STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.

OBJECTIVE: To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction. DESIGN: A randomised placebo-controlled trial. SETTING: Thirteen maternal-fetal medicine units across New Zealand and Australia. POPULATION: Women with singleton pregnancies affected by fetal growth restriction at 22+0 to 29+6 weeks. METHODS: Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32+0 weeks, birth or fetal death (whichever occurred first). MAIN OUTCOME MEASURES: The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia. RESULTS: Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75). CONCLUSIONS: Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing. TWEETABLE ABSTRACT: Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

Effects of pre-eclampsia and fetal growth restriction on C-type natriuretic peptide.

OBJECTIVE: To determine changes in plasma C-type natriuretic peptide (CNP), a paracrine product of the vascular endothelium, in pregnancies with vascular disorders, and relate these to time of presentation and severity. DESIGN: Retrospective nested cases and controls. SETTING: Community study, Auckland New Zealand. POPULATION: Screening for Pregnancy Endpoints (SCOPE) data and bio-bank of maternal plasma. METHODS: Maternal plasma amino terminal proCNP (NTproCNP) was measured by radioimmunoassay in early (14-16 weeks of gestation, and again at 19-21 weeks of gestation) and late (34-36 weeks of gestation) pregnancy in three groups of women (20 per group): pre-eclampsia (pre-eclampsia); gestational hypertension (GHT) with small for gestational age (SGA); and uncomplicated pregnancy. MAIN OUTCOME MEASURES: Change in NTproCNP and associations with concurrent blood pressure, time of case presentation, severity, and infant birthweight. RESULTS: Plasma NTproCNP in early pregnancy in women with vascular disorders did not differ from those found in controls. In late pregnancy, levels in pre-eclampsia (28.8 ± 2.3 pM) and in GHT with SGA (28.6 ± 4.8 pM) were significantly increased (P = 0.01 and 0.027, respectively) compared with controls (21.3 ± 1 pM). In pre-eclampsia, levels were significantly higher (P < 0.03) at 14-16 weeks of gestation in women diagnosed prior to 34 weeks of gestation. Combining all three groups, associations of NTproCNP with concurrent diastolic and mean arterial pressure were found at 34-36 weeks of gestation (r = 0.46). No significant associations were identified with birthweight. CONCLUSIONS: CNP secretion during gestation is responsive to vascular stress. Plasma NTproCNP measurements may have clinical application in late pregnancy in defining the different phenotypes associated with pre-eclampsia.

Calcium influx into neurons can solely account for cell contact-dependent neurite outgrowth stimulated by transfected L1.

We have used monolayers of control 3T3 cells and 3T3 cells expressing transfected human L1 as a culture substrate for rat PC12 cells and rat cerebellar neurons. PC12 cells and cerebellar neurons extended longer neurites on human L1 expressing cells. Neurons isolated from the cerebellum at postnatal day 9 responded equally as well as those isolated at postnatal day 1-4, and this contrasts with the failure of these older neurons to respond to the transfected human neural cell adhesion molecule (NCAM). Human L1-dependent neurite outgrowth could be blocked by antibodies that bound to rat L1 and, additionally, the response could be fully inhibited by pertussis toxin and substantially inhibited by antagonists of L- and N-type calcium channels. Calcium influx into neurons induced by K+ depolarization fully mimics the L1 response. Furthermore, we show that L1- and K+(-)dependent neurite outgrowth can be specifically inhibited by a reduction in extracellular calcium to 0.25 microM, and by pretreatment of cerebellar neurons with the intracellular calcium chelator BAPTA/AM. In contrast, the response was not inhibited by heparin or by removal of polysialic acid from neuronal NCAM both of which substantially inhibit NCAM-dependent neurite outgrowth. These data demonstrate that whereas NCAM and L1 promote neurite outgrowth via activation of a common CAM-specific second messenger pathway in neurons, neuronal responsiveness to NCAM and L1 is not coordinately regulated via posttranslational processing of NCAM. The fact that NCAM- and L1-dependent neurite outgrowth, but not adhesion, are calcium dependent provides further evidence that adhesion per se does not directly contribute to neurite outgrowth.

Variants of human L1 cell adhesion molecule arise through alternate splicing of RNA.

The L1 cell adhesion molecule was initially identified and characterized in mouse as a cell-surface glycoprotein that mediates neuron-neuron and neuron-Schwann cell adhesion. We have characterized L1 in humans using cDNA structural and mRNA expression analyses. We present the entire coding sequence for human L1, which predicts a 1253-amino acid protein displaying a signal sequence, transmembrane segment, RGD sequence, and potential glycosylation and phosphorylation sites. Nucleotide and deduced amino acid sequence identities between human and mouse L1 are 85% and 87%, respectively. In contrast, the amino acid identity between human L1 and the L1-related molecule chicken Ng-CAM is only 45%. Using Northern blot analyses, a single L1 transcript of 5.5 kb is detected in human fetal brain and in neuroblastoma (IMR-32) and retinoblastoma (Y-79) cell lines. L1 is also expressed in the rhabdomyosarcoma cell lines RD and A-204, which display several muscle characteristics. Two forms of L1, which differ by the presence or absence of a 12-bp cytoplasmic segment, are expressed in both human and mouse. This segment is encoded by a single exon that can be alternately spliced to give rise to the two forms, which appear to be expressed in tissue-specific patterns.

Characterization of cDNA clones defining variant forms of human neural cell adhesion molecule N-CAM.

The neural cell adhesion molecule N-CAM has been identified in a number of species and comprises at least three major cell surface polypeptides of different molecular structures and tissue distributions. We report here the isolation and characterization of cDNA clones encoding two of the three major forms of N-CAM from a human neuroblastoma cDNA library. One of the clones, NII-6, provides the first complete sequence of a small cytoplasmic domain (140 kDa) form of the molecule in humans and differs in a number of respects from cDNA clones derived from human muscle. These differences include the presence of a 30-bp insert in the fourth immunoglobulin-like domain of N-CAM, a 3-bp insert in the extracellular portion of the molecule, and an additional 6 bp in the middle of the membrane-spanning segment. Based on the analysis of a genomic DNA clone spanning these regions of N-CAM, the first two differences arise by alternate splicing of RNA and occur in some, but not all clones; the additional 6 bp may reflect a genetic polymorphism. A second cDNA clone, NI-10, encodes the complete sequence of a segment that is specific to the large cytoplasmic domain (180 kDa) polypeptide of human N-CAM and is very similar to corresponding segments of mouse, chicken, and rat N-CAM. This sequence also arises by alternative splicing of RNA. In addition, we have identified a genomic DNA segment encoding sequences specific to the third, small surface domain (120 kDa) polypeptide of N-CAM. The data presented here and previously define the DNA sequences of the membrane-bound forms and known variants of human N-CAM. From these sequences, a wide variety of probes can be generated for investigating the expression of particular N-CAM polypeptides in normal and pathological tissues.

Identification and characterization of the human cell adhesion molecule contactin.

We have prepared a monoclonal antibody, Neuro-1, that recognizes the human homolog of the chicken contactin/F11 and mouse F3 cell adhesion molecules. The Neuro-1 antigen, structurally characterized as a 135 kDa glycosylphosphatidylinositol-linked glycoprotein, was immunoaffinity purified and partially sequenced. Comparison of an internal peptide sequence to that predicted from the chicken contactin/F11, mouse F3 and human contactin (reported herein) cDNA sequence identifies the Neuro-1 antigen as human contactin. Moreover, a polyclonal antisera generated against the purified Neuro-1 antigen was immunoreactive with a fragment of human contactin expressed in bacteria. The complete coding and deduced amino acid sequences of human contactin were determined and are 86% and 95% identical to the respective mouse F3 sequences. Structural features shared with contactin/F11/F3 include six immunoglobulin type C2 and four fibronectin type III-like domains, multiple sites for asn-linked glycosylation and a COOH-terminal signal peptide presumably removed during the generation of a phosphatidylinositol cell surface linkage. The potential for glycosylation and GPI-linkage is also consistent with protein chemical studies of human contactin. Contactin mRNA expression was characterized using Northern blot analyses of human tissues and cell lines. High level expression of a single contactin transcript in adult brain, and low level expression of multiple transcripts in lung, pancreas, kidney and skeletal muscle are observed. Highly expressed multiple transcripts, similar in pattern to that of pancreas, lung, kidney and skeletal muscle, are also observed in human neuroblastoma and retinoblastoma cell lines.

Managing medical supply logistics among health workers in Ecuador.

Operations research techniques are being used to solve business and government problems throughout the world. This paper discusses the use of an analytical technique--the location set covering algorithm--to determine placement of medical supply centers in Ecuador. By establishing the optimum location of supply centers it is possible to effectively utilize scarce health care resources in a developing country and to help community level health workers be better prepared to deliver primary health care services.

Restoring balance to internal medicine training: the case for the teaching office practice.

Medical residents require an experience beyond the tertiary care hospital to understand many aspects of contemporary medical practice and to make informed career choices. To provide this balanced training, the University of Virginia has operated for 10 years an internal medicine teaching office practice to provide an outpatient experience similar to private practice. It allows residents to work closely with general internal medicine faculty and introduces them to the knowledge and skills necessary to establish and manage a successful practice. The curriculum of the 10 week rotation includes patient care in the office and by telephone, nursing home and home visits, tutorials and seminars on primary care and office management topics, and training in the use of microcomputers. A survey of 46 (92%) of the first 50 residents completing the rotation revealed that the content of the rotation was valuable, the rotation substantially influenced career choices, and the rotation helped provide a balanced view of internal medicine practice.

An analysis of the processing of patients in a rural medical care delivery system.

A study of the processing of patients at the rural clinic of a medical care delivery system was done to describe quantitatively the movement of patients from their arrival to their departure. The data collected provided a statistical summary of the sequence and duration of observed events in the medical care process as they related to the patients. An analysis of 485 patients visits that were observed on 60 random days during a 12-month period showed that patient arrival rates were generally higher during the morning. The average visit lasted 74 minutes; 94 percent of this time was spent in the waiting and examination rooms. The period that that the patient spent unattended by clinic personnel represented three-fourths of the average patient's total time in the delivery system. Data analysis indicated that if patients were admitted to an unoccupied examination room as soon as possible after their arrival and if standing orders for the family nurse practitioner were expanded, a significant reduction would occur in the average patient's unattended visit time.

Experience of the Checkerboard Area Health System in planning for rural health care.

The design of rural health care delivery systems often is based on concepts obtained from urban models. The implicit planning premises of successful urban models, however, may be inappropriate for many rural systems. An alternative model planned and implemented in the checkerboard region of rural northwest New Mexico has proved to be successful. This experience may be helpful to health care policymakers and planners confronted with environments that are not congruent with typical urban settings. The checkerboard region presented a challenging health planning environment characterized by formidable geographic, population, economic, and health behavior constraints. The Checkerboard Area Health System (CAHS), designed to provide comprehensive services in an area dominated by these constraints, was formed around a central diagnostic and treatment facility with six satellite clinics. The CAHS used an innovative administrative structure, extended the productivity of traditional providers by extensive use of mid-level and ancillary personnel, and created an effective referral network. These features are distinctly different from those of urban health care models. Overall, the CAHS attained a high rate of inpatient use. Additionally, the performance of the outpatient program indicates that traditional ambulatory care can be integrated with other health services that are more oriented toward health promotion and disease prevention. Finally, the emergency room at the central facility has attained an impressive record that, like the inpatient and outpatient areas, is responsive to the needs of the target population.

Peripheral ameloblastoma.

A peripheral ameloblastoma in a 58-year-old man has been reported. No evidence as to the origin was shown, although the tumor was in apposition with the basal layer.

The checkerboard area health system: delivering comprehensive care in a remote region of New Mexico.

A comprehensive health center is defined as the synergistic coupling of a medical and administrative structure designed to provide inpatient, outpatient, and public health services. While health centers have been widely established in other countries, only limited implementation has occurred in rural areas of the United States. The successful implementation of the health center concept in a sparsely populated area of northwestern New Mexico, which is predominately inhabited by Navajo Indians and Spanish Americans, is descriptively analyzed. The physical environment and the socioeconomic characteristics of the catchment area residents are related to dominant conditions in underdeveloped countries. The evolution of the delivery system with its network of satellite clinics staffed by mid-level primary care providers is documented. The funding and provision of a wide range of preventive and curative health services supported by communication, transportation, outreach, education, public health, and administration components are described. Several problems thought to impede the application of the health center concept to other regions in the United States are identified and discussed relative to this New Mexican experience. Innovative and persevering systems designers who are strongly committed to delivering a balance between preventive and curative services are considered to be absolutely necessary for successful implementation of the health center concept in the United States.

PIP: This article describes the development of a comprehensive health center in a rural area of New Mexico that is inhabited predominantly by indigenous Navajo Indians and Spanish Americans. 1st the physical environment and the population of the catchment area is described in relation to the characteristics of an underdeveloped rural area. The authors then describe the development of the health center in regard to system planning, service implementation, and system maturation. In order to overcome distance and isolation, a system of satellite clinics supported by a central health center was designed and became operational in 1972. The central health center provided a full range of outpatient services, including specialty clinics staffed by physicians, emergency area, and a small inpatient unit. An important step toward coordinating all public health services took place in 1976 when the state health agency awarded a public health contract to the center. Financial stability for the center was achieved in 1975 with the receipt of a 5 year federal grant from the Health for Underserved Rural Areas program. Other important sources of aid included the Indian Health Service and the Robert Wood Johnson Foundation. The authors cite several possible causes for the lack of support for comprehensive health centers in the U.S., including a predominant value system for both providers and patients that emphasizes curative services over preventive measures. The article includes tables demonstrating population by community, spatial relation between system center and satellite clinics, sources of funding, personnel and facility resources, and utilization of the health center.

Productive relationships with mover-and-shakers. Recognizing the agents of influence in your hospital.

Hospital administrators need every available asset these days, and one potential resource is the people in every organization who seem to naturally attract and lead others. The authors tell how to, first, recognize such persons and, second, establish a constructive relationship with them.

Hospital diversification into home health care: examination of strategic issues.

With the trend toward expansion of services and diversification, hospital executives are increasingly considering entering the business of home health care. To be successful, however, home health care must be both feasible and appropriate for the institution. Examined here are the factors that should be considered before entering this growing market.