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Intercellular signalling is limited by the range of cell responsiveness, often mediated by repressors. A recently identified repressor, Sprouty, inhibits MAP kinase signalling in flies, mice and humans and has a conserved function in patterning the airways of these divergent species.

Background: UV radiation causes acute adverse effects like sunburn, photosensitivity reactions, or immunologic suppression, as well as long-term sequelae like photoaging or malignant skin tumors. UV radiation induces tissues to produce reactive oxygen species, eicosanoids and cytokines. Inhibition of these mediators might reduce skin damage. Antioxidants such as ascorbic acid and d-alpha-tocopherol have been found to be photoprotective in some in vitro studies and animal experiments., Objective: Our purpose was to assess the protective effect of systemic vitamins C and E against sunburn in human beings., Methods: In a double-blind placebo-controlled study, each of 10 subjects took daily either 2 gm of ascorbic acid (vitamin C) combined with 1000 IU of d-alpha-tocopherol (vitamin E) or placebo. The sunburn reaction before and after 8 days of treatment was assessed by determination of the threshold UV dose for eliciting sunburn (minimal erythema dose [MED]) and by measuring the cutaneous blood flow of skin irradiated with incremental UV doses against that of nonirradiated skin., Results: The median MED of those taking vitamins increased from 80 to 96.5 mJ/cm2 (p < 0.01), whereas it declined from 80 to 68.5 mJ/cm2 in the placebo group. Cutaneous blood flow changed significantly (p < 0.05) for most irradiation doses with decreases in those given vitamins and increases in the placebo group., Conclusion: Combined vitamins C and E reduce the sunburn reaction, which might indicate a consequent reduced risk for later sequelae of UV-induced skin damage. The increase of sunburn reactivity in the placebo group could be related to "priming" by the previous UV exposure.

Ultraviolet (UV) radiation causes hemolysis of human erythrocytes in the presence of photosensitizers. This can be used as an in vitro model for evaluating photosensitizing properties of substances. Antioxidants such as ascorbic acid (vitamin C) and d-alpha-tocopherol (vitamin E) have been found to be photoprotective in such test systems. We assessed the effect of combined systemic intake of both ascorbic acid and d-alpha-tocopherol by human volunteers on phototoxic in vitro lysis of their erythrocytes. In a double-blind placebo-controlled study, 10 subjects took daily 2 g ascorbic acid combined with 1000 IU d-alpha-tocopherol, and 10 took a placebo. Blood was taken before and after 7 days of treatment, erythrocytes were prepared and then incubated with 10(-3) mol/l fenofibrate, a photosensitizer acting in the UVA and UVB region. The suspensions were exposed to radiation rich in UVA (up to 40 J/cm2 UVA) or to radiation rich in UVB (up to 1.6 J/cm2). Photohemolysis of the samples was calculated as a percentage of complete hemolysis. At the end of the treatment phase, in the placebo group photohemolysis was not significantly reduced compared with the initial values at all irradiation doses except for 1.6 J/cm2 UVB (96% vs 79%; P < 0.01). In the group taking vitamins, photohemolysis was significantly reduced at nearly all UV doses, most impressively after moderate UVA irradiation (20 J/cm2 UVA: 86.5% vs 14.5%; P < 0.01). It is concluded that the results of the photohemolysis test are influenced by the antioxidative status of the cell donor and that ascorbic acid and d-alpha-tocopherol also may protect against phototoxic damage in vivo.

Ventral midline cells at different rostrocaudal levels of the central nervous system exhibit distinct properties but share the ability to pattern the dorsoventral axis of the neural tube. We show here that ventral midline cells acquire distinct identities in response to the different signaling activities of underlying mesoderm. Signals from prechordal mesoderm control the differentiation of rostral diencephalic ventral midline cells, whereas notochord induces floor plate cells caudally. Sonic hedgehog (SHH) is expressed throughout axial mesoderm and is required for the induction of both rostral diencephalic ventral midline cells and floor plate. However, prechordal mesoderm also expresses BMP7 whose function is required coordinately with SHH to induce rostral diencephalic ventral midline cells. BMP7 acts directly on neural cells, modifying their response to SHH so that they differentiate into rostral diencephalic ventral midline cells rather than floor plate cells. Our results suggest a model whereby axial mesoderm both induces the differentiation of overlying neural cells and controls the rostrocaudal character of the ventral midline of the neural tube.

The vertebrate central nervous system comprises an intricate array of neurons generated in a highly organized way. Examination of the genes expressed and required at early stages of neural differentiation reveals that a coordinated signalling cascade transforms progenitor cells into discrete neuronal subsets.

One of the earliest indications of regional patterning in the CNS is the spatially restricted expression of regulatory genes within the neuroepithelium. Many of these genes encode transcription factors and, although little is known of their downstream targets, it seems likely that they control the identity of cells in different regions of the CNS. This review discusses how the expression of these patterning genes might influence the location at which the first axon pathways in the CNS are pioneered. Evidence is described that suggests that the boundary regions between adjacent domains of regulatory gene expression influence where the first axons will extend.

A century has elapsed since Ramón y Cajal proposed his chemotropic theory of axon guidance, i.e. the attraction of developing axons by diffusible molecules emanating from their targets. Although the precise contribution of axonal chemoattractants to guidance in vivo remains to be established, two lines of investigation have provided evidence for their existence and importance. First, concentration gradients of nerve growth factor (NGF) have been shown to orient the growth of regenerating sensory axons in vitro. Although NGF does not appear to guide axons during development, these studies show that growth cones can orient in gradients of diffusible molecules. Second, the cellular targets of several different classes of developing neurons have been shown to secrete as yet unidentified diffusible factors that can orient axons. We review these studies and discuss the potential contribution of chemotropism to the establishment of axonal projection patterns in vertebrates.

Distinct classes of neural cells differentiate at specific locations within the embryonic vertebrate nervous system. To define the cellular mechanisms that control the identity and pattern of neural cells we have used a combination of functional assays and antigenic markers to examine the differentiation of cells in the developing spinal cord and hindbrain in vivo and in vitro. Our results suggest that a critical step in the dorsoventral patterning of the embryonic CNS is the differentiation of a specialized group of midline neural cells, termed the floor plate, in response to local inductive signals from the underlying notochord. The floor plate and notochord appear to control the pattern of cell types that appear along the dorsoventral axis of the neural tube. The fate of neuroepithelial cells in the ventral neural tube may be defined by cell position with respect to the ventral midline and controlled by polarizing signals that originate from the floor plate and notochord.

The provirus of mouse mammary tumour virus (MMTV) is reputed to contain sequences within the viral gag gene that prevent or inhibit its propagation as a recombinant DNA clone in Escherichia coli. Here we report the successful isolation of several lambda and plasmid clones comprising the 5' virus-host DNA junction fragments from integrated MMTV proviruses in BR6 mice. Although the lambda clones appeared intact, almost all of the plasmids were found to contain the bacterial insertion sequences IS1 or IS2 within a small region of the gag gene. One nondisrupted clone was recovered which had undergone multiple G to A transitions, some of which created stop codons in gag. These results have provided more precise information as to the location of the poison sequences and are discussed in relation to possible explanations for the phenomenon.

A case of lateral meningocele associated with deficiency of the thoraco-abdominal wall is reported. It is suggested that both of these defects are due to interference with the development of the paraxial mesoderm by a single injury.

A double-blind randomised trial was carried out in 60 infants with a birth-weight of less than 1500 g or a gestational age below 31 weeks. 30 infants received phenobarbitone (20 mg/kg) within 4 h of birth and 30 infants received a placebo. The two groups of infants were similar in birth-weight, gestational age, frequency of vaginal delivery, sex, Apgar scores, ventilator dependence before the injection, pneumothorax, hypercapnia, and acidosis. Cranial ultrasound scans were carried out daily for 14 days. 12 out of 30 phenobarbitone-treated infants and 11 out of 30 placebo-treated infants had PVH, with parenchymal haemorrhages in 2 of the placebo group. Plasma phenobarbitone was over 15 micrograms/ml in 28 out of 30 of the phenobarbitone-treated infants during the first 72 h. 7 out of 17 spontaneously breathing infants became ventilator-dependent within 12 h of the phenobarbitone injection, whereas only 1 of 18 spontaneously breathing placebo-treated infants became ventilator-dependent within 12 h of injection. Although the possibility of protection against parenchymal haemorrhages may justify further investigation, there is no justification for administration of 20 mg/kg of phenobarbitone to all infants below 1500 g.

Between 1979 and 1982 we reviewed 1000 consecutive admissions to the neonatal intensive care unit of this hospital. Sixty five infants had positive blood cultures. Mortality was 70% among 17 infants who had septicaemia in the first 48 hours of life and for whom appropriate treatment may have been too late because of difficulties of early diagnosis. In the remaining 48 infants mortality was 12%, septicaemia occurred later, and was associated with Staphylococcus epidermidis (56%) and with the presence of an intravascular catheter (50%).

Flexible suction catheters were passed through the endotracheal tubes of infants undergoing mechanical ventilation, just before chest radiographic examination for clinical purposes. With the head straight, 7 of 10 straight catheters entered the right main bronchus but with the head turned, 17 of 20 straight catheters and 19 of 20 curved tip catheters entered the contralateral bronchus.

A sequential series of 100 small bowel mucosal biopsies from children was studied to assess the frequency and pattern of mucosal fat staining, and to compare patterns of fat distribution with mucosal structure and clinical diagnosis. Deep mucosal fat was commonly associated with those clinical groups showing normal mucosal structure. While fine granular surface epithelial fat was common in normal and abnormal biopsies, the presence of large fat globules in the surface epithelium was almost entirely limited to biopsies showing villous shortening. Large fat globules in the surface epithelium in coeliac disease and cow's milk sensitive enteropathy were probably related to the more severe degrees of villous abnormality encountered in these clinical groups. However, large fat globules in surface epithelium were also found in a few cases of cow's milk sensitive enteropathy with normal or minimal villous blunting. Fat staining may be a useful additional histological marker to aid in the interpretation of small intestinal mucosal biopsies.

In the developing nervous system, axons project considerable distances along stereotyped pathways to reach their targets. Axon guidance depends partly on the recognition of cell-surface and extracellular matrix cues derived from cells along the pathways. It has also been proposed that neuronal growth cones are guided by gradients of chemoattractant molecules emanating from their intermediate or final cellular targets. Although there is evidence that the axons of some peripheral neurons in vertebrates are guided by chemotropism and the directed growth of some central axons to their targets is consistent with such a mechanism, it remains to be determined whether chemotropism operates in the central nervous system. During development of the spinal cord, commissural axons are deflected towards a specialized set of midline neural epithelial cells, termed the floor plate, which could reflect guidance by substrate cues or by diffusible chemoattractant molecules. Here we provide evidence in support of chemotropic guidance by demonstrating that the rat floor-plate cells secrete a diffusible factor(s) that influences the pattern and orientation of commissural axon growth in vitro without affecting other embryonic spinal cord axons. These findings support the hypothesis that chemotropic mechanisms guide developing axons to their intermediate targets in the vertebrate CNS.

A 30 week gestation infant developed necrotising enterocolitis associated with Clostridium perfringens septicaemia at 3 weeks of age. He responded to treatment with intravenous fluids, antibiotics, and blood, but his blood haemolysed. Because of anaemia further blood was given, but, within minutes he died. Examination of his red cells showed an increase in T activation.

In the course of analyzing sites of proviral integration in tumors induced by mouse mammary tumor virus (MMTV), we have isolated recombinant DNA clones corresponding to the 5' and 3' ends of four endogenous MMTV proviruses present in BALB/c and BR6 mice. This has permitted the structural characterization of each locus by detailed restriction mapping and the preparation of DNA probes specific for the cellular sequences flanking each provirus. These probes have been used to trace the segregation patterns of the proviruses, designated Mtv-8, Mtv-9, Mtv-17, and Mtv-21, in a panel of inbred strains of laboratory mice and to map Mtv-17 and Mtv-21 to mouse chromosomes 4 and 8, respectively. The unambiguous resolution of these four proviruses on Southern blots has greatly facilitated the analysis of other endogenous MMTV proviruses in these inbred mice.

A reference range of plasma creatinine levels for the first month of life derived from 238 babies of 25-42 weeks' gestation is presented. Measurements were performed on a Beckman Creatinine Analyser 2, which uses the Jaffé rate reaction method. There was a decline in plasma creatinine level with increasing postnatal and gestational age. Infants undergoing mechanical ventilation at age 2 days had a significantly increased creatinine level.

The maturation of visual acuity was studied in 162 neurologically normal and 96 neurologically abnormal newborn infants. Ninety-five percent of the neurologically normal infants developed an acuity of 80 min arc by 35 weeks postmenstrual age (PMA) but only 50% developed an acuity of 40 min arc by 40 weeks PMA. Neurologically abnormal infants, and in particular those with periventricular haemorrhage (PVH), had a delay in the development of acuity. There was a close correlation between the development of 80 min arc acuity and the appearance of the first positivity of the flash visually evoked potential (VEP).

We extended the physical map of the mouse int-2 locus by demonstrating that the site of insertion for mouse mammary tumor virus DNA in plaque-type mammary tumors of GR mice is directly linked to int-2. An additional example of proviral integration is described in which a provirus in a presumed enhancer-insertion mode 15 kilobases upstream of the int-2 promoters is capable of activating expression of the gene at levels typical of other virally induced mammary tumors.

Forty-eight children below 18 months of age suffering from acute gastroenteritis were given a glucose-electrolyte mixture (GEM) for the first 24 h following hospital admission. They were then allocated alternately to the study group which immediately went back to full-strength cow's milk feeds, or to the control group to which milk was reintroduced gradually over a 4-day period. The majority of infants in both groups had an uncomplicated recovery (70 and 96%, respectively). A complicated recovery, however, occurred more commonly in the study group. Seven patients in this group, compared with only one in the control group, had an immediate recurrence of symptoms of such severity that a return to intravenous fluids or the GEM was necessary. These complications were confined to those less than 9 months of age. It is concluded that children over 9 months of age with acute gastroenteritis may be given full-strength milk immediately after 24 h of treatment with a glucose-electrolyte solution, but for children under 9 months the conventional regrading over several days should be retained.

An unusual case of neonatal myasthenia gravis is reported in an infant who had respiratory failure due to diaphragmatic weakness. Although power and tone in the limbs were normal, fatiguability of both diaphragm and peripheral muscles was demonstrated. Acetylcholine receptor antibodies were absent in the mother, which suggests that an alternative humoral mechanism may have been responsible for the transient (6-week) neonatal weakness.

Visual evoked responses (VERs) were elicited in 70 infants with postmenstrual ages between 30 and 39 weeks. On the basis of neurological and ultrasound examinations, 30 of the infants were classed as neurologically normal and 40 as abnormal: 26 of the latter had periventricular haemorrhage. Initially the VER consisted of a negative deflection only, and the appearance of a positive wave immediately preceding the negative deflection was taken to indicate maturation of the VER. Maturation was significantly delayed in the neurologically abnormal infants, and the delay was related to the degree of neurological insult. The visual acuity of 32 infants was estimated within seven days of the VER recording. There was a correlation of 79 per cent between the VER and the data for visual acuity.

The fibroblast growth factor-related protooncogenes, int-2 and hst/k-FGF, are within 17 kilobase pairs of one another on mouse chromosome 7 and are in the same transcriptional orientation. Approximately 70% of tumors induced in BR6 mice by mouse mammary tumor virus have proviral insertions adjacent to the int-2 gene. We find that the murine homolog of the hst/k-FGF gene can also be transcriptionally activated by the insertion of mouse mammary tumor virus DNA either upstream or downstream of the gene. In most tumors, only one of these adjacent genes is activated, but in some cases both genes are expressed. One of the hst-expressing tumors also has a virally activated int-3 gene. At least five distinct cellular genes (int-1, -2, -3, -4, and hst/k-FGF) can therefore contribute, either singly or in concert, to the development of histologically indistinguishable mammary tumors in mice infected by mouse mammary tumor virus.

Little is known about the cellular and molecular mechanisms that determine neuronal cell fate and the patterning of neuronal connections in the vertebrate central nervous system. In this paper we summarize evidence which indicates that some aspects of neuronal differentiation and axon guidance are regulated by specialized epithelial cells that occupy the medial region of the neural plate and, later, the ventral midline of the spinal cord. This cell group, termed the notoplate/floor plate appears to constitute a distinct compartment within the neural plate that is more closely related in lineage and perhaps also in function to axial mesodermal cells of the underlying notochord than to other neural plate cells. Cells of the notoplate exhibit specialized mechanical and adhesive properties that may contribute to neurulation. At later stages of development, the floor plate appears to guide developing axons in the embryonic spinal cord by releasing a diffusible chemoattractant factor and by virtue of its specialized cell surface properties. The floor plate may also play a role in the determination of cell identity and patterning at earlier stages of neural tube development.

Seventy infants with suspected bacterial infection in the first 48 hours of life were treated either with piperacillin and flucloxacillin or with penicillin and gentamicin. Infection was confirmed and successfully eradicated in 6 of the 35 infants receiving piperacillin and flucloxacillin. Four infants treated with penicillin and gentamicin had confirmed infection and one deteriorated initially but then recovered when treated with piperacillin. Serum piperacillin concentrations above 100 mg/l and cerebrospinal fluid piperacillin concentrations of 2.6-6 mg/l were noted for up to four hours and 7 hours respectively, even in the absence of inflamed meninges, after administration of piperacillin 100 mg/kg body weight intravenously. Median half life of piperacillin was 6.5 hours and was prolonged in renal impairment. Piperacillin is considered to be a safe and effective first line single agent treatment for early neonatal infection but because some Escherichia coli are resistant to it we recommend that a second agent be used in critically ill infants with neutropenia or meningitis.