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Development of cerebral arterial innervation: synchronous development of neuropeptide Y (NPY)- and vasoactive intestinal polypeptide (VIP)-containing fibers and some observations on growth cones.

The pre- and postnatal development of sympathetic fibers containing neuropeptide Y (NPY) and parasympathetic fibers containing vasoactive intestinal polypeptide (VIP) supplying the cerebral arteries were studied with immunohistochemistry in rats. The innervation patterns and densities of NPY and VIP fibers were similar at all stages of development and similar to that previously reported for norepinephrine (NE). There was a striking reorganization of the innervation pattern of all three fiber systems between the first and second postnatal weeks. At all stages of development prior to the first postnatal week, growth cones were present on individual fibers at the distal part of major cerebral arteries and the middle segment of the basilar artery. The growth cones had a range of shapes from blunt to stellate, lanceolate or filiform. NPY and VIP immunoreactive granules were commonly present. The present results taken with our earlier developmental study of NE fibers (J. Comp. Neurol., 271 (1988) 435-444), demonstrate that: (1) both sympathetic and parasympathetic perivascular nerves on immature cerebral vessels develop with similar sequences: first longitudinal fibers and fiber bundles are present; these transform to a meshwork pattern and finally transform again into the mature, predominantly circumferential pattern; (2) both the classical (NE) and peptidergic transmitters (NPY) within the sympathetic system appear to develop identically in terms of time of appearance, innervation patterns, densities and reorganization.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Fibers↗

Current approaches to the development of vaccines against disease caused by respiratory syncytial virus (RSV) and parainfluenza virus (PIV). A meeting report of the WHO Programme for Vaccine Development.

The paramyxoviruses respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are the two most common agents of severe lower respiratory tract disease in infants and children throughout the world. RSV causes yearly epidemics of bronchiolitis and pneumonia in infants and young children, while PIV3 is a common cause of bronchiolitis, pneumonia and croup. Together these two agents account for up to 30% of all hospitalizations of infants and young children for respiratory tract disease. A licensed vaccine is not currently available for either of these viruses. Development of vaccines against diseases caused by RSV and PIV3 is one of the priorities of the Global Programme for Vaccines (GPV). On 27 March 1994, GPV sponsored a workshop in Nyon, Switzerland, to review the status of vaccine development for these pathogens and to explore new methods of immunization that might be applied to the prevention of diseases caused by RSV and PIV. Furthermore, the World Health Organization (WHO) wished to assess progress in the development of methodologies to rescue infectious virus from cDNA clones of RSV and PIV3. This technology, when developed, will be extremely valuable in developing new vaccine candidates and in unravelling the genetic basis of attenuation of existing vaccines. This paper summarizes the findings presented at this one-day meeting.

Animals↗

The development of drug resistance by tumor cells in vitro is accompanied by the development of sensitivity to selenite.

The effects of selenite on cell viability and proliferation in a line of drug-sensitive human ovarian tumor (A2780) cells were compared with its effects on a melphalan-resistant derivative of these cells (A2780-ME) which had been developed in vitro (Hamilton et al. (1985) Biochemical Pharmacol., 34, 2583-2586). With the A2780-ME cells there was a 50% decrease in the number of viable cells (i.e. which exclude Trypan Blue dye) after exposure to less than 100 microM selenite for 6 h. In contrast, exposure to more than 300 microM selenite was required to achieve the same effect in the parent line. Similarly, exposure to 10 microM selenite resulted in a 50% decrease in A2780-ME cell proliferation, whereas this treatment had only a small inhibitory effect on proliferation of the parent cells. Thus, the development of melphalan resistance in vitro was accompanied by the development of selenite sensitivity. Pre-exposure of the two cell types to buthionine sulfoximine eliminated the difference in their intracellular glutathione levels, as well as most of their differential sensitivity to selenite. Furthermore, the two cell types did not exhibit a difference in sensitivity to selenodiglutathione, the product of the reaction of selenite with glutathione. Thus, the increase in intracellular glutathione, which has been shown to be responsible for the development of drug resistance in these cells is also responsible for the development of selenite sensitivity.

Cell Division↗

Development of otoacoustic emissions in gerbil: evidence for micromechanical changes underlying development of the place code.

The development of the acoustic distortion product (ADP) 2f1-f2 was studied in gerbils, beginning 12 days after birth (P12). ADPs were measured as a function of stimulus frequency region (1.0 to 13.0 kHz) and level (10 to 80 dB SPL). There was an orderly progression in the appearance and maturation of the emissions, with responses to high-frequency stimuli (f2 = 13.0 kHz) appearing first, at P13-14. Responses to mid and high frequencies (f2 = 3.9 to 13.0 kHz) matured earlier than responses to lower frequencies. Responses to low-frequency stimuli (f2 = 1.3 KHz) did not appear until P18-19 and were not mature until after one month of age. The first emissions to develop in a given frequency region had elevated thresholds, were reduced in amplitude, and displayed monotonic input-output functions. As the auditory system matured, emission growth functions became non-monotonic displaying saturation, but initially retained a reduced dynamic range. Data from the developing gerbil suggest that initially its cochlear mechanics are passive and that active elements associated with normal outer hair cell function mature first in the basal turn and last near the apex. Furthermore, the development of active nonlinear elements underlying ADP generation is consistent with the development of frequency selectivity and developmental shifts in the place code which have been demonstrated in the gerbil.

Acoustic Stimulation↗

Clinical characteristics and long-term outcome of patients in whom congestive heart failure develops after thrombolytic therapy for acute myocardial infarction: development of a predictive model.

Ischemic heart disease is the most common cause of congestive heart failure, which often begins after acute myocardial infarction. To better delineate the clinical characteristics and outcomes of patients in whom congestive heart failure develops after acute myocardial infarction in the thrombolytic era, we prospectively evaluated patients enrolled in six of the TAMI trials. The study cohort comprised 1619 consecutive patients who had at least 1 mm of ST-segment elevation in two contiguous electrocardiographic leads within 6 hours of the onset of acute myocardial infarction and who received intravenous thrombolytic therapy. We prospectively collected clinical characteristics, baseline demographics, acute and 1-week angiographic variables, and in-hospital and 1-year outcome data. We performed stepwise multivariable regression analysis to determine the noninvasive and invasive predictors of the development of in-hospital congestive heart failure. Congestive heart failure developed in 301 patients in the hospital (19% of 1521 patients admitted were not in heart failure). These patients were likely to be older and female, have diabetes mellitus and previous myocardial infarction, and have an anterior wall myocardial infarction. On acute angiography, they had lower ejection fractions and a higher incidence of multivessel disease. Patency at 90 minutes was lower in the patients with congestive heart failure, and acute mitral regurgitation occurred in 1.6% versus 0.21% of patients without congestive heart failure. Patients with congestive heart failure had higher mortality, more in-hospital complications, and longer hospitalizations. At 1-year follow up, 21% of the patients in whom congestive heart failure developed had died versus 5% in the group without congestive heart failure. Predictors of new congestive heart failure included increased age, anterior wall myocardial infarction, lower pulse pressure and systolic blood pressure, diabetes mellitus, and the presence of rales on admission. The acute angiographic variables of reduced ejection fraction, increased number of diseased vessels, and attempted percutaneous intervention improved the concordance of the predictive model by 6%. Congestive heart failure remains a common clinical problem after acute myocardial infarction and is associated with a twofold increase in in-hospital morbidity and a fourfold increase in in-hospital and 1-year mortality. The development of congestive heart failure in the hospital can be predicted from noninvasive and invasive baseline characteristics. We present a simple table to predict congestive heart failure from baseline characteristics and invasive information.

Age Factors↗

Age-specific effects of noradrenergic alpha-2 agonist clonidine on the development of amygdaloid kindling in developing rats.

The effects of clonidine on the development of amygdaloid kindling were studied in rats of various ages (14, 21, 28 and 70 postnatal days). Administration of clonidine (0.2, 0.5 mg/kg i.p.) caused a significant retardation of kindling development in the 28-day-old rats as well as in the adult rats, whereas, in the 14-day-old rats, the development of kindling was significantly facilitated by clonidine. No significant effect of clonidine was observed in the 21-day-old rats. These results indicate that in rats the effects of clonidine on the development of amygdaloid kindling vary during development.

Adrenergic alpha-Agonists↗

Development of the retina is altered in the directly developing frog Eleutherodactylus coqui (Leptodactylidae).

The loss of a free-living larval stage during the evolution of directly developing frogs of the genus Eleutherodactylus resulted in dramatic alterations in ontogeny. Immunostaining for proliferating cell nuclear antigen reveals that in the directly developing frog Eleutherodactylus coqui pervasive cell proliferation occurs throughout the retina even after the plexiform layers have formed. In striking contrast to biphasically developing frogs (e.g. Discoglossus pictus or Xenopus laevis), in E. coqui proliferation becomes restricted to the ciliary margin only after the eye has reached the size typical of a postmetamorphic froglet and after its laminar structure has developed. As a consequence, the retina of E. coqui develops rapidly without recapitulating larva-typical stages. Our results suggest that dissociation of cell proliferation and differentiation can lead to the abbreviation of ontogenies during evolution.

Animals↗

Development of a combined cardiac and aortic transplant model to investigate the development of transplant arteriosclerosis in the mouse.

BACKGROUND: The degree of transplant arteriosclerosis in murine cardiac allografts is difficult to assess. Aortic allografts represent an alternative model for evaluating the impact of novel transplant strategies on transplant arteriosclerosis in which the vascular changes can be quantified easily. However, it remains controversial as to whether vascular lesions seen in this model are equivalent to those that develop in solid-organ transplants. The aim of this study was to develop a model of combined cardiac and aortic transplantation to allow more precise quantification of transplant arteriosclerosis and to establish a correlation between the lesions that develop in the 2 types of graft. METHODS: CBA (H2(k)) recipients received a C57BL/10 (H2(b)) cervical cardiac allograft on Day 0 and a C57BL/10 (H2(b)) abdominal aortic allograft on Day 1. Recipients were treated with anti-CD154 mAb (MR1) on Days 0, 2, and 4. We performed histology and morphometric measurements for both grafts 30 days after transplantation. RESULTS: We observed significant intimal proliferation in both the cervical cardiac and abdominal aortic allografts from recipients treated with anti-CD154 mAb (heart, 64% +/- 9%; aorta, 67% +/- 8%; n = 5). Abdominal aortic grafts transplanted alone into anti-CD154-treated recipients developed a degree of transplant arteriosclerosis equivalent to that seen in the aortic grafts of the combined group (aorta alone, 68% +/- 9%, vs aorta + heart, 67% +/- 8%; n = 5). CONCLUSIONS: This combined cardiac and aortic transplant model permitted quantitative assessment of transplant arteriosclerosis while monitoring graft survival by cardiac palpation. Furthermore, development of transplant arteriosclerosis was equivalent in abdominal aortic allografts either in the presence or absence of an additional solid- organ transplant.

Animals↗

Development of sentence interpretation strategies by typically developing and late-talking toddlers.

Three studies, designed to examine use of word order and animacy for interpretation of sentences by 21 typically-developing two-year-old, 23 typically-developing two-and-one-half-year-old, 16 typically-developing three-year-old, 17 language-delayed two-and-one-half-year-old and 19 language-delayed three-year-old children were carried out. Results indicated that typically-developing two-year olds used neither cue consistently to interpret sentences. Typically-developing two-and-one-half-year olds, on the other hand used a coalition of word order and animacy cues and language-delayed two-and-one-half-year olds used neither cue. At three years of age both groups of children used word order exclusively to interpret sentences.

Child Language↗

Microtubules in the formation and development of the primary mesenchyme in Arbacia punctulata. II. An experimental analysis of their role in development and maintenance of cell shape.

TO EXPERIMENTALLY TEST THE SUGGESTION MADE IN THE PRECEDING PAPER THAT THE MICROTUBULES ARE INVOLVED IN CELL SHAPE DEVELOPMENT DURING THE FORMATION AND DIFFERENTIATION OF THE PRIMARY MESENCHYME, WE APPLIED TO THE EMBRYOS TWO TYPES OF AGENTS WHICH AFFECT CYTOPLASMIC MICROTUBULES: (a) colchicine and hydrostatic pressure, which cause the microtubules to disassemble, and (b) D(2)O, which tends to stabilize them. When the first type of agent is applied to sea urchin gastrulae, the development of the primary mesenchyme ceases, the microtubules disappear, and the cells tend to spherulate. With D(2)O development also ceases, but the tubules appear "frozen," and the cell asymmetries persist unaltered. These agents appear to block development by primarily interfering with the sequential disassembly and/or reassembly of microtubules into new patterns. The microtubules, therefore, appear to be influential in the development of cell form. On the other hand through a careful analysis of the action of these agents and others on both intra- and extracellular factors, we concluded that the microtubules do rather little for the maintenance of cell shape in differentiated tissues.

Animals↗

Sexually dimorphic expression of protease nexin-1 and vanin-1 in the developing mouse gonad prior to overt differentiation suggests a role in mammalian sexual development.

The mammalian sex-determining pathway is controlled by the presence or absence of SRY expression in the embryonic gonad. Expression of SRY in males is believed to initiate a pathway of gene expression resulting in testis development. In the absence of SRY, ovary development ensues. Several genes have now been placed in this pathway but our understanding of it is far from complete and several functional classes of protein appear to be absent. Sex-determining genes frequently exhibit sexually dimorphic patterns of expression in the developing gonad both before and after overt differentiation of the testis or ovary. In order to identify additional sex-determining or gonadal differentiation genes we have examined gene expression in the developing gonads of the mouse using cDNA microarrays constructed from a normalized urogenital ridge library. We screened for genes exhibiting sexually dimorphic patterns of expression in the gonad at 12.5 and 13.5 days post-coitum, after overt gonad differentiation, by comparing complex cDNA probes derived from male and female gonadal tissue at these stages on micro-arrays. Using in situ hybridization analysis we show here that two genes identified by this screen, protease nexin-1 (Pn-1) and vanin-1 (Vnn1), exhibit male-specific expression prior to overt gonadal differentiation and are detected in the somatic portion of the developing gonad, suggesting a possible direct link to the testis-determining pathway for both genes.

Amidohydrolases↗

Developing a research and development strategy for primary care.

General practice research has been a minority activity and underfunded in the past. The creation of the purchaser and provider split, the introduction of medical audit, and the new research and development strategy for the NHS provide an opportunity to focus research on the health needs of the population. FHSAs, with the regional health authority, should develop a local strategy for research and development and appoint a lead officer, who may be the medical adviser. When negotiating contracts FHSAs need to back up their arguments with research evidence. NHS development research should cover quality, distribution, accessibility, outcome, and effectiveness. FHSAs should play a part in disseminating knowledge in the interests of achieving an effective and high quality service. GPs should be encouraged to participate in research by relaxing the regulations of compulsory hours of patient service and by creating a practice development allowance.

Family Health↗

Distinguished Scientists Lecture Series. New developments in kidney development.

BACKGROUND/AIMS: The number of kidney transplantations performed per year is limited due to the availability of donor organs. One possible solution to the organ shortage is the use of renal xenografts. However, the transplantation of xenografts is complicated by rejection. METHODS: It has been postulated that the host immune response might be attenuated following the transplantation of embryonic kidneys (metanephroi) rather than developed (adult kidneys). Transplanted metanephroi become chimeric organs in that their blood supply originates from the host. It is possible to transplant a developing metanephros, without the use of immunosuppression, from one outbred rat to another. RESULTS: Transplanted metanephroi grow, develop, become vascularized, and function in host rats. In contrast, developed adult kidneys transplanted from one rat to another undergo rejection within 7 days after transplantation. CONCLUSIONS: These observations suggest that metanephric tissue may be less immunogenic than adult kidney. Transplantation of metanephroi represents a new development that could lead to a novel therapeutic approach to the treatment of chronic renal failure.

Animals↗

Evolution of nerve development in frogs. I. The development of the peripheral nervous system in Discoglossus pictus (Discoglossidae).

The gross anatomical development of the peripheral nervous system (PNS) during embryogenesis and metamorphosis in the frog Discoglossus pictus is described based on whole-mount immunostaining for nerves and muscles. In the head, neurite outgrowth starts with the mandibular ramus of the trigeminal nerve at the tailbud stage. Cranial muscles are innervated as soon as they differentiate, beginning at mid-embryonic stages. During late embryonic stages, the course of the trigeminal and facial nerves becomes greatly distorted and changes again drastically during metamorphosis accompanying the reorganization of the jaw muscles. Two occipital somites and nerves develop transitorily but degenerate at late embryonic stages. The hypoglossal nerve develops by fusion of the first and second spinal nerves and receives a transitory contribution of the third and fourth spinal nerve at embryonic stages. In the trunk, several classes of Rohon-Beard neurites could be identified at embryonic stages, one of which forms intersegmental sensory nerves that prefigure the course of the sensory rami of spinal nerves at later stages. We give detailed schedules of PNS and cranial muscle development which, in comparison with data on other frog species described in a companion paper, will serve as a basis to evaluate heterochronic shift during evolution of PNS development in frogs.

Animals↗

Progress of clinical oncology guidelines development using the Practice Guidelines Development Cycle: the role of practitioner feedback.

PURPOSE: To present an update on the development of oncology practice guidelines (PGs) using the Practice Guidelines Development Cycle (Cycle), and to present the results of surveys of oncologists on the first 10 guidelines from the Cancer Care Ontario Practice Guidelines Initiative. METHODS: Practitioners' opinions about guidelines in development were sought using a mail survey method with systematic follow-up. Practitioners were identified by cancer center representatives. Survey packages included evidence-based recommendations (EBRs) and a one-page, nine-item feedback questionnaire. Data were collected between February 1995 and February 1996. RESULTS: Nine hundred fourteen surveys that pertained to 10 guidelines were mailed to 423 practitioners in Ontario. Practitioners included 112 medical oncologists/hematologists, 34 radiation oncologists, 195 surgeons, and 82 practitioners from other medical specialities. One hundred practitioners were located in cancer centers and 323 had community-based practices. The overall response rate by practitioner was 72% and by survey questionnaire, 70%. For the five questionnaire items that assessed guideline quality, approval ratings ranged from 86% to 92%. For the 10 recommendations, 77% ( 63% to 82%) of respondents agreed that the EBR could be approved as a PG. Response and approval rates were consistent across medical specialities and locations of practice. CONCLUSION: The process of obtaining practitioner feedback in the development of PGs is both feasible and useful. The high response rates to the survey indicate that it is possible to obtain broad participation in evidence-based guidelines development throughout Ontario. The changes made to the EBRs in response to feedback suggest that practitioners' opinions can be valuable in shaping evidence-based guidelines.

Evidence-Based Medicine↗

[Factors affecting the occurrence and development of invasive meningococcal disease and development of Neisseria meningitis carrier state--results of a nationwide prospective questionnaire survey of cases and controls].

The nationwide prospective questionnaire study of cases and controls was implemented during the period from October 1996 till May 1998. Thirty-nine districts participated (= 54.2% of district hygiene stations) and 107 invasive meningococcal diseases were included in the study (= 76.9% of diseases recorded during the given period in the Czech Republic by active surveillance). A total of 390 subjects were included in the study-107 with invasive meningococcal diseases, 211 healthy controls and 72 healthy carriers of Neisseria meningitidis. This is the first study in the Czech Republic which analyzes comprehensively socioeconomic, health and stress factors in relation to the genesis and development of invasive meningococcal disease or carriership of N. meningitidis. The relationship between these factors and meningococcal disease or carriership was evaluated by the chi square test: odds ratio (OR) and statistical significance (p for chi square-Yates correction or Fischer's exact test). For the development of invasive meningococcal disease in particular, risk factors are significant (p < 0.05) which at the time weaken the overall resistance of the organism: febrile diseases, respiratory diseases, other diseases, exertion, exposure to cold, mental stress, other stress, injury, staying in places outside the home on brigades, training courses, stay in crowded premises. As to long-term factors the development of the disease is influenced by a contaminated environment, passive smoking and lower education of the mother which indicates a different lifestyle. Conversely, factors negatively correlated with the development of the disease are active participation in sports and favourable economic conditions. For death: significant risk factors (p < 0.05) are also factors which weaken the resistance of the organism: exertion, mental stress, other stress (= alcohol consumption), staying outside the home on brigades, training courses etc. For carriership risk factors are significant (p < 0.05) when the mucosal membranes of the upper airways are impaired (staying in a dusty environment, in smoke-filled rooms, contaminated atmosphere, active smoking, passive smoking) and factors where contact with other people is frequent (overcrowded rooms, multi-generation housing, use of public transport, staying outside the home on brigades, training courses etc.). A risk factor is also lower education of parents which indicates a different lifestyle. Conversely, factors negatively correlated with carriership are favourable economic conditions, frequent outdoor stay and active participation in sports. By comparison of factors significantly associated with the development of invasive meningococcal disease or carriership data are assembled for the implementation of effective preventive measures.

Carrier State↗

Urethral development in the fetal rabbit and induction of hypospadias: a model for human development.

PURPOSE: To determine whether the development of the rabbit phallus would be an appropriate model of human phallic development, we evaluated the formation of the fetal rabbit phallus and attempted to induce hypospadias pharmacologically. MATERIALS AND METHODS: New Zealand rabbit fetuses were obtained on gestational days 20 to 24, 26, 28 and 31. Sex was determined by gonadal morphology, and 6 fetuses were obtained at each age. The perineum was dissected, fixed, sectioned and stained with hematoxylin and eosin, and monoclonal antibodies against neuronal specific enolase. Two pregnant rabbits were treated with 10 mg./kg. finasteride orally daily between gestational days 19 and 28. The development of the external genitalia was compared in treated and untreated control rabbits. RESULTS: The rabbit phallus contains 2 corpora cavernosa and dorsolateral nerves similar to the human. In male and female fetuses fusion of the urethral folds progressed in a proximal to distal sequence forming a seam at the point of ventromedial fusion. In male fetuses urethral fold and ventral preputial fusion continued more distally toward the glans compared to females. Thus, in mature males the urethral meatus and ventral prepuce extended to the tip of the phallus, whereas in females the urethral meatus opened on the proximal phallus and the prepuce was deficient ventrally forming a dorsal hood. Male offspring had a significantly larger anogenital distance postnatally than female offspring. In male fetuses exposed to finasteride urethral fusion did not extend distally and the prepuce was deficient ventrally. Also, male offspring exposed to finasteride in utero had a significantly shorter anogenital distance than females and untreated control males at all ages (p <0.05). CONCLUSIONS: Fetal development of the rabbit phallus and urethra is homologous to the human. Although the gestational period is significantly shorter, the temporospatial pattern of external genitalia development is analogous in these species. Feminization of the rabbit urethra, hypospadias, can be induced by inhibiting 5alpha-reductase. Use of this animal model will allow further study of molecular mechanisms involved in urethral fusion and the evaluation of the pathophysiological processes of hypospadias.

Animals↗

[Role of the somitic mesoderm in the development of the rib cage of bird embryos. I. Origin of the sternal component and conditions for the development of the ribs (author's transl)].

The developmental origin of the sternal component of the ribs and the conditions for the development of the rib cage have been elucidated in bird embryos. Experiments consisted in homo- or heterospecific transplantations of 2-day-old quail or chick embryo somitic mesoderm into chick hosts of the same age in ortho- or heterotopic position along the cephalo-caudal axis. Results show that vertebral halves, ribs (not only their vertebral segment, but also their sternal component when they possess one), the trunk and intercostal muscles, as well as at least part of the scapula originate exclusively from the somitic material, while the sternum, ventral muscles and the other parts of the pectoral girdle are derived from the somatopleural mesoderm. The development of the rib basket is subjected to following rules: -only the somitic mesoderm of the prospective thoracic region (somites 19-26) is able to give rise to ribs. -only the somitic mesoderm of the posterior thoacic region (somites 22-26) is able to develop ribs with a sternal component. -the vertebral component of ribs can develop outside the thoracic region. -contrariwise, the sternal component can form only in the vicinity of the sternal anlage, i.e. within about three somites in front and rear of the normal limits of the thoracic region. It is concluded that the somitic mesoderm is already regionalized at a stage slightly preceding its metamerization and that the somatopleural territory of the sternum plays a morphogenetic role in the development of the sternal component of ribs, although it does not make a cellular contribution to their construction.

Animals↗