, we have used in situ hybridization to analyze their expression during mouse development. Both CRABP and CRBP transcripts were detected at embryonic days 9.5-14.5. (i) In the nervous system, CRABP transcripts were found in the mantle layer of the dorsal spinal cord and hindbrain and in the marginal layer of the midbrain, whereas CRBP transcripts were found in the ependymal and mantle layer of the ventral spinal cord and of the forebrain as well as in the spinal nerves and the roof plate of the spinal cord. (ii) In the eye, CRABP is expressed in the retinal layer, and CRBP is expressed in both retinal and pigmented layers. (iii) In the craniofacial region, CRABP transcripts were found in the mesenchyme of the frontonasal mass and mandible, while CRBP transcripts were found in the mesenchyme of the nasolachrymal duct and surrounding the auditory vesicle. Two general conclusions can be made. First, all of the tissues that are known to be teratogenic targets of retinoic acid and retinol also express CRABP and CRBP transcripts. Second, the specific expression of CRABP and CRBP in numerous developing tissues indicates that these proteins may perform specific functions during morphogenesis of a broad variety of embryonic structures.